UJIAN TENGAH SEMESTER (UTS)

KEPERAWATAN ANAK KRITIS

Dosen Koordinnator : Ibu Fauziah Rudhiati M.Kep.,Ns.Sp.Kep.An

Disusun Oleh
Nur Hafni Hasim (215121233)

UNIVERSITAS JENDERAL ACHMAD YANI CIMAHI

FAKULTAS ILMU DAN TEKNOLOGI KESEHATAN
PROGRAM STUDI MAGISTER KEPERAWATAN
CIMAHI
2022
 1. Anak J, laki-laki berusia 12 bulan yang sebelumnya sehat. Dia memerlukan
perawatan di ruang intensif karena ibu mengeluh bahwa anaknya mengalami
kesulitan bernapas. 3 hari sebelum masuk rumah sakit, ibu mengatakan bahwa
anaknya menderita flu biasa, anak rewel, hidungnya meler, demam dan batuk tetapi
ibu menilai bahwa anak J masih dapat bernapas dengan baik. Semakin hari, batuk
anak J semakin memburuk terutama di malam hari. Ibu menilai anak menjadi
bernapas lebih cepat dari biasanya. Dari hasil pengkajian bahwa HR adalah 190
x/menit, RR 65 x/menit, suhu 39.50C, TD 100/54 mmHg dan saturasi oksigen
85%. Terdapat retraksi intercostal dan penarikan di area trakea saat bernapas,
terdengar suara wheezing dan sumbatan jalan nafas bagian atas. Pemberian Oksigen
sebesar 2L melalui nasal kanul hanya meningkatkan saturasi oksigen menjadi 90%.
Usaha bernafas yang berat terus berlanjut. Dokter menegakkan diagnose medis anak J
RSV (respiratory syncytial Virus) yang menyebabkan bronchiolitis. Anak J
membutuhkan alat bantu pernapasan.
a. Jenis alat bantu pernapasan apa yang bisa diberikan pada anak J adalah
b. Jelaskan indikasi, hal yang harus kita pantau/monitoring, dan komplikasi
selama anak J memakai alat bantu napas tersebut!
c. Jelaskan kriteria keberhasilan dan kegagalan pemakaian alat bantu napas
tersebut!
a. Jenis alat bantu yang digunakan pada An J adalah Ventilator dengan mode SIM V.
dengan melihat kriteria HR adalah 190 x/menit, RR 65 x/menit, suhu 39.5 0C, TD 100/54
mmHg dan saturasi oksigen 85%. Terdapat retraksi intercostal dan penarikan di area
trakea saat bernapas, terdengar suara wheezing dan sumbatan jalan nafas bagian atas.
Pemberian Oksigen sebesar 2L melalui nasal kanul hanya meningkatkan saturasi oksigen
menjadi 90%.
Dari data diatas pasien mengalami distress pernafasan sehingga perlu dilakukan
intubasi untuk pemasangan ventilator mekanik dengan mode SIM V. Mode SIM V
untuk ventilasi pada pasien yang mempunyai beberapa kali nafas spontan tetapi belum
adekuat. Mesin ventilator secara Intermiten (Kadang-kadang) akan memberikan nafas
control ke pasien agar mencapai target minute volume yang telah diatur
b. Indikasi pemasangan ventilator adalah : (William Owens, 2012)

1. Pasien dengan gagal nafas.

Pasien dengan distres pernafasan gagal nafas, henti nafas (apnu) maupun hipoksemia
yang tidak teratasi dengan pemberian oksigen merupakan indikasi ventilasi mekanik.
Idealnya pasien telah mendapat intubasi dan pemasangan ventilasi mekanik sebelum
terjadi gagal nafas yang sebenarnya. Distres pernafasan disebabkan ketidakadekuatan
ventilasi dan atau oksigenasi. Prosesnya dapat berupa kerusakan paru (seperti pada
pneumonia) maupun karena kelemahan otot pernafasan dada (kegagalan memompa
udara karena distrofi otot).
RR >35 atau < 5x/m, SaO2 < 90% atau PaO2 <60 mmHg, pCO2 >55mmHg,
peurunan kesadaran GCS , 5ml/kg
2. Insufisiensi jantung.
Tidak semua pasien dengan ventilasi mekanik memiliki kelainan pernafasan primer.
Pada pasien dengan syok kardiogenik dan CHF, peningkatan kebutuhan aliran darah
pada sistem pernafasan (sebagai akibat peningkatan kerja nafas dan konsumsi
oksigen) dapat mengakibatkan jantung kolaps. Pemberian ventilasi mekanik untuk
mengurangi beban kerja sistem pernafasan sehingga beban kerja jantung juga
berkurang.
3. Disfungsi neurologis
Pasien dengan GCS 8 atau kurang yang beresiko mengalami apnu berulang juga
mendapatkan ventilasi mekanik. Selain itu ventilasi mekanik juga berfungsi untuk
menjaga jalan nafas pasien serta memungkinkan pemberian hiperventilasi pada klien
dengan peningkatan tekanan intra cranial.
4. Tindakan operasi
Tindakan operasi yang membutuhkan penggunaan anestesi dan sedative sangat
terbantu dengan keberadaan alat ini. Resiko terjadinya gagal napas selama operasi
akibat pengaruh obat sedative sudah bisa tertangani dengan keberadaan ventilasi
mekanik.
5. Membantu eliminasi carbondioksida
6. Membantu kerja otot pernapasan
Hal yang perlu dipantau yang saat pasien yang di pasang ventilator adalah : (Andre C.
Kalil, 2022)
a. Penilaian ventilasi dan oksigenasi
b. Alarm (pplateu<30 cmH2O). RR < 6x/mnt - > 30x/mnt, MV , 25ml/kg –
125ml/kg, PEEP , 30 cmH2O
c. Klinis : Inspeksi, Palpasi, Perkusi, Auskultasi
 Anallis gas Darah : pCO2, pO2, SaO2
 Fhoto thoraks : posisi ujung ETT, patu pleura
d. Monitor RR, SPO2
e. Ventilator : Tidal Volume respiratory Rat, p Inspriasi, grafik Flow,pressure
dan Volume

Komplikasi pemasangan ventilasi mekanik menurut Bersten dan Soni (2009):

1. Komplikasi akibat peralatan. Terkait malfungsi atau pemutusan alat,
kesalahan tempat dan kontaminasi .
2. Komplikasi terkait dengan paru-paru, seperti intubasi Airway misalnya
kerusakan gigi, pita suara dan trakea, VentilatorAcquired Pneumonia (VAP),
gangguan terkait cedera paru-paru misalnya difusi cedera paru-paru,
barotrauma misalnya pneumothorax dan keracunan O2.
3. Komplikasi yang terkait dengan kardiovaskuler, seperti penurunan preload
ventrikel kanan yang menyebabkan penurunan curah jantung, peningkatan
afterload ventrikel kanan, retensi cairan karena penurunan jantung yang
mengakibatkan penurunan aliran darah di ginjal.
4. Komplikasi lainnya seperti : luka atau perdarahan pada jaringan mukosa,
kelemahan oto-otot pernapasan dan peripheral, gangguan tidur, kecemasan,
ketakutan akibat lamanya waktu setelah masa penyembuhan, distensi akibat
menelan, imobilisasai dan masalah pencernaan
 Kriteria keberhasilan pemasangan Ventilator :
1. Pengkajian subjektif :Batuk adekuat, Tidak menggunakan agent
neuromuscular blocking, Tidak ada produksi mucus yang berlebih pada
trakheobronkhial, Core problem pada pasien sudah teratasi dan Tidak
mendapatkan sedasi yang berkelanjutan
2. Pengukuran objektif : Status kardiovaskuler stabil, HR < 140 x/menit, Tidak
ada iskemik miokard , Tidak anemia (Hb > 8 g/dl), Tekanan darah sistolik 90
– 160 mmHg, GCS > 8, Tidak demam (rentang 36 < suhu < 38℃) 8)
Penggunaan vasopressor dan inotropik pada dosis minimal ( < 5
ug/kgBB/menit untuk dopamin atau dobutamin)
3. Parameter oksigenasi yang adekuat : Nilai tidal volume > 5 cc/kgBB, Nilai
vital capacity > 10 cc/kgB, RR < 35 x/menit 4) SpO2 > 95 % 5) PaO2 > 60
mmHg, dan nilai PCO2 < 60 mmHg

2. Berdasarkan data Kemenkes (2021), 84 % kematian bayi di Indonesia akibat

kelahiran perematur. Bayi prematur memiliki keterbatasan dalam penyimpanan
nutrisi sehingga berpotensi mengalami defisit nutrisi. Sistem gastrointestinal yang
belum berkembang juga berpotensi meningkatkan risiko infeksi pada bayi tersebut.
Silahkan anda analisis bagaimana optimalisasi pemberian nutrisi pada bayi
prematur, agar terhindar dari masalah sistemik. Analisis secara teori dan hasil
penelitian (min.3 penelitian dan lampirkan artikel ilmiah tersebut).

Bayi prematur rentan terhadap penyakit serius atau kematian selama periode
neonatal. Tanpa pengobatan yang tepat, mereka yang dapat bertahan hidup berada
pada situasi peningkatan risiko cacat seumur hidup dan memiliki kualitas hidup yang
buruk.
Asupan nutrisi yang kurang sejak sebelum dan pada masa kehamilan
merupakan pemicu kelahiran bayi dengan BBLR. Kegagalan pertumbuhan bayi pasca
persalinan akibat nutrisi yang tidak memadai akan berhubungan dengan
perkembangan neurokognitif bayi prematur dimasa mendatang. Oleh karena itu,
strategi pemberian nutrisi yang cukup untuk menjamin tumbuh kembang yang
 optimal pada bayi prematur perlu ditekankan. Rekomendasi terapi nutrisi bayi
prematur saat ini didasarkan pada tujuan mencapai tingkat pertumbuhan. Namun,
tujuan ini seringkali sulit dicapai karena keterbatasan fisiologis yang terkait dengan
prematuritas.

1. Menurut The American Academy of Pediatrics (AAP) dan European Society of

Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) Committee on
Nutrition, asupan energi yang harus diberikan pada bayi prematur adalah 105-130
kkal/kg/hari dan 110-135 kkal/kg/hari). Saat terapi ini berlangsung, bayi terkadang
membutuhkan peningkatan asupan kalori karena kebutuhan energi yang lebih tinggi
selama sakit (ESPGHAN Committee on Nutrition et al., 2013).
Saat bayi prematur, bukan saja kebutuhan energi yang diutamakan, namun
dikombinasikan dengan kebutuhan protein. Kebutuhan protein yang
direkomendasikan ESPGHAN adalah 4,0-4,5 dan 3,5-4,0 g/kg/hari pada bayi
prematur dengan berat masing-masing hingga 1.000 g dan 1.000-1.800 g (Wiechers et
al., 2021).
Menurut hasil penelitian yang berjudul Optimizing Nutrition in Preterm Low
Birth Weight Infants—Consensus Summary. Frontiers in Nutrition. (Kumar et al.,
2017). Mendapatkan hasil Asupan protein melalui makanan enteral adalah 150
mL/kg/hari (volume enteral rutin) tidak cukup untuk memenuhi kebutuhan bayi yaitu
1,8-2,1 g/kg/hari untuk ASI tanpa fortifikasi, 1,5 g/kg/hari donor ASI dari manusia
yang tidak diperkaya susu, atau 3,6 g/kg/hari formula khusus untuk bayi prematur.
Penelitian mengatakan Untuk menyediakan 4 g/kg/hari protein, kita perlu
memberi makan bayi 290–340 mL/kg/hari ASI tanpa fortifikasi, 210 mL/kg/hari ASI
yang difortifikasi atau 170 (16% konsentrasi) hingga 190 mL/kg/hari (14%
konsentrasi) formula bayi prematur Penting untuk dicatat bahwa osmolaritas dan
beban zat terlarut ginjal mempengaruhi volume cairan yang diperlukan untuk nutrisi
enteral. Oleh karena itu, fortifikasi untuk bayi yang diberi ASI dan penyesuaian
konsentrasi susu formula untuk bayi prematur yang diberi susu formula diperlukan.
Untuk pemberian makanan enteral rutin, formula prematur atau ASI yang diberikan
 dengan kecepatan 150-180 mL/kg/hari sudah cukup untuk memenuhi kebutuhan
nutrisi yang direkomendasikan
Osmolaritas dan beban zat terlarut ginjal mempengaruhi volume cairan yang
diperlukan untuk nutrisi enteral. Oleh karena itu, fortifikasi untuk bayi yang diberi
ASI dan penyesuaian konsentrasi susu formula untuk bayi prematur yang diberi susu
formula diperlukan. Untuk pemberian makanan enteral rutin, formula prematur atau
ASI yang diberikan dengan kecepatan 150-180 mL/kg/hari sudah cukup untuk
memenuhi kebutuhan nutrisi yang direkomendasikan

2. Terdapat beberapa hal yang perlu diperhatikan dalam pemberian protein

adalah setiap penambahan gram asupan protein untuk bayi prematur disesuaikan
dengan penambahan berat badan 6,5 g/hari dan peningkatan lingkar kepala 0,4
cm/minggu). Saat memantau penambahan berat badan bayi prematur saat perawatan
di rumah sakit, hal-hal kritis yang harus diperhatikan adalah seperti bayi di kuartil
terendah dari kenaikan berat badan di rumah sakit yaitu ≤12 g/kg/hari kemungkinan
menderita cerebral palsy selain itu dikaitkan dengan hasil pemeriksaan
perkembangan menggunakan skala Bayley dan menemukan hasil <70, serta gangguan
perkembangan saraf pada 18-22 bulan
Hal tersebut sesuai dengan judul penelitian yang berjudul Optimizing nutrition of the
preterm infant. Chinese Journal of Contemporary Pediatrics. (William, 2017)
Hasil dari penelitian mengatakan hal yang diharapkan dari terapi nutrisi ini
adalah perkembangan saraf dan pertumbuhan yang lebih baik pada bayi prematur,
penambahan berat badan >18 g/kg/hari dan peningkatan lingkar kepala >0,9
cm/minggu selama masa rawat inap dianggap optimal. Jika tingkat ini tidak dapat
dipenuhi, nutrisi enteral bayi harus ditinjau dan dimodifikasi untuk mencapai tujuan
optimal ini. Tindakan dapat difokuskan pada kandungan protein pada makanan yang
diberikan, evaluasi rasio Protein dan energi serta pemanfaatan sumber makanan yang
kaya nutrisi untuk mengurangi defisit nutrisi.
asupan protein yang memadai dapat meningkatkan pertumbuhan bayi
prematur. Jika Tindakan ini dilakukan dengan baik di NICU, maka resiko kecacatan
saraf akan jauh lebih rendah. Perawat wajib untuk memastikan rasio protein/energi
 untuk mencapai pertumbuhan yang berkualitas selama berada di NICU. Tanda-tanda
pertumbuhan yang baik selama dirawat di NICU adalah peningkatan massa tubuh
tanpa lemak dan timbunan massa lemak yang terbatas. Jika hasil penilaian tumbuh
kembang menunjukan hasil yang optimal maka asupan protein dapat dikurangi
sebagai proses untuk pulang dari rumah sakit.

Implementasi pemberian nutrisi enteral pada bayi prematur

a. Pemberian makanan enteral minimal

Sebaiknya pemberian makanan enteral ditunda dalam beberapa waktu, karena
beresiko terjadinya enterokolitis nekrotikans (NEC) walaupun pada dasarnya
secara teori pemberian makanan enteral dengan volume rendah (biasanya 24
mL/kg/hari) dapat mempercepat maturitas gastrointestinal, fisiologis, endokrin,
dan metabolic. Selain itu, makanan tersebut tidak mengandung kalori yang
cukup untuk mempertahankan pertumbuhan.
Menurut hasil penelitian yang berjudul Early trophic feeding versus enteral
fasting for very preterm or very low birth weight infants. (Morgan et al., 2013)
Penelitian mengevaluasi efek pemberian makanan trofik dini versus puasa
enteral pada bayi berat lahir sangat rendah (BBLSR) dan tidak menemukan
perbedaan dalam toleransi makan, waktu untuk mencapai pemberian makanan
enteral penuh, dan kejadian NEC). Dengan demikian, dapat disimpulkan bahwa
nutrisi enteral dengan volume yang minimal tidak berkaitan dengan efek
menguntungkan atau berbahaya pada bayi prematur sehingga makanan trofik
dapat dimulai sesegera mungkin.

b. Pengenalan makanan enteral progresif

Pengenalan makanan enteral untuk bayi prematur sering tertunda selama
beberapa hari karena kekhawatiran dapat meningkatkan risiko NEC.
Hal tersebut berbeda dengan penelitian yang berjudul Delayed introduction of
progressive enteral feeds to prevent necrotising enterocolitis in very low birth
weight infants. (Morgan et al., 2014b)
 Penelitian mengevaluasi efek pengenalan pemberian makan dini (<4 hari)
dengan pengenalan pemberian makan yang tertunda (4-7 hari) hasil penelitian
tidak menemukan perbedaan yang signifikan dalam hal kejadian NEC
atau penyebab kematian. Namun, bayi dengan pengenalan makanan yang
tertunda membutuhkan waktu yang lebih lama untuk beradaptasi hingga dapat
mengkonsumsi pemberian makanan enteral penuh.

c. Tingkat kemajuan pemberian makanan enteral

Salah satu pendekatan yang dapat dilakukan adalah pemberian makanan
enteral dini sebanyak 20-30 mL/kg/hari pada VLBWI dan 15-25 mL/kg/hari
pada bayi prematur karena dalam beberapa penelitian, tidak terdapat risiko NEC.
Penelitian oleh (Morgan et al., 2014a) mengevaluasi efek dari tingkat kemajuan
pemberian makanan enteral pada kejadian NEC, semua penyebab kematian, dan
morbiditas lain pada bayi prematur dan tidak menemukan perbedaan yang
signifikan. Pada kelompok yang lambat memberikan makanan enteral sejak dini
menyebabkan perkembangan lambat sehingga bayi membutuhkan waktu yang
lebih lama untuk mecapai berat badan lahir yang ideal serta lambat untuk
beradaptasi dengan makanan enteral yang diberikan sesuai panduan.

Pilihan nutrisi enteral

1. Air Susu Ibu
ASI adalah sumber nutrisi utama yang optimal untuk bayi prematur karena
memberikan perlindungan yang kuat terhadap sepsis dan infeksi lainnya, mencegah
terjadinya NEC. Efek jangka Panjang dari pemberian ASI adalah perkembangan saraf
yang baik. Oleh karena itu, AAP sangat merekomendasikan penggunaan ASI untuk
bayi prematur. Tetapi kandungan ASI tidak bisa memenuhi kebutuhan nutrisi bayi
prematur.
Hal tersebut sesuai dengan Peneltian yang berjudul Enteral nutrition for optimal
growth in preterm infants. (Kim, 2016). Strategi laktasi yang dapat dilakukan adalah
pemompaan ASI sesegera mungkin pasca persalinan. jika ibu tidak memiliki ASI
maka harus dilakukan donor asi namun harus melalui proses pasteurisasi. Kelemahan
 dari ASI untuk bayi prematur adalah tidak dapat memenuhi kebutuhan nutrisi bayi
prematur, karena kalori dan protein yang tidak mencukupi, konsentrasi kalsium dan
fosfor dalam ASI juga jauh lebih rendah dari yang diperlukan untuk mendukung
pertumbuhan yang optimal
Terdapat produk dari korea yaitu suplementasi (fortifikasi) dengan multinutrient
human milk fortifiers (HMFs) yang diindikasikan pada bayi prematur berusia kurang
dari 31 minggu kehamilan dan/atau dengan berat lahir kurang dari 1.500g.
Umumnya, fortifikasi dimulai ketika volume makanan enteral mencapai 100
mL/kg/hari dan secara bertahap ditingkatkan. HMF yang dijual
mengandung kandungan protein rata-rata ASI 1,4-1,6 g/dL.
Menurut penelitian yang berjudul Novel multinutrient human milk-based human
milk fortifier promotes growth and tolerance in premature infants. (Gates et al., 2021;
Koo & Tice, 2018). Untuk pemberian suplementasi (fortifikasi) dengan multinutrient
human milk fortifiers (HMFs) harus dilakukan pemeriksaan BUN (blood Ureum
Nitrogen) secara berkala
Teori mengataakan Sebagian besar bayi prematur biasanya dipulangkan dari
NICU pada usia 35 hingga 36 minggu, dan/atau setelah berat badan mencapai 1.800-
2.100gr
Penelitian yang berjudul rowth and Bone Mineralization of Very Preterm Infants
at Term Corrected Age in Relation to Different Nutritional Intakes in the Early
Postnatal Period. (Körnmann et al., 2017). Mendapatkan hasil ibu yang berencana
untuk menyusui bayinya secara langsung setelah keluar, laju pertumbuhan harus
dipantau dengan cermat dalam waktu 48 jam setelah keluar dan dievaluasi kembali
setelah 1 minggu. Bagi bayi yang dipulangkan saat masih menerima ASI perah atau
ASI donor, asi fortifikasi adalah pilihan yang lebih praktis dan berkelanjutan
2. Susu Formula untuk bayi prematur
Susu Formula untuk bayi prematur diberikan jika bayi tidak dapat menerima ASI
dari ibunya sendiri maupun ASI donor.
Menurut penelitian Susu formula harus mengandung protein whey, polimer glukosa,
trigliserida rantai menengah, kalsium, dan fosfor, dan diperkaya dengan mineral,
vitamin, dan elemen untuk mendukung tingkat pertambahan nutrisi intrauterin. Dalam
 praktiknya, dosis inisiasi pemberian susu formula pada bayi prematur adalah 70-72
kkal/100 mL. Jika ditoleransi oleh bayi, maka dapat ditingkatkan menjadi formula
preterm pekat 16% (80-82 kkal/100 mL).
Susu formula untuk bayi prematur umumnya tidak direkomendasikan untuk bayi yang
telah diijinkan pulang, karena sasaran utama telah tercapai. Sehingga susu formula
bayi prematur hanya setelah bayi keluar dari NICU 2. susu formula saat pulang
Saat pulang, bayi prematur yang telah mencapai berat badan optimal dapat
mengkonsumsi susu formula yang mengandung energi pada 75 kkal/100 mL, kaya
protein 2,1 g dan mengandung mineral, vitamin, dan elemen – elemen lain (Aggett et
al., 2006)

3. Jelaskan peran perawat intensif anak pada kasus anak post operasi VSD usia 4
tahun dan identifikasi kebutuhan perawatan perkembangan serta FCC nya!!
Peran perawat Intensive secara Umum
a. Seorang perawat yang bertugas di ruang intensif melaksanakan tiga tugas utama
yaitu, life support, memonitor keadaan pasien dan perubahan keadaan akibat
pengobatan dan mencegah komplikasi yang mungkin terjadi.
b. Di Australia diklasifikasikan empat kriteria perawat intensif yaitu, perawat Intensif
yang telah mendapat pelatihan lebih dari duabelas bulan ditambah dengan
pengalaman, perawat yang telah mendapat latihan sampai duabelas bulan, perawat
yang telah mendapat sertifikat pengobatan kritis (critical care certificate),
dan perawat sebagai pelatih (trainer).
c. Di Indonesia, ketenagaan perawat di ruang intensif diatur dalam Keputusan
Menteri Kesehatan Republik Indonesia Nomor
1778/MENKES/SK/XII/2010 tentang Pedoman Penyelenggaraan Pelayanan Intensif
di Rumah Sakit yaitu, untuk ICU level I maka perawatnya adalah
perawat terlatih yang bersertifikat bantuan hidup dasar dan bantuan lanjut, untuk ICU
level II diperlukan minimal 50% dari jumlah seluruh perawat di ICU merupakan
perawat terlatih dan bersertifikat ICU, dan untuk ICU level III diperlukan minimal
75% dari jumlah seluruh perawat di ICU merupakan perawat terlatih dan bersertifikat
ICU
3. Jelaskan peran perawat intensif anak pada kasus anak post operasi VSD usia 4
tahun dan identifikasi kebutuhan perawatan perkembangan serta FCC nya!!

A. Peran perawat Intensive.

1. Seorang perawat yang bertugas di ruang intensif melaksanakan tiga tugas utama
yaitu, life support, memonitor keadaan pasien dan perubahan keadaan
akibat pengobatan dan mencegah komplikasi yang mungkin terjadi.
2. Di Australia diklasifikasikan empat kriteria perawat intensif yaitu, perawat
Intensif yang telah mendapat pelatihan lebih dari duabelas bulan ditambah
dengan pengalaman, perawat yang telah mendapat latihan sampai duabelas bulan,
perawat yang telah mendapat sertifikat pengobatan kritis (critical care
certificate), dan perawat sebagai pelatih (trainer).
3. Di Indonesia, ketenagaan perawat di ruang intensif diatur dalam
Keputusan Menteri Kesehatan Republik Indonesia Nomor 1778/ME
NKES/SK/XII/2010 tentang Pedoman Penyelenggaraan Pelayanan
Intensif di Rumah Sakit yaitu, untuk ICU level I maka perawatnya
adalah perawat terlatih yang bersertifikat bantuan hidup dasar dan bantuan lanjut,
untuk ICU level II diperlukan minimal 50% dari jumlah seluruh perawat di ICU
merupakan perawat terlatih dan bersertifikat ICU, dan untuk ICU level III
diperlukan minimal 75% dari jumlah seluruh perawat di ICU merupakan perawat
terlatih dan bersertifikat ICU

B. Peran perawat Anak.

Perawat merupakan anggota dari tim pemberi asuhan keperawatan anak dan
orang tuanya. Perawat dapat berperan dalam berbagai aspek dalam memberikan
pelayanan kesehatan dan bekerjasama dengan anggota tim lain, dengan keluarga
terutama dalam membantu memecahkan masalah yang berkaitan dengan
perawatan anak.
Peran perawat dalam merawat pasien post Op VSD yang berusia 4 tahun adalah
sebagai berikut :
1) Sebagai pendidik.
Perawat berperan sebagai pendidik, baik secara langsung dengan memberi
penyuluhan/pendidikan kesehatan pada orang tua maupun secara tidak langsung
dengan menolong orang tua/anak memahami pengobatan dan perawatan anaknya.
Kebutuhan orang tua terhadap pendidikan kesehatan dapat mencakup pengertian
dasar penyakit anaknya, perawatan anak selama dirawat di rumah sakit, serta
perawatan lanjut untuk persiapan pulang ke rumah. Tiga domain yang dapat
dirubah oleh perawat melalui pendidikan kesehatan adalah pengetahuan,
keterampilan serta sikap keluarga dalam hal kesehatan khususnya perawatan anak
sakit.
2) Sebagai konselor
Suatu waktu anak dan keluarganya mempunyai kebutuhan psikologis berupa
dukungan/dorongan mental. Sebagai konselor, perawat dapat memberikan
konseling keperawatan ketika anak dan keluarganya membutuhkan. Hal inilah
yang membedakan layanan konseling dengan pendidikan kesehatan. Dengan cara
mendengarkan segala keluhan, melakukan sentuhan dan hadir secara fisik maka
perawat dapat saling bertukar pikiran dan pendapat dengan orang tua tentang
masalah anak dan keluarganya dan membantu mencarikan alternatif
pemecahannya.
3) Melakukan koordinasi atau kolaborasi
a. Pasien post op VSD akan mendapat obat anastesi yang mengakibatkan
kelemahan otot-otot pernafasan dan memasifkan silia. Sehingga banyak
akumulasi sekret yang berada di saluran pernafasan. Sehingga hal ini
perawat sebagai salah satu tenaga kesehatan yang berada 24 jam di
samping pasien perlu melakukan kolaborasi dengan fisioterapi untuk
dillakuakn fisioterapi untuk Pencegahan akumulasi sekret, karena pasien
dengan post op VSD aktivitasnya dibatasi. Kemudian pasien.
b. Kolaborasi dan Koordinasi dengan adalam ahli gizi terkait pemberian
Nutrisi pada anak Post Op VSD terkait diet tinggi protein dan rendah
natrium .
 c. Melakukan koordinasi atau kolabosi dengan dokter dalam pemantuaun
efek sedasi dan analgesik pasien setelah post Op dan selalu melaporkan
kondisi pasien. Dengan pendekatan interdisiplin, perawat melakukan
koordinasi dan kolaborasi dengan anggota tim kesehatan lain dengan
tujuan terlaksananya asuhan yang holistik dan komprehensif. Perawat
berada pada posisi kunci untuk menjadi koordinator pelayanan kesehatan
karena 24 jam berada di samping pasien.

C. Sebagai advokat pasien,

Dalam perawatan anak dengan post VSD, perawat membantu proses
komunikasi dan permberian informasi yang layak antara pasien , keluarga dan
tenaga kesehatanlainnya dan perawat membantu membantu pasien dan keluarga
mendapatkan hak-haknya. Contohnya perawat menajadi perantara jika kelurga
ingin menanyakan tentang keadaan pasien post Op VSD kepada dokter hal tersebut
juga termasuk dalam hak pasien. Contoh pemenuhan hak yang lain adalah pasien
berhak mendampingi pasien, mendapatkan informasi terkait perawaan anaknya,
serta juga membantu dalam pasien dan keluraga untuk melakuak pemenuhan
spritual ibadah sesuai dengan agama / kepercayaan yang dianutnya selama hal itu
tidak mengganggu pasien lain. Dalam hal perawat dapat menerpakan family
Centered care.
D. Sebagai pemberi asuhan keperawatan,
Dimana perawat dalam hal ini berperan dalam menyesuaikan pemberian
asuhan keperawatan pada pasien dengan post OP VSD tetap memperhatikan
kebutuhan dasar manusia.  merawat membantu pasien VSD untuk pemenuhan
Kebutuhan Fisik-Biomedik (asuh). hiygine, nutrisi, pemenuhan cinta kasih dan
kenyamanan, untuk pemenuhan cinta da kenyaman, pasien bisa melibatkan
keluarga untuk pemenuhannya dengan menganjurakn orang tua untuk selalu berada
di samping anak, karena anak akan merasakan nyaman jika berada dekat dengan
kelurganya, hal tersebut juga dapat mencegah Autraumatik care pada anak.
Bermain merupakan salah satu kebutuhan anak, peran perawat dalam hal ini bisa
membantu pasien bermain di rumah sakit dengam tetap memperhatikan prinsip
bermain pada anak post op, bermain yang bisa dilakukan adalah dengan story
 telling, mendengarkan musik, untuk story telling pasien bisa meminta orang tua
terlibat di dalam hal tersebut.
Salah satu penelitian terkait peran perawat pada pasien post op VSD. Hal ini sesuai
dengan penelitian A nurse‐driven analgesia and sedation protocol reduces length of
PICU stay and cumulative dose of benzodiazepines after corrective surgery for tetralogy
of Fallot.(Hanser et al., 2020). Hasil dalam penelitian ini adalah

Framework Data
item
Patient 1. Jenis pasien yang menjadi responden penelitian ini adalah pasien anak
Problem, (or yang mengalami TOF jenis VSD pasca operasi yang sedang dirawat di
Population PICU
2. Jumlah sampel yang menjadi responden dalam penelitian ini adalah 65
responden yang dibagi menjadi 2 kelompok yaitu kelompok pra-
implementasi (33) dan kelompok post-implementasi (32).
3. Kriteria inklusi dalam penelitian ini adalah pasien TOF VSD usia 2-6
bulan.
4. Kriteria eksklusi dalam penelitian ini adalah pasienyang memiliki
penyakit komorbid seperti kelainan kromosom (misalnya, sindrom
mikrodelesi 22q11, Trisomi 21) serta anomali ekstrakardiak yang
memerlukan perawatan khusus seperti atresia esofagus dan atresia anal.
Intervention, 1. Penelitian ini dilaksanakan dalam 2 tahap yaitu Pre-implementasi (saat
operasi) dan post implementasi (setelah operasi)
2. Pemberian obat pada fase Pre-implementasi (saat operasi) dan post
implementasi (setelah operasi) dilakukan oleh dokter. Namun, pada fase
pre-implementasi tidak dilakukan pengawasan oleh perawat karena
dilakukan di kamar operasi. Perawat hanya mengobservasi gejala klinis
pasien di fase post-implementasi
3. Obat yang diberikan dalam penelitan ini adalah;
a. Kelompok pra-implementasi
1) i.v. infus opioid (morfin: 5–100 µg·kg−1·hr−1 dengan dosis
 awal: 30 g·kg−1/hr−1) dan
2) i.v. infus benzodiazepin (midazolam: 0,05-0,42
mg·kg−1·hr−1; dosis awal: 0,05 mg·kg−1·hr−1).
3) Sevofluran
b. Kelompok post-implementasi
1) i.v. infus opioid (morfin: 5–100 µg·kg−1·hr−1 dengan dosis
awal: 30 g·kg−1/hr−1) dan
2) i.v. infus benzodiazepin (midazolam: 0,05-0,42
mg·kg−1·hr−1; dosis awal: 0,05 mg·kg−1·hr−1).
3) Clonidine diberikan 24 jam setelah operasi dengan
mengurangi dosis opioid dan sedasi. Clonidine di berikan via
intravena/infus dengan dosis : 0,2–2 g·kg−1·hr−1. dosis
awal: 0,04 g·kg−1/jam−1).
4) Melatonin oral (3–5 mg/hari) diberikan setelah 3 hari tinggal
di PICU.
5) Khloral hidrat (sampai 25 mg/kg empat kali sehari)
diberikan tambahan setelah hari kedua pasca operasi
4. Alat ukur yang digunakan adalah COMFORT B untuk mengetahui efek
sedasi dari obat yang diberikan
5. Penggunaan skala NISS untuk mengetahui efek analgesic.
6. Evaluasi dilakukan setiap 8 jam.
Comparison or 1. Penelitian ini dilakukan pada 2 kelompok yaitu kelompok pre-
Control, implementasi (saat operasi) dan kelompok post-implmentasi (setelah
operasi
2. Perbandingan pemberian obat pada kedua kelompok adalah sebagi
berikut;
a. Kelompok pra-implementasi
1) i.v. infus opioid (morfin: 5–100 µg·kg−1·hr−1 dengan dosis
awal: 30 g·kg−1/hr−1) dan
2) i.v. infus benzodiazepin (midazolam: 0,05-0,42
mg·kg−1·hr−1; dosis awal: 0,05 mg·kg−1·hr−1).
 3) Sevofluran
b. Kelompok post-implementasi
1) i.v. infus opioid (morfin: 5–100 µg·kg−1·hr−1 dengan dosis
awal: 30 g·kg−1/hr−1) dan
2) i.v. infus benzodiazepin (midazolam: 0,05-0,42
mg·kg−1·hr−1; dosis awal: 0,05 mg·kg−1·hr−1).
3) Clonidine diberikan 24 jam setelah operasi/berada di PICU
dengan mengurangi dosis opioid dan sedasi. Clonidine di
berikan via intravena/infus dengan dosis : 0,2–2
g·kg−1·hr−1. dosis awal: 0,04 g·kg−1/jam−1).
4) Melatonin oral (3–5 mg/hari) diberikan setelah 3 hari tinggal
di PICU.
5) Khloral hidrat (sampai 25 mg/kg empat kali sehari)
diberikan tambahan setelah hari kedua pasca operasi
Outcome 1. Hasil yang didapatkan dalam penelitian ini adalah
a. Penerapan protokol sedasi yang dipantau oleh perawat dapat
membantu mengurangi dosis opioid dan benzodiazepin, serta
lama rawat inap di PICU.
b. Setelah penerapan protokol analgesia dan sedasi, waktu rata-rata
penggunaan ventilator menjadi lebih pendek (72 [24-141] jam
menjadi 49 jam [24-98]
c. Lama perawatan di PICU berkurang secara signifikan (7 hari
[5–14] menjadi 5 hari [4–7]
d. pasien dari kedua kelompok mendapat dosis kumulatif morfin
yang sama namun mengalami penurunan (1.961 g/kg [1.113–
3.162] menjadi 1.920 g/kg [904–2.687]).
e. Terjadi peningkatan pemberian clonidine setelah 24 jam pada
pasien pasca operasi yaitu (0,53 mg/kg [0,24–0,92] menjadi
6,05 mg/kg [0,81–22,53] disertai dengan penurunan pemberian
dosis kumulatif benzodiazepin secara signifikan yaitu (7,37
mg/kg [4,70-17,65] Menjadi 5,0 mg/kg [2,70–9,12]
 f. Selain itu, dosis morfin dikurangi pasca pemberian clonidine
yaitu (50,0 g·kg−1·jam−1 [39,7–79,9] menjadi. 42,5
g·kg−1·jam−1 [29,7–51,8]) dan midazolam (0,22
mg·kg−1·jam−1 [0,20–0,33] menjadi 0,15 mg·kg−1·jam−1
[0,13–0,20]).
g. Penggunaan klonidin meningkat secara signifikan (0,014
g·kg−1·jam−1 [0,009–0,021] menjadi 0,674 g·kg−1·jam−1
[0.02–1.095]
h. Kelompok pasca implementasi tidak menunjukkan peningkatan
komplikasi pasca operasi dan kejadian dan adverse event.
Time/Type of 1. Tujuan dari penelitian ini adalah untuk mengevaluasi efek dari
Study or implementasi protokol sedasi yang dilakukan oleh perawat dengan
question melihat pada durasi penggunaan ventilasi mekanis, lama perawatan,
dosis puncak dan komulatif dan efek samping dibandingkan dengan
periode praimplementasi yang dilakukan oleh dokter
2. Penelitian ini merupakan penelitian retrospektif dengan studi
observasional
3. Penelitian ini dilakukan dengan 2 tahap yaitu kelompok pra-
implementasi pada Januari 2005 dan Oktober 2010 sebanyak 33
responden dan kelompok post-implementasi pada periode Januari 2012
hingga Juli 2017 yaitu sebanyak 32 responden

E. Sebagai peneliti/pembaharu.
Melakukan penelitiain tentang penanganaan pasien post VSD untuk meningkatkan
kualitas praktik keperawatan anak.
Perawatan dengan memperhatikan perkembangan anak. Anak usia 4 tahun termasuk
dalam anak usia pra sekolah. Anak usia pra sekolah kurang dapat membedakan
antara diri sendiri dan orang lain. Mereka memiliki pemahaman bahasa yang terbatas
dan hanya dapat melihat satu aspek dari suatu objek atau situasi pada satu waktu.
a. Anak usia pra sekolah merasa fenomena nyata yang tidak berhubungan sebagai
penyebab penyakit.
b. Cara berpikir magis menyebabkan anak usia pra sekolah memandang penyakit
sebagai suatu hukuman. Selain itu anak usia pra sekolah mengalami konflik
psikososial dan takut terhadap mutilasi, menyebabkan anak terutama takut
terhadap tindakan tindakan medis
Menurut erikon
Tahap inisiatif vs rasa bersalah (4-6 tahun/pra sekolah) Pada tahap ini anak
mulai berinisiatif dalam belajar mencari pengalaman baru secara aktif melalui
aktivitasnya. Apabila anak dilarang atau dicegah maka akan tumbuh perasaan
bersalah pada dirinya. Anak post VSD akan merasa ingin tau tentang perawatann
yang dilakukannya. Perawat bisa melalukan perannya sebagai pendidik. Anak
usia 4 tahun telah paham dengan pembicaraan orang dewasa, dengan
memberikan pemahaman tentang perawat yang dilakukan yang dilakuan
menjelaskan tentang manfaat alat medis yang digunakan. Perawat bisa
menerapkan terapi bermain dramatic play untuk menjelaskan tetntang alat alat
kesehatan pada anak sehingga mengurangi kecemasan dan autraumatic care
Perkembangan Psikoseksual Menurut Sigmud Freud
Tahap oedipal/phalik (3-5 tahun). Pada tahap ini kepuasan anak terletak pada
rangsangan autoerotic yaitu merabaraba, merasakan kenikmatan dari beberapa
daerah erogennya dan mulai suka pada lawan jenis. Anak laki-laki cenderung
suka pada ibunya daripada ayahnya demikian juga sebaliknya anak perempuan
suka sama ayahnya. Pada kasus pasien post VSD diatas pada tahap ini perawat
Ibu menerapkan family centered dengan melibatkan Ibu pasien untuk memenuhi
kebutuhan psikoseksual
Perkembangan Kognitif Menurut Piaget
Tahap pra operasional (2-7 tahun) Anak mampu mengoperasionalisasikan apa
yang dipikirkan melalui tindakan sesuai dengan pikirannya. Pada saat ini anak
masih bersifat egosentris. Pikirannya masih transduktif, artinya menganggap
semua sama. Pada tahap ini perawat bisa berperan sebagai pendidik ataupun
sebagai konselor untuk memenuhi perkembangam kognitif. (Yuliastati, 2016)
 DAFTAR PUSTAKA

P. J., Agostoni, C., Axelsson, I., De Curtis, M., Goulet, O., Hernell, O., Koletzko, B., Lafeber, H.
N., Michaelsen, K. F., Puntis, J. W. L., Rigo, J., Shamir, R., Szajewska, H., Turck, D.,
Weaver, L. T., & Nutrition, E. C. on. (2006). Feeding Preterm Infants After Hospital
Discharge: A Commentary by the ESPGHAN Committee on Nutrition. Journal of
Pediatric Gastroenterology and Nutrition, 42(5), 596–603.
https://doi.org/10.1097/01.mpg.0000221915.73264.c7
Cooke, R. J. (2016). Post-discharge Nutrition in Preterm Infants. In G. Buonocore, R. Bracci, &
M. Weindling (Eds.), Neonatology: A Practical Approach to Neonatal Diseases (pp. 1–
18). Springer International Publishing. https://doi.org/10.1007/978-3-319-18159-2_189-1
ESPGHAN Committee on Nutrition, Arslanoglu, S., Corpeleijn, W., Moro, G., Braegger, C.,
Campoy, C., Colomb, V., Decsi, T., Domellöf, M., Fewtrell, M., Hojsak, I., Mihatsch,
W., Mølgaard, C., Shamir, R., Turck, D., & van Goudoever, J. (2013). Donor human milk
for preterm infants: Current evidence and research directions. Journal of Pediatric
Gastroenterology and Nutrition, 57(4), 535–542.
https://doi.org/10.1097/MPG.0b013e3182a3af0a
Gates, A., Thompson, A. B., Marin, T., Waller, J. L., Patel, J., & Stansfield, B. K. (2021). Novel
multinutrient human milk-based human milk fortifier promotes growth and tolerance in
premature infants. JPEN. Journal of Parenteral and Enteral Nutrition.
https://doi.org/10.1002/jpen.2249
Hanser, A., Neunhoeffer, F., Hayer, T., Hofbeck, M., Schlensak, C., Mustafi, M., Kumpf, M., &
Michel, J. (2020). A nurse-driven analgesia and sedation protocol reduces length of PICU
stay and cumulative dose of benzodiazepines after corrective surgery for tetralogy of
Fallot. Journal for Specialists in Pediatric Nursing: JSPN, 25(3), e12291.
https://doi.org/10.1111/jspn.12291
Kim, M.-J. (2016). Enteral nutrition for optimal growth in preterm infants. Korean Journal of
Pediatrics, 59(12), 466–470. https://doi.org/10.3345/kjp.2016.59.12.466
Koo, W., & Tice, H. (2018). Human Milk Fortifiers Do Not Meet the Current Recommendation
for Nutrients in Very Low Birth Weight Infants. JPEN. Journal of Parenteral and
Enteral Nutrition, 42(4), 813–820. https://doi.org/10.1177/0148607117713202
Körnmann, M. N., Christmann, V., Gradussen, C. J. W., Rodwell, L., Gotthardt, M., Van
Goudoever, J. B., & Van Heijst, A. F. J. (2017). G. Nutrients, 9(12), 1318.
https://doi.org/10.3390/nu9121318
Kumar, R. K., Singhal, A., Vaidya, U., Banerjee, S., Anwar, F., & Rao, S. (2017). Optimizing
Nutrition in Preterm Low Birth Weight Infants—Consensus Summary. Frontiers in
Nutrition, 4, 20. https://doi.org/10.3389/fnut.2017.00020
Morgan, J., Bombell, S., & McGuire, W. (2013). Early trophic feeding versus enteral fasting for
very preterm or very low birth weight infants. The Cochrane Database of Systematic
Reviews, 3, CD000504. https://doi.org/10.1002/14651858.CD000504.pub4
Morgan, J., Young, L., & McGuire, W. (2014a). Slow advancement of enteral feed volumes to
prevent necrotising enterocolitis in very low birth weight infants. The Cochrane
Database of Systematic Reviews, 12, CD001241.
https://doi.org/10.1002/14651858.CD001241.pub5
Morgan, J., Young, L., & McGuire, W. (2014b). Delayed introduction of progressive enteral
feeds to prevent necrotising enterocolitis in very low birth weight infants. The Cochrane
Database of Systematic Reviews, 2014(12), CD001970.
https://doi.org/10.1002/14651858.CD001970.pub5
Wiechers, C., Bernhard, W., Goelz, R., Poets, C. F., & Franz, A. R. (2021). Optimizing Early
Neonatal Nutrition and Dietary Pattern in Premature Infants. International Journal of
Environmental Research and Public Health, 18(14), 7544.
https://doi.org/10.3390/ijerph18147544
William, W. H., Jr. (2017). Optimizing nutrition of the preterm infant. Chinese Journal of
Contemporary Pediatrics, 19(1), 1–21. https://doi.org/10.7499/j.issn.1008-
8830.2017.01.001
Andre C. Kalil, M. L. M. (2022). Management of VentilatorAssociated Pneumonia Guidelines.
Division of Pulmonary, Critical Care and Sleep Medicine, University of Connecticut
School of Medicine, UConn Health, 263 Farmington Avenue, Farmington, CT 06030-
1321, USA. https://doi.org/10.1016/j.ccm.2018.08.002
Hanser, A., Neunhoeffer, F., Hayer, T., Hofbeck, M., Schlensak, C., Mustafi, M., Kumpf, M., &
Michel, J. (2020). A nurse-driven analgesia and sedation protocol reduces length of PICU
stay and cumulative dose of benzodiazepines after corrective surgery for tetralogy of
 Fallot. Journal for Specialists in Pediatric Nursing: JSPN, 25(3), e12291.
https://doi.org/10.1111/jspn.12291
William Owens. (2012). THE VENTILATOR BOOK. First Draught Press.
Yuliastati, N. (2016). Keperawatan Anak. Pusdik SDM Kesehatan.
 Jurnal Anestesiologi Indonesia

LAPORAN KASUS

Manajemen Perioperatif Operasi Arterial Switch pada

Transposition of The Great Arteries with Intact Ventricular
Septum

Perioperative Management in Arterial Switch Operation of Transposition

of The Great Arteries with Intact Ventricular Septum

Dian Kesumarini, Herdono Poernomo

SMF Anestesiologi dan Terapi Pascabedah, Rumah Sakit Jantung dan Pembuluh Darah Harapan
Kita, Jakarta, Indonesia

Korespondensi: diankesumarini@gmail.com

ABSTRACT
Background: Congenital heart disease (CHD) occurs in one-third of all major
congenital anomalies. Transposition of the great arteries (TGA) is one of the most
complicated congenital heart anomalies. Arterial switch operation (ASO) is a procedure
to repair TGA. This procedure has high mortality rate and morbidity.
Case: A 42-day old infant with body weight of 3100 gram was referred to Rumah Sakit
Jantung dan Pembuluh darah (RSJPD) Harapan Kita due to cardiac anomalies.
echocardiography finding was TGA with intact ventricular septum (TGA-IVS), atrium
septal defect (ASD) secundum L-R shunt, and patent ductus arteriosus (PDA). Procedure
of repair included ASO using Le Compte maneuver, PDA ligation, partial closure of ASD
with 3mm to spare. Duration of cardiopulmonary bypass (CPB) was 136 minutes with
cross clamp of 85 minutes. Transfusion of PRC, FFP, and TC were given and the patient
was transported to intensive care unit (ICU) with haemodynamic support of adrenaline
0.05 mcg/kgBW/minute and milrinone 0.375 mcg/kgBW/minute. Extubation was done 72
hours after the surgery.
Discussion: ASO is a high-risk procedure, with high mortality and morbidity.
Perioperative anesthesia consideration for TGA patients include preanesthesia
management, hemodynamic during anesthesia, inotropic support, arrythmia due to
coronary problem and how to assess epicardial echocardiography after the surgery. In
postoperative period it is important to anticipate the adverse effects of CPB to
myocardium, low cardiac output syndrome ,risk of infection, and other complications
often seen in infants after this procedure.
Conclusion: Preoperative management by recognizing risk factors, intraoperative
anesthesia consideration, myocardial protection, and comprehensive postoperative care
in ICU are important to improve the outcome for patients undergoing this procedure.

Keywords: anesthesia consideration; arterial switch operation; cardiopulmonary

bypass; congenital heart disease; d-TGA

Volume 12, Nomor 2, Tahun 2020 11

 Jurnal Anestesiologi Indonesia

ABSTRAK
Latar belakang: Penyakit jantung bawaan (PJB) berkontribusi terhadap hampir sepertiga
dari kelainan kongenital secara keseluruhan. Transposition of the great arteries (d-TGA)
adalah satu kelainan jantung bawaan (PJB) yang kompleks. Tindakan arterial switch
operation (ASO) menjadi pilihan koreksi pada kasus TGA. Tindakan ini mempunyai
risiko morbiditas dan mortalitas yang cukup tinggi.
Kasus: Bayi berusia 42 hari dengan berat badan 3100 gram dirujuk ke Rumah Sakit
Jantung dan Pembuluh Darah (RSJPD) Harapan Kita karena kelainan jantung. Pasien
dilakukan diagnosik ekokardiografi dan didapatkan TGA dengan septum ventrikular yang
intak (TGA-IVS), atrium septal defect (ASD) sekundum L-R shunt, dan patent ductus
arteriosus (PDA). Prosedur pembedahan meliputi ASO menggunakan manuver Le
Compte, pemotongan PDA, ASD ditutup sebagian dan disisakan 3mm. Durasi
cardiopulmonary bypass (CPB) 136 menit dengan cross clamp 85 menit, diberikan
tranfusi PRC, FFP, dan TC, lalu dipindahkan ke intensive care unit (ICU) dengan support
adrenalin 0.05 mcg/kg/menit dan milrinone 0.375 mcg/kg/menit. Ekstubasi dilakukan 72
jam pascaoperasi.
Pembahasan: Operasi arterial switch merupakan tindakan berisiko tinggi, dengan angka
kematian dan morbiditas yang tinggi. Konsiderasi perianestesia pada pasien TGA ini di
antaranya tatalaksana preanestesi, manajemen selama operasi, topangan hemodinamik,
aritmia yang diakibatkan masalah pembuluh darah koroner, dan penilaian ekokardiografi
epikardial pascaoperasi. Manajemen pascaoperasi penting untuk mengantisipasi efek dari
CPB yang berpengaruh pada miokardium, sindroma curah jantung rendah, risiko infeksi,
dan komplikasi lain yang sering terjadi pada infant setelah pembedahan ini.
Kesimpulan: Manajemen preoperatif dengan mengenali faktor risiko, tatalaksana
anestesia intraoperatif, myocardial protection, serta perawatan komprehensif
pascaoperasi di ICU sangat menentukan outcome pasien yang menjalani prosedur ini.

Kata Kunci: arterial switch operation; cardiopulmonary bypass; d-TGA; penyakit

jantung bawaan; tatalaksana anestesi

Volume 12, Nomor 2, Tahun 2020 12

 Jurnal Anestesiologi Indonesia
PENDAHULUAN
Transposition of the great arteries (d-
TGA) merupakan salah satu kelainan
jantung bawaan yang kompleks di mana
pembuluh darah arteri pulmonal keluar
dari ventrikel kiri dan aorta keluar dari
ventrikel kanan. Kelainan ini
mempunyai angka kejadian 5 % dari
seluruh pasien penyakit jantung bawaan
(PJB). Rumah Sakit Jantung dan
Pembuluh Darah (RSJPD) Harapan Kita
Jakarta merupakan salah satu center
kelainan jantung kongenital yang cukup
banyak melakukan arterial switch
operation (ASO), jumlah kasus pada
periode Maret 2017-Maret 2018
sebanyak 91 pasien dengan angka
mortalitas 11%, yang terdiri dari
transposition of the great arteries with
ventricular septal defect (TGA-VSD)
sebanyak 61 kasus dengan angka
kematian 8 pasien (13%) dan
transposition of the great arteries with
intact ventricular septum (TGA-IVS)
sebanyak 30 kasus dengan angka
kematian 2 pasien (6%). Angka ini
belum mencapai angka mortalitas
internasional pada prosedur serupa,
namun di Indonesia, angka ini adalah
angka yang terbaik. Beberapa penyebab
utama kematian pada prosedur ASO
pada TGA-IVS ini di antaranya
kegagalan fungsi ventrikel, masalah
pembuluh darah koroner, dan infeksi,
sedangkan pada TGA-VSD hipertensi
pulmonal menjadi salah satu
komorbiditas yang meningkatkan angka
mortalitas pascaoperasi arterial switch.
Pengenalan faktor risiko perioperatif,
tatalaksana intraoperatif dan
pascaoperasi sangat berperan penting
dalam menentukan outcome dari
prosedur ini.1
KASUS
Seorang bayi berusia 42 hari dirujuk oleh
rumah sakit lain karena ditemukan
kelainan jantung saat pemeriksaan
Volume 12, Nomor 2, Tahun 2020
ekokardiografi dengan riwayat
sebelumnya dirawat di intensive care
unit (ICU) selama dua hari dengan
keluhan sesak akibat pneumonia aspirasi.
Riwayat kelahiran spontan, usia
kehamilan ibu 36 minggu dan berat lahir
2400 gram. Riwayat kebiruan disangkal.
Riwayat antenatal care (ANC) ibu
teratur.
Dari pemeriksaan fisik didapatkan berat
badan bayi 3100 gram dan panjang badan
49 cm. Tekanan darah 77/40 mmHg, nadi
154 kali per menit, respirasi 36 kali per
menit, dan saturasi oksigen 87%.
Pemeriksaan penunjang laboratorium
didapatkan Hb 14.9, leukosit 9060, CRP
1, ureum 18.5 mg/dl, dan kreatinin
0.36mg/dl. Pada foto thorax ditemukan
cardiothoracic ratio (CTR) 55%,
segmen pulmonal tidak menonjol,
segmen aorta normal, tidak ada infiltrat
maupun kongesti paru. Pasien ini dirawat
di ruang intermediate care unit RSJPD
Harapan Kita dengan menggunakan
prostaglandin 7 unit/kg/menit.
Hasil ekokardiografi didapatkan situs
solitus, AV concordance, VA
discordance, semua PV to LA, ASD
sekundum L-R shunt diameter 3-4mm,
VSD (-), PDA continuous flow diameter
1.5-2 mm, LVEF 70% (Teich), TAPSE
0.9 cm, katup-katup dalam batas normal,
arcus aorta di kiri, coartacio (-). Left
ventricle (LV) mass index 44g/m2,
posterior wall diameter (PWD) 30 mm.
Dari hasil tersebut, disimpulkan
diagnosis pasien adalah TGA-IVS, ASD
sekundum L-R shunt, dan patent ductus
arteriosus (PDA).
Persiapan anestesia meliputi induksi
inhalasi dengan sevoflurane. Pasien
sudah terpasang infus perifer di vena
dorsum manus sinistra. Dilakukan
pemasangan arterial line di arteri
brachialis sinistra, diberikan titrasi
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dengan total dosis fentanyl 10 mcg,
vecuronium 1 mg, midazolam 1 mg.
Dilakukan pemasangan endotracheal
tube (ETT nomor 3,5 non cuff).
Selanjutnya dilakukan pemasangan
kateter vena sentral di vena jugularis
internal dextra. Rumatan anestesi dengan
campuran gas oksigen dan udara dengan
fraksi 50%. Gas sevoflurane 1 vol %,
fentanyl, dan vecuronium.
Analisis gas darah (AGD) sebelum
masuk mesin pintas jantung dan
paru/cardiopulmonary bypass (CPB):
pH 7.28, pCO2 54,9, pO2 59,9, SO2
84,6, BE -0,5, HCO3 26,3, laktat 0,8.
Tekanan darah selama pembedahan
sistolik 45-70 mmHg dan diastolik
diantara 25-40 mmHg. Selama CPB,
didapatkan rentang mean arterial
pressure (MAP) sekitar 32-40 mmHg,
AGD pasca-CPB pH 7.32, pCO2 45.6,
pO2 115,9, SO2 97.1, HCO3 24.4, laktat
2,7.
Temuan intraoperatif didapatkan jantung
ukuran normal, vena inominata (+).
Aorta di anterior main pulmonary artery
(MPA), koroner 1 LCx, 2 R ini
merupakan varian normal dari koroner,
LPA-RPA konfluen diameter 4 mm,
ASD sekundum 6 mm.
Pasien dilakukan arterial switch
operation (ASO) menggunakan manuver
Le Compte, pemotongan PDA, ASD
ditutup sebagian dan disisakan 3mm.
Durasi CPB adalah 136 menit, dengan
cross clamp selama 85 menit. Pasien
menerima transfusi packed red cell 60
ml, fresh frozen plasma 60 ml, dan
thrombocyte concentrate 51 ml. Total
urine output 10 ml dengan perdarahan
200 ml. Durasi operasi adalah 324 menit
dan durasi anestesi adalah 417 menit.
Selesai operasi pasien dipindahkan ke
ruang ICU dengan hemodinamik arterial
Volume 12, Nomor 2, Tahun 2020
blood pressure sebelum dipindahkan
71/38 mmHg, HR 150 x/menit, CVP 10
mmHg, SpO2 99 % dan inotropik
adrenalin 0.05 mcg/kg/menit dan
milrinone 0.375 mcg/kg/menit.
Selesai operasi pasien ditransfer ke ICU
dengan hemodinamik saat admisi ICU
tekanan darah 82/57 (52) mmHg, heart
rate 156x/m, CVP 9, SpO2 97 % dengan
support adrenalin 0.05 mcg/kg/menit,
milrinone 0.375 mcg/kg/menit, diberikan
kalsium glukonas drip 10 mg/kg/jam,
ventilasi dikontrol dengan drip fentanyl 5
mcg/kg/jam, midazolam 0.05
mg/kg/jam, dan vecuronium 0,1
mg/kg/jam, mode ventilator dengan
pressure control, rate 45, P above 13,
PEEP 5 FiO2 50 %. Diberikan lanjutan
antibiotik profilaksis cefuroxime 3 x 30
mg/kg sebanyak 6 dosis, dan pertoneal
dialysis siklus diaktifkan karena
olioguria. Pada hari ke-0 pascaoperasi
(POD-0), dilakukan pemeriksaan AGD
arteri dan vena pada jam I dan jam IV,
serta pemeriksaan laboratorium lengkap.
Dari pemeriksaan AGD arteri ditemukan
pH: 7.22, pO2: 90.2, pCO2: 58.1, HCO3:
24.4, BE: -3.0, SpO2: 95.1, laktat: 1.6.
Dari pemeriksaan AGD vena ditemukan
pH 7.18, pO2 90.2, PCO2: 63.6, HCO3:
24.4, BE: -3.1, SaO2: 55.8, laktat 1.8.
Pemeriksaan laboratorium Hb 9.4 g/dl,
Ht 28%, leukosit 7140 /L, trombosit
108.000 /L, PT : 15,7 detik, aPTT : 95
detik, INR : 1,42, Albumin 3,5 g/dL,
detik, Ureum : 18,3 mg/dL, Cr : 0,35
mg/dL. AGD POD-0, jam ke 4, arteri:
pH: 7.42, PO2: 84.5, pCO2: 40.8, HCO3:
21.8, BE: -2.8, SaO2: 97.2%, laktat: 2.6
mmol/L. Pada AGD vena ditemukan pH:
7.32, pO2: 35.6, pCO2: 40.8, HCO3:
24.1, BE: -1.3, SaO2: 67.1%, laktat: 2.8
mmol/L.
Pada hari ke-0 pascaoperasi (POD-0)
diberikan transfusi PRC 10 ml/kg, dan
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FFP 10 ml/kg, dengan total balans cairan
-170 m/24 jam (-34 ml/kg/24 jam).
24 jam pascaoperasi (POD-1) dilakukan
evaluasi ekokardiografi, LVEF 45 %,
TAPSE 0.5 cm, tidak ada regional wall
motion abnormality (RMWA), gradien
neoaorta 4 mmHg, neopulmonal 5
mmHg, katup-katup baik. Pasien
hemodinamik stabil dengan tekanan
darah 71/40 (57) mmHg, HR: 140
x/menit, support adrenalin 0.05
mcg/kg/menit, dan milrinone 0.75
mcg/kg/menit, Ca glukonas 10
mg/kg/jam. Hasil AGD arteri
menunjukkan pH 7,46, pO2 175, pCO2:
33.9, HCO3: 24.7, BE: 0.8, SpO2:
99.9%, laktat: 1.1mmol/L. Sementara
itu, hasil AGD vena menunjukkan pH:
7.43, PCO2: 40.2, pO2: 40.7, BE: 0.8,
SpO2: 76.8%, laktat: 1 mmol/L. Pasien
diberikan terapi tambahan furosemide 3
x 1 mg/kg intravena dan aldactone 1 x
6,25 mg. 12 jam pascaoperasi pasien
diberikan gut feeding dan dilanjutkan
pemberian nutrisi enteral.
24 jam pascaoperasi pasien
dibangunkan, weaning ventilator
perlahan. 72 jam pascaoperasi pasien
diekstubasi, dengan total balans cairan
selama 3 hari. Pascaekstubasi dosis
milrinone diturunkan secara titrasi,
diganti dengan captopril 3 x 0.3 mg/kg
per oral. Setelah 12 jam pascaoperasi
dilakukan down titrasi adrenalin sampai
dengan stop, diganti dengan dobutamin 5
mcg/kg/menit. Selama target nutrisi per
oral belum tercapai, diberikan
maintenance cairan D40 % NS 3:1 dan
protein parenteral 1 gr/kg/hari.
PEMBAHASAN
Manajemen Perioperatif
Beberapa hal yang harus diperhatikan
pada perioperatif pasien transposition of
the great arteries (TGA) antara lain
status hemodinamik, level support
Volume 12, Nomor 2, Tahun 2020
inotropik, aritmia, akses perifer dan
sentral, laboratorium, x-ray,
electrocardiograpgy (EKG), mode
ventilator yang digunakan, jalan napas
dan status organ nonkardiak.1,2
Faktor risiko yang mempengaruhi
mortalitas antara lain patent foramen
ovale (PFO) atau ASD restriktif,
hipertensi pulmonal persisten, berat
badan lahir rendah (BBLR),
prematuritas, dan usia saat diketahui
terdapat TGA.2,3
Pada kelainan TGA-IVS terjadi fisiologi
paralel sirkulasi di mana tidak ada
hubungan antara darah teroksigenasi
dengan darah tidak teroksigenasi, maka
dari itu pada kelainan ini sangat penting
untuk menjaga kecukupan/keadekuatan
mixing antara darah yang teroksigenasi
dengan darah yang tidak teroksigenasi
antara jantung kanan dengan jantung kiri.
Percampuran (mixing) ini dapat terjadi
pada tingkat atrium ataupun ductus
arteriosus (PDA). Pada pasien dengan
ASD yang kecil (restriktif) perlu
dilakukan ballon atrial septectomy
(BAS), untuk menjaga percampuran
darah teroksigenasi dengan darah yang
tidak teroksigenasi pada tingkat atrial,
karena aliran ke paru berasal dari
ventrikel kiri, sedangkan darah yang
tidak teroksigenasi berasal dari atrium
kanan, maka penting untuk menjaga
percampuran darah teroksigenasi pada
atrium kiri dengan darah tidak
teroksigenasi pada atrium kanan untuk
menjaga aliran ke paru adekuat sehingga
pasien dapat mempertahankan saturasi.
Percampuran ini juga terjadi pada tingkat
PDA di mana terjadi percampuran darah
antara aorta dengan arteri pulmonalis,
untuk itu pada periode preoperatif
penting untuk menjaga patensi PDA
dengan pemberian infus prostaglandine
(PGE1) dengan tujuan mempertahankan
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 Jurnal Anestesiologi Indonesia
kecukupan aliran ke paru dan saturasi
untuk perfusi organ.
Penilaian perioperatif pada pasien TGA-
IVS antara lain evaluasi percampuran
(mixing) pada tingkat atrium setelah
prosedur BAS, evaluasi efek samping
pemakaian PGE1 seperti apneu,
hipotensi, demam, eksitasi sistem saraf
pusat, dan penurunan volume
intravaskular pada lesi ductus dependent.
Adanya patent ductus arteriosus (PDA)
menurunkan aliran darah ke sistem
gastrointestinal sehingga berpotensi
menjadi NEC. Sedangkan, pada pasien
TGA-VSD, evaluasi yang harus dinilai di
antaranya tanda kelebihan sirkulasi ke
paru akibat adanya shunt melalui septum
ventrikel (VSD). Kejadian ini pada
jangka panjang dapat menyebabkan
gagal jantung atau congestive heart
failure (CHF). Tanda gagal jantung ini
antara lain peningkatan heart rate,
kardiomegali, penurunan temperatur,
diaforesis, berat badan rendah, takipneu,
retraksi subkosta dan substernal, prolong
capillary refill.2
Manajemen intraoperatif
Induksi dengan inhalasi dilakukan pada
pasien yang tidak ada akses intravena.
Teknik anestesi opioid base juga
dianjurkan pada pasien ini. Prinsip
manajemen anestesi pada TGA-VSD
yang disertai hipertensi pulmonal antara
lain oksigenasi dan ventilasi yang
adekuat, meningkatkan kedalaman
anestesi tanpa menurunkan kontraktilitas
jantung.1,3
Pada pasien TGA-IVS dengan mixing
yang adekuat pada tingkat atrial maupun
PDA, seringkali terjadi desaturasi pada
saat induksi dan ventilasi positif.
Penyebab penurunan mixing ini
multifaktorial. Ventilasi tekanan positif
dan paralisis yang disertai hilangnya
sekresi katekolamin endogen karena
Volume 12, Nomor 2, Tahun 2020
opioid yang tinggi dikombinasi dengan
berkurangnya preload dan kontraktilitas
kedua ventrikel, menyebabkan aliran
oksigen yang lebih rendah karena mixing
pada tingkat atrial. Penilaian kecukupan
diameter BAS dapat bias karena mixing
pada PDA, PDA dapat menutup bila
prostaglandin dihentikan. Manajemen
pasien TGA termasuk memastikan
oksigenasi dan ventilasi, meningkatkan
kedalaman anestesi tanpa menurunkan
kontraktilitas jantung.1-3
Pada penilaian transesophageal
echocardiography (TEE) hal yang harus
dievaluasi setelah CPB di antaranya lesi
residual, regional dan global ventricular
function untuk memastikan tidak terjadi
insufisiensi koroner akibat pemindahan
pembuluh darah koroner yang tidak
sempurna, fungsi katup-katup, evaluasi
regurgitasi, dan mendeteksi gradien
anastomosis supravalvar pada neoaorta
dan neopulmonal, juga regional wall
motion.3,4
Setelah weaning CPB, TEE dan
monitoring left arterial pressure (LAP)
dilakukan untuk menilai global dan
regional LV function. LAP ini juga dapat
menilai adanya perfusi ke miokardium
yang tidak adekuat. Sebagian pasien
memerlukan inotropik dan beberapa ahli
merekomendasikan pemberian
nitrogliserin 1-2 mcg/kg/menit untuk
dilatasi arteri koroner dan menurunkan
preload. Walaupun tidak umum terjadi,
obstruksi dan translokasi arteri koroner
dapat menjadi masalah serius pada
pasien setelah operasi ASO. Tanda
utama dari kejadian ini adalah disfungsi
miokardia global, yang dapat dilihat dari
ekokardiografi. Regional wall motion
abnormalities (RWMA) tidak
bermanifestasi pada pasien neonatus.
Target hemodinamik saat off bypass pada
pasien TGA adalah cardiac output yang
adekuat, tekanan LA serendah mungkin,
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tekanan darah sistolik berkisar 50-75
mmHg. Bila LV overdistended (ditandai
dengan LAP yang tinggi dan penurunan
tekanan sistemik dan cardiac output),
diuretik dapat diberikan bila
hemodinamik sangat terganggu akibat
peningkatan LAP, untuk mengeluarkan
volume darah melalui CVP sampai LAP
menurun. Pengambilan darah untuk
sampel AGD juga dapat mempengaruhi
volume intravaskular. Pada saat
transport pasien ke ICU harus
diperhatikan airway, ventilasi, patensi
inotropik dan suhu. 3-5
Pada jantung normal, 3 pembuluh darah
arteri utama yang berhubungan dengan
great arteries antara lain: (1) arteri
koroner kanan, merupakan arteri koroner
yang melalui atrioventricular groove;
(2) circumflex coronary artery,
merupakan arteri coroner yang melintasi
atrioventricular groove; (3) anterior
descending artery, arteri koroner yang
paralel dengan interventricular septum
pada permukaan anterior jantung.4,6 Hal
ini diilustrasikan dalam Gambar 1.

Gambar 1. Distribusi arteri koroner pada TGA. Sconamiglio, G6

Volume 12, Nomor 2, Tahun 2020 17

 Jurnal Anestesiologi Indonesia
Bagian atas proyeksi diagnostik
merupakan gambaran ekokardiografi dua
dimensi, sedangkan bagian bawah
frontal view, distribusi koroner dari sisi
anterior (surgeon view).6
Operasi arterial switch melibatkan
pembuluh darah besar (great artery) dan
translokasi pembuluh darah dan asal
pembuluh darah lainnya. Dengan
demikian, membentuk
ventriculoarterial concordance (aorta
ke ventrikel kiri). Translokasi aorta ini
juga termasuk mobilisasi dan
reimplantasi arteri koroner. Pada operasi
arterial switch ini, dibuat “button”
diantara koroner dan dimplantasikan ke
ujung neoaorta. Pada prosedur ini
dealinasi anatomi arteri koroner
sangatlah penting, karena seringkali
terdapat anomali posisi arteri koroner
saat sebelum dikoreksi.3,4,6
Lesi residual yang sering pada operasi
arterial switch di antaranya branch
pulmonary artery stenosis. Stenosis
arteri pulmonalis merupakan salah satu
tanda iskemia koroner dan left arterial
hypertension. Lesi obstruksi residual
pada left and right outflow dapat
menjadi problem paskaoperasi.
Ventrikel kiri harus memompa melawan
tahanan di SVR, sehingga memerlukan
support inotropik dan afterload
reduction. Pemberian volume harus
hati-hati, karena compliance jantung
kurang baik. Sebelum pasien
dipindahkan dari kamar operasi harus
diperhatikan tanda-tanda insufisensi
koroner yang merupakan tanda iskemik
miokard, termasuk evaluasi global
fungsi dari ventrikel kiri.1-5
Pascaoperasi
Pada TGA, target hemodinamik hari
pertama adalah heart rate kurang dari
160 x/menit, tekanan darah sistolik
lebih dari 60 mmHg, tekanan darah
Volume 12, Nomor 2, Tahun 2020
diastolik lebih dari 30 mmHg, MAP
lebih dari 40 mmHg, support
hemodinamik dapat diberikan inotropik
dan inodilator seperti dobutamin atau
adrenalin, dan milrinone. Target perfusi
pada hari pertama yaitu urine output
lebih dari 1 ml/kg/jam. Analisa gas
darah target PH 7,35-7,45, base excess
yang rendah. Bila terjadi sindrom low
cardiac output, harus dilakukan evaluasi
ekokardiografi untuk mengetahui
adanya disfungsi LV, RV, RWMA,
outflow tract obstruction, stenosis
pulmonal dan aorta supravalvar.
Sedangkan pada pasien TGA-VSD
harus dievaluasi adanya VSD, ASD
residual, fungsi katup atrioventrikular,
tanda-tanda hipertensi pulmonal
paskaoperasi, irama jantung, dan tanda-
tanda insufisiensi koroner. Hb
dipertahankan 10, fibrinogen di atas
160, trombosit lebih dari 100.000, PT
kurang dari 15, PTT kurang dari 60, dan
normotermia.7,8
Pada delayed stenal closure, penutupan
dinding dada dilakukan bila status
hemodinamik pasien stabil, termasuk
tekanan darah, heart rate, dan analisa
gas darah arteri.7,8
Hal-hal yang menghambat ekstubasi
antara lain perdarahan, hemodinamik
yang tidak stabil. Hb dipertahankan 12
sampai dengan 13 g/dl, dan faal
koagulasi yang normal, dan keadaan
pasien yang normotermia. Untuk
pemberian nutrisi paskaoperasi jantung
harus memperhatikan status
hemodinamik. Initial feeding dapat
diberikan per NGT, dengan jumlah total
enteral per hari 20 kkal/kg/hari. Bila
toleransi baik, dapat ditingkatkan
bertahap hingga mencapai target
volume enteral 120-140 ml/kg/hari,
dengan catatan peningkatan volume
dapat diberikan 20 ml/kg/hari.
Sedangkan target kalori yang dapat
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dicapai 120-150 kkal/kg/hari, ketika
target volume tercapai maka diberikan
nutrisi padat kalori.7-9
Antibiotik profilaksis merupakan
antibiotik yang diberikan untuk
mencegah infeksi yang belum terjadi.
Antibiotik profilaksis hanya digunakan
pada pasien dengan risiko tinggi infeksi,
Gambar 2. Proses peralihan dari antibiotik profilaksis menjadi empiric
Disfungsi kardiak seringkali terjadi
pada pascaoperasi jantung kongenital,
yang disebabkan oleh inflamasi dari
CPB, yang menyebabkan pelepasan
TNF- yang mempengaruhi fungsi
kontraksi kardiomiosit. Inflamasi juga
menyebabkan perubahan struktur dan
fungsi endotel, yang menyebabkan
edema interstitial sehingga menurunkan
compliance otot miokardium.
Mekanisme utama disfungsi miokardial
adalah adanya periode iskemia
(cardioplegic arrest) dan reperfusion
injury, juga disfungsi miokardial pada
periode preoperatif. Efek mesin CPB
terhadap miokardia pada infant lebih
besar daripada pasien anak-anak
maupun dewasa, hal ini disebabkan
Volume 12, Nomor 2, Tahun 2020
seperti pada pasien dalam terapi
imunosupresi, kanker, dan pada pasien
yang menjalani operasi. Lain halnya
dengan antibiotik empirik yang
diberikan pada pasien yang terbukti
infeksi atau diduga infeksi. Peralihan
dari antibiotik profilaksis menjadi
empirik dapat dilihat pada Gambar 2.10
infant memiliki protein kontraktil yang
lebih sedikit, dan penyimpanan kalsium
dan sarkoplasmik yang lebih sedikit
dibandingkan otot miokardium yang
sudah matur. Sehingga otot miokardium
infant mempunyai compliance yang
lebih rendah dan respon cairan yang
lebih rendah dibandingkan dewasa.
Dengan demikian, sangat mudah terjadi
peningkatan afterload pada infant
dibandingkan anak-anak dan dewasa.
Kebutuhan oksigen pada infant lebih
tinggi daripada anak-anak dan dewasa
sehingga memerlukan cardiac output
dan minute ventilasi yang lebih tinggi.
Pada periode pascaoperasi ventilasi
mekanik digunakan untuk
mengoptimalisasi delivery oxygen dan
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mengurangi konsumsi oksigen yang
dapat meningkat karena napas spontan.
Ventilasi positif mempunyai efek
menurunkan preload dan afterload
ventrikel kiri. Waktu inspirasi dapat
mencegah menurunan filling pressure
ventrikel kiri sehingga cardiac output
lebih optimal. Beberapa literatur
menyatakan bahwa rerata lama periode
ventilasi mekanik pascaoperasi arterial
switch sekitar 3 hari dan proses weaning
ventilator mencapai 12-24 jam.10-12
Pada periode pasca-CPB seringkali
terjadi disfungsi vaskuler yang
menyebabkan peningkatan resistensi
sistemik dan pulmonal. Peningkatan
resistensi paru ini dapat menyebabkan
terjadinya disfungsi ventrikel kanan.
Pada beberapa kasus, pascaoperasi
arterial swtich dilakukan delayed
sternal closure terutama pada pasien
dengan perdarahan, ukuran jantung
lebih besar secara signifikan karena
edema, dan pada keadaan di mana
fungsi ventrikel sangat menurun.11-13
Pada delayed stenal closure, penutupan
dinding dada dilakukan bila status
hemodinamik pasien stabil, termasuk
tekanan darah, heart rate, dan analisis
gas darah arteri.7,8
Tamponade jantung merupakan salah
satu komplikasi serius yang dapat
menyebabkan hipotensi hingga cardiac
arrest. Tamponade didefinisikan sebagai
akumulasi cepat dari cairan, darah, dan
udara pada ruang perikardium yang
meningkatkan tekanan perikardial dan
menurunkan venous return karena
penekanan pada atrium dan ventrikel
kanan. Tanda-tanda impending
tamponade antara lain takikardia, perfusi
perifer yang menurun, dan peningkatan
tekanan vena sentral.11
Pada periode pascaoperasi sangat
penting mempertahankan oksigenasi
Volume 12, Nomor 2, Tahun 2020
jaringan. Syok itu sendiri didefinisikan
sebagai delivery oxygen yang tidak
adekuat atau ketidakseimbangan antara
demand dan supply oksigen.
Peningkatan demand oksigen
pascaoperasi dapat disebabkan oleh
inflamasi sistemik yang merupakan
respon mesin CPB, demam, pelepasan
katekolamin endogen atau eksogen,
stress respon surgery, respon bangun,
dan pernapasan spontan.
Ketidakseimbangan demand-supply
oksigen merupakan hasil dari kurang
adekuatnya delivery oxygen yang
disebabkan anemia dan low cardiac
output. Penyebab low cardiac output itu
sendiri di antaranya venous return yang
tidak adekuat, disfungsi ventrikel,
afterload yang tinggi, atau aritmia yang
mempengaruhi fungsi miokardium,
sehingga mengurangi cardiac output.
Inflamasi sistemik menyebabkan
leakage pembuluh darah sehingga
menurunkan volume intravaskuler, dan
preload di ventrikel. Pada kasus di mana
preload berkurang karena disfungsi
diastolik maka diperlukan peningkatan
filling pressure ventricle untuk
mempertahankan stroke volume yang
adekuat.8,11
Terapi vasoaktif pada pascabedah
jantung kongenital untuk memperbaiki
disfungsi kardiovaskular harus
memperhatikan fungsi sistolik dan
diastolik ventrikel kanan dan kiri.
Vasoaktif yang menyebabkan
venodilatasi dapat menurunkan venous
return sehingga menurunkan volume
dan tekanan diastolik ventrikel,
sehingga tidak terjadi peningkatan
cardiac output. Sebaliknya vasoaktif
yang menyebabkan dilatasi arteri dapat
meningkatkan ejeksi ventrikel, dan tidak
terjadi dilatasi vena, sehingga tidak
terjadi penurunan venous return karena
tidak mempengaruhi kapasitansi
8,11
vena.
20
 Jurnal Anestesiologi Indonesia
Adrenalin merupakan katekolamin yang
terbentuk dari norepinefrin yang disertai
gugus N-methylation. Pada dosis kurang
dari 0.1 mcg/kg/menit adrenalin
menurunkan resistensi vaskuler dan
pulmonal melalui stimulasi reseptor  -2.
Pada dosis tinggi adrenalin
menstimulasi reseptor -1 yang
menyebabkan vasokonstriksi sehingga
meningkatkan kapasitansi arteri dan
vena. Studi yang dilakukan Mekkaw,
dkk menyatakan bahwa ada hubungan
antara lama ischemic time dengan
peningkatan skor inotropik.11,14
Milrinone bekerja dengan menginhibisi
enzim phosphodiesterase inhibitor III
sehingga mengurangi degradasi cAMP
sehingga menyebabkan penurunan
kapasitansi vena dan arteri serta
mempunyai efek inotropik ringan.8,11,15
KESIMPULAN
(1) Penilaian status perioperatif
TGA-IVS terdiri dari kecukupan mixing,
support hemodinamik, efek samping
PGE1, dan status organ nonkardiak; (2)
Evaluasi intraoperatif harus
mempertimbangkan balans anestesia
dengan kedalaman yang cukup tanpa
mengganggu hemodinamik dan
kontraktilitas. Pada penilaian TEE
pascaoperasi harus diperhatikan lesi
residual, regional dan global ventricular
function, fungsi katup-katup, evaluasi
regurgitasi, dan mendeteksi gradien
anastomosis. Setelah weaning CPB, TEE
dan monitoring left arterial pressure
(LAP) untuk menilai global dan regional
LV function, dan LAP ini juga dapat
menilai adanya perfusi ke miokardium
yang tidak adekuat; (3) Hal-hal yang
harus diperhatikan pada pascaoperasi
pasien TGA-IVS antara lain target
perfusi, echo evaluasi, irama jantung,
fungsi koroner, dan hemodinamik.
Volume 12, Nomor 2, Tahun 2020
DAFTAR PUSTAKA
1. Davies LK, Husain A, Weitzel NS.
Anesthetic management for patient
with congenital heart disease: The
pediatric Population. In: Hensley,
FA, Martin DE, Gravlee GP,
editors. A Practical Approach to
Cardiac Anesthesia. 5th Ed.
Philadelphia: Lippincott Williams
and Wilkins; 2013. Chapter 14;
p.389-429
2. Butts RJ, Ellis AR, Bradley SM,
Hulsey TC, Atz AM. Effect of
prostaglandin duration on outcomes
in transposition of the great arteries
with intact ventricular septum.
Congenital Heart Disease. 2012
Sept 23;7(4): 387-91.
3. Gupta S, Saiyed A, Meena R, Dogra
N. Anesthetic management during
transposition of great arteries
(TGA) correction: point to be focus.
British Journal of Medicine
&Medical Research. 2017; 19(8):
1-5
4. Nield LE, Dragulescu A, MacColl
C, Brun H, McCrindle BW, Kuiper
B, et al. Coronary artery doppler
patterns are associated with clinical
outcomes post-arterial switch
operation for transposition of the
great arteries. European Heart
Journal-Cardiovascular Imaging.
2017; 19(4): 461-68.
5. Villafane J, Hermoso RL, Bhatt
AB, Tweddell JS, Geva T, Nathan
M, et al. D-Transposition of the
Great Arteries. The Current Era of
the Arterial Switch Operation.
Journal Of American College Of
Cardiology. Elsevier. 2014; 64
(5):498-511
6. Sconamiglio, G. Arterial switch
operation for transposition of great
arteries: late results in adult
patients. International
Cardiovascular Forum Journal.
2013;1: 8-15
21
 Jurnal Anestesiologi Indonesia
7. Rome J. Inpatient Pathway for
Evaluation/Treatment of the
Newborn with TGA. Children’s
Hospital of Philadelphia. 2016; 1-3.
Available from
https://www.chop.edu/clinical-
pathway/newborn-tga-clinical-
pathway-immediate-post-operative-
cicu-care-hand-or-team.
8. Sarris GE, Balmer C, Bonou P,
Comas JV, Cruz ED, Chiara LD, et
al. Clinical guideline for
management of patients with
transposition of the great arteries
with intact ventricular septum.
European Journal of Cardio-thoracic
Surgery.2017;51:1-32
9. Justice L, Buckley JR, Floh A,
Horsley M, Alten J, Anand V, et al.
Nutrition consideration in the
pediatric cardiac intensive care unit
patient. World Journal for Pediatric
and Congenital Heart Surgery.
2018; 9(3): 333-43.
10. Gallagher JC, MacDougall C.
Antibiotics Simplified. 4th ed.
Philadelphia: Jones &Bartlett Inc:
2017:26-8
11. Bronicki RA, Costello JM, Brown
KL. Postoperative care of the
pediatric cardiac surgical patient. In
Shaffner DH, Nichols DG editors.
Volume 12, Nomor 2, Tahun 2020
Rogers’ Textbook of Pediatric
Intensive Care. 5th ed. Philadelphia:
Wolters Kluwer; 2015. Chapter 79,
p. 1252-60
12. Lu BY, Wu HD, Wang CC, Wu ET,
Huang SC, Ko WJ, et al. The Impact
of Postoperative Ventilator Support
on Outcome of the Arterial Switch
Operation-Report from a Single
Institute. Acta Cardiol Sin.
2010;26:173-8
13. Gocen U. Delayed sternal closure
after arterial switch operations: a
single center experience. 2017;
Cukurova Med J.2017;42(3):540-5
14. Mekkawy A, Ghoneim, El-Haddad
O, & Elmishaway A. Predictors of
early outcome of arterial switch
operation on patient with D-TGA.
Journal of the Egyptian Society of
Cardio-Thoracic Surgery. 2017;
25(1), 52-7
15. Burkhardt BEU, Rücker G, Stiller B.
Prophylactic milrinone for the
prevention of low cardiac output
syndrome and mortality in children
undergoing surgery for congenital
heart disease. Cochrane Database of
Systematic Reviews 2015, Issue 3.
Art. No.: CD009515.
DOI:10.1002/14651858.CD009515.
pub2
22
 International Journal of
Environmental Research
and Public Health

Review
Optimizing Early Neonatal Nutrition and Dietary Pattern in
Premature Infants
Cornelia Wiechers 1, * , Wolfgang Bernhard 1 , Rangmar Goelz 1 , Christian F. Poets 1 and Axel R. Franz 1,2

1 Department of Neonatology, University Children0 s Hospital, Eberhard Karls University, Calwerstr. 7,

72076 Tübingen, Germany; wolfgang.bernhard@med.uni-tuebingen.de (W.B.);
rangmar.goelz@med.uni-tuebingen.de (R.G.); christian-f.poets@med.uni-tuebingen.de (C.F.P.);
Axel.Franz@med.uni-tuebingen.de (A.R.F.)
2 Center for Pediatric Clinical Studies, University Children0 s Hospital, Eberhard Karls University,
72076 Tübingen, Germany
* Correspondence: Cornelia.wiechers@med.uni-tuebingen.de; Tel.: +49-7071-29-62310

Abstract: Providing adequate amounts of all essential macro- and micronutrients to preterm infants
during the period of extraordinarily rapid growth from 24 to 34 weeks’ postmenstrual age to achieve
growth as in utero is challenging yet important, since early growth restriction and suboptimal
neonatal nutrition have been identified as risk factors for adverse long-term development. Along
with now well-established early parenteral nutrition, this review emphasizes enteral nutrition, which
should be started early and rapidly increased. To minimize the side effects of parenteral nutrition
and improve outcomes, early full enteral nutrition based on expressed mothers’ own milk is an



important goal. Although neonatal nutrition has improved in recent decades, existing knowledge


about, for example, the optimal composition and duration of parenteral nutrition, practical aspects of
Citation: Wiechers, C.; Bernhard, W.;
the transition to full enteral nutrition or the need for breast milk fortification is limited and intensively
Goelz, R.; Poets, C.F.; Franz, A.R.
discussed. Therefore, further prospective studies on various aspects of preterm infant feeding are
Optimizing Early Neonatal Nutrition
needed, especially with regard to the effects on long-term outcomes. This narrative review will
and Dietary Pattern in Premature
summarize currently available and still missing evidence regarding optimal preterm infant nutrition,
Infants. Int. J. Environ. Res. Public
Health 2021, 18, 7544. https://
with emphasis on enteral nutrition and early postnatal growth, and deduce a practical approach.
doi.org/10.3390/ijerph18147544
Keywords: preterm infant; nutrition; enteral feeding advancements; growth
Academic Editors:
Luís Pereira-da-Silva, Gustavo Rocha
and Susana Pissarra
1. Background
Received: 28 May 2021 Feeding preterm infants is challenging because their nutritional needs are higher
Accepted: 12 July 2021
than those of term infants. This is due to their 4-fold higher physiological growth rate
Published: 15 July 2021
during this developmental period—the last trimester of fetal development—which occurs
in the neonatal intensive care unit (NICU) rather than in utero. This phase is characterized
Publisher’s Note: MDPI stays neutral
by extraordinarily rapid, exponential growth from 24 to 34 weeks’ postmenstrual age
with regard to jurisdictional claims in
(PMA), and the acquirement of notable amounts of lean body mass, fat and reserves of
published maps and institutional affil-
micronutrients. Remarkably, between 24 and 40 weeks PMA, adipose tissue increases
iations.
80 fold, water 4 fold and lean body mass solid matter 11 fold [1].
Achieving growth rates of all body compartments and organs that are similar to
those in utero should be the primary goal of preterm infant nutrition [2]. Despite more
intensive feeding strategies for preterm infants in recent years, growth failure remains a
Copyright: © 2021 by the authors.
common problem in very preterm infants during their postnatal hospitalization [3,4] and is
Licensee MDPI, Basel, Switzerland.
associated with impaired neurocognitive outcomes [5–8]. Furthermore, premature infants
This article is an open access article
are at an increased risk of cardiovascular disease and insulin resistance in adulthood [9–11].
distributed under the terms and
The underlying link between preterm birth and later metabolic alterations is still poorly
conditions of the Creative Commons
understood, and early-life growth restriction, as well as excessive catch-up growth after
Attribution (CC BY) license (https://
initial growth failure, have been reported [8,12]. Conceivably, the inadequate postnatal
creativecommons.org/licenses/by/
4.0/).
growth of preterm infants may have deleterious “programming” effects on metabolic

Int. J. Environ. Res. Public Health 2021, 18, 7544. https://doi.org/10.3390/ijerph18147544 https://www.mdpi.com/journal/ijerph
Int. J. Environ. Res. Public Health 2021, 18, 7544 2 of 13

health similar to those of intrauterine growth restriction in term infants [13,14], occurring
during the same period of development.
Postnatal growth of preterm infants in the NICU is the result of a complex interaction
of various factors, such as neonatal morbidity and inflammation preventing anabolism,
increased respiratory work causing increased energy requirements and, of course, nutrition
and the immaturity of the gastrointestinal tract [15]. Therefore, providing adequate macro-
and micronutrients to preterm infants and achieving growth similar to that in utero is
challenging [2].
In the last decades, an increasing number of studies has been carried out regarding
the nutrition of premature infants [16–20], but knowledge remains limited, e.g., concerning
the optimal macro- and micronutrient intake through parenteral nutrition (both in the first
week after birth and thereafter), the best way to achieve full enteral feeding, or indications
for and the optimal composition of a breast milk fortifier.
Furthermore, long-term outcome data in infants following various nutritional inter-
ventions are often lacking. This review summarizes the perspective of a level 3 NICU with
a focus on very early enteral nutrition and its repercussions on other aspects of neonatal
nutrition (Tables 1 and 2). Therefore, we searched PubMed and the Cochrane library for
each of the topics addressed above to provide a narrative review of current evidence, open
questions, as well as controversial aspects.

Table 1. Summary of recommendations for postnatal parenteral nutrition in preterm infants according to the ESPGHAN
guideline 2018.

ESPGHAN Recommendations for Parenteral Nutrition

- Start: Day 1 with at least 1.5 g/kg/d, day 2 and onwards 2.5 g/kg/d and 3.5 g/kg/d, accompanied by
Amino acids [21]
non-protein intakes >65 kcal/kg/d
- Start: (a) immediately or no later than 2 days after birth (b) at discontinuation of enteral feeding at the
time of onset of PN
- Intake: parenteral lipid intake should not exceed 4 g/kg/day
- Essential fatty acids: providing a minimum linoleic acid intake of 0.25 g/kg/day
Lipids [22]
- Administration: continuously over 24 h
- Pure soybean oil: May provide a less balanced nutrition than composite intravenous lipid emulsions.
PN lasting longer than a few days, pure SO ILEs should no longer be used
- continuous over 24 h
- Parenteral glucose supply in mg/kg per min (g/kg per day):
Carbohydrates [23] Start: day 1: 4–8 (5.8–11.5), day 2 onwards: target 8–10 (11.5–14.4), min 4 (5.8); max 12 (17.3)
- Glucose blood glucose levels: Avoid Hyperglycemia (>8 mmol/L/145 mg/dL) or Hypoglycemia
(≤2.5 mmol/L/45 mg/dL)
Intake in mmol
Calcium Phosphorus Magnesium
(mg)/kg/d
Calcium,
0.8–2.0 1.0–2.0 0.1–0.2
phosphorus and First days
(32–80) (31–62) (2.5–5.0)
magnesium [24]
Growing 1.6–3.5 1.6–3.5 0.2–0.3
premature (100–140) (77–108) (5.0–7.5)
- Infants receiving PN should receive parenteral vitamins
- Administration of water- and fat-soluble vitamins in fat emulsion to increase vitamin stability
Vitamins [25]
- Recommendations for doses of individual vitamins are provided in the guideline [25], but optimal
doses and infusion conditions for vitamins in infants are not known
- Following trace minerals shoud be provided in preterm infants with PN:
- Zinc: 400–500 µg/kg/day
- Copper: 40 µg/kg/day
Trace minerals [26] - Iodine: 1–10 µg/kg daily
- Selenium: 7 µg/kg/day
- Manganese: in long term PN max. 1 µg /kg/day
- Molybdenum: in long term PN max. 1 µg /kg/day
Int. J. Environ. Res. Public Health 2021, 18, 7544 3 of 13

Table 1. Cont.

ESPGHAN Recommendations for Parenteral Nutrition

- Prefer enteral rather than parenteral administration
- NO administration in short term PN (<3 weeks)
Iron [26] - Monitoring of iron status
- If necessary: 200–250 µg/kg/day
- CAVE: no intravenous iron preparation is approved for pediatric use in Europe

Table 2. Practice Points.

- Bridge the period until full enteral feeding is established [21–23,27]

Parenteral Nutrition
Transition from parenteral
to enteral nutrition
Enteral Nutrition
- Start immediately after birth with glucose, amino acids and fat [21–23]
- Use standardized parenteral nutrition solutions for most preterm patients [28]
- Start enteral nutrition on day 1 [21]
- Accelerate enteral feeding volume in daily increments of 25–30 mL/kg [29]
- Ignore gastric residuals as long as abdominal findings are normal [17,30]
- Promote and support lactation [31]
- Bridge the period until sufficient mother’s own milk production with DHM [2,20,31–33]
- Fortify breastmilk to improve postnatal growth [2,34], consider adapted or individualized
fortification to meet nutritional needs [35]
- Consider short-term pasteurization in ELBW/VLBW to prevent pCMV infection [36,37]

2. Parenteral Nutrition
During the first postnatal days, complementary to enteral feeding, parenteral nutrition
is an integral part of preterm infant care, bridging the period until full enteral feeding is
established. Although neonatal parenteral nutrition has been established since the late
1960s [38], and has improved considerably since, evidence on the optimal composition
of macro- and micronutrients is limited, yet intensively discussed. Several studies and
systematic reviews have shown improved short-term growth and a shortened time to
regain birth weight using neonatal parenteral nutrition. However, according to randomized
controlled trials, its long-term benefit for metabolism and neurological development is still
unclear [39–42]. Nevertheless, data on associations between higher nutrient intake and
improved growth suggest that parenteral nutrition in the first postnatal weeks is likely to
improve cognitive outcomes [5,42,43].
Therefore, initiating parenteral nutrition immediately after delivery is recommended
for preterm infants (Table 1) [27]. Since 2018, the guidelines of the European Society for
Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) recommend an amino
acid supply of at least 1.5 g/kg/d for the first postnatal day, increasing to 2.5–3.5 g/kg/d
from postnatal day 2 onwards [21]. To provide a rich source of energy at low volume,
intravenous lipid emulsions are an indispensable component of neonatal parenteral nu-
trition. These can be started shortly after birth but should not exceed 4 g/kg/d [22]. In a
systematic review including 29 studies with >2000 infants, no benefit of new lipid emul-
sions including fish oil, compared to conventional soybean oil-based lipid emulsions, was
found for the prevention of cholestasis, growth, mortality, retinopathy of prematurity and
bronchopulmonary dysplasia (BPD) [41]. However, according to the current ESPGHAN
recommendation, the latter emulsions should not be used for more than a few days in
term and preterm neonates, as pure soybean oil may provide a less balanced nutrition than
compound fat emulsions (e.g., soybean/olive with or without fish oil) [22].
A parenteral glucose supply should start at 4–8 mg/kg/min, and avoid overfeeding
or excessive glucose load by regular blood glucose measurements [23]. The maximum
endogenous glucose production, as well as the glucose oxidation rate, which both are
approximately 7–8 mg/kg/min (10–11.5 g/kg/day) in preterm infants, should not be
exceeded, at least not initially. In addition, though effects on growth have mostly been
studied for macronutrient intakes, an adequate micronutrient intake is also necessary for
Int. J. Environ. Res. Public Health 2021, 18, 7544 4 of 13

tissue, particularly parenchyma accretion [24,25]. In line with this, early and enhanced post-
natal parenteral nutrition is associated with increased electrolyte requirements, particularly
concerning phosphate and potassium, to meet the increased anabolism of parenchymal
tissues [24,44].
Standardized parenteral nutrition solutions and computerized prescriptions are rec-
ommended to improve patient safety [28]. Therefore, the authors practice nutrition with
standardized in-house “parenteral starter solutions” starting in the first postnatal hour and
containing 3.5 g/kg amino acids and 4.2 mg/kg/min glucose, as well as small amounts of
calcium, phosphate, and sodium. With an additional standardized fat emulsion including
fat- and water-soluble vitamins, a fat intake of 2.5 g/kg/d is achieved from the first day of
life onwards.

3. Transition from Intravenous to Enteral Sources

Prolonged parenteral nutrition is associated with cholestasis, thrombosis, infectious
and metabolic risks [29], partly due to an inadequate composition of existing products.
Hence, meeting nutritional needs through full enteral nutrition is a general goal. Re-
markably, the intestine of an extremely premature infant can already digest, tolerate and
metabolize human milk. In utero, amniotic fluid with its bioactive peptides not only plays
an important role in fetal gastrointestinal development [45], but animal data show that up
to 14% of intrauterine nutrient requirements are supplied and absorbed prenatally through
the intestine [46,47].
Nevertheless, evidence-based recommendations for the transition from intravenous to
enteral nutrient supply are lacking, and the optimal rate of enteral feeding advancements
in preterm infants is unclear [16,29,48,49]. Frequently, there are concerns that rapid enteral
feeding advancements may cause necrotizing enterocolitis (NEC). In a systematic review
of 9 studies including 1106 preterm infants, however, no increased risk of NEC was found
with early enteral feeding starting within 3 days after birth compared to a more delayed
onset [50]. Current evidence suggests that accelerating enteral feeding volume in daily
increments of 30 mL/kg does not increase the risk of NEC, death, or neurodevelopmental
disability at 24 months in preterm infants [16,29,48,51]. Instead, growth rates similar to
intrauterine trajectories can be achieved by rapid increases in enteral feeding volume and by
achieving full enteral nutrition within 5–7 days of birth even in extremely low gestational
age neonates [48,49]. However, even if weight gain along intra-uterine trajectories is
achieved, very preterm infants still show insufficient lean body mass growth and an
increased fraction of body fat at term-equivalent age [52,53]. This can be interpreted as a
lack of essential nutrients required to achieve parenchymal and muscle mass growth as in
utero [54].
Particularly during the transition from intravenous to enteral nutrition, “increased”
gastric residues are detected during routine evaluation. The belief that increased gastric
residuals may be predictive of NEC frequently results in withholding or delaying enteral
feeding advancements [30]. Physiologically, however, 2–4 mL/kg of gastric residual fluid
is regularly aspirated just prior to any scheduled feeding [55]. Similarly, gastric residual
volume varies depending on patient position and feeding tube size and position, further
limiting the clinical usefulness of this practice [56]. A recent systematic review showed
insufficient evidence to support routine surveillance of gastric residuals with the intention
to prevent NEC [30]. In a subsequent randomized controlled trial involving 143 preterm
infants below 1250 g birth weight, no benefit was found for this practice [17]. Obviously, this
small study was under-powered to assess the effect of such a practice on NEC rates, but the
group that had no gastric residues determined showed an advanced enteral feeding pattern
and higher feeding volumes by week 5 [17]. Furthermore, discarding gastric residuals (e.g.,
those showing a dark green color) results in a loss of bile acids and phosphatidylcholine
from bile and digestive enzymes from the pancreas and enterocytes, all playing important
roles in intestinal homeostasis, regulation and digestion [57]. Thus, based on current
evidence, restricting monitoring of gastric residues to infants with symptoms of severe
Int. J. Environ. Res. Public Health 2021, 18, 7544 5 of 13

gastrointestinal dysfunction, such as emesis, abdominal tenderness, absent bowel sounds or

bloody stools likely improves enteral nutrient supply. However, the safety of this approach
remains to be proven.

4. Enteral Nutrition
Unquestionably, mothers’ own milk is the preferred source of nutrition for preterm
infants because of its numerous short- and longer-term health benefits, such as protection
against NEC, late-onset sepsis, and bronchopulmonary dysplasia (BPD), as well as im-
proved neurodevelopment [32,58]. Additionally, early oral administration of colostrum pro-
vides immunological components, probably stimulating the immune system and protecting
from inadequate bacterial colonization by lactoferrin, sIgA and other compounds [59,60].
Moreover, expressed breast milk contains high numbers of myeloid-derived suppressor
cells, which may prevent excessive inflammatory reactions and enhance tolerance to food
antigens [61,62].
However, mothers of preterm infants face a variety of barriers against breastfeeding.
Expressing breast milk approximately eight times/day during the first two weeks after
birth is the only proven way to increase the likelihood of achieving an adequate milk
supply of more than 500 mL per day, necessary for subsequent exclusive or predominant
breastfeeding. To achieve this, mothers must be encouraged to start manual and/or
mechanical breast milk expression shortly after birth [63,64]. In addition to the emotional
stress and concerns about the health of their baby [65], expressing breast milk 2–3 hourly,
as recommended, is time consuming and needs to be included in a tight daily routine with
kangarooing and, if present, caring for older siblings [66]. Appropriate prenatal counselling
and postnatal support for a variety of systems (e.g., double electric, bedside and free home
breast pumps for milk expression) by clinical staff in the NICU, peer support, skin-to-skin
care, staff education and a lactation consultant should therefore be common practice [67].
When mothers’ own milk is available in insufficient quantity or is contraindicated
(e.g., acquired immunodeficiency syndrome, chemotherapy), donor human milk (DHM)
is the adequate substitute for preterm infant feeding, as recommended by all relevant
societies [2,20,31–33]. In 2019, a systematic review of 12 studies, including 1879 infants
<2500 g birth weight, showed that formula feeding, compared to predominantly non-
supplemented DHM, resulted in improved weight gain, linear length and head growth,
indicating an inadequately low nutrient supply through non-supplemented DHM [33].
However, formula feeding also resulted in a higher risk of NEC (typical risk ratio (RR) 1.87,
95% CI 1.23 to 2.85) [33] and was associated with a lower quantity of breast- compared to
formula feeding at discharge [20]. DHM is not available in all NICUs and is considerably
more expensive than formula (e.g., $15/100 mL from a US not-for-profit Human Milk Bank
compared to $3/100 mL for preterm formula) [68]. By contrast, from a societal perspective,
the total cost of providing DHM to preterm infants is equal to formula feeding, due to
a reduced NEC rate [69]. In essence, it is important to reiterate that fresh mothers’ own
milk is the first choice for feeding preterm infants, and that great efforts should be made to
promote lactation, bridging the time to sufficient breast milk supply with (supplemented)
DHM [31].

5. Fortification
Human breast milk is optimally designed for term newborns and infants, who double
their weight within 4–6 months after birth. However, in line with the physiological
intrauterine growth rate during the 3rd trimester, very preterm infants double their weight
within 4–6 weeks. Thus, an increased supply of macro- and micronutrients is necessary for
adequate growth. Requirements for energy, protein, (essential) fatty acids, minerals such as
calcium and phosphate, as well as micronutrients like iron and vitamin D, to name a few,
are higher than in healthy newborns. For additional constitutive components, like choline,
increased requirements compared to current recommendations are debated as well [54].
All these nutrients are principally present in multi-nutrient human milk fortifiers (HMF),
Int. J. Environ. Res. Public Health 2021, 18, 7544 6 of 13

although their quantities are still controversial [54,70]. Hereby, intakes recommended
by ESPGHAN in 2010 (energy: 110–135 kcal/kg/d, protein: 4.0–4.5 g/kg/d (<1 kg) and
3.5–4.0 g/kg/d (1–1.8 kg), carbohydrate: 11.6–13.2 g/kg/d, fat: 4.8–6.6 g/kg/d) should
be achieved [2]. However, several recent studies indicate a ceiling effect for the beneficial
effect of protein intake on growth at approximately 4.5 g/kg/d [18,71].
Although breastmilk fortification is practiced in most NICUs [34], evidence for its
impact on long-term outcomes is remarkably sparse [72]. In a systematic review, multi-
nutrient fortification of human milk vs. non-fortified human milk showed increased
in-hospital growth rates for weight, head circumference and length without increasing
the risk of NEC [72]. However, the limited follow-up data for post-discharge growth and
neurodevelopment in later childhood show no benefit from fortification [72]. A recent
meta-analysis showed that early fortification starting at 20–40 mL/kg/d of enteral feeds
vs. late fortification (starting at 100 mL/kg/d) had little or no effect on short-term growth
outcomes [73].
However, as breast milk has no uniform nutrient content and marked inter- and
intra-individual variability exists [74], there are strategies for individualizing fortifica-
tion to match the nutritional needs of preterm infants [34]. Individual fortification is
performed by measuring the infant’s blood urea nitrogen (‘adjustable’ fortification) or the
macronutrient content of breast milk using a milk analyzer (‘targeted’ fortification). In a
recent review including 7 RCTs with a total of 521 participants, increased growth rates
for weight, length and head circumference were found with moderate to low evidence
following individualized compared to standard non-individualized fortification [35]. In
2021, a double-blind, randomized controlled trial was conducted in 103 preterm infants
<30 weeks comparing standard versus targeted fortification with modular proteins, lipids,
and carbohydrates [52]. The targeted fortification group had higher macronutrient intakes
and higher average growth velocity across the first 21 days of intervention (21.2 ± 2.5 vs.
19.3 ± 2.4 g/kg/d). Not surprisingly, infants born to mothers with a low breast milk protein
content showed the greatest benefit from targeted fortification regarding their weight at
36 weeks, length, head circumference, fat and fat-free mass [52]. Likewise, donor milk often
contains low levels of protein, suggesting targeted fortification to improve growth [75,76].
However, data on the clinical benefit of individual fortification by adjusting breast milk
macronutrients beyond short-term growth are sparse and inconclusive. A secondary analy-
sis of a randomized controlled trial indicated that ‘adapted’ protein supplementation, by
calculating breast milk protein content based on the duration of lactation, may be an easy
and inexpensive alternative to ‘targeted’ protein supplementation for achieving protein
supply on target in >95% of analyzed breast milk samples [77].
In recent years, discussions have addressed the question of whether multi-nutrient
fortifiers (HMF) derived from human rather than bovine milk may further reduce the
risk of NEC. However, the potential benefits of HMF derived from human milk have
been insufficiently investigated, especially in comparison with feeding regimens without
supplementary formula feeding, the latter already known to increase NEC rates. In 127
preterm infants <1250 g, an RCT using human vs. bovine milk-derived HMF in infants
fed human milk failed to improve feeding tolerance [78], but was underpowered to assess
effects on mortality and morbidity such as NEC. Moreover, concerns exist against the
commercialization of human milk, as the milk used to produce the fortifier is no longer
available as donor milk for very preterm infants. Other disadvantages are high cost,
unequal access to these products in different countries, and the fact that the large volume
of such liquid human milk-based HMF reduces the volume of expressed breast milk
administered to the infants by up to 1/3. Therefore, the use of human milk-based HMF is
currently not recommended by most committees and experts on pediatric nutrition [34,79].

6. Breast Milk–Acquired Cytomegalovirus Infection

Cytomegalovirus (CMV) reactivates in the lactating breast of up to 96% of CMV-
seropositive mothers, i.e., in approximately 50–80% of all mothers of preterm infants [19,80].
Int. J. Environ. Res. Public Health 2021, 18, 7544 7 of 13

It can cause severe sepsis-like symptoms with highly variable organ manifestations [80,81].
Postnatal transmission occurs in approximately 40% of infants <32 weeks’ gestation, with
higher transmission rates the lower gestational age is [19,80]. In most cases, at least one
of the following clinical signs is found: apnea and bradycardia, hepatosplenomegaly,
hepatitis, pneumonitis, intestinal distention and altered laboratory parameters (includ-
ing lymphocytopenia, neutropenia, thrombocytopenia, and elevated liver enzymes) [19].
Although most of these symptoms are self-limiting, CMV-related deaths have also been
reported [81]. In addition, an increased risk of developing BPD has been described in
cohorts of 385 extremely [82] and 2132 very low birth weight (VLBW) infants [83], as
well as in a recent study involving >100 000 VLBW infants [84]. NEC also seems to be
associated with postnatal CMV infection (pCMV). In numerous case reports and case series,
pCMV could be identified in gut specimens [85,86]. A recent study enrolling 596 VLBW
infants found an almost 3-times higher risk of NEC in CMV-positive than in CMV-negative
infants [87]. An actual multicenter study comprising 304 VLBW infants with postnatal
CMV observed significant associations with hearing and growth impairment, as well as
a prolonged hospitalization (by 12 days), but not with NEC [88]. Principally, all organ
systems, including the brain, can be involved in pCMV disease, as shown by autopsy
findings [89].
Some controversy exists whether early pCMV has negative consequences for neurocog-
nitive development [81,90,91]. In a recent cohort study involving 356 infants <32 weeks’
gestation [91], no negative impact on neurodevelopment until age six years was found
in a subgroup of 49 CMV-positive infants (14%). In a case-control study of 42 former
VLBW infants, pCMV positive infants had significantly lower test results at age six years
in the simultaneous processing scale of the Kaufman Assessment Battery for Children. In
a further follow-up study on 11–16 year old adolescents born at <32 wk GA (19 with, 23
without early pCMV infection), there was evidence of adverse effects of pCMV infection on
cognitive function [92]. This was supported by their functional magnetic resonance imag-
ing (MRI) results (n = 15) showing different activations in two brain regions for language
performance and differences in grey matter volume compared to children without pCMV
infection (n = 19) [93]. Intellectual deficits resulting from pCMV might be more obvious
in older children with more complex reasoning. These human data are supported by a
neonatal guinea pig model, where postnatally infected pups showed significant cognitive
deficits and brain anomalies compared to controls [94].
Notwithstanding the increasing knowledge about short- and long-term consequences
of pCMV infection, there is currently no consensus about preventive measures, but further
efforts seem justified. The Red Book Committee of the American Academy of Pediatrics
recommends serologic screening of mothers of infants born at <32 weeks and to consider
short-term breast milk pasteurization in those tested CMV-seropositive [36,37]. Others
recommend the pasteurization of breast milk from CMV-positive women in infants born
at <28 0/7 wk GA or with a birth weight <1000 g starting on day four until reaching 32
0/7 weeks post-menstrual age [95]. Further prospective studies are urgently needed.
For effectively eliminating CMV from breast milk, heat inactivation is required,
whereas freeze thawing is not sufficient. Holder pasteurization (63 ◦ C for 30 min) is
safe, but it reduces most of the nutritionally and immunologically relevant components in
human milk, such as immune cells, antibodies, enzymes, growth factors and hormones [96].
The authors’ institution therefore practices short-term heat inactivation (heating to 62 ◦ C
for 5 s) in their patients born at <32 weeks, as this sufficiently prevents CMV transmission
while preserving most benefits of breast milk [81,97].

7. Post-Discharge Nutrition
Achieving percentile-parallel growth using mothers’ own milk is the goal of post-
discharge nutrition [2]. Breastfeeding of preterm infants, starting with skin-to-skin contact
and non-nutritive sucking, should enable predominant breastfeeding at the time of dis-
charge. However, if weaning from the nasogastric tube is impossible, hospital discharge
Int. J. Environ. Res. Public Health 2021, 18, 7544 8 of 13

with tube feeding at home and adequate follow-up is the only feasible perspective [98]. In
Europe, this applies to approximately 40% of infants <32 weeks GA [99]. A recent meta-
analysis of 1251 preterm infants demonstrated that post-discharge formula feeding with
74 kcal/mL does not improve weight or head circumference growth compared to standard
term infant formula (≈67 kcal/100 mL) [100]. Limited evidence suggests that feeding
preterm infant formula (80 kcal/100 mL, usually in-house available only) compared to
standard term formula increases growth rates up to 18 months after birth (mean differences:
500 g weight, 10 mm length, 5 mm head circumference). No convincing evidence exists to
support discharging preterm infants with nutrient-fortified mothers’ milk [101]. Therefore,
the ESPGHAN guideline recommends individualized post-discharge nutrition adapted
to postnatal growth; i.e., for preterm infants with adequate weight gain until discharge,
fortified mothers’ milk or a special discharge formula is not required after discharge [2],
whereas infants who have grown less well initially should receive fortified breast milk
or a special post-discharge formula until at least three months corrected age [2]. This is
because of the common observation that former very preterm infants discharged home
shortly after discontinuation of naso-gastric tube top-up feeding experience a period of
inadequate weight gain [102], which is of unknown clinical importance but at least a major
burden for their parents.

8. Research Perspectives
Based on the concept that postnatal growth and body composition of preterm infants
should ideally mimic intra-uterine growth, and hence that postnatal nutrition should be
oriented at placental supply rather than breast milk composition (which is tailored to term
infants), we postulate that micronutrients that are actively transported to the fetus against a
concentration gradient must be of importance. As an example, fetal plasma concentrations
of choline, an essential nutrient for all age groups, are 3–4 times those of the parturient
throughout gestation, and very rapidly decrease by 50% or more after preterm birth [54,70].
It is also remarkable that the placenta enriches the fetus with docosahexaenoic acid (DHA)
and arachidonic acid (ARA), whereas linoleic acid (LA) is actively held back in the maternal
circulation. Based on current feeding regimens for preterm infants, the resulting fatty acid
profile of fetal lipoprotein phospholipids (high ARA, low LA, increasing DHA towards
term birth) is transformed to adult values (high LA, low ARA, low DHA) within one
week. Consequently, the preterm infant’s lipidome at term-corrected age is dramatically
different from that of term born infants in all compartments yet investigated, indicating
ARA and DHA deficiency and LA-overnutrition [103]. Addressing these and other nutrient
deficiencies and imbalances may help further to improve lean body mass growth and
long-term outcomes.

9. Conclusions
Preterm infants should be provided with all the macro- and micronutrients required to
achieve growth as in utero. To minimize side effects of parenteral nutrition, enteral feeding
should be started in the first days after birth, preferably based on supplemented mother’s
own milk or DHM. Further prospective studies are needed for many aspects of preterm
infant feeding.

Author Contributions: C.W. conceptualized, drafted the initial manuscript, and reviewed and
revised the manuscript. C.F.P., W.B., R.G., A.R.F. revising the article critically for important intellectual
content. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not Applicable.
Informed Consent Statement: Not Applicable.
Data Availability Statement: Not Applicable.
Int. J. Environ. Res. Public Health 2021, 18, 7544 9 of 13

Conflicts of Interest: The authors have no financial relationship relevant to this article to disclose.
The authors declare that they have no competing interests.

Abbreviations

ARA Arachidonic acid

BPD Bronchopulmonary dysplasia
CMV Cytomegalovirus
DHA Docosahexaenoic acid
DHM Donor human milk
ELBW Extremely low birth weight (<1000 g)
GA Gestational Age
HMF Human milk fortifiers
LA Linoleic acid
NEC Necrotizing enterocolitis
NICU Neonatal intensive care unit
pCMV Postnatal cytomegalovirus infection
PMA Postmenstrual age
VLBW Very low birth weight (<1500 g)
wk Week

References
1. Stocker, J.T.; Dehner, L.P.; Husain, A.N. Means and standard deviations of weights and measurements of lifeborn infants by body
weight (Appendix 28–29). In Stocker & Dehner’s Pediatric Pathology, 2nd ed.; Stocker, J.T., Dehner, L.P., Eds.; Lippinkott Williams &
Wilkins: Philadelphia, PA, USA, 2002.
2. Agostoni, C.; Buonocore, G.; Carnielli, V.P.; De Curtis, M.; Darmaun, D.; Decsi, T.; Domellöf, M.; Embleton, N.D.; Fusch, C.;
Genzel-Boroviczeny, O.; et al. Enteral Nutrient Supply for Preterm Infants: Commentary from the European Society of Paediatric
Gastroenterology, Hepatology and Nutrition Committee on Nutrition. J. Pediatr. Gastroenterol. Nutr. 2010, 50, 85–91. [CrossRef]
3. Johnson, M.J.; Wootton, S.A.; Leaf, A.A.; Jackson, A.A. Preterm Birth and Body Composition at Term Equivalent Age: A Systematic
Review and Meta-analysis. Pediatrics 2012, 130, e640–e649. [CrossRef]
4. Cerasani, J.; Ceroni, F.; De Cosmi, V.; Mazzocchi, A.; Morniroli, D.; Roggero, P.; Mosca, F.; Agostoni, C.; Giannì, M.L. Human Milk
Feeding and Preterm Infants’ Growth and Body Composition: A Literature Review. Nutrients 2020, 12, 1155. [CrossRef] [PubMed]
5. Stephens, B.E.; Walden, R.V.; Gargus, R.A.; Tucker, R.; McKinley, L.; Mance, M.; Nye, J.; Vohr, B.R. First-Week Protein and Energy
Intakes Are Associated With 18-Month Developmental Outcomes in Extremely Low Birth Weight Infants. Pediatrics 2009, 123,
1337–1343. [CrossRef] [PubMed]
6. Franz, A.R.; Pohlandt, F.; Bode, H.; Mihatsch, W.A.; Sander, S.; Kron, M.; Steinmacher, J. Intrauterine, Early Neonatal, and
Postdischarge Growth and Neurodevelopmental Outcome at 5.4 Years in Extremely Preterm Infants After Intensive Neonatal
Nutritional Support. Pediatrics 2009, 123, e101–e109. [CrossRef]
7. Ehrenkranz, R.A.; Dusick, A.M.; Vohr, B.R.; Wright, L.L.; Wrage, L.A.; Poole, W.K. Growth in the Neonatal Intensive Care Unit
Influences Neurodevelopmental and Growth Outcomes of Extremely Low Birth Weight Infants. Pediatrics 2006, 117, 1253–1261.
[CrossRef]
8. Martínez-Jiménez, M.D.; Gómez-García, F.J.; Gil-Campos, M.; Pérez-Navero, J.L. Comorbidities in childhood associated with
extrauterine growth restriction in preterm infants: A scoping review. Eur. J. Pediatr. 2020, 179, 1255–1265. [CrossRef] [PubMed]
9. Hovi, P.; Andersson, S.; Eriksson, J.; Järvenpää, A.-L.; Strang-Karlsson, S.; Mäkitie, O.; Kajantie, E. Glucose Regulation in Young
Adults with Very Low Birth Weight. N. Engl. J. Med. 2007, 356, 2053–2063. [CrossRef]
10. Belfort, M.B.; Martin, C.R.; Smith, V.C.; Gillman, M.W.; McCormick, M.C. Infant weight gain and school-age blood pressure and
cognition in former preterm infants. Pediatrics 2010, 125, e1419–e1426. [CrossRef]
11. Singhal, A.; Cole, T.J.; Lucas, A. Early nutrition in preterm infants and later blood pressure: Two cohorts after randomised trials.
Lancet 2001, 357, 413–419. [CrossRef]
12. Kerkhof, G.F.; Willemsen, R.H.; Leunissen, R.W.; Breukhoven, P.E.; Hokken-Koelega, A.C. Health Profile of Young Adults Born
Preterm: Negative Effects of Rapid Weight Gain in Early Life. J. Clin. Endocrinol. Metab. 2012, 97, 4498–4506. [CrossRef]
13. Valdez, R.; Athens, M.A.; Thompson, G.H.; Bradshaw, B.S.; Stern, M.P. Birthweight and adult health outcomes in a biethnic
population in the USA. Diabetologia 1994, 37, 624–631. [CrossRef] [PubMed]
14. Painter, R.C.; Osmond, C.; Gluckman, P.; Hanson, M.; Phillips, D.I.W.; Roseboom, T.J. Transgenerational effects of prenatal
exposure to the Dutch famine on neonatal adiposity and health in later life. BJOG Int. J. Obstet. Gynaecol. 2008, 115, 1243–1249.
[CrossRef] [PubMed]
15. Simon, L.; Frondas-Chauty, A.; Senterre, T.; Flamant, C.; Darmaun, D.; Rozé, J.-C. Determinants of body composition in preterm
infants at the time of hospital discharge. Am. J. Clin. Nutr. 2014, 100, 98–104. [CrossRef]
Int. J. Environ. Res. Public Health 2021, 18, 7544 10 of 13

16. Dorling, J.; Abbott, J.; Berrington, J.; Bosiak, B.; Bowler, U.; Boyle, E.; Embleton, N.; Hewer, O.; Johnson, S.; Juszczak, E.; et al.
Controlled Trial of Two Incremental Milk-Feeding Rates in Preterm Infants. N. Engl. J. Med. 2019, 381, 1434–1443. [CrossRef]
17. Parker, L.A.; Weaver, M.; Torrazza, R.J.M.; Shuster, J.; Li, N.; Krueger, C.; Neu, J. Effect of Gastric Residual Evaluation on Enteral
Intake in Extremely Preterm Infants. JAMA Pediatr. 2019, 173, 534–543. [CrossRef]
18. Maas, C.; Mathes, M.; Bleeker, C.; Vek, J.; Bernhard, W.; Wiechers, C.; Peter, A.; Poets, C.F.; Franz, A.R. Effect of Increased Enteral
Protein Intake on Growth in Human Milk–Fed Preterm Infants: A Randomized Clinical Trial. JAMA Pediatr. 2017, 171, 16–22.
[CrossRef] [PubMed]
19. Hamprecht, K.; Maschmann, J.; Vochem, M.; Dietz, K.; Speer, C.P.; Jahn, G. Epidemiology of transmission of cytomegalovirus
from mother to preterm infant by breastfeeding. Lancet 2001, 357, 513–518. [CrossRef]
20. Kantorowska, A.; Wei, J.C.; Cohen, R.S.; Lawrence, R.A.; Gould, J.B.; Lee, H.C. Impact of Donor Milk Availability on Breast Milk
Use and Necrotizing Enterocolitis Rates. Pediatr. 2016, 137, e20153123. [CrossRef] [PubMed]
21. Van Goudoever, J.; Carnielli, V.; Darmaun, D.; De Pipaon, M.S.; Braegger, C.; Bronsky, J.; Cai, W.; Campoy, C.; Decsi, T.; Domellöf,
M.; et al. ESPGHAN/ESPEN/ESPR/CSPEN guidelines on pediatric parenteral nutrition: Amino acids. Clin. Nutr. 2018, 37,
2315–2323. [CrossRef] [PubMed]
22. Lapillonne, A.; Mis, N.F.; Goulet, O.; van den Akker, C.H.V.D.; Wu, J.; Koletzko, B.; Braegger, C.; Bronsky, J.; Cai, W.; Campoy, C.;
et al. ESPGHAN/ESPEN/ESPR/CSPEN guidelines on pediatric parenteral nutrition: Lipids. Clin. Nutr. 2018, 37, 2324–2336.
[CrossRef] [PubMed]
23. Mesotten, D.; Joosten, K.; van Kempen, A.; Verbruggen, S.; Braegger, C.; Bronsky, J.; Cai, W.; Campoy, C.; Carnielli, V.; Darmaun,
D.; et al. ESPGHAN/ESPEN/ESPR/CSPEN guidelines on pediatric parenteral nutrition: Carbohydrates. Clin. Nutr. 2018, 37,
2337–2343. [CrossRef] [PubMed]
24. Mihatsch, W.; Fewtrell, M.; Goulet, O.; Molgaard, C.; Picaud, J.-C.; Senterre, T.; Braegger, C.; Bronsky, J.; Cai, W.; Campoy, C.; et al.
ESPGHAN/ESPEN/ESPR/CSPEN guidelines on pediatric parenteral nutrition: Calcium, phosphorus and magnesium. Clin.
Nutr. 2018, 37, 2360–2365. [CrossRef]
25. Bronsky, J.; Campoy, C.; Braegger, C.; Cai, W.; Carnielli, V.; Darmaun, D.; Decsi, T.; Domellöf, M.; Embleton, N.; Fewtrell, M.;
et al. ESPGHAN/ESPEN/ESPR/CSPEN guidelines on pediatric parenteral nutrition: Vitamins. Clin. Nutr. 2018, 37, 2366–2378.
[CrossRef] [PubMed]
26. Domellöf, M.; Szitanyi, P.; Simchowitz, V.; Franz, A.; Mimouni, F.; Braegger, C.; Bronsky, J.; Cai, W.; Campoy, C.; Carnielli, V.; et al.
ESPGHAN/ESPEN/ESPR/CSPEN guidelines on pediatric parenteral nutrition: Iron and trace minerals. Clin. Nutr. 2018, 37,
2354–2359. [CrossRef]
27. Joosten, K.; Embleton, N.; Yan, W.; Senterre, T.; Braegger, C.; Bronsky, J.; Cai, W.; Campoy, C.; Carnielli, V.; Darmaun, D.;
et al. ESPGHAN/ESPEN/ESPR/CSPEN guidelines on pediatric parenteral nutrition: Energy. Clin. Nutr. 2018, 37, 2309–2314.
[CrossRef] [PubMed]
28. Riskin, A.; Picaud, J.-C.; Shamir, R.; Braegger, C.; Bronsky, J.; Cai, W.; Campoy, C.; Carnielli, V.; Darmaun, D.; Decsi, T.; et al.
ESPGHAN/ESPEN/ESPR/CSPEN guidelines on pediatric parenteral nutrition: Standard versus individualized parenteral
nutrition. Clin. Nutr. 2018, 37, 2409–2417. [CrossRef] [PubMed]
29. Oddie, S.J.; Young, L.; McGuire, W. Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low
birth weight infants. Cochrane Database Syst. Rev. 2017, 8, 001241. [CrossRef]
30. Abiramalatha, T.; Thanigainathan, S.; Ninan, B. Routine monitoring of gastric residual for prevention of necrotising enterocolitis
in preterm infants. Cochrane Database Syst. Rev. 2019, 7, CD012937. [CrossRef]
31. Arslanoglu, S.; Corpeleijn, W.; Moro, G.; Braegger, C.; Campoy, C.; Colomb, V.; Decsi, T.; Domellöf, M.; Fewtrell, M.; Hojsak, I.;
et al. Donor Human Milk for Preterm Infants. J. Pediatr. Gastroenterol. Nutr. 2013, 57, 535–542. [CrossRef]
32. Beidelman, A.I.; Schanler, R.J. Breastfeeding and the Use of Human Milk: Section on breastfeeding. Pediatrics 2012, 129, e827–e841.
[CrossRef]
33. Quigley, M.; Embleton, N.; McGuire, W. Formula versus donor breast milk for feeding preterm or low birth weight infants.
Cochrane Database Syst. Rev. 2019, 7, CD002971. [CrossRef] [PubMed]
34. Arslanoglu, S.; Boquien, C.-Y.; King, C.; Lamireau, D.; Tonetto, P.; Barnett, D.; Bertino, E.; Gaya, A.; Gebauer, C.; Grovslien, A.;
et al. Fortification of Human Milk for Preterm Infants: Update and Recommendations of the European Milk Bank Association
(EMBA) Working Group on Human Milk Fortification. Front. Pediatr. 2019, 7, 76. [CrossRef] [PubMed]
35. Fabrizio, V.; Trzaski, J.M.; Brownell, E.A.; Esposito, P.; Lainwala, S.; Lussier, M.M.; I. Hagadorn, J. Individualized versus standard
diet fortification for growth and development in preterm infants receiving human milk. Cochrane Database Syst. Rev. 2020, 11,
CD013465. [CrossRef] [PubMed]
36. Osterholm, E.A.; Schleiss, M.R. Impact of breast milk-acquired cytomegalovirus infection in premature infants: Pathogenesis,
prevention, and clinical consequences? Rev. Med. Virol. 2020, 30, 1–11. [CrossRef]
37. Kimberlin, D.W.B.M.; Jackson, M.A.; Long, S.S. American Academy of Pediatrics Human Milk. In Red Book: 2018 Report of the
Committee on Infectious Diseases, 31st ed.; American Academy of Pediatrics: Itasca, IL, USA, 2018; pp. 113–121.
38. Wilmore, D.W.; Dudrick, S.J. Growth and development of an infant receiving all nutrients exclusively by vein. JAMA 1968, 203,
860–864. [CrossRef]
39. Morgan, C.; McGowan, P.; Herwitker, S.; Hart, A.E.; Turner, M. Postnatal Head Growth in Preterm Infants: A Randomized
Controlled Parenteral Nutrition Study. Pediatrics 2013, 133, e120–e128. [CrossRef]
Int. J. Environ. Res. Public Health 2021, 18, 7544 11 of 13

40. Moon, K.; Athalye-Jape, G.K.; Rao, U.; Rao, S.C. Early versus late parenteral nutrition for critically ill term and late preterm
infants. Cochrane Database Syst. Rev. 2020, 2020, CD013141. [CrossRef]
41. Kapoor, V.; Malviya, M.N.; Soll, R. Lipid emulsions for parenterally fed term and late preterm infants. Cochrane Database Syst. Rev.
2019, 6, CD013171. [CrossRef]
42. Isaacs, E.B.; Gadian, D.G.; Sabatini, S.; Chong, W.K.; Quinn, B.T.; Fischl, B.R.; Lucas, A. The Effect of Early Human Diet on
Caudate Volumes and IQ. Pediatr. Res. 2008, 63, 308–314. [CrossRef]
43. Duerden, E.G.; PIANO study group; Thompson, B.; Poppe, T.; Alsweiler, J.; Gamble, G.; Jiang, Y.; Leung, M.; Tottman, A.C.;
Wouldes, T.; et al. Early protein intake predicts functional connectivity and neurocognition in preterm born children. Sci. Rep.
2021, 11, 4085. [CrossRef]
44. Bonsante, F.; Iacobelli, S.; Latorre, G.; Rigo, J.; De Felice, C.; Robillard, P.Y.; Gouyon, J.B. Initial Amino Acid Intake Influences
Phosphorus and Calcium Homeostasis in Preterm Infants—It Is Time to Change the Composition of the Early Parenteral Nutrition.
PLoS ONE 2013, 8, e72880. [CrossRef]
45. Siggers, J.; Østergaard, M.V.; Siggers, R.H.; Skovgaard, K.; Mølbak, L.; Thymann, T.; Schmidt, M.; Møller, H.K.; Purup, S.; Fink,
L.N.; et al. Postnatal amniotic fluid intake reduces gut inflammatory responses and necrotizing enterocolitis in preterm neonates.
Am. J. Physiol. Liver Physiol. 2013, 304, G864–G875. [CrossRef] [PubMed]
46. Mulvihill, S.; Stone, M.; Debas, H.; Fonkalsrud, E. The role of amniotic fluid in fetal nutrition. J. Pediatr. Surg. 1985, 20, 668–672.
[CrossRef]
47. Østergaard, M.V.; Bering, S.B.; Jensen, M.L.; Thymann, T.; Purup, S.; Diness, M.; Schmidt, M.; Sangild, P.T. Modulation of
Intestinal Inflammation by Minimal Enteral Nutrition With Amniotic Fluid in Preterm Pigs. J. Parenter. Enter. Nutr. 2013, 38,
576–586. [CrossRef]
48. Maas, C.; Mitt, S.; Full, A.; Arand, J.; Bernhard, W.; Poets, C.; Franz, A. A Historic Cohort Study on Accelerated Advancement of
Enteral Feeding Volumes in Very Premature Infants. Neonatology 2013, 103, 67–73. [CrossRef] [PubMed]
49. Maas, C.; Franz, A.; Von Krogh, S.; Arand, J.; Poets, C.F. Growth and morbidity of extremely preterm infants after early full
enteral nutrition. Arch. Dis. Child. Fetal Neonatal Ed. 2017, 103, F79–F81. [CrossRef]
50. Morgan, J.; Young, L.; McGuire, W. Delayed introduction of progressive enteral feeds to prevent necrotising enterocolitis in very
low birth weight infants. Cochrane Database Syst. Rev. 2014, 2014, CD001970. [CrossRef] [PubMed]
51. Maas, C.; Wiechers, C.; Bernhard, W.; Poets, C.F.; Franz, A.R. Early feeding of fortified breast milk and in-hospital-growth in very
premature infants: A retrospective cohort analysis. BMC Pediatr. 2013, 13, 178. [CrossRef]
52. Rochow, N.; Fusch, G.; Ali, A.; Bhatia, A.; So, H.Y.; Iskander, R.; Chessell, L.; el Helou, S.; Fusch, C. Individualized target
fortification of breast milk with protein, carbohydrates, and fat for preterm infants: A double-blind randomized controlled trial.
Clin. Nutr. 2021, 40, 54–63. [CrossRef]
53. Wiechers, C.; Doll, J.-N.; Maas, C.; Gründler, K.; Büchner, K.; Bevot, A.; Poets, C.F.; Franz, A.R. Körperfettanteil bei Frühgeborenen
zum Zeitpunkt der Entlassung und im Alter von korrigiert 4 Monaten. Monat.r Kinderh. 2019, 167, S53–S196.
54. Bernhard, W.; Poets, C.F.; Franz, A.R. Choline and choline-related nutrients in regular and preterm infant growth. Eur. J. Nutr.
2019, 58, 931–945. [CrossRef] [PubMed]
55. Mihatsch, W.A.; Von Schoenaich, P.; Fahnenstich, H.; Dehne, N.; Ebbecke, H.; Plath, C.; Von Stockhausen, H.-B.; Muche, R.; Franz,
A.; Pohlandt, F. The Significance of Gastric Residuals in the Early Enteral Feeding Advancement of Extremely Low Birth Weight
Infants. Pediatrics 2002, 109, 457–459. [CrossRef] [PubMed]
56. Chen, S.-S.; Tzeng, Y.-L.; Gau, B.-S.; Kuo, P.-C.; Chen, J.-Y. Effects of prone and supine positioning on gastric residuals in preterm
infants: A time series with cross-over study. Int. J. Nurs. Stud. 2013, 50, 1459–1467. [CrossRef]
57. Gayatri, A.-J.; Megan, N.; Ching-Tat, L.; Elizabeth, N.; Donna, G.; Karen, S.; Sanjay, P. Composition of Coloured Gastric Residuals
in Extremely Preterm Infants-A Nested Prospective Observational Study. Nutrients 2020, 12, 2585. [CrossRef]
58. Victora, C.G.; Bahl, R.; Barros, A.J.D.; França, G.V.A.; Horton, S.; Krasevec, J.; Murch, S.; Sankar, M.J.; Walker, N.; Rollins, N.C.;
et al. Breastfeeding in the 21st century: Epidemiology, mechanisms, and lifelong effect. Lancet 2016, 387, 475–490. [CrossRef]
59. Maffei, D.; Brewer, M.; Codipilly, C.; Weinberger, B.; Schanler, R.J. Early oral colostrum administration in preterm infants. J.
Perinatol. 2019, 40, 284–287. [CrossRef]
60. Nasuf, A.W.A.; Ojha, S.; Dorling, J. Oropharyngeal colostrum in preventing mortality and morbidity in preterm infants. Cochrane
Database Syst. Rev. 2018, 9, CD011921. [CrossRef]
61. Köstlin-Gille, N.; Flaig, L.-A.; Ginzel, M.; Arand, J.; Poets, C.F.; Gille, C. Granulocytic Myeloid-Derived Suppressor Cells in Breast
Milk (BM-MDSC) Correlate with Gestational Age and Postnatal Age and Are Influenced by Infant’s Sex. Nutrients 2020, 12, 2571.
[CrossRef]
62. Köstlin-Gille, N.; Gille, C. Myeloid-Derived Suppressor Cells in Pregnancy and the Neonatal Period. Front. Immunol. 2020, 11,
584712. [CrossRef]
63. Parker, L.A.; Sullivan, S.; Krueger, C.; Kelechi, T.; Mueller, M. Effect of early breast milk expression on milk volume and timing of
lactogenesis stage II among mothers of very low birth weight infants: A pilot study. J. Perinatol. 2011, 32, 205–209. [CrossRef]
64. Parker, L.A.; Sullivan, S.; Kruger, C.; Mueller, M. Timing of milk expression following delivery in mothers delivering preterm
very low birth weight infants: A randomized trial. J. Perinatol. 2020, 40, 1–10. [CrossRef] [PubMed]
65. Sisk, P.M.; Lovelady, C.A.; Dillard, R.G.; Gruber, K. Lactation Counseling for Mothers of Very Low Birth Weight Infants: Effect on
Maternal Anxiety and Infant Intake of Human Milk. Pediatrics 2006, 117, e67–e75. [CrossRef] [PubMed]
Int. J. Environ. Res. Public Health 2021, 18, 7544 12 of 13

66. Hurst, N.; Engebretson, J.; Mahoney, J.S. Providing Mother’s Own Milk in the Context of the NICU. J. Hum. Lact. 2013, 29,
366–373. [CrossRef]
67. Renfrew, M.J.; Dyson, L.; McCormick, F.; Misso, K.; Stenhouse, E.; King, S.E.; Williams, A.F. Breastfeeding promotion for infants
in neonatal units: A systematic review. Child Care Health Dev. 2010, 36, 165–178. [CrossRef]
68. Jegier, B.J.; Johnson, T.J.; Engstrom, J.L.; Patel, A.; Loera, F.; Meier, P. The Institutional Cost of Acquiring 100 mL of Human Milk
for Very Low Birth Weight Infants in the Neonatal Intensive Care Unit. J. Hum. Lact. 2013, 29, 390–399. [CrossRef]
69. Trang, S.; Zupancic, J.A.; Unger, S.; Kiss, A.; Bando, N.; Wong, S.; Gibbins, S.; O’Connor, D. Cost-Effectiveness of Supplemental
Donor Milk Versus Formula for Very Low Birth Weight Infants. Pediatrics 2018, 141, e20170737. [CrossRef] [PubMed]
70. Shunova, A.; Böckmann, K.A.; Minarski, M.; Franz, A.R.; Wiechers, C.; Poets, C.F.; Bernhard, W. Choline Content of Term and
Preterm Infant Formulae Compared to Expressed Breast Milk—How Do We Justify the Discrepancies? Nutrients 2020, 12, 3815.
[CrossRef] [PubMed]
71. Reid, J.; Makrides, M.; McPhee, A.J.; Stark, M.J.; Miller, J.; Collins, C.T. The Effect of Increasing the Protein Content of Human
Milk Fortifier to 1.8 g/100 mL on Growth in Preterm Infants: A Randomised Controlled Trial. Nutrients 2018, 10, 634. [CrossRef]
72. Brown, J.V.E.; Embleton, N.; Harding, J.E.; McGuire, W. Multi-nutrient fortification of human milk for preterm infants. Cochrane
Database Syst. Rev. 2016, CD000343. [CrossRef]
73. Thanigainathan, S.; Abiramalatha, T. Early fortification of human milk versus late fortification to promote growth in preterm
infants. Cochrane Database Syst. Rev. 2020, 7, CD013392. [CrossRef]
74. Weber, A.; Loui, A.; Jochum, F.; Buhrer, C.; Obladen, M. Breast milk from mothers of very low birthweight infants: Variability in
fat and protein content. Acta Paediatr. 2001, 90, 772–775. [CrossRef]
75. Colaizy, T.T.; Carlson, S.; Saftlas, A.F.; Morriss, F.H., Jr. Growth in VLBW infants fed predominantly fortified maternal and donor
human milk diets: A retrospective cohort study. BMC Pediatr. 2012, 12, 124. [CrossRef]
76. Colaizy, T.T. Donor human milk for very low birth weights. Curr. Opin. Pediatr. 2015, 27, 172–176. [CrossRef] [PubMed]
77. Minarski, M.; Maas, C.; Engel, C.; Heinrich, C.; Böckmann, K.; Bernhard, W.; Poets, C.F.; Franz, A.R. Calculating Protein Content of
Expressed Breast Milk to Optimize Protein Supplementation in Very Low Birth Weight Infants with Minimal Effort—A Secondary
Analysis. Nutrients 2020, 12, 1231. [CrossRef] [PubMed]
78. O’Connor, D.L.; Kiss, A.; Tomlinson, C.; Bando, N.; Bayliss, A.; Campbell, D.M.; Daneman, A.; Francis, J.; Kotsopoulos, K.; Shah,
P.S.; et al. Nutrient enrichment of human milk with human and bovine milk–based fortifiers for infants born weighing. Curr. Dev.
Nutr. 2019, 3, nz129.
79. Ernährungskommissionen der Deutschen Gesellschaft für Kinder- und Jugendmedizin e. V. (DGKJ); Österreichischen Gesellschaft
für Kinder- und Jugendheilkunde e. V. (ÖGKJ). Kommerzielle Muttermilchverstärker aus humaner Milch: Unzureichend belegter
Nutzen und hohe Kosten. Monatsschrift Kinderheilkd. 2018, 167, 145–148. [CrossRef]
80. Martins-Celini, F.P.; Yamamoto, A.Y.; Passos, D.M.; Nascimento, S.D.D.; Lima, E.V.; Di Giovanni, C.M.; Quadrado, E.R.S.; Barta,
R.; Aragon, D.C.; Prado, S.I.D.; et al. Incidence, Risk Factors, and Morbidity of Acquired Postnatal Cytomegalovirus Infection
Among Preterm Infants Fed Maternal Milk in a Highly Seropositive Population. Clin. Infect. Dis. 2016, 63, 929–936. [CrossRef]
81. Hamprecht, K.; Goelz, R. Postnatal Cytomegalovirus Infection Through Human Milk in Preterm Infants. Clin. Perinatol. 2017, 44,
121–130. [CrossRef]
82. Yoo, H.S.; Sung, S.I.; Jung, Y.J.; Lee, M.S.; Han, Y.M.; Ahn, S.Y.; Chang, Y.S.; Park, W.S. Prevention of Cytomegalovirus Transmission
via Breast Milk in Extremely Low Birth Weight Infants. Yonsei Med. J. 2015, 56, 998–1006. [CrossRef]
83. Mukhopadhyay, S.; Meyer, S.A.; Permar, S.R.; Puopolo, K.M. Symptomatic Postnatal Cytomegalovirus Testing among Very
Low-Birth-Weight Infants: Indications and Outcomes. Am. J. Perinatol. 2016, 33, 894–902. [CrossRef]
84. Kelly, M.S.; Benjamin, D.K.; Puopolo, K.M.; Laughon, M.M.; Clark, R.; Mukhopadhyay, S.; Smith, P.B.; Permar, S.R. Postnatal
Cytomegalovirus Infection and the Risk for Bronchopulmonary Dysplasia. JAMA Pediatr. 2015, 169, e153785. [CrossRef]
85. Goelz, R.; Hamprecht, K.; Klingel, K.; Poets, C.F. Intestinal manifestations of postnatal and congenital cytomegalovirus infection
in term and preterm infants. J. Clin. Virol. 2016, 83, 29–36. [CrossRef]
86. Omarsdottir, S.; Agnarsdottir, M.; Casper, C.; Orrego, A.; Vanpée, M.; Rahbar, A.; Söderberg-Nauclér, C. High prevalence of
cytomegalovirus infection in surgical intestinal specimens from infants with necrotizing enterocolitis and spontaneous intestinal
perforation: A retrospective observational study. J. Clin. Virol. 2017, 93, 57–64. [CrossRef]
87. Patel, R.M.; Shenvi, N.; Knezevic, A.; Hinkes, M.; Bugg, G.W.; Stowell, S.R.; Roback, J.D.; Easley, K.; Josephson, C. Observational
study of cytomegalovirus from breast milk and necrotising enterocolitis. Arch. Dis. Child. Fetal Neonatal Ed. 2019, 105, 259–265.
[CrossRef]
88. Weimer, K.E.D.; Kelly, M.S.; Permar, S.R.; Clark, R.; Greenberg, R.G. Association of Adverse Hearing, Growth, and Discharge Age
Outcomes With Postnatal Cytomegalovirus Infection in Infants With Very Low Birth Weight. JAMA Pediatr. 2020, 174, 133–140.
[CrossRef]
89. Lopes, A.-A.; Champion, V.; Mitanchez, D. Nutrition of Preterm Infants and Raw Breast Milk-Acquired Cytomegalovirus
Infection: French National Audit of Clinical Practices and Diagnostic Approach. Nutrients 2018, 10, 1119. [CrossRef]
90. Lanzieri, T.M.; Dollard, S.C.; Josephson, C.D.; Schmid, D.S.; Bialek, S.R. Breast Milk-Acquired Cytomegalovirus Infection and
Disease in VLBW and Premature Infants. Pediatrics 2013, 131, e1937–e1945. [CrossRef]
Int. J. Environ. Res. Public Health 2021, 18, 7544 13 of 13

91. Gunkel, J.; De Vries, L.S.; Jongmans, M.; Koopman-Esseboom, C.; Van Haastert, I.C.; Eijsermans, M.C.J.; Van Stam, C.; Van Zanten,
B.G.A.; Wolfs, T.F.W.; Nijman, J. Outcome of Preterm Infants With Postnatal Cytomegalovirus Infection. Pediatrics 2018, 141,
e20170635. [CrossRef]
92. Brecht, K.F.; Goelz, R.; Bevot, A.; Krägeloh-Mann, I.; Wilke, M.; Lidzba, K. Postnatal Human Cytomegalovirus Infection in
Preterm Infants Has Long-Term Neuropsychological Sequelae. J. Pediatr. 2015, 166, 834–839.e1. [CrossRef]
93. Dorn, M.; Lidzba, K.; Bevot, A.; Goelz, R.; Wilke, M.; Hauser, T.-K. Long-term neurobiological consequences of early postnatal
hCMV-infection in former preterms. Hum. Brain Mapp. 2013, 35, 2594–2606. [CrossRef]
94. Fernández-Alarcón, C.; Meyer, L.E.; McVoy, M.A.; Lokensgard, J.R.; Hu, S.; Benneyworth, M.A.; Anderholm, K.M.; Janus, B.C.;
Schleiss, M.R. Impairment in neurocognitive function following experimental neonatal guinea pig cytomegalovirus infection.
Pediatr. Res. 2021, 89, 838–845. [CrossRef]
95. Ernährungskommission der Österreichischen Gesellschaft für Kinder- und Jugendheilkunde; Haiden, N.; Wald, M.; Berger, A.
Prävention von CMV-Infektionen bei Frühgeborenen. Monatsschrift Kinderheilknd. 2019, 167, 323–328. [CrossRef]
96. Goelz, R.; Hihn, E.; Hamprecht, K.; Dietz, K.; Jahn, G.; Poets, C.; Elmlinger, M. Effects of Different CMV-Heat-Inactivation-Methods
on Growth Factors in Human Breast Milk. Pediatr. Res. 2009, 65, 458–461. [CrossRef]
97. Bapistella, S.; Hamprecht, K.; Thomas, W.; Speer, C.P.; Dietz, K.; Maschmann, J.; Poets, C.F.; Goelz, R. Short-term Pasteurization
of Breast Milk to Prevent Postnatal Cytomegalovirus Transmission in Very Preterm Infants. Clin. Infect. Dis. 2018, 69, 438–444.
[CrossRef]
98. Ahnfeldt, A.M.; Stanchev, H.; Jørgensen, H.L.; Greisen, G. Age and weight at final discharge from an early discharge programme
for stable but tube-fed preterm infants. Acta Paediatr. 2015, 104, 377–383. [CrossRef]
99. Wilson, E.; Bonamy, A.-K.E.; Bonet, M.; Toome, L.; Rodrigues, C.E.D.; Howell, E.A.; Cuttini, M.; Zeitlin, J.; The EPICE Research
Group. Room for improvement in breast milk feeding after very preterm birth in Europe: Results from the EPICE cohort. Matern.
Child Nutr. 2017, 14, e12485. [CrossRef]
100. Young, L.; Embleton, N.D.; McGuire, W. Nutrient-enriched formula versus standard formula for preterm infants following
hospital discharge. Cochrane Database Syst. Rev. 2016, 2016, CD004696. [CrossRef]
101. Young, L.; Embleton, N.; McCormick, F.M.; McGuire, W. Multinutrient fortification of human breast milk for preterm infants
following hospital discharge. Cochrane Database Syst. Rev. 2013, CD004866. [CrossRef]
102. Wiechers, C.; Doll, J.-N.; Maas, C.; Gründler, K.; Büchner, K.; Poets, C.F.; Franz, A.R. Enteral feeding advancement and extremely
preterm infants’ growth until 5 years. BMC Pediatr. 2021, in press.
103. Böckmann, K.A.; von Stumpff, A.; Bernhard, W.; Shunova, A.; Minarski, M.; Frische, B.; Warmann, S.; Schleicher, E.; Poets, C.F.;
Franz, A.R. Fatty acid composition of adipose tissue at term indicates deficiency of arachidonic and docosahexaenoic acid and
excessive linoleic acid supply in preterm infants. Eur. J. Nutr. 2021, 60, 861–872. [CrossRef] [PubMed]
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2017 年 1 月 Chin J Contemp Pediatr Jan. 2017

doi: 10.7499/j.issn.1008-8830.2017.01.001

专家讲座

Optimizing nutrition of the preterm infant

William W. Hay, Jr.
(Perinatal Research Center, Child Maternal Health Program, Colorado Clinical and Translational Sciences Institute
University of Colorado School of Medicine, Aurora, Colorado, USA)

Abstract: Objective The goal of nutrition of the preterm infant is to meet the growth rate of the healthy fetus
of the same gestational age and to produce the same body composition of the healthy fetus in terms of organ growth,
tissue components, and cell number and structure. Nutritional quantity and quality are fundamental for normal growth
and development of preterm infants, including neurodevelopmental outcomes. Failure to provide the necessary amounts
of all of the essential nutrients has produced not only growth failure, but also increased morbidity and less than optimal
neurodevelopment. Growth velocities during the NICU hospitalization period for preterm infants exert a significant effect
on neurodevelopmental and anthropometric outcomes. Despite the obvious need for optimal nutrition, growth failure is
almost universal among preterm infants. There is every reason, therefore, to optimize nutrition of the preterm infant, in
terms of total energy and protein, but also in terms of individual components such as amino acids, specific carbohydrates
and lipids, and even oxygen. This review presents scientific rationale for nutrient requirements and practical guidelines
and approaches to intravenous and enteral feeding for preterm infants. Intravenous feeding, including amino acids,
should be started right after birth at rates that are appropriate for the gestational age of the infant. Enteral feeding should
be started as soon as possible after birth, using mother’s colostrum and milk as first choices. Enteral feeding should
begin with trophic amounts and advanced as rapidly as tolerated, decreasing IV nutrition accordingly, while maintaining
nutrient intakes at recommended rates. Feeding protocols are valuable for improving nutrition and related outcomes.
Further research is needed to determine the optimal nutrition and rate of growth in preterm infants that will achieve
optimal neurocognitive benefits while minimizing the longer-term risk of chronic diseases.
[Chin J Contemp Pediatr, 2017, 19(1): 1-21]
Key words: Intravenous feeding; Parenteral feeding; Enteral feeding; Amino acid; Glucose; Lipid; Necrotizing
enterocolitis; Preterm infant

Introduction repair in response to injuries (such as oxygen toxicity

The goal of nutrition of the preterm infant is to
meet the growth rate of the healthy fetus of the same
gestational age[1]. It also is important to produce the
same body composition of the healthy fetus in terms of
organ growth, tissue components, and cell number and
structure. Failure to provide the necessary amounts
of all of the essential nutrients has produced not only
[2]
growth failure , but also increased vulnerability to
infectious diseases arising from suboptimal immune
[3]
defenses , increased respiratory distress from lung
[4]
injury due to muscle weakness , impaired tissue
and barotrauma in the lung, inflammation in the gut,
and wound healing), and general underdevelopment of
all other organs such as intestine[5-6], skeletal muscle[7],
and brain[8-9].
As documented by many studies over many
years, neuronal underdevelopment may be the most
serious adverse consequence of under nutrition of
preterm infants, which clearly leads to later life
cognitive deficiencies[10-13]. The most severe adverse
neurodevelopmental outcomes occur in preterm
infants who had IUGR and also suffered postnatal
under nutrition. While it remains uncertain whether

[Received] August 26, 2016；[Accepted] October 15, 2016

[Biography] William W. Hay, Jr., MD, Professor of Pediatrics (Neonatology)/Scientific Director, Perinatal Research Center/Director, Child
Maternal Health Program, Colorado Clinical and Translational Sciences Institute University of Colorado School of Medicine (Email: bill.
hay@ucdenver.edu).

1
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 第 19 卷 第 1 期
2017 年 1 月
improved neuronal development, brain growth,
and cognitive outcomes are the direct result of
improved nutrition or whether healthier infants can
[14]
be fed more , studies clearly are documenting the
association of improved neurodevelopmental outcome
with improved nutrition and growth of preterm
[15-17]
infants . well as protein fed to preterm infants improved growth
Despite such needs, it remains a challenge to
consistently provide adequate nutrition to preterm
infants, particularly right after birth when nutritional
support is largely dependent on intravenous nutrition
and often is complicated by glucose and lipid
[18-19]
intolerance . During this period, large nutritional
deficits, in particular protein deficits, can rapidly
accumulate in preterm infants. In such infants, protein
stores can decline by as much as 1.5%/day, in contrast
to the normally growing fetus that has a positive
[20]
net protein balance of ~2%/day . Many studies
from around the world have provided consistent
evidence that early amino acid intake, at least
3 g/kg/day, before 5 days of life, can reduce protein
breakdown and deficits and improve protein balance
and growth outcomes in preterm, very-low-birth-
[21-27]
weight infants . This is one of the most consistent
observations among controlled research trials and
[19]
observational studies in neonatal medicine .
Nevertheless, growth failure is almost universal
[28]
among preterm infants . 80% of very low-birth
weight preterm infants involved in studies conducted
by the NIH Neonatal Research Network from 2008
to 2010 had documented growth failure [29-30], and
among infants within the Vermont Oxford Hospital
Network, at least 50% were growth-restricted at the
[2]
time of discharge from the NICU . Such growth
failure is, however, preventable, and so is the
neurodevelopmental impairment that comes from
insufficient nutrition. Protein deficiency is critical, in
this regard, as protein is the nutritional component
most essential for development of neurological
[31]
function , but overall nutritional quantity and
quality also are fundamental for normal growth
and development, including neurodevelopmental
中国当代儿科杂志 Vol.19 No.1
Chin J Contemp Pediatr Jan. 2017
outcomes. Growth velocities during the NICU
hospitalization period for preterm infants exert a
significant, and possibly independent, effect on
neurodevelopmental and anthropometric outcomes[13].
As shown by Lucas and colleagues [32], 4 weeks of
enriched formula with greater amounts of energy as
and neurodevelopmental outcomes at 18 months
corrected gestational age when compared to preterm
infants fed lower amounts of energy and protein
in standard term formulas. At 7.5 years of age, the
infants fed the enriched preterm formula demonstrated
higher cognitive functions[33], and even at age 16,
these infants had larger brain size and larger volumes
of the caudate nucleus measured using MRI F:\
Documents\Neonatal Nutrition, for Bo Sun, Chinese
Journal of Comtemporary Pediatrics\Nutritional_
support_for_extremely_low-birth_weight_infants_
abandoning_cat.html - 134 and higher intelligence
quotient (IQ) scores [16,34]. Regression analysis of
infants from several studies have shown a significant
positive correlation between both cumulative energy
and protein intakes and greater head circumference
at 36 weeks postmenstrual age [35], F:\Documents\
Neonatal Nutrition, for Bo Sun, Chinese Journal of
Comtemporary Pediatrics\Nutritional_support_for_
extremely_low-birth_weight_infants_abandoning_
cat.html - 136and better mental and psychomotor
developmental index (MDI and PDI) scores at 3
months' corrected age [36] . Furthermore, a recent
retrospective study showed that the MDI of ELBW
infants at age 1.5 years increased by 8.2 and
4.6 points, respectively, for every extra gram of
protein/kg per day or every extra 10 kcal/kg per day
they received during the first week of life[37]. This early
postnatal period appeared to be critical, as nutritional
intakes during the next few weeks of life did not show
correlations with neurocognitive outcome. While
continued nutritional support during the NICU period,
as well as after discharge, is fundamental, clearly,
the first few days after birth are most important for
achieving positive protein and energy balance and for
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 第 19 卷 第 1 期 中国当代儿科杂志 Vol.19 No.1
2017 年 1 月 Chin J Contemp Pediatr Jan. 2017

promoting improved growth and development.
There is every reason, therefore, to optimize
nutrition of the preterm infant, in terms of total energy
and protein, but also in terms of individual components
such as amino acids, specific carbohydrates and lipids,
and even oxygen. If this is the case, how successful
is current nutritional practice for preterm infants in
terms of producing optimal nutrition and growth
Most studies also show, however, that most
preterm infants fail to grow well after birth, usually for
many days. They also don’t keep up with intrauterine
growth and thus end up growth restricted by term[41-42]
(Figure 2). This problem has not improved over the past
almost 70 years[43].
2 000

and development of preterm infants? The answer is,

universally, not as well as it should. It is imperative,
1 500

Weight (g)
therefore, to reassess the rate of growth that should be
achieved in preterm infants and the basic nutritional
1 000
requirements needed to achieve this growth rate. Intrauterine growth
24-25 weeks
26-27 weeks
28-29 weeks
How fast should a preterm infant grow? 500

24 28 32 36

Postmenstrual age (weeks)

Direct measurement of normal human fetal
growth is not possible. Most commonly, therefore, Figure 2　Postnal growth of VLBW infants vs.
fetal growth rates have been estimated from expected intrauterine growth[42]

anthropometric measurements at the time of birth

among “healthy”, normal appearing preterm infants
of viable gestational age through to term. Using
this approach, multiple studies have shown that the
average fractional fetal weight gain from 24 to 38
weeks gestation is 17 g/kg/d[38-40] (Figure 1).
4 000
3 500
3 000
Weight (g)
While there are many possible reasons why
preterm infants do not grow after birth as well as the
normal fetus of the same gestational age, including
stress responses (e.g., increased secretion and
plasma concentrations of catabolic hormones such
catecholamines, glucagon, and cortisol, intermittent
hypoxia, respiratory distress, mechanical ventilation,
sepsis, inadequate body temperature maintenance,
Olsen, 2010, Mean boys
and girls
etc.), a principal cause is insufficient nutrition, as
Fenton (boys, 2013)
evidenced by cumulative deficits in energy and

Fenton (girls, 2013)

2 500 Denver
protein, even with more “aggressive” nutrition that
Baltimore
2 000
Montreal provides closer to estimated nutrient requirements[44]
1 500 Portland
(Figure 3) .
Chapel Hill
1 000 12 U.S. Cities

25 30 35 40 45

Gestational age (weeks)

Figure 1　Birth weights by gestaional age[38-40]

Regardless of the growth curve, normal human fetal growth rate is
~17 g/kg/day from 28-40 weeks.

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 第 19 卷 第 1 期 中国当代儿科杂志 Vol.19 No.1
2017 年 1 月 Chin J Contemp Pediatr Jan. 2017

Intake (Kcal/K) 200 10

Intake (G/K)
100 5
0 0
1 3 5 7 9 11 13 15 17 19 21 23 25 27 1 3 5 7 9 11 13 15 17 19 21 23 25 27
-100 -5
Aggressive group
-200 -10
Conventional group Aggressive group
-300
-15 Conventional group
Deficit (Kcal/K)

-400
-20

Deficit (G/K)
-500
-25
-600
-30
-700
-35
Postnatal days Postnatal days

A principal reason-Inadequate Nutrition as evidenced by cumulative deficits in energy and protein, even with more "aggressive" nutrition.

Figure 3　Energy and protein intake and cumulative deficits in the first 28 postnatal days[44]

Why are preterm VLBW infants not fed enough that of the normally nourished and normally growing
to grow as well as the fetus? There are several human fetus of the same gestational age.
practical and common reasons. First, most preterm
infants have a delayed start to receiving nutrients, Nutrient requirements for preterm infants
e.g., low rates of or even no IV amino acids on the
first day of life (to sometimes several days after If we are going to feed preterm infants to grow
birth). Second, enteral feedings often are withheld, as well as the normal, healthy human fetus, we should
sometimes for days. Third, most infants receive very consider the normal fetal nutrient and co-factor
slow advances of nutrient supply, e.g., IV amino acid requirements and at least provide those. There may
infusion rates of <3 g/kg/d. Fourth, there are usually be additional adjustments for conditions that arise
rather slow advances of IV amino acids and lipids after birth, but it is unreasonable to consider nutrition
after starting, and slow advances of enteral feeds. sufficient if it provides less than what the normal fetus
Fifth, most infants receive dilute nutritional mixes, receives. What nutrients and co-factors, therefore,
e.g., unfortified breast milk (mother’s own or banked), should we provide to the preterm infant at the same
and insufficient amounts of essential amino acids in gestational age of the fetus in utero?
TPN mixes. There also are many excuses offered as Oxygen
“reasons” for withholding, slowing down, or stopping 　　First, while not actually a nutrient, oxygen is
feedings, practically none of which has a rational basis necessary for the metabolism of all nutrients and
from controlled trials. For the most part, it is simply particularly for producing growth. Numerous studies
assumed that infants with any kind of physiological have shown that hypoxia and oxygen consumption
instability cannot tolerate normal amounts of nutrition, rates less than normal restrict growth. The normal
either parenteral or enteral (Table 1). As a result, fetus exposed to hypoxia responds by increasing
preterm infants commonly are under nourished from erythropoietin, producing more red blood cells,
birth and often for days to sometimes weeks, and all thereby increasing its blood oxygen content to
of the practical reasons and excuses, justified or not, compensate for the reduction in molecular oxygen
reduce nutrient intake, which leads to growth failure supply[45]. Also, many studies have shown that preterm
and impaired neurodevelopment. It is not unexpected, infants who receive blood transfusions for severe
therefore, that growth, which for the fetal period of anemia not only increase their blood oxygen content
human development requires constant supplies of but also improve their growth rate. In one study, for
nutrients, does not occur or even decreases relative to example, preterm infants did not gain weight as well

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Table 1　“Excuses” for withholding, slowing down, or stopping feeding of preterm infants, with comments about why this
　　　　might be done and why it might not be rational
Item Excuse
1. abdominal distension fear of NEC
2. green gastric aspirates fear of NEC
3. UA and/or UV catheters fear of gut ischemia, and thus NEC
4. GER fear of apnea(actually, it probably is the other way around)
5. tachypnea fear of aspiration
6. heart murmurs fear of PDA and gut ischemia—and NEC
7. PDAs fear of gut ischemia—and NEC
8. indomethacin fear of gut ischemia—and NEC
9. high BUN fear of urea poisoning and amino acid toxicity
10. high bilirubin fear of FFA displacing bilirubin from albumin
11. high WBC/CRP fear of decreased metabolism, proteolysis
12. skin rashes fear of allergies
fear of poor metabolism (though stopping IV lipids and reducing
13. hyperglycemia
dextrose infusion rates at least have a rational basis)
14. hypothermia fear of sepsis
15. hyperthermia fear of sepsis
16. hypo- or hyperkalemia poor gut function, bad IV nutrient mix
17. hypo- or hypernatremia bad IV nutrient mix, dehydrated
18. thrombotic episodes need to use heparin, reduce IV rate
19. polycythemia risk of clots and gut ischemia and NEC
20. SpO2 values are low can’t metabolize nutrients
21. On catecholamines fear of gut ischemia, NEC, hyperglycemia
22. Anemia fear of gut ischemia
23. Transfusions risks of NEC, transfusion related immunomodulation
how does this reduce digestion and nutrient absorption and
24. on a ventilator
anabolism?
this one baffles me; of course it’s low if the baby is under-
25. low energy expenditure
nourished!
26. might need surgery so they should be starved first?
27. “Just doesn’t look good”— I have no response to this one!
28. Mother couldn’t be here so we held the feeding for her to give good for the mother, but bad for the baby!
29. Intermittent hypoxic episodes these get better with starvation??
30. We wanted “fasting” electrolyte values in the morning What does fasting have to do with electrolytes?
31. We wanted to be sure the baby was stable well, sure, and starved, too
always a scapegoat around—the ubiquitous, infamous “other
32. “The other attending” doesn’t like to advance feeds very fast
attending”
And more!

when their Hb concentration was ≤ 8.5 g/dL (Hct
≤ 25%), but their weight gain improved after
transfusion with red blood cells to a blood Hb
concentration of ≥ 11.4 g/dL (Hct ≥ 34%). The more
severe the anemia (lower the blood oxygen content),
therefore, the more likely that growth failure will
[46]
develop . Commonly, however, current practice
usually reduces blood oxygen content by allowing
preterm infants to be more anemic (hematocrits in
lower 20 s) to limit transfusion risks (transfusion-
related inflammatory disorders, e.g., NEC, strokes,
lung injury) and to be maintained at lower PaO 2
values to prevent oxygen toxicity (e.g., ROP,
BPD). Furthermore, preterm infants lose, by adult
standards, enormous amounts of blood for all sorts
of biochemical and hematological measurements.
Unfortunately, we have little capacity to measure
the clinical effect of low O 2 supply on nutrient

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metabolism (energy + protein), protein accretion,
and neuronal growth and development, limiting our
ability to assess the impact, in any given infant, of
different low blood oxygen contents on producing
growth restriction. Our goal, therefore, should be to
determine optimal nutrient and anabolic hormone
supplies to promote growth, especially of neurons/
dendrites, at lower blood O 2 levels. We also might
improve our administration of erythropoietin (give
more, or develop more effective protocols), provide
safer transfusions, use delayed cord clamping and cord
stripping routinely, reduce blood sampling, microsize
blood sample assays, and provide more and better
noninvasive monitoring.
Glucose
　　 Adequate glucose also must be provided to
ensure appropriate growth rates. Glucose is essential
for normal metabolism in all cells, but as the principal
energy substrate of the normal fetus and thus the
preterm infant, glucose is necessary to support growth,
particularly protein synthesis from amino acids and net
protein balance. In fetal studies, for example, reduction
in glucose supply and plasma glucose concentrations
[47]
lead to growth failure . This is a relatively uncommon
problem in preterm infants, however, as most of the
time, they are infused with more glucose than they
can use, resulting in hyperglycemia. Normal neonatal
glucose production and utilization rates have been
[48]
estimated from animal studies and measured in
[49-50]
infants with stable isotope techniques . Preterm
infants at ~28 weeks gestation maintain hepatic
glucose production rates of 2-3 mg/min/kg which are
not easily suppressed, either by glucose or insulin, as
[51]
they are in normal children . Glucose utilization rates
can be as high as 7-9 mg/min/kg, however, largely
for the brain, but also for the heart. Term infants
also produce ~2-3 mg/min/kg of glucose, but their
glucose utilization rates are lower at ~3-5 mg/min/kg
(still largely for the brain). The decrease in weight-
specific glucose utilization rates from very preterm to
term gestational age is the result of increasing body
proportions of organs, such as bone, muscle, lung,
中国当代儿科杂志 Vol.19 No.1
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and the gastrointestinal tract, that do not use glucose
as much as the brain and heart. Regardless of the
utilization or production rates, preterm infant plasma
glucose concentrations should be in the same range
as normal human fetuses of the same gestational age,
i.e., between 3.0 mmol/L and 6 mmol/L[52]. This is the
same range achieved by normal, healthy term newborn
infants after the first 12-24 hours from birth following
the normal nadir in glucose concentration from 1-3
hours of age[53].
Lipids
　　 Normal human fetal development involves
considerable fat deposition in adipose tissue, primarily
peripherally in subcutaneous regions of the body.
Normal human fetuses produce about 15 g/kg body
weight as fat by term. Early in the third trimester
(24-28 weeks), however, there is little lipid uptake,
oxidation, or accretion as fat by the fetus. Lipid supply
and fat accretion increase progressively over the
third trimester. It remains uncertain how much lipid
is oxidized in the human fetus, but likely not very
much, as the concentrations of carnitine palmitoyl
transferase, the enzyme that transports long chain fatty
acids into the mitochondria for lipid oxidation, are
quite low, and glucose and amino acid supplies are
more than sufficient to meet most energy requirements.
After birth, however, even in very preterm infants and
even quite soon after birth, supplemental carnitine
(e.g., in mother’s milk) promotes lipid oxidation.
　　 Extremely preterm infants often are slow to
clear plasma of lipid due to maturational deficiency
of lipases (inversely related to GA), low levels of
carnitine palmitoyltransferase (CPT), and chronically
reduced carnitine intakes >2 weeks after birth with
prolonged IV nutrition[54]. There also is competition
of free fatty acids for oxidation due to early postnatal
hyperglycemia. As a result of such conditions, many
recommend limiting lipid intake to 0.5-1 g/kg/day
in presence of other disorders that limit fatty acid
oxidation, such as sepsis, severe lung disease, surgical
stress, steroid use, persistent hyperglycemia, and
cholestasis. This practice is poorly justified, however,
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with little evidence for mechanisms involved and
how to manipulate them, other than added carnitine to
promote better fatty acid oxidation.
　　 The quality of fatty acids and triglycerides
[55]
and other lipid products also is important . Little
information exists, however, about the actual mix of
such substances in fetal plasma that might provide
guidance for the optimal mix of plasma lipid substances
after birth. A major concern, however, is how to
provide sufficient long chain polyunsaturated essential
fatty acids that are fundamental components of the
[56]
developing nervous system . Normal fetal white
adipose tissue accumulation in the 3rd trimester of the
essential omega 3 long chain polyunsaturated fatty acids
(PUFAs), particularly docosahexaenoic acid (DHA,
22:6n-3) ranges from ~45 to ~70 mg/day. According to
current practice, at 3.7g fat/dL human milk with 0.2-
0.4% fatty acids as 22:6n-3, a 1 kg preterm infant fed
at full enteral feeds of 180 mL/day would get only 13-
25 mg 22:6n-3/day, clearly far below normal in utero
accretion rates. As shown by Lapillone and colleagues,
therefore, postnatal DHA deficiency is an inevitable
consequence of current recommendations and practices
for feeding milk, milk supplements, and formulas in
preterm infants[57]. In terms of potential benefits of
providing greater amounts of DHA, one recent study
g/kg/day
at least this one essential fatty acid, but the long term
significance of this deficiency is not known or how
these infants would develop if fed to sufficiency.
Energy
　　 In terms of total energy (primarily from
carbohydrates and lipids), there is a persistent but
unsubstantiated concern that higher intake rates of
amino acids and protein won’t produce more growth
unless higher calorie intakes also are provided. This
concern is based on the unjustified fixation on a
continuous 22 kcal/g protein ratio. Actually, excessive
caloric intake simply increases body fat content
relative to lean mass. Above 80-90 kcal/kg/day non-
protein caloric intake, there is no further increase in
net protein balance for any further increase in energy
intake. Protein gain primarily depends on protein
intake, regardless of the energy intake [60]. This has
been corroborated by elegant nutritional balance
studies by Kashyap and collegues[61] (Figure 4), who
showed that while greater protein intakes would
increase weight, length, and head circumference,
additional lipid with the greater protein intakes only
increased weight and subcutaneous fat.
30 1.6 1.6 1.2 group 1
25 1.4 1.4 1.0 group 2
20
1.2 1.2
0.8
group 3

1.0 1.0
cm/wk

cm/wk

cm/wk

has shown that higher DHA and lower linoleic acid 15 0.8 0.8 0.6
0.6 0.6
levels in the first few weeks of life are associated with 10
0.4 0.4
0.4
5 0.2 0.2 0.2
decreased intraventricular hemorrhage, improved 0 0.0 0.0 0.0
weight length head triceps
microstructural brain development, and improved circumference skinfold

outcomes in preterm infants[58]. Several other studies

also have shown that preterm infants fed increased
DHA have higher visual acuity, particularly at 2 and 4
months and improved Bayley mental development and
MacArthur Communicative inventories at 12 months[59],
but longer term studies do not show a clear benefit.
Thus, the current diet for preterm infants is deficient in
Figure 4　Growth rates with varying protein and
energy intakes [61]　Preterm infants, birth weight 900-1 750 g：
Group 1, 2.24 g/kg/day and 115 kcal/kg/day; Group 2, 3.6 g/kg/day and
115 kcal/kg/day; Group 3, 3.5 g/kg/day and 149 kcal/kg/day.
*
P<0.05: weight in group 1 less than in group 2 and group 3;
head circumference in group 1 less than in group 2 and group 3; triceps
skinfold greater in group 3 than in group 1 and group 2.

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　　Despite such evidence, recent observations of Amino acids and protein

actual intake of nutrients in clinical neonatal practice
has been weighted to energy, both carbohydrates
and lipids, and not to protein, leading to problems
of carbohydrate and lipid excess and protein
[62]
insufficiency . Such a diet mix leads to fatter,
shorter, less muscular infants, and perhaps to longer
term neurological deficits. Unfortunately, this problem
is most common among the smallest, most preterm
infants who are fed far more energy and much less
protein than needed to meet appropriate growth rate
and body composition[63].
　　The most important requirement for growth is
protein intake, as amino acids intravenously and as
intact to partially or fully hydrolyzed protein enterally.
Lean body mass, which consists mostly of protein,
accounts for 90% of growth in the 3rd trimester
of gestation. Without sufficient protein, cellular
replication, hypertrophy, and development cannot take
place as optimally as they should, and insufficient
protein intake will adversely affect proliferation and
growth of all cells in all organs (Table 2) [28].

Table 2　Feeding guidelines: intake amounts (mL/kg/day), by day of feeding (DOF)

Gestational age
DOF 1 DOF 2 DOF 3 DOF 4 DOF 5 DOF 6 DOF 7 DOF 8 DOF 9 DOF 10
(weeks)
< 26 ≤ 20 ≤ 20 ≤ 20 ≤ 20 ≤ 50 ≤ 80 ≤ 110 ≤ 140 ≤ 160 160-180
(fortify
26-29 ≤ 20 ≤ 20 ≤ 20 ≤ 50 ≤ 80 ≤ 110 ≤ 140 160-180
(fortify
29-32 ≤ 20 ≤ 20 ≤ 50 ≤ 80 ≤ 110 ≤ 140 160-180
(fortify
32-34 ≤ 20 ≤ 50 ≤ 80 ≤ 110 ≤ 140 160-180
(fortify
34-37 ≤ 40 ≤ 80 ≤ 120 ≤ 140 160-180
(fortify
Caveats
• Withhold feeds in infants with defined intestinal obstruction or ileus.
• Asphyxia, respiratory distress, sepsis, hypotension, glucose disturbances, ventilation, and umbilical catheters are not contraindications for
trophic feeds.
• Infants at higher risk (two or more risk factors) may have feeding amounts reduced or initiated at GI priming volumes with advancement as
medically appropriate.
• Infants may nipple bottle feeds up to the maximum feeding volume, or breastfeed as able. Infants should not initially be placed on ad lib
nippling or advanced to higher volumes, due to increased risk for feeding intolerance.
• Breast milk is preferred. Donor milk also is acceptable, but will need fortification even more than mother’s own breast milk.
• Human Milk Fortifiers (HMFs) should contain hydrolyzed protein if based on cow milk protein, or use “human” HMFs.
Risk factors for “more conservative” (but not stopping) advancement of feeding
1) Non-reassuring fetal heart rate tracing with need for resuscitation of the infant after delivery and evidence of asphyxia (severe and prolonged
metabolic acidosis from persistent hypotension).
2) More severe and asymmetric IUGR or IUGR with reversed or absent end-diastolic flow on fetal Doppler ultrasound.
3) Monochorionic twin gestation with twin-twin transfusion syndrome.
4) Marked polycythemia (Hct >65).
5) Significant cardiovascular instability: need for chest compressions, use of vasoactive agents, or need for aggressive volume expansion to
achieve sufficient circulation.
6) Marked and prolonged and recurrent apnea.
7) Symptomatic patent ductus arteriosus with reduced urine flow rate and progressive metabolic acidosis.
8) Clinically significant (cardiovascular compromise) sepsis.
9) Prolonged (> 7 days) absence of enteral feedings.

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　　The reason for this need for protein is that protein
synthesis and accretion rates are very high in the fetus
(net protein balance of ~2%/day) and therefore the
preterm infant of the same gestational age, requiring
large amino acid uptake rates. Fetal animal growth
data, when scaled to human fetal growth rate, predict
fetal amino acid requirements ≈ 3.6-4.8 g/kg/day
at ~24-28 weeks of human gestation. This animal
data has been corroborated for human fetuses by
[64]
the Factorial Method , which predicts that human
fetal amino acid requirements ≈ 4 g/kg/day at 24-28
weeks of gestation. It is important to note, however,
that fractional protein synthesis rates decrease with
gestational age and development. Thus, between 30
and 37 weeks, the protein requirement for growth
decreases to ~ 2-3 g/kg/day and by term, protein
requirements decrease to those of the normal breast
fed infant, or ~ 1.5-2 g/kg/day. Among many studies
in preterm infants, net protein balance as measured by
net nitrogen retention is directly and linearly related
[19,65]
to protein intake . Specific studies demonstrate the
same linear relationship between IV amino acid intake
[22,66]
and protein balance through 3 to 4 g/kg/day
Practical feeding guidelines: intravenous
feeding
　　 The goal of early intravenous feeding is to
maintain normal cellular energy and amino acid
supplies. Metabolic and thus nutritional requirements
do not stop with birth, and the smaller the infant, the
less body stores of nutrients are available to provide
nutrients for metabolic needs. Intravenous feeding,
therefore, is always indicated when normal metabolic
and nutritional needs are not met by normal enteral
feeding. Furthermore, the metabolic and nutrient
requirements of the newborn preterm infant are
equal to or greater than those of the fetus of the same
gestational age. It is reasonable, therefore, to provide
the preterm infant with at least the same nutrient
supplies that the fetus of the same gestational age
receives for nutrition. Although early intravenous
中国当代儿科杂志 Vol.19 No.1
Chin J Contemp Pediatr Jan. 2017
nutrition appears to be a beneficial clinical strategy[67],
the optimal amount of that support is not fully
known[19], including the time after birth to start, the
doses to use, and the rate of advancement[68]. The
Current recommendations are that IV nutrition should
be initiated within a few hours of birth[28].
Amino acids
　　At least 2.0 g/kg/day of amino acids should be
started within 2-3 hours of birth, and increased to 3.5-
4.0 g/kg/day over the first 24-48 h for infants <30
weeks gestation (up to 4.0 g/kg/day for extremely low
birth weight infants <27 weeks gestation).
　　 Even when solutions are infused at these or
yet higher rates, intakes of certain essential amino
acids, particularly the branched-chain amino acids
such as leucine and isoleucine[69], but also threonine
and lysine[70], may not produce high enough plasma
concentrations to promote the rate of cellular essential
amino acid uptake needed to produce appropriate
protein accretion. There has been some concern for
excessively high plasma amino acid concentrations
at infusion rates >3.0-4.0 g/kg/day, particularly in
. sick and physiologically unstable preterm infants[71].
Also, infants who experienced severe and chronic
intrauterine growth restriction may have developed
adaptations that actually limit amino acid synthesis
into protein [72]. There is little evidence, however,
that most preterm infants will have significant
complications from the amino acid infusion rates
noted as necessary to produce in utero protein
accretion and growth rates. In fact, most studies have
noted that current IV amino acid mixtures and infusion
rates produce lower plasma concentrations than are
needed for optimal amino acid metabolism and protein
balance[22,69-70]. The overall impact of such temporarily
insufficient amounts of essential and total amino acids
on growth and neurodevelopment of preterm VLBW
infants is uncertain, but it is quite likely that even
temporary shortfalls limit growth.
Glucose
　　 Glucose (as 10% Dextrose in water) should
be infused as soon as possible after birth to prevent
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hypoglycemia and at the highest rate tolerated without
causing hyperglycemia.
　　Hypoglycemia, defined arbitrarily as a plasma
glucose concentration <45 mg/dL in the 1st 2 days
after birth and <50-60 mg/dL after 2 days of life,
should be avoided as much as possible. While low
glucose concentrations do occur even among preterm
infants receiving IV dextrose infusions or TPN, there
is no evidence that occasional transiently low values
in the 40-50 mg/dL range are a problem.
　　Hyperglycemia, defined arbitrarily as a plasma
glucose concentration >120 mg/dL at any time
after birth, is a more common glucose metabolic
disorder than hypoglycemia in preterm infants
largely the result of excessive dextrose infusion rates
(>6-8 mg/kg/min) in the first hours to days after birth
when stress reactive hormones that independently
contribute to glucose production, such as
norepinephrine and cortisol, are commonly present .
Hyperglycemia increases energy expenditure
(glucose-to-fat synthesis is energy expensive), oxygen
consumption (leading to hypoxia), carbon dioxide
production (leading to tachypnea), fat deposition in
excess of lean mass, and fatty infiltration of heart
and liver. Hyperglycemia in preterm infants also
is a potentially serious cause of cellular and even
systemic inflammation from excess reactive oxygen
[75-76]
species production . Such effects may underlie
the increased risk of retinopathy of prematurity
[77-79]
noted among infants with hyperglycemia
noted in one recent study, at every time point in the
first 12 hours after birth, hyperglycemia produces
more unfavorable outcomes in infants with hypoxia-
[80]
ischemia . There also is the potential for sustained
hyperglycemia in preterm infants to diminish longer
term growth and even cognitive development, while
also more positively diminishing body fat content.
Down-regulation of the growth IGF-1/growth
[81]
hormone axis may be responsible .
　　 While hyperglycemia usually occurs in the
first few days after birth, particularly among the
most immature infants, it can be found at any time
Vol.19 No.1
Chin J Contemp Pediatr Jan. 2017
during IV nutritional support. In addition to the most
common cause of hyperglycemia, which is excessive
dextrose infusion, hyperglycemia also is the result
of persistent hepatic glucose production[50] that is not
down-regulated by increasing plasma concentrations
of glucose or insulin[51]. Hyperglycemia also is caused
by catecholamine treatment of low blood pressure,
hydrocortisone treatment of low blood pressure and
evolving chronic lung disease, and high IV lipid
infusion rates.
　　 Mixed hyper- and hypoglycemia occur quite
commonly in very preterm, IUGR infants, but should
be considered in any very preterm infant, as many
[73]
, of these infants experienced IUGR before their
preterm birth. Hyperglycemia is common in such
infants due to reduced pancreatic β-cell number and
insulin production, hepatic insulin resistance and
increased glucose production, decreased glucose
[74]
disposal capacity because of their smaller brains and
reduced muscle, and higher secretion rates and plasma
concentrations of catecholamines and cortisol that
limit insulin production and action. Hypoglycemia
is common in such infants due to their greater head/
brain to body/liver ratio and thus greater body weight-
specific glucose utilization rate, increased peripheral
tissue glucose uptake capacity from increased or at
least maintained tissue glucose transporters, increased
fractional insulin secretion and susceptibility to
metabolic stimulation of insulin secretion, and good
. As health and care that reduces catecholamine and cortisol
secretion and concentrations and their negative impact
on insulin secretion and action[82].
　　Prevention and treatment of hyperglycemia is
important and is best accomplished by using lower
IV dextrose infusion rates in the first place and
lowering them, along with reducing lipid infusion
rates and catecholamine and cortisol treatments and
preventing hypoxic episodes. Use of insulin should
be reserved for the most serious hyperglycemic
conditions (plasma glucose concentrations >200-
250 mg/dL and unresponsive to other approaches).
There are many complications of using insulin to
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prevent or treat hyperglycemia. Insulin actually
makes the baby fatter (including fatty infiltration
of heart and liver). Insulin increases complications
of excess allostatic load (reactive oxygen species
production and inflammation). Insulin increases the
[83]
risk of hypoglycemia . Furthermore, although not
studied yet in preterm infants, in children with cardiac
disorders in intensive care, tight glucose control did
not improve outcomes, but did result in more cases
of hypoglycemia, and those children had poorer
[84]
neurodevelopmental outcomes . Infused insulin does
not promote glucose uptake or utilization by the brain
or enhance neuronal growth or dendritic development.
Not the least, negative feedback mechanisms limit
the effect of insulin to promote protein synthesis,
net protein balance, and growth; insulin just does
not work as a growth hormone to augment growth
when given in excess. When insulin infusion was
compared to reduced IV glucose infusion rate to treat
[85-86]
hyperglycemia in 500-750 g infants , there were
no differences in all age/weight groups for rates of
death, sepsis, ROP, NEC, intracranial hemorrhage,
chronic lung disease, days in the NICU, or rates of
growth. It makes more sense to just limit the glucose
infusion rate, and perhaps to increase IV amino acid
infusion rates to 4 g/kg/day, which has been shown to
reduce the number of episodes of hyperglycemia and
the time-averaged plasma glucose concentration .
Lipids
　　 Intravenous lipid infusion should be started
within 24 hours of birth and advanced from 2.0
to 3.0-3.5 g/kg/day as tolerated, usually over 2-3
days. Intravenous lipids provide essential carbon for
oxidative metabolism and also provide essential fatty
acids that promote membrane formation, particularly
in the brain, but also in all cells in the body. Excess
lipid infusion rates, however, commonly produce
hypertriglyceridemia (arbitrarily defined as plasma
triglyceride concentrations >150 mg/dL), which has
been associated with adverse lipid deposition and
[62,76]
subsequent inflammation in hepatocytes
underlie the common problem of cholestatic jaundice
中国当代儿科杂志 Vol.19 No.1
Chin J Contemp Pediatr Jan. 2017
and liver failure in infants who experience prolonged
Intravenous nutrition [88]. ELBW infants often are
slow to clear plasma of lipid due to maturational
deficiency of lipases (inversely related to GA), low
levels of carnitine palmitoyltransferase (CPT) and
chronically reduced carnitine intakes >2 weeks after
birth, and competition of FFA oxidation with carbon
from hyperglycemia. In response, many recommend
limiting lipid infusion rates to 0.5-1 g/kg/day in
the first few days of life, particularly in presence of
infection, severe lung disease, surgical stress, and
steroid use. There is little rational justification for this
practice, except when hypertriglyceridemia occurs
in the presence of hyperglycemia, and to prevent
cholestasis. Some have added carnitine to promote
better fatty acid oxidation, but possible benefits only
appear after total IV nutrition of more than 2 weeks[54].
　　It is clear, however, that postnatal deficiencies
of essential fatty acids, particularly the long
c h a i n p o l y u n s a t u r a t e d f a t t y a c i d ( L C P U FA )
docosahexaenoic acid or DHA is an inevitable
consequence of current recommendations and
practices of intravenous lipid feeding, as well as for
feeding milk, milk supplements, and formulas in
preterm infants, leading to increasing cumulative
DHA deficits. Unfortunately, to date, long term
neurodevelopmental benefits of DHA or omega-3
[87]
LCPUFA supplementation are equivocal and shorter
term improvements in BPD, ROP, NEC, sepsis, and
death are uncertain.
Total energy: Intravenous nutrition should
achieve a caloric intake of 50 kcal/kg/day on day 1
and 80 kcal/kg/day by day 3.
Amino acids: Intravenous amino acid infusion
should be started right after birth, at least at 2.0 g/kg per
day, and advanced to gestational age specific protein
needs by day 2 to 3.
　　Between 24-30 weeks, initial intravenous amino
acid infusion rates should range from 3.5 to 4.0 g/kg/
day. Between 30 and 36 weeks, as fractional protein
, that may synthesis rates decline, intravenous amino acid
infusion rates of 3.0 to 3.5 g/kg/day are appropriate.
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At term, amino acid requirements decrease to those
of the normal breast fed infant, or 1.5-2.0 g/kg/day.
While some have questioned whether the early, high
amino acid infusion rate in very preterm infants
might lead to potential adverse outcomes, previous
observational and randomized controlled trials have
not found smaller head circumferences in response
[23-27,89]
to higher amino acid intakes , and one recent
randomized controlled trial showed that higher amino
acid intakes resulted in greater head circumferences .
Even small differences in head circumference are
unlikely to demonstrate developmentally important
differences in brain volumes when early, higher
amino acid infusion rates are used, and the studies
addressing this issue actually have shown that the head
circumferences measured are just above or just below
the 50th percentile for head circumference at 40 weeks
corrected gestational age[90], representing improved
head circumference percentiles from those measured at
birth[19]. Furthermore, even at 3.5 g/kg/day (if actually
achieved), there may be inadequate essential amino
acids to produce plasma concentrations sufficient to
achieve appropriate cellular amino acid uptake rates
[69-70,89,91]
and, thus, rates of protein synthesis . increased rates of sepsis (both due to suppressed
Practical feeding guidelines: transition from
intravenous to enteral feeding
　　During the transition from parenteral to enteral
nutrition, a shortfall of nutrient intakes may lead to
[92]
insufficient protein and energy intakes . This problem
arises when parenteral nutrition is diminished or
terminated early in order to limit the use of indwelling
catheters because of the associated risk of infection
(central line associated blood stream infection) and
to limit total water intake and its potential to produce
metabolic (dilutional acidosis, hyponatremia) and
[93]
cardiopulmonary (PDAs) disorders . As noted by
[28]
Hay and Ziegler , practical solutions to this problem
include temporarily increasing the total and especially
the essential amino acid concentrations in parenteral
nutrition solutions, continuing parenteral nutrition
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Chin J Contemp Pediatr Jan. 2017
for longer periods, and advancing enteral nutrition
and milk fortification sooner and at faster rates[94].
Fortification also should be started before full enteral
feeding rates are achieved, perhaps at 50 mL/kg/day[92].
A recent study in 100 VLBW infants randomized
to early fortification of enteral feeding at a feeding
volume of 20 mL/kg/day or delayed fortification at a
feeding volume of 100 mL/kg/day (all infants were
fed according to a standardized enteral and parenteral
[27]
feeding protocol; fortification was with Mead Johnson
Nutrition acidified human milk fortifier) reported that
the infants randomized to early fortification had a
higher median daily protein intake at 1, 2 and 3 weeks
of age as well as a higher cumulative protein intake
in the first 4 weeks of life. There was no difference
in days to reach full feeding volumes, episodes of
feeding intolerance or necrotizing enterocolitis[95].
Practical feeding guidelines: enteral feeding
　　 There are many adverse consequences of
intravenous feeding only with no enteral nutrition.
Problems of exclusive intravenous feeding include
immunity, reduced milk-associated immune function,
and abnormal gut microbiome, as well as central
line associated bacterial infections or CLABSI),
gut mucosal atrophy and lack of production of gut-
derived trophic hormones, increased adipose tissue
and fatty infiltration of the heart and liver, systemic
inflammatory response syndrome, reduced mucosal
IgA from unstimulated and under developed Payer’s
patches, and increased adhesion molecules and
polymorphonuclear cell attraction. Animal models
such as the neonatal piglet have shown reduced
accretion of lean mass and bone mineral content as
well as increased fat mass when neonatal piglets
were fed TPN exclusively vs. enteral nutrition over
a 16-day period[74]. Studies in adults[96-98] and older
infants and children including term infants[99] have
shown greater rates of various morbidities and even
mortality when enteral nutrition is withheld and
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intravenous nutrition is used exclusively. Some of
these problems most likely are the result of excessive
glucose infusion with hyperglycemia, even when
insulin is added as part of “tight glucose control” to
[100]
maintain normal glycemia . For older infants, as
in children and adults, delaying intravenous nutrition
while optimizing very early enteral nutrition appears
to be safer, with fewer cases of infection and fewer
days to discharge.99 Starting enteral nutrition as
soon as possible, therefore, is beneficial, particularly
when combined with appropriate early intravenous
[101-102]
nutrition . infants. This cannot be reached with a powder fortifier;
　　 Of particular note is the improvement in gut
development and growth using “trophic” or “gut
priming” enteral feeds. Benefits include improved
mucosal growth and development that clearly depend
on enteral (not parenteral) nutrients, improved feeding
tolerance and growth, less need for phototherapy,
decreased cholestasis, decreased osteopenia, improved
gastrointestinal trophic hormone surges, and improved
GI motility, all with no increase in complications (e.g.,
NEC, particularly with colostrum and milk)[103-104]. It
also is important to note that enteral feeding increases
[105]
superior mesenteric artery blood flow , which may
account for the lack of a causal role for PDAs or early
[106]
indomethacin treatment to lead to early NEC
recent retrospective cohort study from a single NICU
evaluated 415 infants over a 5-year period who were
treated with indomethacin for PDA closure. The
infants were divided into three groups based on enteral
feed volume during treatment: those whose feeds were
held (n=229), those whose feeds were ≤60 mL/kg/day
(n=142), and those whose feeds were >60 mL/kg/day
(n=44). This study found no significant difference in
incidence of NEC (≥ Bell stage IIa) and noted that a
preemptive reduction in enteral feeds was associated
with a significantly longer time to reach full feeds
　　As with intravenous nutrition, enteral nutrient
regimens also must provide sufficient protein to
meet the growth rates of the normally growing fetus
of the same gestational age. Several studies have
noted declining growth and head circumference
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Chin J Contemp Pediatr Jan. 2017
Z-score changes (birth to hospital discharge) by
year of study as human milk (mother’s and donor)
feeding increased [108] . For infants <28-30 weeks
gestation, to provide about 4.0 g/kg/day of protein,
the amount needed to duplicate fetal growth, a protein
concentration of ≥2.8 g/100 mL of milk must be
reached. While mother’s milk primarily, but also
donor milk (secondarily), are the recommended enteral
feeding products for newborn infants, their nutrient
concentrations generally are too low, particularly of
protein, to meet the growth requirements of preterm
thus, protein intakes remain below adequate intake
levels with use of powder fortifiers. Liquid fortifiers
add greater amounts of protein (around 1.7 g of protein
per 100 mL of milk) and satisfactory protein intakes are
achieved most of the time. The customary formulation
to do this involves adding 1 mL of liquid protein
fortifier per 25 mL of milk, which will increase protein
intake by 1 g/kg/day at 150 mL/kg/day of enteral
feeds[109]. This approach increases protein gain and
growth, as nearly all milk but particularly donor milk
contains insufficient amounts of protein, especially
as lactation matures[110-111]. While a systematic review
did not find significant increases in the rate of NEC
.A infants whose mother’s milk was supplemented with
cow milk derived protein fortifiers[112], recent studies
have documented lower rates of NEC when human
milk derived protein fortifiers were used[113].
Summary and recommendation
　　 Growth outcomes of ELBW infants remain
suboptimal, because they are not fed enough,
especially of protein. Early protein losses are
minimized by providing 3-4 g/kg/day of amino acids;
[107]
. less amino acids and protein could lead to neurological
deficits. In general, preterm infants have been fed
excessive energy, which only makes them fatter;
but they still lack essential fatty acids, particularly
the LC PUFAs, particularly DHA. Providing at
least ~70 (intravenous) to 90 (enteral) non-protein
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kcal/kg/day and 3-4 g/kg/day of amino acids or protein
may approximate fetal protein accretion and growth
in reasonably healthy ELBW infants. Late preterm or
moderately preterm infants also receive suboptimal
nutrition and do not grow optimally for the same
reasons—insufficient protein and suboptimal amounts
of mother’s milk with insufficient fortification.
Research also is needed to determine optimal amino
acid and energy supplies in sick infants and those who
have experienced significant intrauterine and postnatal
growth restriction.
　　Only a few pre-discharge intervention studies
to promote growth in preterm infants during their
NICU stay have information on later neurocognitive,
adiposity, and insulin resistance/cardiovascular risk
factor outcomes. Abundant and consistent evidence
from observational studies link faster postnatal
growth to better neurocognitive outcomes in preterm
infants, but these studies show no obvious windows of
association and there is a high risk of confounding by
other factors/disease processes that affect both growth
and cognition. Where associations are reported in
observational studies linking faster postnatal growth to
adverse cardiovascular risk markers in preterm infants,
the findings have often not been adjusted for body size
at the time of the outcome measurements. Moreover,
comparisons were often not made to the normal
ranges of these outcome parameters in unselected
populations. Present evidence suggests that even brief
periods of relative undernutrition during a sensitive
period of development have significant adverse effects
[114]
on later development . produces hyperglycemia, which leads to inflammation
　　It also is worth noting that there still is much yet
to learn about how to optimally feed preterm infants.
The balance of studies, for example, have shown that
growth between birth and expected term and 12-18
months post-term has little or no significant effect on
later blood pressure and metabolic syndrome, whereas
reduced growth during the NICU hospitalization very
clearly adversely impacts later neurodevelopment.
There is, however, a paucity of well-designed,
controlled studies in preterm infants of the effects
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of nutrition during NICU hospitalization and after
discharge on neurodevelopment or the risk of
developing later life disorders such as hypertension,
obesity, or insulin resistance[115]. Further research is
needed to determine the optimal nutrition and rate of
growth in preterm infants that will achieve optimal
neurocognitive benefits while minimizing the longer-
term risk of chronic diseases.
Practical recommendations
　　Normal fetal nutrition is a reasonable guide to the
nutrient requirements for preterm infants of the same
gestational age. Several aspects of fetal nutrition are
important to recognize. First, amino acids are pumped
into the fetus by active transport in the placenta at
rates that are higher than the fetus can use for protein
synthesis and net protein accretion. The excess amino
acid load is oxidized for energy. Secondly, glucose
is taken up and used to meet energy needs according
to the metabolic rate of the fetus, which does not
increase significantly with excess glucose. Excess
glucose not only causes hypoxia and acidosis, but
also leads to various forms of toxicity that impair
insulin secretion and induce cellular and systemic
inflammation. Fetal nutrition, therefore, is designed
for growth and to maintain energy balance. In contrast
“customary” ELBW/VLBW Nutrition is aimed at an
excess of energy and insufficient amounts of protein.
Glucose is pumped into the infant at rates that are
higher than the infant can use. The excess glucose load
and cellular toxicity. Furthermore, amino acids are
provided at rates that are less than needed for normal
growth rates.
　　 To more appropriately support growth of the
preterm infant to meet the growth rates and body
compositions of the normal fetus of the same
gestational age, preterm neonatal nutrition should be
aimed at supporting growth and maintaining energy.
IV nutrition should begin right after birth, and amino
acids should be infused at rates just higher than
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2017 年 1 月
the infant needs (3-4 g/kg/day). The excess amino
acid load will be oxidized, providing useful energy
and diminishing hyperglycemia. Glucose should be
infused to meet glucose needs, adjusting the infusion
rate to maintain normal glucose concentrations (50-
100 mg/dL). Maximum intravenous glucose infusion
rates should not exceed 6-10 mg/kg/min = 27-
42 kcal/kg/day. Lipids should be provided to meet
additional energy (and EFA) needs: 2-3 g/kg/day = 18-
36 kcal/kg/day. Intravenous feeding should be started
right after birth.
　　Enteral feeding should be started as soon as the
[116-117]
infant is stable , but for most preterm infants,
mother’s colostrum should be provided within the
first hour or two after birth, and buccal swabbing
with colostrum should be done immediately to help
establish an appropriate oral and gastrointestinal
[118]
microflora in the infant . Subsequent feeding should
preferably use fresh mother’s milk, with donor milk an
acceptable alternative. Protein (and minerals) should
be used to supplement mother’s milk and especially
donor milk to meet the gestational age-specific protein
requirements necessary for normal fetal growth rates.
Liquid fortifiers provide more protein than powder
fortifiers and they do not lead to infections since they
can be sterilized in contrast to the powder fortifiers.
　　 Trophic or gut priming enteral feeding with
milk should be advanced progressively according
to standard protocols to avoid too many delays or
stopping feedings for events, such as gastric residuals,
that have no bearing on adverse clinical conditions,
particularly necrotizing enterocolitis [119]. An every
3-hour feeding schedule works for most preterm
infants, though there might be an advantage to every
2 hour feeds in the smallest infants. Many studies
and meta-analyses have documented that there is no
increase in the rate of NEC or other major morbidities
when feedings were advanced at 30-35 mL/kg/day vs.
slower rates of advancement(15-20 mL/kg/day[120-121]).
Achieving full enteral feedings sooner reduces the
risk from TPN and infections associated with invasive
catheters [122]
. [11] Hack M, Breslau N, Weissman B, et al. Effect of very low birth
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Chin J Contemp Pediatr Jan. 2017
　　There also is little evidence to support delayed
enteral nutrition, both in terms of starting time after
birth and rate of advancement, in infants who had
IUGR with abnormal antenatal Doppler values,
particularly absent or reversed end diastolic flow
(AREDF) in the umbilical artery, in whom elective
preterm delivery is common[123]. Such infants do have
increased rates of NEC and feeding intolerance, which
indicates that in addition to using fresh mother’s
milk, feedings should not be started until the infant
is physiologically stable, and should be advanced
cautiously, though there is no reason to restrict early
oral colostrum administration both to the buccal
mucosa and into the stomach[124] .
　　 Table 2 below is one example of a feeding
advancement protocol that adjusts for gestational age
and prior growth restriction.
[References]
[1] American Academy of Pediatrics, Committee on Nutrition:
Nutritional needs of low-birth-weight infants[J]. Pediatrics,
1985, 75(5): 976-985.
[2] Hobar JD, Ehrenkranz RA, Badger GJ, et al. Weight growth
velocity and postnatal growth failure in infants 501 to 1500
grams: 2000-2013[J]. Pediatrics, 2015, 136(1): e84-e92.
[3] Lafeber HN, Westerbeek EA, van den Berg A, et al. Nutritional
factors influencing infections in preterm infants[J]. J Nutr, 2008,
138(9): 1813S-1817S.
[4] Bhatia J, Parish A. Nutrition and the lung[J]. Neonatology, 2009,
95(4): 362-367.
[5] Commare CE, Tappenden KA. Development of the infant
intestine: implications for nutrition support[J]. Nutr Clin Pract,
2007, 22(2): 159-173.
[6] Berni Canani R, Passariello A, Buccigrossi V, et al. The
nutritional modulation of the evolving intestine[J]. J Clin
Gastroenterol, 2008, 42(Suppl 3 Pt 2): S197-S200.
[7] Yau KI, Chang MH. Growth and body composition of preterm,
small-for-gestational-age infants at a postmenstrual age of 37-40
weeks[J]. Early Hum Dev, 1993, 33(2): 117-131.
[8] Smart JL. Vulnerability of developing brain to undernutrition[J].
Ups J Med Sci, 1990, 48(Suppl): 21-41.
[9] Smart JL. Critical periods in brain development[M]//Bock GR,
Whelan J. The Childhood Environment and Adult Disease. Ciba
Found Symp, Chichester. Wiley, 1991: 109-128.
[10] Georgieff MK, Hoffman JS, Pereira GR, et al. Effect of neonatal
caloric deprivation on head growth and 1-year developmental
status in preterm infants[J]. J Pediatr, 1985, 107(4): 581-587.
·15·
 第 19 卷 第 1 期 中国当代儿科杂志
2017 年 1 月 Chin J Contemp Pediatr
weight and subnormal head size on cognitive abilities at school
age[J]. N Engl J Med, 1991, 325(4): 231-237.
[12] Ghods E, Kreissl A, Brandstetter S, et al. Head circumference
catch-up growth among preterm very low birth weight infants:
effect on neurodevelopmental outcome[J]. J Perinat Med, 2011,
39 (5): 579-586.
[13] Ehrenkranz RA, Dusick AM, Vohr BR, et al. Growth in the
neonatal intensive care unit influences neurodevelopmental
and growth outcomes of extremely low birth weight infants[J].
Pediatrics, 2006, 117(4): 1253-1261.
[14] Belfort MB, Kuban KC, O'Shea TM, et al; Extremely Low
Gestational Age Newborn (ELGAN) Study Investigators;
Extremely Low Gestational Age Newborn ELGAN Study
Investigators. Weight status in the first 2 years of life and
neurodevelopmental impairment in extremely low gestational
age newborns[J]. J Pediatr, 2016,168(e2): 30-35.
[15] Lodygensky GA, Seghier ML, Warfield SK, et al. Intrauterine
growth restriction affects the preterm infant’s hippocampus[J].
Pediatr Res, 2008, 63(4): 438-443.
[16] Isaacs EB, Gadian DG, Sabatini S, et al. The effect of early
human diet on caudate volumes and IQ[J]. Pediatr Res, 2008,
63(4): 229-231.
[17] Belfort MB, Rifas-Shiman SL, Sullivan T, et al. Infant growth
before and after term: effects on neurodevelopment in preterm
infants[J]. Pediatrics, 2011, 128(4): e899-e906.
[18] Vasu V, Modi N. Assessing the impact of preterm nutrition[J].
Early Hum Dev, 2007, 83 (12): 813-818.
[19] Denne SC. Early nutritional support for extremely premature
infants: what amino acid amount should be given? [J]. Am J
Clin Nutr, 2016, 103(6): 1383-1384.
[20] Denne SC, Poindexter BB. Evidence supporting early nutritional
support with parenteral amino acid infusion[J]. Semin Perinatol,
2007, 31(2): 56-60.
[21] Van Goudoever JB, Colen T, Wattimena JL, et al. Immediate
commencement of amino acid supplementation in preterm
infants: effect on serum amino acid concentrations and protein
kinetics on the first day of life[J]. J Pediatr, 1995, 127(3): 458-
465.
[22] Thureen PJ, Melara D, Fennessey PV, et al. Effect of low versus
high intravenous amino acid intake on very low birth weight
infants in the early neonatal period[J]. Pediatr Res, 2003, 53(1):
24-32.
[23] Poindexter BB, Langer JC, Dusick AM, et al; National
Institute of Child Health and Human Development Neonatal
Research Network. Early provision of parenteral amino acids
in extremely low birth weight infants: relation to growth and
neurodevelopmental outcome[J]. J Pediatr, 2006, 148(3): 300-
305.
[24] Cormack BE, Bloomfield FH. Increased protein intake decreases
postnatal growth faltering in ELBW babies[J]. Arch Dis Child
Fetal Neonatal Ed, 2013, 98(5): F399-F404.
[25] Bolisetty S, Pharande P, Nirthanakumaran L, et al. Improved
nutrient intake following implementation of the consensus
standardised parenteral nutrition formulations in preterm
neonates: a before-after intervention study[J]. BMC Pediatr,
2014, 14: 309-315.
16·
·
Vol.19 No.1
Jan. 2017
[26] Wilson DC, Cairns P, Halliday HL, et al. Randomised controlled
trial of an aggressive nutritional regimen in sick very low
birthweight infants[J]. Arch Dis Child Fetal Neonatal Ed, 1997,
77(1): F4-F11.
[27] Morgan C, McGowan P, Herwitker S, et al. Postnatal head
growth in preterm infants: a randomized controlled parenteral
nutrition study[J]. Pediatrics, 2014, 133(1): e120-e128.
[28] Hay WW Jr, Ziegler EE. Growth failure among preterm infants
is not innocuous and must be prevented. Commentary[J]. J
Perinatol, 2016, 36(7): 500-502.
[29] Poindexter B. Approaches to growth faltering[M]//Koletzko
B, Poindexter B, Uauy R. Nutritional Care of Preterm Infants.
Karger: Basel, 2014: 228-238.
[30] Stoll BJ, Hansen NI, Bell EF, et al; Eunice Kennedy Shriver
National Institute of Child Health and Human Development
Neonatal Research Network. Neonatal outcomes of extremely
preterm infants from the NICHD Neonatal Research Network[J].
Pediatrics, 2010, 126(3): 443-456.
[31] Morgane PJ, Mokler DJ, Galler JR. Effects of prenatal protein
malnutrition on the hippocampal formation[J]. Neurosci
Biobehav Rev, 2002, 26(4): 471-483.
[32] Lucas A, Morley R, Cole TJ, et al. Early diet in preterm babies
and developmental status at 18 months[J]. Lancet, 1990,
335(8704): 1477-1481.
[33] Lucas A, Morley R, Cole TJ. Randomised trial of early diet in
preterm babies and later intelligence quotient[J]. BMJ, 1998,
317(7171): 1481-1487.
[34] Isaacs EB, Morley R, Lucas A. Early diet and general cognitive
outcome at adolescence in children born at or below 30 weeks
gestation[J]. J Pediatr, 2009, 155(2): 229-234.
[35] Tan MJ, Cooke RW. Improving head growth in very preterm
infants–a randomised controlled trial I: neonatal outcomes[J].
Arch Dis Child Fetal Neonatal Ed, 2008, 93(5): F337-F341.
[36] Tan M, Abernethy L, Cooke R. Improving head growth in
preterm infants – a randomised controlled trial II: MRI and
developmental outcomes in the first year[J]. Arch Dis Child
Fetal Neonatal Ed, 2008, 93 (5): F342-F346.
[37] Stephens BE, Walden RV, Gargus RA, et al. First-week protein
and energy intakes are associated with 18-month developmental
outcomes in extremely low birth weight infants[J]. Pediatrics,
2009, 123(5): 1337-1343.
[38] Naeye R, Dixon J. Distortions in fetal growth standards[J].
Pediatr Res, 1978, 12 (10): 987-991.
[39] Fenton TR, Kim JH. A systematic review and meta-analysis
to revise the Fenton growth chart for preterm infants[J]. BMC
Pediatr, 2003, 13: 59.
[40] Olsen IE, Groveman SA, Lawson ML, et al. New intrauterine
growth curves based on United States data[J]. Pediatrics, 2010,
125(2): e214-e224.
[41] Carlson SJ, Ziegler EE. Nutrient intakes and growth of very low
birth weight infants[J]. J Perinatol, 1998, 18(4): 252-258.
[42] Ehrenkranz RA, Younes N, Lemons JA, et al. Longitudinal
growth of hospitalized very low birth weight infants[J].
Pediatrics, 1999, 104(2 Pt 1): 280-289.
[43] Dancis J, O'connell Jr, Holt LE Jr. A grid for recording the
weight of premature infants[J]. J Pediatrics, 1948, 33(1): 570-
 第 19 卷 第 1 期 中国当代儿科杂志
2017 年 1 月 Chin J Contemp Pediatr
572.
[44] Dinerstein A, Solana CL, Perez GP, et al. Early and aggressive
nutritional strategy (parenteral and enteral) decreases postnatal
growth failure in very low birth weight infants[J]. J Perinatol,
2006, 26(7): 436-442.
[45] Kitanaka T, Alonso JG, Gilbert RD, et al. Fetal responses to
long-term hypoxemia in sheep[J]. Am J Physiol, 1989, 256(6 Pt
2): R1348-R1354.
[46] Stockman JA, Clark DA. Weight gain: a response to transfusion
in selected preterm infants[J]. Am J Dis Child, 1984, 138(9):
828-830.
[47] Carver TD, Anderson SM, Aldoretta PA, et al. Glucose
suppression of insulin secretion in chronically hyperglycemic
fetal sheep[J]. Pediatr Res, 1995, 38(5): 754-762.
[48] Hay WW Jr, Sparks JW, Quissell BJ, et al. Simultaneous
measurements of umbilical uptake, fetal utilization rate, and
fetal turnover rate of glucose [J]. Am J Physiol, 1981, 240(6):
E662-E668,.
[49] Zarlengo KM, Battaglia FC, Fennessey P, et al. Relationship
between glucose utilization rate and glucose concentration in
preterm infants[J]. Biol Neonate, 1986, 49(4): 181-189.
[50] Sunehag A, Ewald U, Larsson A, et al. Glucose production rate
in extremely immature neonates (< 28 weeks) studied by use of
deuterated glucose[J]. Pediatr Res, 1993, 33(2): 97-100.
[51] Marconi AM, Paolini C, Buscaglia M, et al.The impact of
gestational age and fetal growth on the maternal-fetal glucose
concentration difference[J]. Obstet Gynecol, 1996, 87(6): 937-
942.
[52] Srinivasan G, Pildes RS, Cattamanchi G, et al. Plasma glucose
values in normal neonates: a new look[J]. J Pediatr, 1986,
109(1): 114-117.
[53] Helms RA, Mauer EC, Hay WW Jr, et al. Effect of intravenous
L-carnitine on growth and fat metabolism parameters during
parenteral nutrition in neonates[J]. JPEN J Parenter Enteral Nutr,
1990,14(5): 448-453.
[54] Sellmayer A, Koletzko B. Long-chain polyunsaturated
fatty acids and eicosanoids in infants – Physiological and
pathophysiological aspects and open questions[J]. Lipids, 1999,
34(2): 199-205.
[55] Carlson SE. Docosahexaenoic acid and arachidonic acid in
infant development[J]. Semin Neonatol, 2001, 6(5): 437-449.
[56] Chacko SK, Ordonez J, Sauer PJ, et al. Gluconeogenesis is not
regulated by either glucose or insulin in extremely low birth
weight infants receiving total parenteral nutrition[J]. J Pediatr,
2011, 158 (6): 891-896.
[57] Lapillonne A, Eleni dit Trolli SE, Kermorvant-Duchemin E.
Postnatal DHA deficiency is an inevitable consequence of
current recommendations and practices in preterm infants[J].
Neonatology, 2010, 98(4): 397-403.
[58] Tam EWY, Chau V, Barkovich AJ, et al. Early postnatal
docosahexaenoic acid levels and improved preterm brain
development[J]. Pediatr Res, 2016, 79(5): 723-730.
[59] Carlson SE, Werkman SH, Rhodes PG, et al. Visual acuity
development in healthy preterm infants: effect of marine oil
supplementation[J]. Am J Clin Nutr, 1993, 58(1): 35-42.
[60] Micheli JL, Schutz Y. Protein[M]//Tsang RC. Nutritional
17·
·
Vol.19 No.1
Jan. 2017
Needs of the Preterm Infant. Pawling, NY: Caduceus Medical
Publishers, 1993: 29-46.
[61] Kashyap S, Forsyth M, Zucker C, et al. Effects of varying
protein and energy intakes on growth and metabolic response in
low birth weight infants[J]. J Pediatr, 1986, 108(6): 955-963.
[62] Vasu V , Thomas EL, Durighel G, et al. Early nutritional
determinants of intrahepatocellular lipid deposition in preterm
infants at term age[J]. Int J Obes (Lond), 2013, 37(4): 500-504.
[63] Olsen IE, Lawson ML, Ferguson AN, et al. BMI curves for
preterm infants[J]. Pediatrics, 2015, 135(3): e572-e581.
[64] Ziegler EE, O'Donnell AM, Nelson SE, et al. Body composition
of the reference fetus[J]. Growth, 1976, 40(4): 329-341.
[65] Embleton ND. Optimal protein and energy intakes in preterm
infants[J]. Early Human Dev, 2007, 83(12): 831-837.
[66] Thureen PJ, Anderson AH, Baron KA, et al. Protein balance in
the first week of life in ventilated neonates receiving parenteral
nutrition[J]. Am J Clin Nutr, 1998, 68(5): 1128-1135.
[67] Morgan C. Early amino acid administration in very preterm
infants: Too little, too late, or too much, too soon? [J]. Semin
Fetal Neonatal Med, 2013, 18: 160-165.
[68] Uthaya S, Modi N. Practical preterm parenteral nutrition:
systematic literature review and recommendations for
practice[J]. Early Human Dev, 2014, 90(11): 747-753.
[69] Clark RH, Chace DH, Spitzer AR; Pediatrix Amino Acid
Study Group. Effects of two different doses of amino acid
supplementation on growth and blood amino acid levels in
premature neonates admitted to the neonatal intensive care unit:
a randomized, controlled trial[J]. Pediatrics, 2007,120(6): 1286-
1296.
[70] Thureen PJ, Hay WW. Early aggressive nutrition in preterm
infants[J]. Semin Neonatol, 2001, 6(5): 403-415.
[71] Embleton ND, Morgan C, King C. Balancing the risks and
benefits of parenteral nutrition for preterm infants: can we define
the optimal composition[J]. Arch Dis Child Fetal Neonatal Ed,
2015, 100(1): F72-F75.
[72] Brown LD, Rozance PJ, Thorn SR, et al. Acute supplementation
of amino acids increases net protein accretion in IUGR fetal
sheep[J]. Am J Physiol Endocrinol Metab, 2012, 303(3):
E352-E364.
[73] Sunehag AL. Hyperglycemia is a risk factor for early death and
morbidity in extremely low birth-weight infants[J]. Pediatrics,
2006, 118(5): 1811-1818.
[74] Stensvold HJ, Strommen K, Lang AM, et al. Early enhanced
parenteral nutrition, hyperglycemia, and death among extremely
low-birth-weight infants[J]. JAMA Pediatr, 2015, 169(11):
1003-1010.
[75] Picard M, Juster RP, McEwen BS. Mitochondrial allostatic load
puts the 'gluc' back in glucocorticoids[J]. Nat Rev Endocrinol,
2014, 10(5): 303-310.
[76] Stoll B, Horst DA, Cui L, et al. Chronic parenteral nutrition
induces hepatic inflammation, steatosis, and insulin resistance in
neonatal pigs[J]. J Nutr, 2010, 140(12): 2193-2200.
[77] Chavez-Valdez R, McGowan J, Cannon E, et al. Contribution of
early glycemic status in the development of severe retinopathy
of prematurity in a cohort of ELBW infants[J]. J Perinatology,
2011, 31(12): 749-756.
 第 19 卷 第 1 期 中国当代儿科杂志
2017 年 1 月 Chin J Contemp Pediatr
[78] Mohsen L, Abou-Alam M, El-Dib M, et al. A prospective
study on hyperglycemia and retinopathy of prematurity[J]. J
Perinatology, 2014, 34(6): 453-457.
[79] Garg R, Agthe AG, Donohue PK, et al. Hyperglycemia and
Retinopathy of Prematurity in Very Low Birth Weight Infants[J].
J Perinatology, 2003, 23(3): 186-194.
[80] Basu SK, Kaiser JR, Guffey D, et al; CoolCap Study Group.
Hypoglycaemia and hyperglycaemia are associated with
unfavourable outcome in infants with hypoxic ischaemic
encephalopathy: a post hoc analysis of the CoolCap Study[J].
Arch Dis Child Fetal Neonatal Ed, 2016, 101(2): F149-F155.
[81] Scheurer JM, Gray HL, Demerath EW, et al. Diminished growth
and lower adiposity in hyperglycemic very low birth weight
neonates at 4 months corrected age[J]. J Perinatol, 2016, 36(2):
145-150.
[82] Hay WW Jr, Brown LD, Rozance PJ, et al. Challenges in
nourishing the intrauterine growth-restricted foetus - Lessons
learned from studies in the intrauterine growth-restricted foetal
sheep[J]. Acta Paediatr, 2016, 105(8): 881-889.
[83] Beardsall K, Vanhaesebrouck S, Ogilvy-Stuart AL, et al. A
randomised controlled trial of early insulin therapy in very low
birth weight infants, "NIRTURE" (neonatal insulin replacement
therapy in Europe) [J]. BMC Pediatr, 2007, 7: 29.
[84] Sadhwani A, Asaro LA, Goldberg C, et al. Impact of tight
glycemic control on neurodevelopmental outcomes at 1 year
of age for children with congenital heart disease: a randomized
controlled trial[J]. J Pediatrics, 2016, 174: 193-198.
[85] Bottino M, Cowett RM, Sinclair JC. Interventions for treatment
of neonatal hyperglycemia in very low birth weight infants[J].
Cochrane Database Syst Rev, 2009, (1): CD007453.
[86] Meetze W, Bowsher R, Compton J, et al. Hyperglycemia in
extremely-low-birth-weight infants[J]. Biol Neonate, 1998,
74(3): 214-21.
[87] Burattini I, Bellagamba MP, Spagnoli C, et al; Marche Neonatal
Network. Targeting 2.5 versus 4 g/kg/day of amino acids for
extremely low birth weight infants: a randomized clinical
trial[J]. J Pediatr, 2013, 163(5): 1278-1282.
[88] Wang H, Khaoustov VI, Krishnan B, et al. Total parenteral
nutrition induces liver steatosis and apoptosis in neonatal
piglets[J]. J Nutr, 2006, 136(10): 2547-2552.
[89] Clark RH, Chace DH, Spitzer AR. Effects of two different doses
of amino acid supplementation on growth and blood amino acid
levels in premature neonates admitted to the neonatal intensive
care unit: a randomized, controlled trial[J]. Pediatrics, 2007,
120(6): 1286-1296.
[90] Uthaya S, Liu X, Babalis D, et al. Nutritional evaluation and
optimisation in neonates: a randomized, double-blind controlled
trial of amino acid regimen and intravenous lipid composition
in preterm parenteral nutrition[J]. Am J Clin Nutr, 2016, 103(6):
1443-1452.
[91] Morgan C, Burgess L. High protein intake does not prevent
low plasma levels of conditionally essential amino acids in
very preterm infants receiving parenteral nutrition[J]. JPEN
J Parenter Enteral Nutr, 2015, Jul 6. pii: 0148607115594009,
Epub ahead of print.
[92] Senterre T, Rigo J. Optimizing early nutritional support based on
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·
Vol.19 No.1
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recent recommendations in VLBW infants and postnatal growth
restriction[J]. J Pediatr Gastroenterol Nutr, 2011, 53(5): 536-
542.
[93] Miller M, Vaidya R, Rastogi D, et al. From parenteral to enteral
nutrition: a nutrition-based approach for evaluation of postnatal
growth failure in preterm infants[J]. J Parenter Enteral Nutr,
2014, 38(4): 489-497.
[94] The SIFT Investigators Group. Early enteral feeding strategies
for very preterm infants: current evidence from Cochrane
reviews[J]. Arch Dis Child Fetal Neonatal Ed, 2013, 98(6):
F470-F472.
[95] Shah SD, Dereddy N, Jones TL, et al. Early versus delayed
human milk fortification in very low birth weight infants-a
randomized controlled trial[J]. J Pediatr, 2016, 174: 126-131.
[96] Casaer MP, Mesotten D, Hermans G, et al. Early versus late
parenteral nutrition in critically ill adults[J]. N Engl J Med,
2011, 365(6): 506-517.
[97] Gramlich L, Kichian K, Pinilla J, et al. Does enteral nutrition
compared to parenteral nutrition result in better outcomes
in critically ill adult patients? A systematic review of the
literature[J]. Nutrition, 2004, 20(10): 843-848.
[98] Seres DS, Valcarcel M, Guillaume M. Advantages of enteral
nutrition over parenteral nutrition[J]. Therap Adv Gastroenterol,
2013, 6(2): 157-167.
[99] Fivez T, Kerklaan D, Mesotten D, et al. Early versus late
parenteral nutrition in critically ill children[J]. N Engl J Med,
2016, 374(12): 1111-1122.
[100] Srinivasan V, Agus MS. Tight glucose control in critically ill
children—a systematic review and metab-analysis[J]. Pediatr
Diabetes, 2014, 15(2): 75-83.
[101] Ohnishi S, Ichiba H, Tanaka Y, et al. Early and intensive
nutritional strategy combining parenteral and enteral feeding
promotes neurodevelopment and growth at 18months of
corrected age and 3years of age in extremely low birth weight
infants[J]. Early Hum Dev, 2016, 100: 35-41.
[102] Liu J, Kong K, Tao Y, et al. Optimal timing for introducing
enteral nutrition in the neonatal intensive care unit[J]. Asia Pac J
Clin Nutr, 2015, 24(2): 219-226.
[103] Owens L, Burrin DG, Berseth CL. Minimal enteral feeding
induces maturation of intestinal motor function but not mucosal
growth in neonatal dogs[J]. J Nutr, 2002, 132(9): 2717-2722.
[104] Morgan J, Young L, McGuire W. Delayed introduction of
progressive enteral feeds to prevent necrotizing enterocolitis in
very low birth weight infants[J]. Cochrane Database Syst Rev,
2011, 16(3): CD001970.
[105] Niinikoski H, Stoll B, Guan X, et al. Onset of small intestinal
atrophy is associated with reduced intestinal blood flow in TPN-
fed neonatal piglets[J]. J Nutr, 2004, 134(6): 1467-1474.
[106] Clyman R, Wickremasinghe A, Jhaveri N, et al. Ductus
Arteriosus Feed or Fast with Indomethacin or Ibuprofen
(DAFFII) Investigators. Enteral feeding during indomethacin
and ibuprofen treatment of a patent ductus arteriosus[J]. J
Pediatr, 2013, 163(2): 406-411.
[107] Louis D, Torgalkar R, Shah J, et al. Enteral feeding during
indomethacin treatment for patent ductus arteriosus: association
with gastrointestinal outcomes[J]. J Perinatol, 2016, 36(7): 544-
 第 19 卷 第 1 期 中国当代儿科杂志
2017 年 1 月 Chin J Contemp Pediatr
548.
[108] Chowning R, Radmacher P, Lewis S, et al. A retrospective
analysis of the effect of human milk on prevention of necrotizing
enterocolitis and postnatal growth[J]. J Perinatol, 2016, 36(3):
221-224.
[109] Ziegler EE. Human milk and human milk fortifiers[J]. World
Rev Nutr Diet, 2014, 110: 215-227.
[110] Arslanoglu S, Moro GE, Ziegler EE; The Wapm Working
Group On Nutrition. Optimization of human milk fortification
for preterm infants: new concepts and recommendations[J]. J
Perinat Med, 2010, 38(3): 233-238.
[111] Rochow N, Fusch G, Choi A, et al. Target fortification of breast
milk with fat, protein, and carbohydrates for preterm infants[J].
J Pediatrics, 2013, 163(4): 1001-1007.
[112] Kuschel CA, Harding JE. Multicomponent fortified human milk
for promoting growth in preterm infants[J]. Cochrane Database
Syst Rev, 2004, (1): CD000343.
[113] Sullivan S, Schanler RJ, Kim JH, et al. An exclusively human
milk-based diet is associated with a lower rate of necrotizing
enterocolitis than a diet of human milk and bovine milk-based
products[J]. J Pediatr, 2010, 156(4): 562.e1-567.e1.
[114] Ong KK, Kennedy K, Castañeda-Gutiérrez E, et al. Postnatal
growth in preterm infants and later health outcomes: a
systematic review[J]. Acta Paediatr, 2015, 104(10): 974-986.
[115] Lapillone A, Griffin IJ. Feeding preterm infants today for later
metabolic and cardiovascular outcomes[J]. J Pediatr, 2013,
162(3 Suppl): S7-S16.
[116] Leaf A. Introducing enteral feeds in the high-risk preterm
附 "Optimizing nutrition of the preterm infant" 一文的中文摘译
早产儿营养的最优化 （黑明燕 摘译）
［摘要］　早产儿营养补给的目标是使早产儿能够达到同胎龄健康胎儿的正常生长速率，并且在器官生长、
组织成分、以及细胞数量和结构方面也能达到健康胎儿水平。营养物质的数量与质量对于早产儿的正常生长发
育、包括神经系统发育是至关重要的。基本营养素的供给不足不仅会造成生长受限，而且会增加病死率或影响
神经发育结局。早产儿在 NICU 住院期间的生长速率在神经发育及整个人体发育的结局中发挥了重要作用。尽
管对于最佳营养的需求非常明显，但早产儿生长落后的例子比比皆是。因此，根据总的能量及蛋白质需求以及
个体成分如氨基酸、碳水化合物及脂肪，甚至细化到氧气的需求来优化早产儿的营养是非常必要的。该综述阐
述了早产儿科学合理的营养需求、具有实用性的营养指南以及早产儿静脉营养、肠内营养的方法步骤。包括氨
基酸在内的静脉营养，应该从一出生便按照相应胎龄所适合的速率开始补充。肠内营养则应在出生后尽早开始，
首选母亲的初乳和牛奶。肠内营养应根据热能需要开始建立并在能耐受的范围内快速增加，保持营养摄入在推
荐速率的同时相应地减少静脉营养摄入量。制定一个合理的喂养方案对于改善营养状况及相关的转归是重要的。
什么是早产儿的最佳营养和生长速率尚有待于进一步的研究来确定，这种最佳营养不仅能使早产儿神经认知得
到最充分的发育，同时还要最大程度地限制其远期发生慢性疾病的风险。
［关键词］ 静脉营养；胃肠外营养；肠内营养；氨基酸；葡萄糖；脂肪；坏死性小肠结肠炎；早产儿
1　概述
早产儿营养补给的目标是达到同胎龄健康胎儿的
正常生长速率。基本营养素的供给不足不仅会造成生长
受限，同时会导致免疫防御不足而增加早产儿对感染性
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infant[J]. Semin Fetal Neonatal Med, 2013, 18: 150-154.
[117] Dutta S, Singh B, Chessell L, et al. Guidelines for feeding very
low birth weight infants[J]. Nutrients, 2015, 7(1): 423-442.
[118] Rodriguez NA, Meier PP, Groer MW, et al. A pilot study
to determine the safety and feasibility of oropharyngeal
administration of own mother’s colostrum to extremely low-
birth-weight infants[J]. Adv Neonatal Care, 2010, 10(4): 206-
212.
[119] Rochow N, Fusch G, Muhlinghaus A, et al. A nutritional
program to improve outcome of very low birth weight infants[J].
Clin Nutr, 2012, 31(1): 124-131.
[120] Morgan J, Young L, McGuire W. Slow advancement of enteral
feed volumes to prevent necrotizing enterocolitis in very low
birth weight infants[J]. Cochrane Database Syst Rev, 2011,
16(3): CD001241.
[121] Dorling J. How quickly should we aim for full milk feeds? [J].
Infant, 2012, 8: 167168.
[122] Härtel C, Haase B, Browning-Carmo K, et al. Does the enteral
feeding advancement affect short-term outcomes in very low
birth weight infants? [J]. J Pediatr Gastroenterol Nutr, 2009,
48(4): 464-470.
[123] Mihatsch WA, Pohlandt F, Franz AR, et al. Early feeding
advancement in very low-birth-weight infants with intrauterine
growth retardation and increased umbilical artery resistance[J]. J
Pediatr Gastroenterol Nutr, 2002, 35(2): 144-148.
[124] Dorling J, Kempley S, Leaf A. Feeding growth restricted
preterm infants with abnormal antenatal Doppler results[J]. Arch
Dis Child Fetal Neonatal Ed, 2005, 90(5): F359-F363.
疾病的易感性，增加呼吸窘迫的发生率，降低损伤组织
的修复能力以及影响大脑发育。神经元发育障碍可能是
早产儿营养缺失所造成的最严重的后遗症，可导致认知
缺陷，神经发育结局的改善与早产儿营养状况的提高相
关。
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2017 年 1 月 Chin J Contemp Pediatr
根据总的能量及蛋白质需求以及个体成分如氨基
酸、碳水化合物及脂肪，甚至细化到氧气的需求来优化
早产儿的营养是非常必要的。临床上给早产儿提供充
足的营养一直面临着挑战，特别是早产儿刚出生时依
赖静脉营养的情况下，此时蛋白质储存的降低每天可
达 1.5%。在出生后最初 5 d 保证每天至少 3 g/kg 氨基酸
摄入量可以减少极低出生体重早产儿的蛋白质分解和缺
失，并可提高蛋白质平衡和生长结局。营养物质的数量
与质量对于早产儿的正常生长发育（包括神经系统发育
的结局）至关重要，但临床上早产儿生长发育受限的现
象较普遍。早产儿在 NICU 住院期间的生长速率在早产
儿神经系统发育结局和体型发育方面发挥了关键的、不
可被取代的作用。Lucas 等的研究显示，给予 4 周充足
剂量的蛋白质及能量的早产儿，在纠正胎龄 18 个月时
生长发育及神经发育得到明显改善，7.5 岁时的认知能
力高于对照组，16 岁时头颅 MRI 影像学检查显示其头
围和尾状核体积高于对照组且智商（IQ）评分较高。
然而目前的营养方案仍很难实现早产儿最佳营养
管理从而达到最佳生长发育状态，因此，有必要重新评
估早产儿应该达到的生长率以及实现该生长率的基本营
养需求。
2　关于早产儿生长速度
直接测量正常的胎儿生长是不可能的。目前根
据貌似“正常”的存活早产儿间接估算的数据，妊娠
24~38 周胎儿体重平均增加 17 g/kg/d（图 1），但实际
上大多数早产儿出生后达不到宫内生长的速度（图 2），
主要的原因就是营养不足（图 3）。首先，大多数早产
儿出生后第一日（甚至数日）的静脉氨基酸量很低甚至
没有；其次，开始肠内喂养的时间滞后；第三，大多数
婴儿只能耐受有限的营养支持，如静脉氨基酸的输注率
<3 g/kg/d；第四，在开始营养支持后，静脉氨基酸、脂
类和肠内营养的增加都很缓慢；第五，大部分婴儿应用
的是未强化母乳或必需氨基酸含量不足的完全胃肠外营
养。多数情况下人们只是假设生理上尚不稳定的早产儿
不能承受正常量肠外或肠内营养。
3　关于全静脉注射
氨基酸：应在生后 2~3 h 内开始注射至少 2 g/kg/d
的氨基酸，<30 周孕龄的早产儿应在第一个 24 ~ 48 h 增
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加至 3.5~4 g/kg/d（极低出生体重儿 <27 周妊娠增加至
4 g/kg/d）。
葡萄糖：出生后葡萄糖（10% 葡萄糖液）的输注
速度应以新生儿能耐受且不引起高血糖的最大速率予以
输注，以防低血糖的发生。高血糖的定义为出生后任意
血糖浓度 >120 mg/dL。出生后 1 h 到几天，各种应激反
应导致体内去甲肾上腺素和皮质醇的水平较高，因此葡
萄糖输注过快时（> 6~8 mg/kg/min）会造成高血糖。早
产儿高血糖是加重全身炎症反应的潜在因素，且高血糖
的早产儿患视网膜病变的风险增加。
脂质：静脉脂质输注应在出生后 24 h 内开始，并
提高到可耐受的 2.0 至 3.0~3.5 g/kg/d，通常持续 2~3 d。
静脉中的脂质为氧化代谢提供了碳，并且提供了有利于
全身细胞特别是脑组织细胞膜的合成所需的脂肪酸。但
是，过多的脂质输注会导致高甘油三酯血症（定义为任
意血甘油三酯浓度大于 150 mg/dL），会导致脂质的不
良沉积及肝细胞发生炎症，这可能也是长期静脉营养的
患儿常发生胆管性黄疸和肝衰竭的原因。极低出生体重
儿清除血浆脂质的能力降低，建议出生后头几天的脂质
输注率为 0.5~1.0 g/kg/d，特别是合并感染、严重肺疾病、
外科应激、使用激素时。
热 卡： 第 1 天 为 50 kcal/kg/d， 至 第 3 天 应 达 到
80 kcal/kg/d。
4　关于静脉营养向肠内营养的过渡
在肠外营养向肠内营养过渡期间，由于营养摄入
量的暂时性下降，蛋白质和能量的摄入可能会下降。解
决这一问题的办法是尽快增加肠内营养和应用母乳强化
剂。母乳强化剂可在肠内喂养量达到 50 mL/kg/d 时就开
始。一项对 100 个极低出生体重儿的随机研究显示，在
肠内喂养量仅 20 mL/kg/d 的时候就开始早期添加母乳强
化剂，与肠内喂养达到 100 mL/kg/d 后才开始添加母乳
强化剂相比，早期开始添加母乳强化剂的婴儿在第 1、2、
3 周龄的每日蛋白摄入量更高，在第 4 周龄的累计蛋白
摄入量也更高，但两组在达到完全喂养量所需的天数、
喂养耐受和坏死性小肠结肠炎发生率方面没有差异。
5　关于肠内营养
长时间肠外营养可导致感染率增加（由于免疫抑
制、肠道菌群失调以及中心静脉置管相关的细菌感染几
 第 19 卷 第 1 期 中国当代儿科杂志 Vol.19 No.1
2017 年 1 月 Chin J Contemp Pediatr Jan. 2017

率增加）、肠黏膜萎缩、肠道分泌的消化酶减少、心肝 地维持早产儿的生长以达到相同胎龄儿的生长速率和身
脂肪浸润增加、全身炎症反应综合征、IgA 减少等。在 体成分，早产儿的营养应旨在支持生长和维持能量。静
成人和年长儿、足月儿的研究中，当肠内营养受限而静 脉营养应在出生后立即开始，并且氨基酸的输注率应稍
脉营养过多时，多种疾病的发生率或病死率均增加。这 高于婴儿所需（3~4 g/kg/d），这样有助于减少高血糖的
些问题很可能是过多输注葡萄糖导致高血糖的结果。尽 发生。葡萄糖的供给应满足机体需要、维持正常的血糖
早开始肠内营养，同时适度给予静脉营养才是有益的。 浓度（50~100 mg/dL），葡萄糖静脉输注的最大速度应
与静脉营养一样，肠内营养应提供可以满足相 不超过 10 mg/kg/min（27~42 kcal/kg/d）。脂质供给应满
同 胎 龄 胎 儿 正 常 生 长 发 育 所 需 的 蛋 白 质。 对 于 胎 龄 足额外的能量的需要：2~3 g/kg/d（18~36 kcal/kg/d）。
<28~30 周的婴儿，必须提供≥ 2.9 g/100 mL 蛋白浓度的 肠内喂养应在婴儿稳定后尽早开始。对于大多数
奶，以满足胎儿生长所需的 4.0 g/kg/d 的蛋白质。尽管 早产儿，在出生后的 1~2 h 内可予以口服初乳，并且立
母亲的母乳（首选）或供者的母乳（次选）都是新生儿 即再在口颊部位用初乳进行涂抹，这样做将有助于早产
肠内营养所推荐的食物，但它们的营养素浓度特别是蛋 儿建立正常的口腔和肠道菌群。后续的喂养则最好使用
白质的浓度太低，不能满足早产儿的生长需求。液体母 新鲜的母乳，在亲母母乳不足时，也可选用捐赠母乳。
乳强化剂与粉状母乳强化剂相比，液体强化剂可以添加 可在母乳中添加母乳强化剂以增加蛋白质和矿物质的含
的蛋白质较多（每 100 mL 牛奶大约 1.7 g 蛋白质），通 量，液体母乳强化剂比粉末母乳强化剂提供的蛋白质更
常可达到满意的蛋白摄入量。 多且不会导致感染，因为液体母乳强化剂可被消毒而粉
液态母乳强化剂的添加量为每 25 mL 奶加 1 mL 母 末状母乳强化剂不易消毒。
乳强化剂，肠内喂养 150 mL/kg/d 添加了强化剂的母乳， 肠内喂养量应按照喂养指南的要求逐步增加，要
可提高 1 g/kg/d 的蛋白摄入量。系统回顾研究并未发现 尽量避免因婴儿存在胃残留 , 或担心坏死性小肠结肠炎
牛奶来源的母乳强化剂可导致婴儿坏死性小肠结肠炎的 的发生而延迟或停止肠内营养。每 3 h 喂一次的方法适
发生率提高。最新研究发现，使用人乳来源的母乳强化 用于大部分早产儿。关于加奶速度，临床研究和 Meta
剂时婴儿坏死性小肠结肠炎的发生率更低。 分析结果显示，以 30~35 mL/kg/d 的速度增加肠内喂养
量与以 15~20 mL/kg/d 的速度增加肠内喂养量相比，坏
6　其他建议 死性小肠结肠炎的发生率并没有增加。对于产前脐血彩
超不正常（特别是脐动脉血液断流或者母胎输血）的宫
胎儿营养是专为生长和维持能量平衡设计的，应 内生长受限患儿，尽管坏死性小肠结肠炎或喂养不耐受
注意到胎儿营养的以下几个方面的问题：首先，氨基酸 的风险会增加，但目前没有证据显示对这部分早产儿需
是在胎盘以主动转运的方式摄入到胎儿体内的，其速率 延迟开奶或减慢肠内喂养添加速度。所有早产儿都可以
高于胎儿蛋白质合成及净蛋白累积所需；其次，葡萄糖 尽早开始应用初乳进行口腔颊黏膜的擦拭。
的摄入和利用依据的是胎儿代谢所需的热卡。为了更好
（本文编辑：邓芳明）

· 21·
713202
research-article2017
PENXXX10.1177/0148607117713202Journal of Parenteral and Enteral NutritionKoo and Tice

Original Communication
Journal of Parenteral and Enteral
Nutrition
Human Milk Fortifiers Do Not Meet the Current Volume XX Number X
Month 201X 1­–8
Recommendation for Nutrients in Very Low © 2017 American Society

Birth Weight Infants for Parenteral and Enteral Nutrition

DOI: 10.1177/0148607117713202
https://doi.org/10.1177/0148607117713202
journals.sagepub.com/home/pen

Winston Koo, MBBS1,2; and Hilary Tice, PharmD1,3

Abstract
Background: Use of multinutrient fortifiers is standard of care for small preterm infants fed exclusively human milk. However, adequacy
of human milk fortifiers (HMFs) to meet the recommended intake for macronutrients and micronutrients is now known. Materials and
Methods: Nutrient content of human milk fortified according to manufacturer’s recommendations was compared at isocaloric levels for 1
human milk–based (HMF-A), 2 bovine milk protein–based (HMF-B, HMF-C), and 2 preterm infant formulas (PTF-B, PTF-C). In addition,
4 multivitamin supplements were compared. Results: At 130 kcal/kg, intake of macronutrients was similar to the recommendation,
although deficient and excess intake of micronutrient occurred with all fortifiers. Four to 9 micronutrients were absent in HMF or PTF
(biotin, choline, inositol, carnitine, taurine, molybdenum, iodine, selenium, or chromium). For the remainder, HMF resulted in deficient
intake for 1–13 micronutrients, occurring most frequently with HMF-A. Excess micronutrients (3–15 at <50% and 1–3 at 109%–437%)
occurred with all HMF and most frequently with HMF-B and HMF-C. At 150 kcal/kg, deficient intake improved but generally remained
below recommendation, while excess intake became exaggerated. PTF and multivitamin formulations do not fully compensate for the
deficiencies and can result in extremely high micronutrient intake. Conclusions: At the recommended energy intake for very low birth
weight infants, many micronutrients are absent or are present in grossly inadequate amounts, and several micronutrients are in excess.
Reformulation of HMF is urgently needed since PTF or multivitamin supplement only partially corrects some deficiencies while providing
some nutrients in excess. (JPEN J Parenter Enteral Nutr. XXXX;xx:xx-xx)

Keywords
prematurity; human milk; human milk fortifier; vitamin supplement; preterm infant formula; micronutrients; macronutrients; milk
fortification; very low birth weight

Clinical Relevancy Statement
Nutrition support of small preterm infants receiving human
milk includes fortification with multiple nutrients. Knowledge
of the limitations of various commercial human milk fortifiers
to meet the recommended intake for macronutrients and micro-
nutrients allows the industry to make necessary formulation
changes to improve the nutrition support of infants most vul-
nerable to the ill effects from deficient or excess intake of
nutrients.
nutrition support of all VLBW infants fed own mother’s milk
or donor human milk.3-5
For VLBW infants, recommended ranges of intake to mini-
mize the risk of nutrition deficiency and excess are
available.1,2,6,7 Multiple commercial human milk–based or
bovine milk protein–based human milk fortifiers (HMFs) as liq-
uid or powder preparations and nutrient-enriched preterm infant
formulas (PTFs) are used as fortification of human milk.
However, there is a lack of comparative data on the adequacy to

From the 1Department of Pediatrics, Louisiana State University Health

Background
Nutrition support for the small preterm infant is complicated at
birth by the low or absent nutrient reserve and after birth by
issues related to delivery, tolerance, and utilization of the nutri-
ents and by greater demands of nutrients for catch-up growth
after recovery from illnesses. Deficiencies in energy, macronu-
trients, and multiple micronutrients are well documented to
have adverse effects on physiologic function and postnatal
growth of very low birth weight (VLBW) infants (<1500 g).1,2
Small preterm infants fed exclusively human milk are at risk
for deficiency of multiple nutrients, and the use of fortifiers
containing multiple nutrients is now the standard of care in the
Sciences Center, Shreveport, Louisiana, USA; 2Department of Nutrition
and Food Science, Wayne State University, Detroit, Michigan, USA; and
the 3Department of Clinical Sciences, University of Louisiana, Monroe,
Louisiana, USA
Financial disclosure: None declared.
Conflicts of interest: None declared.
Received for publication March 23, 2017; accepted for publication May
11, 2017.
Corresponding Author:
Winston Koo, MBBS, Department of Nutrition and Food Science, Wayne
State University, Detroit, MI 48202, USA.
Email: wkoo@lsuhsc.edu
2 Journal of Parenteral and Enteral Nutrition XX(X)
provide the recommended quantity of macronutrients and micro-
nutrients from the use of different HMFs or PTFs as fortification
of human milk for VLBW infants. The goal of this study is to
determine whether the nutrient contents of human milk after for-
tification with different commercial HMFs or PTFs can meet the
current recommended range of intake.2
Materials and Methods
Data for the nutrients from HMF were based on the final con-
tent in the human milk fortified according to the HMF manu-
facturer’s recommendation. These data were obtained from
product information at the manufacturer’s website, and nutri-
ent contents were calculated and compared according to the
energy intake recommended by the American Academy of
Pediatrics Committee of Nutrition.2 Data for liquid and powder
(where available) HMF were obtained. In addition, the nutrient
content of human milk fortified by PTF with the highest energy
content (≈1 kcal/mL) as recommended by manufacturers at the
volume ratio of 1:1 with human milk was obtained via the
same procedure. The macronutrient and micronutrient data
were compared with the recommended enteral intake2 at isoca-
loric levels.
Data on commercial infant multivitamins preparations were
obtained from Lexicomp Pediatric and Neonatal Lexi-Drugs
(http://online.lexi.com). All websites were accessed multiple
times, and data were confirmed by both investigators and an
assistant.
Results
There are 3 manufacturers of HMF in the United States. One
HMF is human milk based (HMF-A: Prolacta Bioscience,
Monrovia, CA; www.prolacta.com) and is available only as a
liquid preparation. Two HMFs are bovine milk protein based
(HMF-B and HMF-C) and are available as liquid and powder
preparations. HMF-B is from Ross Products (Abbott Lab,
Columbus, OH; www.abbottnutrition.com), and HMF-C is
from Mead Johnson Nutritional (Evansville, IN; www.enfamil.
com). PTFs (PTF-B, PTF-C) from the aforementioned manu-
facturers also are recommended by the manufacturers as forti-
fiers for human milk.
In addition to the recommended intake for enteral protein,
fat, and carbohydrate, there are recommendations for the
enteral intake of 31 micronutrients,2 including 4 fat-soluble
vitamins, 9 water-soluble vitamins, 4 other organic com-
pounds, 8 trace minerals, and 3 electrolytes. However, differ-
ent manufacturers have 4–9 micronutrients absent from HMFs
or PTFs (Table 1).
For infants with weights 1–1.5 kg, the recommended ranges
of enteral intake/kg/d for energy (110–130 kcal), protein (3.4–
4.2 g), fat (5.3–7.2 g), and carbohydrate (7–17 g) are slightly
lower than the recommended ranges for infants with weights
<1 kg: energy (130–150 kcal), protein (3.8–4.4 g), fat (6.2–8.4
g), and carbohydrate (9–20 g).2 The recommended ranges of
intake of micronutrients are the same for all VLBW infants.2
However, there is a range of recommended intakes for indi-
vidual micronutrients, as indicated by the difference between
the upper and lower recommended intakes for fat-soluble vita-
mins (A = 114%, D = 167%, E = 100%, K = 25%), water-solu-
ble vitamins (B1 = 33%, B2 = 44%, B3 = 33%, B5 = 42%, B6 =
40%, B7 = 67%, B9 = 100%, B12 = 0%, C = 33%), other organic
compounds (choline = 94%, inositol = 153%, carnitine = 0,
taurine = 100%), minerals (Ca = 120%, P = 133%, Mg = 90%),
trace minerals (Fe = 100%, Mo = 0%, Zn = 200%, Cu = 25%,
I = 500%, Se = 246%, Mn = 1007%, Cr = 125%), and electro-
lytes (Na = 67%, K = 50%, Cl = 133%).
There are 2 commercial liquid fortifiers from 1 manufac-
turer (Ross Products; HMF hydrolyzed protein–concentrated
liquid and HMF-concentrated liquid). While these products
have similar energy content, the former provides slightly
higher protein and lower fat and carbohydrate content and
some minor variability in micronutrient content. For the pur-
pose of comparison, only the former product is used in this
report. Furthermore, comparison of HMFs from various manu-
facturers is based on the use of liquid products.
Based on the standard fortifications recommended by manu-
facturers, the percentage differences between the macronutri-
ents and micronutrients in human milk after fortification versus
the recommended intake2 are shown in Table 2. When human
milk was fortified to the recommended caloric intake of 130
kcal/kg for VLBW infants, HMF-A provided lower than the
recommended minimum quantity of protein, all fat-soluble
vitamins, all water-soluble vitamins, and Fe but higher than the
maximum recommended quantity of K, Cu, and Mn. However,
HMF-B provided lower than the recommended quantity of ino-
sitol, Na, and Fe but higher than the recommended quantity of
2 fat-soluble vitamins, 8 water-soluble vitamins, Mg, P, Cu, and
Mn. HMF-C provided lower than the recommended quantity of
Mg but higher than the recommended quantity of protein, 2 fat-
soluble vitamins, 5 water-soluble vitamins, K, and Mn. At the
upper recommended caloric intake of 150 kcal/kg, HMF-C was
the only HMF that achieved greater than the recommended
minimum micronutrient intake, whereas excess intake of micro-
nutrients from all HMF became exaggerated (Table 2).
Based on the maximum amount of HMF or the use of PTF
to fortify human milk as recommended by manufacturers, the
percentage differences between the fortified human milk and
the recommended intake2 for various macronutrients and
micronutrients are shown in Table 3. At the caloric intake of
130 kcal/kg, HMF-A provides protein content at slightly higher
than the maximum recommended quantity, although the pat-
tern of micronutrient deficiencies and excesses remains similar
to the use of standard volumes of HMF-A. However, the use of
PTF-B provided lower than the recommended quantity of
protein, vitamins D and E, Na, and Fe but higher than the
Koo and Tice 3

Table 1.  AAPCON Recommended Intake of Micronutrients as Compared With the Composition of Commercial Human Milk
Fortifiers.

Commercial Liquid Human Milk Fortifiers

a
AAPCON Recommendation HMF-A HMF-B HMF-C PTF-B PTF-C
Fat-soluble vitamins A, D, E, K All All All All All
Water-soluble vitamins B1 (thiamin), B2 No biotin All All All All
(riboflavin), B3 (niacin), B5 (pantothenic
acid), B6, B7 (biotin), B9 (folate), B12, and C
Choline, inositol, carnitine, taurine None No carnitine or None No carnitine No carnitine or
taurine or taurine taurine
Calcium, magnesium, phosphorus All All All All All
Sodium, potassium, chloride All All All All All
Iron, zinc, copper, manganese, iodine Mo, Cr, I, Mo, Cr: absent Mo, Cr, I, Mo, Cr: absent Mo, Cr: absent
(I), selenium (Se), molybdenum (Mo), Se: absent Se: absent
chromium (Cr)

AAPCON, American Academy of Pediatrics Committee of Nutrition; HMF-A, human milk–based fortifier from Prolacta Bioscience (Monrovia, CA);
HMF-B, bovine milk protein–based fortifier from Ross Products (Abbott Lab, Columbus, OH); HMF-C, bovine milk protein–based fortifier from Mead
Johnson Nutritional (Evansville, IN); PTF-B and PTF-C, preterm infant formula at energy density of ≈1 kcal/mL from same manufacturers as HMF-B
and HMF-C, respectively.
a
Recommended enteral intake for very low birth weight infants.

recommended quantity of 5 water-soluble vitamins, K, Cu and Discussion

Mn. PTF-C provided lower than the recommended quantity of
protein, vitamins E and K, and 6 water-soluble vitamins. At the
upper recommended caloric intake of 150 kcal/kg, HMF-A
provided higher than the maximum range of protein and fat but
a similar pattern of micronutrient deficiencies and excesses
when compared with the lower energy intake of 130 kcal/kg.
PTF fortification of human milk provided macronutrients at
the recommended range or higher, while the extent of micronu-
trient deficiencies improved but the micronutrient excesses
became exaggerated (Table 3).
The compositions of powder and liquid formulation of
HMF from the same manufacturer were the same. However,
the quantity of most nutrients for the powder HMF is some-
what higher than the liquid HMF, and the pattern of differences
of fortified milk from the recommended intake2 was similar
regardless of the liquid or powder formulation used.
There are 4 commercial infant multivitamin preparations
available: Poly-Vi-Sol with iron (Mead Johnson & Co, LLC,
Evansville, IN), Quflora (CarWin Pharmaceutical Associates,
LLC, Slidell, LA), Floriva Plus (BonGeo Pharmaceuticals, Inc,
Roseland, NJ), and AquADEKs (Actavis Pharma, Inc,
Parsippany, NJ). When supplemented at 1 mL daily to the
human milk fortified with standard volume of HMF-A at 130
kcal/kg, none of the preparations can correct all micronutrient
deficiencies, while 2 multivitamin products could not provide
the minimum recommended intake for ≥1 water-soluble vita-
mins. All preparations resulted in higher than the maximum
recommended intake of multiple fat-soluble vitamins by 6%–
3900%, water-soluble vitamins by 72%–610%, and mineral
and trace minerals by 43%–688% (Table 4).
There are numerous potential benefits to exclusive human milk
feeding for VLBW infants,3 but its use alone, even at very high
volumes, is associated with deficits in the intake of energy and
multiple nutrients, which results in significant growth restric-
tion during an infant’s stay in the neonatal intensive care unit.
Much progress has been made to minimize the energy and
macronutrient deficit by starting parenteral nutrition within
hours of birth and with early transition to enteral feeding. In
contrast, data to define the needs of many micronutrients are
relatively limited, but sufficient data, albeit incomplete, are
available to generate consensus on recommended intake for 31
micronutrients.1,2
The commercial availability of HMF provided a means to
minimize the deficit in energy, macronutrients, and micronutri-
ents for human milk–fed VLBW infants and is the standard of
care in neonative intensive care unit.3-5 However, postnatal
growth deficit continues despite the routine use of HMF and
early transition to enteral feeding.8,9 Compared with the use of
PTFs, the extent of growth deficit increases with increased vol-
ume of fortified human milk consumed by VLBW infants.8,9
To our knowledge, this is the first systematic review of
commercially available HMFs in the United States to deter-
mine whether their use in recommended quantities can meet
the recommended intake for specific nutrients.2 The liquid-
based HMF was used as the principal source for comparison
among manufacturers because of its superiority in maintaining
sterility compared with powder HMF, although it limits the
volume of human milk to about 80% of desired fluid goal due
to the volume of displacement by liquid HMF. Comparison at
4
Table 2.  Percentage Difference in Macronutrients and Micronutrients in Fortified Human Milk Versus the Recommended Enteral Intake at 2 Isocaloric Levels (130 vs 150 kcal/
kg) Based on the Use of Standard Volume of Human Milk Fortifiers Recommended by the Manufacturers.a

Energy, 130 kcal/kg Energy, 150 kcal/kg

Nutrients HMF-A HMF-B HMF-C HMF-A HMF-B HMF-C

Fortifier:human milk, mL 5:20 5:25 5:25 5:20 5:25 5:25
b
Macronutrients
Protein −4 6 18 WR 22 36
Fat WR WR WR 7 WR 7
Carbohydrate WR WR WR WR WR WR
Micronutrientsc
Fat-soluble vitamins A, D, E, K A, –16; D, –71; E, A, 7; K, 34 A, 8; K, 3 A, –3; D, –66; E, A, 24; K, 55 A, 25; K, 19
–65; K, –95 –60; K, –94
Water-soluble vitamins B1, B2, B3, B5, B6, B7, absent; B1, –82; B1, 21; B2, 31; B3, B1, 8; B2, 8; B3, 8; B7, absent; B1, B1, 40; B2, 51; B3, B1, 25; B2, 25; B3,
B7, B9, B12, C B2, –66; B3, –92; 16; B5, 14; B6, B12, 195, C, 14 –79; B2, –61; B3, 34; B5, 32; B6, 61; 25; B5, 5; B6, 8;
B5, –71; B6, –83; 40; B7, 437; B12, –91; B5, –67; B6, B7, 520; B12, 200, B9, 5; B12, 240,
B9, –49; B12, –57, 160, C, 137 –81; B9, –41; B12, C, 173 C, 31
C, –23, –50, C, –12
Choline, inositol (Ino), carnitine (Car), Absent Car, Tau: absent; Absent Absent Car, Tau: absent Absent
taurine (Tau) Ino, –8
Calcium (Ca), magnesium (Mg), WR P, 18; Mg, 5 Mg, –13 Ca, 2 Ca, 4; P, 36; Mg, 21 WR
phosphorus (P)
Sodium (Na), potassium (K), chloride (Cl) K, 30 Na, –11; K, 64 K, 9 K, 50 K, 90 K, 26
Iron (Fe), zinc, copper (Cu), manganese Mo, Cr, I, Se: Mo, Cr: absent; Mo, Cr, I, Se: Mo, Cr, I, Se: Mo, Cr: absent; Mo, Cr, I, Se:
(Mn), iodine (I), selenium (Se), absent; Fe, –84; Fe, –62; Cu, 14; absent; Mn, 79 absent; Fe, –82; Fe, –56; Cu, 31; absent; Cu, 1;
molybdenum (Mo), chromium (Cr) Cu, 21; Mn, 109 Mn, 66 Cu, 40; Mn, 152 Mn, 92 Mn, 107

HMF-A, human milk–based fortifier from Prolacta Bioscience (Monrovia, CA); HMF-B, bovine milk protein–based fortifier from Ross Products (Abbott Lab, Columbus, OH); HMF-C, bovine milk
protein–based fortifier from Mead Johnson Nutritional (Evansville, IN); WR, within range of recommended intake.
a
Content of each nutrient is within the range recommended by American Academy of Pediatrics Committee of Nutrition2 unless there is a trailing number which indicates the percent above the maximum
or below the minimum (as indicated by negative symbol) recommended.
b
Intake of macronutrients versus the recommended intake2 for infants with weights <1 kg.
c
Intake of micronutrients versus the recommended intake2 for all infants with weights ≤1.5 kg.
 Table 3.  Percentage Difference in Macronutrients and Micronutrients in Fortified Human Milk Versus the Recommended Enteral Intake at 2 Isocaloric Levels (130 vs 150 kcal/
kg) Based on the Use of Maximum Volume of Human Milk Fortifier or Preterm Infant Formula Recommended by the Manufacturers.a

Energy, 130 kcal/kg Energy, 150 kcal/kg

Nutrients HMF-A PTF-B PTF-C HMF-A PTF-B PTF-C

Fortifier:human milk, mL 50:50 50:50 50:50 50:50 50:50 50:50
Macronutrientsb
Protein 5 −9 −4 21 WR WR
Fat WR WR WR 12 13 WR
Carbohydrate WR WR WR WR WR WR
Micronutrientsc
Fat-soluble vitamins A, D, E, K A, –38; D, –45; E, D, –20; E, –32 E, –4; K, –10 A, –28; D, –37; E, D, –7; E, –22; K, 8 A, 4
–68; K, –95 –63; K, –94
Water-soluble vitamins B1, B2, B3, B5, B6, B7, B9, B7: absent; B1, –86; B2, 49; B6, 4; B7, B1, –4; B3, –10; B5, B7: absent; B1, B1, 2; B2, 72; B5, 6; B6, –1; B7, –1; B12,
B12, C B2, –69; B3, –93; 388; B12, 54; –10; B6, –14; B7, –84; B2, –64; B3, B6, 20; B7, 463; –10; C, 15
B5, –71; B6, –85; C, 55 –14; B12, –22 –92; B5, –67; B6, B12, 78; C, 78
B9, –24; B12, –44; –83; B9, –12; B12,
C, –61 –35; C, –55
Choline, inositol, carnitine (Car), taurine (Tau) Absent Car, Tau: absent Car, Tau: absent Absent Car, Tau: absent Car, Tau: absent
Calcium, magnesium, phosphorus WR WR WR WR WR WR
Sodium (Na), potassium (K), chloride (Cl) Cl, –14; K, 2 Na, –24; K, 24 WR Cl, –1; K, 18 Na, –12; K, 43 K, 13
Iron (Fe), zinc, copper (Cu), manganese (Mn), Fe, –81; Mn, 481; Fe, –25; Cu, 64; Fe, –25; Mo, Cr: Fe, –78; Cu, 11; Fe, –13; Cu, 89; Fe, –14; Cu, 10;
iodine (I), selenium (Se), molybdenum (Mo), Mo, Cr, I, Se: Mn, 29; Mo, Cr: absent Mn, 481; Mo, Cr, Mn, 49; Mo, Cr: Mn, 9; Mo, Cr:
chromium (Cr) absent absent I, Se: absent absent absent

HMF-A, human milk–based fortifier from Prolacta Bioscience (Monrovia, CA); PTF-B and PTF-C, preterm infant formula at energy density of ≈1 kcal/mL from Ross Products (Abbott Lab, Columbus,
OH) and Mead Johnson Nutritional (Evansville, IN), respectively; WR, within range of recommended intake.
a
Content of each nutrient is within the range recommended by American Academy of Pediatrics Committee of Nutrition2 unless there is a trailing number which indicates the percent above the maximum
or below the minimum (as indicated by negative symbol) recommended.
b
Intake of macronutrients versus the recommended intake2 for infants with weights <1 kg.
c
Intake of micronutrients versus the recommended intake2 for all infants with weights ≤1.5 kg.

5
6 Journal of Parenteral and Enteral Nutrition XX(X)

Table 4.  Micronutrient Content of Human Milk Fortified With Standard Volume of HMF-A to 130 and 150 kcal/kg and Supplemented
With 1 mL of Commercial Multivitamins.a

Compared With Recommendedb Energy, 130 kcal/kg Energy, 150 kcal/kg

Poly-Vi-Sol With Iron Contains Vitamins A, D, E, B1, B2, B3, B6, C, Iron
Lower None None
Higher B1 (122), B2 (90), B3 (72), B6 (102), C (103), D B1 (124), B2 (94), B3 (73), B6 (104), C
(11), iron (158) (112), D (13), iron (159)
Quflora Contains Vitamins A, D, E, B1, B2, B3, B6, B9, B12, C; Magnesium (Mg), Fluoride (F), Copper (Cu)
Lower B3 (70) B3 (69)
Higher A (6), B1 (122), B2 (90), B6 (102), B12 (610), C A (12), B1 (124), B2 (94), B6 (104), B12
(103), D (11), Mg (43), Cu (688), Fc (617), C (112), D (13), Mg (55), Cu
(707), Fc
Floriva Plus Contains Vitamins A, D, E, B1, B2, B3, B5, B6, B7, B9, B12, C; Fluoride (F)
Lower B3 (37), B7 (17) B3 (36), B7 (17)
Higher A (16), B1 (122), B2 (90), B6 (1817), B12 (610), C A (22), B1 (124), B2 (94), B6 (1819), B12
(91), D (11), Fc (617), C (100), D (13), Fc
AquADEKs Contains Vitamins A, D, E, K, B1, B2, B3, B5, B6, B7, C; Zinc (Zn), Selenium (Se)
Lower None None
Higher A (323), B1 (164), B2 (90), B3 (90), B5 (97), B6 A (329), B1 (166), B2 (94), B3 (32), B5
(198), B7 (150), C (145), D (61), E (334), K (100), B6 (200), B7 (150), C (154), D (63),
(3904), Zn (118), Se (222) E (337), K (3905), Zn (126), Se (222)

HMF-A, human milk-based fortifier from Prolacta Bioscience, Monrovia, CA.

a
Poly-Vi-Sol with iron from MeadJohnson & Co, LLC (Evansville, IN). Quflora from CarWin Pharmaceutical Associates, LLC (Slidell, LA). Floriva
Plus from BonGeo Pharmaceuticals, Inc (Roseland, NJ). AquADEKs from Actavis Pharma, Inc (Parsippany, NJ).
b
Number in parentheses indicates the percentage lower or higher than the respective minimum or maximum intake recommended by the American
Academy of Pediatrics Committee of Nutrition.2
c
Fluoride—no recommendation by the American Academy of Pediatrics Committee of Nutrition.

isocaloric levels provided a valid comparison of the quantita-
tive difference in nutrient contents provided by different means
to fortify human milk.
Our data indicate that at the isocaloric level of 130 kcal/kg,
all HMFs generally provide macronutrients in the recom-
mended range. However, when used to deliver lower total
energy intake, there is a risk of delivering less than the mini-
mum recommended protein intake, especially with the use of
human milk–based fortifier. The major deficiency with all
HMFs is the inadequate provision of multiple micronutrients.
None of the commercial HMFs provide all recommended
micronutrients, and human milk–based fortifier contains the
least number of micronutrients, which results in the highest
number of micronutrients delivered below the minimum rec-
ommended intake.
The lack of multiple micronutrients (biotin, choline, inosi-
tol, carnitine, taurine, molybdenum, iodine, selenium, or chro-
mium) from HMF is of concern, since these nutrients are
essential or conditionally essential nutrients for VLBW
infants.1,2,6,7 Unlike the regulatory guidelines for the manufac-
ture of infant formulas for term infants (https://www.fda.gov/
food/guidanceregulation/guidancedocumentsregulatoryinfor-
mation/ucm384451.htm; accessed April 30, 2017), there is
apparently no regulatory mandate on the composition of HMF
or PTF. However, the extent of work needed to ensure nutrient
compatibility and bioavailability and to satisfy good manufac-
turing practices (https://www.fda.gov/food/guidanceregula-
tion/cgmp/; accessed April 30, 2017) is likely dependent on the
number and type of ingredients added to HMF and PTF. These
issues presumably contributed to the varied composition of
HMFs and PTFs among manufacturers.
The recommended range of intake for micronutrients is
much more varied when compared with that for macronutrient
intake, since there are limited data on the development of defi-
ciency and toxicity at specific intakes. However, the recom-
mended intake is consistent with the concept of reasonable
range of intake (RRI), defined as the range of average intakes
derived from observations or evaluated under controlled con-
ditions that appear to sustain adequate nutrition without clini-
cal, functional, or biochemical abnormalities.7 The lower RRI
is generally the estimated average requirement, while the upper
RRI, if the upper tolerable nutrient intake is not available
(https://ods.od.nih.gov/pubs/conferences/tolerable_upper_
intake.pdf; accessed March 21, 2017), is based on an intake
that is considered to be safe for medically stable VLBW
infants. Thus, it is prudent to maintain the nutrient intake
Koo and Tice 7
within the range recommended by the American Academy of
Pediatrics Committee of Nutrition.2
Clinical and biochemical adverse effects have been
reported from deficiency in energy, macronutrients, and many
micronutrients including all fat-soluble vitamins, some water-
soluble vitamins, Fe, Zn, and Cu.1,7,10-13 Our data indicate that
VLBW infants receiving less than the minimum recommended
intake are at risk of developing deficiency in multiple nutri-
ents, and it is unlikely that endogenous synthesis of some
micronutrients, such as vitamin D, or renal conservation of
sodium can compensate for the extent of deficient intake
regardless of the HMF used. Because of the limited number of
nutrients in HMFs, especially the human milk–based fortifier,
their chronic use might have contributed to the lower growth
for VLBW infants fed “fortified” human milk8,9 and poten-
tially other clinical or subclinical ill effects.
Our data demonstrate that excessive intake of macronu-
trients and micronutrients can occur with the use of any
HMF, although it is more likely with the use of bovine milk
protein–based fortifiers. Most of the excess intake is within
50% of the maximum recommended intake. However,
HMF-A provided Mn at up to 109%; HMF-B provided vita-
mins B7, B12, and C at 137%–437%; and HMF-C provided
vitamin B12 at 195% above the maximum recommended
intake.2 With an increase in energy intake to 150 kcal/kg,
the excessive intake of nutrients is exaggerated—for exam-
ple, the Mn intake from HMF-A, HMF-B, and HMF-C
could increase up to 152%, 92%, and 107% above the maxi-
mum recommended intake. Although the tolerable upper
limits of intake for infants are not well defined, chronic
excess intake of certain nutrients, such as Mn and Cu,
increases the risk for toxicity.7,10-13 In addition, excessive
intake of some nutrients may exacerbate the deficiency state
of another nutrient—for example, excessive Fe and polyun-
saturated fatty acid intake can exacerbate vitamin E defi-
ciency, resulting in hemolytic anemia in VLBW infants.14
Additionally, a modest increase in folate intake at twice the
recommended dietary allowance may adversely affect vita-
min B12-related function in elderly adults.15
Nutrient content of infant formulas is typically higher
than the average level in human milk. This provides most
infants with at least as much as they would receive from
human milk, and when coupled with the manufacturing pro-
cess of providing extra nutrients (overage) to maintain the
labeled content of nutrients throughout the shelf life,16 it is
possible that the excessive intake of nutrients from the use of
HMF and PTF is underestimated. It is possible that one may
compensate for the excessive intake of any nutrient by
decreasing its bioavailability from decreased intestinal
absorption, increased hepatobiliary or renal excretion, or
increased metabolism before the storage capacity is over-
whelmed with subsequent adverse effects. However, the
extent of these compensatory mechanisms in small preterm
infants is limited, especially for those with hepatic or renal
impairment. Thus, prolonged intake of any nutrient above
the maximum recommended range is to be avoided.
When higher volumes of human milk–based fortifier are
used in a 1:1 ratio by volume with human milk as recom-
mended by the manufacturer, it is possible to meet the desired
increase in energy, macronutrients, minerals, and electrolytes,
but its use cannot compensate for the lack of multiple other
micronutrients. Additionally, this further lowers the volume of
human milk with its associated decrease in potential benefits
from bioactive and other factors4,17 present in human milk,
although the extent of these benefits in human milk, especially
frozen mother’s milk and processed donor human milk,5,18
remain ill defined. The potential for excess intake of Mn from
human milk–based fortifier could raise the risk for toxicity.
The use of concentrated PTF up to 50% of volume of intake
lessens the extent of deficiency for micronutrients when com-
pared with the use of the same volume of HMF. However, at
the usual caloric intake, the intake of protein, some fat-soluble
and water-soluble vitamins, and iron remains lower than the
minimum quantity recommended. The number and extent of
deficiency or excess of micronutrients vary between the 2
PTFs with the risk for deficiency increasing at energy intakes
<130 kcal/kg/d. Our data also indicate that the use of any type
of fortifier in quantities greater than the manufacturer’s recom-
mendation should be avoided, since it may satisfy the energy
and macronutrient intake but runs the risk of greater imbal-
ances in micronutrient intake.
The use of multivitamin supplements is a common practice
in nutrition support for VLBW infants, and their use with iron
is recommended for preterm infants fed human milk.3 However,
our data show that none of the commercial multivitamin for-
mulations provide all recommended vitamins and that they
lack multiple other micronutrients. Their use improves but
does not eliminate the deficiency of micronutrients for those
receiving human milk–based fortifiers. For infants receiving
bovine milk protein–based fortifier, multivitamin supplements
are of little use, since there is already an excess of multiple
vitamins. One of the bovine milk protein–based fortifiers con-
tains less than the minimum recommended iron; therefore, iron
supplementation is warranted. One multivitamin formulation
designed for infants with hepatobiliary dysfunction contains
large quantities of micronutrients, which should preclude its
long-term use in otherwise stable and growing preterm infants.
One limitation of this study is the inability to take into
account all of the extensive biological variabilities of human
milk composition.1,3,5,18 However, the nutrient needs of VLBW
infants are much higher than the nutrient content present in
unfortified human milk. To achieve appropriate nutrition sup-
port, it is probably more important to consider overall nutrient
profile rather than individual nutrients. Chronic excessive or
deficient intake in ≥1 nutrients has the potential to adversely
influence metabolism with unintended consequences on
growth and development. Thus, the final nutrient content of
human milk fortified with various HMFs or PTFs provides a
8 Journal of Parenteral and Enteral Nutrition XX(X)
sound basis to reformulate the HMF to meet the VLBW infant’s
need. The incomplete provision of all recommended nutrients
in PTF (and HMF) presumably is due to the lack of informa-
tion on many of the currently recommended micronutrients
when these products were initially formulated.6
We conclude that at the recommended energy intake for
VLBW infants, commercial HMFs—when used according to
manufacturer’s recommendations—generally provide ade-
quate quantities of protein, fat, and carbohydrate. However,
many essential micronutrients are not present or are present in
grossly inadequate amounts, especially with human milk–
based fortifier, while several micronutrients are present in
extremely high doses. The use of PTF and multivitamin formu-
lations do not fully compensate for the deficiencies and can
result in extremely high intake of some micronutrients. Since
supplement of individual nutrients is impractical, reformula-
tion of HMF to provide an improved nutrient profile is urgently
needed.
Statement of Authorship
W. Koo contributed to the conception and design of the research;
both authors equally contributed to the acquisition, analysis, and
interpretation of data; and W. Koo drafted the manuscript. Both
authors critically revised the manuscript, agree to be fully account-
able for ensuring the integrity and accuracy of the work, and read
and approved the final manuscript.
References
1. Tsang RC, Uauy R, Tsang RC, Koletzko B, Zlotkin SH, eds. Nutrition
of the Preterm Infant: Scientific Basis and Practice Guidelines. 2nd ed.
Cincinnati, OH: Digital Education Publishing Inc; 2005.
2. American Academy of Pediatrics. Nutritional needs of the preterm infants.
In: Kleinman RE, Greer FR, eds. Pediatric Nutrition. 7th ed. Elk Grove
Village, IL: American Academy of Pediatrics; 2014:83-121.
3. Section on Breastfeeding, American Academy of Pediatrics. Breastfeeding
and the use of human milk. Pediatr. 2012;129:e827-e841.
4. American Academy of Pediatrics. Breast feeding. In: Kleinman RE, Greer
FR, eds. Pediatric Nutrition. 7th ed. Elk Grove Village, IL: American
Academy of Pediatrics; 2014:41-60.
5. Committee on Nutrition, Section on Breastfeeding, Committee on Fetus
and Newborn. Donor human milk for the high risk infant: preparation,
safety, and usage options in the United States. Policy statement, American
Academy of Pediatrics. Pediatrics. 2017;139(1):e20163044.
6. Klein CJ. Nutrient requirements for preterm infant formulas. J Nutr.
2002;132(6)(suppl 1):1395s-577s.
7. Uauy R, Koletzko B, Zlotkin SH. Concepts, definitions and approaches
to define the nutritional needs of LBW infants. In: Tsang RC, Uauy R,
Tsang RC, Koletzko B, Zlotkin SH, eds. Nutrition of the Preterm Infant:
Scientific Basis and Practice Guidelines. 2nd ed. Cincinnati, OH: Digital
Education Publishing Inc; 2005:1:21.
8. Maas C, Wiechers C, Bernhard W, Poets CF, Franz AR. Early feeding of
fortified breast milk and in-hospital-growth in very premature infants: a
retrospective cohort analysis. BMC Pediatr. 2013;13:178.
9. O’Connor DL, Gibbins S, Kiss A, et al. Effect of supplemental donor
human milk compared with preterm formula on neurodevelopment of very
low-birth-weight infants at 18 months: a randomized clinical trial. JAMA.
2016;316:1897-1905.
10. Koo W, Lulic-Botica M, Saba M, Warren L. Minerals. In: Corkins MR,
ed. The ASPEN Pediatric Nutrition Support Core Curriculum. 2nd ed.
Silver Spring, MD: American Society for Parenteral and Enteral Nutrition;
2015:57-68.
11. Koo W, Saba M, Lulic-Botica M, Christie J. Fat soluble vitamins.
In: Corkins MR, ed. The ASPEN Pediatric Nutrition Support Core
Curriculum. 2nd ed. Silver Spring, MD: American Society for Parenteral
and Enteral Nutrition; 2015:91-106.
12. Koo W, Christie J, Saba M, Lulic-Botica M, Warren L. Water soluble
essentials micronutrients. In: Corkins MR, ed. The ASPEN Pediatric
Nutrition Support Core Curriculum. 2nd ed. Silver Spring, MD: American
Society for Parenteral and Enteral Nutrition; 2015:69-90.
13. Vanek VW, Borum P, Buchman A, et al. A call to action to bring safer
parenteral micronutrient products to the US market. Nutr Clin Pract.
2015;30:559-569.
14. Williams ML, Shoot RJ, O’Neal PL, Oski FA. Role of dietary iron and
fat on vitamin E deficiency anemia of infancy. N Engl J Med. 1975;
292:887-889.
15. Brito A, Verdugo R, Hertrampf E, et al. Vitamin B-12 treatment of asymp-
tomatic, deficient, elderly Chileans improves conductivity in myelinated
peripheral nerves, but high serum folate impairs vitamin B-12 status
response assessed by the combined indicator of vitamin B-12 status. Am J
Clin Nutr. 2016;103:250-257.
16. Hansen JW, Cook DA, Cordano A, Miguel SG. Human milk substitutes.
In: Tsang RC, Nichols BL, eds. Nutrition During Infancy. Philadelphia,
PA: Hanley & Belfus Inc; 1988:378-398.
17. Ballard O, Morrow AL. Human milk composition: nutrients and bioactive
factors. Ped Clin North Amer. 2013;60:49-74.
18. Meier P, Patel A, Esquerra-Zwiers A. Donor human milk update: evi-
dence, mechanisms, and priorities for research and practice. J Pediatr.
2017;180:15-21.
 Early trophic feeding versus enteral fasting for very preterm
or very low birth weight infants (Review)

Morgan J, Bombell S, McGuire W

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2013, Issue 3
http://www.thecochranelibrary.com

Early trophic feeding versus enteral fasting for very preterm or very low birth weight infants (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
Analysis 1.1. Comparison 1 Effects of trophic feeding versus enteral fasting, Outcome 1 Days to reach full enteral feeding. 21
Analysis 1.2. Comparison 1 Effects of trophic feeding versus enteral fasting, Outcome 2 Incidence of necrotising
enterocolitis. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
Analysis 1.3. Comparison 1 Effects of trophic feeding versus enteral fasting, Outcome 3 Mortality. . . . . . . . 23
Analysis 1.4. Comparison 1 Effects of trophic feeding versus enteral fasting, Outcome 4 Days to regain birth weight. 24
Analysis 1.5. Comparison 1 Effects of trophic feeding versus enteral fasting, Outcome 5 Incidence of invasive infection. 25
Analysis 1.6. Comparison 1 Effects of trophic feeding versus enteral fasting, Outcome 6 Duration of phototherapy (days). 26
Analysis 1.7. Comparison 1 Effects of trophic feeding versus enteral fasting, Outcome 7 Days of hospital stay. . . . 27
WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 27
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

Early trophic feeding versus enteral fasting for very preterm or very low birth weight infants (Review) i
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Review]

Early trophic feeding versus enteral fasting for very preterm

or very low birth weight infants

Jessie Morgan1 , Sarah Bombell2 , William McGuire1

1 HullYork Medical School & Centre for Reviews and Dissemination, University of York, York, UK. 2 Centre for Newborn Care,
Australian National University, Canberra, Australia

Contact address: William McGuire, Hull York Medical School & Centre for Reviews and Dissemination, University of York, York,
Y010 5DD, UK. William.McGuire@hyms.ac.uk.

Editorial group: Cochrane Neonatal Group.

Publication status and date: New search for studies and content updated (conclusions changed), published in Issue 3, 2013.
Review content assessed as up-to-date: 27 December 2012.

Citation: Morgan J, Bombell S, McGuire W. Early trophic feeding versus enteral fasting for very preterm or very low birth weight
infants. Cochrane Database of Systematic Reviews 2013, Issue 3. Art. No.: CD000504. DOI: 10.1002/14651858.CD000504.pub4.

Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT

Background

The introduction of enteral feeds for very preterm (< 32 weeks) or very low birth weight (< 1500 grams) infants is often delayed due to
concern that early introduction may not be tolerated and may increase the risk of necrotising enterocolitis. However, prolonged enteral
fasting may diminish the functional adaptation of the immature gastrointestinal tract and extend the need for parenteral nutrition with
its attendant infectious and metabolic risks. Trophic feeding, giving infants very small volumes of milk to promote intestinal maturation,
may enhance feeding tolerance and decrease the time taken to reach full enteral feeding independently of parenteral nutrition.

Objectives

To determine the effect of early trophic feeding versus enteral fasting on feed tolerance, growth and development, and the incidence of
neonatal morbidity (including necrotising enterocolitis and invasive infection) and mortality in very preterm or VLBW infants.

Search methods

We used the standard search strategy of the Cochrane Neonatal Review Group. This included electronic searches of the Cochrane
Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2012, Issue 12), MEDLINE, EMBASE and CINAHL (1980
until December 2012), conference proceedings and previous reviews.

Selection criteria

Randomised or quasi-randomised controlled trials that assessed the effects of early trophic feeding (milk volumes up to 24 ml/kg/day
introduced before 96 hours postnatal age and continued until at least one week after birth) versus a comparable period of enteral fasting
in very preterm or very low birth weight infants.

Data collection and analysis

We extracted data using the standard methods of the Cochrane Neonatal Review Group with separate evaluation of trial quality and
data extraction by two authors and synthesis of data using risk ratio, risk difference and mean difference.
Early trophic feeding versus enteral fasting for very preterm or very low birth weight infants (Review) 1
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Main results

Nine trials in which a total of 754 very preterm or very low birth weight infants participated were eligible for inclusion. Few participants
were extremely preterm (< 28 weeks) or extremely low birth weight (< 1000 grams) or growth restricted. These trials did not provide
any evidence that early trophic feeding affected feed tolerance or growth rates. Meta-analysis did not detect a statistically significant
effect on the incidence of necrotising enterocolitis: typical risk ratio 1.07 (95% confidence interval 0.67 to 1.70); risk difference 0.01
(-0.03 to 0.05).

Authors’ conclusions

The available trial data do not provide evidence of important beneficial or harmful effects of early trophic feeding for very preterm or
very low birth weight infants. The applicability of these findings to extremely preterm, extremely low birth weight or growth restricted
infants is limited. Further randomised controlled trials would be needed to determine how trophic feeding compared with enteral
fasting affects important outcomes in this population.

PLAIN LANGUAGE SUMMARY

Early trophic feeding versus enteral fasting for very preterm or very low birth weight infants

There is insufficient evidence to determine whether feeding very preterm or very low birth weight infants small quantities of milk during
the first week after birth (early trophic feeding) compared with fasting helps bowel development and improves subsequent feeding,
growth and development. Analysis of nine trials does not suggest that this practice increases the risk of a severe bowel disorder called
’necrotising enterocolitis’. Further trials could provide more robust evidence to inform this key area of care.

BACKGROUND
Description of the condition
Necrotising enterocolitis is an important cause of morbidity and
mortality in very preterm (< 32 weeks) or very low birth weight
(VLBW: < 1500 grams) infants. Extremely low birth weight
(ELBW: < 1000 grams) and extremely preterm (< 28 weeks) infants
are at highest risk (Rees 2007). Intrauterine growth restriction may
be an additional specific risk factor, especially if associated with
circulatory redistribution demonstrated by absent or reversed end-
diastolic flow velocities (AREDFV) in antenatal Doppler studies
of the fetal aorta or umbilical artery (Bernstein 2000; Dorling
2005).
Most very preterm or VLBW infants who develop necrotising en-
terocolitis have received enteral milk feeds. Evidence exists that
feeding with formula milk rather than breast milk increases the risk
(Lucas 1990; Quigley 2007; Meinzen-Derr 2009). The timing of
the introduction of enteral feeding may also be an important mod-
ifiable risk factor for the development of necrotising enterocolitis
(Henderson 2009). Observational data suggest that feeding strate-
gies that include delaying the introduction of progressive enteral
feeds until after five to seven days postnatally reduces the risk of
Early trophic feeding versus enteral fasting for very preterm or very low birth weight infants (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
necrotising enterocolitis in very preterm or VLBW infants (Patole
2005). However, enteral fasting during the early neonatal period
also has potential disadvantages. Because gastrointestinal hormone
secretion and motility are stimulated by enteral milk, delayed en-
teral feeding could diminish the functional adaptation of the im-
mature gastrointestinal tract (Johnson 1976; Aynsley-Green 1983;
Berseth 1990). Consequent intestinal dysmotility may exacerbate
feed intolerance leading to a delay in establishing enteral feeding
independently of parenteral nutrition. Enteral fasting might also
cause hyperbilirubinaemia by increasing enterohepatic recircula-
tion of bilirubin and delaying hepatic enzyme maturation. Pro-
longing the duration of use of parenteral nutrition may be asso-
ciated with infectious and metabolic complications that have ad-
verse consequences for survival, duration of hospital stay, growth
and development (Flidel-Rimon 2004; Flidel-Rimon 2006).
Description of the intervention
Trophic feeding (also referred to as minimal enteral nutrition, gut
priming and hypocaloric feeding) was developed and adopted into
clinical practice as an alternative to complete enteral fasting for
very preterm or VLBW infants during the early neonatal period
2
(Klingenberg 2012). Early trophic feeding is conventionally de-
fined as giving small volumes of milk (typically 12 to 24 ml/kg/
day) intragastrically starting within the first few days after birth,
without advancing the feed volumes during the first week postna-
tally (McClure 2001). The primary aim of trophic feeding is to
accelerate gastrointestinal physiological, endocrine and metabolic
maturity and so allow infants to transition to full enteral feeding
independent of parenteral nutrition more quickly. However, any
beneficial effects may be negated if early trophic feeding increases
the risk of necrotising enterocolitis in very preterm or VLBW in-
fants.
Why it is important to do this review
This review focuses on the question of whether early trophic feed-
ing compared with a similar period of enteral fasting improves
feed tolerance without increasing the risk of necrotising entero-
colitis in very preterm or VLBW infants. Other Cochrane reviews
address the questions of whether introducing progressive enteral
milk feeds (beyond trophic volumes) later or slowing the rate of
advancement of feed volumes affects the risk of necrotising entero-
colitis, mortality and other morbidities (Morgan 2011a; Morgan
2011b).
OBJECTIVES
To determine the effect of early trophic feeding versus enteral fast-
ing on feed tolerance, growth and development, and the incidence
of neonatal morbidity (including necrotising enterocolitis and in-
vasive infection) and mortality in very preterm or VLBW infants.
METHODS
Criteria for considering studies for this review
Types of studies
Randomised or quasi-randomised controlled trials including clus-
ter-randomised trials.
Types of participants
VLBW (< 1500 grams) or very preterm (< 32 weeks) newborn
infants.
Early trophic feeding versus enteral fasting for very preterm or very low birth weight infants (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Types of interventions
Early trophic feeding: enteral feeding with milk volumes up to 24
ml/kg/day (1 ml/kg/hour) beginning within four days after birth
and continued for at least five days or until at least one week after
birth versus enteral fasting for the same period.
Once progressive enteral feeding has started, infants should have
received the same type of milk (breast milk or formula), the same
route and mode of feeding (intragastric or transpyloric, bolus gav-
age or continuous) and the same rate of feed volume advancement
in both groups.
Types of outcome measures
Primary outcomes
1. Feed intolerance: days to establish full enteral feeding
independently of parenteral nutrition.
2. Necrotising enterocolitis confirmed by at least two of the
following features:
• abdominal radiograph showing pneumatosis intestinalis or
gas in the portal venous system or free air in the abdomen;
• abdominal distension with abdominal radiograph with
gaseous distension or frothy appearance of bowel lumen (or
both);
• blood in stool;
• lethargy, hypotonia or apnoea (or combination of these);
or a diagnosis confirmed at surgery or autopsy (Walsh 1986).
Secondary outcomes
1. All-cause mortality prior to hospital discharge.
2. Growth: (i) Time to regain birth weight and rates of weight
gain, linear growth, head growth or skinfold thickness growth up
to six months of age corrected for preterm birth; (ii) Long-term
growth: weight, height or head circumference and/or proportion
of infants who remain below the 10th percentile for the index
population’s distribution assessed at intervals from six months of
age.
3. Neurodevelopment: death or severe neurodevelopmental
disability defined as any one or combination of the following:
non-ambulant cerebral palsy, developmental delay
(developmental quotient less than 70), auditory and visual
impairment. Each component will be analysed individually as
well as part of the composite outcome.
4. Incidence of invasive infection as determined by culture of
bacteria or fungus from blood, cerebrospinal fluid, urine or from
a normally sterile body space.
5. Duration of phototherapy for hyperbilirubinaemia (days).
6. Duration of hospital stay (days).
3
Search methods for identification of studies
We used the standard search strategy of the Cochrane Neonatal
Group (http://neonatal.cochrane.org/).
Electronic searches
We searched the Cochrane Central Register of Controlled Trials
(CENTRAL, The Cochrane Library 2012, Issue 12), MEDLINE
(1980 to December 2012), EMBASE (1980 to December 2012)
and CINAHL (1982 to December 2012) using the following text
words and MeSH terms: [Infan*, OR Infant/, OR Preterm, OR
Prem*, OR Infant premature/, OR Neonat*, OR New ADJ born,
OR New?born, Infant newborn/, OR Very Low Birth Weight, OR
VLBW, OR Extremely Low Birth Weight, OR ELBW, OR Infant
Very Low Birth Weight/ OR Infant Extremely Low Birth Weight/
] AND [Breast feeding, OR Breast feeding/, OR human milk, OR
human milk/, OR formula, Infant formula/, OR Trophic feeding,
OR minimal enteral nutrition, OR MEN, OR minimal enteral
feeding, OR MEF, OR gut priming, OR enteral feed*, OR enteral
nutrition/].
The search outputs were limited with the relevant search filters for
clinical trials. We did not apply any language restriction.
We searched ClinicalTrials.gov and Current Controlled Trials for
completed or ongoing trials.
Searching other resources
We examined reference lists in previous reviews and studies.
We examined the references in studies identified as potentially rel-
evant. We also searched the abstracts from the annual meetings
of the Pediatric Academic Societies (1993 to 2012), the European
Society for Pediatric Research (1995 to 2012), the UK Royal Col-
lege of Paediatrics and Child Health (2000 to 2012) and the Peri-
natal Society of Australia and New Zealand (2000 to 2012). We
considered trials reported only as abstracts to be eligible if suffi-
cient information was available from the report, or from contact
with the authors, to fulfil the inclusion criteria.
Data collection and analysis
We used the standard methods of the Cochrane Neonatal Review
Group (http://neonatal.cochrane.org/).
Selection of studies
Two review authors screened the title and abstract of all studies
identified by the above search strategy. We reassessed the full text
of any potentially eligible reports and excluded those studies that
did not meet all of the inclusion criteria. Review authors discussed
any disagreements until consensus was achieved.
Early trophic feeding versus enteral fasting for very preterm or very low birth weight infants (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Data extraction and management
We used a data collection form to extract relevant information
from each included study. Two review authors extracted the data
separately. We discussed any disagreements with the third author
until we reached consensus.
Assessment of risk of bias in included studies
We used the criteria and standard methods of the Cochrane
Neonatal Review Group to assess the methodological quality of
any included trials. We requested additional information from the
trial authors to clarify methodology and results as necessary. We
evaluated and reported the following issues in the ’Risk of bias’
tables:
1. Sequence generation: We categorised the method used to
generate the allocation sequence as:
i) low risk: any random process e.g. random number
table; computer random number generator;
ii) high risk: any non random process e.g. odd or even
date of birth; patient case-record number;
iii) unclear.
2. Allocation concealment: We categorised the method used
to conceal the allocation sequence as:
i) low risk: e.g. telephone or central randomisation;
consecutively numbered sealed opaque envelopes;
ii) high risk: open random allocation; unsealed or non-
opaque envelopes, alternation; date of birth;
iii) unclear.
3. Blinding: We assessed blinding of participants, clinicians
and care givers, and outcome assessors separately for different
outcomes and categorised the methods as:
i) low risk;
ii) high risk;
iii) unclear.
4. Incomplete outcome data: We described the completeness
of data including attrition and exclusions from the analysis for
each outcome and any reasons for attrition or exclusion where
reported. We assessed whether missing data were balanced across
groups or were related to outcomes. Where sufficient information
was reported or supplied by the trial authors, we re-included
missing data in the analyses. We categorised completeness as:
i) low risk: < 20% missing data;
ii) high risk: > 20% missing data;
iii) unclear.
Measures of treatment effect
We calculated risk ratio (RR) and risk difference (RD) for dichoto-
mous data and mean difference (MD) for continuous data, with
respective 95% confidence intervals (CI). We used a fixed-effect
model for meta-analysis.
4
Assessment of heterogeneity
We examined the treatment effects of individual trials and hetero-
geneity between trial results by inspecting the forest plots if more
than one trial was included in a meta-analysis. We calculated the
I² statistic for statistical heterogeneity. If substantial (I² > 50%)
heterogeneity was detected, we explored the possible causes (for
example, differences in study design, participants, interventions
or completeness of outcome assessments) in sensitivity analyses.
Subgroup analysis and investigation of heterogeneity
We planned the following subgroup analyses:
1. trials in which most infants were exclusively formula-fed;
2. trials in which most infants were at least partially fed with
human milk (maternal or donor);
3. trials in which most participants were of ELBW (< 1000
grams) or extremely preterm (< 28 weeks);
4. trials in which participants were infants with intrauterine
growth restriction, or infants with absent or reversed end-
diastolic flow velocities detected on antenatal Doppler studies of
the fetal aorta or umbilical artery.
RESULTS
Description of studies
See: Characteristics of included studies; Characteristics of excluded
studies.
We identified 17 articles using the above search strategy.
Included studies
Nine trials fulfilled the inclusion criteria (Dunn 1988; Meetze
1992; Troche 1995; Becerra 1996; Schanler 1999; McClure 2000;
Sáenz de Pipaón 2003; van Elburg 2004; Mosqueda 2008; see
table ’Characteristics of included studies’).
Participants
The included studies were all undertaken since the late 1980s
by investigators attached to neonatal units in Europe and North
America. Most were small single-centre studies. 754 infants par-
ticipated in total (range 29 to 190). Most participants were ap-
propriate-for-gestational age VLBW or very preterm infants re-
ceiving standard intensive care interventions such as mechanical
ventilation and parenteral nutrition. In van Elburg 2004, partici-
pants were infants of birth weight less than 2000 grams who were
small for gestational age (< 10th percentile for birth weight). We
included this study because > 80% of participating infants were
Early trophic feeding versus enteral fasting for very preterm or very low birth weight infants (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
VLBW. Most of the other trials specifically excluded infants who
were small for gestational age at birth and infants with congenital
anomalies, gastrointestinal problems or neurological problems.
Interventions
Trophic feeding was generally started within the first three days
after birth and continued for varying durations; either until in-
fants were judged to be clinically stable (for example following
endotracheal extubation or removal of umbilical catheters) or for
pre-defined intervals, generally 7 to 10 days after birth. Feeding
volumes ranged from about 12 to 24 ml/kg/day. One trial admin-
istered milk at a rate of 25 ml/kg/day with no intention to increase
this volume for six to eight days (Becerra 1996). Although this
rate exceeded our definition of minimal enteral nutrition by 1 ml/
kg/day, we made a consensus decision to include the trial.
In most trials, infants received either expressed breast milk or for-
mula milk (diluted or full-strength) or a mixture of breast milk and
formula. In two trials, infants received only formula milk (Dunn
1988; Meetze 1992). Control infants received no enteral nutrition
for at least one week after birth. Infants in both comparison groups
received standard parenteral nutrition during the trial period.
In most trials, milk was administered by intermittent bolus gavage
feeds via oro or nasogastric tube. In Schanler 1999, participating
infants were also allocated to either bolus or continuous feeding
using a factorial design. In Troche 1995, infants weighing < 800
grams at birth received feeds via a continuous infusion whereas
those weighing > 800 grams at birth received intermittent bolus
feeds.
Outcomes
Most trials assessed feed intolerance (variously defined) and inci-
dence of necrotising enterocolitis. Short-term growth parameters
were reported in a variety of ways, most commonly time to regain
birth weight and weight gain during the neonatal period (either
as median and range or as mean and standard deviation). Most
reports also gave information on adverse outcomes including mor-
tality. None of the trials reported long-term growth and neurode-
velopmental outcomes for surviving infants.
Excluded studies
We excluded eight studies (LaGamma 1985; Ostertag 1986; Slagle
1988; Berseth 1992; Berseth 1993; Berseth 2003; Weiler 2006;
Said 2008; see table ’Characteristics of excluded studies’).
Risk of bias in included studies
Most of the trials had some methodological weaknesses. In four
trials it was unclear whether allocation was concealed. Care givers
5
were not blinded to treatment group in any trial. Few trials un-
dertook blinded assessments for any of the outcomes, and several
of the trials did not include results for all infants randomised (see
table ’Characteristics of included studies’).
Effects of interventions
Primary outcomes
Feed intolerance: time to establish full enteral feeding
(outcome 1.1; eight trials)
Meta-analysis of data from six trials that reported mean and stan-
dard deviation (SD) did not detect a statistically significant effect:
mean difference (MD) -1.05 (95% confidence interval (CI) -2.61
to 0.51) days. The meta-analysis contained significant statistical
heterogeneity in (I² = 73%) (Analysis 1.1).
Two trials reported median and range data. Neither detected a sta-
tistically significant difference: 32 days versus 32 days (Mosqueda
2008); 13 days versus 13 days (van Elburg 2004).
Necrotising enterocolitis (outcome 1.2; nine trials)
Meta-analysis did not detect a statistically significant effect: typical
risk ratio (RR) 1.07 (95% CI 0.67 to 1.70); typical risk difference
(RD) 0.01 (95% CI -0.03 to 0.05). There was no evidence of
heterogeneity (I² = 0%) (Analysis 1.2).
Secondary outcomes
Mortality (outcome 1.3; eight trials)
Meta-analysis did not detect a statistically significant effect: typical
RR 0.66 (95% CI 0.41 to 1.07); typical RD -0.04 (95% CI -
0.10 to 0.01). There was no evidence of heterogeneity (I² = 0%)
(Analysis 1.3).
Growth (outcome 1.4; eight trials)
None of the trials reported a statistically significant difference in
the time to regain birth weight. Meta-analysis of five trials with data
as mean and SD: MD -0.01 (95% CI -0.96 to 0.95) days. There
was no evidence of statistical heterogeneity (I² = 23%) (Analysis
1.4).
Two trials reported median and range data. Neither detected a sta-
tistically significant difference: 13 days versus 12 days (Mosqueda
2008); 11 days versus 10 days (van Elburg 2004).
McClure 2000 reported that the average rate of weight gain and
head circumference gain during the six weeks after birth was bor-
derline significantly higher in infants who had received trophic
feeds:
Early trophic feeding versus enteral fasting for very preterm or very low birth weight infants (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
• Weight: reported MD 130 (95% CI 1 to 250) grams/week.
• Head circumference: reported MD 0.7 (95% CI 0.1 to 1.3)
cm/week
Mosqueda 2008 reported no statistically significant difference in
rates of weight gain during the trial period: MD -7.3 (95% CI -
19.2 to 4.6) grams/week.
Sáenz de Pipaón 2003 reported that the weight above birth weight
attained by day 21 was not statistically significantly different (188
grams versus 190 grams).
Troche 1995 reported that infants in the trophic feeding group
had a higher increase in weight over birth weight to day 30 (223
(SD 125) versus 95 (SD 161) grams).
Meetze 1992 reported no statistically significant difference in
weight gain between the groups at day 30: 264 (SD 126) grams ver-
sus 213 (SD 142) grams. Increases in head circumference, length
and mid-arm circumference were reported to be similar for both
groups.
Dunn 1988 measured growth throughout the study period up
until 60 days of life and did not detect any significant differences
between the two groups.
Long-term growth parameters were not reported by any of the
trials.
Neurodevelopment
None of the trials assessed neurodevelopmental outcomes.
Incidence of invasive infection (outcome 1.5; four trials)
Meta-analysis of three trials did not detect a statistically significant
difference: typical RR 1.06 (95% CI 0.72 to 1.56); typical RD 0.02
(95% CI -0.10 to 0.13). There was no evidence of heterogeneity
(I² = 25%) (Analysis 1.5).
McClure 2000 reported that infants in the minimal enteral nutri-
tion group had a statistically significantly lower mean number of
episodes of “culture-confirmed sepsis” (0.5 versus 1.2 in control
group). These data could not be included in the meta-analysis.
Duration of phototherapy (days) (outcome 1.6; three trials)
Meta-analysis did not detect a statistically significant effect: MD
0.35 (95% CI -0.29 to 0.99) days (Analysis 1.6).
Duration of hospital stay (outcome 1.7; five trials)
Meta-analysis of four trials that reported data as mean and SD
did not detect a statistically significant effect: MD -3.9 (95% CI -
11.5 to 3.8) days (Analysis 1.7). There was evidence of borderline
statistical heterogeneity (I² = 48%).
One trial that reported median and range data did not find a statis-
tically significant difference: 81 days versus 79.5 days (Mosqueda
2008).
6
Subgroup analyses
1. Exclusively formula milk-fed infants: In two trials, infants
received only formula milk as trophic feeds (Dunn 1988; Meetze
1992). In the other trials, infants received either breast milk or
formula milk or a mixture. Subgroup data were not available.
2. Infants at least partially fed with breast milk: Subgroup data
were not available.
3. Extremely low birth weight (ELBW) or extremely preterm
infants: One trial restricted participation to ELBW infants
(Mosqueda 2008). In the other trials, it is likely that less than
one-third of all participants were ELBW or extremely preterm
but subgroup data were not available.
4. Infants with intrauterine growth restriction or infants with
absent or reversed end-diastolic flow velocities (AREDFV): In
those trials where birth weight < 10th percentile was not an
exclusion criterion, subgroup data were not available. One trial
restricted participation to infants who were small for gestational
age (birth weight < 10th percentile for reference population)
(van Elburg 2004).
DISCUSSION
Summary of main results
The available data from randomised controlled trials do not pro-
vide evidence that early trophic feeding compared to enteral fast-
ing confers any substantial benefits for very preterm or very low
birth weight (VLBW) infants. Although some trials reported that
minimal enteral nutrition reduced the time taken to establish full
enteral feeds, meta-analysis of all of the available data did not de-
tect a statistically significant effect.
The trial data do not suggest that minimal enteral nutrition is
associated with important harms. Meta-analyses did not detect
statistically significant effects on the incidence of necrotising en-
terocolitis, invasive infection or all-cause mortality. Only limited
data on growth outcomes were found. Trials found inconsistent
effects on short-term growth and meta-analysis did not reveal a
significant difference in the time taken to regain birth weight. The
clinical importance of any short-term effects is unclear as no long-
term growth or developmental outcomes were assessed.
Overall completeness and applicability of
evidence
These findings should be applied with caution. Although we did
not find evidence of an effect on feed intolerance, the existence of
Early trophic feeding versus enteral fasting for very preterm or very low birth weight infants (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
substantial statistical heterogeneity in the meta-analysis limits the
validity of this finding. The heterogeneity was not explained by
differences between trials in methodological quality or the type of
intervention or participants. It may be that variations in enteral
feeding protocols and practices contributed to heterogeneity.
These findings may not be applicable to some infants at high-
est risk of developing feed intolerance or necrotising enterocol-
itis. Only a minority of participants in the included trials were
extremely low birth weight (ELBW) or extremely preterm infants
or had evidence of intrauterine growth restriction. None of the
trials specifically recruited infants with absent or reversed end-
diastolic flow velocities on Doppler ultrasound of the umbilical
arteries. Furthermore, the risk-benefit balance of enteral feeding
strategies may differ between breast milk-fed and formula-fed very
preterm or VLBW infants. One study reported that mothers who
expressed breast milk for early trophic feeding were more likely to
continue to provide breast milk as the ongoing principal form of
nutrition for their infants (Schanler 1999). Further study to con-
firm and define the mechanism of this association is merited given
that feeding with breast milk compared to formula reduces the
risk of necrotising enterocolitis in very preterm or VLBW infants
(Quigley 2007).
It is also unclear whether the findings can be applied to infants
who receive continuous infusion of milk feeds as all of the infants
in the included trials received enteral feeds as interval boluses. A
recently described issue is that bolus administration of volumes
up to 0.5 ml results in substantial retention of milk within stan-
dard gastric feeding tubes (which will then be aspirated prior to
the next feed). Consequently, infants will not actually receive any
milk intragastrically unless trophic feeding is delivered continu-
ously (McHale 2010). Randomised controlled trials have reported
conflicting findings about the effect on continuous enteral infu-
sion on feed tolerance in very preterm and VLBW infants (Premji
2011).
Quality of the evidence
The included trials were generally of good methodological qual-
ity but in common with other trials of feeding interventions in
this population it was not possible to mask care givers and clin-
ical assessors to the nature of the intervention (Figure 1). This
may be an important source of bias particularly in trials that did
not use prespecified definitions of feed intolerance that mandated
interrupting or ceasing feed volume advancement. Care givers or
clinicians who were aware of the treatment group may have de-
fined feed intolerance subjectively and differentially. Any surveil-
lance and ascertainment biases secondary to the lack of blinding
are more likely to have caused an over-estimation of the incidence
of feed intolerance or necrotising enterocolitis in infants who re-
ceived minimal enteral nutrition.
7
 Figure 1. ’Risk of bias’ graph: review authors’ judgements about each risk of bias item presented as
percentages across all included studies.
AUTHORS’ CONCLUSIONS
Implications for practice
The available trial data do not provide strong evidence that early
trophic feeding has important effects on feed intolerance, growth
or development. There is no evidence that trophic feeding has ad-
verse effects. For necrotising enterocolitis, the lower and bounds
of the 95% CI of the number needed to treat for an additional
harmful outcome (NNTH) estimate are consistent with either five
more cases or three fewer cases in every 100 infants who receive
early trophic feeding. For mortality, the NNTH 95% CI is con-
sistent with one more case or 10 fewer cases in every 100 infants
who receive early trophic feeding.
Implications for research
Any new randomised controlled trials of early trophic feeding ver-
sus enteral fasting should aim to ensure the participation of ex-
tremely low birth weight (ELBW) and extremely preterm infants as
well as infants with evidence of compromised intrauterine growth
REFERENCES
References to studies included in this review
Becerra 1996 {published and unpublished data}
Becerra M, Ambiado S, Kuntsman G, Figueroa A, Balboa
P, Fernandez P, et al.Feeding VLBW infants; Effect of early
enteral stimulation (EES) [abstract]. Pediatric Research
1996;39:304A.
Dunn 1988 {published data only}
Dunn L, Hulman S, Weiner J, Kleigman R. Beneficial
effects of early hypocaloric enteral feeding on neonatal
Early trophic feeding versus enteral fasting for very preterm or very low birth weight infants (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
so that findings are applicable to these infants at highest risk of
necrotising enterocolitis. Undertaking trials of feeding interven-
tions in this population is problematic (Tyson 2007). It is diffi-
cult to perform a pragmatic trial that will ensure that care givers
and investigators are unaware of the allocated feeding regimen. A
priori agreements on objective definitions of feed intolerance and
indications for interruption of enteral feeding and for investiga-
tion of necrotising enterocolitis may help minimise the impact of
this source of bias. Trials should also aim to assess more objective
outcomes, principally mortality and long-term growth and devel-
opment.
ACKNOWLEDGEMENTS
We thank Dr Schanler for providing further data from Schanler
1999 and Dr Sáenz de Pipaón for clarification on data from Sáenz
de Pipaón 2003.
We are grateful to Ms Bethan Carter for developing and running
the electronic search.
gastrointestinal function: preliminary report of a
randomized trial. Journal of Pediatrics 1988;112(4):622–9.
McClure 2000 {published and unpublished data}
∗
McClure RJ, Newell SJ. Randomised controlled trial of
clinical outcome following trophic feeding. Archives of
Disease in Childhood. Fetal and Neonatal Edition 2000;82
(1):F29–F33.
McClure RJ, Newell SJ. Randomised controlled trial of
trophic feeding and gut motility. Archives of Disease in
8
 Childhood. Fetal and Neonatal Edition 1999;80(1):F54–8.
McClure RJ, Newell SJ. Randomized controlled study of
digestive enzyme activity following trophic feeding. Acta
Paediatrica 2002;91(3):292–6.
Meetze 1992 {published data only}
Meetze WH, Valentine C, McGuigan JE, Conlon M,
Sacks N, Neu J. Gastrointestinal priming prior to full
enteral nutrition in very low birth weight infants. Journal
of Pediatric Gastroenterology and Nutrition 1992;15(2):
163–70.
Mosqueda 2008 {published data only}
Mosqueda E, Sapiegiene L, Glynn L, Wilson-Costello
D, Weiss M. The early use of minimal enteral nutrition
in extremely low birth weight newborns. Journal of
Perinatology 2008;28(4):264–9.
Sáenz de Pipaón 2003 {published and unpublished data}
Sáenz de Pipaón M, VanBeek RH, Quero J, Perez J,
Wattimena DJ, Sauer PJ. Effect of minimal enteral feeding
on splanchnic uptake of leucine in the postabsorptive state
in preterm infants. Pediatric Research 2003;53(2):281–7.
Schanler 1999 {published and unpublished data}
Schanler RJ, Shulman RJ, Lau C, Smith EO, Heitkemper
MM. Feeding strategies for premature infants: randomized
trial of gastrointestinal priming and tube-feeding method.
Pediatrics 1999;103(2):434–9.
Shulman RJ, Schanler RJ, Lau C, Heitkemper M, Ou C,
Smith EO. Early feeding, antenatal glucocorticoids, and
human milk decrease intestinal permeability in preterm
infants. Pediatric Research 1998;44(4):519–23.
Shulman RJ, Schanler RJ, Lau C, Heitkemper M, Ou C,
Smith EO. Early feeding, feeding tolerance, and lactase
activity in preterm infants. Journal of Pediatrics 1998;133
(5):645–9.
Troche 1995 {published data only}
Troche B, Harvey-Wilkes K, Engle WD, Nielsen HC,
Frantz ID, Mitchell ML, et al.Early minimal feedings
promote growth in critically ill premature infants. Biology of
the Neonate 1995;67(3):172–81.
van Elburg 2004 {published data only}
van Elburg RM, van den Berg A, Bunkers CM, van
Lingen RA, Smink EW, van Eyck J, et al.Minimal enteral
feeding, fetal blood flow pulsatility, and postnatal intestinal
permeability in preterm infants with intrauterine growth
retardation. Archives of Disease in Childhood, Fetal and
Neonatal Edition 2004;89(4):F293–6.
References to studies excluded from this review
Berseth 1992 {published data only}
Berseth CL. Effect of early feeding on maturation of the
preterm infant’s small intestine. Journal of Pediatrics 1992;
120(6):947–53.
Berseth 1993 {published data only}
Berseth CL, Nordyke C. Enteral nutrients promote
postnatal maturation of intestinal motor activity in preterm
infants. American Journal of Physiology 1993;264(6 Pt 1):
G1046–51.
Early trophic feeding versus enteral fasting for very preterm or very low birth weight infants (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Berseth 2003 {published and unpublished data}
Berseth CL, Bisquera JA, Paje VU. Prolonging small feeding
volumes early in life decreases the incidence of necrotizing
enterocolitis in very low birth weight infants. Pediatrics
2003;111(3):529–34.
LaGamma 1985 {published data only}
LaGamma EF, Ostertag S, Birenbaum H. Failure of delayed
oral feedings to prevent necrotizing enterocolitis. American
Journal of Diseases of Children 1985;139(4):385–9.
Ostertag 1986 {published data only}
Ostertag SG, LaGamma EF, Reisen CE, Ferrentino FL.
Early enteral feeding does not affect the incidence of
necrotizing enterocolitis. Pediatrics 1986;77(3):275–80.
Said 2008 {published data only}
Said H, Elmetwally D, Said D. Randomised controlled trial
of early versus late enteral feeding of prematurely born
infants with birth weight <1200 grams. Kasr El Aini Medical
Journal 2008;14:1–10.
Slagle 1988 {published data only}
Slagle TA, Gross SJ. Effect of early low-volume enteral
substrate on subsequent feeding tolerance in very low birth
weight infants. Journal of Pediatrics 1988;113(3):526–31.
Weiler 2006 {published data only}
Weiler HA, Fitzpatrick-Wong SC, Schellenberg JM, Fair
DE, McCloy UR, Veitch RR, et al.Minimal enteral feeding
within 3 d of birth in prematurely born infants with birth
weight < or = 1200 g improves bone mass by term age.
American Journal of Human Nutrition 2006;83(1):155–62.
Additional references
Aynsley-Green 1983
Aynsley-Green A. Hormones and postnatal adaptation to
enteral nutrition. Journal of Pediatric Gastroenterology and
Nutrition 1983;2(3):418–27.
Bernstein 2000
Bernstein IM, Horbar JD, Badger GJ, Ohlsson A, Golan
A. Morbidity and mortality among very-low-birth-weight
neonates with intrauterine growth restriction. The Vermont
Oxford Network. American Journal of Obstetrics and
Gynecology 2000;182(1 Pt 1):198–206.
Berseth 1990
Berseth CL. Neonatal small intestinal motility: the motor
responses to feeding in term and preterm infants. Journal of
Pediatrics 1990;117(5):777–82.
Dorling 2005
Dorling J, Kempley S, Leaf A. Feeding growth restricted
preterm infants with abnormal antenatal Doppler results.
Archives of Disease in Childhood. Fetal and Neonatal Edition
2005;90(5):F359–63.
Flidel-Rimon 2004
Flidel-Rimon O, Friedman S, Lev E, Juster-Reicher
A, Amitay M, Shinwell ES. Early enteral feeding and
nosocomial sepsis in very low birthweight infants. Archives
of Disease in Childhood. Fetal and Neonatal Edition 2004;89
(4):289–92.
9
Flidel-Rimon 2006
Flidel-Rimon O, Branski D, Shinwell ES. The fear of
necrotizing enterocolitis versus achieving optimal growth in
preterm infants--an opinion. Acta Paediatrica 2006;95(11):
1341–4.
Henderson 2009
Henderson G, Craig S, Brocklehurst P, McGuire W. Enteral
feeding regimens and necrotising enterocolitis in preterm
infants: a multicentre case-control study. Archives of Disease
in Childhood. Fetal and Neonatal Edition 2009;94(2):
F120–3.
Johnson 1976
Johnson CR. The trophic action of gastrointestinal
hormones. Gastroenterology 1976;70(2):278–88.
Klingenberg 2012
Klingenberg C, Embleton ND, Jacobs SE, O’Connell LAF,
Kuschel CA. Enteral feeding practices in very preterm
infants: an international survey. Archives of Disease in
Childhood. Fetal and Neonatal Edition 2012;97(1):F56–61.
Lucas 1990
Lucas A, Cole TJ. Breast milk and neonatal necrotising
enterocolitis. Lancet 1990;336(8730):1519–23.
McClure 2001
McClure RJ. Trophic feeding of the preterm infant. Acta
Paediatrica. Supplement 2001;90(436):19–21.
McHale 2010
McHale SM, McCarthy R, O’Donnel CPF. How minimal is
“minimal” enteral feeding?. Archives of Disease in Childhood.
Fetal and Neonatal Edition 2010;95(2):F149–50.
Meinzen-Derr 2009
Meinzen-Derr J, Poindexter B, Wrage L, Morrow AL, Stoll
B, Donovan EF. Role of human milk in extremely low birth
weight infants’ risk of necrotizing enterocolitis or death.
Journal of Perinatology 2009;29(1):57–62.
Morgan 2011a
Morgan J, Young L, McGuire W. Delayed introduction of
progressive enteral feeds to prevent necrotising enterocolitis
in very low birth weight infants. Cochrane Database
of Systematic Reviews 2011, Issue 3. [DOI: 10.1002/
14651858.CD001970.pub3]
Morgan 2011b
Morgan J, Young L, McGuire W. Slow advancement of
enteral feed volumes to prevent necrotising enterocolitis
in very low birth weight infants. Cochrane Database
of Systematic Reviews 2011, Issue 3. [DOI: 10.1002/
14651858.CD001241.pub3]
Early trophic feeding versus enteral fasting for very preterm or very low birth weight infants (Review)
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Patole 2005
Patole SK, de Klerk N. Impact of standardised feeding
regimens on incidence of neonatal necrotising enterocolitis:
a systematic review and meta-analysis of observational
studies. Archives of Disease in Childhood. Fetal and Neonatal
Edition 2005;90(2):147–51.
Premji 2011
Premji SS, Chessell L. Continuous nasogastric milk feeding
versus intermittent bolus milk feeding for premature
infants less than 1500 grams. Cochrane Database of
Systematic Reviews 2011, Issue 11. [DOI: 10.1002/
14651858.CD001819.pub2]
Quigley 2007
Quigley MA, Henderson G, Anthony MY, McGuire
W. Formula milk versus donor breast milk for feeding
preterm or low birth weight infants. Cochrane Database
of Systematic Reviews 2007, Issue 4. [DOI: 10.1002/
14651858.CD002971.pub2]
Rees 2007
Rees CM, Pierro A, Eaton S. Neurodevelopmental outcomes
of neonates with medically and surgically treated necrotizing
enterocolitis. Archives of Disease in Childhood. Fetal and
Neonatal Edition 2007;92(3):193–8.
Tyson 2007
Tyson JE, Kennedy KA, Lucke JF, Pedroza C. Dilemmas
initiating enteral feedings in high risk infants: how can they
be resolved?. Seminars in Perinatology 2007;31(2):61–73.
Walsh 1986
Walsh MC, Kliegman RM. Necrotizing enterocolitis:
treatment based on staging criteria. Pediatric Clinics of
North America 1986;33(1):179–201.
References to other published versions of this review
Bombell 2009
Bombell S, McGuire W. Early trophic feeding for
very low birth weight infants. Cochrane Database of
Systematic Reviews 2009, Issue 3. [DOI: 10.1002/
14651858.CD000504.pub3]
Tyson 1997
Tyson JE, Kennedy KA. Minimal enteral nutrition for
promoting feeding tolerance and preventing morbidity
in parenterally fed infants. Cochrane Database of
Systematic Reviews 1997, Issue 4. [DOI: 10.1002/
14651858.CD000504]
Tyson 2005
Tyson JE, Kennedy KA. Trophic feedings for parenterally
fed infants. Cochrane Database of Systematic Reviews 2005,
Issue 3. [DOI: 10.1002/14651858.CD000504.pub2]
∗
Indicates the major publication for the study
10
CHARACTERISTICS OF STUDIES

Characteristics of included studies [ordered by study ID]

Becerra 1996

Methods Randomised controlled trial

Participants VLBW infants with asphyxia, respiratory distress syndrome, suspected or documented
sepsis, hypotension, hypo- or hyperglycaemia, or anaemia or polycythaemia. The pro-
portion who received mechanical ventilation was not stated. Exclusions included immi-
nently expected death, major congenital anomalies or metabolic conditions

Interventions Minimal enteral nutrition (N = 96) vs. enteral fasting (N = 94) until 7 days after birth.
Intervention group received minimal enteral feeds of breast milk or preterm formula
milk at 25 ml/kg/day for 1 week. Control infants were not fed until 6 to 8 days after
birth

Outcomes Time to establish full enteral feeds

Incidence of necrotising enterocolitis
Time to regain birth weight

Notes Data as reported in abstract or in correspondence with the principal investigator

The method of administration of feeds was not described

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Not described - reported in abstract form only
bias)

Allocation concealment (selection bias) Unclear risk Unclear

Blinding (performance bias and detection High risk Not reported by likely that care givers and investigators
bias) were aware of allocation groups
All outcomes

Blinding of outcome assessment (detection Unclear risk Not reported

bias)
All outcomes

Incomplete outcome data (attrition bias) Low risk All data were accounted for
All outcomes

Early trophic feeding versus enteral fasting for very preterm or very low birth weight infants (Review) 11
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Dunn 1988

Methods Randomised controlled trial

Participants VLBW infants with respiratory distress syndrome treated with mechanical ventilation
and with an umbilical artery catheter in situ.
Setting: Rainbow Babies and Children’s Hospital, Cleveland, USA

Interventions Minimal enteral nutrition (N = 19) vs. enteral fasting (N = 20) until 9 days after birth.
Intervention group infants received minimal enteral feeds from 48 hours at 15 to 20 ml/
kg/day of diluted preterm formula milk

Outcomes Time to establish full enteral feeds

Incidence of necrotising enterocolitis
Growth: time to regain birth weight and growth throughout study period
Duration of phototherapy
Mortality
Incidence of sepsis
Duration of hospital stay

Notes All infants received formula milk. Feeds were given by intermittent gavage nasogastric
technique
Data enabling calculation of SD relating to duration of hospital stay were not provided.
We have imputed this information from standard deviations provided by Meetze 1992,
a trial with similar sample size, as recommended by the Cochrane Handbook

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Stratified into groups according to birth weight then ran-
bias) domised using cards in paired envelopes

Allocation concealment (selection bias) High risk Unclear if envelopes were sealed - possibility that alloca-
tion groups could have been predicted

Blinding (performance bias and detection Unclear risk No blinding of care givers or investigators after allocation
bias)
All outcomes

Blinding of outcome assessment (detection Unclear risk No reference to whether interpretation of radiographs
bias) was blind
All outcomes

Incomplete outcome data (attrition bias)
All outcomes
Unclear risk 9 infants were excluded from some of the outcome data:
5 deaths in the control group, 1 death in the interven-
tion group and 3 infants removed from the minimal en-
teral nutrition group due to severe unrecognised aortic
coarctation, systemic candidiasis and ileus precluding the
introduction of feeds. These infants have been included
in intention-to-treat analysis. Uncertainty exists about

Early trophic feeding versus enteral fasting for very preterm or very low birth weight infants (Review) 12
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Dunn 1988 (Continued)

whether these infants went on to develop necrotising en-

terocolitis as this is not formally reported. We have as-
sumed they did not

McClure 2000

Methods Randomised controlled trial

Participants Infants weighing < 1750 grams at birth with respiratory distress syndrome who required
mechanical ventilation beyond 48 hours
Setting: Leeds General Infirmary, UK

Interventions Minimal enteral nutrition (N = 48) vs. enteral fasting (N = 52). Minimal enteral nutrition
(0.5 to 1 ml/hour of expressed maternal breast milk or preterm formula) was given from
day 3 until mechanical ventilation was discontinued. The control group received no
enteral feeding while mechanical ventilation was provided

Outcomes Feeding tolerance; days to full enteral feeding

Incidence of necrotising enterocolitis
Time to regain birth weight and growth parameters during hospital admission
Days to full oral intake, duration of parenteral nutrition
Incidence of invasive infection

Notes Both groups received parenteral nutrition. Following discontinuation of mechanical

ventilation, “nutritive” enteral feedings were initiated at 1 ml/kg/hour and increased by
1 ml/kg/hour every 8 to 12 hours as tolerated
All feeds were given by intermittent gavage

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk Computer-generated sequence

bias)

Allocation concealment (selection bias) Low risk Blinding of investigators at the time of randomisation

Blinding (performance bias and detection High risk Care givers and investigators were not blinded to alloca-
bias) tion groups after randomisation had occurred
All outcomes

Blinding of outcome assessment (detection Unclear risk No description of whether radiological assessment was
bias) blind. Laboratory staff were blinded to allocation groups
All outcomes

Incomplete outcome data (attrition bias) Low risk All data were accounted for
All outcomes

Early trophic feeding versus enteral fasting for very preterm or very low birth weight infants (Review) 13
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Meetze 1992

Methods Randomised controlled trial

Participants Infants of birth weight 501 to 1250 grams and gestational age at birth 25 to 32 weeks
Proportion of infants receiving mechanical ventilation not stated
Setting: neonatal unit, Gainesville, USA

Interventions Minimal enteral nutrition (N = 22) vs. enteral fasting (N = 25). The minimal enteral
nutrition group received preterm formula beginning at 2.5 ml/kg/day on day 3 advancing
to 22 ml/kg/day on day 14. During this time controls were not fed. Both groups received
progressive enteral feeds from day 15

Outcomes Incidence of necrotising enterocolitis

Growth at day 30
Mortality
Duration of phototherapy
Duration of hospital stay

Notes Infants receiving breast milk were excluded

All feeds were given by intermittent bolus orogastric administration

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Stratified randomisation based on birth weight (method
bias) of randomisation not described)

Allocation concealment (selection bias) Unclear risk Unclear

Blinding (performance bias and detection Unclear risk Care givers and investigators not blinded to intervention
bias) group
All outcomes

Blinding of outcome assessment (detection Unclear risk Not described

bias)
All outcomes

Incomplete outcome data (attrition bias)
All outcomes
Low risk Not all data were accounted for. 7 infants were not in-
cluded in all components of the final analyses: 1 infant
in the minimal enteral nutrition group developed necro-
tising enterocolitis on day 7 and was subsequently ex-
cluded from further analyses, 2 infants died and 4 parents
withdrew consent. This accounts for 15% of all infants
participating at time of randomisation. 6 other infants
developed necrotising enterocolitis after day 20 and were
included in all components of the analysis

Early trophic feeding versus enteral fasting for very preterm or very low birth weight infants (Review) 14
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Mosqueda 2008

Methods Randomised controlled trial

Participants ELBW infants < 24 hours old

Infants with congenital anomalies, infants receiving inotrope support or exchange trans-
fusion and infants with severe acidaemia were ineligible
Setting: Neonatal Intensive Care Unit of Loyola University Medical Center, Maywood,
USA

Interventions Minimal enteral nutrition (N = 41) vs. enteral fasting (N = 43). Minimal enteral nutrition
(12 ml/kg/day) with expressed breast milk or standard formula milk was given from
day 2 until day 7. The control group received no enteral feeding. Both groups received
standard parenteral nutrition. Both groups received progressive enteral feeds (increasing
by 10 ml/kg/day) from day 8

Outcomes Feeding tolerance; days to full enteral feeding

Incidence of necrotising enterocolitis
Time to regain birth weight and growth parameters during hospital admission
Duration of hospital admission

Notes Feeds were given intermittently as boluses of nasogastric or orogastric feeds

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Not stated

bias)

Allocation concealment (selection bias) Low risk Sealed envelopes

Blinding (performance bias and detection High risk Not stated but unlikely that care givers and investigators
bias) were blinded to allocation groups
All outcomes

Blinding of outcome assessment (detection Unclear risk Unclear if interpretation of abdominal X-rays was blind
bias)
All outcomes

Incomplete outcome data (attrition bias)
All outcomes
High risk Overall 23 out of 84 infants were not included in all
components of the analysis due to protocol violation,
withdrawal of consent or death (8 in the minimal enteral
feeding group, 15 in the control group). This equates to
27% of the initial infants at randomisation

Early trophic feeding versus enteral fasting for very preterm or very low birth weight infants (Review) 15
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Schanler 1999

Methods Randomised controlled trial

Participants Infants 26 to 30 weeks’ gestation whose birth weight was appropriate for gestational age,
who had no major congenital anomalies
Setting: Texas Children’s Hospital, Texas, USA

Interventions Minimal enteral nutrition (N = 82) vs. enteral fasting (N = 89). The minimal enteral
feeding group received 20 ml/kg/day of expressed breast milk or half-strength preterm
formula from day 4 to 14 after birth

Outcomes Feeding tolerance; days to full enteral feeding

Incidence of necrotising enterocolitis
Time to regain birth weight and growth parameters during hospital admission
Incidence of invasive infection
Mortality

Notes This study used a factorial design in which infants were randomised to 4 groups (con-
tinuous minimal enteral feeds, intermittent bolus minimal enteral feeds, enteral fast-
ing followed by continuous feeding, enteral fasting followed by bolus feeding) to allow
simultaneous assessment of the use of both minimal enteral nutrition and continuous
feedings vs. bolus. In this review, Schanler 1999 refers to outcomes reported for all infants
in trophic feedings group vs. all control infants
[February 2009: mortality data received from Dr Schanler.] [June 2012: incidence of
infection data received from Dr Schanler]

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Stratification by gestational age and type of milk followed
bias) by randomisation using sealed opaque envelopes

Allocation concealment (selection bias) Low risk Adequate given the use of sealed envelopes

Blinding (performance bias and detection Unclear risk Care givers and investigators not blinded following ran-
bias) domisation
All outcomes

Blinding of outcome assessment (detection Unclear risk Not described

bias)
All outcomes

Incomplete outcome data (attrition bias) Unclear risk Intention-to-treat analysis

All outcomes

Early trophic feeding versus enteral fasting for very preterm or very low birth weight infants (Review) 16
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Sáenz de Pipaón 2003

Methods Randomised controlled trial

Participants Infants weighing < 1600 grams at birth. Exclusions included infants of diabetic mothers,
major congenital anomalies and proven sepsis
Setting: La Paz University Hospital, Madrid, Spain

Interventions Minimal enteral nutrition (N = 24) vs. enteral fasting (N = 12). On day 1, infants were
randomly allocated to either minimal enteral nutrition (10 ml/kg/day on day 1, then 20
ml/kg/day through until day 7) or enteral fasting for 7 days

Outcomes This was primarily a metabolic study examining whether enteral leucine uptake was
affected by trophic feeding
Authors also reported time to establish full feeds
Communication with authors revealed data were collected on the incidence of necrotising
enterocolitis and mortality

Notes March 2009: clarification of methods and outcome data received from Dr Saenz de
Pipaon (principal investigator):
“If the mother wished to give breast milk and the baby was allocated to the minimal
enteral nutrition group, he or she started on day one to receive breast milk. If the mother
was not able or did not wish to give breast milk the infant received formula. If the baby
was allocated to the enteral fasting group, breast milk or formula was given from day
seven.”

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk Correspondence with principal investigator revealed ran-
bias) domisation involved sealed opaque envelopes with 2:1
allocation ratio

Allocation concealment (selection bias) Low risk Satisfactory

Blinding (performance bias and detection High risk No blinding of care givers or investigators
bias)
All outcomes

Blinding of outcome assessment (detection Unclear risk No statement about blinding of radiological assessment
bias)
All outcomes

Incomplete outcome data (attrition bias) Low risk All data were accounted for
All outcomes

Early trophic feeding versus enteral fasting for very preterm or very low birth weight infants (Review) 17
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Troche 1995

Methods Randomised controlled trial

Participants Infants born at 25 to 30 weeks’ gestation with respiratory distress, an umbilical artery
catheter in situ, and an anticipated need for mechanical ventilation for at least 3 days.
Infants with asphyxia or respiratory failure despite ventilatory support were excluded
Setting: University of Boston, USA

Interventions Minimal enteral nutrition (N = 16) vs. enteral fasting (N = 13)

Infants in the minimal enteral nutrition group received maternal breast milk or standard
formula beginning within 24 hours after birth at a rate of 0.5 to 1.0 ml/hour until the
umbilical artery catheter was removed. Controls were fasted until the umbilical arterial
catheter was removed. Both groups received parenteral nutrition beginning on day 3

Outcomes Feeding tolerance; days to full enteral feeding

Incidence of necrotising enterocolitis
Time to regain birth weight
Mortality

Notes In infants < 800g at birth, feeds were given by continuous infusion, for those > 800 g
feeds were given as boluses

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk Random numbers table

bias)

Allocation concealment (selection bias) Unclear risk Unclear

Blinding (performance bias and detection High risk Not stated but likely that care givers and investigators
bias) were aware of intervention group after allocation
All outcomes

Blinding of outcome assessment (detection Unclear risk Not stated

bias)
All outcomes

Incomplete outcome data (attrition bias) Low risk 2 infants developed necrotising enterocolitis but were
All outcomes then subsequently excluded from growth data

van Elburg 2004

Methods Randomised controlled trial

Participants Infants of birth weight < 2000 grams who were small for gestational age (< 10th percentile
for birth weight)

Early trophic feeding versus enteral fasting for very preterm or very low birth weight infants (Review) 18
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
van Elburg 2004 (Continued)

Interventions Minimal enteral nutrition (N = 28) vs. enteral fasting (N = 28)

Minimal enteral nutrition (0.5 ml every 2 hours for infants < 1000 grams, 1 ml every
2 hours for infants > 1000 grams) with expressed breast milk or preterm formula milk
was given from day 2 for 5 days. The control group received no enteral feeding. Both
groups received standard parenteral nutrition. Both groups received progressive enteral
feeds (increasing by 10 ml/kg/day) from day 8

Outcomes Feeding tolerance; days to full enteral feeding

Incidence of necrotising enterocolitis
Time to regain birth weight and growth parameters during hospital admission
Duration of intensive care admission

Notes The primary aim of this study was to assess the effect of minimal enteral nutrition on
intestinal permeability in preterm infants with intra-uterine growth restriction
The method of administration of feeds was not described

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk Selection of cards designating the allocation group in
bias) sealed envelopes

Allocation concealment (selection bias) Low risk Sealed opaque envelopes

Blinding (performance bias and detection Unclear risk Care givers and investigators were not blinded to alloca-
bias) tion groups
All outcomes

Blinding of outcome assessment (detection Unclear risk Unclear if interpretation of radiological images was blind
bias)
All outcomes

Incomplete outcome data (attrition bias) High risk Not all data were accounted for - 25% lost to follow-up
All outcomes due to incomplete data collection, death and one case of
congenital CMV infection

ELBW: extremely low birth weight

SD: standard deviation
VLBW: very low birth weight

Early trophic feeding versus enteral fasting for very preterm or very low birth weight infants (Review) 19
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Berseth 1992 This trial compared 2 minimal enteral nutrition regimens. Infants were randomly assigned to receive minimal
enteral nutrition on postnatal days 3 to 5 (early feeding) or on days 10 to 14 (late feeding). The trial was excluded
because infants did not have the same feeding regimen after completion of the early trophic feeding versus enteral
fasting phase

Berseth 1993 This trial did not assess the effect of minimal enteral nutrition. Both groups were fasted enterally during the first
week after birth. In the intervention group, minimal enteral feeding was introduced 8 days after birth and controls
were given the same volume of water enterally

Berseth 2003 This randomised controlled trial compared minimal enteral nutrition with progressive enteral feed volume ad-
vancement (at daily increments of 20 ml/kg)

LaGamma 1985 Although not clearly stated in the title or abstract, this was not a randomised controlled trial

Ostertag 1986 This trial compared delayed versus early introduction of progressive enteral feeds (advanced by 10 ml/kg/day).
This trial has been included in the Cochrane review of ’Delayed enteral feeding to prevent necrotising enterocolitis
in very low birth weight infants’ (Morgan 2011a)

Said 2008 This trial compared delayed versus early introduction of enteral nutrition and may be eligible for inclusion in an
update of the Cochrane review of ’Delayed enteral feeding to prevent necrotising enterocolitis in very low birth
weight infants’ (Morgan 2011a)

Slagle 1988 This trial did not assess the effect of early minimal enteral nutrition. Both groups were fasted enterally during the
first week after birth. Minimal enteral nutrition was introduced after 8 days in the intervention group

Weiler 2006 Infants were randomly allocated to minimal enteral nutrition starting on either day 2 or day 4 after birth, that is
both groups received ’minimal enteral nutrition’

Early trophic feeding versus enteral fasting for very preterm or very low birth weight infants (Review) 20
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
DATA AND ANALYSES

Comparison 1. Effects of trophic feeding versus enteral fasting

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Days to reach full enteral feeding 6 556 Mean Difference (IV, Fixed, 95% CI) -1.05 [-2.61, 0.51]
2 Incidence of necrotising 9 748 Risk Ratio (M-H, Fixed, 95% CI) 1.07 [0.67, 1.70]
enterocolitis
3 Mortality 8 558 Risk Ratio (M-H, Fixed, 95% CI) 0.66 [0.41, 1.07]
4 Days to regain birth weight 5 518 Mean Difference (IV, Fixed, 95% CI) -0.01 [-0.96, 0.95]
5 Incidence of invasive infection 3 237 Risk Ratio (M-H, Fixed, 95% CI) 1.06 [0.72, 1.56]
6 Duration of phototherapy (days) 3 170 Mean Difference (IV, Fixed, 95% CI) 0.35 [-0.29, 0.99]
7 Days of hospital stay 4 341 Mean Difference (IV, Fixed, 95% CI) -3.85 [-11.54, 3.84]

Analysis 1.1. Comparison 1 Effects of trophic feeding versus enteral fasting, Outcome 1 Days to reach full
enteral feeding.

Review: Early trophic feeding versus enteral fasting for very preterm or very low birth weight infants

Comparison: 1 Effects of trophic feeding versus enteral fasting

Outcome: 1 Days to reach full enteral feeding

Mean Mean
Study or subgroup Trophic feeding Enteral fasting Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Becerra 1996 96 18.2 (10.3) 94 16.8 (7.7) 36.5 % 1.40 [ -1.18, 3.98 ]

Dunn 1988 15 31.2 (9.4) 15 47.3 (26.7) 1.2 % -16.10 [ -30.42, -1.78 ]

McClure 2000 48 24.8 (11.9) 52 36.1 (23.2) 4.8 % -11.30 [ -18.45, -4.15 ]

Schanler 1999 82 35 (32) 89 32 (20) 3.7 % 3.00 [ -5.08, 11.08 ]

S enz de Pipa n 2003 24 17 (5) 14 17 (5) 22.4 % 0.0 [ -3.30, 3.30 ]

Troche 1995 16 10 (3) 11 13 (4) 31.4 % -3.00 [ -5.78, -0.22 ]

Total (95% CI) 281 275 100.0 % -1.05 [ -2.61, 0.51 ]

Heterogeneity: Chi2 = 18.84, df = 5 (P = 0.002); I2 =73%
Test for overall effect: Z = 1.32 (P = 0.19)
Test for subgroup differences: Not applicable

-20 -10 0 10 20
Favours trophic Favours fasting

Early trophic feeding versus enteral fasting for very preterm or very low birth weight infants (Review) 21
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Analysis 1.2. Comparison 1 Effects of trophic feeding versus enteral fasting, Outcome 2 Incidence of
necrotising enterocolitis.

Review: Early trophic feeding versus enteral fasting for very preterm or very low birth weight infants

Comparison: 1 Effects of trophic feeding versus enteral fasting

Outcome: 2 Incidence of necrotising enterocolitis

Study or subgroup Trophic feeding Enteral fasting Risk Ratio Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Becerra 1996 8/96 6/94 1.31 [ 0.47, 3.62 ]

Dunn 1988 3/19 1/20 3.16 [ 0.36, 27.78 ]

McClure 2000 1/48 2/52 0.54 [ 0.05, 5.78 ]

Meetze 1992 3/20 4/21 0.79 [ 0.20, 3.09 ]

Mosqueda 2008 3/41 4/43 0.79 [ 0.19, 3.30 ]

Schanler 1999 13/82 10/89 1.41 [ 0.65, 3.04 ]

S enz de Pipa n 2003 0/24 0/14 0.0 [ 0.0, 0.0 ]

Troche 1995 0/16 2/13 0.16 [ 0.01, 3.16 ]

van Elburg 2004 0/28 1/28 0.33 [ 0.01, 7.85 ]

Total (95% CI) 374 374 1.07 [ 0.67, 1.70 ]

Total events: 31 (Trophic feeding), 30 (Enteral fasting)
Heterogeneity: Chi2 = 4.35, df = 7 (P = 0.74); I2 =0.0%
Test for overall effect: Z = 0.27 (P = 0.78)
Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours trophic Favours fasting

Early trophic feeding versus enteral fasting for very preterm or very low birth weight infants (Review) 22
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Analysis 1.3. Comparison 1 Effects of trophic feeding versus enteral fasting, Outcome 3 Mortality.

Review: Early trophic feeding versus enteral fasting for very preterm or very low birth weight infants

Comparison: 1 Effects of trophic feeding versus enteral fasting

Outcome: 3 Mortality

Study or subgroup Trophic feeding Enteral fasting Risk Ratio Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Dunn 1988 1/19 5/20 0.21 [ 0.03, 1.64 ]

McClure 2000 6/48 11/52 0.59 [ 0.24, 1.47 ]

Meetze 1992 0/20 2/23 0.23 [ 0.01, 4.50 ]

Mosqueda 2008 7/41 11/43 0.67 [ 0.29, 1.55 ]

Schanler 1999 6/82 6/89 1.09 [ 0.36, 3.23 ]

S enz de Pipa n 2003 0/24 0/12 0.0 [ 0.0, 0.0 ]

Troche 1995 1/16 1/13 0.81 [ 0.06, 11.77 ]

van Elburg 2004 2/28 1/28 2.00 [ 0.19, 20.82 ]

Total (95% CI) 278 280 0.66 [ 0.41, 1.07 ]

Total events: 23 (Trophic feeding), 37 (Enteral fasting)
Heterogeneity: Chi2 = 3.41, df = 6 (P = 0.76); I2 =0.0%
Test for overall effect: Z = 1.67 (P = 0.094)
Test for subgroup differences: Not applicable

0.01 0.1 1 10 100

Favours trophic Favours fasting

Early trophic feeding versus enteral fasting for very preterm or very low birth weight infants (Review) 23
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Analysis 1.4. Comparison 1 Effects of trophic feeding versus enteral fasting, Outcome 4 Days to regain birth
weight.

Review: Early trophic feeding versus enteral fasting for very preterm or very low birth weight infants

Comparison: 1 Effects of trophic feeding versus enteral fasting

Outcome: 4 Days to regain birth weight

Mean Mean
Study or subgroup Trophic feeding Enteral fasting Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Becerra 1996 96 14.3 (5.5) 94 13.5 (5.2) 39.4 % 0.80 [ -0.72, 2.32 ]

Dunn 1988 15 19.9 (6.2) 15 24.4 (8.5) 3.2 % -4.50 [ -9.82, 0.82 ]

McClure 2000 48 16.4 (6) 52 18.2 (9.2) 10.0 % -1.80 [ -4.82, 1.22 ]

Schanler 1999 82 12.5 (5) 89 12.5 (6) 33.5 % 0.0 [ -1.65, 1.65 ]

Troche 1995 16 19 (2) 11 19 (4) 13.9 % 0.0 [ -2.56, 2.56 ]

Total (95% CI) 257 261 100.0 % -0.01 [ -0.96, 0.95 ]

Heterogeneity: Chi2 = 5.17, df = 4 (P = 0.27); I2 =23%
Test for overall effect: Z = 0.02 (P = 0.98)
Test for subgroup differences: Not applicable

-10 -5 0 5 10
Favours trophic Favours fasting

Early trophic feeding versus enteral fasting for very preterm or very low birth weight infants (Review) 24
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Analysis 1.5. Comparison 1 Effects of trophic feeding versus enteral fasting, Outcome 5 Incidence of
invasive infection.
Review: Early trophic feeding versus enteral fasting for very preterm or very low birth weight infants

Comparison: 1 Effects of trophic feeding versus enteral fasting

Outcome: 5 Incidence of invasive infection

Study or subgroup Trophic feeding Enteral fasting Risk Ratio Weight Risk Ratio
n/N n/N M-H,Fixed,95% CI M-H,Fixed,95% CI
Dunn 1988 6/19 4/20 11.2 % 1.58 [ 0.53, 4.74 ]

Mosqueda 2008 13/41 9/43 25.2 % 1.51 [ 0.73, 3.16 ]

Schanler 1999 17/55 23/59 63.6 % 0.79 [ 0.48, 1.32 ]

Total (95% CI) 115 122 100.0 % 1.06 [ 0.72, 1.56 ]

Total events: 36 (Trophic feeding), 36 (Enteral fasting)
Heterogeneity: Chi2 = 2.67, df = 2 (P = 0.26); I2 =25%
Test for overall effect: Z = 0.31 (P = 0.76)
Test for subgroup differences: Not applicable

0.5 0.7 1 1.5 2

Favours trophic Favours fasting

Early trophic feeding versus enteral fasting for very preterm or very low birth weight infants (Review) 25
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Analysis 1.6. Comparison 1 Effects of trophic feeding versus enteral fasting, Outcome 6 Duration of
phototherapy (days).

Review: Early trophic feeding versus enteral fasting for very preterm or very low birth weight infants

Comparison: 1 Effects of trophic feeding versus enteral fasting

Outcome: 6 Duration of phototherapy (days)

Mean Mean
Study or subgroup Trophic feeding Enteral fasting Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Dunn 1988 15 6.8 (2.4) 15 9.5 (4) 7.4 % -2.70 [ -5.06, -0.34 ]

McClure 2000 48 2.3 (1.7) 52 1.8 (1.8) 87.1 % 0.50 [ -0.19, 1.19 ]

Meetze 1992 19 6.3 (5.2) 21 4.3 (3.2) 5.6 % 2.00 [ -0.71, 4.71 ]

Total (95% CI) 82 88 100.0 % 0.35 [ -0.29, 0.99 ]

Heterogeneity: Chi2 = 8.02, df = 2 (P = 0.02); I2 =75%
Test for overall effect: Z = 1.07 (P = 0.29)
Test for subgroup differences: Not applicable

-4 -2 0 2 4
Favours trophic Favours fasting

Early trophic feeding versus enteral fasting for very preterm or very low birth weight infants (Review) 26
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Analysis 1.7. Comparison 1 Effects of trophic feeding versus enteral fasting, Outcome 7 Days of hospital stay.

Review: Early trophic feeding versus enteral fasting for very preterm or very low birth weight infants

Comparison: 1 Effects of trophic feeding versus enteral fasting

Outcome: 7 Days of hospital stay

Mean Mean
Study or subgroup Trophic feeding Enteral fasting Difference Weight Difference
N Mean(SD) N Mean(SD) IV,Fixed,95% CI IV,Fixed,95% CI

Dunn 1988 15 98 (20.9) 15 102 (33) 15.1 % -4.00 [ -23.77, 15.77 ]

McClure 2000 48 70.3 (27.2) 52 92.4 (58.3) 19.1 % -22.10 [ -39.72, -4.48 ]

Meetze 1992 19 73 (20.9) 21 76 (33) 20.6 % -3.00 [ -19.96, 13.96 ]

Schanler 1999 82 84 (43) 89 80.5 (32) 45.2 % 3.50 [ -7.94, 14.94 ]

Total (95% CI) 164 177 100.0 % -3.85 [ -11.54, 3.84 ]

Heterogeneity: Chi2 = 5.72, df = 3 (P = 0.13); I2 =48%
Test for overall effect: Z = 0.98 (P = 0.33)
Test for subgroup differences: Not applicable

-20 -10 0 10 20
Favours trophic Favours fasting

WHAT’S NEW
Last assessed as up-to-date: 27 December 2012.

Date Event Description

6 February 2013 New citation required and conclusions have changed The title has been amended to ’Early trophic feeding
versus enteral fasting for very preterm or very low birth
weight infants’ to emphasise the comparison with fast-
ing rather than progressive feeding
The search strategy was updated in December 2012.
One new study was assessed for eligibility but was ex-
cluded based on the definition of the interventions
Further (unpublished) data were obtained from cur-
rent included trials and added to the meta-analyses

27 December 2012 New search has been performed This updates the review ’Early trophic feeding for very
low birth weight infants’ (Bombell 2009).

Early trophic feeding versus enteral fasting for very preterm or very low birth weight infants (Review) 27
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
HISTORY
Protocol first published: Issue 4, 1997
Review first published: Issue 4, 1997

Date Event Description

7 March 2009 New citation required and conclusions have changed New authorship: Sarah Bombell, William McGuire.

7 March 2009 New search has been performed This updates the review ’Trophic feedings for parenter-
ally fed infants’ by Tyson JE, Kennedy KA, Cochrane
Database of Systematic Reviews 2005, Issue 3 (Tyson
2005).
The title has been modified to ’Early trophic feeding for
very low birth weight infants’ and has a new authorship
of Sarah Bombell and William McGuire. Changes made
to the original protocol are outlined below:
1. The population has been restricted to very low birth
weight and very preterm infants
2. Early trophic feeding is defined as enteral feeding up
to 24 ml/kg/day (1 ml/kg/hour) beginning within four
days after birth and continued until at least one week
after birth versus enteral fasting for at least one week af-
ter birth. On the subsequent introduction of progressive
enteral feeding, infants should have received the same
type of milk (breast milk or formula), the same route
and mode of feeding (intragastric or transpyloric, bolus
gavage or continuous), and the same rate of feed volume
advancement in both groups
3. Subgroup analyses of extremely low birth weight and
extremely preterm infants and infants with evidence of
intrauterine growth restriction or absent or reversed end-
diastolic flow velocities in Doppler studies of the fetal
aorta or umbilical artery were prespecified.

Search updated February 2009. Three new trials were

included (Sáenz de Pipaón 2003; van Elburg 2004;
Mosqueda 2008).
Five trials included in the previous version of this review
have been excluded because they did not fulfil the stricter
definition of the intervention and comparison (Ostertag
1986; Slagle 1988; Berseth 1992; Berseth 1993; Berseth
2003).
The main change to the findings and implications for
practice is that the typical estimate for feed tolerance
(time to full enteral feeding) is no longer statistically
significant

28 October 2008 Amended Converted to new review format.

Early trophic feeding versus enteral fasting for very preterm or very low birth weight infants (Review) 28
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)

31 March 2005 New search has been performed This review updates the existing review of ’Minimal
enteral nutrition in parenterally fed neonates’ that was
published in The Cochrane Library, Disk Issue 4, 1997.
Three new eligible trials (Berseth 2003; McClure 2000;
Schanler 1999) have been found.

31 March 2005 New citation required and conclusions have changed Substantive amendment.

CONTRIBUTIONS OF AUTHORS
The review authors developed the protocol, undertook the literature search, appraised the articles, extracted and entered the data, and
completed the review jointly.

DECLARATIONS OF INTEREST
None.

SOURCES OF SUPPORT
Internal sources
• Centre for Reviews and Dissemination, University of York, UK.

External sources
• NIHR, UK.
• Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health,
Department of Health and Human Services, USA.
The Cochrane Neonatal Review Group has been funded in part with Federal funds from the Eunice Kennedy Shriver National
Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA,
under Contract No. HHSN267200603418C

INDEX TERMS

Early trophic feeding versus enteral fasting for very preterm or very low birth weight infants (Review) 29
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Medical Subject Headings (MeSH)
∗ Milk;Adaptation, Physiological; Child Development [∗ physiology]; Enteral Nutrition [adverse effects; ∗ methods]; Enterocolitis,
Necrotizing [prevention & control]; Infant Formula; Infant, Newborn; Infant, Premature; Infant, Very Low Birth Weight [growth &
development; ∗ physiology]; Milk, Human; Parenteral Nutrition [adverse effects; methods]; Randomized Controlled Trials as Topic

MeSH check words

Animals; Humans

Early trophic feeding versus enteral fasting for very preterm or very low birth weight infants (Review) 30
Copyright © 2013 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Slow advancement of enteral feed volumes to prevent
necrotising enterocolitis in very low birth weight infants
(Review)

Morgan J, Young L, McGuire W

This is a reprint of a Cochrane review, prepared and maintained by The Cochrane Collaboration and published in The Cochrane Library
2014, Issue 12
http://www.thecochranelibrary.com

Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 TABLE OF CONTENTS
HEADER . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
ABSTRACT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
PLAIN LANGUAGE SUMMARY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
BACKGROUND . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
OBJECTIVES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
METHODS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
RESULTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Figure 1. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
Figure 2. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
Figure 3. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
Figure 4. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
DISCUSSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9
Figure 5. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
AUTHORS’ CONCLUSIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
ACKNOWLEDGEMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11
CHARACTERISTICS OF STUDIES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13
DATA AND ANALYSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
WHAT’S NEW . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
HISTORY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
CONTRIBUTIONS OF AUTHORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
DECLARATIONS OF INTEREST . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
SOURCES OF SUPPORT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
INDEX TERMS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22

Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants (Review) i
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
[Intervention Review]

Slow advancement of enteral feed volumes to prevent

necrotising enterocolitis in very low birth weight infants

Jessie Morgan1 , Lauren Young2 , William McGuire1

1 Hull
York Medical School & Centre for Reviews and Dissemination, University of York, York, UK. 2 Neonatal Unit, Mercy Hospital
for Women, Heidelberg, Australia

Contact address: William McGuire, Hull York Medical School & Centre for Reviews and Dissemination, University of York, York,
Y010 5DD, UK. William.McGuire@hyms.ac.uk.

Editorial group: Cochrane Neonatal Group.

Publication status and date: New search for studies and content updated (no change to conclusions), published in Issue 12, 2014.
Review content assessed as up-to-date: 3 October 2014.

Citation: Morgan J, Young L, McGuire W. Slow advancement of enteral feed volumes to prevent necrotising enterocoli-
tis in very low birth weight infants. Cochrane Database of Systematic Reviews 2014, Issue 12. Art. No.: CD001241. DOI:
10.1002/14651858.CD001241.pub5.

Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT

Background

Early enteral feeding practices are potentially modifiable risk factors for necrotising enterocolitis in very preterm or very low birth weight
(VLBW) infants. Observational studies suggest that conservative feeding regimens, including slowly advancing enteral feed volumes,
reduce the risk of necrotising enterocolitis. However, slow feed advancement may delay establishment of full enteral feeding and be
associated with metabolic and infectious morbidities secondary to prolonged exposure to parenteral nutrition.

Objectives

To determine the effect of slow rates of enteral feed advancement on the incidence of necrotising enterocolitis, mortality, and other
morbidities in very preterm or VLBW infants.

Search methods

We used the standard search strategy of the Cochrane Neonatal Review Group Specialised Register. We searched the Cochrane Central
Register of Controlled Trials (CENTRAL 2014, Issue 8), MEDLINE, EMBASE, and CINAHL (to September 2014), conference
proceedings, and previous reviews.

Selection criteria

Randomised or quasi-randomised controlled trials that assessed the effect of slow (up to 24 ml/kg per day) versus faster rates of
advancement of enteral feed volumes upon the incidence of necrotising enterocolitis in very preterm or VLBW infants.

Data collection and analysis

Two review authors independently assessed trial eligibility and risk of bias and undertook data extraction. We analysed the treatment
effects in the individual trials and reported the risk ratio and risk difference for dichotomous data and mean difference for continuous
data, with respective 95% confidence intervals. We used a fixed-effect model in meta-analyses and explored the potential causes of
heterogeneity in sensitivity analyses.
Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants (Review) 1
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Main results

We identified six randomised controlled trials in which a total of 618 infants participated. Most participants were stable preterm infants
of birth weight between 1000 g and 1500 g. Few participants were extremely preterm, extremely low birth weight, or growth-restricted.
The trials typically defined slow advancement as daily increments of 15 ml/kg to 20 ml/kg and faster advancement as 30 ml/kg to
35 ml/kg. Meta-analyses did not detect statistically significant effects on the risk of necrotising enterocolitis (typical risk ratio (RR)
0.96, 95% confidence interval (CI) 0.55 to 1.70) or all-cause mortality (typical RR 1.57, 95% CI 0.92 to 2.70). Infants who had slow
advancement took significantly longer to regain birth weight (reported median differences 2 to 6 days) and to establish full enteral
feeding (1 to 5 days).

Authors’ conclusions

The available trial data suggest that advancing enteral feed volumes at daily increments of 30 ml/kg to 35 ml/kg does not increase
the risk of necrotising enterocolitis in very preterm or VLBW infants. Advancing the volume of enteral feeds at slow rates resulted in
several days delay in regaining birth weight and establishing full enteral feeds. The applicability of these findings to extremely preterm,
extremely low birth weight, or growth-restricted infants is limited. Further randomised controlled trials in these populations may be
warranted to resolve this uncertainty.

PLAIN LANGUAGE SUMMARY

Slowly advancing milk feeds does not reduce the risk of necrotising enterocolitis in very low birth weight infants

Very preterm (born before 32 weeks’ gestation) or very low birth weight (less than 1500 g) infants are at risk of developing a severe
bowel disorder known as necrotising enterocolitis. It is thought that one possible way to prevent this condition is to limit the amount
of milk feeds that infants receive each day for the first few weeks after birth. Six randomised controlled trials have assessed the effect of
slowly (rather than more quickly) increasing the volume of milk feeds given to very preterm or very low birth weight infants. Combined
analysis of these trials did not reveal any effect of the intervention on the risk of necrotising enterocolitis. Infants fed more slowly
regained birth weight and attained full enteral feeding several days later than infants fed more quickly.

BACKGROUND Description of the intervention

Description of the condition
Necrotising enterocolitis (NEC), a syndrome of acute intestinal
necrosis of unknown aetiology, affects about 5% of very preterm
(less than 32 weeks) or very low birth weight (VLBW) (less than
1500 g) infants (Holman 1997). Infants who develop NEC expe-
rience more nosocomial infections, have lower levels of nutrient
intake, grow more slowly, and have longer durations of intensive
care and hospital stay than gestation-comparable infants who do
not develop NEC (Bisquera 2002; Guthrie 2003). The associ-
ated mortality rate is more than 20%. Compared with their peers,
infants who develop NEC have a higher incidence of long-term
neurological disability, which may be a consequence of infection
and under-nutrition during a critical period of brain development
(Stoll 2004; Soraisham 2006; Rees 2007; Pike 2012).
Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Short gestational age at birth is the major clinical risk factor for
developing NEC (Beeby 1992; Luig 2005). The other putative
major risk factor is intrauterine growth restriction, especially if
associated with absent or reversed end-diastolic flow velocities in
Doppler studies of the fetal aorta or umbilical artery (Bernstein
2000; Garite 2004; Dorling 2005). Most very preterm or VLBW
infants who develop NEC have received enteral milk feeds. Evi-
dence exists that feeding with artificial formula rather than human
milk increases the risk of developing NEC (Quigley 2014). Other
differences in enteral feeding regimens, such as the timing of intro-
duction of feeds and the size of the daily volume increments, may
also contribute to inter-unit variation in the incidence of NEC.
Multicentre benchmarking studies have found that those neona-
tal centres where enteral feeding is introduced earlier and feeding
volumes advanced more quickly tend to have higher incidences
of NEC (Uauy 1991). Observational studies have suggested that
2
delaying the introduction of enteral feeds beyond the first few days
after birth, or increasing the volume of feeds by less than about
20 ml/kg to 24 ml/kg body weight each day, is associated with a
lower risk of developing NEC in very preterm or VLBW infants
(Brown 1978; McKeown 1992; Patole 2005; Henderson 2009).
Why it is important to do this review
Potential disadvantages associated with slowing the advancement
of enteral feed volumes include delaying the establishment of full
enteral nutrition and extending the duration of receipt of par-
enteral nutrition (Flidel-Rimon 2004). Prolonged use of parenteral
nutrition is associated with infectious and metabolic risks that may
have adverse consequences for survival, growth, and development
(Stoll 2004). It has been argued that the risk of NEC should not be
considered in isolation of these other potential clinical outcomes
when determining feeding policies and practice for very preterm
or VLBW infants (Flidel-Rimon 2006; Chauhan 2008; Härtel
2009).
Other Cochrane reviews have addressed the questions of whether
delaying the introduction of any enteral milk feeding or restricting
feed volumes to trophic levels (minimal enteral nutrition) affect
the risk of NEC in very preterm or VLBW infants (Bombell
2009; Morgan 2011). This review focussed on the question of
whether advancing feed volumes at slow rates compared to faster
rates affects the risk of NEC, mortality, and other morbidities.
OBJECTIVES
To determine the effect of slow rates of enteral feed advancement
on the incidence of NEC, mortality, and other morbidities in very
preterm or VLBW infants.
METHODS
Criteria for considering studies for this review
Types of studies
Controlled trials utilising either random or quasi-random partic-
ipant allocation.
Types of participants
Enterally fed very preterm (less than 32 weeks) or VLBW (less
than 1500 g) newborn infants.
Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Types of interventions
Advancement of enteral feeds at no more than 24 ml/kg (birth
weight or current body weight) per day versus faster rates of feeds
advancement. Infants should have received the same type of milk
and in both groups the advancement of feed volume should have
commenced within five days of introduction of enteral feeds.
Types of outcome measures
Primary outcomes
1. NEC confirmed by at least two of the following features:
• abdominal radiograph showing pneumatosis intestinalis or
gas in the portal venous system or free air in the abdomen;
• abdominal distension with abdominal radiograph with
gaseous distension or frothy appearance of bowel lumen (or
both);
• blood in stool;
• lethargy, hypotonia, or apnoea (or a combination of these);
or a diagnosis confirmed at surgery or autopsy (Walsh 1986).
2. All-cause mortality during the neonatal period and prior to
hospital discharge.
Secondary outcomes
1. Growth
i) Time to regain birth weight and subsequent rates of
weight gain, linear growth, head growth, or skinfold thickness
growth up to six months (corrected for preterm birth).
ii) Long-term growth: weight, height, or head
circumference (or proportion of infants who remained below the
10th percentile for the index population’s distribution) assessed
at intervals from six months of age.
2. Neurodevelopment
i) Death or severe neurodevelopmental disability defined
as any one or a combination of the following: nonambulant
cerebral palsy, developmental delay (developmental quotient less
than 70), auditory and visual impairment. Each component was
to be analysed individually as well as part of the composite
outcome.
ii) Neurodevelopmental scores in survivors aged greater
than or equal to 12 months measured using validated assessment
tools.
iii) Cognitive and educational outcomes in survivors aged
more than five years.
3. Time to establish full enteral feeding (independently of
parenteral nutrition).
4. Time to establish oral feeding (independently of parenteral
nutrition or enteral tube feeding, or both).
5. Feed intolerance (defined as a requirement to cease enteral
feeds).
3
 6. Incidence of invasive infection as determined by culture of
bacteria or fungus from blood, cerebrospinal fluid, urine, or from
a normally sterile body space.
7. Duration of hospital stay (days).
Search methods for identification of studies
We used the standard search strategy of the Cochrane Neonatal
Review Group (http://neonatal.cochrane.org/).
Electronic searches
We searched the Cochrane Central Register of Controlled Tri-
als (CENTRAL 2014, Issue 8), MEDLINE (1966 to September
2014), EMBASE (1980 to September 2014), and CINAHL (1982
to September 2014) using a combination of the following text
words and MeSH terms: [Infant, Newborn OR Infant, Premature
OR Infant, Low Birth Weight OR Infant, Very Low Birth Weight/
OR infan* OR neonat* OR preterm OR prem*] AND “Infant-
Nutrition”/all subheadings OR Infant Formula OR milk OR for-
mula OR trophic feeding OR minimal enteral nutrition OR gut
priming]. We limited the search outputs with the relevant search
filters for clinical trials. We did not apply any language restrictions.
We searched ClinicalTrials.gov for completed or ongoing trials.
Searching other resources
We examined the reference lists of all studies identified as poten-
tially relevant.
We searched the abstracts from the annual meetings of the Pedi-
atric Academic Societies (1993 to 2014), the European Society
for Pediatric Research (1995 to 2013), the UK Royal College of
Paediatrics and Child Health (2000 to 2014), and the Perinatal
Society of Australia and New Zealand (2000 to 2014). Trials re-
ported only as abstracts were eligible if sufficient information was
available from the report or from contact with the authors to fulfill
the inclusion criteria.
Data collection and analysis
We used the standard methods of the Cochrane Neonatal Review
Group (http://neonatal.cochrane.org/).
Selection of studies
Two review authors screened the titles and abstracts of all studies
identified by the above search strategy. We assessed the full texts
of any potentially eligible reports, and those studies that did not
meet all of the inclusion criteria were excluded. We discussed any
disagreements until consensus was achieved.
Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Data extraction and management
We used a data collection form to aid extraction of relevant infor-
mation from each included study. Two review authors extracted
the data separately. Any disagreements were discussed until con-
sensus was achieved. We contacted the investigators for further
information if data from the trial reports were insufficient.
Assessment of risk of bias in included studies
We used the criteria and standard methods of The Cochrane
Collaboration and the Cochrane Neonatal Group to assess the
methodological quality of any included trials (Higgins 2011). We
requested additional information from the trial authors to clarify
methodology and results as necessary. We evaluated and reported
the following issues in the ’Risk of bias’ tables:
Sequence generation (the method used to generate the allocation
sequence):
• low risk: any truly random process, e.g. random number
table, computer random number generator;
• high risk: any nonrandom process, e.g. odd or even date of
birth, hospital or clinic record number;
• unclear risk: no or unclear information provided.
Allocation concealment (the method used to conceal the allocation
sequence):
• low risk: e.g. telephone or central randomisation;
consecutively numbered, sealed, opaque envelopes;
• high risk: open random allocation, e.g. unsealed or
nonopaque envelopes, alternation, date of birth;
• unclear: no or unclear information provided.
Blinding (the methods used to ensure blinding of participants,
clinicians and caregivers, and outcome assessors):
• low risk;
• high risk;
• unclear.
Incomplete outcome data (completeness of data including attri-
tion and exclusions from the analysis for each outcome and any
reasons for attrition or exclusion where reported): We will assess
whether missing data are balanced across groups or are related to
outcomes. Where sufficient information is reported or supplied
by the trial authors, we will reinstate missing data in the analyses.
We will categorise completeness as:
• low risk: adequate (< 10% missing data);
• high risk: inadequate (> 10% missing data);
• unclear risk: no or unclear information provided.
Measures of treatment effect
We calculated risk ratio (RR) and risk difference (RD) for dichoto-
mous data and mean difference (MD) for continuous data, with
respective 95% confidence intervals (CI). When it was deemed
appropriate to combine two or more study arms, we obtained the
4
treatment effects from the combined data using the methods de-
scribed in the Cochrane Handbook for Systematic Reviews of Inter-
ventions (Higgins 2011). We determined the number needed to
treat to benefit (NNTB) or harm (NNTH) for a statistically sig-
nificant difference in the RD.
Unit of analysis issues
The unit of analysis was the participating infant in individually
randomised trials and the neonatal unit (or subunit) for cluster
randomised trials.
Assessment of heterogeneity
If more than one trial was included in a meta-analysis, we exam-
ined the treatment effects of individual trials and the heterogeneity
between trial results by inspecting the forest plots. We calculated
the I² statistic for each analysis to quantify inconsistency across
studies and to describe the percentage of variability in effect esti-
mates that may be due to heterogeneity rather than sampling er-
ror. If we detected substantial (I² greater than 50%) heterogeneity,
we explored the possible causes (for example, differences in study
design, participants, interventions, or completeness of outcome
assessments) in sensitivity analyses.
Data synthesis
We used the fixed-effect model in RevMan 5 (RevMan 2011) for
meta-analysis.
Subgroup analysis and investigation of heterogeneity
We planned the following subgroup analyses:
1. trials in which most infants were exclusively formula fed;
2. trials in which most infants were at least partially fed with
human milk (maternal or donor);
3. trials in which most participants were of extremely low
birth weight (ELBW) (< 1000 g) or extremely preterm
gestational age (< 28 weeks);
4. trials in which participants were infants with intrauterine
growth restriction or infants with absent or reversed end-diastolic
flow velocities detected on antenatal Doppler studies of the fetal
aorta or umbilical artery.
RESULTS
Description of studies
Six randomised controlled trials fulfilled the review eligibility cri-
teria: Rayyis 1999; Caple 2004; Salhotra 2004; Krishnamurthy
Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
2010; Karagol 2012; Mukhopadhyay 2014 (see Characteristics of
included studies).
Included studies
Population
A total of 618 infants participated in the six included trials. The
trials were undertaken in neonatal care centres in North America
(Rayyis 1999; Caple 2004), India (Salhotra 2004; Krishnamurthy
2010; Mukhopadhyay 2014), and Turkey (Karagol 2012) within
the past 10 to 15 years.
All of the trials specified participant birth weight eligibility criteria:
• Rayyis 1999 < 1500 g
• Caple 2004 1000 g to 2000 g
• Salhotra 2004 < 1250 g
• Krishnamurthy 2010 1000 g to 1500 g
• Karagol 2012 750 g to 1250 g
• Mukhopadhyay 2014 1000 g to 1250 g
Since most participants in Caple 2004 were of birth weight less
than 1500 g or gestational age less than 32 weeks, we made a
consensus decision to include the trial. Infants born ’small for
gestational age’ (birth weight less than 10th percentile of the index
population’s distribution) were not eligible to participate in Caple
2004 but were included in the other trials. More than 95% of
the participants in Salhotra 2004 were ’small for gestational age’.
One-third of participants in Karagol 2012 were ELBW infants.
All participants in Mukhopadhyay 2014 had antenatal evidence
of absent or reversed end-diastolic flow.
Interventions and comparisons
All trials commenced interval bolus intragastric feeding within one
to five days after birth. Infants were randomly allocated to one of
two rates of daily increments in enteral feed volume:
• Rayyis 1999 15 versus 35 ml/kg/day
• Caple 2004 20 versus 35 ml/kg/day
• Salhotra 2004 15 versus 30 ml/kg/day
• Krishnamurthy 2010 20 versus 30 ml/kg/day
• Karagol 2012 20 versus 30 ml/kg/day
• Mukhopadhyay 2014 20 versus 30 ml/kg/day
In one trial, only formula-fed infants were eligible to participate
(Rayyis 1999). In Caple 2004, Krishnamurthy 2010, Karagol
2012, and Mukhopadhyay 2014, infants received either expressed
breast milk or formula, or a combination of the two. In Salhotra
2004, all participating infants were fed exclusively expressed breast
milk. All of the trial protocols specified indications for interrupt-
ing or ceasing enteral feeding, such as residual gastric contents of
more than about one-third of the previous feed volume, frequent
vomiting, abdominal distention, or detection of blood in the stools
(including occult blood).
5
Outcomes
All of the trials reported the incidence of NEC confirmed radi-
ologically or at surgery or autopsy. The other reported outcomes
included time to regain birth weight, time to establish full enteral
feeding, duration of hospital stay, and rates of invasive infection.
Excluded studies
tion concealment and reported complete or near-complete assess-
ments of the primary outcomes. None of the trials were able to
conceal the feeding strategies from parents, caregivers, or clinical
investigators. Three studies clearly masked the assessment of ab-
dominal radiographs (for diagnosis of NEC). In Salhotra 2004 and
Karagol 2012, it was unclear whether precautions had been taken
to ensure that radiological assessors were blinded to the allocation
group.

Two trials were excluded (Book 1976; Berseth 2003) (see

Characteristics of excluded studies). In Book 1976, enteral feeding
volumes were advanced at 10 ml/kg/day versus 20 ml/kg/day, that Effects of interventions
is both groups received ’slow’ advancement of feed volumes. In
Berseth 2003, infants were randomly allocated to either a stable
(not progressively increased) trophic feeding volume or to feed Primary outcomes
volume advancement at 20 ml/kg/day.

Incidence of necrotising enterocolitis (Outcome 1.1)

Meta-analysis did not detect a statistically significant effect: typical
Risk of bias in included studies RR 0.96 (95% CI 0.55 to 1.63); typical RD -0.00 (95% CI -
The methodological quality of the included trials was generally 0.04 to 0.04) (6 trials, 618 infants) (Figure 1). There was not any
good. All six trials employed methods to ensure adequate alloca- statistical evidence of heterogeneity (I² = 0%).

Figure 1. Forest plot of comparison: 1 Slow versus faster rates of feed advancement, outcome: 1.1
Incidence of necrotising enterocolitis.

ical RR 1.57 (95% CI 0.92 to 2.70); typical RD 0.04 (95% CI -

Mortality (Outcome 1.2)
0.01 to 0.09) (5 trials, 460 infants) (Figure 2). There was not any
Meta-analysis did not find a statistically significant difference: typ-
Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants (Review) 6
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
statistical evidence of heterogeneity (I² = 0%).

Figure 2. Forest plot of comparison: 1 Slow versus faster rates of feed advancement, outcome: 1.2 Mortality.

Time to establish full enteral feeding

Secondary outcomes
Growth
Five trials reported that infants in the slow-rate-of-advancement
group took a statistically significantly longer time to regain birth
weight:
• Rayyis 1999 median difference 3 days
• Caple 2004 mean difference 2 (95% CI 1 to 3) days
• Salhotra 2004 median difference 5 days
• Krishnamurthy 2010 median difference 6 days
• Karagol 2012 mean difference 3.8 (95% CI not given) days
Mukhopadhyay 2014 did not report this outcome.
None of the trials reported longer-term growth parameters.
Neurodevelopment
None of the trials assessed neurodevelopmental outcomes.
All of the trials reported that it took statistically significantly longer
to establish full enteral feeds in infants in the slow-rate-of-advance-
ment group:
• Rayyis 1999 median difference 4 days
• Caple 2004 mean difference 3 (95% CI 2 to 3) days
• Salhotra 2004 mean difference 4.8 (95% CI not given) days
• Krishnamurthy 2010 median difference 2 days
• Karagol 2012 mean difference 3.2 (95% CI not given) days
• Mukhopadhyay 2014 mean difference 0.6 (95% CI not
given) days
Time to establish full oral feeding
Not reported by any of the included trials.
Feeds intolerance (causing interruption of enteral feeding)
(Outcome 1.3)
Meta-analysis of data from four trials (275 infants) did not find a
statistically significant difference: typical RR 1.23 (95% CI 0.87
to 1.73); typical RD 0.06 (95% CI -0.04 to 0.17) (Figure 3).

Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants (Review) 7
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Figure 3. Forest plot of comparison: 1 Slow versus faster rates of feed advancement, outcome: 1.3 Feeds
intolerance (causing interruption of enteral feeding).

Incidence of invasive infection (Outcome 1.4)

Meta-analysis of data from three trials (222 infants) did not detect
a statistically significant effect: typical RR 1.58 (95% CI 0.81 to
3.09); typical RD 0.06 (95% CI -0.03 to 0.15) (Figure 4).

Figure 4. Forest plot of comparison: 1 Slow versus faster rates of feed advancement, outcome: 1.4
Incidence of invasive infection.

1. Exclusively formula-fed infants (Rayyis 1999). No statistically

Duration of hospital stay
significant differences:
Two trials did not detect a statistically significant difference: • NEC: RR 1.44 (95% CI 0.63 to 3.32); RD 0.04 (95% CI -
• Rayyis 1999 median difference 4 days 0.05 to 0.13)
• Caple 2004 mean difference 5 (95% CI -1 to 8) days • Mortality: RR 0.59 (95% CI 0.10 to 3.46); RD -0.01 (95%
CI -0.06 to 0.03)
Two trials reported that the duration of hospital stay was statis-
tically significantly longer in infants in the slow-rate-of-advance- 2. Infants at least partially fed with human milk. Subgroup data
ment group: not available.
• Krishnamurthy 2010 median difference 1.5 days 3. ELBW or extremely preterm infants. None of the trials recruited
• Karagol 2012 mean difference 6 (95% CI not given) days predominantly ELBW or extremely preterm infants.
4. Infants with intrauterine growth restriction or absent or reversed
end-diastolic flow velocities (Salhotra 2004; Mukhopadhyay
2014). No statistically significant difference in NEC, but border-
Subgroup analyses
line significant increase in mortality in slow group:
Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants (Review) 8
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 • NEC: typical RR 0.34 (95% CI 0.06 to 2.04); typical RD -
0.07 (95% CI -0.18 to 0.04) (Figure 1)
• Mortality: typical RR 2.13 (95% CI 1.02 to 4.47); typical
RD 0.02 (95% CI 0.02 to 0.38); number needed to treat to
harm 5 (95% CI 3 to 50), 2 trials, 83 infants (Figure 2)
DISCUSSION
Summary of main results
The currently available trial data do not suggest that advancing
enteral feed volumes at slow rates (typically 15 ml/kg/day to 20 ml/
kg/day) compared to faster rates (30 ml/kg/day to 35 ml/kg/day)
reduces the risk of NEC in very preterm or VLBW infants. The
boundaries of the 95% CI for the estimate of effect are consistent
with either four extra or four fewer cases of NEC in every 100
infants who have slow rates of feed advancement. Similarly, a meta-
analysis of data from these trials does not indicate an effect on
all-cause mortality, with the 95% CI boundaries being consistent
with either nine extra or one fewer death in every 100 infants who
have slow rates of feed advancement. A pre-specified subgroup
analysis showed a borderline statistically significant increase in risk
of death with slow feeding in infants with growth restriction or
antenatal absent end-diastolic flow velocities. However, given that
this finding was based on data from only two small trials with a
total of 83 participants, it should be interpreted cautiously.
Infants who had slow advancement of feed volumes regained their
birth weight several days later than infants who had faster rates
of advancement of feed volumes. The clinical importance of this
effect is unclear as long-term growth or developmental outcomes
have not been assessed. Similarly, infants who had slow advance-
ment of feed volumes established full enteral feeding one to five
days later than infants who had faster rates of advancement of feed
volumes. Whether this is associated with such important adverse
clinical consequences as a higher rate of nosocomial infection sec-
ondary to prolonged use of parenteral nutrition is not yet known,
as few studies have reported this outcome. Despite the effect on
the establishment of enteral feeding, the included trials did not
find consistent evidence of an important effect on the duration of
hospital admission.
Overall completeness and applicability of
evidence
These findings should be applied with caution for several reasons.
Few of the trial participants were ELBW or extremely preterm
infants. One-third of the participants in Karagol 2012 were of
ELBW, but only a minority of infants in the two larger trials
weighed less than 1000 g or were less than 28 weeks gestation at
birth, or had evidence of intrauterine growth restriction (Rayyis
Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
1999; Caple 2004). Infants who had severe respiratory distress
requiring oxygen supplementation or ventilatory support were
not eligible to participate in three of the trials (Salhotra 2004;
Krishnamurthy 2010; Karagol 2012). The findings may not be
applicable to these populations, which are at highest risk of devel-
oping feed intolerance or NEC (Luig 2005).
Fewer than half of all of the participating infants were fed with
breast milk. Evidence exists that artificial-formula feeding increases
the risk of feed intolerance and NEC (Quigley 2014). The risk-
benefit balance of enteral feeding strategies may differ between
human milk-fed and formula-fed very preterm or VLBW infants.
It is also unclear whether the findings can be applied to infants
who receive continuous infusion of intragastric feeds, as all of
the infants in the included trials received enteral feeds as interval
boluses. Randomised controlled trials have reported conflicting
findings about the effect of continuous enteral infusion on feed
tolerance in very preterm or VLBW infants (Premji 2011).
Although the finding that slow enteral feed volume advancement
delays the establishment of full enteral feeds may seem intuitive,
it is also plausible that advancing feed volumes faster could have
resulted in more feed intolerance and therefore a delay in the estab-
lishment of full enteral feeding. The included trials pre-specified
definitions of feed intolerance that mandated interrupting or ceas-
ing feed volume advancement, principally the detection of ’gastric
residuals’ (the gastric content aspirated prior to a planned gastric
tube feed) and abdominal distension. However, the trial reports
presented only limited data on the frequency of these outcomes.
Furthermore, there is only limited evidence that the volume or
colour of gastric residuals is predictive of the risk of NEC for in-
fants whose feed volumes are advanced conservatively (Mihatsch
2002; Cobb 2004; Bertino 2009). Similarly, the clinical impor-
tance of abdominal distension or bowel loops visible through the
abdominal wall (without other features of intra-abdominal pathol-
ogy) is unclear, especially in the modern era, when early and pro-
longed use of continuous positive airway pressure results in in-
testinal gaseous distension.
Quality of the evidence
The included trials were generally of good methodological qual-
ity, but, in common with other trials of feeding interventions in
this population, it was not possible to mask caregivers and clinical
assessors to the nature of the intervention (Figure 5). Although
the lack of blinding may have resulted in surveillance and ascer-
tainment biases, it is more likely to have caused an overestimation
of the incidence of feed intolerance and NEC in infants whose
feed volumes were advanced faster. The assessment of abdominal
radiographs for signs of NEC was masked in most trials to en-
sure that the diagnosis of severe NEC (confirmed by the radio-
logical detection of gas in the bowel wall or portal tract) was not
prone to bias. However, since the microbial generation of gas in
the bowel wall is substrate dependent, infants who received more
9
enteral milk (substrate) may have been more likely to demonstrate
this radiological sign than infants with equally severe bowel disease
who had less intraluminal substrate. This ’substrate effect’ is also
more likely to cause overascertainment of NEC in the infants who
had faster rates of feed volume advancement (Tyson 2007).

Figure 5. Risk of bias graph: review authors’ judgements about each risk of bias item presented as
percentages across all included studies.

Agreements and disagreements with other
studies or reviews
This review focused specifically on the comparison of slow ver-
sus faster rates of feed volume advancement and did not compare
progressive advancement with enteral fasting or trophic feeding
(minimal enteral nutrition). Only one randomised controlled trial
has compared trophic feeding with progressive enteral feed volume
advancement (at daily increments of 20 ml/kg) (Berseth 2003).
Although the trial found the risk of NEC to be statistically sig-
nificantly higher in the infants whose feed volumes were progres-
sively advanced, this finding should be interpreted cautiously. The
trial was stopped early following an interim analysis, therefore the
finding of an effect on the incidence of NEC may be spurious
(Montori 2005). Caregivers and assessors were not blind to the
intervention. As discussed above, this may have resulted in several
sources of bias that are likely to cause an overestimation of the inci-
dence of NEC in infants whose feed volumes are being advanced.
AUTHORS’ CONCLUSIONS
Implications for practice
These data suggest that advancing enteral feed volumes at daily
increments of up to 30 ml/kg to 35 ml/kg does not increase the
risk of NEC in very preterm or VLBW infants. Increasing the
Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
volume of enteral feeds at slow rates (less than 24 ml/kg/day)
results in several days delay in the time taken to regain birth weight
and establish full enteral feeds. Only limited data are available on
the effect of this intervention on outcomes for extremely preterm
or ELBW infants or infants who are growth-restricted. Although
current practice tends to favour a conservative approach to enteral
feeding in these populations, clinicians should consider that there
are other possible consequences of advancing feed volumes slowly,
such as prolonging the use of parenteral nutrition, that may be
associated with important adverse clinical outcomes.
Implications for research
Further randomised controlled trials could provide more precise
estimates of the effects of different rates of daily increases in en-
teral feed volumes on important outcomes for extremely preterm
or ELBW infants. Trials should aim to ensure the participation
of infants with evidence of compromised intrauterine growth, so
that subgroup analyses can be planned for this population at high
risk of NEC. Masking caregivers and investigators to the nature
of this intervention is likely not possible. Since the unblinded
evaluation of feed intolerance and NEC is subject to surveillance
and ascertainment biases, trials could aim to assess more objective
outcomes, principally mortality and long-term growth and devel-
opment. Furthermore, since conservative feeding strategies may
result in such ’competing outcomes’ as invasive infection that may
affect long-term survival and neurodisability rates, it is essential
10
that trials are powered and structured to assess these outcomes.
ACKNOWLEDGEMENTS
We are grateful to Drs Namasivayam Ambalavanan and Kanya
Mukhopadhyay for providing further details and data (Rayyis
1999; Mukhopadhyay 2014).
This report is independent research funded by a UK National In-
stitute for Health Research Grant (NIHR) Cochrane Programme
Grant (13/89/12). The views expressed in this publication are
those of the authors and not necessarily those of the National
Health Service, the NIHR, or the UK Department of Health.
REFERENCES
References to studies included in this review
Caple 2004 {published data only}
Caple J, Armentrout D, Huseby V, Halbardier B, Garcia J,
Sparks JW, et al.Randomized, controlled trial of slow versus
rapid feeding volume advancement in preterm infants.
Pediatrics 2004;114(6):1597–600. [PUBMED: 15574620]
Karagol 2012 {published data only}
Karagol BS, Zenciroglu A, Okumus N, Polin RA.
Randomized controlled trial of slow versus rapid enteral
feeding advancements on the clinical outcomes of preterm
infants with 750-1250g. Journal of Parenteral and Enteral
Nutrition 2013;37(2):223–8. [PUBMED: 22664861]
Krishnamurthy 2010 {published data only}
Krishnamurthy S, Gupta P, Debnath S, Gomber S. Slow
versus rapid enteral feeding advancement in preterm
newborn infants 1000-1499 g: a randomized controlled
trial. Acta Paediatrica 2010;99(1):42–6. [PUBMED:
20002013]
Mukhopadhyay 2014 {published data only}
Mukhopadhyay K, Jain S. Feed intolerance and necrotising
enterocolitis in rapid vs slow feeding in preterm neonates
with absent end diastolic flow: a randomised controlled
trial. Pediatric Academic Societies and Asian Society for
Pediatric Research Joint Meeting. Vancouver, Canada:
Pediatric Academic Societies, 2014.
Rayyis 1999 {published data only}
Rayyis SF, Ambalavanan N, Wright L, Carlo WA.
Randomized trial of “slow” versus “fast” feed advancements
on the incidence of necrotizing enterocolitis in very low
birth weight infants. Journal of Pediatrics 1999;134(3):
293–7. [PUBMED: 10064664]
Salhotra 2004 {published data only}
Salhotra A, Ramji S. Slow versus fast enteral feed
advancement in very low birth weight infants: a randomized
control trial. Indian Pediatrics 2004;41(5):435–41.
[PUBMED: 15181294]
Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
References to studies excluded from this review
Berseth 2003 {published data only}
Berseth CL, Bisquera JA, Paje VU. Prolonging small feeding
volumes early in life decreases the incidence of necrotizing
enterocolitis in very low birth weight infants. Pediatrics
2003;111(3):529–34. [PUBMED: 12612232]
Book 1976 {published data only}
Book LS, Herbst JJ, Jung AL. Comparison of fast- and slow-
feeding rate schedules to the development of necrotizing
enterocolitis. Journal of Pediatrics 1976;89(3):462–6.
[PUBMED: 989057]
Additional references
Beeby 1992
Beeby PJ, Jeffery H. Risk factors for necrotising enterocolitis:
the influence of gestational age. Archives of Disease in
Childhood 1992;67(4 Spec No):423–5. [PUBMED:
1586186]
Bernstein 2000
Bernstein IM, Horbar JD, Badger GJ, Ohlsson A, Golan
A. Morbidity and mortality among very-low-birth-weight
neonates with intrauterine growth restriction. The Vermont
Oxford Network. American Journal of Obstetrics and
Gynecology 2000;182(1 Pt 1):198–206. [PUBMED:
10649179]
Bertino 2009
Bertino E, Giuliani F, Prandi G, Coscia A, Martano C,
Fabris C. Necrotizing enterocolitis: risk factor analysis and
role of gastric residuals in very low birth weight infants.
Journal of Pediatric Gastroenterology and Nutrition 2009;48
(4):437–42. [PUBMED: 19330932]
Bisquera 2002
Bisquera JA, Cooper TR, Berseth CL. Impact of necrotizing
enterocolitis on length of stay and hospital charges in very
low birth weight infants. Pediatrics 2002;109(3):423–8.
[PUBMED: 11875136]
11
Bombell 2009
Bombell S, McGuire W. Early trophic feeding for
very low birth weight infants. Cochrane Database of
Systematic Reviews 2009, Issue 3. [DOI: 10.1002/
14651858.CD000504.pub3; PUBMED: 19588318]
Brown 1978
Brown EG, Sweet AY. Preventing necrotizing enterocolitis
in neonates. JAMA 1978;240(22):2452–4.
Chauhan 2008
Chauhan M, Henderson G, McGuire W. Enteral
feeding for very low birth weight infants: reducing the
risk of necrotising enterocolitis. Archives of Disease in
Childhood. Fetal and Neonatal Edition 2008;93(2):F162–6.
[PUBMED: 18006565]
Cobb 2004
Cobb BA, Carlo WA, Ambalavanan N. Gastric residuals
and their relationship to necrotizing enterocolitis in very
low birth weight infants. Pediatrics 2004;113(1 Pt 1):50–3.
[PUBMED: 14702446]
Dorling 2005
Dorling J, Kempley S, Leaf A. Feeding growth restricted
preterm infants with abnormal antenatal Doppler results.
Archives of Disease in Childhood. Fetal and Neonatal Edition
2005;90(5):F359–63. [PUBMED: 16113150]
Flidel-Rimon 2004
Flidel-Rimon O, Friedman S, Lev E, Juster-Reicher
A, Amitay M, Shinwell ES. Early enteral feeding and
nosocomial sepsis in very low birthweight infants. Archives
of Disease in Childhood. Fetal and Neonatal Edition 2004;89
(4):F289–92. [PUBMED: 15210657]
Flidel-Rimon 2006
Flidel-Rimon O, Branski D, Shinwell ES. The fear of
necrotizing enterocolitis versus achieving optimal growth in
preterm infants--an opinion. Acta Paediatrica 2006;95(11):
1341–4. [PUBMED: 17062457]
Garite 2004
Garite TJ, Clark R, Thorp JA. Intrauterine growth
restriction increases morbidity and mortality among
premature neonates. American Journal of Obstetrics and
Gynecology 2004;191(2):481–7. [PUBMED: 15343225]
Guthrie 2003
Guthrie SO, Gordon PV, Thomas V, Thorp JA, Peabody J,
Clark RH. Necrotizing enterocolitis among neonates in the
United States. Journal of Perinatology 2003;23(4):278–85.
[PUBMED: 12774133]
Henderson 2009
Henderson G, Craig S, Brocklehurst P, McGuire W. Enteral
feeding regimens and necrotising enterocolitis in preterm
infants: a multicentre case-control study. Archives of Disease
in Childhood. Fetal and Neonatal Edition 2009;94(2):
F120–3. [PUBMED: 17768154]
Higgins 2011
Higgins JPT, Green S (editors). Cochrane Handbook
for Systematic Reviews of Interventions Version 5.1.0
[updated March 2011]. The Cochrane Collaboration,
2011. Available from www.cochrane-handbook.org.
Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Holman 1997
Holman RC, Stoll BJ, Clarke MJ, Glass RI. The
epidemiology of necrotizing enterocolitis infant mortality in
the United States. American Journal of Public Health 1997;
87(12):2026–31. [PUBMED: 9431297]
Härtel 2009
Härtel C, Haase B, Browning-Carmo K, Gebauer C, Kattner
E, Kribs A, et al.Does the enteral feeding advancement
affect short-term outcomes in very low birth weight infants?
. Journal of Pediatric Gastroenterology and Nutrition 2009;48
(4):464–70. [PUBMED: 19322056]
Luig 2005
Luig M, Lui K, NSW & ACT NICUS Group.
Epidemiology of necrotizing enterocolitis--Part II: Risks
and susceptibility of premature infants during the surfactant
era: a regional study. Journal of Paediatrics and Child Health
2005;41(4):174–9. [PUBMED: 15813870]
McKeown 1992
McKeown RE, Marsh TD, Amarnath U, Garrison CZ,
Addy CL, Thompson SJ, et al.Role of delayed feeding and
of feeding increments in necrotizing enterocolitis. Journal of
Pediatrics 1992;121(5 Pt 1):764–70. [PUBMED: 1432431]
Mihatsch 2002
Mihatsch WA, von Schoenaich P, Fahnenstich H, Dehne
N, Ebbecke H, Plath C, et al. The significance of
gastric residuals in the early enteral feeding advancement of
extremely low birth weight infants. Pediatrics 2002;109(3):
457–9. [PUBMED: 11875141]
Montori 2005
Montori VM, Devereaux PJ, Adhikari NK, Burns KE,
Eggert CH, Briel M, et al.Randomized trials stopped early
for benefit: a systematic review. JAMA 2005;294(17):
2203–9. [PUBMED: 16264162]
Morgan 2011
Morgan J, Young L, McGuire W. Delayed introduction of
progressive enteral feeds to prevent necrotising enterocolitis
in very low birth weight infants. Cochrane Database
of Systematic Reviews 2011, Issue 3. [DOI: 10.1002/
14651858.CD001970.pub3; PUBMED: 21412877]
Patole 2005
Patole SK, de Klerk N. Impact of standardised feeding
regimens on incidence of neonatal necrotising enterocolitis:
a systematic review and meta-analysis of observational
studies. Archives of Disease in Childhood. Fetal and Neonatal
Edition 2005;90(2):F147–51. [PUBMED: 15724039]
Pike 2012
Pike K, Brocklehurst P, Jones D, Kenyon S, Salt A, Taylor
D, et al.Outcomes at 7 years for babies who developed
neonatal necrotising enterocolitis: the ORACLE Children
Study. Archives of Disease in Childhood. Fetal and Neonatal
Edition 2012;97(5):F318–22. [PUBMED: 22933088]
Premji 2011
Premji SS, Chessell L. Continuous nasogastric milk feeding
versus intermittent bolus milk feeding for premature
infants less than 1500 grams. Cochrane Database of
12
 Systematic Reviews 2011, Issue 11. [DOI: 10.1002/
14651858.CD001819.pub2; PUBMED: 22071802]
Quigley 2014
Quigley MA, McGuire W. Formula versus donor breast
milk for feeding preterm or low birth weight infants.
Cochrane Database of Systematic Reviews 2014, Issue 4.
[DOI: 10.1002/14651858.CD002971.pub2; PUBMED:
24752468]
Rees 2007
Rees CM, Pierro A, Eaton S. Neurodevelopmental outcomes
of neonates with medically and surgically treated necrotizing
enterocolitis. Archives of Disease in Childhood. Fetal
and Neonatal Edition 2007;92(3):F193–8. [PUBMED:
16984980]
RevMan 2011
The Nordic Cochrane Centre, The Cochrane Collaboration.
Review Manager (RevMan). 5.1. Copenhagen: The Nordic
Cochrane Centre, The Cochrane Collaboration, 2011.
Soraisham 2006
Soraisham AS, Amin HJ, Al-Hindi MY, Singhal N,
Sauve RS. Does necrotising enterocolitis impact the
neurodevelopmental and growth outcomes in preterm
infants with birthweight < or =1250 g?. Journal of Paediatrics
and Child Health 2006;42(9):499–504. [PUBMED:
16925534]
Stoll 2004
Stoll BJ, Hansen NI, Adams-Chapman I, Fanaroff AA,
Hintz SR, Vohr B, et al.Neurodevelopmental and growth
impairment among extremely low-birth-weight infants
with neonatal infection. JAMA 2004;292(19):2357–65.
[PUBMED: 15547163]
Tyson 2007
Tyson JE, Kennedy KA, Lucke JF, Pedroza C. Dilemmas
initiating enteral feedings in high risk infants: how can they
be resolved?. Seminars in Perinatology 2007;31(2):61–73.
[PUBMED: 17462490]
Uauy 1991
Uauy RD, Fanaroff AA, Korones SB, Phillips EA,
Phillips JB, Wright LL. Necrotizing enterocolitis in very
Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
low birth weight infants: biodemographic and clinical
correlates. National Institute of Child Health and Human
Development Neonatal Research Network. Journal of
Pediatrics 1991;119(4):630–8. [PUBMED: 1919897]
Walsh 1986
Walsh MC, Kliegman RM. Necrotizing enterocolitis:
treatment based on staging criteria. Pediatric Clinics of North
America 1986;33(1):179–201. [PUBMED: 3081865]
References to other published versions of this review
Kennedy 2005
Kennedy KA, Tyson JE, Chamnanvanakij S. Rapid versus
slow rate of advancement of feedings for promoting growth
and preventing necrotizing enterocolitis in parenterally
fed low-birth-weight infants. Cochrane Database of
Systematic Reviews 2005, Issue 2. [DOI: 10.1002/
14651858.CD001241.pub2]
McGuire 2008
McGuire W, Bombell S. Slow advancement of enteral
feed volumes to prevent necrotising enterocolitis in
very low birth weight infants. Cochrane Database of
Systematic Reviews 2008, Issue 2. [DOI: 10.1002/
14651858.CD001241.pub2; PUBMED: 18425870]
Morgan 2011a
Morgan J, Young L, McGuire W. Slow advancement of
enteral feed volumes to prevent necrotising enterocolitis
in very low birth weight infants. Cochrane Database
of Systematic Reviews 2011, Issue 3. [DOI: 10.1002/
14651858.CD001241.pub3; PUBMED: 21412870]
Morgan 2013
Morgan J, Young L, McGuire W. Slow advancement of
enteral feed volumes to prevent necrotising enterocolitis
in very low birth weight infants. Cochrane Database
of Systematic Reviews 2013, Issue 3. [DOI: 10.1002/
14651858.CD001241.pub4; PUBMED: 23543511]
∗
Indicates the major publication for the study
13
CHARACTERISTICS OF STUDIES

Characteristics of included studies [ordered by study ID]

Caple 2004

Methods Randomised controlled trial

Participants Preterm infants of birth weight 1000 g to 2000 g (appropriate birth weight for gestational
age and of gestational age < 35 weeks at birth), who were starting formula feeds
Setting: Neonatal Unit, Department of Pediatrics, University of Texas Medical School,
Houston, Texas, USA

Interventions Feeds advancement at 20 ml/kg/day (N = 74) versus 30 ml/kg/day (N = 84)

Outcomes NEC (Bell stage II/III)

Time to regain birth weight, time to achieve full enteral feeds, and time to hospital
discharge

Notes Feeds were ceased if the residual gastric aspirate was more than one-third of the previous
feed volume, or if there was frequent vomiting, abdominal distention, or bloody stools
(including occult blood)
We have not been able to obtain data on all-cause mortality from the principal investi-
gators

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk Random number sequence

bias)

Allocation concealment (selection bias) Low risk Blinded draw from envelope by caregivers not involved
in study

Blinding (performance bias and detection High risk Caregivers and clinical investigators were not blinded
bias) once allocation to intervention groups had occurred
Clinical assessments

Blinding (performance bias and detection Low risk Radiologists interpreting X-rays were blinded to the in-
bias) tervention group
Radiological assessments

Incomplete outcome data (attrition bias)
All outcomes
Low risk Three infants excluded after enrolment because of proto-
col violations have been included in this review and meta-
analysis. Two infants (one in each group) were excluded
because they were determined not eligible for enrolment
because of an in utero gastrointestinal perforation and
fetal alcohol syndrome; these infants were not included
in the meta-analysis

Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants (Review) 14
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Karagol 2012

Methods Randomised controlled trial

Participants Preterm infants < 32 weeks gestation with birth weights of 750 g to 1250 g. 32% of
participants weighed < 1000 g. Exclusion criteria included major congenital malforma-
tions, severe respiratory distress, presence of umbilical vessel catheters, contraindications
to enteral feeding, perinatal asphyxia, or cardiovascular compromise
Setting: Division of Neonatology, Dr Sami Ulus Maternity, Children’s Education and
Research Hospital, Ankara, Turkey

Interventions Slow advancement at 20 ml/kg/day (N = 46) versus rapid advancement at 30 ml/kg/day

(N = 46)

Outcomes NEC (stage II/III), all-cause mortality, time to regain birth weight, time to reach full
enteral feeds, feed intolerance, duration of hospital stay, rates of invasive infection
Subgroup analysis for ELBW infants

Notes Feeds were ceased if any of the following occurred: gastric residuals > 5 ml/kg or > 50%
of feed volume, vomiting > 3 times in 24 hours, increase in abdominal girth > 2 cm
between feeds, abdominal tenderness or erythema, reduced bowel sounds, blood in the
stools, or recurrent apnoea

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk Computer-generated sequence

bias)

Allocation concealment (selection bias) Low risk Opaque, sealed envelopes

Blinding (performance bias and detection High risk Caregivers and study investigators were not blinded.
bias)
Clinical assessments

Blinding (performance bias and detection Unclear risk No reference to whether staff interpreting radiological
bias) images were blinded to the study groups
Radiological assessments

Incomplete outcome data (attrition bias) Low risk No participants lost to follow-up
All outcomes

Krishnamurthy 2010

Methods Randomised controlled trial

Participants Preterm infants (birth weight 1000 g to 1499 g) and gestational age < 34 weeks at birth.
Exclusion criteria included respiratory distress, mechanical ventilation, inotrope support,
and umbilical arterial or venous catheterisation

Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants (Review) 15
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Krishnamurthy 2010 (Continued)

Setting: Department of Paediatrics, University College of Medical Sciences, Dehli, India

Interventions Feeds advancement at 20 ml/kg/day (N = 50) versus 30 ml/kg/day (N = 50)

Outcomes NEC (stage II/III)

Incidence of nosocomial infection, in-hospital mortality, time to regain birth weight,
time to achieve full enteral feeds, and time to hospital discharge

Notes All feeds were delivered by gavage via nasogastric tubes at 2-hour intervals
Feeds were ceased if any of the following occurred: residual gastric contents more than
50% of the previous feed volume (delayed if volume was 25% to 50%); more than 3
episodes of apnoea in the preceding hour; abdominal distention or tenderness; or bloody
stools (including occult blood)
Parenteral nutrition was not available.

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk Computer-generated sequence

bias)

Allocation concealment (selection bias) Low risk Opaque, sealed envelopes

Blinding (performance bias and detection High risk Caregivers and investigators were not blinded to the in-
bias) terventions
Clinical assessments

Blinding (performance bias and detection Low risk Radiologist interpreting X-rays was blinded to the inter-
bias) vention group
Radiological assessments

Incomplete outcome data (attrition bias) Low risk No loss to follow-up

All outcomes

Mukhopadhyay 2014

Methods Randomised controlled trial

Participants Preterm infants (birth weight 1000 g to 1249 g) and gestational age > 30 weeks at
birth who have antenatal evidence of absent end diastolic flow velocities (presumed in
umbilical artery)
Setting: Department of Paediatrics, Postgraduate Institute of Medical Education & Re-
search, Chandigarh, India

Interventions Feeds advancement at 20 ml/kg/day (N = 15) versus 30 ml/kg/day (N = 15)

Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants (Review) 16
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Mukhopadhyay 2014 (Continued)

Outcomes NEC (all stages)

Late-onset bloodstream (culture-positive) infection, in-hospital mortality, time to achieve
full enteral feeds

Notes Pre-specified subgroup of larger trial that enrolled infants with birth weight > 1250 g
and compared feed advancement at 30 ml/kg/day versus 40 ml/kg/day
Published as conference abstract; further data courtesy of Dr Mukhopadhyay (September
2014)

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk Computer-generated

bias)

Allocation concealment (selection bias) Low risk Sealed, opaque envelopes

Blinding (performance bias and detection High risk Caregivers and investigators were not blinded to the in-
bias) terventions
Clinical assessments

Blinding (performance bias and detection Unclear risk Not stated

bias)
Radiological assessments

Incomplete outcome data (attrition bias) Low risk Complete follow-up for primary outcomes
All outcomes

Rayyis 1999

Methods Randomised controlled trial

Participants Very low birth weight infants of gestational age < 34 weeks at birth
Setting: Neonatal Unit, Department of Pediatrics, University of Alabama, Birmingham,
Alabama, USA

Interventions Feeds advancement at 15 ml/kg/day (N = 98) versus 35 ml/kg/day (N = 87)

Outcomes NEC (stage II/III)

Time to regain birth weight, time to achieve full enteral feeds, and time to hospital
discharge

Notes Infants for whom full or partial feeding with expressed breast milk was planned were not
eligible to participate. Feeding was commenced using standard ’term’ artificial formula,
then switched to nutrient-enriched ’preterm’ formula when full enteral feeding had been
achieved.Feeds were ceased if any of the following occurred: residual gastric contents
more than 30% of the previous feed volume, abdominal distention or tenderness, or

Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants (Review) 17
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Rayyis 1999 (Continued)

bloody stools (including occult blood)

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Unclear risk Not stated

bias)

Allocation concealment (selection bias) Low risk Opaque, sealed envelopes

Blinding (performance bias and detection High risk Caregivers and investigators not blinded to the interven-
bias) tion groups
Clinical assessments

Blinding (performance bias and detection Low risk Radiologist interpreting the X-rays was blinded to the
bias) study group
Radiological assessments

Incomplete outcome data (attrition bias) Low risk 7 protocol violations occurred after enrolment, but all
All outcomes infants were included the final data analysis

Salhotra 2004

Methods Randomised controlled trial

Participants Preterm infants of birth weight < 1250 g. More than 95% of the participants were ’small
for gestational age’. Exclusion criteria included recurrent apnoea, respiratory distress
requiring supplemental oxygen, and receipt of inotrope support
Setting: Neonatal Unit , Maulana Azad Medical College (tertiary-level teaching hospital)
, New Delhi, India

Interventions Feeds advancement at 15 ml/kg/day (N = 26) versus 30 ml/kg/day (N = 27)

Outcomes NEC (stage II/III)

Neonatal mortality, time to regain birth weight, time to achieve full enteral feeds, and
time to hospital discharge

Notes Feeds were ceased if the residual gastric content was more than 30% of the previous feed
volume or if there was abdominal distention
Mortality data courtesy of Dr Namasivayam Ambalavanan

Risk of bias

Bias Authors’ judgement Support for judgement

Random sequence generation (selection Low risk Computer-generated sequence

bias)

Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants (Review) 18
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Salhotra 2004 (Continued)

Allocation concealment (selection bias) Low risk Opaque, sealed envelopes

Blinding (performance bias and detection High risk Investigators were blinded at allocation stage, but it is
bias) unclear if they remained blinded thereafter. Caregivers
Clinical assessments were not blinded to intervention group

Blinding (performance bias and detection Unclear risk No statement about blinding of radiological assessors to
bias) intervention group
Radiological assessments

Incomplete outcome data (attrition bias) Low risk No losses to follow-up

All outcomes

Characteristics of excluded studies [ordered by study ID]

Study Reason for exclusion

Berseth 2003 Infants were randomly allocated to either a stable (not progressively increased) trophic feeding volume or to feed
volume advancement at 20 ml/kg/day

Book 1976 Enteral feeding volumes were advanced at 10 ml/kg/day versus 20 ml/kg/day, that is both groups received ’slow’
advancement of feed volumes

Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants (Review) 19
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
DATA AND ANALYSES

Comparison 1. Slow versus faster rates of feed advancement

No. of No. of
Outcome or subgroup title studies participants Statistical method Effect size

1 Incidence of necrotising 6 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
enterocolitis
1.1 All trials 6 618 Risk Ratio (M-H, Fixed, 95% CI) 0.96 [0.55, 1.70]
1.2 Trials in which most 2 83 Risk Ratio (M-H, Fixed, 95% CI) 0.34 [0.06, 2.04]
infants were small for
gestational age or growth
restricted
2 Mortality 5 Risk Ratio (M-H, Fixed, 95% CI) Subtotals only
2.1 All trials 5 460 Risk Ratio (M-H, Fixed, 95% CI) 1.57 [0.92, 2.70]
2.2 Trials in which most 2 83 Risk Ratio (M-H, Fixed, 95% CI) 2.13 [1.02, 4.47]
infants were small for
gestational age or growth
restricted
3 Feeds intolerance (causing 4 275 Risk Ratio (M-H, Fixed, 95% CI) 1.23 [0.87, 1.73]
interruption of enteral feeding)
4 Incidence of invasive infection 3 222 Risk Ratio (M-H, Fixed, 95% CI) 1.58 [0.81, 3.09]

WHAT’S NEW
Last assessed as up-to-date: 3 October 2014.

Date Event Description

3 October 2014 New search has been performed This updates the review ’Slow advancement of enteral
feed volumes to prevent necrotising enterocolitis in very
low birth weight infants’ (Morgan 2013).

3 October 2014 New citation required but conclusions have not changed Updated search in September 2014 identified one new
trial for inclusion (Mukhopadhyay 2014), increasing the
total number of participating infants to 618 (from 588)
and narrowing confidence intervals for the estimates of
effect

Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants (Review) 20
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
HISTORY
Protocol first published: Issue 4, 1998
Review first published: Issue 4, 1998

Date Event Description

11 January 2011 New citation required and conclusions have changed Addition of new data, and increasing the total number
of participating infants to 496, narrowed the confi-
dence intervals for the estimates of effect and modified
the implications for practice and research

15 December 2010 New search has been performed This updates the review “Slow advancement of en-
teral feed volumes to prevent necrotising enterocoli-
tis in very low birth weight infants” published in the
Cochrane Database of Systematic Reviews, Issue 2,
2008 (McGuire 2008).
Search updated in December 2010. One new trial in-
cluded (Krishnamurthy 2010).
New co-authors: Jessie Morgan and Lauren Young.

13 February 2008 New citation required but conclusions have not New authorship: Bombell S, McGuire W
changed

2 February 2008 New search has been performed This updates the review “Rapid versus slow rate of
advancement of feedings for promoting growth and
preventing necrotizing enterocolitis in parenterally fed
low-birth-weight infants” by Kennedy and Tyson,
published in the Cochrane Database of Systematic Re-
views, Issue 2, 2000 (Kennedy 2000)
The title has been modified to read “Slow advancement
of enteral feed volumes to prevent necrotising entero-
colitis in very low birth weight infants” and has a new
authorship of Sarah Bombell and William McGuire.
Changes made to the original protocol are outlined
below:

1. “Slow” rate of feed advancement has been defined

as daily increments up to 24 ml/kg (body weight).
2. The population has been restricted to very low birth
weight and very preterm infants.
3. Mortality, adverse neurodevelopment, growth pa-
rameters, and infection rates have been included as
outcomes of interest.

Search updated December 2007. One new trial has

been included (Salhotra 2004). One trial previously
included has now been excluded (Book 1976).

Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants (Review) 21
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
(Continued)

The findings and implications for practice and research

of the review have not changed overall

11 January 2008 Amended Converted to new review format.

CONTRIBUTIONS OF AUTHORS
Drs Young and McGuire updated the search, independently determined the eligibility of identified studies, assessed the methodological
quality of the included trials, and extracted the relevant information and data.

DECLARATIONS OF INTEREST
None

SOURCES OF SUPPORT
Internal sources
• Centre for Reviews and Dissemination, Hull York Medical School, UK.

External sources
• National Institute for Health Research (NIHR), UK.
NIHR Cochrane Programme Grant (13/89/12)
• Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health,
Department of Health and Human Services, USA.
Editorial support of the Cochrane Neonatal Review Group has been funded with Federal funds from the Eunice Kennedy Shriver
National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human
Services, USA, under Contract No. HHSN267200603418C.

INDEX TERMS

Medical Subject Headings (MeSH)

∗ Infant,
Very Low Birth Weight; Enteral Nutrition [∗ methods]; Enterocolitis, Necrotizing [∗ prevention & control]; Infant, Low Birth
Weight; Infant, Newborn; Infant, Premature; Infant, Premature, Diseases [∗ prevention & control]; Parenteral Nutrition [adverse effects];
Randomized Controlled Trials as Topic

Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants (Review) 22
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
MeSH check words
Humans

Slow advancement of enteral feed volumes to prevent necrotising enterocolitis in very low birth weight infants (Review) 23
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Review article
Kim Enteral2016;59(12):466-470
MJ J•Pediatr
Korean nutrition
https://doi.org/10.3345/kjp.2016.59.12.466
pISSN 1738-1061•eISSN 2092-7258
Korean J Pediatr

Enteral nutrition for optimal growth in preterm

infants
Myo-Jing Kim, MD
Department of Pediatrics, Dong-A University College of Medicine, Busan, Korea

Early, aggressive nutrition is an important contributing factor of long-term neurodevelopmental Corresponding author: Myo-Jing Kim, MD
outcomes. To ensure optimal growth in premature infants, adequate protein intake and optimal protein/ Department of Pediatrics, Dong-A University Col-
lege of Medicine, 32 Daesingongwon-ro, Seo-gu,
energy ratio should be emphasized rather than the overall energy intake. Minimal enteral nutrition should Busan 49201, Korea
be initiated as soon as possible in the first days of life, and feeding advancement should be individualized Tel: +82-51-240-2589
according to the clinical course of the infant. During hospitalization, enteral nutrition with preterm formula Fax: +82-51-242-2765
and fortified human milk represent the best feeding practices for facilitating growth. After discharge, the E-mail: myojing@dau.ac.kr
enteral nutrition strategy should be individualized according to the infant’s weight at discharge. Infants Received: 9 September, 2015
with suboptimal weight for their postconceptional age at discharge should receive supplementation with Revised: 13 October, 2015
human milk fortifiers or nutrient-enriched feeding, and the enteral nutrition strategy should be reviewed Accepted: 16 November, 2015
and modified continuously to achieve the target growth parameters.

Key words: Enteral nutrition, Infant, Premature

Introduction
The current recommendations for nutrition of preterm infants are based on the goal of
achieving the growth rate and body composition of a normal fetus at the same postmens­
trual age1). However, this goal is often difficult to achieve because of the physiologic limita­
tions associated with prematurity. Postnatal growth restrictions remain a clinical complica­
tion of prematurity, especially in extremely low birth weight infants (ELBWI)2). Inadequate
nutrition has long been considered a cause of growth retardation. The association between
postnatal growth failure due to inadequate nutrition and impaired long-term neurocogni­
tive development is of particular concern. Therefore, a strategy for providing adequate
nutrition to ensure optimal growth in premature infants needs to be emphasized.

Principles of enteral nutrition

The American Academy of Pediatrics (AAP) and the European Society of Paediatric
Gastroenterology, Hepatology, and Nutrition (ESPGHAN) Committee on Nutrition recom­
mended an energy intake of 105–130 kcal/kg/day3) and 110–135 kcal/kg/day4) for preterm
infants, respectively. Infants sometimes require increased caloric intake owing to a higher Copyright © 2016 by The Korean Pediatric Society
energy demand during an illness. Thus, simply meeting these recommended energy re­
quirements may not be sufficient. Failure to provide adequate protein can result in adverse This is an open-access article distributed under the
terms of the Creative Commons Attribution Non-
long-term outcomes in premature infants. Each additional gram of protein intake for Commercial License (http://creativecommons.org/
licenses/by-nc/4.0/) which permits unrestricted non-
ELBWI is associated with additional weight gains of 6.5 g/day and head circumference commercial use, distribution, and reproduction in any
increase of 0.4 cm/wk5). The National Institute of Child Health and Human Development’s medium, provided the original work is properly cited.

466 https://doi.org/10.3345/kjp.2016.59.12.466

Neonatal Research Network evaluated the association between
weight gain in the neonatal intensive care unit (NICU) and long-
term neurodevelopmental outcomes in ELBWI. Infants in the
lowest quartile of in-hospital weight gain (≤12 g/kg/day) were as­
sociated with higher odds of cerebral palsy, Bayley scales of In­
fant Development II mental developmental index <70, and
neurodevelopmental impairment at 18–22 months of corrected
age, as compared with infants in the highest quartile of in-
hospital weight gain (≥21 g/kg/day). Similar findings have also
been reported for in-hospital head circumference growth6).
These findings suggest that adequate protein intake can im­
prove the growth of ELBWI and that adequate growth in the
NICU is associated with a lower risk of long-term neurodevelop­
mental outcomes. Moreover, an increased protein/energy (P/E)
ratio is mandatory to ensure quality growth, presenting as in­
creased lean body mass and limited fat mass deposits. The
ESPGHAN recommends protein intakes of 4.0–4.5 and 3.5–4.0 g/
kg/day in preterm infants weighing up to 1,000 g and 1,000–
1,800 g, respectively4). With optimal infant growth status, the
protein intake can be reduced in anticipation of hospital dis­
charge. However, achieving the recommended protein intake by
enteral nutrition remains a difficult task. The protein intake by
enteral feeding at 150 mL/kg/day (routine enteral volume) is
insufficient for meeting the infant’s requirements of 1.8–2.1 g/kg/
day of unfortified preterm human milk, 1.5 g/kg/day of unforti­
fied donor human milk, or 3.6 g/kg/day of preterm formula7).
Hence, the question remains as to how much we need to feed
ELBWI in order to achieve the recommended daily protein intake.
To provide 4 g/kg/day of protein, we need to feed the infant
290–340 mL/kg/day of unfortified preterm human milk, 210 mL/
kg/day of fortified human milk (1 pack/60 mL, Maeil Babywell
Human Milk Fortifier, Maeil Co. Ltd., Seoul, Korea), or 170 (16%
concentration) to 190 mL/kg/day (14% concentration) of preterm
formula (Maeil Babywell Preemie, Maeil Co. Ltd.; Namyang
Premie Formula, Namyang Dairy Products Co., Ltd., Seoul,
Korea). It is important to note that osmolarity and the renal solute
load influence the fluid volumes that are necessary for enteral
nutrition. The ESPGHAN reported that 135 and 2004) mL/kg/day
should be considered the minimum and maximum fluid volume,
respectively. Hence, fortification for human milk-fed infants and
adjustment of the formula concentration for preterm formula-fed
infants are needed. For routine enteral feeding, preterm formula
or fortified human milk that is fed at rates of 150–180 mL/kg/day
is sufficient for attaining the recommended nutrient require­
ments4).
Moreover, as growth in the NICU is associated with long-term
neurodevelopmental outcomes, the goal of growth in the NICU
may be questioned.
For better neurodevelopmental and growth outcomes in
ELBWI, weight gains of >18 g/kg/day and head circumference
Korean J Pediatr 2016;59(12):466-470
increase >0.9 cm/wk during the hospitalization period are con­
sidered optimal6). If these rates cannot be met, the infant’s enteral
nutrition should be reviewed and modified to achieve this optimal
goal. Focus should be placed on the protein content, P/E ratio,
and utilization of nutrient-enriched feeding sources to reduce
nutritional deficits.
Practice of enteral nutrition
1. Minimal enteral feeding
Although trophic or minimal enteral feedings involve hypo­
caloric, low-volume (typically ≤24 mL/kg/day) nutrition to ac­
celerate gastrointestinal, physiological, endocrine, and meta­bolic
maturity, they do not contain sufficient calories to sustain soma­
tic growth8). The most common reason for delays in enteral feed­
ing is the clinicians’ concern for the risk of necrotizing entero­
colitis (NEC). A recent meta-analysis evaluated the effects of early
trophic feeding versus enteral fasting in very low birth weight
infants (VLBWI), and found no differences in the feeding tole­
rance, time to reach full enteral feeding, and incidence of NEC9).
Thus, the authors concluded that minimal enteral nutrition was
not associated with important beneficial or harmful effects in
VLBWI and confirmed the absence of reasons for not starting tro­
phic feeding as soon as possible.
2. Introduction of progressive enteral feedings
The introduction of enteral feeds for VLBWI is often delayed
for several days or longer after birth because of concerns that
early introduction may not be tolerated and/or may increase the
risk of NEC. A systemic review evaluated the effects of early feed­
ing introduction (<4 days) versus delayed feeding introduc­tion
(4–7 days) and found no significant differences in terms of the
incidence of NEC or all-cause mortality. However, infants with
delayed feeding introduction required longer periods before
achieving full enteral feedings and delays in hospitaldischarge10).
3. Rate of advancement of enteral feedings
The appropriate rate of enteral feeding advancement has also
been the subject of much debate, and an association between
rapidly advanced enteral feeding and the risk of NEC has been
suggested. However, a recent Cochrane review evaluated the ef­
fects of the rate of enteral feeding advancement on the incidence
of NEC, all-cause mortality, and other morbidities in VLBWI and
found no significant differences between the rates. In the slow
advancement group, the infants required a longer period to regain
the birth weight and to reach full enteral feeding11). One reason­
able approach is to advance enteral feeds by 20–30 mL/kg/day in
VLBWI and by 15–25 mL/kg/day in ELBWI7).
https://doi.org/10.3345/kjp.2016.59.12.466 467
Kim MJ • Enteral nutrition

Choice of enteral nutrition to be the best solution for inadequate protein intake with standard
fortification14). Currently, two methods have been proposed for
1. Human milk individualization. Evaluated through periodic determinations of
Human milk is the optimal primary nutritional source for pre­ the blood urea nitrogen, targeted and adjustable fortifications are
term infants because it offers strong protection against sepsis and designed based on the analyses of the mother’s own milk and
other infections and offers short-term protection against NEC. de5pend on the metabolic response of each infant, respectively.
Regarding the long-term effects, human milk improves neurode­ The use of individualized fortification is recommended to allow
velopmental outcomes, and has a dose-dependent effect until 30 adequate protein intake and growth15). The compositions of the
months of corrected age12). Accordingly, the AAP strongly recom­ commercially available HMFs16) in Korea are shown in Table 1.
mends the use of human milk for preterm infants3). Lactation
strategies that increase the mother’s own milk production should 2. Preterm formulas
be emphasized in order to enable pumping immediately after Preterm formula is available for preterm infants who are un­
delivery1). In the absence of maternal human milk, pasteurized able to receive their mother’s own milk and donor human milk.
donor human milk is a good option for initiating feeding13). How­ In general, these formulas predominantly contain whey protein,
ever, despite these benefits, human milk does not completely meet glucose polymers, medium-chain triglycerides, calcium, and
the nutritional needs of preterm infants, owing to insuffici­ent phosphorus, and they are variably enriched with minerals,
calories and proteins necessary to support the optimal growth vitamins, and trace elements to support intrauterine nutrient
and lean body mass accretion. In addition, the concentrations of accretion rates. The compositions of the commercially available
calcium and phosphorus in human milk are also significantly formulas for preterm infants in Korea are shown in Table 2. In
lower than the required levels7). practice, a preterm formula of 70–72 kcal/100 mL is initially used.
For these reasons, supplementation (fortification) with multinu­ If tolerated by the infants, a higher energy formula consisting of
trient human milk fortifiers (HMFs) is needed in order to meet the 16% concentrated preterm formula (80–82 kcal/100 mL) may be
nutritional requirements and improve postnatal growth. HMFs used to meet the energy demand.
are indicated in preterm infants aged less than 31 gestational
weeks and/or with a birth weight less than 1,500 g. No definite
guidelines regarding the timing for starting HMFs currently exist.
Postdischarge nutrition
However, fortification of human milk does not need to be delayed
until full enteral feedings achieved. Generally, fortification com­ At the time of birth, approximately 20% of VLBWI are small
mences when the enteral feeding volume reaches 100 mL/kg/day for gestational age. After NICU care, however, 79% of these
and is gradually increased from half to full strength. Whereas the infants experience poor growth and weigh less than the 10th per­
protein content of human milk declines over the first few weeks centile at 36 weeks’ postconceptional age (PCA)17). Achieving
from 1.7 g/dL at 7 days to 1.2 g/dL at 42 days, commercial HMFs postdischarge catch-up growth, especially during the vital period
assume an average protein content of human milk of 1.4–1.6 g/ between 40 and 48 weeks PCA, is critical for optimal neurode­
dL7). Therefore, protein content from standard fortification does velopment in premature infants. The rate of weight gain is depen­
not reach the amount present in preterm formula, thereby re­ dent on the absolute intakes of protein and energy. A high P/E
sulting in slower growth compared to preterm formula-fed in­ ratio is required to increase lean body mass and protein accretion
fants. Consequently, individualized fortification is now believed and to limit fat mass deposition1). Major strategies to reach this
goal include continuing preterm formula, human milk alone/
Table 1. Comparison between the nutrient composition of preterm
human milk and Korean human milk fortifier
Table 2. Comparison between the nutrient composition of Korean
Maeil Babywell Human Milk Fortifier premature formulas (per 100 mL)
Preterm human milk
Nutrients 1.6 pack HMF+PHM (1 pack/60 mL) Maeil Babywell Preemie Namyang Premie Formula
/100 kcal /100 mL /100 kcal /100 mL Nutrients
14% 16% 14% 16%
Calory (kcal) 100 67 14 100 71 Calory (kcal) 70 80 72 82
Protein (g) 2.1 1.4 0.8 2.8 1.9 Protein (g) 2.1 2.4 2.1 2.4
P/E ratio 2.1 2.1 - 2.8 2.7 P/E ratio 3.0 3.0 2.9 2.9
Fat (g) 5.8 3.9 0.32 5.2 3.7 Fat (g) 3.6 4.1 3.8 4.3
Carbohydrate (g) 9.9 6.6 1.9 10.6 7.5 Carbohydrate (g) 7.4 8.5 7.3 8.3
Volume (mL) 149 100 15.5 142 100 Modified from Korean Society of Neonatology. Manual of neonatal care. 3rd
HMF, human milk fortifier; PHM, preterm human milk; P/E, protein/energy. ed., with permission of The Korean Society of Neonatology16).

468 https://doi.org/10.3345/kjp.2016.59.12.466

partially, full nutrient-fortified human milk, nutrient-enriched
postdischarge formula (PDF), and term formula.
1. Preterm formula
The high amount of protein, vitamins, minerals, and electro­
lytes present in preterm formulas are required in order to meet the
increased needs associated with rapid growth, decreased intestinal
absorption, and limited fluid tolerance. However, preterm formula
is not generally recommended for postdischarge nutrition and is
only used until discharge or before switching to PDF.
2. Postdischarge formula
PDF is specially designed for preterm infants after hospital
discharge. PDF is less nutrient-dense than preterm formula, but
provides energy at 75 kcal/100 mL (vs. 68 kcal/dL for term for­
mula), is protein-enriched (2.1 g vs. 1.4–1.5 g/dL), and contains a
variable amount of mineral, vitamins, and trace elements. Al­
though many studies have reported the benefits of PDF, commer­
cial PDF products are currently unavailable in Korea. The use of
PDF has been shown to result in more complete catch-up and
greater linear growth, weight gain, and bone mineralization than
term formula18). Moreover, some studies have reported that after
term, PDF cannot change the quantity of growth but rather im­
proves the quality of growth and lowers the fat mass compared to
term formula19). Generally, PDF use is recommended until 9-
month PCA2). However, a recent meta-analysis concluded that the
use of PDF is not supported by the available evidence, because
there were no consistent effects on growth at 12–18 months’
corrected age20). Further research on the effects of PDF on later
growth and neurodevelopmental outcomes are needed.
3. Breast feeding
Most preterm infants are usually discharged by 35- to 36-week
PCA, and/or once a weight of 1,800–2,100 g is achieved. How­
ever, maximal oral feeding performance occurs by 35- to 37-
week PCA. Therefore, preterm infants are unable to manage suffi­
cient volumes to meet their nutritional requirements. For this
reason, if the mother plans to breastfeed the infant directly fol­
low­ing discharge, the growth rate should be monitored carefully
within 48 hours after discharge and reevaluated after 1 week21).
For those infants who are discharged while still receiving ex­
pressed or donor human milk, fortification is a more practical,
continuous option22).
The AAP reported that, by the time of discharge, many VLBWI
will have achieved growth at an intrauterine rate but remain
below the 10th percentile for their PCA. The AAP further stated
that more information is needed on what to feed breastfed pre­
term infants after discharge, and close growth monitoring is
indicated3). On the other hand, the ESPGHAN recommends that
infants with an appropriate weight for their PCA at discharge
Korean J Pediatr 2016;59(12):466-470
should be breastfed when possible. When formula-fed, such in­
fants should be fed standard formula with long-chain polyunsa­
turated fatty acids. Human milk-fed infants with subnormal
weight for their PCA after discharge should receive supplemen­
tation with HMFs to provide adequate nutrients. If formula-fed
with suboptimal weight for their PCA, such infants should receive
special PDF to decrease the risk of long-term growth failure4).
Nevertheless, if the infants in Korea are discharged with a sub­
optimal weight for PCA, preterm formula is used until a weight of
3.5–4.0 kg is achieved after discharge, enhanced nutrient intake
may be achieved by the replacement of one third, half, or two-
thirds of daily energy intake with a preterm formula, restricted
fortification with HMFs (half strength), or human milk fortified
with a preterm formula (80, 90, or 100 kcal/100 mL).
Conclusions
To reach the goals of nutrition for preterm infants, “aggressive”
and adequate enteral nutrition are needed. In recent years, focus
has shifted from the overall energy intake to the optimal protein
intake and P/E ratio. A high overall energy intake may result in
excess accretion of adipose tissue, whereas high protein intake
may have beneficial effects on the quality of growth and long-
term neurodevelopmental outcomes. Minimal enteral nutrition
should begin as soon as possible during the 1st day of life, and
feeding advancement should be conducted based on the clinical
course of each infant. During hospitalization, enteral nutrition
with preterm formula and human milk with HMFs are the best
feeding practices to improve growth. After discharge, the enteral
nutrition strategy should be individualized according to the
weight at discharge and should be reviewed and modified conti­
nuously to achieve the target growth parameters.
Conflict of interest
No potential conflict of interest relevant to this article was
reported.
References
1. Su BH. Optimizing nutrition in preterm infants. Pediatr Neonatol
2014;55:5-13.
2. American Academy of Pediatrics Committee on Nutrition: Nutri­
tional needs of low-birth-weight infants. Pediatrics 1985;75:976-
86.
3. American Academy of Pediatrics. Nutritional needs of preterm
infants. Pediatric nutrition handbook. Elk Grove Village (IL):
American Academy of Pediatrics, 2009.
https://doi.org/10.3345/kjp.2016.59.12.466 469
Kim MJ • Enteral nutrition
4. Agostoni C, Buonocore G, Carnielli VP, De Curtis M, Darmaun D,
Decsi T, et al. Enteral nutrient supply for preterm infants: com­
mentary from the European Society of Paediatric Gastroen­
terology, Hepatology and Nutrition Committee on Nutrition. J
Pediatr Gastroenterol Nutr 2010;50:85-91.
5. Ernst KD, Radmacher PG, Rafail ST, Adamkin DH. Postnatal
malnutrition of extremely low birth-weight infants with catch-up
growth postdischarge. J Perinatol 2003;23:477-82.
6. Ehrenkranz RA, Dusick AM, Vohr BR, Wright LL, Wrage LA, Poole
WK. Growth in the neonatal intensive care unit influences neuro­
developmental and growth outcomes of extremely low birth
weight infants. Pediatrics 2006;117:1253-61.
7. Poindexter BB, Ehrenkranz RA. Nutrient requirements and pro­
vision of nutritional support in the premature neonate. In: Martin
RJ, Fanaroff AA, Walsh MC, editors, Fanaroff and Martin's neo­
natal-perinatal medicine: diseases of the fetus and infant. 10th ed.
Philadelphia (PA): Elsevier Saunders, 2015:592-612.
8. Cho SJ. Enteral nutrition of the premature infant. Korean J Pediatr
2010;53:7-13.
9. Morgan J, Bombell S, McGuire W. Early trophic feeding versus
enteral fasting for very preterm or very low birth weight infants.
Cochrane Database Syst Rev 2013;(3):CD000504.
10. Morgan J, Young L, McGuire W. Delayed introduction of progres­
sive enteral feeds to prevent necrotising enterocolitis in very low
birth weight infants. Cochrane Database Syst Rev 2014;(12):
CD001970.
11. Morgan J, Young L, McGuire W. Slow advancement of enteral feed
volumes to prevent necrotising enterocolitis in very low birth
weight infants. Cochrane Database Syst Rev 2014;(12):CD001241.
12. Vohr BR, Poindexter BB, Dusick AM, McKinley LT, Higgins RD,
Langer JC, et al. Persistent beneficial effects of breast milk ingested
in the neonatal intensive care unit on outcomes of extremely low
birth weight infants at 30 months of age. Pediatrics 2007;120:
e953-9.
470 https://doi.org/10.3345/kjp.2016.59.12.466
13. ESPGHAN Committee on Nutrition, Arslanoglu S, Corpeleijn W,
Moro G, Braegger C, Campoy C, et al. Donor human milk for pre­
term infants: current evidence and research directions. J Pediatr
Gastroenterol Nutr 2013;57:535-42.
14. Arslanoglu S, Moro GE, Ziegler EE, The Wapm Working Group On
Nutrition. Optimization of human milk fortification for preterm
infants: new concepts and recommendations. J Perinat Med 2010;
38:233-8.
15. Polberger S, Räihä NC, Juvonen P, Moro GE, Minoli I, Warm A. In­
dividualized protein fortification of human milk for preterm in­
fants: comparison of ultrafiltrated human milk protein and a bo­
vine whey fortifier. J Pediatr Gastroenterol Nutr 1999;29:332-8.
16. The Korean Society of Neonatology. Manual of neonatal care. 3rd
ed. Seoul: EUIHAK Publishing Corp., 2014;96-112.
17. Stoll BJ, Hansen NI, Bell EF, Shankaran S, Laptook AR, Walsh MC,
et al. Neonatal outcomes of extremely preterm infants from the
NICHD Neonatal Research Network. Pediatrics 2010;126:443-56.
18. Griffin IJ, Cooke RJ. Nutrition of preterm infants after hospital
discharge. J Pediatr Gastroenterol Nutr 2007;45 Suppl 3:S195-203.
19. Amesz EM, Schaafsma A, Cranendonk A, Lafeber HN. Optimal
growth and lower fat mass in preterm infants fed a protein-enri­
ched postdischarge formula. J Pediatr Gastroenterol Nutr 2010;50:
200-7.
20. Young L, Morgan J, McCormick FM, McGuire W. Nutrient-enriched
formula versus standard term formula for preterm infants follow­
ing hospital discharge. Cochrane Database Syst Rev 2012;(3):
CD004696.
21. O'Connor DL, Unger S. Post-discharge nutrition of the breastfed
preterm infant. Semin Fetal Neonatal Med 2013 May 21 [Epub].
http://doi.org/10.1016/j.siny.2013.05.001.
22. Picaud JC, Decullier E, Plan O, Pidoux O, Bin-Dorel S, van Egroo
LD, et al. Growth and bone mineralization in preterm infants fed
preterm formula or standard term formula after discharge. J
Pediatr 2008;153:616-21, 621.e1-2.
A Novel Multi-Nutrient Human Milk Based Human Milk Fortifier Promotes Growth and Tolerance in
Premature Infants.

Amy Gates PhD, RDN, CSP, LD1, Amy B. Thompson MD1, Terri Marin PhD NNP-BC,
FAAN, CAANP, MBA2, Jennifer L. Waller PhD3, Jenny Patel MD1, Brian K. Stansfield MD1

Affiliations:
1. Department of Pediatrics, Division of Neonatology, Medical College of Georgia, Augusta
University, Augusta, GA, United States
2. College of Nursing, Augusta University, Augusta, GA, United States
3. Department of Population Health Sciences, Division of Biostatistics and Data Science,
Medical College of Georgia, Augusta University, Augusta, GA, United States

Address correspondence to:

Brian K. Stansfield, MD
Department of Pediatrics
Medical College of Georgia at Augusta University
1120 15th Street, BI 6033
Augusta, GA, 30912
bstansfield@augusta.edu
P: 706.721.2331

Funding Source: Medolac Laboratories, A Public Benefit Company (Medolac) provided

Fortify MVP™ (Novel HMF) in kind for the trial.

Role of Funder: Medolac designed and produced the human milk fortifier and provided the
fortifier for the study. Medolac did not participate or assist with study design, study conduct,
data analysis, or study reports.

Financial Disclosures:
Amy Gates
Mead Johnson Nutrition – Medical Science Liaison
Mead Johnson Nutrition – Speaker’s Bureau, Advisory Board, Grant Recipient
Medolac Laboratories – In-Kind Grant Recipient

Terri Marin
Mead Johnson Nutrition – Speaker’s Bureau

Brian Stansfield
Medolac – Medical Consultant for FDA review of clinical data

Jennifer Waller
Medolac – Statistical Consultant for FDA review of clinical data

Amy Thompson and Jenny Patel have nothing to disclose

This article has been accepted for publication and undergone full peer review but has not been
through the copyediting, typesetting, pagination and proofreading process, which may lead to
differences between this version and the Version of Record. Please cite this article as doi:
10.1111/jpen.2249.

This article is protected by copyright. All rights reserved.

 2

Abstract

Background: The objective of this study was to determine whether human milk

supplemented with a novel human milk-based HMF (Novel HMF), compared with a bovine

milk-based HMF (Bovine HMF), supports preterm infant growth through 36 weeks post-

menstrual age (PMA).

Methods: This single center, prospective trial compared growth and nutritional outcomes of

preterm infants provided a human milk-based diet (mother’s own milk or donor milk)

supplemented with a Novel HMF to historic controls provided Bovine HMF. Preterm infants

with an estimated gestational age (EGA) between 23 and 33 weeks PMA and birth weight

between 750 and 1,800 grams provided an exclusive human milk diet were eligible for study

inclusion. Weight, length, head circumference (HC) were monitored weekly. The occurrence

of late-onset sepsis, days of nil per os (NPO), necrotizing enterocolitis (NEC), metabolic

acidosis, and serious adverse events were monitored.

Results: Birth weight, length, HC, and EGA were similar between the Novel HMF (n = 37)

and Bovine HMF (n = 49) groups. The days to regain birth weight was shorter in the Novel

HMF group (9.4  4.0 vs. 11.4  4.8, p=0.0343) with similar weight gain (g/day) from birth

to 36 weeks PMA. Adjusted weight growth velocity (g/kg/day) was significantly higher in the

Novel HMF group at 14 and 21 days, but similar at 36 weeks PMA. The Novel HMF group

experienced fewer NPO days with similar total number of feeding days.

Conclusions: A novel, multi-nutrient human milk-based HMF is well tolerated and meets the

nutritional needs of preterm infants.

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 3

Clinical Relevancy Statement: Fortification of human milk is necessary to support

physiologic preterm infant growth and human milk-based human milk fortifiers (HMF)

provide an option for a truly exclusive human milk diet. However, the only commercially

available human milk-derived HMF is unsterile and lacks supplemental vitamins, which are

critical for physiologic development. We provide evidence that a sterile, multi-nutrient,

protein enriched human milk-based HMF is well-tolerated and supports physiologic preterm

infant growth.

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 4

Introduction

A growing body of evidence suggests that human milk for preterm infants is associated with

both short and long-term benefits including lower risk for necrotizing enterocolitis (NEC) and

bronchopulmonary dysplasia (BPD) as well as better cognitive outcomes that may persist into

adolescence1-10. The advantages for mother’s milk for the preterm infant are clear 11
;

however, several obstacles must be overcome to provide sufficient energy and nutrients to

support appropriate linear growth in the immediate post-natal period. The content of human

milk evolves over time and clear differences between preterm and term human milk have
12-14
been described . For example, preterm human milk is protein rich as compared to term

human milk, which influences postnatal growth for preterm infants who receive supplemental

or exclusive donor human milk derived from full term pregnancies. More importantly, the

nutrient requirements of the preterm infant must be supplied in a weight-appropriate volume

of human milk, which is often insufficient to provide adequate concentrations of micro- and

macronutrients and often requires supplementation in the form of human milk fortifiers
15, 16
(HMF) . The addition of HMF to human milk is well-tolerated and improves short term

gains in weight, length, and head circumference and may have benefits for bone

mineralization and neurocognitive outcomes 17.

Until recently, HMFs were bovine-derived, and offering high concentrations of

protein, vitamins, and minerals in an enteral supplement. Sterile infant formulas, calorie and

protein modulars, and HMF are preferred because of the risk of Enterobacter sakazakii

contamination. However, bovine-derived HMFs are associated with lower feeding tolerance
18
and higher risk for metabolic acidosis, when compared to human milk derived HMF. . The

recent development of a human-milk based HMF provided an option for a truly exclusive

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 5

human milk diet (mother’s own milk or donor milk plus a human milk derived HMF) for
19
preterm infants and may have some clinical benefit in reducing NEC . Although a recent

randomized trial failed to show benefit for human-milk based HMF in the prevention of

NEC, the study did show similar postnatal growth between the two groups, which has been a

concern related to the use of human milk-based HMFs 20, 21. However, the only commercially

available human milk-based HMF lacks important characteristics available in bovine milk-

based HMFs including supplemental vitamins and sterilization. In spite of the limited data on

human milk-based HMFs and their relatively high acquisition costs, approximately 20% of

NICUs in the United States use a human-milk based HMF 22.

Given the potential benefit of sterile human milk-based HMFs and limited availability

of such products to meet current demands, we prospectively assigned preterm infants to a

novel, multi-nutrient human milk-based HMF and compared growth metrics and biochemical

markers of metabolism between the prospective cohort and a historical cohort provided a

Bovine HMF to supplement human milk feedings.

Methods

Study Population

The prospective arm of this study was reviewed and approved by the Augusta University

Internal Review Board (IRB) and registered with ClinicalTrials.gov (NCT03839173). A

parent or guardian was approached for study participation and written informed consent was

obtained prior to study participation. Eligibility criteria for the prospective and historical

cohorts included 1) birth weight between 750 and 1,800 grams, 2) estimated gestational age

(EGA) between 23 and 33 completed weeks, 3) admission to the Children’s Hospital of

Georgia NICU prior to 24 hours of life, 4) commitment to a human milk diet (mother’s own

milk or Medolac Benefit-20™ donor milk, Medolac Laboratories, Boulder City, NV)), and 5)

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 6

initiation of enteral feedings by day of life 7 (DOL). Eligible subjects from both the

prospective and historical cohorts were excluded for: 1) intrauterine growth restriction

(IUGR) with birth weight less than 3rd centile, 2) known congenital or acquired renal

condition affecting electrolyte metabolism and/or excretion prior to DOL 7, 3) known or

acquired gastrointestinal condition affecting nutrient absorption prior to DOL 7, 4) five

minute APGAR score ≤ 3, 5) Grade III or IV intraventricular hemorrhage (IVH), 6) major

congenital anomalies, or 7) use of bovine-based infant formula or fortifier prior to DOL 7.

Figure 1 describes the number of infants excluded for each exclusion criteria.

Manufacture of the Novel Human Milk Fortifier

During manufacturing, a fractionated, concentrated product is created by separating whole

human donor milk into cream and skim. Skim milk is filtered at refrigeration temperatures

with ultrafiltration (used commonly in the dairy industry for the same purpose), then

blended with human milk cream and whole human milk to meet the macronutrient (fat,

protein, and carbohydrate) specifications of Fortify MVP™. After homogenization, selected

minerals and vitamins are added to the protein and fat enriched milk concentrate to reach

the finished product specification. The vitamins and minerals are blended with a high sheer

mixer until completely incorporated, then packaged in 50mL increments into standard 4oz

spouted retort pouches.

Study Design

This was a single-center, prospective observational cohort study with historical cohort

comparison of preterm infants who received human milk fortified with a human milk-based

HMF (termed Novel HMF) with a historical control of preterm infants who received human

milk fortified with a bovine-based HMF (termed Bovine HMF) from birth through 36 weeks

This article is protected by copyright. All rights reserved.

 7

PMA. Participants in the prospective arm received a sterile, multi-nutrient, protein enriched

human milk based HMF (Fortify MVP™ Medolac, Boulder City, Nevada), while infants in

the historical control received a commercially sterile, multi-nutrient, acidified protein

enriched bovine based HMF (Enfamil Human Milk Fortifier, Mead Johnson Nutrition,

Evansville, IN). During both study periods, a standard institution-specific feeding protocol

based on birth weight was used. Feeding protocols were specific for birth weights <750

grams, 750-1000 grams, 1000-1250 grams, 1250-1500 grams, and 1500-1800 grams. Initial

feeding volumes and frequency of volume advancement differed between the feeding

protocols. The complete feeding protocols can be found in Supplemental file XX. Enteral

feeds were initiated prior to DOL 7 in both cohorts and advanced by 10-20 mL/kg/day per the

feeding protocol to an enteral feeding volume goal of 150 mL/kg/day. For both groups, HMF

was added to human milk when infants achieved an enteral feeding volume of 80 mL/kg/day

for at least 24 hours with a fortification target of 24 kcal/ounce assuming a caloric density for

human milk of 20 kcal/ounce. If mother’s own milk was not available Medolac Benefit-20™

donor milk was used (20 calories/ounce and 1.5 grams protein/100 calories). Infants in both

cohorts who experienced extrauterine growth failure, defined as crossing two percentile

curves or deviation away from the 3rd percentile on the gender-specific Fenton Growth

Curve23, could be transitioned to a bovine-based premature infant formula prior to 36 weeks.

A description of the estimated nutrient composition for the Novel and Bovine HMF when

added to human milk (24kcal/ounce) (Supplementary Table I). The reporting of this study

conforms to the STROBE statement.

Outcomes

The primary objective was to determine whether human milk supplemented with a novel

human milk-based fortifier (HMF) with increased protein, as compared to a bovine milk-

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 8

based HMF, supports optimal preterm infant weight, length, and head circumference growth

through 36 weeks post-menstrual age (PMA). Differences in feeding-relevant outcomes

including feeding tolerance, rates of necrotizing enterocolitis24 (NEC), and biochemical

markers of metabolism were assessed as secondary outcomes.

Anthropometric Measures

Each week from birth to 36 weeks PMA, infants in both cohorts were weighed unclothed and

without a diaper on the same electronically calibrated scale. For the prospective arm, length

was measured weekly by the lead clinical investigator (A.G.) and one clinician using the

Tanis Fenton method with a Premie Stadiometer infant length board. Similarly, head

circumference was measured each week by the lead investigator using the Tanis Fenton

method with a flexible, non-stretchable vinyl tape25 (Seca, Hamburg, Germany). For infants

in the historical cohort, length and head circumference measurements were performed weekly

by the bedside nurse using an infant length board and a flexible, non-stretchable vinyl tape,

respectively. Weight gain was calculated as grams per day (g/day) from birth to 36 weeks

PMA. Weight growth velocity (GV) was calculated from birth to days 14, 21, and 36 weeks

PMA as:

( )
( )
( )
( )

where

= weight at the start of feeds

= weight at day of calculation

= date on day N where N = date corresponding to DOL 14, 21 and 36 weeks

PMA

= date of birth

This article is protected by copyright. All rights reserved.

 9

Head circumference and length growth velocities were calculated as centimeters per week

(cm/week) from birth to 36 weeks PMA.

Clinical Outcomes

Metabolic acidosis was defined as serum CO2 value of ≤ 17 mEq/L accompanied by

treatment with a sodium or potassium citrate salt. Suspected and/or confirmed NEC was

determined using Bell’s staging criteria. Late-onset sepsis (LOS) was defined as any positive

blood culture between DOL seven and 36 weeks PMA associated with antimicrobial therapy

for at least 72 hours. All cases of potential LOS, suggested by a positive blood culture, were

reviewed by two clinicians to limit bias.

Sample Size

Based on a sample of recent patients that met inclusion and exclusion criteria, the study was

powered to show a 20% difference in weight growth velocity at 36 weeks PMA between the

Novel and Bovine HMF groups. The sample size was also examined for other variables

including serum magnesium and CO2. Assuming an alpha level of 0.05 and power of 0.80,

and a mixed model for weight velocity, the sample size was determined for interaction

between HMF group and time under a compound symmetric correlation structure with a

correlation between measurement times of 0.5. A sample size of 33 infants per group was

adequate to show differences in weight gain, and serum magnesium and CO2.

Statistical Methods

All statistical analysis was performed using SAS 9.4 and statistical significance was assessed

using an alpha level of 0.05. Descriptive statistics by HMF group (Bovine or Novel) were

determined on all variables and included the frequency and percent for categorical variables,

medians and interquartile ranges for ordinal variables, or the mean and standard deviation for

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 10

continuous variables. chi-square tests for categorical variables, Kruskal-Wallis tests for

ordinal variables, and two-sample t-tests for continuous variables were used to examine

differences between HMF groups for demographic and baseline measurements, feeding and

clinical outcomes, markers of protein metabolism, electrolytes, and bone health.

Analysis of covariance (ANCOVA) was used to examine differences between HMF

types for return-to-birth-weight day (RTBW), average weight-gain-per-day, head

circumference growth velocity, and length growth velocity at 36-weeks PMA. Each

ANCOVA model controlled for EGA, race, sex, multiple birth, birth weight percentile, birth

head circumference percentile, and birth length percentile. Due to the proximity to birth and

lack of measurements on the day of feeding initiation, birth head circumference and birth

length were controlled for in the average weight gain per day analysis.

For 36-week growth velocity for length and head circumference and for average

weight gain per day, an ANCOVA model was used to examine differences between HMF

groups controlling for EGA and the measure at start of feed. A repeated measures mixed

model was used to examine differences over time (14d, 21d, and 36wk PMA) between HMF

groups for weight growth velocity. The model included main effects and the two-factor

interaction between HMF group and time controlling for EGA and the measure at start of

feed. The subject nested within group was considered a random effect. A Kenward-Rogers

adjustment to the degrees of freedom for testing and assumed an unstructured correlation

structure between measurement times was used. A Bonferroni adjustment to the overall

alpha level (adjusted alpha=0.05/9=0.0056) was used to examine post hoc pairwise

differences between HMF groups within measurement time and between measurement times

within HMF group.

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 11

Results

Participant characteristics in the Novel and Bovine HMF groups and unadjusted measures are

described in Table 1. No differences in birth weight or gestational age were identified;

however, participants in the Novel HMF group had statistically lower weight- and length-for-

gestational age at birth and at the start of feeds when compared with the Bovine HMF group.

The number of days to return-to-birth-weight (RTBW) was also lower in the Novel HMF

group when compared with the Bovine HMF group. Based on the unadjusted difference

between groups in RTBW days, we examined the difference in RTBW controlling for

demographic and birth characteristics. The Novel HMF group had a lower (8.92  1.09d vs.

10.96  0.93d, p = 0.0601), but not statistically significant, adjusted mean number of days to

return-to-birth-weight when compared to the Bovine HMF group after controlling for

gestational age, race, sex, multiple births, and percentiles for birth weight, length, and head

circumference (Supplementary Table II).

Next, we compared weight gain (grams/day), length growth velocity, and head

circumference growth velocity between the Novel and Bovine HMF. While controlling for

weight, length, and head circumference at the start of feeds, no statistically significant

differences between the groups in weight gain, length growth velocity, or head circumference

growth velocity were identified (Supplementary Table III). Similar results were observed

after controlling for gestational age, race, sex, multiple births, and for weight, length, and

head circumference at birth (Supplementary Table IV).

In order to examine differences between groups in weight growth velocity

(grams/kg/day) over time, we used repeated measures mixed models to adjust for birth weight

in both models, and gestational age, race, sex, multiple births, and birth length and head

circumference in the final model. In both adjusted models, the interaction between HMF type

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 12

and time was statistically significant indicating that the pattern of mean weight growth

velocity across time was different between the Novel and Bovine HMF groups (Table 2).

Weight growth velocity from 14 days to 21 days was greater in the Bovine HMF group when

compared with the Novel HMF group, but similar between groups from 21 days to 36 weeks.

Post hoc pairwise comparisons between HMF groups indicated that the Novel HMF group

had significantly greater growth velocity at days 14 (p<0.0001) and 21 (p=0.0020) but not at

36 weeks (p=0.3727). Within each HMF group, post hoc pairwise comparisons between

measurement times showed that there were statistically significant differences between

measurement times (14 days vs 21 days p=0.0005 for Novel HMF and p<0.0001 for Bovine

HMF; 14 days vs 36 weeks p<0.0001 for Novel and Bovine HMF; and 21 days vs 36 weeks

p<0.0001 for Novel and Bovine HMF).

Next, we identified and compared feeding relevant outcomes between HMF groups.

The timing of feeding initiation, total HMF days, and total feeding days did not differ

between groups, but HMF was introduced at an earlier DOL in the Novel HMF group when

compared with the Bovine HMF group (Table 3). The Novel HMF group also had

significantly greater total estimated energy intake and significantly less days without any

feedings (i.e. nil per os). Importantly, no differences in necrotizing enterocolitis were

observed between HMF groups, but the percentage of study participants requiring oxygen at

36 weeks PMA was higher in the Novel HMF group when compared with the Bovine HMF

group (Supplementary Table V).

Finally, we measured serum and urine electrolytes, vitamin D concentration, and

hemoglobin and hematocrit at 21 days of life. The Bovine HMF group had significantly

higher blood urea nitrogen (BUN) (16.7  10.1 vs. 11.0  9.7, p = 0.0112) and serum calcium

(10.0  0.4 vs. 9.7  0.5, p = 0.0128) concentrations at DOL 21 when compared with the

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 13

Novel HMF group, although mean values for BUN and calcium were within traditional

normal ranges (Supplementary Table VI).

Discussion

A substantial body of literature supports the routine use of human milk in the diet of preterm

infants and this practice is emerging as a standard of care after policy statements by the

American Academy of Pediatrics among other professional organizations7, 26, 27. Audacious

goals to provide all preterm infants with an exclusive human milk diet have been proposed

with present recommendations focused on providing human milk to the highest risk preterm

population. Regardless of the source of human milk, fortification of both mother’s own milk

or donor human milk is necessary to support proper extrauterine growth and improved

neurodevelopmental outcomes. The present study provides promising evidence that a novel

human milk-based HMF is well tolerated and supports the nutritional needs of preterm

infants.

Early postnatal weight loss is a physiological response that is exaggerated in preterm

infants and reaches a nadir towards the end of the first week, which is followed by a

downward growth trajectory that continues for at least 2 more weeks28. Thus, a shorter

duration to return to birth weight likely reflects earlier nutritional adequacy that meets the

high metabolic demands of the preterm infant. The mean number of postnatal days required

to regain birth weight was two days lower in the Novel HMF group when compared with the

Bovine HMF group in unadjusted analysis, but failed to reach statistical significance (p=0.06)

when accounting for covariates associated with preterm infant growth and outcomes.

Reflecting an earlier return to birth weight, mean growth velocity (g/kg/day) at postnatal days

14 and 21 was higher in the Novel HMF group when compared with the Bovine HMF group.

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 14

Relevant to the interpretation of these data, birth weight and weight at the start of feedings

did not differ between groups, but HMF was introduced at an earlier postnatal day in the

Novel HMF group when compared with the Bovine HMF group. Earlier fortification in the

Novel HMF cohort is likely to underlie the enhanced growth velocity at these early time

points. However, it must also be acknowledged that mean total HMF days did not differ

between groups.

Weight gain (g/day), length and head circumference growth velocity at 36 weeks

postmenstrual age (PMA) were similar between groups and were largely influenced by the

particular measurement at the start of feedings and the estimated gestational age. Monitoring

weight gain across time does not clearly represent the patterns of growth for preterm infants

of different gestational ages since weight gain is relatively flat for extremely preterm infants

(i.e. < 28 weeks) on the lower percentile curves while preterm infants on the upper percentile

curves experience positive linear growth beginning soon after birth. This trend is unique to

weight-for-age percentile charts and the dispersion between upper and lower percentiles

continues to diverge through term corrected age. On the other hand, growth velocity

(g/kg/day) provides a more consistent expression of growth over time irrespective of

gestational age 25, 28. Weight growth velocity was nearly two-fold higher throughout the study

period and was consistently higher at 14 days, 21 days, and 36 weeks PMA in the Novel

HMF group when compared with the Bovine HMF group. Taken together, the early return to

birth weight coupled with the higher growth velocity suggests that human milk fortified with

the Novel HMF meets the energy needs of preterm infants.

In order to more accurately assess growth characteristics in the Novel HMF group, we

compared feeding-relevant outcomes between cohorts. Several key feeding outcomes were

similar between groups including DOL for start of feedings, total feeding days, and days of

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 15

parenteral nutrition. Together, these data suggest that early feeding patterns were largely

similar between the study periods with the exception of earlier introduction of fortifier in the

Novel HMF group. While it is certainly reasonable to conclude that earlier fortification

enhances growth velocity, particularly in the first weeks of life, the total number of HMF

days did not differ between groups. Further, the differences in weight growth velocity

persisted to 36 weeks PMA suggesting that the Novel HMF group continued to demonstrate

an advantage in growth velocity through term corrected age. Whether the early growth

advantages demonstrated in the Novel HMF group reflects earlier fortification and place

these groups on different growth trajectories and are maintained throughout the first months

of life is an important and clinically relevant question that remains.

Mean total feeding days with an exclusive human milk-based diet was marginally, but

not statistically higher (p=0.0759) in the Bovine HMF group when compared with the Novel

HMF group. Historically, a concern for preterm infants provided an exclusive human milk

diet was the poor growth observed in these infants when compared with preterm infants

provided a bovine-based preterm formula. This relationship appears to be particularly true

with donor human milk. Donor human milk appears to exert a linear and negative effect on

weight and head circumference growth velocity at 36 weeks PMA in preterm infants in
29
comparison to mother’s own milk and preterm formula . Others have shown similar

impaired growth in preterm infants provided a high percentage of donor human milk and has

been attributed to reduced fat, protein, and energy in donor human milk as compared to
30-32 33
mother’s own milk , but this relationship is not universally observed . In our study

population, differences in total volume or percent of mother’s own milk did not differ

between HMF groups. The emergence of fortifiers and improved growth tracking has largely

removed the barriers to growth that were previously observed and impeded the widespread
25
adoption of exclusive human milk diets . Fortification of human milk in particular has

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 16

greatly improved anthropometric outcomes in preterm infants provided a human milk diet 34.

In our own study, both fortification strategies achieved a minimum target > 10 g/kg/day for

weight growth velocity with higher, but not statistically significant, growth velocity observed

in the Novel HMF group when compared with the Bovine HMF group at 36 weeks PMA.

This growth advantage was likely achieved through greater total estimated energy intake in

the Novel HMF group while also maintaining similar protein delivery when compared with

the Bovine HMF group. The higher energy intake and growth velocity in the Novel HMF

cohort is an important finding that opposes a recent systematic review and meta-analysis

demonstrating improved growth in preterm infants provided different Bovine HMFs when

compared with a human milk-derived HMF35. Direct comparisons between bovine and

human milk-derived HMFs are limited and our findings directly contribute to this growing
36, 37
body of evidence . The improved growth velocity may also reflect the lower number of

NPO days in the Novel HMF group. Total days of parenteral nutrition did not differ between

groups suggesting that prolonged NPO was uncommon in both groups, but the lower mean

number of NPO days may reflect better feeding tolerance in the Novel HMF group.

The frequency of clinically important outcomes including death, medical or surgical

NEC, late onset sepsis, and retinopathy of prematurity (ROP) did not differ between groups.

ROP is often identified in preterm infants who experience extrauterine growth failure and

improving growth with a variety of dietary interventions is efficacious in reducing ROP38-42.

Similarly, BPD is a multifactorial outcome that is closely tied to postnatal growth. Poor

postnatal growth due to higher oxygen consumption or demand or inadequate nutrient supply
43, 44
are linked to higher rates of BPD . We did observe a statistically significant increase in

infants requiring oxygen at 36 weeks PMA, the clinical definition of BPD, in the Novel HMF

group when compared with the Bovine HMF group. As both groups experienced acceptable

growth velocity with the Novel HMF group achieving an even higher growth velocity than

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 17

the Bovine HMF group, it is unlikely that nutritional inadequacy or insufficient energy supply

contributed to the observed difference in outcome. Rather, the Novel HMF group was

statistically smaller-for-gestational age and includes more infants who experienced slow

intrauterine growth. Further, it is plausible that an earlier return to birth weight reflects a

shorter diuretic phase and potentially greater fluid retention in the immediate post-partum

period. Both, small-for-gestational age and higher fluid intake/retention in the first week of

life are important risk factor for BPD 45-49. While these potential explanations are reasonable,

it must be noted that the mean percent weight loss between birth and start of feeds was

similar between the cohorts (5.9%  6.7 vs. 6.1%  6.1, p=0.93), and the Novel HMF group

continued to be smaller-for-age at feeding initiation when compared with the Bovine HMF

group. A limitation to our study was that the weight, length and head circumference

measurements for the retrospective cohort group were not taken by one trained individual but

were collected from the electronic medical record. For the prospective group, weight, length

and head circumference measurements were taken by the principal investigator plus one

trained neonatal nurse practitioner.

Finally, we examined serum electrolyte concentrations along with measures of bone

mineralization and blood volume at the end of the first month of life in both cohorts. Both

groups displayed similar values within the expected normal range for all electrolytes with a

statistically higher serum calcium concentration observed in the Bovine HMF group when

compared with the Novel HMF group. Serum alkaline phosphatase and phosphorus were

within normal limits for both groups. Vitamin D status and hemoglobin values were similar

between groups.

Several limitations for this study are acknowledged. First, the use of a historical

control to compare nutritional outcomes and growth does not provide a true comparison

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 18

between the novel and Bovine HMF. Our goal in this cohort study was to identify whether

appropriate growth outcomes for preterm infants could be achieved with the Novel HMF;

thus, we feel that a historical control provided a sufficient comparison group and recognize

that superiority of the Novel HMF is not truly evaluated. Relevant to this point, feeding

protocols were unchanged during both study periods and the prospective and historical

cohorts did not differ for important demographics such as EGA and birth weight or total

feeding days and exposure to mother’s own milk. We also recognize that the lack of

randomization and blinding in the prospective cohort does introduce potential bias. All

measurements were made by a single member of the investigative team during both cohorts

(AG) and outcomes in the prospective group were confirmed by the investigative team (AG

and BKS) as well as a member of the healthcare team that is not involved in the study.

Finally, we acknowledge that limited data for some measurements in the historical control

precludes true comparisons between the groups.

The present study provides evidence that a novel human milk-based HMF is well-

tolerated and supports the nutritional needs of preterm infants. When added to human milk,

maternal or donor, the novel human milk-based HMF meets the recommendations for protein

and micro-nutrients. Furthermore, the novel fortifier provides healthcare providers with a

potential alternative to bovine based HMFs and supports a complete human milk diet for

premature infants.

Statement of Authorship

This article is protected by copyright. All rights reserved.

 19

A. Gates and B.K. Stansfield equally contributed to the conception and design of the

research; A. Gates, A. B. Thompson, and J. Patel contributed to the acquisition of the data; J.

L. Waller contributed to the analysis of the data; A. Gates, A. B. Thompson, T. Marrin, J.L.

Waller, and B.K. Stansfield contributed to the interpretation of the data; and A. Gates and

B.K. Stansfield drafted the manuscript. All authors critically revised the manuscript, agree to

be fully accountable for ensuring the integrity and accuracy of the work, and read and

approved the final manuscript.

Supplementary Material

Supplementary table 1-6 are online at

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 20

References

1. Sullivan. An Exlusively Human Milk-Based Diet is Associated with a Lower Rate of Necrotizing
Enterocolitis than a Diet of Human Milk and Bovine Milk-Based Products. The Journal of
Pediatrics. 2010:562-567.
2. Cristofalo EA, Schanler, Richard, Blanco, Cynthia, Sullivan, Sandra, et. al. Randomized Trial of
Exclusive Human Milk versus Preterm Formula Diets in Extremely Premature Infants. The
Journal of Pediatrics. 2013:1592-1595.
3. Ghandehari Heli LML, Rechtman David. An exclusive human milk-based diet in extremely
premature infants reduces the probability of remaining on total parenteral nutrition: a
reanalysis of the data. BMC Research Notes. 2012:1-5.
4. Stoll Barbara HN, Bell Edward, Shankaran Seetha, Laptook Abbot, Walsh Michele, et. al.
Neonatal Outcomes of Extremely Preterm Infants from the NICHD Neonatal Research
Network. Pediatrics. 2010;3(126):443-456.
5. Madore LS, Bora S, Erdei C, Jumani T, Dengos AR, Sen S. Effects of Donor Breastmilk Feeding
on Growth and Early Neurodevelopmental Outcomes in Preterm Infants: An Observational
Study. Clinical Therapies. 2017:1210-1120.
6. Feldman R EA. Direct and indirect effects of breast milk on the neurobehavioral and
cognitive development of premature infants. Developmental Psychobiology.
2003:43(42):109-119.
7. Quigley M, Embleton ND, McGuire W. Formula versus donor breast milk for feeding preterm
or low birth weight infants. Cochrane Database Syst Rev. Jul 19 2019;7:CD002971.
8. Meinzen-Derr J, Poindexter B, Wrage L, Morrow AL, Stoll B, Donovan EF. Role of human milk
in extremely low birth weight infants' risk of necrotizing enterocolitis or death. J Perinatol.
Jan 2009;29(1):57-62.
9. Ghandehari H, Lee ML, Rechtman DJ. An exclusive human milk-based diet in extremely
premature infants reduces the probability of remaining on total parenteral nutrition: a
reanalysis of the data. BMC Res Notes. Apr 25 2012;5:188.
10. Victoria CG BR, Barros AJD, Franca GVA, Horton S, Krasevec J. Breastfeeding in the 21st
century: epidemiology, mechanisms, and lifelong effect. The Lancet. January 30
2016;387(10017):475-490.
11. Breastfeeding and the Use of Human Milk. Pediatrics. 2012;123(3):e827-e841.
12. Gates A, Marin T, Leo G, Stansfield BK. Review of Preterm Human-Milk Nutrient
Composition. Nutr Clin Pract. Aug 30 2020.
13. Bhatia J. Human milk and the premature infant. Ann Nutr Metab. 2013;62 Suppl 3:8-14.
14. Underwood MA. Human milk for the premature infant. Pediatr Clin North Am. Feb
2013;60(1):189-207.
15. Koletzko B PB, Uauy R. Recommended Nutrient Intake Levels for Stable, Fully Enterally Fed
Very Low Birth Weight Infants. Nutritional Care of Preterm Infants. Scientific Basis and
Practical Guidelines. . Basel, Switzerland: Karger; 2010:297-299.
16. Casavale KO, Ahuja JKC, Wu X, et al. NIH workshop on human milk composition: summary
and visions. Am J Clin Nutr. Sep 1 2019;110(3):769-779.
17. Arslanoglu S, Boquien CY, King C, et al. Fortification of Human Milk for Preterm Infants:
Update and Recommendations of the European Milk Bank Association (EMBA) Working
Group on Human Milk Fortification. Front Pediatr. 2019;7:76.
18. Thoene M, Hanson C, Lyden E, Dugick L, Ruybal L, Anderson-Berry A. Comparison of the
effect of two human milk fortifiers on clinical outcomes in premature infants. Nutrients. Jan
3 2014;6(1):261-275.

This article is protected by copyright. All rights reserved.

 21

19. Sullivan S, Schanler RJ, Kim JH, et al. An exclusively human milk-based diet is associated with
a lower rate of necrotizing enterocolitis than a diet of human milk and bovine milk-based
products. J Pediatr. Apr 2010;156(4):562-567 e561.
20. O'Connor DL, Kiss A, Tomlinson C, et al. Nutrient enrichment of human milk with human and
bovine milk-based fortifiers for infants born weighing <1250 g: a randomized clinical trial.
Am J Clin Nutr. Jul 1 2018;108(1):108-116.
21. Eibensteiner F, Auer-Hackenberg L, Jilma B, Thanhaeuser M, Wald M, Haiden N. Growth,
Feeding Tolerance and Metabolism in Extreme Preterm Infants under an Exclusive Human
Milk Diet. Nutrients. Jun 26 2019;11(7).
22. Perrin MT. Donor Human Milk and Fortifier Use in United States Level 2, 3, and 4 Neonatal
Care Hospitals. J Pediatr Gastroenterol Nutr. Apr 2018;66(4):664-669.
23. Fenton TR, Nasser R, Eliasziw M, Kim JH, Bilan D, Sauve R. Validating the weight gain of
preterm infants between the reference growth curve of the fetus and the term infant. BMC
Pediatr. Jun 11 2013;13:92.
24. Juhl SM, Hansen ML, Gormsen M, Skov T, Greisen G. Staging of necrotising enterocolitis by
Bell's criteria is supported by a statistical pattern analysis of clinical and radiological
variables. Acta Paediatr. May 2019;108(5):842-848.
25. Fenton TR, Chan HT, Madhu A, et al. Preterm Infant Growth Velocity Calculations: A
Systematic Review. Pediatrics. Mar 2017;139(3).
26. Committee On N, Section On B, Committee On F, Newborn. Donor Human Milk for the High-
Risk Infant: Preparation, Safety, and Usage Options in the United States. Pediatrics. Jan
2017;139(1).
27. Section on B. Breastfeeding and the use of human milk. Pediatrics. Mar 2012;129(3):e827-
841.
28. Cole TJ, Statnikov Y, Santhakumaran S, et al. Birth weight and longitudinal growth in infants
born below 32 weeks' gestation: a UK population study. Arch Dis Child Fetal Neonatal Ed. Jan
2014;99(1):F34-40.
29. Brownell EA, Matson AP, Smith KC, et al. Dose-response Relationship Between Donor Human
Milk, Mother's Own Milk, Preterm Formula, and Neonatal Growth Outcomes. J Pediatr
Gastroenterol Nutr. Jul 2018;67(1):90-96.
30. Soldateli B, Parker M, Melvin P, Gupta M, Belfort M. Human milk feeding and physical
growth in very low-birth-weight infants: a multicenter study. J Perinatol. Aug
2020;40(8):1246-1252.
31. Castellano Yanez C, Castillo Barrio B, Munoz Labian MDC, et al. Providing very preterm
infants with donor human milk led to faster breastfeeding rates but worse biometric gains.
Acta Paediatr. Apr 2019;108(4):766-767.
32. Perrin MT, Belfort MB, Hagadorn JI, et al. The Nutritional Composition and Energy Content of
Donor Human Milk: A Systematic Review. Adv Nutr. Jul 1 2020;11(4):960-970.
33. Sisk PM, Lambeth TM, Rojas MA, et al. Necrotizing Enterocolitis and Growth in Preterm
Infants Fed Predominantly Maternal Milk, Pasteurized Donor Milk, or Preterm Formula: A
Retrospective Study. Am J Perinatol. Jun 2017;34(7):676-683.
34. Kuschel CA, Harding JE. Multicomponent fortified human milk for promoting growth in
preterm infants. Cochrane Database Syst Rev. 2004(1):CD000343.
35. Ananthan A, Balasubramanian H, Rao S, Patole S. Human Milk-Derived Fortifiers Compared
with Bovine Milk-Derived Fortifiers in Preterm Infants: A Systematic Review and Meta-
Analysis. Adv Nutr. Sep 1 2020;11(5):1325-1333.
36. Ananthan A, Balasubramanian H, Rao S, Patole S. Response to comments by Prof Abrams
and Prof Lucas on "Human Milk-Derived Fortifiers Compared with Bovine Milk-Derived
Fortifiers in Preterm Infants: A Systematic Review and Meta-Analysis". Adv Nutr. Nov 16
2020;11(6):1713-1715.

This article is protected by copyright. All rights reserved.

 22

37. Lucas A, Abrams SA. Comment on "Human Milk-Derived Fortifiers Compared with Bovine
Milk-Derived Fortifiers in Preterm Infants: A Systematic Review and Meta-Analysis". Adv
Nutr. Nov 16 2020;11(6):1712-1713.
38. Aydemir O, Sarikabadayi YU, Aydemir C, et al. Adjusted poor weight gain for birth weight and
gestational age as a predictor of severe ROP in VLBW infants. Eye (Lond). Jun
2011;25(6):725-729.
39. Binenbaum G, Ying GS, Quinn GE, et al. The CHOP postnatal weight gain, birth weight, and
gestational age retinopathy of prematurity risk model. Arch Ophthalmol. Dec
2012;130(12):1560-1565.
40. Porcelli PJ, Weaver RG, Jr. The influence of early postnatal nutrition on retinopathy of
prematurity in extremely low birth weight infants. Early Hum Dev. Jun 2010;86(6):391-396.
41. VanderVeen DK, Martin CR, Mehendale R, et al. Early nutrition and weight gain in preterm
newborns and the risk of retinopathy of prematurity. PLoS One. 2013;8(5):e64325.
42. Wallace DK, Kylstra JA, Phillips SJ, Hall JG. Poor postnatal weight gain: a risk factor for severe
retinopathy of prematurity. J AAPOS. Dec 2000;4(6):343-347.
43. Biniwale MA, Ehrenkranz RA. The role of nutrition in the prevention and management of
bronchopulmonary dysplasia. Semin Perinatol. Aug 2006;30(4):200-208.
44. Wemhoner A, Ortner D, Tschirch E, Strasak A, Rudiger M. Nutrition of preterm infants in
relation to bronchopulmonary dysplasia. BMC Pulm Med. Feb 3 2011;11:7.
45. Rocha G, de Lima FF, Machado AP, et al. Small for gestational age very preterm infants
present a higher risk of developing bronchopulmonary dysplasia. J Neonatal Perinatal Med.
2019;12(4):419-427.
46. Reiss I, Landmann E, Heckmann M, Misselwitz B, Gortner L. Increased risk of
bronchopulmonary dysplasia and increased mortality in very preterm infants being small for
gestational age. Arch Gynecol Obstet. Nov 2003;269(1):40-44.
47. Kewitz G, Wudel S, Hopp H, Hopfenmuller W, Vogel M, Roots I. Below median birth weight in
appropriate-for-gestational-age preterm infants as a risk factor for bronchopulmonary
dysplasia. J Perinat Med. 2008;36(4):359-364.
48. Havinga J, Williams A, Hassan N, et al. Individualized fluid management in extremely preterm
neonates to ensure adequate diuresis without increasing complications. J Perinatol. Feb
2021;41(2):240-246.
49. Oh W, Poindexter BB, Perritt R, et al. Association between fluid intake and weight loss during
the first ten days of life and risk of bronchopulmonary dysplasia in extremely low birth
weight infants. J Pediatr. Dec 2005;147(6):786-790.

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 23

Table 1: Descriptive statistics by HMF type and test for differences for demographic and other
preterm infant characteristics

Test p-
Variable Bovine HMF Novel HMF
Statistic value

Birthweight†, g 1130.9 (186.7) n=49 1146.0 (238.6) n=37 0.33 0.7435

z-score† 0.4 (0.7) n=49 -0.1 (0.8) n=37 -3.00 0.0035

Percentile†, % 63.4 (23.1) n=49 46.6 (23.3) n=37 -3.33 0.0013

Birth Class ƒ 0.20 0.6576

≤1000g 15 (30.6) 13 (35.1)

>1000g 34 (69.4) 24 (64.9)

Feeding Protocol Birthweight Ranges ƒ * 0.2390

750-999g 15 (30.6) 12 (32.4)

1000-1499g 33 (67.4) 21 (56.8)

1500g 1 (2.0) 4 (10.8)

RTBW†, d 11.4 (4.8) n=49 9.4 (4.0) n=37 -2.15 0.0343

Birth Length†, cm 36.4 (2.6) n=49 36.8 (3.0) n=37 0.54 0.5895

z-score† 0.2 (0.7) n=49 -0.2 (1.0) n=37 -1.65 0.1047

Percentile†, % 56.6 (22.2) n=49 44.9 (28.1) n=37 -2.14 0.0351

Birth Head Circumference†, cm 25.2 (1.8) n=49 25.8 (1.8) n=37 1.54 0.1263

z-score† -0.1 (0.9) n=49 -0.3 (0.9) n=37 -0.86 0.3947

Percentile†, % 47.7 (27.3) n=49 40.9 (26.9) n=37 -1.15 0.2536

Estimated Gestational Age†, weeks 27.9 (1.9) n=49 28.8 (2.2) n=37 1.91 0.0601

Apgar score at 5 minutes‡ 6.0 (5.0-8.0) n=49 6.0 (5.0-7.0) n=37 4.17 0.0411

Gender ƒ 0.23 0.6343

Female 20 (40.8) 17 (46.0)

Male 29 (59.2) 20 (54.0)

Race ƒ * 0.1426

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 24

White 14 (28.6) 8 (21.6)

Black 31 (63.3) 29 (78.4)

Hispanic 4 (8.1) 0 (0.0)

Multiples ƒ 3.04 0.0811

Yes 6 (12.2) 10 (27.0)

No 43 (87.8) 27 (73.0)

Start of Feeds

Weight at start of feeds†, g 1064.9 (183.7) n=49 1073.5 (219.6) n=37 0.20 0.8440

Percentile†, % 45.6 (22.9) n=49 31.8 (20.8) n=37 -2.89 0.0050

Length at start of feeds†, g 36.4 (2.6) n=49 36.9 (3.0) n=37 0.68 0.4983

Percentile†, % 56.6 (22.2) n=49 45.0 (28.0) n=37 -2.14 0.0353

36-week PMA Measurements

Weight†, g 2226.7 (314.9) n=46 2142.3 (297.5) n=35 -1.22 0.2245

Percentile†, % 22.0 (20.6) n=45 16.4 (18.2) n=35 -1.26 0.2122

Weight gain†, g/day 20.0 (5.1) n=45 20.3 (4.9) n=35 0.30 0.7673

Weight Growth Velocity†, g/kg/day 11.8 (2.0) n=45 12.3 (2.4) n=35

Length†, cm 44.5 (2.0) n=39 43.7 (2) n=35 -1.59 0.1160

Percentile†, % 21.3 (21.4) n=39 17.0 (17.3) n=35 -0.94 0.3486

Growth Velocity†, cm/week 1.0 (0.3) n=39 1.0 (0.2) n=35

Head Circumference†, cm 30.7 (1.3) n=47 30.9 (1.3) n=35 0.51 0.6142

Percentile†, % 19.6 (18.6) n=47 20.2 (18.9) n=35 0.15 0.8802

Growth Velocity†, cm/week 0.7 (0.2) n=47 0.7 (0.1) n=35

†
mean (SD) n, t-statistic presented
‡
median (IQR) n , Kruskal-Wallis chi-square statistic presented
ƒ
n (%), chi-square statistics presented
* Fisher’s Exact test performed
HMF=Human Milk Fortifier

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 25

Table 2: Mixed model results for difference in weight growth velocity over time between
HMF types, simple and final adjusted model

Adjusted LS
Effect in Model F p-value
Mean (SE)

Simple Model

HMF Type 17.10 <0.0001

Bovine-based HMF 6.05 (0.45)

Novel 8.89 (0.52)

Time Point 204.75 <0.0001

14d 3.43 (0.53)

21d 6.97 (0.40)

36wk 12.02 (0.24)

HMF Type x Time Point 17.28 <0.0001

Bovine-based HMF

14d (N=48) 0.66 (0.070)

21d (N=46) 5.54 (0.53)

36wk (N=47) 11.84 (0.32)

Novel

14d (n=36) 6.20 (0.79)

21d (N=36) 8.28 (0.60)

36wk (N=35) 12.20 (0.36)

Birth Weight, g 0.04 0.8346

Final Adjusted Model

HMF Type 15.80 <0.0001

Bovine-based HMF 6.14 (0.59)

Novel 9.08 (0.67)

Time Point 202.65 <0.0001

14d 3.56 (0.65)

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 26

21d 7.10 (0.55)

36wk 12.16 (0.45)

HMF Type x Time Point 16.79 <0.0001

Bovine-based HMF

14d (N=48) 0.75 (0.079)

21d (N=46) 5.76 (0.65)

36wk (N=47) 11.91 (0.49)

Novel

14d (n=36) 6.37 (0.91)

21d (N=36) 8.45 (0.74)

36wk (N=35) 12.41 (0.56)

Birth Weight, g 0.02 0.9002

EGA, weeks 0.17 0.6846

Race 1.22 0.3000

Sex 1.30 0.2576

Multiple Birth 1.16 0.2841

Birth Head Circumference, cm 1.64 0.2036

Birth Length, cm 0.72 0.3985

HMF=Human Milk Fortifier, EGA=Estimated Gestational Age, LS=Least Squares, SE=Standard

Error

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 27

Table 3: Descriptive statistics [mean (SD) n] by HMF type and test for differences for feeding outcomes

t-
Variable Bovine HMF Novel HMF p-value
statistic

Days of Parenteral Feeding, d 17.4 (8.4) n=49 16.2 (7.8) n=37 -0.69 0.4931

DOL Feeding Started, d 2.4 (1.5) n=49 2.1 (1.2) n=37 -1.04 0.3001

Total Feeding Days, d 50.4 (13.8) n=49 45.4 (14.8) n=37 -1.60 0.1129

DOL HMF Started, d 16.4 (8.1) n=49 12.0 (5.3) n=36 -3.03 0.0032

Total HMF Days, d 28.7 (12.7) n=49 30.5 (11.3) n=37 0.70 0.4875

DOL Full Feeds Reached, d 20.5 (8.6) n=48 18.9 (9.8) n=36 -0.77 0.4430

Total Volume MOM, mL/kg 3355.0 (4265.3) n=49 2880.6 (3627.7) n=37 -0.54 0.5880

Total Volume Donor Milk, mL/kg 2954.4 (3173.9) n=49 3982.8 (3325.3) n=37 1.46 0.1487

Percent of Volume from MOM, % 47.4 (49.6) n=49 42.7 (42.6) n=37 -0.47 0.6408

Total estimated energy Intake,

82.2 (17.3) n=45 95.2 (17.0) n=35 3.36 0.0012
kcal/kg/day

Days NPO, d 2.1 (3.3) n=49 0.7 (1.8) n=37 -2.45 0.0166

Total Protein Intake, g/kg/day 3.1 (0.8) n=45 3.0 (0.6) n=35 -1.16 0.2480

DOL=Day of Life, HMF=Human Milk Fortifier, MOM=Mother’s Own Milk, kcal=kilocalories,

NPO=Nothing per OS

This article is protected by copyright. All rights reserved.

 28

This article is protected by copyright. All rights reserved.


Edited by:
Donato F. Romagnolo,
University of Arizona, United States
Reviewed by:
Pedro Magalhães,
Agostinho Neto University, Angola
Sharon Ross,
National Cancer Institute (NIH),
United States
*Correspondence:
Fahmina Anwar
fahmina.anwar@in.nestle.com
Specialty section:
This article was submitted
to Clinical Nutrition,
a section of the journal
Frontiers in Nutrition
Received: 09 January 2017
Accepted: 29 April 2017
Published: 26 May 2017
Citation:
Kumar RK, Singhal A, Vaidya U,
Banerjee S, Anwar F and Rao S
(2017) Optimizing Nutrition in Preterm
Low Birth Weight Infants—
Consensus Summary.
Front. Nutr. 4:20.
doi: 10.3389/fnut.2017.00020
Frontiers in Nutrition  |  www.frontiersin.org
Review
published: 26 May 2017
doi: 10.3389/fnut.2017.00020
Optimizing Nutrition in Preterm Low
Birth weight infants—Consensus
Summary
R. Kishore Kumar1, Atul Singhal 2, Umesh Vaidya 3, Saswata Banerjee 4, Fahmina Anwar 5*
and Shashidhar Rao 5
1
 Cloudnine Hospital, Bangalore, Karnataka, India, 2 Institute of Child Health, UCL, London, United Kingdom, 3 KEM Hospital,
Pune, India, 4 Nestle Nutrition, Kolkata, India, 5 Medical and Scientific Affairs, Nestle Nutrition, South Asia Region, Gurgaon, India
Preterm birth survivors are at a higher risk of growth and developmental disabilities
compared to their term counterparts. Development of strategies to lower the com-
plications of preterm birth forms the rising need of the hour. Appropriate nutrition is
essential for the growth and development of preterm infants. Early administration of
optimal nutrition to preterm birth survivors lowers the risk of adverse health outcomes
and improves cognition in adulthood. A group of neonatologists, pediatricians, and
nutrition experts convened to discuss and frame evidence-based recommendations for
optimizing nutrition in preterm low birth weight (LBW) infants. The following were the
primary recommendations of the panel: (1) enteral feeding is safe and may be preferred
to parenteral nutrition due to the complications associated with the latter; however,
parenteral nutrition may be a useful adjunct to enteral feeding in some critical cases;
(2) early, fast, or continuous enteral feeding yields better outcomes compared to late,
slow, or intermittent feeding, respectively; (3) routine use of nasogastric tubes is not
advisable; (4) preterm infants can be fed while on ventilator or continuous positive air-
way pressure; (5) routine evaluation of gastric residuals and abdominal girth should be
avoided; (6) expressed breast milk (EBM) is the first choice for feeding preterm infants
due to its beneficial effects on cardiovascular, neurological, bone health, and growth
outcomes; the second choice is donor pasteurized human milk; (7) EBM or donor milk
may be fortified with human milk fortifiers, without increasing the osmolality of the milk, to
meet the high protein requirements of preterm infants; (8) standard fortification is effective
and safe but does not fulfill the high protein needs; (9) use of targeted and adjustable
fortification, where possible, helps provide optimal nutrition; (10) optimizing weight gain
in preterm infants prevents long-term cardiovascular complications; (11) checking for
optimal weight and sucking/swallowing ability is essential prior to discharge of preterm
infants; and (12) appropriate counseling and regular follow-up and monitoring after
discharge will help achieve better long-term health outcomes. This consensus summary
serves as a useful guide to clinicians in addressing the challenges and providing optimal
nutrition to preterm LBW infants.
Keywords: optimizing nutrition, preterm low birth weight infants, enteral feeding, expressed breast milk, donor
pasteurized human milk, fortification
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Kumar et al.
INTRODUCTION
About 15 million preterm births are recorded each year world-
wide. According to the World Health Organization, there has
been an increase in the incidence of preterm births over the past
20 years in 62 of the 65 countries with available trend data. Over
one million children die from preterm birth-related complica-
tions annually. Preterm births are the leading cause of newborn
deaths and the second leading cause of death, after pneumonia,
in children under the age of 5 years. Furthermore, survivors of
preterm birth are at a higher risk of adverse developmental dis-
abilities (1). They have higher rates of adverse health outcomes in
early adulthood compared with their term counterparts (2). The
various adverse developmental outcomes in adults born preterm
have been outlined in Table 1 (3–9).
Although there has been an improvement in the overall mor-
tality in extremely premature infants in recent times, there is a
rising need to develop newer strategies for lowering the potential
complications of preterm birth (10).
Nutrition—An Important Factor Influencing
Developmental Outcomes in Preterm
Infants
Nutrition is essential for growth, metabolism, and immunity in
a preterm newborn low birth weight (LBW) infant (11–13). In
a preterm infant, poor nutrition is associated with poorer head
growth; persistent smaller head size results in poor psychomotor
and mental skills, higher rates of cerebral palsy, and autism (14).
Impaired weight and growth in preterm infants are significantly
associated with adverse neurodevelopmental outcomes in later
life (15). Barker’s hypothesis also states that infants with LBW are
at a higher risk of coronary heart disease, hypertension, and type
2 diabetes in adulthood (16, 17).
OBJECTIVES AND METHODS
Considering the significant contribution of nutrition to the
development of preterm newborn LBW infants, a key opinion
leader who has extensive expertise in the related domain
reached out to other experts who had proficiency in various
areas related to the topic/s proposed to be discussed during
Table 1 | Adverse developmental sequelae in adults born preterm.
Parameter Adverse sequelae in adults born preterm
Neurological • Significant decrease in brain volume (3).
• Increased risk of neurological disabilities (4).
Cardiovascular and metabolic • Low insulin sensitivity and high blood
pressure (5).
• Increased intra-abdominal fat and higher risk
of metabolic complications (6).
• Increased arterial stiffness (7).
• Reduced ventricular size and volume;
impaired systolic function (8).
Bone health • Significantly lower bone mineral density (9).
Others • Increased risk of social disabilities in adulthood
(in terms of educational level attained, income,
and establishment of family) (4).
Frontiers in Nutrition  |  www.frontiersin.org
Nutrition in Preterm LBW Infants
the consensus meeting. This was followed by the selection of
a group of neonatologists, pediatricians, and nutrition experts,
who convened in August 2016 to brainstorm and address the
various challenges in providing optimal nutrition to preterm
LBW infants. The panel discussion also focused at highlight-
ing the advantages and disadvantages, optimal intakes, and
practical recommendations for various enteral nutrition sup-
plementation strategies.
This consensus summary paper compiles the evidence-based
recommendations from the Expert panel and serves as a useful
tool to the clinicians in optimizing nutrition in LBW preterm
infants for beneficial health outcomes in the long term.
EFFECTS OF EARLY AND AGGRESSIVE
NUTRITIONAL STRATEGIES
It has been noted that better nutrition in the early postnatal phases
in preterm infants results in higher verbal intelligence quotient (IQ)
scores and improved cognitive function in the long term (18, 19).
Higher protein and energy intake during the first week after birth in
extremely LBW infants is associated with higher mental development
index scores and lower risk of growth retardation at 18 months after
birth (20). Early and higher protein and energy intake have also been
correlated with faster head growth and an increase in head circumfer-
ence in preterm infants (21, 22); increase in head circumference has
been positively correlated with improved cognitive outcomes (23).
Therefore, the administration of early aggressive nutritional enteral
and parenteral support may help improve growth and developmental
outcomes in preterm newborn LBW infants (24).
CHALLENGES IN PROVIDING NUTRITION
TO PRETERM INFANTS
Parenteral versus Enteral Feeding
Enteral feeding is preferred to parenteral feeding, as the latter may
be associated with catheter-related complications, infections,
and sepsis, among others (25, 26). However, institution of early
parenteral nutrition can sometimes be critical and a necessary
adjunct to enteral therapy.
Does Enteral Feeding Carry an Increased
Risk of Necrotizing Enterocolitis (NEC)
and Infections?
One of the most feared complications of enteral feeding of a pre-
term infant is the risk of NEC; this came into limelight based on a
study published in The Lancet in 1990. In this study, NEC was more
common in preterm infants fed formula milk compared to infants
fed breast milk (27). However, there have been improvements in
feeding regimens and methods since this publication. In studies
published after this paper, there has been no increase in the risk
of NEC with fast or early enteral feeding of expressed breast milk
(EBM) or formula milk as compared to slow or delayed introduc-
tion of enteral feeding in LBW infants (28, 29). Furthermore,
enteral feeding has been found to aid in the development of the
gut and lower the risk of infections and sepsis (26, 30).
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Kumar et al.
When Should Enteral Feeding Be Started:
Early or Late?
Delaying the administration of progressive enteral feeding to
reduce the risk of NEC may not be an appropriate approach.
Systematic reviews have reported that delaying enteral feeding
does not lead to a reduction in the risk of NEC. On the contrary,
this approach may prolong the time to achieve full enteral
feeding (31). Furthermore, early versus late (<48 versus >72 h
after birth) initiation of enteral feeding has been found to be
associated with a significantly lesser time to gain birth weight,
and shorter duration of parenteral nutrition and hospital stay,
without any increase in the complication rate (32). A reduced
incidence of osteopenia of prematurity and jaundice has also
been noted with early versus late enteral feeding in very LBW
infants (33).
Advancement of Volume of Enteral Feed:
Rapid versus Slow
Several studies have assessed the outcomes with rapid versus slow
advancement of enteral feeding in preterm infants. In a study
conducted in neonates with LBW (<1,250 g), rapid versus slow
advancement of enteral feeding was associated with a significantly
lesser time required to achieve full enteral feeding and regain
birth weight; a shorter duration of hospital stay; comparable feed
tolerance; and no increase in the risk of NEC. EBM was used in
this study (28). Several other randomized studies and systematic
reviews using formula milk have also reported similar findings
(31, 34, 35).
Frequency of Feeding: Continuous versus
Hourly
Continuous nasogastric versus intermittent bolus milk feeding
in preterm LBW infants has long been a topic of debate. While
a few studies reveal comparable outcomes with the two feeding
methods, a few others support a significantly faster growth rate
and achievement of full enteral feeding with the continuous
feeding technique (36, 37). A systematic review of these feeding
methods in infants weighing less than 1,500  g reported faster
weight gain and earlier hospital discharge with the continuous
tube feeding method (38). Furthermore, a significant increase in
pulmonary resistance, airflow, and respiratory instability and a
decrease in cerebral perfusion have been noted with the bolus
feeding method (39, 40) Therefore, continuous feeding seems
to be logical in preterm infants till the development of sucking–
swallowing coordination.
How to Feed Enterally: Nasogastric versus
Orogastric Route
The passage of nasogastric tube has been noted to increase air-
way resistance in preterm infants by 30–50% (41). An increased
incidence of periodic breathing and central apnea has also been
noted with nasogastric tubes, in preterm infants (42). Hence,
the routine use of nasogastric tubes is not advisable in preterm
infants.
Frontiers in Nutrition  |  www.frontiersin.org
Nutrition in Preterm LBW Infants
Can Preterm Infants Be Fed While on
Ventilator or Continuous Positive Airway
Pressure (CPAP)?
Ventilator or CPAP treatment should not serve as a hindrance
to enteral feeding. Assisted ventilation does not increase the
risk of gastroesophageal reflux and is, therefore, not a con-
traindication to enteral feeding in preterm LBW infants (43).
Although nasal CPAP therapy results in gaseous bowel
distension or the CPAP belly syndrome in the majority of very
LBW infants, this may not be attributed to NEC; the feeding
method has no correlation with the occurrence of the CPAP belly
syndrome (44).
Is Routine Evaluation of Gastric Aspiration
and Abdominal Girth Justified?
Gastric aspiration and evaluation of gastric residuals may delay
enteral tube feeding and cause damage to the gastric mucosa
(45, 46). Increase in abdominal girth < 1.5 cm occurs normally,
and in the absence of any clinical signs, this may not be indica-
tive of any disease (47). Therefore, it is advisable to avoid routine
checking of gastric residuals and abdominal girth.
NUTRITION TO PRETERM INFANTS—
WHAT TO FEED?
Growth Rate with Standard Nutritional
Practices
The prevailing nutritional practices for preterm infants include
minimal enteral feeds (10 mL/kg/day); use of breast milk, donor
milk (if maternal milk is not available), or fortified human milk;
feed advancements of 20  mL/kg/day; and parenteral nutrition
with amino acids and lipids (48). Despite following standard
practices, the growth in preterm infants may not be optimal
in most cases. Current nutritional strategies or practices being
followed for intrauterine growth restriction (IUGR)/preterm
infants are not able to prevent postnatal growth restriction (49).
Extrauterine growth restriction (EUGR) is a serious issue in
preterm LBW infants, with an incidence of about 28, 34, and 16%
for weight, length, and head circumference, respectively (50).
The growth rate of preterm and extremely LBW infants during
hospitalization in the neonatal intensive care unit significantly
impacts neurodevelopmental and growth outcomes in later
life (51).
Current Enteral Nutritional Strategies—
Pros and Cons
The enteral nutrition options for preterm infants include EBM,
fortified EBM, and formula milk (52).
Expressed Breast Milk
Breast milk should be the milk of choice for providing nutrition
to preterm LBW infants, due to its several inherent advantages
(Table 2) (53–69).
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Kumar et al.
Consensus recommendations on the use of mother’s milk for feeding
preterm infants.
• The first choice of human milk for feeding preterm infants is expressed
breast milk from the mother; the second choice is donor pasteurized
human milk.
• “Donor pasteurized human milk” should be the term used for donor milk.
• A pasteurizer should be used for pasteurization of human milk; unpasteur-
ized milk should not be used in case of donor human milk.
• Donor pasteurized human milk should be screened for human immuno-
deficiency virus (HIV), hepatitis C virus (HCV), hepatitis B antigen (HBsAg),
venereal disease, and bacteria, using relevant tests/cultures.
• The donor mother should also be screened for HIV, HCV, HBsAg, and venereal
disease within 6 months of donating milk.
• If milk banks exist locally, pooled milk may be used, provided proper
consent has been obtained.
• Milk banks should liaise with agencies for pasteurization of pooled small
aliquots of breast milk.
• Donor human milk may be stored at −20°C for 6 months; preterm infants
should not be fed milk stored for more than 3 months.
• Although the human milk analyzer is a useful tool to analyze the nutrient
content of human milk and enable subsequent fortification, it is currently
being used as only a research tool and not in day-to-day clinical prac-
tice. The standard fortification method is recommended in daily clinical
settings.
Table 2 | Advantages of feeding breast milk.
Overall outcomes
• Better feed tolerance (53, 54).
• Lower risk of NEC, sepsis, and late-onset sepsis (53–55).
• Reduced length of hospital stay and risk of rehospitalization (56, 57).
Microvascular outcome
• Protective role in preventing retinopathy of prematurity (58).
Cardiovascular outcomes
• Lower risk of hypertension and atherosclerosis later in life (59, 60).
• Improved left and right ventricular end-diastolic volume index and stroke
volume index, and beneficial long-term cardiovascular outcomes (61).
Bone health
• Significant increase in whole-body bone area and bone mineral content (62).
Neurological outcomes
• Improved neurological development in later years (53).
• Significantly higher IQ in later years, even after adjusting for maternal IQ
(63–65).
• Better receptive language at 3 years and verbal and non-verbal IQ at
7 years. This outcome has been noted with a longer duration of feeding
breast milk; each month of feeding breast milk may increase verbal IQ by 0.35
points and non-verbal IQ by 0.29 points (66).
• Significant improvement in white matter microstructure, which may translate
to improved cognitive, behavioral, and real-world academic performance
(67, 68).
• Significantly higher brain volume and white matter volume, which in turn
correlates with significantly improved verbal IQ, especially in boys (25%
increase in IQ) (69).
• Improved mental and psychomotor development, and behavioral scores
(57).
Although feeding human milk has several proven benefits, it is
essential to determine whether it can meet the higher nutritional
needs of preterm infants. The recommended enteral macro and
micronutrient intakes for preterm infants according to the
European Society of Pediatric Gastroenterology, Hepatology, and
Nutrition (ESPGHAN) have been summarized in Table 3 (70).
Frontiers in Nutrition  |  www.frontiersin.org
Nutrition in Preterm LBW Infants
Table 3 | Recommended enteral nutrient intakes for preterm infants.
Nutrient Per kg per day Nutrient Per kg per day
Fluid, mL 135–200 Calcium, mg 120–140
Energy, kcal 110–135 Phosphate, mg 60–90
Protein, g 3.5–4.5 Vitamin D, IU 800–1,000
Fat, g 4.8–6.6 Vitamin A, IU 1,300–3,300
Carbohydrates, g 11.6–13.2 Iron, mg 2–3
Given the high nutrient needs of preterm infants, human milk
alone may not be able to comprehensively provide the preterm
infants’ requirement of proteins, energy, minerals, vitamins, and
trace elements (71). Furthermore, feeding preterm infants with
human milk alone may result in slower growth rates and lesser
increase in head circumference as compared to feeding with for-
tified human milk (72). According to ESPGHAN, the preferred
nutrition for premature infants is fortified human milk, prefer-
ably from the infant’s own mother, or formula milk designed for
preterm infants (70).
Fortified Human Milk
Fortifying breast milk helps in providing additional nutrients
to LBW infants whose needs are not met by EBM alone (53).
Fortification is based on the principle of increasing the concentra-
tion of nutrients to such levels that the infant’s needs are met with
customary feeding volumes (73). Fortification may be done with
any one nutrient (monocomponent) or multiple nutrients (mul-
ticomponent). Although there is a lack of evidence supporting
the benefits of monocomponent fortification with carbohydrates
and fats, fortification with proteins has been found to result in
an increase in weight gain, linear growth, and head growth in
preterm infants. However, protein-alone fortification has not
been associated with long-term growth and neurodevelopmental
outcomes (74, 75). While fortifying human milk, it is essential to
balance the osmolality of the feed, as fortification increases the
osmolality of the feed (53).
The benefits of enteral feeds rich in docosahexaenoic acid
(DHA) are debatable. Dietary DHA has been reported to be an
important nutrient affecting neurological development in pre-
term infants, in some reviews (76). Furthermore, studies report
significantly improved cognitive function in preterm girls fed
enteral feeds high in DHA (77). However, a few other systematic
reviews indicate no benefit or harm with long-chain polyunsatu-
rated fatty acid supplementation in preterm infants (78).
Multicomponent fortification has been associated with
short-term weight gain and linear and head growth in preterm
infants. However, long-term evidences are lacking (72, 79). The
National Neonatology Forum of India recommends the use
of multicomponent fortification to infants born at <32  weeks’
gestation, or with <1,500 g birth weight who fail to gain weight
despite receiving full volumes of breast milk (up to 180–200 mL/
kg/day) (80).
Clinical Evidences on Fortified Human Milk
Few Indian studies have reported the outcomes of feed-
ing fortified human milk to preterm infants. In a study
4 May 2017 | Volume 4 | Article 20
Kumar et al.
by Mukhopadhyay et  al., in 166 preterm infants weighing
≤1,500 g, infants fed fortified EBM experienced significantly
better growth in terms of weight gain, length, and head circum-
ference when compared to infants exclusively fed human milk.
This effect was more evident in infants who were small for
gestational age; length and weight were significantly increased
in this group, which was fed fortified EBM (81). In a study by
Gathwala et al., fortification of EBM was not associated with
delayed gastric emptying or feed intolerance in preterm neo-
nates (82). In a study by Agarwal et al., there was an increase
in osmolality of breast milk after the addition of human milk
fortifier (HMF). However, the osmolality did not change after
storage at 4°C for 6 h (83). These results are in contrast to those
noted in an international study by Henriksen et al. in preterm
very LBW infants fed fortified milk. The EUGR of these infants
increased to 58% at hospital discharge, from 33% at birth (84).
Therefore, the outcomes may not be optimal in all cases; this
may be due to the low energy and protein content of the feeds
(84, 85).
Standard fortification of human milk may be associated
with protein deficits, as the protein content is low during
fortification, assuming the availability of higher amounts of
protein in human milk (86). However, it must be noted that
the protein content of EBM is variable and may differ based
on the duration of lactation and from sample to sample (86,
87). Therefore, standard fortification of human milk may not
meet the recommended protein intake in preterm infants (88).
To overcome this limitation and optimize human milk forti-
fication, the concept of individualized fortification has been
introduced.
Individualized Fortification
Two methods of individualized fortification have been pro-
posed—targeted and adjustable (86).
Targeted fortification—this method involves analyzing the
protein content of human milk and fortifying it to meet the
infant’s nutrient requirement. A target protein intake is chosen
based on predefined infant requirements. This method helps in
individualized fortification of preterm infants (89).
Adjustable fortification—the protein intake in this method
is periodically adjusted based on the metabolic response of the
infant evaluated from the blood urea nitrogen tests. This method
is more suitable for stable preterm infants. Furthermore, it is a
more practical and feasible method that does not require frequent
analyses of the milk (86). In comparison to the standard fortifica-
tion method, the adjustable protein fortification technique has
been found to result in a significant improvement in growth
indices, weight gain, and head circumference in preterm very
LBW infants. This improvement significantly correlated with the
higher protein intake in infants fed using the adjustable regimen
(90, 91).
In this context, it may be pertinent to mention that excess
protein intake to promote faster postnatal growth may not nec-
essarily be beneficial; it may result in increased blood pressure
in the long term (92). Therefore, it is essential to optimize the
nutrient intake based on the infants’ requirements.
Frontiers in Nutrition  |  www.frontiersin.org
Nutrition in Preterm LBW Infants
Consensus recommendations on the supplementation of protein,
calories, and calcium in daily clinical practice, for the optimum
growth of preterm infants.
• HMF may be used only when the infant reaches a feed of 100 mL/kg/day.
However, based on the clinical situation, appropriate amounts of HMF may
be used even before the set feed limit has been achieved.
• In clinical practice, one sachet (1 g) of HMF may be used for 20 or 25 mL
of expressed or donor pasteurized human milk, depending on the product
guideline.
• It is advisable to monitor the calorie and protein intake of the infant to
evaluate the protein requirements.
• The recommended protein intake should be 3.5–4 g/kg/day, depending on
the birth weight and desired growth.
• It is important to monitor the growth velocity of the infant, along with
monitoring for osteopenia of maturity.
• The calorie requirement of a preterm infant is usually met with the addition
of HMF, which provides about 4 g/kg/day of protein and 3.5–4 g/kg/day
of fats.
• A higher protein and higher calorie strategy will help optimize nutrition in
preterm infants.
• Calculation of protein intake while adding HMF to EBM will help in the
simultaneous monitoring of the requirements for carbohydrates, fats, and
calories.
• There is no need to monitor and supplement additional calcium in preterm
infants on total parenteral nutrition and HMF; additional supplementation of
calcium may result in nephrocalcinosis.
• Serum calcium may be measured at 12–24 h after birth, followed by regular
monitoring, to prevent hypercalcemia.
• Serum phosphorus and alkaline phosphatase may be measured once a
week after 2 weeks of birth, to detect any osteopenia of prematurity and to
take appropriate measures.
Side Effects of Fortification
• Earlier studies report significantly delayed gastric emptying
in some preterm infants who cannot tolerate fortified milk
(93). However, recent studies suggest that fortifying breast
milk may not result in clinically significant feeding intoler-
ance if the recommended concentrations of fortifier are used
(94).
• The use of fortifiers containing iron may decrease the antibac-
terial action of preterm milk (95).
• There is no clear evidence linking human milk fortification
with NEC risk (72). Hence, weighing the benefits of growth
and neurodevelopment with fortification versus possible
feed intolerance and NEC is at the sole discretion of the
clinician.
Formula Milk
Formula milk contains all essential nutrients and is specifically
designed to meet the requirements of LBW infants (53).
Consensus recommendations on choosing the right preterm formula.
• Osmolality is a key factor that needs to be taken into consideration when
choosing a preterm formula.
• Preterm formula can be used in preterm infants weighing less than
1.5 kg.
• Docosahexaenoic acid (DHA) is an important part of preterm formula.
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Kumar et al. Nutrition in Preterm LBW Infants

OPTIMIZING GROWTH IN PRETERM is advised to initiate expression of breast milk soon after birth.
INFANTS TO LOWER CARDIOVASCULAR Relaxation, massaging, and warming the breasts, hand expres-
sion, and the use of low-cost pumps may be some cost-effective
RISK interventions for expressing breast milk (108). Combining pump
Faster weight gain in preterm infants may be associated with suction, breast compression, and hand expression has been found
an increased risk of overweight and obesity; higher body fat to enhance breast milk production (109). In any case, early nutri-
percentage, waist circumference, serum triglycerides, and blood tion in preterm LBW infants should be critically optimized to have
pressure; endothelial dysfunction; and adverse long-term cardio- beneficial effects, both in the short term and the long term (110).
vascular outcomes (96–99). Therefore, monitoring and ensuring
optimal weight gain is essential throughout the entire gestational KEY CONCLUSION
spectrum, to prevent long-term complications.
• Preterm birth survivors present with higher rates of adverse
developmental disabilities and health outcomes compared to
POSTDISCHARGE NUTRITION their term counterparts.
OF PRETERM INFANTS • Optimal nutrition is highly essential for growth, metabolism,
and immunity in preterm LBW infants; it lowers the risk of
Although there is no clear evidence on the added benefit of
adverse morbidities in adulthood.
administering a nutrient-enriched diet to preterm infants after
• Enteral feeding may be preferred to parenteral feeding due to
discharge, a few reviews suggest an improvement in growth
the complications associated with the latter.
parameters with no effect on neurodevelopmental outcomes
• Early and rapid initiation of enteral feeding has several advan-
(100, 101). Studies indicate that variations in dietary nutrient
tages compared to late and slow feeding; continuous feeding
intake can contribute significantly to growth deficits in preterm
may be preferred to intermittent hourly feeding.
infants, thus highlighting the choice of appropriate nutrition in
• Early enteral feeding does not carry any additional risk of NEC
this cohort (102, 103).
in preterm infants; on the contrary, it aids in the development
The numerous benefits of mother’s milk have been discussed
of the gut and reduces the risk of infections.
previously. While a few studies have reported comparable
• EBM should be the first choice for feeding preterm infants
outcomes, a few others have reported better short-term growth
due to its numerous inherent advantages; donor pasteurized
rates in preterm infants fed human milk compared to formula
human milk is the second choice.
milk (104, 105). A meta-analysis of 14 randomized clinical trials
• Given the high nutrient requirements of preterm infants, espe-
reveals increased short-term growth rates with fortified human
cially the requirements of proteins, EBM or donor milk should
milk compared to unfortified breast milk, with no increase in the
be fortified with HMF without increasing the osmolality of the
risk of NEC (72). Furthermore, fortifying human milk using a
milk.
human milk-based fortifier has been found to have a significantly
• In routine clinical practice, standard fortification may be fol-
lower risk of NEC and lower morbidity and mortality compared
lowed. However, the use of targeted and adjustable fortification,
to bovine milk-based fortifier (106, 107).
where possible, may help in optimal nutrient supplementation
Owing to the beneficial effects of breast milk and the para-
to preterm infants.
doxical inability of preterm LBW infants to feed at the breast, it
• Monitoring the growth velocity is essential, as rapid weight
gain in preterm infants may be associated with future cardio-
Consensus recommendations on postdischarge nutrition. vascular risk. Hence, optimal weight gain should be the target.
• Counseling and regular follow-up after discharge and moni-
• The ideal discharge weight of preterm infants may be dependent on several
factors, including the ability of local services to take care of the infant after
toring of the preterm infant, preferably until adolescence, are
discharge. advisable.
• The sucking/swallowing ability of infants should be good at discharge.
• The following signs should be monitored and immediate medical attention
should be sought for: inability to feed, lethargy, temperature alterations, and
AUTHOR CONTRIBUTIONS
mottling/cyanosis.
• Counseling should be provided for resuscitation prior to discharge.
All the authors contributed equally to the Conceptualization,
• The first follow-up should be done within 3–7 days, followed by a weekly review, and finalization of the manuscript.
follow-up.
• Preterm infants should be monitored for up to a minimum of 2 years and
preferably till adolescence.
ACKNOWLEDGMENTS
• In preterm infants who are on formula milk, switching to a standard formula
is recommended after they have reached their birth centile (i.e., after
We would like to acknowledge BioQuest Solutions for their sup-
catch-up has been completed). There is not much evidence on the benefits port in editorial services.
of switching after an increase in weight beyond this.
• Complementary feeding may be initiated at the corrected age of
4 months. No special attention is required while initiating complementary
FUNDING
feeding.
The program is funded by Nestle Nutrition Institute, South Asia.

Frontiers in Nutrition  |  www.frontiersin.org 6 May 2017 | Volume 4 | Article 20

Kumar et al.
REFERENCES
1. March of Dimes, Partnership for Maternal Newborn and Child Health, Save
the Children, World Health Organization. Howson CP, Kinney MV, Lawn
JE, editors. Born Too Soon: the Global Action Report on Preterm Birth (2012).
Available from: http://www.who.int/pmnch/media/news/2012/201204_born-
toosoon-report.pdf
2. Doyle LW, Anderson PJ. Adult outcome of extremely preterm infants. Pediatrics
(2010) 126:342–51. doi:10.1542/peds.2010-0710
3. Nosarti C, Al-Asady MH, Frangou S, Stewart AL, Rifkin L, Murray RM.
Adolescents who were born very preterm have decreased brain volumes. Brain
(2002) 125(Pt 7):1616–23. doi:10.1093/brain/awf157
4. Moster D, Lie RT, Markestad T. Long-term medical and social conse-
quences of preterm birth. N Engl J Med (2008) 359:262–73. doi:10.1056/
NEJMoa0706475
5. Rotteveel J, van Weissenbruch MM, Twisk JW, Delemarre-Van de Waal HA.
Infant and childhood growth patterns, insulin sensitivity, and blood pressure
in prematurely born young adults. Pediatrics (2008) 122:313–21. doi:10.1542/
peds.2007-2012
6. Uthaya S, Thomas EL, Hamilton G, Doré CJ, Bell J, Modi N. Altered adiposity
after extremely preterm birth. Pediatr Res (2005) 57:211–5. doi:10.1203/01.
PDR.0000148284.58934.1C
7. Rossi P, Tauzin L, Marchand E, Boussuges A, Gaudart J, Frances Y. Respective
roles of preterm birth and fetal growth restriction in blood pressure and arterial
stiffness in adolescence. J Adolesc Health (2011) 48:520–2. doi:10.1016/
j.jadohealth.2010.08.004
8. Lewandowski AJ, Bradlow WM, Augustine D, Davis EF, Francis J, Singhal A,
et  al. Right ventricular systolic dysfunction in young adults born preterm.
Circulation (2013) 128:713–20. doi:10.1161/CIRCULATIONAHA.113.002583
9. Hovi P, Andersson S, Järvenpää AL, Eriksson JG, Strang-Karlsson S, Kajantie E,
et  al. Decreased bone mineral density in adults born with very low birth
weight: a cohort study. PLoS Med (2009) 6:e1000135. doi:10.1371/journal.
pmed.1000135
10. Patel RM, Kandefer S, Walsh MC, Bell EF, Carlo WA, Laptook AR, et al. Causes
and timing of death in extremely premature infants from 2000 through 2011.
N Engl J Med (2015) 372:331–40. doi:10.1056/NEJMoa1403489
11. Hanson C, Sundermeier J, Dugick L, Lyden E, Anderson-Berry AL. Imple­
mentation, process, and outcomes of nutrition best practices for infants
<1500 g. Nutr Clin Pract (2011) 26:614–24. doi:10.1177/0884533611418984
12. Donovan R, Puppala B, Angst D, Coyle BW. Outcomes of early nutrition
support in extremely low-birth-weight infants. Nutr Clin Pract (2006)
21:395–400. doi:10.1177/0115426506021004395
13. Ganapathy S. Long chain polyunsaturated fatty acids and immunity in infants.
Indian Pediatr (2009) 46(9):785–90.
14. Lee KA, Hayes BC. Head size and growth in the very preterm infant: a litera-
ture review. Res Rep Neonatol (2015) 5:1–7. doi:10.2147/RRN.S74449
15. Vinall J, Grunau RE, Brant R, Chau V, Poskitt KJ, Synnes AR, et al. Slower post-
natal growth is associated with delayed cerebral cortical maturation in preterm
newborns. Sci Transl Med (2013) 5:168ra8. doi:10.1126/scitranslmed.3004666
16. Barker DJ, Winter PD, Osmond C, Margetts B, Simmonds SJ. Weight in
infancy and death from ischaemic heart disease. Lancet (1989) 2:577–80.
doi:10.1016/S0140-6736(89)90710-1
17. Barker DJ, Eriksson JG, Forsén T, Osmond C. Fetal origins of adult disease:
strength of effects and biological basis. Int J Epidemiol (2002) 31:1235–9.
doi:10.1093/ije/31.6.1235
18. Isaacs EB, Gadian DG, Sabatini S, Chong WK, Quinn BT, Fischl BR, et  al.
The effect of early human diet on caudate volumes and IQ. Pediatr Res (2008)
63:308–14. doi:10.1203/PDR.0b013e318163a271
19. Franz AR, Pohlandt F, Bode H, Mihatsch WA, Sander S, Kron M, et  al.
Intrauterine, early neonatal, and postdischarge growth and neurodevel-
opmental outcome at 5.4 years in extremely preterm infants after intensive
neonatal nutritional support. Pediatrics (2009) 123:e101–9. doi:10.1542/
peds.2008-1352
20. Stephens BE, Walden RV, Gargus RA, Tucker R, McKinley L, Mance M, et al.
First-week protein and energy intakes are associated with 18-month devel-
opmental outcomes in extremely lowbirth weight infants. Pediatrics (2009)
123:1337–43. doi:10.1542/peds.2008-0211
21. Brandt I, Sticker EJ, Lentze MJ. Catch-up growth of head circumference of
very low birth weight, small for gestational age preterm infants and mental
Frontiers in Nutrition  |  www.frontiersin.org
Nutrition in Preterm LBW Infants
development to adulthood. J Pediatr (2003) 142:463–8. doi:10.1067/mpd.
2003.149
22. Morgan C, McGowan P, Herwitker S, Hart AE, Turner MA. Postnatal head
growth in preterm infants: a randomized controlled parenteral nutrition
study. Pediatrics (2014) 133:e120–8. doi:10.1542/peds.2013-2207
23. Leppänen M, Lapinleimu H, Lind A, Matomäki J, Lehtonen L, Haataja L, et al.
Antenatal and postnatal growth and 5-year cognitive outcome in very preterm
infants. Pediatrics (2014) 133(1):63–70. doi:10.1542/peds.2013-1187
24. Ehrenkranz RA. Early, aggressive nutritional management for very low
birth weight infants: what is the evidence? Semin Perinatol (2007) 31:48–55.
doi:10.1053/j.semperi.2007.02.001
25. Maroulis J, Kalfarentzos F. Complications of parenteral nutrition at the end of
the century. Clin Nutr (2000) 19:295–304. doi:10.1054/clnu.1999.0089
26. Leaf A. Early enteral feeding in high-risk preterm infants. Nutrition (2007)
3(1):27–30.
27. Lucas A, Cole TJ. Breast milk and neonatal necrotising enterocolitis. Lancet
(1990) 336:1519–23. doi:10.1016/0140-6736(90)93304-8
28. Salhotra A, Ramji S. Slow versus fast enteral feed advancement in very low
birth weight infants: a randomized control trial. Indian Pediatr (2004)
41(5):435–41.
29. Morgan J, Young L, McGuire W. Slow advancement of enteral feed volumes
to prevent necrotising enterocolitis in very low birth weight infants. Cochrane
Database Syst Rev (2014) (12):CD001241. doi:10.1002/14651858.CD001241.
pub5
30. Flidel-Rimon O, Friedman S, Lev E, Juster-Reicher A, Amitay M, Shinwell ES.
Early enteral feeding and nosocomial sepsis in very low birthweight infants.
Arch Dis Child Fetal Neonatal Ed (2004) 89:F289–92. doi:10.1136/adc.
2002.021923
31. Morgan J, Young L, McGuire W. Delayed introduction of progressive enteral
feeds to prevent necrotising enterocolitis in very low birth weight infants.
Cochrane Database Syst Rev (2014) (12):CD001970. doi:10.1002/14651858.
CD001970.pub5
32. Sallakh-Niknezhad A, Bashar-Hashemi F, Satarzadeh N, Ghojazadeh M,
Sahnazarli G. Early versus late trophic feeding in very low birth weight
preterm infants. Iran J Pediatr (2012) 22(2):171–6.
33. Dunn L, Hulman S, Weiner J, Kliegman R. Beneficial effects of early hypo-
caloric enteral feeding on neonatal gastrointestinal function: preliminary
report of a randomized trial. J Pediatr (1988) 112:622–9. doi:10.1016/
S0022-3476(88)80185-9
34. Rayyis SF, Ambalavanan N, Wright L, Carlo WA. Randomized trial of “slow”
versus “fast” feed advancements on the incidence of necrotizing enterocolitis
in very low birth weight infants. J Pediatr (1999) 134:293–7. doi:10.1016/
S0022-3476(99)70452-X
35. Karagol BS, Zenciroglu A, Okumus N, Polin RA. Randomized controlled trial
of slow vs rapid enteral feeding advancements on the clinical outcomes of
preterm infants with birth weight 750–1250 g. J Parenter Enteral Nutr (2013)
37:223–8. doi:10.1177/0148607112449482
36. Silvestre MA, Morbach CA, Brans YW, Shankaran S. A prospective random-
ized trial comparing continuous versus intermittent feeding methods in very
low birth weight neonates. J Pediatr (1996) 128:748–52. doi:10.1016/S0022-
3476(96)70324-4
37. Dsilna A, Christensson K, Alfredsson L, Lagercrantz H, Blennow M.
Continuous feeding promotes gastrointestinal tolerance and growth in very
low birth weight infants. J Pediatr (2005) 147:43–9. doi:10.1016/j.jpeds.
2005.03.003
38. Premji SS, Chessell L. Continuous nasogastric milk feeding versus intermit-
tent bolus milk feeding for premature infants less than 1500 grams. Cochrane
Database Syst Rev (2011) (11):CD001819. doi:10.1002/14651858.CD001819.
pub2
39. Blondheim O, Abbasi S, Fox WW, Bhutani VK. Effect of enteral gavage feeding
rate on pulmonary functions of very low birth weight infants. J Pediatr (1993)
122:751–5. doi:10.1016/S0022-3476(06)80021-1
40. Nelle M, Hoecker C, Linderkamp O. Effects of bolus tube feeding on cerebral
blood flow velocity in neonates. Arch Dis Child Fetal Neonatal Ed (1997)
76:F54–6. doi:10.1136/fn.76.1.F54
41. Stocks J. Effect of nasogastric tubes on nasal resistance during infancy. Arch
Dis Child (1980) 55:17–21. doi:10.1136/adc.55.1.17
42. van Someren V, Linnett SJ, Stothers JK, Sullivan PG. An investigation into
the benefits of resiting nasoenteric feeding tubes. Pediatrics (1984) 74:379–83.
7 May 2017 | Volume 4 | Article 20
Kumar et al.
43. Newell SJ, Morgan ME, Durbin GM, Booth IW, McNeish AS. Does mechan-
ical ventilation precipitate gastro-oesophageal reflux during enteral feeding?
Arch Dis Child (1989) 64:1352–5. doi:10.1136/adc.64.10_Spec_No.1352
44. Jaile JC, Levin T, Wung JT, Abramson SJ, Ruzal-Shapiro C, Berdon WE. Benign
gaseous distension of the bowel in premature infants treated with nasal con-
tinuous airway pressure: a study of contributing factors. AJR Am J Roentgenol
(1992) 158:125–7. doi:10.2214/ajr.158.1.1727337
45. McClave SA, Snider HL. Clinical use of gastric residual volumes as a monitor
for patients on enteral tube feeding. JPEN J Parenter Enteral Nutr (2002)
26:S43–8. doi:10.1177/014860710202600607
46. Parker L, Torrazza RM, Li Y, Talaga E, Shuster J, Neu J. Aspiration and evalu-
ation of gastric residuals in the neonatal intensive care unit: state of the science.
J Perinat Neonatal Nurs (2015) 29:51–9. doi:10.1097/JPN.0000000000000080
47. Bhatia P, Johnson KJ, Bell EF. Variability of abdominal circumference
of premature infants. J Pediatr Surg (1990) 25:543–4. doi:10.1016/0022-
3468(90)90569-U
48. Ziegler EE, Carlson SJ.  Early nutrition of very low birth weight infants. J Matern
Fetal Neonatal Med (2009) 22:191–7. doi:10.1080/14767050802630169
49. Puntis JW. Nutritional support in the premature newborn. Postgrad Med J
(2006) 82:192–8. doi:10.1136/pgmj.2005.038109
50. Clark RH, Thomas P, Peabody J. Extrauterine growth restriction remains a
serious problem in prematurely born neonates. Pediatrics (2003) 111:986–90.
doi:10.1542/peds.111.5.986
51. Ehrenkranz RA, Dusick AM, Vohr BR, Wright LL, Wrage LA, Poole WK.
Growth in the neonatal intensive care unit influences neurodevelopmental
and growth outcomes of extremely low birth weight infants. Pediatrics (2006)
117:1253–61. doi:10.1542/peds.2005-1368
52. Su BH. Optimising nutrition in preterm infants. Pediatr Neonatol (2014)
55:5–13. doi:10.1016/j.pedneo.2013.07.003
53. Preterm and low birth weight babies. In: Bentley D, Aubrey S, Bentley M,
editors. Infant Feeding and Nutrition for Primary Care. Abingdon: Radcliffe
Medical Press Ltd (2004). p. 47–51.
54. Section on Breastfeeding. Breastfeeding and the use of human milk. Pediatrics
(2012) 129:e827–41. doi:10.1542/peds.2011-3552
55. Schanler RJ, Shulman RJ, Lau C. Feeding strategies for premature infants:
beneficial outcomes of feeding fortified human milk versus preterm formula.
Pediatrics (1999) 103:1150–7. doi:10.1542/peds.103.6.1150
56. Ganapathy V, Hay JW, Kim JH. Costs of necrotizing enterocolitis and
cost-effectiveness of exclusively human milk-based products in feeding
extremely premature infants. Breastfeed Med (2012) 7:29–37. doi:10.1089/
bfm.2011.0002
57. Vohr BR, Poindexter BB, Dusick AM, McKinley LT, Higgins RD, Langer JC,
et al. Persistent beneficial effects of breast milk ingested in the neonatal inten-
sive care unit on outcomes of extremely low birth weight infants at 30 months
of age. Pediatrics (2007) 120:e953–9. doi:10.1542/peds.2006-3227
58. Zhou J, Shukla VV, John D, Chen C. Human milk feeding as a protective
factor for retinopathy of prematurity: a meta-analysis. Pediatrics (2015)
136:e1576–86. doi:10.1542/peds.2015-2372
59. Singhal A, Cole TJ, Lucas A. Early nutrition in preterm infants and later
blood pressure: two cohorts after randomised trials. Lancet (2001) 357:413–9.
doi:10.1016/S0140-6736(00)04004-6
60. Singhal A, Cole TJ, Fewtrell M, Lucas A. Breastmilk feeding and lipoprotein
profile in adolescents born preterm: follow-up of a prospective randomised
study. Lancet (2004) 363:1571–8. doi:10.1016/S0140-6736(04)16198-9
61. Lewandowski AJ, Lamata P, Francis JM, Piechnik SK, Ferreira VM, Boardman H,
et  al. Breast milk consumption in preterm neonates and cardiac shape in
adulthood. Pediatrics (2016) 138(1):e20160050. doi:10.1542/peds.2016-0050
62. Fewtrell MS, Williams JE, Singhal A, Murgatroyd PR, Fuller N, Lucas A.
Early diet and peak bone mass: 20 year follow-up of a randomized trial of early
diet in infants born preterm. Bone (2009) 45:142–9. doi:10.1016/j.bone.2009.
03.657
63. Lucas A, Morley R, Cole TJ, Lister G, Leeson-Payne C. Breast milk and
subsequent intelligence quotient in children born preterm. Lancet (1992)
339:261–4. doi:10.1016/0140-6736(92)91329-7
64. Anderson JW, Johnstone BM, Remley DT. Breast-feeding and cognitive
development: a meta-analysis. Am J Clin Nutr (1999) 70:525–35.
65. Horta BL, Loret de Mola C, Victora CG. Breastfeeding and intelligence: a sys-
tematic review and meta-analysis. Acta Paediatr (2015) 104:14–9. doi:10.1111/
apa.13139
Frontiers in Nutrition  |  www.frontiersin.org
Nutrition in Preterm LBW Infants
66. Belfort MB, Rifas-Shiman SL, Kleinman KP, Guthrie LB, Bellinger DC,
Taveras EM, et  al. Infant feeding and childhood cognition at ages 3 and 7
years: effects of breastfeeding duration and exclusivity. JAMA Pediatr (2013)
167:836–44. doi:10.1001/jamapediatrics.2013.455
67. Deoni SC, Dean DC III, Piryatinsky I, O’Muircheartaigh J, Waskiewicz N,
Lehman K, et  al. Breastfeeding and early white matter development: a
cross-sectional study. Neuroimage (2013) 82:77–86. doi:10.1016/j.neuroimage.
2013.05.090
68. Northam GB, Liégeois F, Chong WK, Wyatt JS, Baldeweg T. Total brain white
matter is a major determinant of IQ in adolescents born preterm. Ann Neurol
(2011) 69:702–11. doi:10.1002/ana.22263
69. Isaacs EB, Fischl BR, Quinn BT, Chong WK, Gadian DG, Lucas A. Impact of
breast milk on intelligence quotient, brain size, and white matter development.
Pediatr Res (2010) 67:357–62. doi:10.1203/PDR.0b013e3181d026da
70. ESPGHAN Committee on Nutrition, Agostoni C, Braegger C, Decsi T,
Kolacek S, Koletzko B, et al. Role of dietary factors and food habits in the devel-
opment of childhood obesity: a commentary by the ESPGHAN Committee
on Nutrition. J Pediatr Gastroenterol Nutr (2011) 52:662–9. doi:10.1097/MPG.
0b013e3182169253
71. Kumar P, Sundaram V. Protein Supplementation of Human Milk for Promoting
Growth in Preterm Infants. (2011). Available from: https://extranet.who.int/
rhl/topics/newborn-health/newborn-nutrition-and-feeding/protein-
supplementation-human-milk-promoting-growth-preterm-infants
72. Brown JV, Embleton ND, Harding JE, McGuire W. Multi-nutrient fortifica-
tion of human milk for preterm infants. Cochrane Database Syst Rev (2016)
(5):CD000343. doi:10.1002/14651858.CD000343.pub3
73. Di Natale C, Coclite E, Di Ventura L, Di Fabio S. Fortification of maternal milk
for preterm infants. J Matern Fetal Neonatal Med (2011) 24(Suppl 1):41–3.
doi:10.3109/14767058.2011.607569
74. Kuschel CA, Harding JE. Protein supplementation of human milk for
promoting growth in preterm infants. Cochrane Database Syst Rev (2000)
(2):CD000433. doi:10.1002/14651858.CD000433
75. Fenton TR, Premji SS, Al-Wassia H, Sauve RS. Higher versus lower protein
intake in formula-fed low birth weight infants. Cochrane Database Syst Rev
(2014) (4):CD003959. doi:10.1002/14651858.CD003959.pub3
76. Szajewska H, Makrides M. Is early nutrition related to short-term health
and long-term outcome? Ann Nutr Metab (2011) 58(Suppl 1):38–48.
doi:10.1159/000323465
77. Makrides M, Gibson RA, McPhee AJ, Collins CT, Davis PG, Doyle LW, et al.
Neurodevelopmental outcomes of preterm infants fed high-dose docosa-
hexaenoic acid: a randomized controlled trial. JAMA (2009) 301:175–82.
doi:10.1001/jama.2008.945
78. Schulzke SM, Patole SK, Simmer K. Long-chain polyunsaturated fatty acid
supplementation in preterm infants. Cochrane Database Syst Rev (2011)
(2):CD000375. doi:10.1002/14651858.CD000375.pub4
79. Kuschel CA, Harding JE. Multicomponent fortified human milk for promoting
growth in preterm infants. Cochrane Database Syst Rev (2004) (1):CD000343.
doi:10.1002/14651858.CD000343.pub2
80. National Neonatology Forum, India. Bhakoo ON, Kumar P, Jain N, Thakre R,
Murki S, Venkataseshan S, editors. Evidence Based Clinical Practice Guidelines.
(2010). Available from: http://www.nnfi.org/images/pdf/nnf_cpg_consoli-
dated_file-january102011.pdf
81. Mukhopadhyay K, Narnag A, Mahajan R. Effect of human milk fortification in
appropriate for gestation and small for gestation preterm babies: a randomized
controlled trial. Indian Pediatr (2007) 44(4):286–90.
82. Gathwala G, Shaw C, Shaw P, Yadav S, Sen J. Human milk fortification and
gastric emptying in the preterm neonate. Int J Clin Pract (2008) 62:1039–43.
doi:10.1111/j.1742-1241.2006.01201.x
83. Agarwal R, Singal A, Aggarwal R, Deorari AK, Paul VK. Effect of fortification
with human milk fortifier (HMF) and other fortifying agents on the osmolality
of pretermbreast milk. Indian Pediatr (2004) 41(1):63–7.
84. Henriksen C, Westerberg AC, Rønnestad A, Nakstad B, Veierød MB, Drevon CA,
et  al. Growth and nutrient intake among very-low-birth-weight infants fed
fortified human milk during hospitalisation. Br J Nutr (2009) 102:1179–86.
doi:10.1017/S0007114509371755
85. Carlson SJ, Ziegler EE. Nutrient intakes and growth of very low birth weight
infants. J Perinatol (1998) 18:252–8.
86. Arslanoglu S, Moro GE, Ziegler EE; The Wapm Working Group On Nutrition.
Optimization of human milk fortification for preterm infants: new concepts
8 May 2017 | Volume 4 | Article 20
Kumar et al.
and recommendations. J Perinat Med (2010) 38:233–8. doi:10.1515/JPM.
2010.073
87. Lemons JA, Moye L, Hall D, Simmons M. Differences in the composition
of preterm and term human milk during early lactation. Pediatr Res (1982)
16:113–7. doi:10.1203/00006450-198202000-00007
88. Corvaglia L, Aceti A, Paoletti V, Mariani E, Patrono D, Ancora G, et  al.
Standard fortification of preterm human milk fails to meet recommended
protein intake: bedside evaluation by near-infrared-reflectance-analysis. Early
Hum Dev (2010) 86:237–40. doi:10.1016/j.earlhumdev.2010.04.001
89. Polberger S, Räihä NC, Juvonen P, Moro GE, Minoli I, Warm A. Individualized
protein fortification of human milk for preterm infants: comparison of
ultrafiltrated human milk protein and a bovine whey fortifier. J Pediatr
Gastroenterol Nutr (1999) 29:332–8. doi:10.1097/00005176-199909000-00017
90. Arslanoglu S, Moro GE, Ziegler EE. Adjustable fortification of human milk
fed to preterm infants: does it make a difference? J Perinatol (2006) 26:614–21.
doi:10.1038/sj.jp.7211571
91. Alan S, Atasay B, Cakir U, Yildiz D, Kilic A, Kahvecioglu D, et al. An intention
to achieve better postnatal in-hospital-growth for preterm infants: adjustable
protein fortification of human milk. Early Hum Dev (2013) 89:1017–23.
doi:10.1016/j.earlhumdev.2013.08.015
92. Singhal A, Cole TJ, Fewtrell M, Kennedy K, Stephenson T, Elias-Jones A, et al.
Promotion of faster weight gain in infants born small for gestational age: is
there an adverse effect on later blood pressure? Circulation (2007) 115:213–20.
doi:10.1161/CIRCULATIONAHA.106.617811
93. Ewer AK, Yu VY. Gastric emptying in pre-term infants: the effect of breast
milk fortifier. Acta Paediatr (1996) 85:1112–5. doi:10.1111/j.1651-2227.1996.
tb14227.x
94. Yigit S, Akgoz A, Memisoglu A, Akata D, Ziegler EE. Breast milk fortification:
effect on gastric emptying. J Matern Fetal Neonatal Med (2008) 21:843–6.
doi:10.1080/14767050802287176
95. Chan GM. Effects of powdered human milk fortifiers on the antibac-
terial actions of human milk. J Perinatol (2003) 23:620–3. doi:10.1038/
sj.jp.7211003
96. Wang G, Johnson S, Gong Y, Polk S, Divall S, Radovick S, et al. Weight gain
in infancy and overweight or obesity in childhood across the gestational
spectrum: a prospective birth cohort study. Sci Rep (2016) 6:29867. doi:10.1038/
srep29867
97. Singhal A, Cole TJ, Fewtrell M, Deanfield J, Lucas A. Is slower early growth
beneficial for long-term cardiovascular health? Circulation (2004) 109:
1108–13. doi:10.1161/01.CIR.0000118500.23649.DF
98. Kerkhof GF, Willemsen RH, Leunissen RW, Breukhoven PE, Hokken-
Koelega ACS. Health profile of young adults born preterm: negative effects
of rapid weight gain in early life. J Clin Endocrinol Metab (2012) 97:4498–506.
doi:10.1210/jc.2012-1716
99. Belfort MB, Martin CR, Smith VC, Gillman MW, McCormick MC. Infant
weight gain and school-age blood pressure and cognition in former preterm
infants. Pediatrics (2010) 125:e1419–26. doi:10.1542/peds.2009-2746
100. Henderson G, Fahey T, McGuire W. Nutrient-enriched formula milk versus
human breast milk for preterm infants following hospital discharge. Cochrane
Frontiers in Nutrition  |  www.frontiersin.org
Nutrition in Preterm LBW Infants
Database Syst Rev (2007) (4):CD004862. doi:10.1002/14651858.CD004862.
pub2
101. Teller IC, Embleton ND, Griffin IJ, van Elburg RM. Post-discharge formula
feeding in preterm infants: a systematic review mapping evidence about
the role of macronutrient enrichment. Clin Nutr (2016) 35:791–801.
doi:10.1016/j.clnu.2015.08.006
102. Embleton NE, Pang N, Cooke RJ. Postnatal malnutrition and growth
retardation: an inevitable consequence of current recommendations in
preterm infants? Pediatrics (2001) 107:270–3. doi:10.1542/peds.107.2.270
103. Olsen IE, Richardson DK, Schmid CH, Ausman LM, Dwyer JT. Intersite dif-
ferences in weight growth velocity of extremely premature infants. Pediatrics
(2002) 110:1125–32. doi:10.1542/peds.110.6.1125
104. Corpeleijn WE, de Waard M, Christmann V, van Goudoever JB, Jansen-van
der Weide MC, Kooi EM, et  al. Effect of donor milk on severe infections
and mortality in very low-birth-weight infants: the early nutrition study
randomized clinical trial. JAMA Pediatr (2016) 170:654–61. doi:10.1001/
jamapediatrics.2016.0183
105. Quigley M, McGuire W. Formula versus donor breast milk for feeding
preterm or low birth weight infants. Cochrane Database Syst Rev (2014)
(4):CD002971. doi:10.1002/14651858.CD002971.pub3
106. Sullivan S, Schanler RJ, Kim JH, Patel AL, Trawöger R, Kiechl-
Kohlendorfer U, et al. An exclusively human milk-based diet is associated
with a lower rate of necrotizing enterocolitis than a diet of human milk
and bovine milk-based products. J Pediatr (2010) 156:562–7. doi:10.1016/j.
jpeds.2009.10.040
107. Abrams SA, Schanler RJ, Lee ML, Rechtman DJ. Greater mortality and mor-
bidity in extremely preterm infants fed a diet containing cow milk protein
products. Breastfeed Med (2014) 9:281–5. doi:10.1089/bfm.2014.0024
108. Becker GE, Smith HA, Cooney F. Methods of milk expression for lactating
women. Cochrane Database Syst Rev (2016) 9:CD006170. doi:10.1002/
14651858.CD006170.pub5
109. Morton J, Hall JY, Wong RJ, Thairu L, Benitz WE, Rhine WD. Combining
hand techniques with electric pumping increases milk production in
mothers of preterm infants. J Perinatol (2009) 29:757–64. doi:10.1038/
jp.2009.87
110. van den Akker CH, Vlaardingerbroek H, van Goudoever JB. Nutritional
support for extremely low-birth weight infants: abandoning catabolism in
the neonatal intensive care unit. Curr Opin Clin Nutr Metab Care (2010)
13:327–35. doi:10.1097/MCO.0b013e328337d925
Conflict of Interest Statement: RK, AS, and UV have none to declare. SB, FA, and
SR are employees of Nestle Nutrition.
Copyright © 2017 Kumar, Singhal, Vaidya, Banerjee, Anwar and Rao. This is an
open-access article distributed under the terms of the Creative Commons Attribution
License (CC BY). The use, distribution or reproduction in other forums is permitted,
provided the original author(s) or licensor are credited and that the original publica-
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distribution or reproduction is permitted which does not comply with these terms.
9 May 2017 | Volume 4 | Article 20
 Journal of Pediatric Gastroenterology and Nutrition
42:596 Y 603 Ó May 2006 Lippincott Williams & Wilkins, Philadelphia

Medical Position Paper

Feeding Preterm Infants After Hospital Discharge

A Commentary by the ESPGHAN Committee on Nutrition
ESPGHAN Committee on Nutrition: *Peter J. Aggett2, †Carlo Agostoni, ‡Irene Axelsson,
§Mario De Curtis4, kOlivier Goulet, ¶Olle Hernell, LBerthold Koletzko1, **Harry N. Lafeber,
††Kim F. Michaelsen, ‡‡John W.L. Puntis, §§Jacques Rigo, kkRaanan Shamir,
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¶¶Hania Szajewska3, ##Dominique Turck, and ***Lawrence T. Weaver

*University of Central Lancashire, Preston, UK; †University of Milan, Milan, Italy; ‡University of Lund, Lund, Sweden;
§University of Rome and INRAN, Rome, Italy; ¬Hôpital Necker Enfants-Malades, Paris, France; ¶Umea University, Umea, Sweden;
#Ludwig-Maximilians-University, Munich, Germany; **Free University of Amsterdam, Amsterdam, The Netherlands; ††The Royal
Veterinary and Agricultural University, Frederiksberg, Denmark; ‡‡The General Infirmary, Leeds, UK; §§University of Liege,
Liege, Belgium; ¬¬Meyer Children’s Hospital of Haifa, Haifa, Israel; ¶¶The Medical University of Warsaw, Warsaw, Poland;
##University of Lille, Lille, France; and ***University of Glasgow, Glasgow, UK
1
Committee Chair; 2Past Committee Chair; 3Committee Secretary; 4Guest

ABSTRACT provision of long-chain polyunsaturated fatty acids. Infants

Survival of small premature infants has markedly improved
during the last few decades. These infants are discharged from
hospital care with body weight below the usual birth weight of
healthy term infants. Early nutrition support of preterm infants
influences long-term health outcomes. Therefore, the ESPGHAN
Committee on Nutrition has reviewed available evidence on
feeding preterm infants after hospital discharge. Close monitor-
ing of growth during hospital stay and after discharge is
recommended to enable the provision of adequate nutrition
support. Measurements of length and head circumference, in
addition to weight, must be used to identify those preterm infants
with poor growth that may need additional nutrition support.
Infants with an appropriate weight for postconceptional age at
discharge should be breast-fed when possible. When formula-
fed, such infants should be fed regular infant formula with
discharged with a subnormal weight for postconceptional age
are at increased risk of long-term growth failure, and the human
milk they consume should be supplemented, for example, with a
human milk fortifier to provide an adequate nutrient supply. If
formula-fed, such infants should receive special postdischarge
formula with high contents of protein, minerals and trace
elements as well as a long-chain polyunsaturated fatty acid
supply, at least until a postconceptional age of 40 weeks, but
possibly until about 52 weeks postconceptional age. Continued
growth monitoring is required to adapt feeding choices to the
needs of individual infants and to avoid underfeeding or
overfeeding. JPGN 42:596 Y 603, 2006. Key Words: Infant
nutritionVPrematureVVLBWVGrowth and develop-
mentVESPGHAN Committee on NutritionVNutrition assess-
ment. Ó 2006 by Lippincott Williams & Wilkins

The survival of small premature infants has markedly
improved during the last few decades because of refine-
ments in obstetric and neonatal care. These changes have
raised further questions with regard to immediate and
long-term effects of nutritional care in premature infants.
In most parts of Europe, preterm infants tend to be
discharged from hospital care earlier than before for
economic and other reasons, with body weights far below
typical birth weights of healthy term infants. The
question has arisen whether such infants might require
special nutritional regimens or special discharge formulae.
Received February 28, 2006; accepted March 7, 2006.
Reprints: Jacques Rigo, MD, PhD, Department of Neonatology and
Nutrition, University of Liege, CHR Citadelle, Boulevard du XII de
Ligne 1, 4000 Liège, Belgium. (e-mail: j.rigo@ulg.ac.be).
In this article, the ESPGHAN Committee on Nutrition
reviews the available evidence on feeding human milk
and milk formulae postdischarge in preterm infants,
based on an electronic literature search (PubMed) of
randomised controlled trials performed until September
2004 and offers recommendations for practice and for
further research.
GROWTH OF PREMATURE INFANTS
IN THE HOSPITAL
Numerous studies underline the importance of early
feeding of very low birth weight (VLBW; G1500 g) and
extremely low birth weight (ELBW; G1000 g) infants
for their short- and long-term development (1Y 8). The

596

Copyr ight © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
 ESPGHAN COMMITTEE ON NUTRITION
incidence of intrauterine growth retardation (IUGR) is high
(10% Y 30%) in VLBW infants and postnatal weight and
length gain often does not match intrauterine growth rates,
because postnatal parenteral and enteral nutrition usually
do not achieve quantitative and qualitative nutrient provi-
sion that would allow to approximate normal intrauterine
growth (9 Y 11). Increasing immaturity and morbidity with
decreasing gestational age (GA) are major factors limiting
nutrient intakes achieved during the first weeks of life.
Moreover, in practice, the recommended intakes are often
not prescribed, and even the prescribed intakes are
frequently not achieved, for example, because of concerns
of intolerance or the occurrence of adverse events (10 Y 12).
In many neonatal units throughout Europe, stable
VLBW and ELBW infants are discharged from hospital
care at postconceptional ages of about 35 to 36 weeks
and with body weights of about 1800 to 2100 g,
respectively. For the feeding of such infants after dis-
charge, human milk with or without added nutrient sup-
plements, standard infant formulae designed for healthy
term infants, preterm formulae designed for feeding im-
mature babies and special postdischarge formulae de-
signed for low birth weight infants with increased
density of nutrients are used. In making feeding choices,
considerations may include the aim of achieving early
catch-up growth (an increased growth velocity after a
temporary growth retardation) as well as reducing long-
term growth deficits and risk of potential adverse effects
in adulthood (13 Y 15).
Nutritional recommendations of various expert groups
(16 Y 19) are based primarily on the studies of stable
preterm infants with few complications and aimed at
providing amounts of nutrients that may approximate
intrauterine growth. These recommended intakes often
do not cover added nutrient requirements that may be
needed to compensate for nutritional deficits accumu-
lated during the early postnatal period (3,11,20,21).
Because of these cumulative nutritional deficits during
the first weeks or even months of life, some postnatal
growth retardation is regularly observed in VLBW and
ELBW infants (3,9 Y 11,20,21). During hospital stay, the
feeding of both human milk with an added human milk
fortifier and of preterm formulae often generates a
slower growth rate and different body composition than
that achieved by the fetus in utero, with a relative low
lean body mass and a lower bone mineral content
associated with osteopenia and a risk of fractures in
early life (22 Y 26).
Nutritional evaluation of a newborn begins at birth
with anthropometric assessment that provides informa-
tion on intrauterine growth and continues up to
discharge to evaluate postnatal growth. Anthropometric
measurements most commonly used for assessment of
nutritional status are weight, length and head circum-
ference plotted against GA. Plotting birth weight against
GA helps determine whether an infant is appropriate for
GA (AGA; birth weight, 10th Y 90th percentile or mean
Copyr ight © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
597
T 2 SD), small for GA (SGA; birth weight, G10th
percentile or Gmean j 2 SD) or large for GA (LGA;
birth weight, 990th percentile or 9mean + 2 SD). The
comparison of weight, length and head circumference
measurements provides information as to whether the
anthropometric parameters are proportionate or dispro-
portionate. Even if AGA, SGA and LGA are defined by
statistical criteria rather than clinical end points, they
allow identification of subjects with growth abnormal-
ities (27).
At the time of hospital discharge, the growth of
preterm infants can be classified into 4 different patterns:
1. infants with a birth weight and a body weight at
discharge appropriate for postconceptional age (appro-
priate growth);
2. infants born AGA but with a discharge weight below the
reference growth chart (postnatal growth restriction);
3. infants born SGA with a discharge weight still below
the reference growth chart (IUGR);
4. infants born SGA with a discharge weight appro-
priate for postconceptional age (early postnatal
catch-up growth).
The relative proportion of these 4 main categories of
preterm infants discharged from neonatal units differs
according to GAs of the patients’ population and the
nutritional policy during the first weeks of life. How-
ever, during the early neonatal period full catch-up
growth (pattern 4) is exceptional in clinical practice.
GROWTH OF PREMATURE INFANTS AFTER
HOSPITAL DISCHARGE
Numerous studies have evaluated longitudinal growth
in VLBW infants (2,13,21,28 Y 30). Some degree of
catch-up growth is observed in most VLBW premature
infants during the first months of life, although the rate
differs between studies partly related to sex and period
of growth restriction (prenatal or postnatal). Although
infants appropriate for corrected age at discharge usually
maintain normal growth subsequently (pattern 1), about
80% of VLBW infants with postnatal growth retardation
(pattern 2) and SGA populations (patterns 3 and 4) show
catch-up growth by 2 to 3 years old (21). Catch-up
growth of VLBW preterm infants appears to be faster
and more complete in girls than in boys, although data
are controversial (11,28), and in growth restricted AGA
(pattern 2) than in SGA (patterns 3 and 4) VLBW
preterm infants (2,31). These studies suggest that
subgroups of preterm infants with a higher risk for
long-term growth restriction can be defined (patterns 2
and 3). In contrast to body weight, reduced bone
mineralisation generally improves rapidly during the
first months of life. Between 6 and 12 months of age,
J Pediatr Gastroenterol Nutr, Vol. 42, No. 5, May 2006
598 POSTDISCHARGE NUTRITION IN PRETERM INFANTS
bone mineralisation of infants born preterm reaches
values, adjusted for anthropometric parameters, similar
to healthy term infants (32,33) and appears appropriate
for the skeletal and body size achieved.
POTENTIAL CONSEQUENCES OF PRENATAL
AND POSTNATAL NUTRITION
Adequate nutrition during early infancy is essential
for the overall well-being of the child and can have a
major impact on long-term development. Preterm and
term infants born SGA carry a high risk for continued
growth deficits, neurodevelopmental abnormalities and
behavioural problems (34 Y 38). Increasing evidence
suggests that either low birth weight or rapid postnatal
weight gain or the combination of both may predispose
to adverse long-term effects, such as increased risk for
hypertension, cardiovascular diseases, type 2 diabetes
and osteoporosis in adulthood (39 Y 47). Those preterm
infants who fail to achieve their growth potential during
the first weeks of postnatal life have a less favourable
outcome with respect to growth and neurodevelopment
(48 Y 50) and could therefore be subject to the same
influences as infants born growth retarded at term
(51,52). The window for catch-up in growth-retarded
babies appears to be narrow. If catch-up growth does
not take place in early life, the chances that it will occur
later are limited (6,28,31,53). In human infants, this
critical period may approximate to the first year with
respect to development of head circumference and the
first 3 years with respect to final height (54,55).
For VLBW infants, the consequences of postnatal
nutrition deficits for neurodevelopmental outcomes
have been difficult to document because the neuro-
development of preterm infants is a composite of
multiple factors including genetics, morbidity such as
intraventricular hemorrhage, periventricular leukoma-
lacia and chronic lung disease, nutritional intake and
other factors. In a recent study on VLBW infants,
postnatal growth pattern rather than SGA status was
significantly associated with neurodevelopmental out-
come at 2 years (49). A better neurodevelopmental
outcome was observed in AGA preterm infants main-
taining favourable growth velocity or in SGA demon-
strating early catch-up growth after the term equivalent
(1,49). Similar results were observed among SGA
preterm infants with catch-up growth from birth to term
as well as from term equivalent up to 8 months of age or
older (30,56 Y 58). On the basis of these studies,
neonatologists were encouraged to promote early
Baggressive[ nutrition (ie, provision of high energy
and nutrient intakes) to promote early catch-up growth
in VLBW infants (59 Y 61). However, potential unto-
ward effects of prolonged use of formulae with high
protein and mineral density during the first year of life
need to be considered. In a recent randomised controlled
J Pediatr Gastroenterol Nutr, Vol. 42, No. 5, May 2006
Copyr ight © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
trial, enriched postdischarge formula was evaluated with
regard to growth (59 Y 62) and neurodevelopmental out-
come in SGA term infants. Infants receiving enriched
formula showed greater gains in length and head cir-
cumference than those fed term formula, not only
during the 9 month intervention period but also up to
18 months, and the differences were larger in girls than
in boys (62). Girls fed the enriched formula had sig-
nificantly lower scores in all subscales and in overall
developmental quotient compared with girls fed term
infant formula at 9 months, although no difference
between the groups was present at 18 months of age
(63). A breast-fed reference group was also evaluated as
nonrandomised control group and demonstrated a sig-
nificant growth and neurodevelopmental advantage
compared with formula-fed infants (62,63). The ques-
tions raised here deserve careful evaluation in future
studies with long-term follow-up that includes a detailed
description of early growth patterns, dietary intakes and
potential confounders.
STUDIES ON THE USE OF NUTRIENT
ENRICHED FORMULAE IN PRETERM
INFANTS AFTER DISCHARGE
At the time of discharge, many VLBW and ELBW
infants have cumulative deficits in the accretion of
energy, protein, minerals and other nutrients, resulting
in higher nutrient requirements per kilogram of body
weight than healthy AGA term infants. Therefore, the
potential benefits of diets providing a higher concen-
tration of energy, protein and specific nutrients, such as
long-chain polyunsaturated fatty acids (LCPUFAs),
minerals, electrolytes and trace elements, on growth,
bone mineralisation and developmental outcomes have
been investigated in several studies since 1992 (Tables 1
and 2) (15,64 Y 72).
All these studies had methodological limitations, for
example, related to inclusion criteria, the selection of
major end points or completeness of follow-up (Table 2).
The inclusion of premature infants with a birth weight
TABLE 1. Macronutrient composition of standard,
postdischarge and preterm formula
Standard Postdischarge Preterm
formula formula formula
Protein 1.4 Y 1.5 1.8 Y 1.9 2.2 Y 2.3
(g/100 mL)
Energy 67 72 Y 74 80 Y 90
(kcal/100 mL)
Calcium 35 Y 54 70 Y 80 100 Y 108
(mg/100 mL)
Protein T 2.2 T 2.5 T 2.8
(g/100 kcal)
 ESPGHAN COMMITTEE ON NUTRITION
below 1650 to 1800 g or a GA below 34 to 37 weeks
selects a high-risk population for long-term growth
impairment, such as preterm infants with weight or
length below the reference curves at the time of
discharge. Analysis of growth indices during an inter-
mediate period (2 Y 18 months) as the end point may not
allow a clear evaluation of the potential for catch-up
growth resulting from a change in the protein and
mineral density of the formula. Because approximately
80% of preterm infants whose size is not appropriate for
postconceptional age at the time of discharge show
catch-up growth by the age of 2 to 3 years, the effects
of dietary interventions should be evaluated at this age
in a high-risk population. However, such studies are
difficult to perform. Considering a 20% risk of long-
term growth restriction in a high-risk population and a
target reduction of 50%, more than 200 infants would
need to be included into such a study. In addition, it is
also desirable to study neurodevelopment to inves-
tigate the potential effects of dietary interventions and
early catch-up growth. Similarly, the relative contribu-
tion of a preexisting intrauterine growth restriction
needs to be considered as an additional confounding
factor that could influence long-term growth and
development.
Although the available studies differed in design and
reported conflicting results (Table 2), they provide
valuable information. Comparing the various studies,
the use of preterm formula does not seem to induce
more positive effects than that observed with the use of
postdischarge formula. Compared with controls, for-
mulae with an increased energy density tended to be
consumed at lower volume intakes and thus did not
increase total energy supply (15,64,66,72). In contrast,
increased protein density led to higher protein intake
influencing nitrogen metabolism and blood urea ni-
trogen concentration (64,66). A positive effect on
growth parameters was not observed in all studies
(Table 2), but when seen occurred mainly during the
early postdischarge period approximately until the first
weeks after the equivalent of term birth, particularly in
VLBW infants and in boys (62,68,69). In studies
evaluating body composition, an observed enhanced
weight gain did not seem to affect preferentially the lean
body mass deposition and may be limited to preterm
infants who are AGA at the time of discharge without
any positive effect in those with growth restriction (70).
In addition, evaluating the neurodevelopment outcomes at
18 months, Cooke et al. (68) reported that the use of
preterm formula as postdischarge formula had no impact
on neurodevelopmental outcome.
Recently, a Cochrane review on the effect of energy-
and protein-enriched formula for improving growth and
development in preterm or low birth weight infants after
hospital discharge has been published (73). Evaluating
much the same studies, the authors found little evidence
that feeding with energy- and protein-enriched formula
Copyr ight © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
599
milk affected growth and development. Because of
differences in the way individual trials measured and
presented outcomes, data synthesis was limited. Meta-
analysis of data from 2 trials (62,66 Y 68) found a
statistically significant effect on crown-to-heel length at
18 months postterm (weighted mean difference, 9.7 mm).
Meta-analysis of data from the same 2 trials (62,66 Y 68)
that assessed neurodevelopment at 18 months postterm
did not reveal a statistically significant difference in
either Bayley Mental Development Index or Psychomo-
tor Development Index. At the end of their evaluation,
the authors conclude that the limited available data do
not provide strong evidence that feeding preterm or
low birth weight infants after hospital discharge with
energy- and protein-enriched formula compared with
standard term formula affects growth rates and devel-
opment up to 18 months postterm.
The prolonged use of postdischarge or preterm
formulae (Table 2) instead of standard formulae in
preterm infants may considerably modify the intake of
nutrients such as protein, LCPUFA, minerals and trace
elements. The role of these individual substrates de-
serves further attention. The supply of lipids providing
LCPUFAs may benefit visual acuity and cognitive
development in VLBW infants (74), but some studies
also reported a significant advantage on weight and
length growth independently of the protein supply
(74,75). Similarly, an increased zinc intake could play
an independent significant role on growth and motor
development (76,77).
Two of the cited studies (62,64) evaluated the feeding
of human milk after discharge, but human milk could
not be allocated by randomisation and depended on
maternal choice. These studies suggest that the use of
nutrient-rich formulae increases weight gain after dis-
charge without any benefit on developmental score as
compared with feeding of human milk. This issue was
recently evaluated by O’Connor et al. (78) who
compared growth and development in 4 groups of
premature infants fed fortified human milk (980%),
preterm formula (980%) or a combination of human
milk and preterm formula (950% and G50%, respec-
tively) from birth to corrected age at term followed by
human milk or postdischarge formula up to 12 months
of corrected age. Human milk provision was based on
maternal choice. This study showed that the growth of
VLBW infants was inversely related to human milk
consumption up to corrected term, but despite the
slower early growth, human milkYfed low birth weight
infants had development at least comparable to that of
infants fed enriched formula from birth to 12 months of
corrected age. It is important to stress that in this study
an early catch-up growth for length (G9 months) and
head circumference (G4 months) was reported in the
group fed predominantly with human milk for more
than 6 months. A positive relationship between duration
of human milk feeding and the later Bayley Mental
J Pediatr Gastroenterol Nutr, Vol. 42, No. 5, May 2006
600 POSTDISCHARGE NUTRITION IN PRETERM INFANTS

TABLE 2. Summary of the study design and main results observed on the prolonged use of enriched formula in preterm infants
after discharge

Author (year) Study Allocation Completeness of

and ref number design concealment* Blinding ITT† follow-up‡

Lucas et al RCT Unclear Reported as double-blinded; No Yes

(1992Y1993)(15,62) not stated who was blinded
Wheeler and Hall RCT Unclear Reported as double-blinded; No Yes
(1996)(64) not stated who was blinded
Brunton et al (1998)(65) RCT Unclear Reported as blinded; No Yes
not stated who was blinded
Cooke et al (2001)(66 Y 68) RCT Unclear Reported as blinded; No Yes
not stated who was blinded
Carver et al (2001)(69) RCT Unclear Reported as double-blind; No 6 mo, 74/125
not stated who was blinded (59%)
Lucas et al (2001)(62) RCT Adequate Yes (investigators, caregivers, Yes Yes
outcome assessors
and data analysis)
De Curtis et al (2002)(70) RCT Unclear Reported as blinded; No Yes
not stated who was blinded
HM, human milk; PDF, postdischarge formula; PTF, preterm formula; SF, standard formula; BDP, bronchopulmonary dysplasia; RTC,
randomised controlled trial; ITT, intention to treat; HC, head circumference; BMC , bone mineral content.
*Allocation concealment: adequate, randomisation method described that would not allow investigator/caregivers to know or influence
intervention group before eligible participant entered in the study; unclear, randomisation stated but no information on method used is available;
inadequate, method of randomisation used such as alternate medical record numbers or unsealed envelopes; any information in the study that
indicated that investigators or participants could influence intervention group.
†ITT, intention-to-treat analysis: yes, specifically reported by authors that intention-to-treat analysis was undertaken, and this was confirmed on
study assessment; yes, not stated but confirmed upon study assessment; no, not reported, and lack of intention-to-treat analysis was confirmed on
study assessment. Patients who were randomised were not included in the analysis because they did not receive the study intervention, withdrew
from the study or were not included because of protocol violation); no, stated but not confirmed upon study assessment.
‡Completeness of follow-up: trials with more than 80% follow-up of participants.

Index was observed, with a more marked benefit in in-
fants with chronic lung disease. In addition, human milk
feeding was also associated with a reduction in serious
adverse events, specifically in the number of hospital-
isation days after discharge. However, confounding
effects such as socioeconomic factors related to maternal
choice to provide breast milk cannot be excluded.
The literature review revealed only limited informa-
tion on the possible effects of the type and time of
introduction of complementary feeding in infants born
preterm (63,76,78 Y 81). Although not the focus of this
article, the committee recommends that these questions
should be studied in further well designed trials.
CONCLUSIONS
Early nutritional support of preterm infants is impor-
tant because it influences long-term health and develop-
ment. Growth monitoring up to discharge and thereafter
must be based on regular measurements of weight,
length and head circumference to identify those preterm
infants with poor growth that may need additional
nutritional support. Continued growth monitoring is
required to adapt feeding choices to the needs of
individual infants and to avoid underfeeding and over-
feeding. Early nutritional support can reduce the degree
of growth failure and may limit the need for high
nutrient supplies for preterm infants after discharge.
Infants with an appropriate weight for postconceptional
age at discharge should be breast-fed when possible.
When formula-fed, such infants may be given standard
infant formula with provision of LCPUFA. Infants
discharged with a subnormal weight for postconceptional
age and thus with an increased risk of long-term growth
failure, if fed on human milk should be supplemented to
provide an adequate nutrient intake, for example with a
human milk fortifier. If such infants are fed formula, they
should receive special postdischarge formula with high
contents of protein, minerals and trace elements as well
as LCPUFA, at least until a postconceptional age of
40 weeks, but possibly until about 52 weeks. Further
research is required to determine the specific nutritional
needs of infants born preterm with prenatal and postnatal
growth restriction during and particularly after hospital
stay and to evaluate the effects of nutritional interven-
tions on long-term growth, neurodevelopment and other
health outcomes. More research is also needed on the
effects of different types of complementary feeding and
their time of introduction. Such studies are expected to
contribute to development of better nutritional support in
these groups of infants.

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 ESPGHAN COMMITTEE ON NUTRITION 601

TABLE 2. (continued)
Duration of
Follow-up intervention
n Population (mo) Diet (mo) Main outcomes Effects on outcome measures
31 Preterm; G1850 g 9 SF, PDF 9 Weight, length, HC, SF G PDF
BMC SF = PDF
59 G35 wk; G1800 g 3 HM, SF, PTF 2 Weight, HM G SF, PTF
Length, HC HM, SF G PTF
60 VLBW G1500 g 3 SF, PTF 3 Weight, HC, ST = PTF
+ BPD length, BMC ST G PTF
Body composition BMC, LBM ST G PTF mainly for boys
113 e34 wk, e1750 g 18 SF, PTF 6 Weight, length, HC, BMC SF G PTF in boys
Developmental Score SF = PTF
125 G37 wk; G1800 g 12 SF, PDF 12 Weight, length, HC SF 9 PDF mainly for BW
G1250 g and boys
229 G37 wk; G1750 g 18 HM, SF, PDF 9 Weight, length, HM = FS G PDF mainly for boys
HC, Developmental Score FS = PDF
33 G34 wk; G1800 g 2 SF, PDF 2 Weight, length, HC SF = PDF
Weight gain composition SF = PDF

REFERENCES
1. Lucas A, Morley R, Cole TJ. Randomised trial of early diet in
preterm babies and later intelligence quotient. BMJ 1998;317:
1481Y7.
2. Hack M, Schluchter M, Cartar L, Rahman M, Cuttler L, Borawski
E. Growth of very low birth weight infants to age 20 years.
Pediatrics 2003;112:e30 Y 8.
3. Clark RH, Thomas P, Peabody J. Extrauterine growth restriction
remains a serious problem in prematurely born neonates.
Pediatrics 2003;111:986 Y 90.
4. Singhal A, Wells J, Cole TJ, Fewtrell M, Lucas A. Programming
of lean body mass: a link between birth weight, obesity, and
cardiovascular disease? Am J Clin Nutr 2003;77:726 Y 30.
5. Dobbing J. Nutrition and the developing brain. Lancet 1973;1:48.
6. Dobbing J, Sands J. Quantitative growth and development of
human brain. Arch Dis Child 1973;48:757Y767.
7. Lemons JA, Bauer CR, Oh W, et al. Very low birth weight
outcomes of the National Institute of Child health and human
development neonatal research network, January 1995 through
December 1996. NICHD Neonatal Research Network. Pediatrics
2001;107:E1.
8. Mortaz M, Fewtrell MS, Cole TJ, Lucas A. Cholesterol metabo-
lism in 8 to 12-year-old children born preterm or at term. Acta
Paediatr 2003;92:525 Y 30.
9. Bloom BT, Mulligan J, Arnold C, et al. Improving growth of very
low birth weight infants in the first 28 days. Pediatrics 2003;
112:8 Y 14.
10. Dusick AM, Poindexter BB, Ehrenkranz RA, Lemons JA. Growth
failure in the preterm infant: can we catch up? Semin Perinatol
2003;27:302 Y 10.
11. Embleton NE, Pang N, Cooke RJ. Postnatal malnutrition and
growth retardation: an inevitable consequence of current recom-
mendations in preterm infants? Pediatrics 2001;107:270 Y 3.
12. Rigo J. Protein, amino acid and other nitrogen compounds. In:
Tsang RCUR, Koletzko B, Zlotkin SH, eds. Nutrition of the
Preterm Infant: Scientific Basis and Practice, 2nd ed. Cincinnati,
OH: Digital Educational Publishing, 2005:45 Y 80.
13. Fewtrell MS. Growth and nutrition after discharge. Semin
Neonatol 2003;8:169 Y 76.
14. Griffin IJ. Postdischarge nutrition for high risk neonates. Clin
Perinatol 2002;29:327 Y 44.
15. Lucas A, Bishop NJ, King FJ, Cole TJ. Randomised trial of nutri-
tion for preterm infants after discharge. Arch Dis Child 1992;
67:324 Y 7.
16. American Academy of Pediatrics Committee on Nutrition. Nutri-
tional needs of low-birth weight infant. Pediatrics 1985;75:
976 Y 86.
17. Wharton B. Protein. In: Osney Mead O, ed. Nutrition and
Feeding of Preterm infants. Blackwell Scientific Publications,
1987:37 Y 46.
18. Tsang RCLA, Uauy R, Zlotkin S, ed. Nutritional Needs of the
Preterm Infant: Scientific Basis and Practical Guidelines. Williams &
Wilkins, Baltimore, ed. Baltimore, MD: Williams & Wilkins, 1993.
19. Nutrients needs and feeding of premature infants. Can Med Assoc
J 1995;152:1765 Y 85.
20. Rigo J, Boboli H, Franckart G, Pieltain C, De Curtis M.
Surveillance of the very-low birthweight infant: growth and nu-
trition. Arch Pe´diatr 1998;5:449 Y 53.
21. Rigo J, de Curtis M, Pieltain C. Nutritional assessment in preterm
infants with special reference to body composition. Semin
Neonatol 2001;6:383 Y 91.

J Pediatr Gastroenterol Nutr, Vol. 42, No. 5, May 2006

Copyr ight © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
602 POSTDISCHARGE NUTRITION IN PRETERM INFANTS
22. Pieltain C, De Curtis M, Gerard P, Rigo J. Weight gain com-
position in preterm infants with dual energy X-ray absorptiometry.
Pediatr Res 2001;49:120 Y 4.
23. Lucas A, Gore SM, Cole TJ, Bamford MF, Dossetor JF, Barr I.
Multicentre trial on feeding low birthweight infants: effects of diet
on early growth. Arch Dis Child 1984;59:722 Y 30.
24. Rigo J, De Curtis M, Pieltain C, Picaud JC, Salle BL, Senterre J.
Bone mineral metabolism in the micropremie. Clin Perinatol
2000;27:147 Y 70.
25. Reichman B, Chessex P, Verellen G, et al. Dietary composition
and macronutrient storage in preterm infants. Pediatrics 1983;
72:322 Y 8.
26. Kashyap S, Ohira-Kist K, Abildskov K, et al. Effects of quality of
energy intake on growth and metabolic response of enterally fed
low-birth-weight infants. Pediatr Res 2001;50:390 Y 7.
27. Lee PACS, Hokken-Koelega ACS, Czernichow P. International
small for gestational age advisory board consensus development
conference statement: management of short children born small
for gestational age. Pediatrics 2001;111:1253 Y 61.
28. Guo SS, Roche AF, Chumlea WC, Casey PH, Moore WM.
Growth in weight, recumbent length, and head circumference for
preterm low-birthweight infants during the first three years of life
using gestation-adjusted ages. Early Hum Dev 1997;47:305 Y 25.
29. Hack M, Merkatz IR, McGrath SK, Jones PK, Fanaroff AA.
Catch-up growth in very-low-birth-weight infants. Clinical corre-
lates. Am J Dis Child 1984;138:370 Y 5.
30. Hack M, Weissman B, Borawski-Clark E. Catch-up growth during
childhood among very low-birth-weight children. Arch Pediatr
Adolesc Med 1996;150:1122 Y 9.
31. Harding JE, McCowan LM. Perinatal predictors of growth
patterns to 18 months in children born small for gestational age.
Early Hum Dev 2003;74:13 Y 26.
32. Fewtrell MS, Prentice A, Jones SC, et al. Bone mineralization and
turnover in preterm infants at 8-12 years of age: the effect of early
diet. J Bone Miner Res 1999;14:810 Y 20.
33. Salle BL, Putet G. Calcium, phosphorus and vitamin D require-
ments in premature infants. In: Salle BL, ed. Nutrition of the Low
Birth Weight. Nestle´ Nutrition Workshop Series, 1993:125 Y 35.
34. Westwood M, Kramer MS, Munz D, Lovett JM, Watters GV.
Growth and development of full-term nonasphyxiated small-
for-gestational-age newborns: follow-up through adolescence.
Pediatrics 1983;71:376 Y 82.
35. Grantham-McGregor SM. Small for gestational age, term babies,
in the first six years of life. Eur J Clin Nutr 1998;52(Suppl 1):
S59 Y 64.
36. Richards M, Hardy R, Kuh D, Wadsworth ME. Birth weight and
cognitive function in the British 1946 birth cohort: longitudinal
population based study. BMJ 2001;322:199 Y 203.
37. Strauss RS. Adult functional outcome of those born small for
gestational age: twenty-six-year follow-up of the 1970 British
Birth Cohort. JAMA 2000;283:625 Y 32.
38. Dörner G. Perinatal hormone levels and brain organization. In:
Stumpf WEGL, ed. Anatomical Neuroendocrinology. Basel:
Karger, 1975:142 Y 252.
39. Tu Y, West R, Ellison G, Gilthorpe M. Why evidence for the fetal
origins of adult disease might be a statistical artifact: the Breversal
paradox[ for the relation between birth weight and blood pressure
in later life. Am J Epidemiol 2005;161(1):27 Y 32.
40. Barker DJ, Eriksson JG, Forsen T, Osmond C. Fetal origins of
adult disease: strength of effects and biological basis. Int J
Epidemiol 2002;31:1235 Y 9.
41. Toschke A, Grote V, Koletzko B, von Kries R. Identifying
children at high risk for overweight at school entry by weight gain
during the first 2 years. Arch Pediatr Adolesc Med 2004;158:
449 Y 52.
42. Eriksson JG, Forsen T, Tuomilehto J, Jaddoe VW, Osmond C,
Barker DJ. Effects of size at birth and childhood growth on the
insulin resistance syndrome in elderly individuals. Diabetologia
2002;45:342 Y 8.
J Pediatr Gastroenterol Nutr, Vol. 42, No. 5, May 2006
Copyr ight © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
43. Hales CN, Ozanne SE. The dangerous road of catch-up growth.
J Physiol 2003;547:5 Y 10.
44. Metcalfe N, Monaghan P. Compensation for a bad start: grow
now, pay later? Trends Ecol Evol 2001;16:254 Y 60.
45. Hales CN, Ozanne SE. Reply to Comment on: Hales CN, Ozanne
SE (2003). For debate: fetal and early postnatal growth restriction
lead to diabetes, the metabolic syndrome and renal failure.
Diabetologia 2004;47:1336.
46. Fagerberg B, Bondjers L, Nilsson P. Low birth weight in
combination with catch-up growth predicts the occurrence of
the metabolic syndrome in men at late middle age: the Athero-
sclerosis and Insulin Resistance study. J Intern Med 2004;256:
254 Y 9.
47. Cole T. Modeling postnatal exposures and their interactions with
birth size. J Nutr 2004;134:201 Y 4.
48. Brandt I, Sticker EJ, Lentze MJ. Catch-up growth of head
circumference of very low birth weight, small for gestational age
preterm infants and mental development to adulthood. J Pediatr
2003;142:463 Y 8.
49. Latal-Hajnal B, von Siebenthal K, Kovari H, Bucher HU, Largo
RH. Postnatal growth in VLBW infants: significant association
with neurodevelopmental outcome. J Pediatr 2003;143:163 Y 70.
50. Luo ZC, Albertsson-Wikland K, Karlberg J. Length and body
mass index at birth and target height influences on patterns of
postnatal growth in children born small for gestational age.
Pediatrics 1998;102:E72.
51. Hofman P, Regan F, Harris M, Robinson E, Jackson W, Cutfield
W. The metabolic consequences of prematurity. Growth Horm
IGF Res 2004;14:S136 Y 9.
52. Hofman P, Regan F, Jackson W, et al. Premature birth and later
insulin resistance. N Engl J Med 2004;351:2179 Y 2186.
53. Gale CR, O’Callaghan FJ, Godfrey KM, Law CM, Martyn CN.
Critical periods of brain growth and cognitive function in children.
Brain 2004;127:321 Y 9.
54. Eriksson J. Commentary: early Fcatch-up_ growth is good for later
health. Int J Epidemiol 2001;30:1330 Y 31.
55. Victora CG, Barros FC, Horta BL, Martorell R. Short-term
benefits of catch-up growth for small-for-gestational-age infants.
Int J Epidemiol 2001;30:1325 Y 30.
56. Lucas A, Fewtrell MS, Davies PS, Bishop NJ, Clough H, Cole TJ.
Breastfeeding and catch-up growth in infants born small for
gestational age. Acta Paediatr 1997;86:564 Y 9.
57. Georgieff MK, Hoffman JS, Pereira GR, Bernbaum J, Hoffman-
Williamson M. Effect of neonatal caloric deprivation on head
growth and 1-year developmental status in preterm infants. J Pediatr
1985;107:581 Y 7.
58. Lundgren EM, Cnattingius S, Jonsson B, Tuvemo T. Intellectual
and psychological performance in males born small for gesta-
tional age with and without catch-up growth. Pediatr Res 2001;50:
91 Y 6.
59. Wilson DC, Cairns P, Halliday HL, Reid M, McClure G, Dodge
JA. Randomised controlled trial of an aggressive nutritional
regimen in sick very low birthweight infants. Arch Dis Child
Fetal Neonatal Ed 1997;77:F4 Y 11.
60. Ziegler EE, Thureen PJ, Carlson SJ. Aggressive nutrition of the
very low birthweight infant. Clin Perinatol 2002;29:225 Y 44.
61. Thureen PJ, Hay WW Jr. Early aggressive nutrition in preterm
infants. Semin Neonatol 2001;6:403 Y 15.
62. Lucas A, Fewtrell MS, Morley R, et al. Randomized trial of
nutrient-enriched formula versus standard formula for post-
discharge preterm infants. Pediatrics 2001;108:703 Y 11.
63. Morley R, Fewtrell MS, Abbott R, Stephenson T, MacFayden U,
Lucas A. Neurodevelopment in children born small for gestational
age: a randomized trial of nutrient-enriched versus standard
formula and comparison with a reference breastfed group.
Pediatrics 2004;113:515 Y 21.
64. Wheeler RE, Hall RT. Feeding of premature infant formula after
hospital discharge of infants weighing less than 1800 grams at
birth. J Perinatol 1996;16:111 Y 6.
 ESPGHAN COMMITTEE ON NUTRITION
65. Brunton JA, Saigal S, Atkinson SA. Growth and body composition
in infants with bronchopulmonary dysplasia up to 3 months
corrected age: a randomized trial of a high-energy nutrient-enriched
formula fed after hospital discharge. J Pediatr 1998;133:340 Y5.
66. Cooke RJ, Griffin IJ, McCormick K, et al. Feeding preterm infants
after hospital discharge: effect of dietary manipulation on nutrient
intake and growth. Pediatr Res 1998;43:355 Y 60.
67. Cooke RJ, McCormick K, Griffin IJ, et al. Feeding preterm infants
after hospital discharge: effect of diet on body composition.
Pediatr Res 1999;46:461 Y 4.
68. Cooke RJ, Embleton ND, Griffin IJ, Wells JC, McCormick KP.
Feeding preterm infants after hospital discharge: growth and
development at 18 months of age. Pediatr Res 2001;49:719 Y 22.
69. Carver J, Wu P, Hall R, et al. Growth of preterm infants fed
nutrient-enriched or term formula after hospital discharge.
Pediatrics 2001;107:683 Y 9.
70. De Curtis M, Pieltain C, Rigo J. Body composition in preterm
infants fed standard term or enriched formula after hospital
discharge. Eur J Nutr 2002;41:177 Y 82.
71. Bishop NJ, King FJ, Lucas A. Increased bone mineral content of
preterm infants fed with a nutrient enriched formula after
discharge from hospital. Arch Dis Child 1993;68:573 Y 8.
72. Lucas A, Kirkwood CD, Bishop NJ. Postdischarge formula con-
sumption in infants born preterm. Arch Dis Child 1992;67:691 Y 2.
73. Henderson GFT, McGuire W. Caloric and protein-enriched formula
versus standard term formula for improving growth and development
in preterm or low birth weight infants following hospital discharge.
Cochrane Database Syst Rev 2005;18:CD00 4696.
Copyr ight © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
603
74. O’Conner D, Hall R, Adamkin D, et al. Growth and development
in preterm infants fed long-chain polyunsatured fatty acids: a
prospective, randomized controlled trial. Pediatrics 2001;108:
359 Y 71.
75. Fewtrell MS, Abbott R, Kennedy K, et al. Randomized, double-
blind trial of long chain polyunsaturated fatty acid supplementation
with fish oil and borage oil in preterm infants. J Pediatr 2004;
144:471 Y 9.
76. Friel J, Andrews W, Matthew J, et al. Zinc supplementation in
very-low-birth-weight infants. J Pediatr Gastroenterol Nutr 1993;
17:97 Y 104.
77. Castillo-Duran C, Weisstaub G. Zinc supplementation and growth
of the fetus and low birth weight infant. J Nutr 2003;133:
1494S Y 7S.
78. O’Connor D, Jacobs J, Hall RT, et al. Growth and development of
premature infants fed predominantly human milk, predominantly
premature infant formula, or a combination of human milk and
premature formula. J Pediatr Gastroenterol Nutr 2003;37:
437 Y 46.
79. Marriott L, Foote K, Bishop NJ, Kimber A, Morgan J. Weaning
preterm infants: a randomised controlled trial. Arch Dis Child
Fetal Neonatal Ed 2003;88:F302 Y 07.
80. Fewtrell M, Lucas A, Morgan J. Factors associated with weaning
in full term and preterm infants. Arch Dis Child Fetal Neonatal Ed
2003;88:F296 Y 301.
81. Norris F, Larkin M, Williams C, Hampton S, Morgan J. Factors
affecting the introduction of complementary foods in the preterm
infants. Eur J Clin Nutr 2002;56:448 Y 54.
J Pediatr Gastroenterol Nutr, Vol. 42, No. 5, May 2006
 Post-discharge Nutrition in Preterm
Infants

Richard J. Cooke

Contents Abstract
The fundamental principle underlying nutri-
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
tional support is that intake meets needs,
Postnatal Malnutrition and Growth Failure in thereby ensuring the best outcome, in the case
Preterm VLBWI . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
of the preterm infant, optimal growth, and
Importance of Postnatal Malnutrition and development. Achieving this goal is problem-
Growth Failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
atic and most, if not all, very-low-birth-weight
Catch-Up Growth, Insulin Resistance, and infants (VLBWI) are undernourished and
Visceral Obesity in Preterm Infants . . . . . . . . . . . . 7 undergrown when first discharged home. This
Post-discharge Nutritional Support in Preterm has important implications for nutritional care
Infant . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 of these high-risk infants after hospital
Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8
discharge.
Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10
Breastfeeding . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12
Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
Introduction
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
The fundamental principle underlying nutritional
support is that intake meets needs, thereby ensur-
ing the best outcome, in the case of the preterm
infant, optimal growth, and development. Achiev-
ing this goal is problematic and most, if not all,
\very-low-birth-weight infants (VLBWI) are
undernourished and undergrown when first
discharged home. This has important implications
for nutritional care of these high-risk infants after
hospital discharge.
In this chapter the following issues will be
addressed:

• Postnatal malnutrition and growth failure

R.J. Cooke (*) (PGF) between birth and hospital discharge in
Department of Pediatrics, University of Tennessee Health
preterm infants
Science Center, Memphis, TN, USA
e-mail: richardjcooke@mac.com

# Springer International Publishing Switzerland 2016 1

G. Buonocore et al. (eds.), Neonatology,
DOI 10.1007/978-3-319-18159-2_189-1
2 R.J. Cooke
Fig. 1 Growth curve for a
24-week AGA preterm 3500
infant who regains birth
weight by 7, 14, and 21 days 3000
and then grows at a rate of
17 g/kg/day 2500
Weight (g)
2000
1500
1000
500
0
23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38
• Regaining birth weight at 1,2 and 3 w and growing at 17 g/kg/d
• Catch-up growth, insulin resistance, and vis-
ceral obesity in preterm infants
• Nutritional care of VLBWI after hospital
discharge
Postnatal Malnutrition and Growth
Failure in Preterm VLBWI
Several studies have examined postnatal growth
in preterm infants during initial hospital stay and
noted that most preterm, if not all very-low-birth-
weight infants (VLBWI), are growth retarded at
hospital discharge (Wilson et al. 1997; Carlson
and Ziegler 1998; Embleton et al. 2001; Clark
et al. 2003; Olsen et al. 2002; Ehrenkranz
et al. 1999; Cooke et al. 2004). In studies where
nutritional intake was measured, recommended
dietary intakes (RDIs) took time to establish, and
infants accrued a significant nutrient deficit that
was directly related to the growth deficit (Wilson
et al. 1997; Carlson and Ziegler 1998; Embleton
et al. 2001; Clark et al. 2003; Olsen et al. 2002).
In studies where intake was not measured, poor
growth was related to non-nutritional factors such
as “illness” (Ehrenkranz et al. 1999; Cooke
et al. 2004). In the recent study of Griffin
et al. (2016), necrotizing enterocolitis was noted
to have a significant negative on growth (Griffin
et al. 2016). This is not surprising because
Postnatal Growth In A 24 w 690 AGA Infant*
Fetus 3058 g
1 w – 2792 g
2 w – 2527 g
3 w – 2285 g
Gestational Age w
intercurrent “illness” not only reduces intake but
also may alter nutrient assimilation and increase
requirements (Mehta et al. 2013). However, other
factors underpin the development of growth fail-
ure in these infants.
Current recommendations are that the rate of
weight gain parallels that of the fetus of the same
gestational age once birth weight has been
regained (AAPCON 1998; Klein 2002). Yet, a
24-week appropriately grown (AGA) infant
weighing ~690 g at birth who regains birth weight
by 2 weeks of age and grows at the recommended
rate, i.e., 17 g/kg/day, will weigh 2,527 g, ~531 g
less than the fetus, and be growth retarded at
37 weeks (Fig. 1). If the same infant takes
3 weeks to regain birth weight and grows at the
same rate, then she/he will weigh 2,285 g, 773 g
less than the fetus at 37 weeks.
Up to 40 % of infants born prematurely are
undergrown or small for gestational age (SGA)
at birth (Larsen et al. 1990). A 24-week 550 g
SGA infant who regains birth weight at 2 weeks
and then gains at the recommended rate of 17 g/
kg/day will weigh 1,727 g at 37 weeks, 800 g less
than the 690 AGA infant at the same gestational
age and ~1,300 g less than the fetus at the same
gestational age (Fig. 2). Recommendations related
to suboptimal weight will systematically underes-
timate needs and growth potential in these high-
risk infants.
Post-discharge Nutrition in Preterm Infants
Fig. 2 Growth curve for a
24-week AGA and SGA 3000
preterm infants who regain
birth weight by 14 and then
2500
grow at a rate of 17 g/kg/day
2000
Weight (g)
1500
1000
500
0
23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38
Table 1 Protein and energy needs in preterm infants
Weight g 500–700
Protein g/kg/day 4.0
Energy kcal/kg/day 105
P:E g/100 kcal 3.8
At the same time, current recommendations
assume that nutritional requirements are consis-
tent throughout gestation for all preterm VLBWI
(AAPCON 1998; Klein 2002). However, Ziegler
et al. have noted that protein and energy require-
ments change with advancing gestation (Ziegler
et al. 2002; Table 1). In effect, a formula
containing a protein-energy ratio of 3.0 g/
100 kcal, as is currently fed to preterm infants,
does not meet the protein needs of the infants
weighing 1,500 g at birth, i.e., the VLBWI.
Recommended dietary intakes are based on
needs for maintenance and normal growth
(AAPCON 1998; Klein 2002), and no allowance
is made for recovery or “catch-up” growth (Heird
2001). In the study of Embleton et al., the accrued
protein deficit at hospital discharge varied from
15 to 25 g/kg (Embleton et al. 2001). An addi-
tional protein intake of 0.5–1.0 g/kg/day would
have been required to recoup this deficit before
hospital discharge, further compounding the
problem.
To further examine this issue, body size and
body composition were measured in preterm
3
Postnatal Growth in 24 w AGA and SGA Infant*
AGA – 2527 g
SGA – 1727 g
Gestational Age w
• Regaining birth weight at 2 w and growing at 17 g/kg/d
700–900 900–1,200 1,200–1,500
4.0 4.0 3.9
108 119 127
3.7 3.4 3.1
infants (n = 149) at hospital discharge (Cooke
and Griffin 2009). Weight, length, and head cir-
cumference were measured using standard meth-
odology (Cooke et al. 1998). Body composition
was measured using dual-emission x-ray absorp-
tiometry (Cooke et al. 1999).
The post-menstrual age at discharge was
37  1.2 weeks. However, Z-score for head cir-
cumference ( 0.1  0.6) was significantly
greater than that for weight ( 1.4  0.6) which
in turn was greater than for crown-heel length
( 1.9  0.6; p < 0.0001) (Cooke and Griffin
2009). Body composition results are compared
to the reference infant at the same weight and
same gestation in Table 2.
Global fat-free mass was less in study infants
than the reference infant at the same weight
(2,062 < 2,252 g; p < 0.0001) or gestation
(2,062 < 2,667 g; p < 0.0001). Global fat mass
was greater in study infants than the reference
infant at the same weight (307 > 198 g,
13 > 8 %) or gestation (307 > 273 g;
13 > 9 %; p < 0.0001) (Cooke and Griffin
2009).
4 R.J. Cooke

Table 2 Body size and composition of study infants com- dietary protein and energy intakes in these
pared to the reference infant at the same weight and same infants.
gestation (Cooke and Griffin 2009)
Reference Reference
Study at at
infantsa 35 weeksa 37 weeksa Importance of Postnatal Malnutrition
Body 2,369  305 2,450 2,940 and Growth Failure
weight
g The importance of malnutrition cannot be
Fat-free 2,062  277a 2,252a 2,667a underestimated. Nutrients play a critical role on
mass g the promotion of normal health and prevention of
Fat-free 87  3.4 91.9 90.7
disease (Shils et al. 2006). It is not surprising,
mass %
Fat 307  130b 198b 273b
therefore, that it can be directly related to alter-
mass g ations in organ structure and function which, in
Fat 13  3.4b 8.1b 9.3b turn, are paralleled by an increased morbidity and
mass % mortality in adults and children (Shils et al. 2006).
a
Study infants < reference at 35 week or 37 weeks However, the effects of malnutrition are greater
( p < 0.0001) during infancy than later in life. There are several
b
Study infants > reference at 35 week or 37 weeks
( p < 0.001)
reasons for this.
Requirements are a function of growth rate; the
greater the rate, the greater the requirement and the
A reduced body size that is paralleled by more likely that deficiency will occur. Growth rates
reduced linear growth and a reduced fat-free are greater during infancy than later in life; i.e., the
mass indicate that dietary protein needs were term infant will double birth weight by 4–5 m,
not met in these infants before hospital dis- triple birth weight by 12 m, and approximately
charge, as has been previously suggested quadruple it by 24 m.
(Ziegler et al. 2002). A reduced fat-free mass Growth is also thought to be “preprogrammed”
coupled with an increased global and central fat to occur at a certain time or “critical” epoch which
mass echoes concerns about visceral obesity and if missed may not be recoverable (Dobbing 1981).
the development of insulin resistance in these Thus, even short periods of nutritional deprivation
high-risk infants (Uthaya et al. 2005; Yeung may not only affect somatic but also brain growth
2006). and development (Dobbing 1981), the area of the
Although many factors contribute to the devel- brain that is “programmed” to grow fastest being
opment of PGF and the degree of which will vary, the most affected (Bedi 1987).
depending upon the level of maturity/size of the In term infants, malnutrition during infancy is
infant (Embleton et al. 2001), it is clear that: associated with permanent alterations in brain
growth and function. Brain size is reduced (Galler
1. It is not preventable given current recommen- et al. 1996; Stoch et al. 1982; Dobbing 1987;
dations and the way infants are fed; i.e., target Winick and Rosso 1969a, b), the brain cortex is
growth rates related to a suboptimal body thinner (Dobbing and Sands 1971), neuronal
ensure that most, if not all, infants will be numbers are decreased (Dobbing et al. 1971),
moderately/severely growth retarded at hospi- myelination is reduced (Krigman and Hogan
tal discharge. 1976), and dendritic morphology is altered
2. Close attention must be paid to nutritional (Benitez-Bribiesca et al. 1999; Cordero
support and growth of these infants after et al. 1993), all of which can be related to poorer
hospital discharge. A reduced body size neurodevelopmental outcome (Pryor et al. 1995;
that is paralleled by a reduction in fat-free Ounsted et al. 1988; Gross et al. 1983; Hack and
mass but a relative increase in fat mass indi- Breslau 1986; Hack et al. 1991; Kitchen
cates that particular attention be paid to
Post-discharge Nutrition in Preterm Infants
et al. 1992a; Cooke and Foulder-Hughes 2003;
Stathis et al. 1999; Peterson et al. 2006).
These concerns are greater in preterm infants.
Growth rates are greater. A preterm infant is
“programmed” to quadruple brain weight
between 24 and 40 weeks gestation or 16 weeks
(Alexander et al. 1996), almost six times faster
than the term infant. Preterm infants are also more
vulnerable to the effects of perinatal ischemia and
inflammation, therefore the development of
periventricular intraventricular hemorrhage and
periventricular leukomalacia (Volpe 2008).
Compared to term, preterm infants are also
more likely to be fetally and/or postnatally mal-
nourished. Up to 40 % of preterm infants are
growth retarded or small for gestational age
(SGA) at birth (Greisen 1992). At the same time,
up to 100 % of preterm VLBWI undergo signifi-
cant postnatal growth failure and are SGA at hos-
pital discharge (Ehrenkranz et al. 1999).
Poor fetal growth is paralleled by reduced
organ growth as well as altered structure and
function (McCance and Widdowson 1974) but
not all organ systems are affected equally. This is
well illustrated in the study of Myers
et al. (1971). In this study, 30 % reduction in
body weight in SGA monkeys was associated
with an 8 % reduction in brain weight but
35 % reduction in lung, liver, pancreatic, and
spleen weights when compared to their AGA
counterparts (Myers et al. 1971). Thus, the
brain is “spared” at the expense of other organs
which, e.g., through the development of chronic
lung disease, sepsis, etc., may amplify undernu-
trition by reducing intake and/or increasing
requirements.
In the late 1980s and early 1990s, studies indi-
cated that poor growth between birth-hospital dis-
charge was associated with poorer
neurodevelopment (Morley 1999; Ehrenkranz
et al. 2006) and that better growth, as achieved
by feeding a nutrient-enriched formula, was asso-
ciated with better developmental outcomes (Lucas
et al. 1998, 1990). More recently, early parenteral
nutrition coupled with the early introduction and
advancement of enteral feeds has been associated
with better growth but many infants continue to be
SGA at hospital discharge (Evans and Thureen
5
2001; Dinerstein et al. 2006; Ibrahim et al. 2004;
Donovan et al. 2006).
While a clear relationship exists between
“catch-up” growth and development in preterm
infants, the time frame within which it needs to
occur is not well delineated. In most studies,
infants who “catch up” or “catch back” by
6–9 m corrected age have better neurodeve-
lopmental outcome (Morley 1999; Scott and
Usher 1966; Hack et al. 1982; Hack and Fanaroff
1984; Latal-Hajnal et al. 2003). This is illustrated
in the study of Latal-Hajnal et al. (2003).
In this study, infants were stratified at birth and
into those who were appropriate size for gesta-
tional age (AGA weight 10th percentile) and
SGA (weight <10th percentile). This process
was repeated at 2 years of age. Four groups
emerged: (a) AGA at birth and 2 years
(AGA-AGA), (b) AGA at birth and SGA at
2 years (AGA-SGA), (c) SGA at birth and AGA
at 2 years (SGA-AGA), and (d) SGA at birth and
2 years (SGA-SGA).
No differences were noted in development
between the AGA-AGA and SGA-SGA infants.
After adjusting for co-variables, infants who
“caught up,” i.e., SGA-AGA, had greater Bayley
PDIs than those who did not (SGA-SGA). Infants
who “faltered” (AGA-SGA) had lower PDIs and
MDIs than those who continued to thrive
(AGA-AGA). These authors concluded that the
course of postnatal growth primarily determined
later development.
To more closely examine this issue,
Dharmaraj et al. prospectively followed growth
between birth and18 months corrected age (mca)
and developmental outcome at 18 mca
(Dharmaraj et al. 2005). It was hypothesized
that the greater the degree of early growth failure
(birth to 28 days), the poorer the development at
18 mca. Infants were stratified at 28 days into
those with mild (fall in weight Z-score % 1.0;
MGF) and severe (fall in weight Z-score >1.0;
SGF) growth failure. This process was repeated
at 18 mca.
The characteristics of the study infants are
presented in Table 3. No differences were noted
with the exception that gestational age was less
(SGR-SGR < MGR-MGR, MGR-SGR,
 6 R.J. Cooke

Table 3 Characteristics of study infants (Dharmaraj et al. 2005)

Group (N) MGR-MGR (50) MGR-SGR (18) SGR-SGR (16) SGR-MGR (24)
Birth weight (g) 1,320  339 1,348  387 1,312  559 1,271  408
Gestation (w) 30  1.6a 30  1.8a 28  3.0a 29  2.3
BPD 13 (26 %) 3 (17 %) 6 (38 %) 10 (42 %)
Abnormal CUS 10 (20 %) 5 (28 %) 3 (19 %) 6 (25 %)
PVL 3 (6 %) 2 (11 %) 1 (6 %) 3 (13 %)
Cerebral palsy 4 (8 %) 3 (17 %) 5 (30 %)b 2 (8 %)
a
SGR-SGR < MGR-MGR, MGR-SGR, p < 0.05
b
SGR-SGR > MGR-MGR, SGR-MGR, p < 0.10

Fig. 3 Growth, i.e., change Postnatal Growth in Study Infants*

in weight Z-score between 1.0
Change In Weight Z-score From Birth

birth and 28 days, term and

one through 18 month 0.5 MGF-MGF
corrected age in infants in
the study of Dharmaraj et al. 0
SGF-MGF
−0.5

−1.0
−1.5 MGF-SGF

−2.0 SGF-SGF

Birth 28d Disc EDD +1m +2m +3m +6m + 9m + 12m +18m

* Dharmaraj et al60

Table 4 MDI and PDI in study infants (Dharmaraj et al. 2005)

Group (N) MGR-MGR MGR-SGR SGR-MGR SGR-SGR
MDIa 93  18 91  18 95  1 77  19
PDIa 90  17a 83  19 87  19b 77  22a
MDIb 96  15 93  20 98  16 88  11
PDIb 94  13 89  15 91  14 89  16
MDI ~ MGR-MGR, SGR-MGR > SGR-SGR. p < 0.05
a
PDI ~ MGR-MGR ( p < 0.05), SGR-MGR ( p < 0.10) > SGR-SGR
b
Infants with cerebral palsy excluded. MDI ~ MGR-MGR ( p < 0.05), SGR-MGR ( p < 0.10) > SGR-SGR

p < 0.05) and the frequency of cerebral palsy 18 mca (MGF-MGF) and SGF at 28 days but
tended to be greater (SGR-SGR > MGR-MGR, mild growth failure (SGF-MGF) at 18 mca. How-
SGR-MGR, p < 0.10) in infants with severe ever, growth faltered in the other groups, that is,
growth failure at 28 days and 18 m corrected age. MGF-SGF and SGF-SGF.
Growth of these infants is presented in Fig. 3. The developmental outcome data are
Between birth and 28 days, Z-scores for weight presented in Table 4. MDI and PDI were less
decreased and then recovered to some degree in in SGF-SGF than MGF-MGF infants,
all groups. After 28 days, growth continued to supporting the primary hypothesis that poor
improve in infants with MGF at 28 days and growth between birth and 28 days is a marker
Post-discharge Nutrition in Preterm Infants
for poor development. MDI and PDI were also
greater in infants who recovered after 28 days
(SGF-MGF) than those who did not
(SGF-SGF), indicating that “catch-up” growth
between 28 days and 18 mca is paralleled by
markedly improved development.
Collectively, these data support the conclu-
sions of Latal-Hajnal et al.; i.e., it is the course
of postnatal growth that determines later develop-
mental outcome in preterm infants. The data of
Dharmaraj et al. also indicate that a “critical win-
dow of opportunity” exists between 28 days and
1–2 mca during which “recovery” or “catch-up”
growth, to birth-weight percentile, is paralleled by
better neurodevelopmental outcome. If infants are
to “recover,” this is the time frame within which to
do it.
Catch-Up Growth, Insulin Resistance,
and Visceral Obesity in Preterm Infants
Despite the prevalence/severity of PGF that is
paralleled by an increased morbidity/mortality
before/after hospital discharge, concern has been
expressed about measures taken to improve
growth after hospital discharge. Concern largely
relates to “catch-up” growth and the subsequent
development of insulin resistance (Singhal
et al. 2001, 2003) and metabolic syndrome X
(Ong and Loos 2006) leading to the idea that
“bigger might not be better,” even in preterm
VLBWI (Singhal et al. 2003).
However, a certain amount of confusion exists
when the terms “rapid” and “catch-up” growth are
used; i.e., they are sometimes used interchange-
ably (Ong and Loos 2006) but are not the same.
“Rapid” growth is “an abnormal growth pattern
that moves upward beyond the original growth
percentile on a distance growth chart”
(Hermanussen 2013a). “Catch-up” is a physio-
logic condition of temporary overgrowth that
occurs after illness and/or starvation, and in the
process, the original growth percentile is
reestablished (Hermanussen 2013b).
The extent to which “catch-up” occurs depends
on many factors, including timing of the insult.
Growth/development is thought to be
7
programmed within a specific time frame or crit-
ical epoch which if missed may not be recoverable
(McCance and Widdowson 1974; Widdowson
and McCance 1975). It also depends upon the
severity and duration of the insult; the more severe
and prolonged the insult, the greater the accrued
nutritional deficit. Intake, therefore, must not only
replace the deficit but also meet needs for mainte-
nance and normal growth.
With acute illness, infants develop a
hypermetabolic state, and there is an acute deple-
tion of body protein to meet energy needs (Lowry
and Perez 2006). With chronic protein-energy
malnutrition during infancy, visceral tissue is con-
served at the expense of protein and fat (Ashworth
and Millward 1986). Nutritional rehabilitation in
these infants with high-energy intakes largely
results in increased weight gain (MacLean and
Graham 1980) and body fat (MacLean and Gra-
ham 1980; Jackson 1990); i.e., the nature of the
gain is dependent upon the compositional nature
of intake.
At hospital discharge, all preterm VLBWI
have accrued a significant protein and energy
deficit (Embleton et al. 2001) and are lighter and
shorter and have a reduced lean but greater fat
mass than the reference infant at the same body
weight or gestation (Uthaya et al. 2005). Thereaf-
ter, a diet that is relatively high in energy will
promote “catch-up” that is paralleled by increased
fat deposition. A diet that better meets protein
needs will be paralleled by increased lean mass
accretion.
Energy density is the prime determinant of
volume of intake in infants (Fomon 1993a;
Cooke et al. 1998). Yet at borderline low protein
intakes, volume/energy intake is increased to
compensate and is associated with increased fat
accretion (Fomon 1993b). The energy cost of lean
mass accretion is ~13.4 kcal/g and that of fat
accretion is 10.6 kcal/g (Roberts and Young
1988). At equivalent energy intakes, therefore,
the greater the rate of lean mass accretion, the
lesser the tendency to fat accretion. A little more
rather than less protein, therefore, might be con-
sidered appropriate.
The relative roles of genetic, intrauterine, and
environmental factors in the pathogenesis of
8 R.J. Cooke

Postnatal Growth in Study Infants* formula (protein content 1.8 g/100 kcal, discharge
0 6 m) (B), a preterm formula to term and then a
-.5 term formula to 6 m (C), or unfortified breast milk
(D) (Cooke et al. 1998, 1999). The results are
-.1
presented in Fig. 4.
-1.5 “Rapid” growth was not noted in either treat-
-2 * ment group; i.e., Z-scores for weight did not
* * exceed birth percentile. Between discharge and
-2.5
term, “catch-up” growth in weight and length
-3
Weight Z-score occurred in the formula but not the breastfed
-3.5 infants. Thereafter, “catch-up” occurred in all
0 groups and was faster and more complete in
-.5 infants fed the preterm formula. Infants with the
-1 poorest growth were those fed the preterm for-
-1.5 mula between discharge and term and the term
-2
* * * formula thereafter (Fig. 4).
-2.5 * * More complete “catch-up” growth was
-3 * paralleled by an increase in fat-free mass and
-3.5 total fat mass but not % fat mass (Table 5). No
-4 Length Z-score differences were detected in central fat mass
-4.5 between the groups, but leg fat mass was greater
Group Preterm Term Cross-Over Breast in infants fed the preterm formula (Table 6). In
* Cooke et al 16,
effect, “catch-up” growth was paralleled by an
Discharge Term 12 w 6m 12 m increase in linear growth, lean, and fat mass accre-
tion, the latter reflecting increased peripheral not
Fig. 4 Growth between discharge and 12 months in central fat mass accretion.
infants fed a preterm infant formula, a term formula, or a
preterm formula (discharge-term)/term formula (after term,
Collectively, these data:
crossover) or breastfed
(a) Do not support concerns about altered adipos-
ity in preterm infants fed a nutrient-enriched
insulin resistance are unclear, but diet also plays a formula after hospital discharge
key role (Cornier et al. 2008). A high energy, i.e., (b) Indicate that rate and composition of growth
glycemic or fat content, increases insulin needs, are dependent upon the composition of the
fat synthesis, storage, etc. (Bremer et al. 2012). diet
Whether a “normal” infant diet, i.e., that appro- (c) Do not support the recommendation that a
priate for a term infant, is likely to do so in preterm formula be fed to term and
VLBWI with PGF is unclear. What is clear is discontinued thereafter (Aggett et al. 2006)
that growth and nutritional need to be closely
monitored during the first 1–2 m after hospital
discharge, with particular attention paid to ade- Post-discharge Nutritional Support
quacy of protein intake and protein-energy status, in Preterm Infant
i.e., monitoring linear growth and biochemical
measures of status if needed, i.e., blood urea nitro- Overview
gen, prealbumin, and albumin levels.
To more closely examine this issue, body size Before hospital discharge, it is important that
and composition were measured in preterm the method of feeding and growth patterns are
infants fed either a preterm formula (protein con- well established. Nutritional status of each
tent = 2.7 g/100 kcal, discharge 6 m) (A), a term infant should be closely evaluated, with the
 Post-discharge Nutrition in Preterm Infants 9

Table 5 Body composition of preterm infants fed either preterm formula, term formula, preterm formula (to term)/term
formula (after term, crossover), or breastfed (Cooke et al. 1999)
Term 12 weeks 6 months 12 months
Group (n = 148) (n = 141) (n = 145) (n = 138)
Fat-free Preterm 2,745  445 4,270  452 5,208  638 6,872  806 A>
mass (g) (A)
Term (B) 2,393  276 4,022  411 5,139  515 6,592  738 B
( p < 0.05)
Crossover 2,507  244 3,948  431 4,978  541 6,399  881 C
(C) ( p < 0.001)
Breastfed 2,171  296 3,762  1,051 5,063  568 6,451  746 D
(D) ( p < 0.005)
Fat mass (g) Preterm 570  256 1,455  461 2,033  686 2,332  679 A>
(A)
Term (B) 511  222 1,367  419 1,940  586 2,058  477 B
( p < 0.05)
Crossover 566  204 1,188  366 1,815  632 2,077  623 C
(C) ( p < 0.005)
Breastfed 331  128 1,365  527 1,934  658 2,153  645
(D)
Fat mass % Preterm 17  5.5 25  4.7 28  5.9 25  5.3
(A)
Term (B) 17  6.0 25  5.5 27  5.1 24  4.4
Crossover 18  4.7 23  4.1 26  5.8 24  4.5
(C)
Breastfed 13  3.2 25  8.2 27  6.8 25  4.8
(D)

Table 6 Regional body composition of preterm infants fed either preterm formula, term formula, preterm formula
(to term)/term formula (after term, crossover), or breastfed
G Group Term 12 weeks 6 months 12 months
Trunk Preterm (A) 172  65 532  168 651  218 699  249
Term (B) 182  71 485  154 635  170 613  160
Crossover (C) 186  67 394  136 579  221 573  162
Breastfed (D) 147  54 503  183 688  229 657  230
Legs Preterm (A) 159  58 500  155 736  270 975  354 A>
Term (B) 133  73 451  168 652  300 830  271 B ( p < 0.01)
Crossover (C) 129  75 458  133 602  247 822  409 C ( p < 0.001)
Breastfed (D) 98  58 454  183 654  289 897  254 D ( p < 0.10)

information communicated to the primary care
physician and arrangements for follow-up
clearly defined.
Intake after discharge must not only meet
needs for maintenance and normal growth but
also “catch-up” growth. It is assumed that needs
for normal growth are similar in preterm boys and
girls. Yet, preterm boys grow faster in utero and
accrete more lean mass than girls during the first
2–3 m of life (Rawlings et al. 1999). They are also
more susceptible to even marginal levels of intake
and benefit more when fed nutrient-enriched for-
mulas before (Lucas et al. 1989a, 1990, 1994;
Morley and Lucas 1997) and after hospital dis-
charge (Cooke et al. 1999; Lucas et al. 2001; Car-
ver et al. 2001; Agosti et al. 2003).
It is also assumed that needs for “recovery” are
similar for all preterm infants. This is not the case.
10
Up to 40 % of infants prematurely are small for
gestational age (SGA) at birth. Needs are likely to
differ between the AGA and SGA infants. At the
same time, the severity of PGF not only varies
widely between infants discharged from a given
NICU (Embleton et al. 2001); i.e., the smaller and
more immature the infant, the greater the accrued
nutrient deficit, but also between NICUs (Olsen
et al. 2002; Cooke et al. 2004; Griffin et al. 2016;
Horbar et al. 2015). In effect, needs for “recovery”
are also highly variable.
Collectively, these data emphasize the
importance of individualized assessment before
discharge and, irrespective of what an infant is
fed, close nutritional monitoring after dis-
charge. Not surprisingly, many questions
remain unanswered. How often should growth
be monitored?
In the follow-up study of Dharmaraj
et al. (2005), growth velocity was greatest
between discharge and term, continuing to
1–2 mca, a time frame within which brain growth
velocity is also greatest and likely to be function-
ally significant (Fig. 3). Growth monitoring dur-
ing this time frame should be done at least weekly,
if not more often in high-risk infants; i.e., the
greater the degree of PGF, the greater the level
of concern, until an acceptable growth pattern is
achieved and maintained.
In the study of Cooke et al. (1998), significant
growth faltering was noted:
(a) In breastfed but not formula-fed infants
between discharge and term (Fig. 4)
(b) When a dietary change was made, i.e., infants
fed a preterm formula between discharge and
term and then the term formula thereafter
(Fig. 4)
More frequent growth monitoring would also
appear prudent under these circumstances.
Which growth parameters should be monitored
and evaluated? Accurate measurement of body
weight and head circumference, with subsequent
conversion to Z-scores, is necessary to determine
whether or not an infant is “tracking” toward
original birth-weight centile. Accurate measure-
ment of body length, while difficult and time-
R.J. Cooke
consuming, is also important to ensure that the
composition of growth is also appropriate
(Singhal et al. 2003).
Studies
Formula Feeding
Growth
Many studies have examined post-discharge
growth in preterm infants (Kitchen et al. 1992a, b;
Ernst et al. 1990; Casey et al. 1990; Fitzhardinge
and Inwood 1989; Fenton et al. 1990; Ross
et al. 1990). Although some “catch-up” growth
has been observed, preterm infants do not grow as
well as their term counterparts and are smaller at
3 years (Casey et al. 1991), 8 years (Hack
et al. 1993), and adulthood (Hack et al. 2003).
There are several possible reasons for this.
Current in-hospital feeding practices ensure
that most, if not all, VLBWI are undernourished
and growth retarded at initial hospital discharge
(Embleton et al. 2001; Cooke et al. 2004). A
“critical epoch” of growth may, therefore, have
been missed. Preterm infants also have greater
morbidity than term infants during the first year
of life (McCormick et al. 1980; Hack et al. 1983;
Navas et al. 1992; Thomas et al. 2000; Wang
et al. 1995a), and intercurrent illness will affect
growth, irrespective of whether infants are admit-
ted to hospital or not.
Until relatively recently, little attention had
been paid to nutritional factors in the pathogen-
esis of this problem. For most early studies,
infants were fed either unfortified human milk
or a term infant formula after hospital discharge
(Kitchen et al. 1992a, b; Ernst et al. 1990; Casey
et al. 1990; Fitzhardinge and Inwood 1989;
Fenton et al. 1990; Ross et al. 1990). Both feed-
ing regimens were designed to meet nutritional
needs of the term rather than the rapidly growing
preterm infant. Infants, therefore, may have been
partly underfed during the first 6–12 months
of life.
More recently, studies have examined the
effects of feeding nutrient-enriched formulas,i.e.,
formulas with a greater nutrient density than a
Post-discharge Nutrition in Preterm Infants
Weight Gain in Study Infants*
55
Weight Gain (g/d)
50
45
40
35
30
25
20
15
Preterm ( ) > Term ( ),
10 Cross-Over (x) (p <.001)
5 (e) outcomes evaluated.
Disc - 38w - Term - 4w - 8w - 12w - 4m - 5m - 6m
* Cooke et al 16,
Fig. 5 Growth velocity in study infants fed either a pre-
term infant formula (closed circle), a term formula (open
circle) or a preterm infant formula (discharge-term), or
term infant formula (X)
term infant formula, to preterm infants after hos-
pital discharge (Cooke et al. 1998, 1999, 2001;
Lucas et al. 1992, 2001; Carver et al. 2001; Agosti
et al. 2003; Bishop et al. 1993; Chan et al. 1994;
Wheeler and Hall 1996; Lapillonne et al. 2004;
Koo and Hockman 2006; De Curtis et al. 2002). In
this respect, two meta-analyses are relevant.
Reviewing the results of studies published before
2005 Henderson et al. concluded that feeding with
nutrient-enriched formulas had little effect on
growth (Henderson et al. 2005). As such, their
conclusions on growth merit examination.
The first outcome variable evaluated was
“growth during the trial period.” The results of
one study were used, i.e., de Curtis et al. (2002)
wherein the sample size was 33 and the end point
was gain in weight and crown-heel length and
head circumference between 36 wca and 2 mca.
Furthermore, growth velocity changes rapidly
during this time frame (Fig. 5) and that which is
averaged over a 12-week period may not reflect
early but significant differences between the treat-
ment groups (Cooke et al. 1998).
The second end point was “longer-term
growth,” i.e., weight, length, and head circumfer-
ence at 6 m, 9 m, and 18 m corrected age. Data
from only one study was used at 6 mca
(Litmanovitz et al. 2004) and one at 9 mca
(Lucas et al. 2001), again not entirely
11
representative. The conclusions drawn by Hen-
derson et al. on growth, therefore, must be
questioned.
The more recent and more comprehensive
meta-analysis of Teller et al. is very informative
(Teller et al. 2016). Thirty-one eligible studies
were identified which were noted to differ signif-
icantly in study design, i.e., (a) inclusion criteria,
(b) point of enrolment, (c) nutrient content of
formula fed, (d) duration of intervention, and
In the main, no consistent differences were
detected in body weight, length, or head circum-
ference between treatment groups. What was
noted was a consistent dose-response effect, i.e.,
protein-energy ratios of 2.5–3.0 g/100 ml were
associated with increased linear growth as well as
increased weight and head circumference noted at
3, 6, 9, and 12 mca (Teller et al. 2016).
Where body composition was measured using
dual-emission x-ray absorptiometry (DEXA),
increased linear growth was associated with
increased lean mass accretion, which was
paralleled by a reduced or increased fat mass but
not increased adiposity (Cooke et al. 1999;
Lapillonne et al. 2004; Roggero et al. 2012). An
exception to these observations was the study of
Koo et al. where reduced weight gain and linear
growth were associated with reduced lean and fat
mass accretion (Koo and Hockman 2006).
Development
In the meta-analyses of Henderson et al. (2005)
and of Teller et al. (2016), no consistent effects
were detected on neurodevelopment. This is not
entirely surprising. In the meta-analysis of Teller
et al., it was only in infants who were fed the
formula with the highest protein content
(2.5–3.0 g/100 ml) that consistent effects were
noted on growth, an effect that was more pro-
nounced in boys than girls. Yet, these studies
were not “powered” to control for the
confounding effect of sex on head growth and
development.
In the study of Lucas et al. (1989a, 1990), sex
was a confounding variable but sample size
(n = 219) was large enough, therefore adequately
“powered,” to detect differences in development
12
between treatment groups. Such was not the case
for the studies of Agosti et al. (2003) (n = 121)
and Jeon et al. (2011) (n = 90) and Cooke
et al. (2001) (n = 113) where sample sizes are
much smaller. In the latter study, boys fed the
term formula had the poorest head growth,
which in turn was paralleled by ten-point reduc-
tion in MDI when compared to girls fed the term
formula, suggesting that boys are at a disadvan-
tage when fed a term infant formula.
An additional consideration is as follows.
Brain growth is rapid during the last trimester
and first 2 years of life, a time when even minor
insults may have significant effects (Dobbing
1981). But not all parts of the brain are developing
at the same rate, therefore not equally vulnerable
(Dobbing 1981). In effect global measures of
function, such as Bayley’s assessment, may not
be sensitive enough to detect minor or focal dif-
ferences in developmental outcome (Singer
et al. 1994).
Dabydeen et al. prospectively randomized
term and preterm infants with perinatal brain
injury to either a control or high-energy and
high-protein diet after perinatal brain injury dur-
ing the first year of life (Dabydeen et al. 2008).
Infants fed the high-energy and high-protein diet
had a greater head growth and axonal diameters
when compared to the control group. It was con-
cluded that infants with significant perinatal brain
injury had increased nutritional requirements and
that inadequate intake, as is commonly noted in
neurologically impaired infants, may compromise
subsequent brain growth and development
(Dabydeen et al. 2008).
Collectively, these studies (Lucas et al. 2001;
Agosti et al. 2003; Cooke et al. 2001; Dabydeen
et al. 2008) suggest that the feeding with a formula
with a protein-energy ratio of 2.5–3.0 g/100 ml
is associated with better head growth and trends
toward better post-developmental outcome. In the
case of the otherwise “normal” preterm infant,
male infants are most likely to benefit. In infants
with perinatal brain injury, both term and preterm
infants may benefit. Further more appropriately
“powered” studies are needed to address these
issues.
R.J. Cooke
Breastfeeding
Human milk has been recommended as the pre-
ferred method of feeding for preterm infants after
hospital discharge (Canada 2004; AAPCON
2009; Agostoni et al. 2009; Lapillonne
et al. 2013). In a nutritional sense this, at first
glance, is puzzling. Before hospital discharge,
preterm infants fed human milk do not grow as
well as infants fed nutrient-enriched formulas
(Tyson et al. 1983; Gross 1983). It is, therefore,
recommended that human milk be fortified with
additional nutrients (Klein 2002). Growth
improves but it is still not as good as in infants
fed a preterm infant formula (Carlson and Ziegler
1998). The reasons for this are not entirely clear.
Fortifiers differ in nutrient composition and it
is unclear which, if any, really meets require-
ments. The composition of human milk varies
widely (Atkinson et al. 1995), and because it is
not consistently measured, there is no way of
knowing what the infant is really receiving. In
effect, intake less adequately meets requirements
and growth is poorer. Nonetheless, because of
lower rates of morbidity, e.g., sepsis and necrotiz-
ing enterocolitis (Schanler et al. 1999), and
improved developmental outcome (Morley
et al. 1988a), it is recommended that fortified
human milk be fed whenever possible before hos-
pital discharge (Klein 2002).
After hospital discharge, breastfed infants also
grow more poorly than those fed nutrient-
enriched formulas (Lucas et al. 2001; Chan
et al. 1994; Wauben et al. 1998). This again is
not surprising. Before discharge, intake less ade-
quately meets requirements, the accrued nutri-
tional deficit, and, therefore, needs for
“recovery” are greater. Mature human milk is
designed to meet the needs of the term infant
and not the preterm infant, and there are signifi-
cant differences in nutrient content between
mature human milk and formulas used to feed
infants before and after discharge (Table 7).
Poorer growth after discharge is paralleled by
alterations in bone mineral metabolism and body
composition. Bone mineral accretion is less in
infants fed un-supplemented human milk after
discharge (Lucas et al. 2001; Chan et al. 1994;
Post-discharge Nutrition in Preterm Infants
Table 7 A comparison of nutrient content of human milk with preterm, nutrient-enriched, and term infant formulas
Per liter Human milk
Energy kcal 670
Protein g 10
Fat g 35
Carbohydrate g 70
Calcium mg 260
Phosphorus mg 140
Sodium mmol 9 15
Chloride mmol 16
Zinc mg 3.2
Vitamin A mg 0.7
Wauben et al. 1998; Kurl et al. 2003; Schanler
et al. 1992). This, in turn, can be related to out-
come on a short-term, e.g., osteopenia (Lucas
et al. 1989b) and fractures (Koo et al. 1988), and
long-term, e.g., poorer linear growth (Fewtrell
et al. 2000), basis. Interestingly, infants fed
human milk also have increased fat accretion
when compared to those fed a nutrient-enriched
formula (Wauben et al. 1998).
Thus, infants grow as they are fed. When min-
eral intake is inadequate, bone mineral accretion is
decreased. Whether the latter in some way alters
“programming” and, therefore, health in adult life
is unclear. What is clear is that the assessment of
bone mineral status, i.e., serum phosphorus and
alkaline phosphatase, is also an important consid-
eration during this critical time frame (Schanler
2005).
Several studies have examined the effect of
nutrient fortification of human milk after hospital
discharge. In a randomized controlled pilot trial,
preterm infants (750–1,800 g) were fed unfortified
(n = 20) or fortified (n = 19) human milk after
hospital discharge-12 week (O’Connor
et al. 2008). A multi-nutrient fortifier, estimated
to ensure an energy and protein density of 80 kcal
and 2.2 g/100 ml, was added to 50 % of feeds.
Weight tended to be greater (all infants), while
length (all infants) and head circumference,
infants 1,250 g only, were greater in the fortified
group. In a follow-up of the same infants, weight,
linear growth, bone mineral content, and head
growth (infants <1,250 g only) but not Bayley’s
13
Preterm Post-discharge Term
810 730 67
23 20 14
42 40 36
88 78 73
1,400 850 530
700 480 330
11 8
19 17 12
12.1 9 6
3 1 0.6
II developmental scores were greater in infants fed
fortified human milk (Aimone et al. 2009).
In a larger more recent randomized controlled
trial between hospital discharge and 4 m corrected
age, Zacharisson et al. fed preterm VLBWI
(24–32 weeks; 535–2,255 g) either unfortified
(n = 102; group A) or fortified (n = 105; group
B) human milk and compared their growth to a
group of infants fed a preterm formula (n = 113;
group C, preterm formula) (Zachariassen
et al. 2011). No differences were detected in
growth between groups A and B at 12 mca, and
it was concluded that while fortification did not
affect the durations of breastfeeding, it also did
not influence growth at 1 year of age.
Yet, important and consistent differences were
noted in breastfed and the formula-fed infants.
Infants in C had a greater increase in weight
Z-score between discharge and term and in length
Z-score until 6 months CA. At 12 mca, boys in C
were longer and heavier than in groups A and B,
while girls in group C were longer and heavier
than in group A only. Greater protein intakes in C
were also related to increased serum urea nitrogen
levels.
The results of this much larger scale study are
puzzling in that no significant differences were
detected in growth between infants fed unfortified
and fortified milk. One possibility relates to the
small sample size in the original study (O’Connor
et al. 2008), n ~ 20/treatment group; i.e., the
results are not generalizable. Alternatively, the
level of fortification used in the latter study may
have been inadequate to consistently improve
14
growth in such a heterogeneous population. It is
notable that the timing of introduction of comple-
mentary foods was later with nutrient enrichment,
perhaps suggesting that energy needs were more
adequately met and infants satiated longer.
The results of these studies raise more ques-
tions than answers:
(a) Should all preterm VLBWI be fortified human
milk after hospital discharge? Since all
VLBWI accrue a significant nutrient deficit
between birth and hospital discharge and
mature human milk is designed for the needs
of “normal” infants, i.e., needs for mainte-
nance and normal growth, it seems prudent
to fortify in all breastfed infants after
discharge.
(b) What is the best way to fortify human milk?
The nutritional content of fortifiers differs. Is
one better than another? Further studies are
needed to examine this issue. In the mean-
time, the level of fortification should be
adjusted to ensure that growth, in terms of
weight and length gain, is “tracking” in the
right direction (Arslanoglu et al. 2006; Cooke
2006).
(c) How long should fortification be continued?
There are no data in this area. Data in formula-
fed infants indicate that discontinuation of
preterm formula and then feeding a term for-
mula at term is paralleled by a rapid deceler-
ation in growth that is not entirely recovered
by 6 or 12 m corrected age (Fig. 4; Cooke
et al. 1998). At least, 1–2 mca, therefore,
seems advisable since this is also the period
of greatest brain growth velocity and appears
to be functionally significant (Dharmaraj
et al. 2005).
Summary
Many questions remain unanswered about what to
feed preterm, particularly VLBWI, infants after
hospital discharge but several things are clear:
1. Nutritional status of all infants should be
closely evaluated before discharge and the
R.J. Cooke
information relayed to the primary care physi-
cian. Infants with the greatest degree of growth
failure at discharge are at greatest risk for fur-
ther “growth faltering.”
2. Irrespective of what is fed, growth should be
closely monitored and intake adjusted with the
goal that birth centile, at least for weight, is
reestablished between discharge and 1–2 mca.
3. Continuing and close communication between
designated personnel in the neonatal intensive
care unit and the infant’s family as well as the
primary care providers is essential during this
critical “epoch” of growth and development.
References
AAPCON (1998) Nutritional needs of preterm infants. In:
Kleinman RE (ed) Pediatric nutrition handbook. Amer-
ican Academy of Pediatrics, Elk Grove Village, pp
55–88
AAPCON (2009) Nutritional needs of the preterm infant.
In: Kleinman RE (ed) Pediatric nutrition handbook, 6th
edn. American Academy of Pediatrics, Elk Grove Vil-
lage, pp 79–104
Aggett PJ, Agostoni C, Axelsson I et al (2006) Feeding
preterm infants after hospital discharge: a commentary
by the ESPGHAN committee on nutrition. J Pediatr
Gastroenterol Nutr 42:596–603
Agosti M, Vegni C, Calciolari G, Marini A (2003) Post-
discharge nutrition of the very low-birthweight infant:
interim results of the multicentric GAMMA study. Acta
Paediatr Suppl 91:39–43
Agostoni C, Braegger C, Decsi T et al (2009) Breast-
feeding: a commentary by the ESPGHAN committee
on nutrition. J Pediatr Gastroenterol Nutr 49:112–125
Aimone A, Rovet J, Ward W et al (2009) Growth and body
composition of human milk-fed premature infants pro-
vided with extra energy and nutrients early after hospi-
tal discharge: 1-year follow-up. J Pediatr Gastroenterol
Nutr 49:456–466
Alexander GR, Himes JH, Kaufman RB, Mor J, Kogan M
(1996) A United States national reference for fetal
growth. Obstet Gynecol 87:163–168
Arslanoglu S, Moro GE, Ziegler EE (2006) Adjustable
fortification of human milk fed to preterm infants:
does it make a difference? J Perinatol 26:614–621
Ashworth A, Millward DJ (1986) Catch-up growth in
children. Nutr Rev 44:157–163
Atkinson SA, Alston-Mills B, Lonnerdal B, Neville MC
(1995) Major minerals and ionic constituents of human
and bovine milks. In: Jensen RG (ed) Handbook of
milk composition. Academic, San Diego, pp 593–622
Bedi KS (1987) Lasting neuroanatomical changes follow-
ing undernutrition during early life. In: Dobbing J
Post-discharge Nutrition in Preterm Infants
(ed) Early nutrition and later achievement. Academic,
London, pp 1–49
Benitez-Bribiesca L, De la Rosa-Alvarez I, Mansilla-
Olivares A (1999) Dendritic spine pathology in infants
with severe protein-calorie malnutrition. Pediatrics
104:e21
Bishop NJ, King FJ, Lucas A (1993) Increased bone min-
eral content of preterm infants fed with a nutrient
enriched formula after discharge from hospital. Arch
Dis Child 68:573–578
Bremer AA, Mietus-Snyder M, Lustig RH (2012) Toward
a unifying hypothesis of metabolic syndrome. Pediat-
rics 129:557–570
Carlson SJ, Ziegler EE (1998) Nutrient intakes and growth
of very low birth weight infants. Perinatology
18:252–258
Carver JD, Wu PY, Hall RT et al (2001) Growth of preterm
infants fed nutrient-enriched or term formula after hos-
pital discharge. Pediatrics 107:683–689
Casey PH, Kraemer HC, Bernbaum J et al (1990) Growth
patterns of low birth weight preterm infants: a longitu-
dinal analysis of a large, varied sample. J Pediatr
117:298–307
Casey PH, Kraemer HC, Bernbaum J, Yogman MW, Sells
JC (1991) Growth status and growth rates of a varied
sample of low birth weight, preterm infants: a longitu-
dinal cohort from birth to three years of age. J Pediatr
119:599–605
Chan GM, Borschel MW, Jacobs JR (1994) Effects of
human milk or formula feeding on the growth, behav-
ior, and protein status of preterm infants discharged
from the newborn intensive care unit. Am J Clin Nutr
60:710–716
Clark RH, Thomas P, Peabody J (2003) Extrauterine
growth restriction remains a serious problem in prema-
turely born neonates. Pediatrics 111:986–990
Cooke RJ (2006) Adjustable fortification of human milk
fed to preterm infants. J Perinatol 26:591–592
Cooke RW, Foulder-Hughes L (2003) Growth impairment
in the very preterm and cognitive and motor perfor-
mance at 7 years. Arch Dis Child 88:482–487
Cooke RJ, Griffin I (2009) Altered body composition in
preterm infants at hospital discharge. Acta Paediatr
98:1269–1273
Cooke RJ, Griffin IJ, McCormick K et al (1998) Feeding
preterm infants after hospital discharge: effect of die-
tary manipulation on nutrient intake and growth.
Pediatr Res 43:355–360
Cooke RJ, McCormick K, Griffin IJ et al (1999) Feeding
preterm infants after hospital discharge: effect of diet
on body composition. Pediatr Res 46:461–464
Cooke RJ, Embleton ND, Griffin IJ, Wells JC, McCormick
KP (2001) Feeding preterm infants after hospital dis-
charge: growth and development at 18 months of age.
Pediatr Res 49:719–722
Cooke RJ, Ainsworth SB, Fenton AC (2004) Postnatal
growth retardation: a universal problem in preterm
infants. Arch Dis Child Fetal Neonatal Ed 89:
F428–F430
15
Cordero ME, D’Acuna E, Benveniste S, Prado R, Nunez
JA, Colombo M (1993) Dendritic development in neo-
cortex of infants with early postnatal life undernutri-
tion. Pediatr Neurol 9:457–464
Cornier MA, Dabelea D, Hernandez TL et al (2008) The
metabolic syndrome. Endocr Rev 29:777–822
Dabydeen L, Thomas JE, Aston TJ, Hartley H, Sinha SK,
Eyre JA (2008) High-energy and -protein diet increases
brain and corticospinal tract growth in term and preterm
infants after perinatal brain injury. Pediatrics
121:148–156
De Curtis M, Pieltain C, Rigo J (2002) Body composition
in preterm infants fed standard term or enriched for-
mula after hospital discharge. Eur J Nutr 41:177–182
Dharmaraj ST, Henderson M, Embleton ND, Fenton AC,
Cooke RJ (2005) Postnatal growth retardation, catch-
up growth and developmental outcome in preterm
infants. Arch Dis Child 90:11A
Dinerstein A, Nieto RM, Solana CL, Perez GP, Otheguy
LE, Larguia AM (2006) Early and aggressive nutri-
tional strategy (parenteral and enteral) decreases post-
natal growth failure in very low birth weight infants. J
Perinatol 26:436–442
Dobbing J (1981) The later development of the brain and
its vulnerability. In: Davis JA, Dobbing J (eds) Scien-
tific foundations of pediatrics. University Park Press,
Baltimore, pp 744–758
Dobbing J (1987) Early nutrition and later achievement.
Academic, London
Dobbing J, Sands J (1971) Vulnerability of developing
brain. IX. The effect of nutritional growth retardation
on the timing of the brain growth-spurt. Biol Neonate
19:363–378
Dobbing J, Hopewell JW, Lynch A (1971) Vulnerability of
developing brain. VII. Permanent deficit of neurons in
cerebral and cerebellar cortex following early mild
undernutrition. Exp Neurol 32:439–447
Donovan R, Puppala B, Angst D, Coyle BW (2006) Out-
comes of early nutrition support in extremely low-
birth-weight infants. Nutr Clin Pract 21:395–400
Ehrenkranz RA, Younes N, Lemons JA et al (1999) Lon-
gitudinal growth of hospitalized very low birth weight
infants. Pediatrics 104:280–289
Ehrenkranz RA, Dusick AM, Vohr BR, Wright LL, Wrage
LA, Poole WK (2006) Growth in the neonatal intensive
care unit influences neurodevelopmental and growth
outcomes of extremely low birth weight infants. Pedi-
atrics 117:1253–1261
Embleton NE, Pang N, Cooke RJ (2001) Postnatal malnu-
trition and growth retardation: an inevitable conse-
quence of current recommendations in preterm
infants? Pediatrics 107:270–273
Ernst JA, Bull MJ, Rickard KA, Brady MS, Lemons JA
(1990) Growth outcome and feeding practices of the
very low birth weight infant (less than 1500 grams)
within the first year of life. J Pediatr 117:S156–S166
Evans RA, Thureen P (2001) Early feeding strategies in
preterm and critically ill neonates. Neonatal Netw
20:7–18
16
Fenton TR, McMillan DD, Sauve RS (1990) Nutrition and
growth analysis of very low birth weight infants. Pedi-
atrics 86:378–383
Fewtrell PA, Cole TJ, Lucas A (2000) Effects of growth
during infancy and childhood on bone mineralization
and turnover in preterm children aged 8–12 years. Acta
Paediatr 89:148–153
Fitzhardinge PM, Inwood S (1989) Long-term growth in
small-for-date children. Acta Paediatr Scand – Suppl
349:27–33, discussion 4
Fomon S (1993a) Energy. In: Fomon SJ, Bell EF (eds)
Nutrition of normal infants, 2nd edn. Mosby, St
Louis, pp 103–120
Fomon S (1993b) Protein. In: Fomon SJ (ed) Nutrition
of normal infants, 2nd edn. Mosby, St Louis, pp
121–139
Galler J, Shumsky J, Morgane PJ (1996) Malnutrition and
brain development. In: Walker AW, Watkins J (eds)
Paediatric nutrition. Decker, New York, pp 196–212
Greisen G (1992) Estimation of fetal weight by ultrasound.
Horm Res 38:208–210
Griffin IJ, Tancredi DJ, Bertino E, Lee HC, Profit J (2016)
Postnatal growth failure in very low birthweight infants
born between 2005 and 2012. Arch Dis Child Fetal
Neonatal Ed 101:50–55
Gross SJ (1983) Growth and biochemical response of
preterm infants fed human milk or modified infant
formula. N Engl J Med 308:237–241
Gross SJ, Oehler JM, Eckerman CO (1983) Head growth
and developmental outcome in very low-birth-weight
infants. Pediatrics 71:70–75
Hack M, Breslau N (1986) Very low birth weight infants:
effects of brain growth during infancy on intelligence
quotient at 3 years of age. Pediatrics 77:196–202
Hack M, Fanaroff AA (1984) The outcome of growth
failure associated with preterm birth. Clin Obstet
Gynecol 27:647–663
Hack M, Merkatz IR, Gordon D, Jones PK, Fanaroff AA
(1982) The prognostic significance of postnatal growth
in very low – birth weight infants. Am J Obstet Gynecol
143:693–699
Hack M, Caron B, Rivers A, Fanaroff AA (1983) The very
low birth weight infant: the broader spectrum of mor-
bidity during infancy and early childhood. J Dev Behav
Pediatr 4:243–249
Hack M, Breslau N, Weissman B, Aram D, Klein N,
Borawski E (1991) Effect of very low birth weight
and subnormal head size on cognitive abilities at school
age [see comments]. N Engl J Med 325:231–237
Hack M, Weissman B, Breslau N, Klein N, Borawski-
Clark E, Fanaroff AA (1993) Health of very low birth
weight children during their first eight years. J Pediatr
122:887–892
Hack M, Schluchter M, Cartar L, Rahman M, Cuttler L,
Borawski E (2003) Growth of very low birth weight
infants to age 20 years. Pediatrics 112:e30–e38
Health Canada (2004) Breast feeding duration
recommendations
R.J. Cooke
Heird WC (2001) Determination of nutritional require-
ments in preterm infants, with special reference to
‘catch-up’ growth. Semin Neonatol 6:365–375
Henderson G, Fahey T, McGuire W (2005) Calorie and
protein-enriched formula versus standard term for-
mula for improving growth and development in
preterm or low birth weight infants following hos-
pital discharge. Cochrane Database Syst Rev
CD004696
Hermanussen M (2013a) Basics. Rapid growth. In:
Hermanussen M (ed) Auxology studying human
growth and development. Schweizerbart’sche,
Stuttgaart, pp 18–19
Hermanussen M (2013b) Basics. In: Hermanussen M
(ed) Auxology studying human growth and develop-
ment. Schweizerbart’sche, Stuttgart
Horbar JD, Ehrenkranz RA, Badger GJ et al (2015) Weight
growth velocity and postnatal growth failure in infants
501 to 1500 grams: 2000–2013. Pediatrics 136:
e84–e92
Ibrahim HM, Jeroudi MA, Baier RJ, Dhanireddy R,
Krouskop RW (2004) Aggressive early total parental
nutrition in low-birth-weight infants. J Perinatol
24:482–486
Jackson AA (1990) Protein requirements for catch-up
growth. Proc Nutr Soc 49:507–516
Jeon GW, Jung YJ, Koh SY et al (2011) Preterm infants fed
nutrient-enriched formula until 6 months show
improved growth and development. Pediatr Int: Off J
Jpn Pediatr Soc 53:683–688
Kitchen WH, Doyle LW, Ford GW, Callanan C, Rickards
AL, Kelly E (1992a) Very low birth weight and growth
to age 8 years. II: head dimensions and intelligence.
Am J Dis Child 146:46–50
Kitchen WH, Doyle LW, Ford GW, Callanan C (1992b)
Very low birth weight and growth to age 8 years. I:
weight and height. Am J Dis Child 146:40–45
Klein CJ (2002) Nutrient requirements for preterm infant
formulas. J Nutr 132:1395S–1577S
Koo WW, Hockman EM (2006) Posthospital discharge
feeding for preterm infants: effects of standard com-
pared with enriched milk formula on growth, bone
mass, and body composition. Am J Clin Nutr
84:1357–1364
Koo WW, Sherman R, Succop P et al (1988) Sequential
bone mineral content in small preterm infants with and
without fractures and rickets. J Bone Miner Res
3:193–197
Krigman MR, Hogan EL (1976) Undernutrition in the
developing rat: effect upon myelination. Brain Res
107:239–255
Kurl S, Heinonen K, Lansimies E (2003) Pre- and post-
discharge feeding of very preterm infants: impact on
growth and bone mineralization. Clin Physiol Funct
Imaging 23:182–189
Lapillonne A, Salle BL, Glorieux FH, Claris O (2004)
Bone mineralization and growth are enhanced in pre-
term infants fed an isocaloric, nutrient-enriched
Post-discharge Nutrition in Preterm Infants
preterm formula through term. Am J Clin Nutr
80:1595–1603
Lapillonne A, O’Connor DL, Wang D, Rigo J (2013)
Nutritional recommendations for the late-preterm
infant and the preterm infant after hospital discharge.
J Pediatr 162:S90–S100
Larsen T, Petersen S, Greisen G, Larsen JF (1990) Normal
fetal growth evaluated by longitudinal ultrasound
examinations. Early Hum Dev 24:37–45
Latal-Hajnal B, von Siebenthal K, Kovari H, Bucher HU,
Largo RH (2003) Postnatal growth in VLBW infants:
significant association with neurodevelopmental out-
come. J Pediatr 143:163–170
Litmanovitz I, Dolfin T, Arnon S et al (2004) Bone strength
and growth of preterm infants fed nutrient-enriched or
term formula after hospital discharge. Pediatr Res
55:274A
Lowry S, Perez JM (2006) The hypercatabolic state. In:
Shils M, Shike M, Ross CA, Caballero B, Cousins R
(eds) Modern nutrition in health and disease, 10th edn.
Lippincott, Williams & Wilkins, Philadelphia, pp
1381–1400
Lucas A, Morley R, Cole TJ et al (1989a) Early diet in
preterm babies and developmental status in infancy
[see comments]. Arch Dis Child 64:1570–1578
Lucas A, Brooke OG, Baker BA, Bishop N, Morley R
(1989b) High alkaline phosphatase activity and growth
in preterm neonates. Arch Dis Child 64:902–909
Lucas A, Morley R, Cole TJ et al (1990) Early diet in
preterm babies and developmental status at 18 months.
Lancet 335:1477–1481
Lucas A, Bishop NJ, King FJ, Cole TJ (1992) Randomised
trial of nutrition for preterm infants after discharge [see
comments]. Arch Dis Child 67:324–327
Lucas A, Morley R, Cole TJ, Gore SM (1994) A
randomised multicentre study of human milk versus
formula and later development in preterm infants.
Arch Dis Child Fetal Neonatal Ed 70:F141–F146
Lucas A, Morley R, Cole TJ (1998) Randomised trial of
early diet in preterm babies and later intelligence quo-
tient. BMJ 317:1481–1487
Lucas A, Fewtrell MS, Morley R et al (2001) Randomized
trial of nutrient-enriched formula versus standard for-
mula for postdischarge preterm infants. Pediatrics
108:703–711
MacLean WC Jr, Graham GG (1980) The effect of energy
intake on nitrogen content of weight gained by recov-
ering malnourished infants. Am J Clin Nutr
33:903–909
McCance RA, Widdowson EM (1974) The determinants of
growth and form. Proc R Soc Lond B Biol Sci
185:1–17
McCormick MC, Shapiro S, Starfield BH (1980)
Rehospitalization in the first year of life for high-risk
survivors. Pediatrics 66:991–999
Mehta NM, Corkins MR, Lyman B et al (2013) Defining
pediatric malnutrition: a paradigm shift toward
etiology-related definitions. JPEN J Parenter Enteral
Nutr 37:460–481
17
Morley R (1999) Early growth and later development. In:
Ziegler EE, Lucas A, Moro GE (eds) Nutrition of the
very low birth weight infant. Lippincott Williams and
Wilkins, Philadelphia, pp 19–32
Morley R, Lucas A (1997) Nutrition and cognitive devel-
opment. Br Med Bull 53:123–134
Morley R, Cole TJ, Powell R, Lucas A (1988) Mother’s
choice to provide breast milk and developmental out-
come. Arch Dis Child 63:1382–1385
Myers RE, Hill DE, Holt AB, Scott RE, Mellits ED, Cheek
DB (1971) Fetal growth retardation produced by exper-
imental placental insufficiency in the rhesus monkey.
I. Body weight, organ size. Biol Neonate 18:379–394
Navas L, Wang E, de Carvalho V, Robinson J, PICNIC
(1992) Improved outcome of respiratory syncytial virus
infection in a high-risk hospitalized population of
Canadian children. J Pediatr 121:348–354
O’Connor DL, Khan S, Weishuhn K et al (2008) Growth
and nutrient intakes of human milk-fed preterm infants
provided with extra energy and nutrients after hospital
discharge. Pediatrics 121:766–776
Olsen IE, Richardson DK, Schmid CH, Ausman LM,
Dwyer JT (2002) Intersite differences in weight growth
velocity of extremely premature infants. Pediatrics
110:1125–1132
Ong KK, Loos RJ (2006) Rapid infancy weight gain and
subsequent obesity: systematic reviews and hopeful
suggestions. Acta Paediatr 95:904–908
Ounsted M, Moar VA, Scott A (1988) Head circumference
and developmental ability at the age of seven years.
Acta Paediatr Scand 77:374–379
Peterson J, Taylor HG, Minich N, Klein N, Hack M (2006)
Subnormal head circumference in very low birth
weight children: neonatal correlates and school-age
consequences. Early Hum Dev 82:325–334
Pryor J, Silva PA, Brooke M (1995) Growth, development
and behaviour in adolescents born small-for-gesta-
tional-age. J Paediatr Child Health 31:403–407
Rawlings DJ, Cooke RJ, McCormick K et al (1999) Body
composition of preterm infants during infancy. Arch
Dis Child Fetal Neonatal Ed 80:F188–F191
Roberts SB, Young VR (1988) Energy costs of fat and
protein deposition in the human infant. Am J Clin
Nutr 48:951–955
Roggero P, Gianni ML, Piemontese P, Amato O, Agosti M,
Mosca F (2012) Effect of nutrition on growth and body
composition in infants born preterm. J Matern Fetal
Neonatal Med 25(Suppl 3):49–52
Ross G, Lipper EG, Auld PA (1990) Growth achievement
of very low birth weight premature children at school
age. J Pediatr 117:307–309
Schanler RJ (2005) Post-discharge nutrition for the preterm
infant. Acta Paediatr Suppl 94:68–73
Schanler RJ, Burns PA, Abrams SA, Garza C (1992) Bone
mineralization outcomes in human milk-fed preterm
infants. Pediatr Res 31:583–586
Schanler RJ, Shulman RJ, Lau C (1999) Feeding strategies
for premature infants: beneficial outcomes of feeding
18
fortified human milk versus preterm formula [com-
ment]. Pediatrics 103:1150–1157
Scott KE, Usher R (1966) Fetal malnutrition: its incidence,
causes, and effects. Am J Obstet Gynecol 94:951–963
Shils ME, Shike M, Ross AC, Caballero B, Cousins RJ
(2006) Modern nutrition in health and disease.
Lippincott Williams and Wilkins, Philadelphia
Singer L, Arendt R, Song LY, Warshawsky E, Kliegman R
(1994) Direct and indirect interactions of cocaine with
childbirth outcomes. Arch Pediatr Adolesc Med
148:959–964
Singhal A, Cole TJ, Lucas A (2001) Early nutrition in
preterm infants and later blood pressure: two cohorts
after randomised trials. Lancet 357:413–419
Singhal A, Fewtrell M, Cole TJ, Lucas A (2003) Low
nutrient intake and early growth for later insulin resis-
tance in adolescents born preterm. Lancet
361:1089–1097
Stathis SL, O’Callaghan M, Harvey J, Rogers Y (1999)
Head circumference in ELBW babies is associated with
learning difficulties and cognition but not ADHD in the
school-aged child. Dev Med Child Neurol 41:375–380
Stoch MB, Smythe PM, Moodie AD, Bradshaw D (1982)
Psychosocial outcome and CT findings after gross
undernourishment during infancy: a 20-year develop-
mental study. Dev Med Child Neurol 24:419–436
Teller IC, Embleton ND, Griffin IJ, van Elburg RM (2016)
Post-discharge formula feeding in preterm infants: a
systematic review mapping evidence about the role of
macronutrient enrichment. Clin Nutr 35(4):791–801
Thomas M, Bedford-Russel A, Sharland M (2000)
Hospitalisation of RSV infection in ex-preterm infants
– implications for RSV immune globulin. Arch Dis
Child 183:122–127
Tyson JE, Lasky RE, Mize CE et al (1983) Growth, met-
abolic response, and development in very-low-birth-
weight infants fed banked human milk or enriched
formula. I. Neonatal findings. J Pediatr 103:95–104
R.J. Cooke
Uthaya S, Thomas EL, Hamilton G, Dore CJ, Bell J, Modi
N (2005) Altered adiposity after extremely preterm
birth. Pediatr Res 57:211–215
Volpe JJ (2008) Neurology of the newborn, 5th edn.
Saunders Elsevier, Philadelphia
Wang E, Law B, Stephens D, PICNIC (1995) Prospective
study of risk factors and outcomes in patients
hospitalised with respiratory syncytial viral lower
respiratory tract infection. J Pediatr 126:212–219
Wauben IP, Atkinson SA, Shah JK, Paes B (1998) Growth
and body composition of preterm infants: influence of
nutrient fortification of mother’s milk in hospital and
breastfeeding post- hospital discharge (in process cita-
tion). Acta Paediatr 87:780–785
Wheeler RE, Hall RT (1996) Feeding of premature infant
formula after hospital discharge of infants weighing
less than 1800 grams at birth. J Perinatol 16:111–116
Widdowson EM, McCance RA (1975) A review: new
thoughts on growth. Pediatr Res 9:154–156
Wilson DC, Cairns P, Halliday HL, Reid M, McClure G,
Dodge JA (1997) Randomised controlled trial of an
aggressive nutritional regimen in sick very low
birthweight infants. Arch Dis Child Fetal Neonatal Ed
77:F4–F11
Winick M, Rosso P (1969a) The effect of severe early
malnutrition on cellular growth of human brain. Pediatr
Res 3:181–184
Winick M, Rosso P (1969b) Head circumference and cel-
lular growth of the brain in normal and marasmic chil-
dren. J Pediatr 74:774–778
Yeung MY (2006) Postnatal growth, neurodevelopment
and altered adiposity after preterm birth – from a clin-
ical nutrition perspective. Acta Paediatr 95:909–917
Zachariassen G, Faerk J, Grytter C et al (2011) Nutrient
enrichment of mother’s milk and growth of very pre-
term infants after hospital discharge. Pediatrics 127:
e995–e1003
Ziegler EE, Thureen PJ, Carlson SJ (2002) Aggressive
nutrition of the very low birthweight infant. Clin
Perinatol 29:225–244
 
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Delayed introduction of progressive enteral feeds to prevent
necrotising enterocolitis in very low birth weight infants (Review)

  Morgan J, Young L, McGuire W  

  Morgan J, Young L, McGuire W.  

Delayed introduction of progressive enteral feeds to prevent necrotising enterocolitis in very low birth weight infants.
Cochrane Database of Systematic Reviews 2014, Issue 12. Art. No.: CD001970.
DOI: 10.1002/14651858.CD001970.pub5.

  www.cochranelibrary.com  

 
Delayed introduction of progressive enteral feeds to prevent necrotising enterocolitis in very low birth weight
infants (Review)
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TABLE OF CONTENTS
HEADER......................................................................................................................................................................................................... 1
ABSTRACT..................................................................................................................................................................................................... 1
PLAIN LANGUAGE SUMMARY....................................................................................................................................................................... 2
BACKGROUND.............................................................................................................................................................................................. 3
OBJECTIVES.................................................................................................................................................................................................. 3
METHODS..................................................................................................................................................................................................... 3
RESULTS........................................................................................................................................................................................................ 5
Figure 1.................................................................................................................................................................................................. 6
Figure 2.................................................................................................................................................................................................. 7
Figure 3.................................................................................................................................................................................................. 7
Figure 4.................................................................................................................................................................................................. 8
Figure 5.................................................................................................................................................................................................. 9
DISCUSSION.................................................................................................................................................................................................. 9
AUTHORS' CONCLUSIONS........................................................................................................................................................................... 10
ACKNOWLEDGEMENTS................................................................................................................................................................................ 10
REFERENCES................................................................................................................................................................................................ 11
CHARACTERISTICS OF STUDIES.................................................................................................................................................................. 14
DATA AND ANALYSES.................................................................................................................................................................................... 22
Analysis 1.1. Comparison 1 Delayed versus early introduction of progressive enteral feeding, Outcome 1 Necrotising 22
enterocolitis...........................................................................................................................................................................................
Analysis 1.2. Comparison 1 Delayed versus early introduction of progressive enteral feeding, Outcome 2 Mortality prior to 23
discharge................................................................................................................................................................................................
Analysis 1.3. Comparison 1 Delayed versus early introduction of progressive enteral feeding, Outcome 3 Feed intolerance........ 24
Analysis 1.4. Comparison 1 Delayed versus early introduction of progressive enteral feeding, Outcome 4 Incidence of invasive 24
infection.................................................................................................................................................................................................
Analysis 1.5. Comparison 1 Delayed versus early introduction of progressive enteral feeding, Outcome 5 Duration of hospital 24
admission (days)...................................................................................................................................................................................
WHAT'S NEW................................................................................................................................................................................................. 24
HISTORY........................................................................................................................................................................................................ 25
CONTRIBUTIONS OF AUTHORS................................................................................................................................................................... 26
DECLARATIONS OF INTEREST..................................................................................................................................................................... 26
SOURCES OF SUPPORT............................................................................................................................................................................... 26
INDEX TERMS............................................................................................................................................................................................... 26

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[Intervention Review]

Delayed introduction of progressive enteral feeds to prevent necrotising

enterocolitis in very low birth weight infants

Jessie Morgan1, Lauren Young2, William McGuire1

1Hull York Medical School & Centre for Reviews and Dissemination, University of York, York, UK. 2Neonatal Unit, Mercy Hospital for
Women, Heidelberg, Australia

Contact address: William McGuire, Hull York Medical School & Centre for Reviews and Dissemination, University of York, York, Y010 5DD,
UK. William.McGuire@hyms.ac.uk.

Editorial group: Cochrane Neonatal Group

Publication status and date: New search for studies and content updated (no change to conclusions), published in Issue 12, 2014.

Citation: Morgan J, Young L, McGuire W. Delayed introduction of progressive enteral feeds to prevent necrotising enterocolitis
in very low birth weight infants. Cochrane Database of Systematic Reviews 2014, Issue 12. Art. No.: CD001970. DOI:
10.1002/14651858.CD001970.pub5.

Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.

ABSTRACT

Background
The introduction of enteral feeds for very preterm (less than 32 weeks' gestation) or very low birth weight (VLBW; less than 1500 g) infants
is often delayed for several days or longer after birth due to concern that early introduction may not be tolerated and may increase the risk
of necrotising enterocolitis (NEC). However, delaying enteral feeding could diminish the functional adaptation of the gastrointestinal tract
and prolong the need for parenteral nutrition with its attendant infectious and metabolic risks.

Objectives
To determine the effect of delayed introduction of progressive enteral feeds on the incidence of NEC, mortality and other morbidities in
very preterm or VLBW infants.

Search methods
We searched the Cochrane Central Register of Controlled Trials (CENTRAL, 2014, Issue 8), MEDLINE (1966 to September 2014), EMBASE
(1980 to September 2014), CINAHL (1982 to September 2014), conference proceedings and previous reviews.

Selection criteria
We included randomised or quasi-randomised controlled trials that assessed the effect of delayed (more than four days after birth) versus
earlier introduction of progressive enteral feeds on the incidence of NEC, mortality and other morbidities in very preterm or VLBW infants.

Data collection and analysis

Two review authors independently assessed trial eligibility and risk of bias and undertook data extraction. We analysed the treatment
effects in the individual trials and reported the risk ratio (RR) and risk difference for dichotomous data and mean difference for continuous
data, with respective 95% confidence intervals (CI). We used a fixed-effect model in meta-analyses and explored the potential causes of
heterogeneity in sensitivity analyses.

Main results
We identified nine randomised controlled trials in which 1106 infants participated. Few participants were extremely preterm (less 28 weeks'
gestation) or extremely low birth weight (less than 1000 g). The trials defined delayed introduction of progressive enteral feeds as later than
four to seven days after birth and early introduction as four days or less after birth. Meta-analyses did not detect statistically significant
effects on the risk of NEC (typical RR 0.93, 95% CI 0.64 to 1.34; 8 trials; 1092 infants) or all-cause mortality (typical RR 1.18, 95% CI 0.75

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to 1.88; 7 trials; 967 infants). Four of the trials restricted participation to growth-restricted infants with Doppler ultrasound evidence of
abnormal fetal circulatory distribution or flow. Planned subgroup analyses of these trials found no statistically significant effects on the risk
of NEC or all-cause mortality. Infants who had delayed introduction of enteral feeds took longer to establish full enteral feeding (reported
median differences two to four days).

Authors' conclusions
The evidence available from randomised controlled trials suggested that delaying the introduction of progressive enteral feeds beyond
four days after birth did not reduce the risk of developing NEC in very preterm or VLBW infants, including growth-restricted infants. Delaying
the introduction of progressive enteral feeds resulted in a few days' delay in establishing full enteral feeds but the clinical importance
of this effect was unclear. The applicability of these findings to extremely preterm or extremely low birth weight was uncertain. Further
randomised controlled trials in this population may be warranted.

PLAIN LANGUAGE SUMMARY

No evidence that delayed introduction of progressive enteral feeds prevents necrotising enterocolitis in very low birth weight
infants

Background

Very preterm (less than 32 weeks' gestation) or very low birth weight (less than 1500 g) infants are at risk of developing a severe bowel
disorder called necrotising enterocolitis, where parts of the bowel become inflamed and start to die. One possible way to prevent this
condition is to delay the introduction of milk feeds until several days (or longer) after birth.

Study characteristics

We search scientific databases for clinical trials assessing the effect of delayed (more than four days after birth) versus earlier introduction
of progressive enteral feeds (where breast or formula milk is fed directly by a tube into the stomach) on the incidence of necrotising
enterocolitis, death and general health in very low birth weight infants. The evidence is current to September 2014.

Key results

We found nine trials with 1106 infants that assessed the effect of delayed rather than early introduction of milk feeds for very preterm or very
low birth weight infants. Data from these trials did not provide any evidence that delaying enteral feeding reduces the risk of necrotising
enterocolitis.

Quality of the evidence

The included trials were generally of reasonable methodological quality but, in common with other trials of feeding interventions in infants,
it was not possible to mask carers and clinical assessors to the given treatment.

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BACKGROUND
Description of the condition
Necrotising enterocolitis (NEC) is an important cause of morbidity,
mortality and neuro-disability in very preterm (less than 32 weeks'
gestation) or very low birth weight (VLBW: less than 1500 g)
infants. Extremely low birth weight (ELBW: less than 1000 g) and
extremely preterm (less than 28 weeks' gestation) infants are at
greatest risk (Bisquera 2002; Holman 2006; Rees 2007; Berrington
2012). Intrauterine growth restriction may be an additional specific
risk factor, especially if associated with circulatory redistribution
demonstrated by absent or reversed end-diastolic flow velocities
in antenatal Doppler studies of the fetal aorta or umbilical artery
(Bernstein 2000; Garite 2004; Dorling 2005; Kamoji 2008).
Description of the intervention
Most very preterm or VLBW infants who develop NEC have received
enteral milk feeds. Evidence exists that feeding with artificial
formula rather than human milk increases the risk of developing
NEC (Quigley 2014). The timing of the introduction and the rate
of progression of enteral feed volumes may also be modifiable
risk factors for the development of NEC (Brown 1978; Uauy 1991;
Henderson 2009). Data from observational studies suggest that
using feeding regimens that include delaying the introduction of
progressive enteral feeds until beyond about four to seven days
after birth reduces the risk of NEC (Patole 2005; Hay 2008).
Why it is important to do this review
In current clinical practice, the introduction of progressive enteral
feeds for very preterm or VLBW infants is often preceded by a period
of enteral fasting or 'minimal enteral nutrition' (Boyle 2004; Patole
2004; Hay 2008; Klingenberg 2012). However, there may also be
potential disadvantages associated with delaying the introduction
of progressive enteral feeds. Because gastrointestinal hormone
secretion and motility are stimulated by enteral milk, delayed
enteral feeding could diminish the functional adaptation of the
gastrointestinal tract (Berseth 1990; Burrin 2002). Prolonging the
duration of use of parenteral nutrition may be associated with
infectious and metabolic complications that increase mortality and
morbidity, prolong hospital stay, and adversely affect growth and
development (Flidel-Rimon 2004; Stoll 2004). It has been argued
that the risk of NEC should not be considered in isolation of
these other potential clinical outcomes when determining feeding
policies and practice for very preterm or VLBW infants (Flidel-Rimon
2006; Hay 2008; Hartel 2009).
This review focused on the comparison of delayed versus earlier
introduction of progressive enteral feeding; that is, advancing the
volume of milk feeds beyond minimal enteral nutrition levels.
We addressed the effect of minimal enteral nutrition, the early
introduction of small volume enteral feeds (up to 24 mL/kg/day)
without advancing the feed volumes for at least five days versus
enteral fasting in another Cochrane review (Morgan 2013a).
OBJECTIVES
To determine the effect of delayed introduction of progressive
enteral feeds on the incidence of NEC, mortality and other
morbidities in very preterm or VLBW infants.
Delayed introduction of progressive enteral feeds to prevent necrotising enterocolitis in very low birth weight infants (Review)
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Cochrane Database of Systematic Reviews
METHODS
Criteria for considering studies for this review
Types of studies
Randomised or quasi-randomised controlled trials or cluster-
randomised trials.
Types of participants
VLBW (less than 1500 g) or very preterm (less than 32 weeks'
gestation) newborn infants.
Types of interventions
Delayed introduction (four or more days after birth) of progressive
enteral feeds versus earlier introduction of enteral feeds. We
defined progressive enteral feeding as the intention to advance
feed volumes in excess of minimal enteral nutrition levels (24 mL/
kg/day) within five days of commencement or by one week after
birth.
Infants in each group should have received the same type of milk
(breast milk or formula), the same route and mode of feeding
(intragastric or transpyloric, bolus gavage or continuous) and the
same rate of feed volume advancement in both groups.
Types of outcome measures
Primary outcomes
1. NEC confirmed by at least two of the following features:
a. abdominal radiograph showing pneumatosis intestinalis or gas
in the portal venous system or free air in the abdomen;
b. abdominal distension with abdominal radiograph with gaseous
distension or frothy appearance of bowel lumen (or both);
c. blood in stool;
d. lethargy, hypotonia or apnoea (or combination of these).
Or by a diagnosis confirmed at surgery or autopsy (Walsh 1986).
2. All-cause mortality during the neonatal period and prior to
hospital discharge.
Secondary outcomes
3. Growth:
a. time to regain birth weight and subsequent rates of weight gain,
linear growth, head growth or skinfold thickness growth up to six
months (corrected for preterm birth);
b. long-term growth: weight, height or head circumference (with or
without proportion of infants who remain below the 10th percentile
for the index population's distribution) assessed at intervals from
six months of age.
4. Neurodevelopment:
a. death or severe neurodevelopmental disability defined as any
one or combination of the following: non-ambulant cerebral
palsy, developmental delay (developmental quotient less than 70),
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auditory and visual impairment. Each component was analysed
individually as well as part of the composite outcome;
b. neurodevelopmental scores in survivors aged 12 months or
greater measured using validated assessment tools;
c. cognitive and educational outcomes in survivors aged more than
five years old.
5. Time to establish full enteral feeding (independently of
parenteral nutrition).
6. Time to establish oral feeding (independently of parenteral
nutrition or enteral tube feeding, or both).
7. Feed intolerance (defined as a requirement to cease enteral
feeds).
8. Incidence of invasive infection as determined by culture of
bacteria or fungus from blood, cerebrospinal fluid, urine or from a
normally sterile body space.
9. Duration of hospital stay (days).
Search methods for identification of studies
We used the standard search strategy of the Cochrane Neonatal
Review Group (neonatal.cochrane.org/).
Electronic searches
We searched the Cochrane Central Register of Controlled Trials
(CENTRAL, 2014, Issue 8), MEDLINE (1966 to September 2014),
EMBASE (1980 to September 2014) and CINAHL (1982 to September
2014) using a combination of the following text words and MeSH
terms: [Infant, Newborn OR Infant, Premature OR Infant, Low Birth
Weight OR Infant, Very Low Birth Weight/ OR infan* OR neonat*
OR preterm OR prem*] AND "Infant-Nutrition"/ all subheadings OR
Infant Formula OR milk OR formula OR trophic feeding OR minimal
enteral nutrition OR gut priming]. We limited the search outputs
with the relevant search filters for clinical trials as recommended
in the Cochrane Handbook for Systematic Reviews of Interventions
(Higgins 2011). We applied no language restrictions.
We searched ClinicalTrials.gov (clinicaltrials.gov) and Current
Controlled Trials (www.controlled-trials.com/) for completed or
ongoing trials.
Searching other resources
We examined the references in all studies identified as potentially
relevant.
We searched the abstracts from the annual meetings of the
Pediatric Academic Societies (1993 to 2014), the European Society
for Pediatric Research (1995 to 2014), the UK Royal College of
Paediatrics and Child Health (2000 to 2014) and the Perinatal
Society of Australia and New Zealand (2000 to 2013). Trials
reported only as abstracts were eligible if sufficient information was
available from the report, or from contact with the authors, to fulfil
the inclusion criteria.
Data collection and analysis
We used the standard methods of the Cochrane Neonatal Review
Group (neonatal.cochrane.org/).
Delayed introduction of progressive enteral feeds to prevent necrotising enterocolitis in very low birth weight infants (Review)
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Selection of studies
Two review authors screened the title and abstract of all studies
identified by the above search strategy. We assessed the full text
of any potentially eligible reports and excluded those studies
that did not meet all of the inclusion criteria. We discussed any
disagreements until we achieved consensus.
Data extraction and management
We used a data collection form to aid extraction of relevant
information from each included study. Two review authors
extracted the data separately. We discussed any disagreements
until we reached consensus. We contacted the investigators for
further information if data from the trial reports were insufficient.
Assessment of risk of bias in included studies
We used the criteria and standard methods of the Cochrane
Neonatal Review Group to assess the methodological quality of any
included trials (neonatal.cochrane.org/). We requested additional
information from the trial authors to clarify methodology and
results as necessary. We evaluated and reported the following
issues in the 'Risk of bias' tables:
1. Sequence generation: we categorised the method used to
generate the allocation sequence as:
a. low risk: any random process (e.g. random number table,
computer random number generator);
b. high risk: any non-random process (e.g. odd or even date of
birth, participant case-record number);
c. unclear risk.
2. Allocation concealment: we categorised the method used to
conceal the allocation sequence as:
a. low risk (e.g. telephone or central randomisation,
consecutively numbered sealed opaque envelopes);
b. high risk (e.g. open random allocation; unsealed or non-
opaque envelopes, alternation; date of birth);
c. unclear risk.
3. Blinding: we assessed blinding of participants, clinicians and
carers, and outcome assessors separately for different outcomes
and categorised the methods as:
a. low risk;
b. high risk;
c. unclear risk.
4. Incomplete outcome data: we described the completeness of
data including attrition and exclusions from the analysis for
each outcome and any reasons for attrition or exclusion where
reported. We assessed whether missing data were balanced
across groups or were related to outcomes. Where sufficient
information was reported or supplied by the trial authors,
we re-included missing data in the analyses. We categorised
completeness as:
a. low risk: less than 20% missing data;
b. high risk: 20% or greater missing data;
c. unclear risk.
Measures of treatment effect
We calculated risk ratio (RR) and risk difference (RD) for
dichotomous data and mean difference (MD) for continuous data,
with respective 95% confidence intervals (CI). We planned to
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determine the number needed to treat for an additional beneficial
outcome (NNTB) or additional harmful outcome (NNTH) for any
statistically significant differences in the RD.
Unit of analysis issues
The unit on analysis was the participating infant in individually
randomised trials and the neonatal unit (or sub-unit) for cluster-
randomised trials.
Assessment of heterogeneity
If we included more than one trial in a meta-analysis, we examined
the treatment effects of individual trials and heterogeneity between
trial results by inspecting the forest plots. We calculated the I2
statistic for each analysis to quantify inconsistency across studies
and describe the percentage of variability in effect estimates
that may be due to heterogeneity rather than sampling error.
If we detected substantial (I2 greater than 50%) heterogeneity,
we explored the possible causes (e.g. differences in study
design, participants, interventions or completeness of outcome
assessments) in sensitivity analyses.
Data synthesis
We used the fixed-effect model in Review Manager 5 for meta-
analysis (RevMan 2011).
Subgroup analysis and investigation of heterogeneity
We planned the following subgroup analyses:
1. trials in which most infants were exclusively formula-fed;
2. trials in which most infants were at least partially fed with
human milk (maternal or donor);
3. trials in which most participants were of ELBW (less than 1000 g)
or extremely preterm (less than 28 weeks' gestation);
4. trials in which participants were infants with intrauterine growth
restriction, or infants with absent or reversed end-diastolic flow
velocities detected on antenatal Doppler studies of the fetal
aorta or umbilical artery.
RESULTS
Description of studies
We identified 13 reports for screening.
Included studies
Nine trials fulfilled the review eligibility criteria: Ostertag
1986; Khayata 1987; Davey 1994; Karagianni 2010; Pérez 2011;
Abdelmaaboud 2012; Leaf 2012; Armanian 2013; Arnon 2013 (see
Characteristics of included studies table).
Population
A total of 1106 infants participated in the included trials.
The three smallest trials were undertaken in neonatal care centres
in North America during the 1980s and early 1990s.
1. Ostertag 1986: 38 VLBW infants assessed to be at high risk of
developing NEC.
2. Khayata 1987: 12 VLBW infants.
Delayed introduction of progressive enteral feeds to prevent necrotising enterocolitis in very low birth weight infants (Review)
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Cochrane Database of Systematic Reviews
3. Davey 1994: 62 clinically stable preterm infants of birth weight
less than 2000 g who had a low umbilical artery catheter in situ.
Since most participants were of birth weight less than 1500 g
or gestational age less than 32 weeks, we made a consensus
decision to include the trial.
The six more recent trials were performed in the 2000s to 2010s.
1. Karagianni 2010: single-centre study in Greece, 84 infants less
than 35 weeks' gestation with a birth weight less than 10th
percentile and evidence of abnormal fetal blood flow patterns
on Doppler ultrasound of the umbilical artery.
2. Pérez 2011: single-centre study in Columbia, 239 very preterm or
VLBW infants.
3. Leaf 2012: 54-centre trial in the UK and Ireland, 404 infants
(a) less than 35 weeks' gestation, (b) birth weight less than
10th percentile and (c) evidence of abnormal fetal blood flow
patterns on Doppler ultrasound studies. Since most participants
were of birth weight less than 1500 g, we made a consensus
decision to include the trial.
4. Abdelmaaboud 2012: single-centre study in Qatar, 125 preterm
infants with intrauterine growth restriction and abnormal
Doppler flow patterns on ultrasound of the umbilical artery.
Since most participants were of birth weight less than 1500 g, we
made a consensus decision to include the trial.
5. Armanian 2013: single-centre study in Iran, 82 VLBW infants.
6. Arnon 2013: single-centre study in Israel, 60 small for gestation
age preterm infants. Since most participants were of birth
weight less than 1500 g, we made a consensus decision to
include the trial.
Interventions/comparisons
1. Eight trials defined 'delayed' introduction of enteral feeds as
later than day four to seven after birth (Ostertag 1986; Davey
1994; Karagianni 2010; Pérez 2011; Abdelmaaboud 2012; Leaf
2012; Armanian 2013; Arnon 2013) and one trial defined it as day
10 after birth (Khayata 1987).
2. 'Early' feeding varied from day one to four after birth.
In seven trials, infants received breast milk, artificial formula or
a combination of the two (Davey 1994; Karagianni 2010; Pérez
2011; Abdelmaaboud 2012; Leaf 2012; Armanian 2013; Arnon 2013).
In two trials, infants received only formula-feed (Ostertag 1986;
Khayata 1987). Infants received enteral feeds by gavage at one-
or two-hourly intervals in all of the trials except Ostertag 1986,
where infants received feeds by continuous intragastric infusion. In
Ostertag 1986, infants were initially fed with a sterile water infusion
slowly progressing to a 2.5% dextrose solution followed by half-
strength formula. They reached full-strength formula milk seven
days after initiating enteral feeds.
All of the trial protocols, except that of the smallest trial (Khayata
1987), specified criteria and indications for advancing (daily
increments of 15 to 30 mL/kg) or interrupting enteral feed (e.g.
residual gastric contents not greater than 3 to 5 mL or one-
third to one-half of the previous feed volume, frequent vomiting,
abdominal distention or detection of blood in the stools).
Outcomes
Eight of the trials reported the incidence of NEC (confirmed
radiologically, or at surgery or autopsy) (Ostertag 1986; Davey
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1994; Karagianni 2010; Pérez 2011; Abdelmaaboud 2012; Leaf
2012; Armanian 2013; Arnon 2013). The other reported outcomes
included mortality, time to establish full enteral feeding, growth
and duration of hospital stay. Only two trials reported the incidence
of invasive infection (Leaf 2012; Arnon 2013).
Excluded studies
Sanghvi 2013; Chetry 2014) (see Characteristics of excluded studies
table).
Risk of bias in included studies
Quality assessments are described in the Characteristics of
included studies table and summarised in Figure 1.

We excluded eight studies after full-text screening (Higgs 1974;

Glass 1984; LaGamma 1985; Wilson 1997; Weiler 2006; Said 2008;
 
Figure 1.   'Risk of bias' graph: review authors' judgements about each risk of bias item presented as percentages
across all included studies.

The smallest trial (12 infants) was reported in abstract form only
and methodological details were not described (Khayata 1987).
The other trials had various methodological weaknesses. In five
trials, methods to ensure adequate allocation concealment were
not described. None of the trials concealed the feeding strategies
from parents, carers or clinical investigators. Complete or near-
complete assessments of the primary outcomes were reported and
data were available to undertake intention-to-treat analyses as
required.
Effects of interventions
Primary outcomes
Necrotising enterocolitis (Outcome 1.1)
Meta-analysis did not detect a statistically significant effect (typical
RR 0.93, 95% CI 0.64 to 1.34; typical RD -0.01, 95% CI -0.04 to
0.03; 8 trials; 1092 infants). There was no statistical evidence of
heterogeneity (Figure 2).

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Figure 2.   Forest plot of comparison: 1 Delayed versus early introduction of progressive enteral feeding, outcome:
1.1 Necrotising enterocolitis.

 
Mortality prior to discharge (Outcome 1.2) 0.04; 7 trials, 967 infants). There was no statistical evidence of
heterogeneity (Figure 3).
Meta-analysis did not detect a statistically significant effect (typical
RR 1.18, 95% CI 0.75 to 1.88; typical RD 0.01, 95% CI -0.02 to
 
Figure 3.   Forest plot of comparison: 1 Delayed versus early introduction of progressive enteral feeding, outcome:
1.2 Mortality prior to discharge.

Delayed introduction of progressive enteral feeds to prevent necrotising enterocolitis in very low birth weight infants (Review) 7
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Secondary outcomes Time to establish full enteral feeding

Growth The median time to establish full enteral feeding was longer in the
delayed introduction group but the reports did not provide data to
Two trials did not detect a statistically significant difference in the
allow quantitative synthesis:
median time to regain birth weight:
1. Ostertag 1986: not reported;
1. Davey 1994: 13 days for both groups (range not reported; 62
infants); 2. Khayata 1987: not reported;
2. Abdelmaaboud 2012: 13 days in the delayed group compared 3. Davey 1994: three days;
with 14 days in the early introduction group (range not reported; 4. Karagianni 2010: three days;
125 infants). 5. Pérez 2011: four days;
6. Abdelmaaboud 2012: two days;
Two trials did not detect statistically significant differences in the
rate of weight gain but the reports did not provide data to allow 7. Leaf 2012: three days;
quantitative synthesis (Khayata 1987; Pérez 2011). 8. Armanian 2013: five days;
9. Arnon 2013: three days.
None of the other trials reported hospital growth parameters.
Time to establish full oral feeding
None of the trials assessed any long-term (post-hospital discharge)
growth parameters. None of the trials assessed time to establish full oral feeding.

Neurodevelopment Feed intolerance (Outcome 1.3)

None of the trials assessed neurodevelopmental outcomes. Meta-analysis of data from three trials did not detect a statistically
significant difference in feed intolerance (typical RR 0.84, 95% CI
0.62 to 1.15; typical RD -0.06, 95% CI -0.17 to 0.05; 288 infants; Figure
4) (Karagianni 2010; Abdelmaaboud 2012; Armanian 2013).
 
Figure 4.   Forest plot of comparison: 1 Delayed versus early introduction of progressive enteral feeding, outcome:
1.3 Feed intolerance.

 
One trial did not detect a statistically significant difference but the Duration of hospital stay (Outcome 1.5)
report did not provide data to allow quantitative synthesis (Davey
Meta-analysis from three trials showed a statistically significant
1994).
longer duration in the delayed feeding group (MD 2.11 days, 95%
None of the other trials reported the incidence of feed intolerance. CI 0.31 to 3.90; 346 infants; Figure 5). The meta-analysis contained
substantial heterogeneity (Chi2 = 7.66; degrees of freedom (df) = 2;
Incidence of invasive infection (Outcome 1.4) P value = 0.02; I2 = 74%).
Meta-analysis of data from two trials did not detect a statistically
significant difference (typical RR 1.27, 95% CI 0.95 to 1.70; typical
RD 0.07, 95% CI -0.01 to 0.15; 457 infants) (Leaf 2012; Arnon 2013).
 

Delayed introduction of progressive enteral feeds to prevent necrotising enterocolitis in very low birth weight infants (Review) 8
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Cochrane Trusted evidence.
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Figure 5.   Forest plot of comparison: 1 Delayed versus early introduction of progressive enteral feeding, outcome:
1.5 Duration of hospital admission (days).
Another two trials did not detect a statistically significant effect but
the reports did not provide data to allow quantitative synthesis
(Abdelmaaboud 2012; Leaf 2012).
Subgroup analyses
1. Two trials only recruited exclusively formula-fed infants
(Ostertag 1986; Khayata 1987). Only Ostertag 1986 reported the
effect on NEC (RR 1.08, 95% CI 0.40 to 2.94; RD 0.02, 95% CI -0.27
to 0.31; 38 infants) or mortality (RR 1.44, 95% CI 0.57 to 3.61; RD
0.12, 95% CI -0.18 to 0.42; 38 infants).
2. Trials in which most infants were at least partially fed with
human milk (maternal or donor): subgroup data not available.
3. ELBW or extremely preterm infants: none of the trials recruited
predominantly ELBW or extremely preterm infants.
4. Four trials recruited only infants with intrauterine growth
restriction and abnormal flow velocities detected on antenatal
Doppler studies (Karagianni 2010; Abdelmaaboud 2012; Leaf
2012; Arnon 2013). Meta-analysis did not detect any statistically
significant differences in the incidence of NEC (typical RR 0.87,
95% CI 0.54 to 1.41; typical RD -0.01, 95% CI -0.06 to 0.03; 673
infants; Figure 2) or mortality (typical RR 1.06, 95% CI 0.55 to
2.05; typical RD 0.00, 95% CI -0.04 to 0.05; 548 infants; Figure 3).
DISCUSSION
Summary of main results
Analyses of data from nine randomised controlled trials with 1106
infants did not provide evidence that delayed introduction of
progressive enteral feeds reduced the risk of NEC. The boundaries
of the 95% CI for the estimate of effect are consistent with either
four fewer or three extra cases of NEC in every 100 infants who had
delayed introduction of progressive enteral feeds. Meta-analysis
of data from these trials did not indicate an effect on all-cause
mortality with the 95% CI boundaries being consistent with either
two fewer or four more deaths in every 100 infants who had
delayed introduction of progressive enteral feeds. Similarly, pre-
specified subgroup meta-analyses showed no effect of delayed
introduction of enteral feeds on NEC or mortality in infants with
growth restriction or antenatal evidence of absent end-diastolic
flow velocities.
Infants who had delayed introduction of feeds achieved full enteral
feeding several days later than infants who had earlier introduction.
Whether this was associated with important clinical adverse
consequences, such as a higher rate of nosocomial infection
secondary to prolonged use of parenteral nutrition or a longer
duration of hospital admission, remains unclear.
Delayed introduction of progressive enteral feeds to prevent necrotising enterocolitis in very low birth weight infants (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Cochrane Database of Systematic Reviews
Overall completeness and applicability of evidence
These data are relevant to current practice since most of
the included trials were conducted in the 2000s with infants
receiving 'modern' antenatal care including exposure to antenatal
corticosteroids and exogenous surfactant, interventions that
reduce the risk of NEC or death in this population (Roberts 2006;
Seger 2009; Soll 2009; Soll 2010). Four of these trials specifically
recruited infants thought to be at higher risk of developing NEC due
to intrauterine growth restriction and abnormal fetal circulatory
distribution or flow. This widens the applicability of the findings
since this is the population for which most clinical uncertainty
and variation in practice with regard to early feeding strategies
exists (Boyle 2004). Previously, this population of infants has been
specifically excluded from participating in many trials of early
enteral feeding practices (Tyson 2007).
Evidence exists that artificial formula feeding increases the risk
NEC (Quigley 2014). The risk-benefit balance of enteral feeding
strategies may differ between human milk-fed and formula-fed very
preterm or VLBW infants. Currently there are insufficient data to
comment on whether there is a differential effect of the timing
of the introduction of enteral feeds depending on whether infants
received human breast milk versus formula.
It is also unclear whether the findings can be applied to infants
who receive continuous infusion of intragastric feeds, as most
of the infants in the included trials received enteral feeds
as interval gastric boluses. Randomised controlled trials have
reported conflicting findings about the effect on continuous enteral
infusion on feed tolerance in VLBW (and especially ELBW) infants
(Premji 2011).
Most of the included trials were undertaken in neonatal care
centres in middle- or high-income countries. It is less clear how
applicable this evidence is to neonatal care practices in low-income
countries. Conservative strategies, such as delayed introduction of
enteral feeds, may confer substantial nutritional disadvantage in
settings with less technologically developed healthcare provision
where adjunctive parenteral nutrition is not readily and safely
available. In some low- or middle-income countries where severe
infection (diarrhoea, pneumonia, septicaemia) is a much more
important cause of mortality and morbidity, the nutritional and
immunological advantages of early feeding, particularly with breast
milk, may outweigh any risks associated with enteral feeding for
very preterm or VLBW infants (Narayanan 1981; de Silva 2004). We
identified two feasibility trials undertaken in India in the late 2000s/
early 2010s that compared exclusive enteral feeding (no parenteral
fluid) from birth with gradual introduction of enteral feeds over
several days in VLBW infants with birth weight greater than 1000 g
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Informed decisions.
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(Sanghvi 2013; Chetry 2014). While these trials were not eligible for
inclusion in this review, neither found evidence of an effect on NEC
or other adverse outcomes.
Quality of the evidence
The included trials were generally of reasonable methodological
quality but, in common with other trials of feeding interventions
in this population, it was not possible to mask carers and clinical
assessors to the nature of the intervention. Although the lack
of blinding may have resulted in surveillance and ascertainment
biases, this is more likely to have caused an underestimation of the
incidence of NEC in infants whose enteral feeding was delayed. The
assessment of abdominal radiographs was masked in three studies
to ensure that the diagnosis of stage II/III NEC (confirmed by the
radiological detection of gas in the bowel wall or portal tract) was
not prone to bias. However, since the microbial generation of gas in
the bowel wall is substrate dependent, infants who received more
enteral milk (substrate) may have been more likely to demonstrate
this radiological sign than infants with equally severe bowel disease
who had less intraluminal substrate. This 'substrate effect' is also
more likely to cause under-ascertainment of NEC in the infants
whose enteral feeding was delayed (Tyson 2007).
Potential biases in the review process
The definition of delayed introduction of progressive feeds may
vary between different subpopulations of very preterm or VLBW
infants who have different empiric risks for developing feed
intolerance and NEC. The effects of enteral feeding are likely to be
very different for a mechanical ventilator-dependent or inotrope-
dependent infant of birth weight less than 700 g compared with
a clinically stable infant of birth weight greater than 1400 g. For
this Cochrane review, we defined delayed introduction as later
than four days after birth since some observational studies have
found the risk of NEC to be lower when feeds are introduced five to
seven days after birth (Patole 2005). For ELBW or extremely preterm
infants, it may be more appropriate to define delayed introduction
as more than seven days after birth (or even later). Small-intestinal
motility is poorly organised before about 28 weeks' gestation
resulting in a higher risk of feed intolerance. In addition, enteral
feeds are often delayed in this population because of respiratory
or metabolic instability or because of other putative risk factors
for NEC, such as the existence of a patent ductus arteriosus, the
use of non-steroidal anti-inflammatory drugs or the presence of an
umbilical arterial catheter (Boyle 2004).
Delayed introduction of progressive enteral feeds to prevent necrotising enterocolitis in very low birth weight infants (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Cochrane Database of Systematic Reviews
AUTHORS' CONCLUSIONS
Implications for practice
The available data from randomised controlled trials do not
provide evidence that delaying the introduction of progressive
enteral feeds beyond four days after birth reduces the risk of
necrotising enterocolitis (NEC), mortality, and other morbidities
in very preterm or very low birth weight (VLBW) infants. Delaying
the introduction of progressive enteral feeds may result in several
days' delay in establishing full enteral feeds but the long-term
clinical importance of these effects is unclear. Subgroup analyses
of trials in which participating infants had evidence of intrauterine
growth restriction or abnormal circulatory distribution or flow did
not find any statistically significant effects. However, only limited
data are available on the effect of this intervention on outcomes for
extremely preterm or extremely low birth weight (ELBW) infants.
Implications for research
Further randomised controlled trials of delayed versus early
introduction of progressive enteral feeds could provide more
precise estimates of the effects on important outcomes for
extremely preterm or ELBW infants. With regard to stable VLBW
infants with birth weight greater than 1000 g (or very preterm
infants with gestational age 28 to 31 weeks), the key research
question is now whether exclusive enteral feeding from birth is
better than gradual introduction.
Masking carers and investigators to the nature of this intervention
is unlikely to be possible. Since the unblinded evaluation of feed
intolerance and NEC is subject to surveillance and ascertainment
biases, trials could aim to assess more objective outcomes,
principally mortality and long-term growth and development.
Furthermore, since conservative feeding strategies may result in
other 'competing outcomes', such as invasive infection that may
affect long-term survival and neuro-disability rates, it is essential
that trials are powered and structured to assess these outcomes.
ACKNOWLEDGEMENTS
This report is independent research funded by a UK National
Institute of Health Research Grant (NIHR) Cochrane Programme
Grant (13/89/12). The views expressed in this publication are those
of the authors and not necessarily those of the National Health
Service (NHS), the NIHR or the UK Department of Health.
10
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Informed decisions.
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REFERENCES
References to studies included in this review
Abdelmaaboud 2012 {published data only}
Abdelmaaboud M, Mohammed A. A randomized controlled trial
on early versus late minimal enteral feeding in preterm growth-
restricted neonates with abnormal antenatal Doppler studies.
Journal of Neonatal-Perinatal Medicine 2012;5(2):1-8.
Armanian 2013 {published and unpublished data}
Armanian AM, Mirbod SM, Kazemipour S, Hassanzade A.
Comparison of prolonged low volume milk and routine volume
milk on incidence of necrotizing enterocolitis in very low birth
weight neonates. Pakistan Journal of Medical Sciences 2013;29(1
Suppl):312-6.
Arnon 2013 {published data only}
Arnon S, Sulam D, Konikoff F, Regev RH, Litmanovitz I, Naftali T.
Very early feeding in stable small for gestational age preterm
infants: a randomized clinical trial. Jornal de Pediatria
2013;89(4):388-93.
Davey 1994 {published data only (unpublished sought but not
used)}
Davey AM, Wagner CL, Cox C, Kendig JW. Feeding premature
infants while low umbilical artery catheters are in place: a
prospective, randomized trial. Journal of Pediatrics 1994;124(5
Pt 1):795-9. [PUBMED: 8176571]
Karagianni 2010 {published data only}
Karagianni P, Briana DD, Mitsiakos G, Elias A, Theodoridis T,
Chatziioannidis E, et al. Early versus delayed minimal enteral
feeding and risk for necrotizing enterocolitis in preterm growth-
restricted infants with abnormal antenatal Doppler results.
American Journal of Perinatology 2010;27(5):367-73. [DOI:
10.1055/s-0029-1243310; PUBMED: 20013579]
Khayata 1987 {published data only (unpublished sought but not
used)}
Khayata S, Gutcher G, Bamberger J, Heimler R. Early versus late
feeding of low birth weight (LBW) infants: effect on growth and
hyperbilirubinemia. Pediatric Research 1987;21:431A.
Leaf 2012 {published data only}
Kempley S, Gupta N, Linsell L, Dorling J, McCormick K,
Mannix P. Feeding infants below 29 weeks' gestation with
abnormal antenatal Doppler: analysis from a randomised trial.
Archives of Disease in Childhood. Fetal and Neonatal Edition
2014;99(1):F6-11. [PUBMED: 23973795]
Leaf A, Dorling J, Kempley S, McCormick K, Mannix P,
Brocklehurst P. ADEPT - Abnormal Doppler Enteral Prescription
Trial. BMC Pediatrics 2009;9:63. [DOI: 10.1186/1471-2431-9-63;
PUBMED: 19799788]
Leaf A, Dorling J, Kempley S, McCormick K, Mannix P,
Brocklehurst P. When should feeds be started in the high risk
preterm infant? The Abnormal Doppler Enteral Prescription Trial
(ADEPT). E-PAS20101670.7. 2010.
Delayed introduction of progressive enteral feeds to prevent necrotising enterocolitis in very low birth weight infants (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Cochrane Database of Systematic Reviews
* Leaf A, Dorling J, Kempley S, McCormick K, Mannix P, Linsell L,
et al. on behalf of ADEPT Clinical Investigators Group. Early or
delayed enteral feeding for preterm growth-restricted infants:
a randomized trial. Pediatrics 2012;129(5):1-9. [DOI: 10.1542/
peds.2011-2379; PUBMED: 22492770]
Leaf A,  Dorling J,  Kempley S,  McCormick K,  Mannix P,
Brocklehurst P. Abnormal Doppler enteral prescription
trial study: the results of a trial of feeding in a high risk
group of premature babies. Archives of Disease in Childhood.
Fetal and Neonatal Edition 2010;95:Fa9. [DOI: 10.1136/
adc.2010.192310.4.1]
Ostertag 1986 {published and unpublished data}
Ostertag SG, LaGamma EF, Reisen CE, Ferrentino FL. Early
enteral feeding does not affect the incidence of necrotizing
enterocolitis. Pediatrics 1986;77(3):275-80. [PUBMED: 3081868]
Pérez 2011 {published data only}
Pérez LA, Pradilla GL, Díaz G, Bayter SM. Necrotising
enterocolitis among preterm newborns with early feeding
[Incidencia de enterocolitis necrosante en niños prematuros
alimentados precozmente]. Biomédica 2011;31(4):485-91. [DOI:
10.1590/S0120-41572011000400003; PUBMED: 22674359]
 
References to studies excluded from this review
Chetry 2014 {published data only}
Chetry S, Kler N, Saluja S, Garg P, Soni A, Thakur A, et al. A
randomised control trial comparing initiation of total enteral
feeds on 1st day of life with standard feeding regimen in stable
very low birth weight infants born between > 30-34 weeks
gestation and 1000-1500 gms. Pediatric Academic Societies
[2930.442]. 2014.
Glass 1984 {published data only}
Glass EJ, Hume R, Lang MA, Forfar JO. Parenteral nutrition
compared with transpyloric feeding. Archives of Disease in
Childhood 1984;59(2):131-5. [PUBMED: 6422864]
Higgs 1974 {published data only}
Higgs SC, Malan AF, De Heese HV. A comparison of oral feeding
and total parenteral nutrition in infants of very low birthweight.
South African Medical Journal 1974;48(52):2169-73. [PUBMED:
4215158]
LaGamma 1985 {published data only}
LaGamma EF, Ostertag S, Birenbaum H. Failure of delayed oral
feedings to prevent necrotizing enterocolitis. Results of study in
very-low-birth-weight neonates. American Journal of Diseases of
Children 1985;139(4):385-9. [PUBMED: 3919570]
Said 2008 {published data only}
Said H, Elmetwally D, Said N. Randomized controlled trial of
early versus late enteral feeding in prematurely born infants
with birth weight ≤ 1200 grams. Kasr El Aini Medical Journal
2008;14:1-10.
11
 Cochrane Trusted evidence.
Informed decisions.
Library Better health.
Sanghvi 2013 {published data only}
Sanghvi KP, Joshi P, Nabi F, Kabra N. Feasibility of exclusive
enteral feeds from birth in VLBW infants >1200 g - an RCT. Acta
Paediatrica 2013;102(7):e299-304. [DOI: 10.1111/apa.12254;
PUBMED: 23621289]
Weiler 2006 {published data only}
Weiler HA, Fitzpatrick-Wong SC, Chellenberg JM, Fair DE,
McCloy UR, Veitch RR, et al. Minimal enteral feeding within 3 d of
birth in prematurely born infants with birth weight < or = 1200g
improves bone mass by term age. American Journal of Clinical
Nutrition 2006;83(1):155-62. [PUBMED: 16403735]
Wilson 1997 {published data only}
Wilson DC, Cairns P, Halliday HL, Reid M, McClure G, Dodge JA.
Randomised controlled trial of an aggressive nutritional
regimen in sick very low birthweight infants. Archives of Disease
in Childhood. Fetal and Neonatal Edition 1997;77(1):F4-11.
[PUBMED: 9279175]
 
Additional references
Bernstein 2000
Bernstein IM, Horbar JD, Badger GJ, Ohlsson A, Golan A.
Morbidity and mortality among very-low-birth-weight neonates
with intrauterine growth restriction. The Vermont Oxford
Network. American Journal of Obstetrics and Gynecology
2000;182(1 Pt 1):198-206. [PUBMED: 10649179]
Berrington 2012
Berrington JE, Hearn RI, Bythell M, Wright C, Embleton ND.
Deaths in preterm infants: changing pathology over 2 decades.
Journal of Pediatrics 2012;160(1):49-53. [DOI: 10.1016/
j.jpeds.2011.06.046; PUBMED: 21868028]
Berseth 1990
Berseth CL. Neonatal small intestinal motility: motor responses
to feeding in term and preterm infants. Journal of Pediatrics
1990;117(5):777-82. [PUBMED: 2121949]
Bisquera 2002
Bisquera JA, Cooper TR, Berseth CL. Impact of necrotizing
enterocolitis on length of stay and hospital charges in very low
birth weight infants. Pediatrics 2002;109(3):423-8. [PUBMED:
11875136]
Boyle 2004
Boyle EM, Menon G, Elton R, McIntosh N. Variation in feeding
practice in preterm and low birth weight infants in Scotland.
Early Human Development 2004;77:125-6.
Brown 1978
Brown EG, Sweet AY. Preventing necrotizing enterocolitis in
neonates. JAMA 1978;240(22):2452-4. [PUBMED: 101680]
Burrin 2002
Burrin DG, Stoll B. Key nutrients and growth factors for
the neonatal gastrointestinal tract. Clinics in Perinatology
2002;29(1):65-96. [PUBMED: 11917740]
Delayed introduction of progressive enteral feeds to prevent necrotising enterocolitis in very low birth weight infants (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Cochrane Database of Systematic Reviews
de Silva 2004
de Silva A, Jones PW, Spencer SA. Does human milk reduce
infection rates in preterm infants? A systematic review.
Archives of Disease in Childhood. Fetal and Neonatal Edition
2004;89(6):F509-13. [PUBMED: 15499143]
Dorling 2005
Dorling J, Kempley S, Leaf A. Feeding growth restricted
preterm infants with abnormal antenatal Doppler results.
Archives of Disease in Childhood. Fetal and Neonatal Edition
2005;90(5):F359-63. [PUBMED: 16113150]
Flidel-Rimon 2004
Flidel-Rimon O, Friedman S, Lev E, Juster-Reicher A, Amitay M,
Shinwell ES. Early enteral feeding and nosocomial sepsis in very
low birthweight infants. Archives of Disease in Childhood. Fetal
and Neonatal Edition 2004;89(4):F289-92. [PUBMED: 15210657]
Flidel-Rimon 2006
Flidel-Rimon O, Branski D, Shinwell ES. The fear of necrotizing
enterocolitis versus achieving optimal growth in preterm infants
- an opinion. Acta Paediatrica 2006;95(11):1341-4. [PUBMED:
17062457]
Garite 2004
Garite TJ, Clark R, Thorp JA. Intrauterine growth restriction
increases morbidity and mortality among premature
neonates. American Journal of Obstetrics and Gynecology
2004;191(2):481-7. [PUBMED: 15343225]
Hartel 2009
Hartel C, Haase B, Browning-Carmo K, Gebauer C, Kattner E,
Kribs A, et al. Does the enteral feeding advancement affect
short-term outcomes in very low birth weight infants?. Journal
of Pediatric Gastroenterology and Nutrition 2009;48(4):464-70.
[DOI: 10.1097/MPG.0b013e31818c5fc3; PUBMED: 19322056]
Hay 2008
Hay WW Jr. Strategies for feeding the preterm infant.
Neonatology 2008;94(4):245-54. [DOI: 10.1159/000151643;
PUBMED: 18836284]
Henderson 2009
Henderson G, Craig S, Brocklehurst P, McGuire W. Enteral
feeding regimens and necrotising enterocolitis in preterm
infants: a multicentre case-control study. Archives of Disease
in Childhood. Fetal and Neonatal Edition 2009;94(2):F120-3.
[PUBMED: 17768154]
Hershkovitz 2000
Hershkovitz R, Kingdom JC, Geary M, Rodeck CH. Fetal cerebral
blood flow redistribution in late gestation: identification
of compromise in small fetuses with normal umbilical
artery Doppler. Ultrasound in Obstetrics & Gynecology
2000;15(3):209-12. [PUBMED: 10846776]
Higgins 2011
Higgins JPT, Green S, editors. 2011. Cochrane Handbook for
Systematic Reviews of Interventions Version 5.1.0 [updated
March 2011]. The Cochrane Collaboration, 2011. Available from
www.cochrane-handbook.org.
12
 Cochrane Trusted evidence.
Informed decisions.
Library Better health.
Holman 2006
Holman RC, Stoll BJ, Curns AT, Yorita KL, Steiner CA,
Schonberger LB. Necrotising enterocolitis hospitalisations
among neonates in the United States. Paediatric and Perinatal
Epidemiology 2006;20(6):498-506. [PUBMED: 17052286]
Kamoji 2008
Kamoji VM, Dorling JS, Manktelow B, Draper ES, Field DJ.
Antenatal umbilical Doppler abnormalities: an independent
risk factor for early onset neonatal necrotizing enterocolitis
in premature infants. Acta Paediatrica 2008;97(3):327-31.
[10.1111/j.1651-2227.2008.00671.x; PUBMED: 18298781]
Klingenberg 2012
Klingenberg C, Embleton ND, Jacobs SE, O'Connell LA,
Kuschel CA. Enteral feeding practices in very preterm infants:
an international survey. Archives of Disease in Childhood.
Fetal and Neonatal Edition 2012;97(1):F56-61. [DOI: 10.1136/
adc.2010.204123; PUBMED: 21856644]
Morgan 2013a
Morgan J, Bombell S, McGuire W. Early trophic feeding versus
enteral fasting for very preterm or very low birth weight infants.
Cochrane Database of Systematic Reviews 2013, Issue 3. [DOI:
10.1002/14651858.CD000504.pub3]
Narayanan 1981
Narayanan I, Prakash K, Gujral VV. The value of human milk in
the prevention of infection in the high-risk low-birth-weight
infant. Journal of Pediatrics 1981;99(3):496-8. [PUBMED:
6790690]
Patole 2004
Patole S, Muller R. Enteral feeding of preterm neonates: a
survey of Australian neonatologists. Journal of Maternal-Fetal &
Neonatal Medicine 2004;16(5):309-14. [PUBMED: 15621549]
Patole 2005
Patole SK, de Klerk N. Impact of standardised feeding
regimens on incidence of neonatal necrotising enterocolitis: a
systematic review and meta-analysis of observational studies.
Archives of Disease in Childhood. Fetal and Neonatal Edition
2005;90(2):F147-51. [PUBMED: 15724039]
Premji 2011
Premji SS, Chessell L. Continuous nasogastric milk feeding
versus intermittent bolus milk feeding for premature infants
less than 1500 grams. Cochrane Database of Systematic Reviews
2011, Issue 11. [DOI: 10.1002/14651858.CD001819.pub2]
Quigley 2014
Quigley MA, McGuire W. Formula versus donor breast milk
for feeding preterm or low birth weight infants. Cochrane
Database of Systematic Reviews 2014, Issue 4. [DOI:
10.1002/14651858.CD002971.pub2]
Rees 2007
Rees CM, Pierro A, Eaton S. Neurodevelopmental outcomes
of neonates with medically and surgically treated necrotizing
enterocolitis. Archives of Disease in Childhood. Fetal and
Neonatal Edition 2007;92(3):F193-8. [PUBMED: 16984980]
Delayed introduction of progressive enteral feeds to prevent necrotising enterocolitis in very low birth weight infants (Review)
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Cochrane Database of Systematic Reviews
RevMan 2011 [Computer program]
Nordic Cochrane Centre. The Cochrane Collaboration. Review
Manager (RevMan). Version 5.1. Copenhagen: Nordic Cochrane
Centre. The Cochrane Collaboration, 2011.
Roberts 2006
Roberts D, Dalziel S. Antenatal corticosteroids for accelerating
fetal lung maturation for women at risk of preterm birth.
Cochrane Database of Systematic Reviews 2006, Issue 3. [DOI:
10.1002/14651858.CD004454.pub2]
Seger 2009
Seger N, Soll R. Animal derived surfactant extract for
treatment of respiratory distress syndrome. Cochrane
Database of Systematic Reviews 2009, Issue 2. [DOI:
10.1002/14651858.CD007836]
Soll 2009
Soll R, Ozek E. Multiple versus single doses of exogenous
surfactant for the prevention or treatment of neonatal
respiratory distress syndrome. Cochrane Database of Systematic
Reviews 2009, Issue 1. [DOI: 10.1002/14651858.CD000141.pub2]
Soll 2010
Soll R, Ozek E. Prophylactic protein free synthetic surfactant
for preventing morbidity and mortality in preterm infants.
Cochrane Database of Systematic Reviews 2010, Issue 1. [DOI:
10.1002/14651858.CD001079.pub2]
Stoll 2004
Stoll BJ, Hansen NI, Adams-Chapman I, Fanaroff AA, Hintz SR,
Vohr B, et al. Neurodevelopmental and growth impairment
among extremely low-birth-weight infants with neonatal
infection. JAMA 2004;292(19):2357-65. [PUBMED: 15547163]
Tyson 2007
Tyson JE, Kennedy KA, Lucke JF, Pedroza C. Dilemmas initiating
enteral feedings in high risk infants: how can they be resolved?.
Seminars in Perinatology 2007;31(2):61-73. [PUBMED: 17462490]
Uauy 1991
Uauy RD, Fanaroff AA, Korones SB, Phillips EA, Phillips JB,
Wright LL. Necrotizing enterocolitis in very low birth weight
infants: biodemographic and clinical correlates. National
Institute of Child Health and Human Development Neonatal
Research Network. Journal of Pediatrics 1991;119(4):630-8.
[PUBMED: 1919897]
Walsh 1986
Walsh MC, Kliegman RM. Necrotizing enterocolitis: treatment
based on staging criteria. Pediatric Clinics of North America
1986;33(1):179-201. [PUBMED: 3081865]
 
References to other published versions of this review
Bombell 2008
Bombell S, McGuire W. Delayed introduction of progressive
enteral feeds to prevent necrotising enterocolitis in very low
birth weight infants. Cochrane Database of Systematic Reviews
2008, Issue 2. [DOI: 10.1002/14651858.CD001970.pub2]
13
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Library Better health. Cochrane Database of Systematic Reviews

Kennedy 2005 very low birth weight infants. Cochrane Database of Systematic
Kennedy KA, Tyson JE, Chamnanvanikij S. Early versus Reviews 2011, Issue 3. [DOI: 10.1002/14651858.CD001970.pub3]
delayed initiation of progressive enteral feedings for
Morgan 2013b
parenterally fed low birth weight or preterm infants.
Cochrane Database of Systematic Reviews 2005, Issue 1. [DOI: Morgan J, Young L, McGuire W. Delayed introduction of
10.1002/14651858.CD001970.pub2] progressive enteral feeds to prevent necrotising enterocolitis in
very low birth weight infants. Cochrane Database of Systematic
Morgan 2011 Reviews 2013, Issue 5. [DOI: 10.1002/14651858.CD001970.pub4]
Morgan J, Young L, McGuire W. Delayed introduction of
 
progressive enteral feeds to prevent necrotising enterocolitis in
* Indicates the major publication for the study
 
CHARACTERISTICS OF STUDIES

Characteristics of included studies [ordered by study ID]

 
Abdelmaaboud 2012 
Methods Randomised controlled trial

Participants Preterm infants, 28-36 weeks' gestation with birth weight < 10th centile, antenatal ultrasound showing
intrauterine growth restriction, absent or reversed end diastolic flow on Doppler waveforms of the um-
bilical artery with evidence of cerebral redistribution, arterial cord pH ≥ 7.0 and base deficit ≥ -12 and 5-
minute Apgar score of > 5.

Infants were excluded if there was any major congenital abnormality, twin-twin transfusion, intrauter-
ine transfusion, exchange transfusion, rhesus iso-immunisation, significant multi-organ failure, in-
otropic drug support or minimal enteral feeding had already started

Setting: single centre: Women's Hospital, Hamad Medical Corporation, Qatar

Interventions Early introduction of progressive enteral feeds on day 3 (62 infants) versus late introduction of enteral
feeds on day 6 (63 infants)

Outcomes Incidence of NEC (stage II/III), time to reach full enteral feeds (sustained for 72 hours), rates of feed in-
tolerance, mortality and duration of hospital stay

Notes > 90% of participants were VLBW

Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- Low risk Computer-generated tables

tion (selection bias)

Allocation concealment Unclear risk Not stated

(selection bias)

Blinding (performance High risk Carers not blinded to intervention group

bias and detection bias)
Clinical assessments

Blinding (performance Unclear risk No information on blinding of radiological assessors to intervention groups
bias and detection bias)
Radiological assessments

Incomplete outcome data Low risk Complete follow-up assessment

(attrition bias)
All outcomes

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Armanian 2013 
Methods Randomised controlled trial

Participants VLBW infants

Infants were excluded if there was a congenital abnormality

Setting: Isfahan Faculty of Medicine, Iran

Interventions Delayed introduction of progressive enteral feeds (only minimal volumes until day 7 (47 infants) versus
early introduction on day 3 (35 infants)

Infants received either unfortified breast milk or formula (no subgroup data available). Volumes and
rates of advancement or progressive feeds were the same in both groups (20 mL/kg/day)

Outcomes Incidence of NEC, mortality, days to full enteral feeds, duration of hospital stay

Notes  

Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- Unclear risk Not stated

tion (selection bias)

Allocation concealment Unclear risk Not stated

(selection bias)

Blinding (performance High risk Carers not blinded to intervention group

bias and detection bias)
Clinical assessments

Blinding (performance Unclear risk No information on blinding of radiological assessors to intervention groups
bias and detection bias)
Radiological assessments

Incomplete outcome data Low risk Complete follow-up assessment

(attrition bias)
All outcomes

 
 
Arnon 2013 
Methods Randomised controlled trial

Participants Preterm infants, birth weight < 10th centile*, and antenatal evidence of absent or reversed end dias-
tolic flow on Doppler waveforms of the umbilical artery

Infants were excluded if there was a major congenital abnormality, receipt of mechanical ventilation or
enteral feeding had already started

Setting: single centre: Meir Medical Centre, Kfar Saba, Tel Aviv, Israel

Interventions Delayed progressive enteral feeding (day 4-5 after birth, 30 infants) versus earlier enteral feeding (day 2
after birth, 30 infants)

Delayed introduction of progressive enteral feeds to prevent necrotising enterocolitis in very low birth weight infants (Review) 15
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Arnon 2013  (Continued)
Infants received expressed breast or formula or both

Outcomes Incidence of NEC, mortality, nosocomial infection, days to reach full enteral feeds, duration of hospital
stay

Notes *Most participants were VLBW (range 963-1683 g)

Original study published in Portuguese

Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- Unclear risk Not stated

tion (selection bias)

Allocation concealment Unclear risk Not stated

(selection bias)

Blinding (performance High risk Carers not blinded to intervention group

bias and detection bias)
Clinical assessments

Blinding (performance Unclear risk No information on blinding of radiological assessors to intervention groups
bias and detection bias)
Radiological assessments

Incomplete outcome data Low risk Complete follow-up assessment

(attrition bias)
All outcomes

 
 
Davey 1994 
Methods Randomised controlled trial

Participants 62 preterm infants with birth weight < 2000 g who were clinically stable and who had an umbilical
artery catheter in place

Infants were excluded if they had a lethal condition or had received a double-volume exchange transfu-
sion

Setting: Division of Neonatology, Department of Pediatrics, University of Rochester Medical Center, US

Interventions Delayed introduction of enteral feeds (median 5 days; 31 infants) versus earlier introduction (median 2
days; 31 infants)

Infants received either breast milk or diluted formula (no subgroup data available). Volumes and rates
of advancement were the same in both groups

Outcomes Days to regain birth weight, days to full enteral feeding, duration of hospital stay, incidence of NEC and
mortality

Notes The trial inclusion criterion for birth weight was < 2000 g. Since > 80% of infants were VLBW or very
preterm, we decided to include the trial

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Davey 1994  (Continued)
Infants in the delayed introduction group commenced enteral feeds when the umbilical artery catheter
had been removed for 24 hours and the infant was clinically stable. Infants in the earlier introduction
group commenced feeds with the umbilical artery catheter in situ

Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- Unclear risk Sequence generation method not reported
tion (selection bias)

Allocation concealment Low risk Sealed opaque envelopes

(selection bias)

Blinding (performance High risk Not stated but unlikely that carers were blinded to intervention groups
bias and detection bias)
Clinical assessments

Blinding (performance Unclear risk Not described

bias and detection bias)
Radiological assessments

Incomplete outcome data Low risk The trial excluded 2 infants in the early introduction group post-randomisation
(attrition bias) due to protocol violation. All other participants were accounted for
All outcomes

 
 
Karagianni 2010 
Methods Randomised controlled trial

Participants 84 singleton newborn infants of gestational age 27- 34 weeks' and birth weight < 10th percentile who
also had antenatal Doppler ultrasound evidence within 7 days before birth of 'pathological fetal perfu-
sion', defined as uterine or umbilical arterial pulsatility index > 90th percentile and middle cerebral ar-
terial pulsatility index < 10th percentile for gestational age

Infants were excluded with a major congenital anomaly or infection or had received exchange transfu-
sion or inotrope support

Setting: Neonatology Department, Aristotle University, Thessaloniki, Greece

Interventions Delayed (> 5 days after birth; 42 infants) versus early (≤ 5 days; 42 infants) introduction of enteral feeds
(expressed breast milk or preterm formula milk)

Minimal enteral feeding was continued until day 7 after birth and then feed volumes were advanced at
daily targeted increments of 15 mL/kg

Outcomes Incidence of NEC, mortality*, days to full enteral feeds*, duration of hospital stay*

Notes *Unpublished data courtesy of Dr Karagianni

Of the 84 infants enrolled, 81 completed the study. 3 infants died before 5 days after birth. We have in-
cluded these infants in the intention-to-treat analysis of mortality > 90% of infants were VLBW

Risk of bias

Bias Authors' judgement Support for judgement

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Karagianni 2010  (Continued)
Random sequence genera- Low risk Computer-generated sequence
tion (selection bias)

Allocation concealment Low risk Opaque sealed envelopes

(selection bias)

Blinding (performance High risk Carers and clinical assessors not blinded to allocation groups
bias and detection bias)
Clinical assessments

Blinding (performance Unclear risk No information available about blinding of radiological assessors
bias and detection bias)
Radiological assessments

Incomplete outcome data Low risk All data were included in the analyses
(attrition bias)
All outcomes

 
 
Khayata 1987 
Methods Randomised controlled trial

Participants 12 VLBW infants

Interventions Delayed introduction of enteral feeds (day 10 after birth; 7 infants) versus earlier introduction (< 4 days;
5 infants)

All infants received standard calorie formula. Volumes and rates of advancement were the same in both
groups

Outcomes Growth during the first 6 weeks after birth

Notes This trial was reported as an abstract only. Further (unpublished) methodological or outcome data
were not available

Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- Unclear risk Not described

tion (selection bias)

Allocation concealment Unclear risk Not described

(selection bias)

Blinding (performance High risk Not described but unlikely to be blinded

bias and detection bias)
Clinical assessments

Blinding (performance Unclear risk Not described

bias and detection bias)
Radiological assessments

Incomplete outcome data Unclear risk Not described

(attrition bias)

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Khayata 1987  (Continued)
All outcomes

 
 
Leaf 2012 
Methods Randomised controlled trial

Participants 404 preterm infants < 35 weeks' gestation and birth weight < 10th percentile and antenatal Doppler ul-
trasound evidence of:

1. absent or reversed end diastolic flow velocities on at least 50% of the Doppler waveforms from the
umbilical artery on at least 1 occasion during pregnancy

or

2. 'cerebral redistribution', defined as occurring when both the umbilical artery pulsatility index > 95th
percentile and the middle cerebral artery pulsatility index < 5th percentile for gestational age (Her-
shkovitz 2000)

Infants were excluded with a major congenital anomaly, receipt of in-utero transfusion, multi-organ
failure or need for inotrope support

Setting: 54 neonatal care centres in UK and Ireland

Interventions Delayed (day 5 after birth; 202 infants) versus early (day 2 after birth; 202 infants) introduction of milk
feeds

Protocol for advancing feed volumes was the same in both groups

Outcomes Days to full feeds (150 mL/kg/day) sustained for 3 days, incidence of NEC (all stages, and stage II/III),
mortality, invasive infection, time to regain birth weight, duration of hospital stay

Notes > 90% of infants were VLBW

Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- Low risk Computer-generated sequence

tion (selection bias)

Allocation concealment Low risk Central telephone randomisation

(selection bias)

Blinding (performance High risk Carers were not blinded to the allocation groups
bias and detection bias)
Clinical assessments

Blinding (performance Low risk All cases of NEC were reviewed independently by a committee that were blind-
bias and detection bias) ed to the study groups
Radiological assessments

Incomplete outcome data Unclear risk 2 infants (1 from each group) were excluded from the trial after randomisation
(attrition bias) occurred (error in recruitment and consent withdrawal)
All outcomes

 
 

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Ostertag 1986 
Methods Randomised controlled trial

Participants 38 VLBW infants assessed to be at 'high risk' of developing NEC based on a risk assessment score

Setting: Perinatology Center, New York Hospital-Cornell Medical Center, New York, USA

Interventions Delayed introduction of enteral feeds (day 7 after birth; 20 infants) versus earlier introduction (day 1; 18
infants)

Infants received feeds by continuous intragastric infusion starting initially with sterile water, then pro-
gressing to 2.5% dextrose, diluted formula, then full-strength standard calorie formula milk. Volumes
and rates of advancement were the same in both groups: constant infusion at 1 mL/hour for 7 days
then daily increments of 10 mL/kg/day

Outcomes Incidence of NEC and mortality

Notes Further details about exclusions after randomisation kindly provided by Dr La Gamma (March 2009)

Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- Low risk Random number table

tion (selection bias)

Allocation concealment Unclear risk Not described

(selection bias)

Blinding (performance High risk Carers not blinded to allocation groups

bias and detection bias)
Clinical assessments

Blinding (performance Low risk Radiologists reviewing abdominal films were blinded to the group assign-
bias and detection bias) ments
Radiological assessments

Incomplete outcome data Low risk 3 infants died before 7 days after birth. The investigators excluded 1 infant be-
(attrition bias) fore day 14 because of a feeding protocol violation. We have included all of
All outcomes these infants in the relevant intention-to-treat analyses

 
 
Pérez 2011 
Methods Randomised controlled trial

Participants 239 very preterm or VLBW infants. Included infants had not received any previous enteral feeds

Infants were excluded with congenital anomalies of the gastrointestinal tract, intrauterine growth re-
striction and respiratory or haemodynamic instability

Setting: Ramón González Valencia de Bucaramanga University Hospital, Columbia

Interventions Delayed enteral feeding (day 5 after birth, 104 infants) versus earlier enteral feeding (day 1-2 after birth,
135 infants)

All infants received a combination of breast and formula milk. Feed volumes exceeded trophic volumes
by the third day of enteral feeding

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Pérez 2011  (Continued)
Outcomes Incidence of NEC, mortality, duration of hospital stay, growth, days to reach full feeds (150 mL/kg/day)

Notes Original study published in Spanish

Risk of bias

Bias Authors' judgement Support for judgement

Random sequence genera- Unclear risk Not described (states "randomly assigned", and "controlled clinical trial")
tion (selection bias)

Allocation concealment Low risk Not described

(selection bias)

Blinding (performance High risk Carers or investigators not blinded to allocation groups
bias and detection bias)
Clinical assessments

Blinding (performance Low risk Abdominal radiographs interpreted by radiologist who was independent from
bias and detection bias) the study and blind to the allocation groups
Radiological assessments

Incomplete outcome data Low risk Complete follow-up assessment for primary outcomes
(attrition bias)
All outcomes

NEC: necrotising enterocolitis; VLBW: very low birth weight.

 
Characteristics of excluded studies [ordered by study ID]
 
Study Reason for exclusion

Chetry 2014 Both groups received early enteral feeds

Glass 1984 Infants were allocated alternately to either early (first day after birth) or delayed transpyloric enter-
al feeding. The delayed feeding group commenced enteral nutrition when assessed to be "clinically
stable" but this included initiation within 4 days after birth

Higgs 1974 Infants in the delayed progressive enteral feeds group received total parenteral nutrition as a co-in-
tervention

LaGamma 1985 This was not a randomised controlled trial

Said 2008 Infants in the delayed progressive enteral feeding group received minimal enteral nutrition prior to
feed advancement as a co-intervention

Sanghvi 2013 Both groups received early enteral feeds

Weiler 2006 Infants in both groups received some enteral feeds before 4 days after birth

Wilson 1997 Infants in the delayed progressive enteral feeds group also received delayed advancement of par-
enteral nutrition as a co-intervention

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DATA AND ANALYSES
 
Comparison 1.   Delayed versus early introduction of progressive enteral feeding

Outcome or subgroup title No. of No. of Statistical method Effect size

studies partici-
pants

1 Necrotising enterocolitis 8   Risk Ratio (M-H, Fixed, 95% CI) Subtotals only

1.1 All trials 8 1092 Risk Ratio (M-H, Fixed, 95% CI) 0.93 [0.64, 1.34]

1.2 Trials of infants with intrauterine 4 673 Risk Ratio (M-H, Fixed, 95% CI) 0.87 [0.54, 1.41]
growth restriction or abnormal ante-
natal Doppler flow velocities

2 Mortality prior to discharge 7   Risk Ratio (M-H, Fixed, 95% CI) Subtotals only

2.1 All trials 7 967 Risk Ratio (M-H, Fixed, 95% CI) 1.18 [0.75, 1.88]

2.2 Trials of infants with intrauterine 3 548 Risk Ratio (M-H, Fixed, 95% CI) 1.06 [0.55, 2.05]
growth restriction or abnormal ante-
natal Doppler flow velocities

3 Feed intolerance 3 288 Risk Ratio (M-H, Fixed, 95% CI) 0.84 [0.62, 1.15]

4 Incidence of invasive infection 2 457 Risk Ratio (M-H, Fixed, 95% CI) 1.27 [0.95, 1.70]

5 Duration of hospital admission (days) 3 346 Mean Difference (IV, Fixed, 95% CI) 2.11 [0.31, 3.90]

 
 
Analysis 1.1.   Comparison 1 Delayed versus early introduction of
progressive enteral feeding, Outcome 1 Necrotising enterocolitis.
Study or subgroup Favours Early Risk Ratio Weight Risk Ratio
Delayed
  n/N n/N M-H, Fixed, 95% CI   M-H, Fixed, 95% CI
1.1.1 All trials  
Abdelmaaboud 2012 6/63 8/62 15.38% 0.74[0.27,2]
Armanian 2013 1/35 1/47 1.63% 1.34[0.09,20.74]
Arnon 2013 0/30 0/30   Not estimable
Davey 1994 4/31 2/29 3.94% 1.87[0.37,9.46]
Karagianni 2010 4/42 6/42 11.44% 0.67[0.2,2.19]
Leaf 2012 18/202 18/202 34.33% 1[0.54,1.87]
Ostertag 1986 6/20 5/18 10.04% 1.08[0.4,2.94]
Pérez 2011 9/104 14/135 23.24% 0.83[0.38,1.85]
Subtotal (95% CI) 527 565 100% 0.93[0.64,1.34]
Total events: 48 (Favours Delayed), 54 (Early)  
Heterogeneity: Tau2=0; Chi2=1.5, df=6(P=0.96); I2=0%  
Test for overall effect: Z=0.38(P=0.7)  
   
1.1.2 Trials of infants with intrauterine growth restriction or abnormal  
antenatal Doppler flow velocities
Favours Delayed 0.05 0.2 1 5 20 Favours Early

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Study or subgroup Favours Early Risk Ratio Weight Risk Ratio

Delayed
  n/N n/N M-H, Fixed, 95% CI   M-H, Fixed, 95% CI
Abdelmaaboud 2012 6/63 8/62 25.15% 0.74[0.27,2]
Arnon 2013 0/30 0/30   Not estimable
Karagianni 2010 4/42 6/42 18.71% 0.67[0.2,2.19]
Leaf 2012 18/202 18/202 56.14% 1[0.54,1.87]
Subtotal (95% CI) 337 336 100% 0.87[0.54,1.41]
Total events: 28 (Favours Delayed), 32 (Early)  
Heterogeneity: Tau2=0; Chi2=0.49, df=2(P=0.78); I2=0%  
Test for overall effect: Z=0.56(P=0.58)  
Test for subgroup differences: Chi2=0.05, df=1 (P=0.83), I2=0%  

Favours Delayed 0.05 0.2 1 5 20 Favours Early

 
 
Analysis 1.2.   Comparison 1 Delayed versus early introduction of
progressive enteral feeding, Outcome 2 Mortality prior to discharge.
Study or subgroup Favours Early Risk Ratio Weight Risk Ratio
Delayed
  n/N n/N M-H, Fixed, 95% CI   M-H, Fixed, 95% CI
1.2.1 All trials  
Armanian 2013 0/35 2/47 7.31% 0.27[0.01,5.39]
Arnon 2013 0/30 0/30   Not estimable
Davey 1994 0/31 1/29 5.28% 0.31[0.01,7.38]
Karagianni 2010 4/42 4/42 13.65% 1[0.27,3.74]
Leaf 2012 13/202 12/202 40.95% 1.08[0.51,2.32]
Ostertag 1986 8/20 5/18 17.96% 1.44[0.57,3.61]
Pérez 2011 8/104 5/135 14.85% 2.08[0.7,6.16]
Subtotal (95% CI) 464 503 100% 1.18[0.75,1.88]
Total events: 33 (Favours Delayed), 29 (Early)  
Heterogeneity: Tau2=0; Chi2=2.94, df=5(P=0.71); I2=0%  
Test for overall effect: Z=0.71(P=0.48)  
   
1.2.2 Trials of infants with intrauterine growth restriction or abnormal  
antenatal Doppler flow velocities
Arnon 2013 0/30 0/30   Not estimable
Karagianni 2010 4/42 4/42 25% 1[0.27,3.74]
Leaf 2012 13/202 12/202 75% 1.08[0.51,2.32]
Subtotal (95% CI) 274 274 100% 1.06[0.55,2.05]
Total events: 17 (Favours Delayed), 16 (Early)  
Heterogeneity: Tau2=0; Chi2=0.01, df=1(P=0.92); I2=0%  
Test for overall effect: Z=0.18(P=0.86)  
Test for subgroup differences: Chi2=0.07, df=1 (P=0.79), I2=0%  

Favours Delayed 0.02 0.1 1 10 50 Favours Early

 
 

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Analysis 1.3.   Comparison 1 Delayed versus early introduction

of progressive enteral feeding, Outcome 3 Feed intolerance.
Study or subgroup Delayed Early Risk Ratio Weight Risk Ratio
  n/N n/N M-H, Fixed, 95% CI   M-H, Fixed, 95% CI
Abdelmaaboud 2012 23/63 22/62 39.02% 1.03[0.64,1.64]
Armanian 2013 9/35 24/47 36.05% 0.5[0.27,0.94]
Karagianni 2010 15/41 14/40 24.94% 1.05[0.58,1.87]
   
Total (95% CI) 139 149 100% 0.84[0.62,1.15]
Total events: 47 (Delayed), 60 (Early)  
Heterogeneity: Tau2=0; Chi2=3.8, df=2(P=0.15); I2=47.32%  
Test for overall effect: Z=1.07(P=0.29)  

Favours delayed 0.5 0.7 1 1.5 2 Favours early

 
 
Analysis 1.4.   Comparison 1 Delayed versus early introduction of
progressive enteral feeding, Outcome 4 Incidence of invasive infection.
Study or subgroup Delayed Early Risk Ratio Weight Risk Ratio
  n/N n/N M-H, Fixed, 95% CI   M-H, Fixed, 95% CI
Arnon 2013 4/30 2/30 3.5% 2[0.4,10.11]
Leaf 2012 69/199 55/198 96.5% 1.25[0.93,1.68]
   
Total (95% CI) 229 228 100% 1.27[0.95,1.7]
Total events: 73 (Delayed), 57 (Early)  
Heterogeneity: Tau2=0; Chi2=0.32, df=1(P=0.57); I2=0%  
Test for overall effect: Z=1.64(P=0.1)  

Favours delayed 0.1 0.2 0.5 1 2 5 10 Favours early

 
 
Analysis 1.5.   Comparison 1 Delayed versus early introduction of progressive
enteral feeding, Outcome 5 Duration of hospital admission (days).
Study or subgroup Delayed Early Mean Difference Weight Mean Difference
  N Mean(SD) N Mean(SD) Fixed, 95% CI   Fixed, 95% CI
Arnon 2013 30 46 (12) 30 37 (9) 11.21% 9[3.63,14.37]
Davey 1994 31 37.5 (3.8) 29 36.6 (4.5) 72.24% 0.9[-1.21,3.01]
Pérez 2011 96 30.1 (18) 130 27.4 (14.9) 16.55% 2.7[-1.72,7.12]
   
Total *** 157   189   100% 2.11[0.31,3.9]
Heterogeneity: Tau2=0; Chi2=7.66, df=2(P=0.02); I2=73.88%  
Test for overall effect: Z=2.3(P=0.02)  

Favours Delayed -10 -5 0 5 10 Favours Early

 
WHAT'S NEW
 

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Date Event Description

3 October 2014 New citation required but conclusions Updated search in September 2014 identified two new trials for
have not changed inclusion in this review update (Armanian 2013; Arnon 2013).

3 October 2014 New search has been performed This updates the review "Delayed introduction of progressive en-
teral feeds to prevent necrotising enterocolitis in very low birth
weight infants" (Morgan 2013b).

 
HISTORY
Protocol first published: Issue 4, 1998
Review first published: Issue 4, 1998

 
Date Event Description

13 January 2011 New search has been performed This updates the review "Delayed introduction of progressive en-
teral feeds to prevent necrotising enterocolitis in very low birth
weight infants" published in the Cochrane Database of Systemat-
ic Reviews, Issue 2, 2008 (Bombell 2008).

Updated search includes three new trials (Ostertag 1986; Kara-

gianni 2010; Leaf 2012).

New authorship for this review update.

13 January 2011 New citation required and conclusions The addition of new trial data has increased the total number
have changed of participating infants to 600 and modified the implications for
practice and research.

2 February 2008 New search has been performed This updates the review "Early versus delayed initiation of pro-
gressive enteral feedings for parenterally fed low birth weight or
preterm infants" published in the Cochrane Database of System-
atic Reviews, Issue 1, 2000 (Kennedy 2000).

The title has been changed to "Delayed introduction of progres-

sive enteral feeds to prevent necrotising enterocolitis in very low
birth weight infants" and has a new authorship of Sarah Bombell
and William McGuire. Changes made to the original protocol are
outlined below:

1. Introduction of progressive enteral feeds is defined as feed

volumes more than 24 ml/kg/day (1 ml/kg/hour).
2. The population has been restricted to very low birth weight
and very preterm infants
3. Subgroup analyses of extremely low birth weight and extreme-
ly preterm infants, and infants with evidence of intrauterine
growth restriction or absent or reversed end-diastolic flow veloc-
ities in Doppler studies of the fetal aorta or umbilical artery were
prespecified.

Search updated December 2007. No new trials were included,

but one on-going trial was identified.

The findings and implications for practice and research of the re-
view have not changed overall.

11 January 2008 Amended Converted to new review format.

Delayed introduction of progressive enteral feeds to prevent necrotising enterocolitis in very low birth weight infants (Review) 25
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 Cochrane Trusted evidence.
Informed decisions.
 
 
Library Better health. Cochrane Database of Systematic Reviews

 
CONTRIBUTIONS OF AUTHORS
Lauren Young and William McGuire updated the search, independently determined the eligibility of identified studies, assessed the
methodological quality of the included trials, and extracted the relevant information and data.

All authors completed the final review.

DECLARATIONS OF INTEREST
None known.

SOURCES OF SUPPORT

Internal sources
• Centre for Reviews and Dissemination, Hull York Medical School, UK.

External sources
• National Institute for Health Research, UK.
• Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health
and Human Services, USA.

Editorial support of the Cochrane Neonatal Review Group was funded with Federal funds from the Eunice Kennedy Shriver National
Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under
Contract No. HHSN267200603418C

INDEX TERMS

Medical Subject Headings (MeSH)

*Infant, Low Birth Weight;  *Infant, Premature;  Cause of Death;  Enteral Nutrition  [*methods];  Enterocolitis, Necrotizing  [*prevention
& control];  Infant, Extremely Low Birth Weight;  Infant, Extremely Premature;  Infant, Very Low Birth Weight;  Parenteral Nutrition; 
Randomized Controlled Trials as Topic;  Time Factors

MeSH check words

Humans; Infant, Newborn

Delayed introduction of progressive enteral feeds to prevent necrotising enterocolitis in very low birth weight infants (Review) 26
Copyright © 2014 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
 SOCIETY COMMENTARY

Donor Human Milk for Preterm Infants: Current Evidence

and Research Directions

y
Sertac Arslanoglu, zWillemijn Corpeleijn,
Guido Moro, §Christian Braegger,
jj
Cristina Campoy, ôVirginie Colomb, #Tamas Decsi,

Magnus Domellöf, yyMary Fewtrell,
zz
Iva Hojsak, §§Walter Mihatsch, jjjjChristian Mølgaard, ôôRaanan Shamir, ##Dominique Turck, and
z
Johannes van Goudoever, ESPGHAN Committee on Nutrition

ABSTRACT
The Committee on Nutrition of the European Society for Pediatric Gastro-
enterology, Hepatology, and Nutrition aims to document the existing
evidence of the benefits and common concerns deriving from the use of
donor human milk (DHM) in preterm infants. The comment also outlines
gaps in knowledge and gives recommendations for practice and suggestions
for future research directions. Protection against necrotizing enterocolitis is
the major clinical benefit deriving from the use of DHM when compared
with formula. Limited data also suggest unfortified DHM to be associated
with improved feeding tolerance and with reduced cardiovascular risk
factors during adolescence. Presence of a human milk bank (HMB) does
not decrease breast-feeding rates at discharge, but decreases the use of
formula during the first weeks of life. This commentary emphasizes that
fresh own mother’s milk (OMM) is the first choice in preterm infant feeding
and strong efforts should be made to promote lactation. When OMM is not
available, DHM is the recommended alternative. When neither OMM nor
DHM is available, preterm formula should be used. DHM should be
provided from an established HMB, which follows specific safety
Received June 11, 2013; accepted June 11, 2013.
From the
Italian Association of Human Milk Banks, Milan, Italy, the
yDivision of Neonatology, İzmir Dr Behçet Uz Children’s Hospital,
İzmir, Turkey, the zPaediatrics, VU University Medical Center, Amster-
dam, the Netherlands, and Paediatrics, Emma Children’s Hospital-AMC,
Amsterdam, The Netherlands, the §University Children’s Hospital,
Zurich, Switzerland, the jjDepartment of Paediatrics, University of
Granada, Granada, Spain, the ôHospital Necker Paris, Paris, France,
the #Department of Paediatrics, University of Pecs, Pecs, Hungary, the


Department of Clinical Sciences, Paediatrics, Umeå University,
Umeå, Sweden, the yyMRC Childhood Nutrition Research Centre,
UCL Institute of Child Health, London, UK, the zzReferral Center
for Pediatric Gastroenterology and Nutrition, Children’s Hospital
Zagreb, Zagreb, Croatia, the §§Department of Paediatrics, Harlaching,
Munich Municipal Hospitals, Munich, Germany, the jjjjDepartment of
Nutrition, Exercise and Sports, Faculty of Science, University of Copen-
hagen, Denmark, the ôôSchneider Children’s Medical Center of Israel,
Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel, and
the ##Jeanne de Flandre Children’s Hospital, Lille University Faculty of
Medicine, Lille, France.
Address correspondence and reprint requests to Sertac Arslanoglu, MD,
Associate Professor of Neonatology, Division of Neonatology, İzmir
Dr. Behçet Uz Children’s Hospital, İzmir 35210, Turkey (e-mail:
asertac@tiscali.it).
Drs Arslanoglu, Corpeleijn, and Moro are the guests; Dr Mihatsch is a
Committee secretary; and Dr Goudoever is a Committee chairman.
The authors report no conflicts of interest.
Copyright # 2013 by European Society for Pediatric Gastroenterology,
Hepatology, and Nutrition and North American Society for Pediatric
Gastroenterology, Hepatology, and Nutrition
DOI: 10.1097/MPG.0b013e3182a3af0a
guidelines. Storage and processing of human milk reduces some biological
components, which may diminish its health benefits. From a nutritional point
of view, DHM, like HM, does not meet the requirements of preterm infants,
necessitating a specific fortification regimen to optimize growth. Future
research should focus on the improvement of milk processing in HMB,
particularly of heat treatment; on the optimization of HM fortification; and
on further evaluation of the potential clinical benefits of processed and
fortified DHM.
Key Words: donor milk, human milk, human milk banking, pasteurization,
preterm infant
(JPGN 2013;57: 535–542)
I n a recent position paper by the European Society for Pediatric
Gastroenterology, Hepatology, and Nutrition Committee on
Nutrition, it was concluded that breast-feeding is the natural and
advisable way of supporting the growth and development of healthy
term infants (1). Human milk (HM) also offers benefits to preterm
infants (2–4); however, in preterm infants, breast-feeding may not
be possible, and own mother’s milk (OMM) may not be available.
In this situation, donor HM (DHM) and preterm infant formula are
the alternatives.
Official bodies such as the World Health Organization (5)
and the American Academy of Pediatrics (6) recommend the use
of donated breast milk as the first alternative, when maternal milk
is not available. American Academy of Pediatrics states that in
such a situation, pasteurized DHM should be the first choice for
preterm infants. To offer this opportunity to preterm infants, HM
should be obtained from a HM bank (HMB). The number of
HMBs is rapidly increasing worldwide. At present, in Europe,
there are 186 HMBs, and new banks will be established with the
support of the European Milk Bank Association (www.european-
milkbanking.com); however, DHM is not available to all preterm
infants.
In many countries, national policies to improve infant health
outcomes consider DHM obtained from an HMB to be a reasonable
and effective tool in the delivery of health care to infants and
children (7). Some countries have developed national guidelines
that are published in English (8–11).
This review aims to document the published evidence
regarding the benefits deriving from the use of DHM for preterm
infants, and to address the main concerns limiting its widespread
adoption as a standard care. It also outlines the gaps in knowledge,
and gives recommendations for practice and suggestions for
future research.

JPGN  Volume 57, Number 4, October 2013 535

Copyright 2013 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
 Arslanoglu et al
METHODS
The literature review included electronic searches of
MEDLINE (1966 –October 2011), EMBASE (1980–October
2011), CINAHL (1981–October 2011), the Cochrane Library,
and conference proceedings. The electronic search used the
following text words and MeSH terms: donor milk, human milk,
breast milk, banked milk, milk bank, milk banking, (human
milk OR breast milk) AND outcomes, (human milk OR breast
milk) AND necrotizing enterocolitis, (human milk OR breast milk)
AND infection, (human milk OR breast milk) AND neurodevelop-
ment, (human milk OR breast milk) AND bronchopulmonary
dysplasia, (human milk OR breast milk) AND (pasteurization OR
heat).
Reference lists of the previous reviews and relevant studies
were examined. Trials that had been reported only as abstracts were
eligible for inclusion if sufficient information was available from
the report.
CLINICAL BENEFITS DERIVING FROM
THE USE OF DHM
Randomized controlled trials (RCTs) focusing specifically
on pasteurized DHM as a sole diet are sparse because it is no longer
considered acceptable to randomize infants to any other diet if
OMM is available. In most of the studies randomly assigning
infants to HM or formula, the HM group includes both OMM
and DHM.
Necrotizing Enterocolitis (NEC)
Three systematic reviews (2,12,13) addressed specifically
the effect of DHM versus formula on clinical outcomes. All of these
reviews suggest that the use of DHM has a protective effect against
NEC in premature infants.
The Cochrane review in 2007 (12) considered 5 RCTs
conducted in preterm and low-birth-weight infants: Gross et al
1983, Lucas et al 1984 (trials 1 and 2), Schanler et al 2005, and
Tyson et al 1983 (14–18). In these studies, Gross et al (14)
compared term formula with unfortified DHM, whereas Lucas
et al (15,16) and Tyson et al (17) compared preterm formula
(PF) with unfortified DHM. Lucas trial 1 provides NEC incidence
comparing an exclusively DHM diet with PF in 159 infants,
whereas Lucas trial 2 compares DHM with PF as a supplement
to OMM (15,16). The RCT conducted by Schanler et al (18) is the
only one comparing PF with fortified DHM. DHM was pasteurized
in all of the studies except the Tyson RCT (17). A meta-analysis of
data from 5 trials demonstrated a significantly higher incidence of
NEC in formula-fed infants (typical relative risk 2.5, with 95%
confidence interval [CI] 1.2–5.1). The observed effect sizes were
similar across 5 studies, and there was no statistical evidence of
heterogeneity. The pooled estimate suggests that 1 extra case of
NEC will occur in every 33 infants who receive formula milk. The
systematic review and meta-analysis of Boyd et al in 2007 (2) and
an earlier systematic review and meta-analysis by McGuire et al in
2003 (13) came to similar conclusions. The paucity of data on
comparison of formula milk with nutrient-fortified HM (only 1
study) is the limitation in these reviews and highlights the need for
new RCTs comparing the effect of fortified donor milk versus PF on
NEC occurrence.
An intriguing point is the mechanism through which DHM
may be offering protection against NEC. This protection may be
through the supply of immunoprotective factors to the immature
mucosa; however, the absence of harmful antigens may also be a
contributing factor (19). NEC may be caused by the detrimental
536
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JPGN  Volume 57, Number 4, October 2013
effect of native cow’s-milk protein on the developing human
intestine. A recent multicenter RCT compared the outcomes of
very-low-birth-weight (VLBW) infants fortified by 2 different
kinds of HM fortifier (HMF) (20). One group received HM-based
HMF (HM concentrate with minerals and vitamins), whereas the
other received bovine milk–based HMF and PF. The HM-based
fortifier group had a significantly lower incidence of overall and
surgical NEC than the other group.
Conclusion and Comments on NEC
 Feeding preterm infants with DHM is associated with
a decreased risk of NEC when compared with formula
feeding.
 There are limited data on the comparison of feeding with
fortified DHM versus PF. Because fortification of HM is the
present practice for preterm and particularly for VLBW
infants, future studies should compare the effect of feeding
with fortified DHM versus formula on the NEC incidence.
 An exclusive HM diet (HM þ HM-based fortifier) may
reduce the NEC incidence even further, but this needs to
be confirmed.
Feeding Tolerance
Concerns regarding feeding intolerance and the perceived
risk of NEC are the main obstacles for initiation and advancement
of enteral feeds in VLBW infants. Three intervention trials
(14,15,21,22) conducted in the 1980s and included in the recent
2 systematic reviews (2,13) reported significantly fewer episodes
of feeding intolerance (14,15,21), withdrawals because of
intolerance (14), and diarrhoea (22) in the unfortified DHM
group compared with the formula group. In the large multicenter
English trial (15,21), infants fed exclusively unfortified DHM
(trial 1) and as a supplement to OMM (trial 2) were found to
establish full enteral feeds earlier and had fewer vomits and signs
of gastric stasis compared with those who received infant
formula; however, the data have not been published as a full
article. All of the studies have been performed using native
protein formula in contrast to hydrolyzed protein preterm infant
formula, which has been shown to significantly improve feeding
tolerance.
Conclusion and Comments on Feeding Tolerance
 Limited available data from the1980s support the hypothesis
that unfortified DHM results in improved feeding tolerance
compared with formula.
 Studies comparing the effect of fortified DHM versus formula
on feeding tolerance are lacking.
Bronchopulmonary Dysplasia
One RCT (18) designed to compare the incidence of infec-
tion-related events in extremely premature infants (<30 weeks of
gestation) observed a reduction in the incidence of bronchopul-
monary dysplasia (BPD) (oxygen need at postmenstrual age of
36 weeks) in the fortified DHM-fed infants compared with those fed
PF (15% vs 28%; P ¼ 0.048).
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 JPGN  Volume 57, Number 4, October 2013
Conclusion and Comment on BPD
DHM may be protective against BPD. This needs to be deter-
mined by further RCTs.
Long-Term Cardiovascular Risk Factors
Data on cardiovascular risk factors during adolescence are
available from follow-up of a single randomized trial conducted in
5 neonatal units in the UK in the early 1980s. In 1 limb of the
original study (15), preterm infants were randomized to receive
either unfortified DHM or a PF; randomization was stratified
according to whether or not the mother provided her own milk.
This is the only trial in which infants have been randomized to HM
versus formula without confounding by the mother’s decision to
breast-feed (23).
Adolescents (ages 13 to 16 years) who had been random-
ized to receive DHM, either as sole diet or as a supplement to
maternal breast milk during the neonatal period, had significantly
lower mean blood pressure (BP) (mean differences 4.1); how-
ever, follow-up was 26% only (24). Adolescents who had been
randomized to DHM also had a more favorable plasma lipid
profile, with a lower ratio of low-density to high-density lipo-
protein cholesterol than those fed PF (25). Owing to the low
percentage of follow-up (26%), the significance of these findings
is uncertain.
Conclusion and Comments on Cardiovascular Risk Factors

DHM in early life may have beneficial effects on cardiovas-
cular risk factors measured during adolescence; the signifi-
cance of these findings for the development of cardiovascular
disease is uncertain.
 A limitation in the evaluation of these findings is that the
comparison was made between PF and unfortified DHM.
This practice does not reflect the present feeding strategies
in neonatal intensive care units (NICUs). If the underlying
mechanism for these effects relates to slower early growth,
it is important to consider whether these effects would persist if
fortified DHM is used and early growth rates are faster.
 Further studies should compare the long-term outcomes
between fortified DHM versus PF fed infants.
Long-Term Neurodevelopment
The only RCT reporting impact of DHM on neurocognitive
outcomes is the English 3-center study (26). In this study, 502
preterm infants were assigned to receive either unfortified mature
DHM or PF as sole enteral feeds or as supplements to OMM. PF was
associated with an improved neurocognitive outcome at 1 year and
no difference in neurocognitive outcomes (Bayley scores) was seen
between the 2 diet groups at 18 months, but it must be noted that the
DHM collected in the United Kingdom in the early 1980 s had an
energy content of 50 kcal/100 mL. The low energy content was the
result of the fact that collected DHM was frequently drip milk which
had a lower fat content (26). Despite the importance of this outcome
parameter, no further follow-up results have been published by the
authors with regard to long-term neurodevelopment, whereas other
parameters such as cardiovascular biomarkers in adolescence have
been published.
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Copyright 2013 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
Donor Human Milk for Preterm Infants
Conclusion and Comments on Neurodevelopment
 No beneficial effect on neurocognitive outcome has been
shown in the only available RCT.
 The comparison was made between PF and unfortified
DHM, which was frequently drip milk having low energy
content. This practice does not reflect the current feeding
strategies in NICUs.
 Studies comparing fortified DHM and PF groups with regard
to neurodevelopment are needed.
Allergy
The neonatal period is a critical window of opportunity for
immunological adaptation. HM plays an important role in the
development of the immune system through its immunoactive
factors. Among these factors, HM oligosaccharides and long-chain
polyunsaturated fatty acids are well-known key immunomodulating
components (27,28). Recently, HM transforming growth factor-b
has been indicated as an immunoregulatory cytokine, particularly
for allergy prevention (29,30). The English multicenter trial eval-
uating the effect of feeding in the early postnatal period on allergic
manifestations at 18 months after term found no difference in the
incidence of allergic reactions between the DHM- and formula-fed
groups (31); however, in a subgroup of preterm infants with high
risk for allergy, cow’s-milk–based formula increased the risk of
developing 1 allergic manifestations (particularly eczema) (odds
ratio 3.6; 95% CI 1.4–9.1). High risk was defined as having a first-
degree relative with a history of atopic disease (eczema, asthma, hay
fever, drug reactions, or confirmed food allergy). No studies are
available examining the influence of HM as compared with formula
in infants with a high risk for developing allergy.
Conclusion and Comment on Allergy
 The only available RCT shows that DHM does not have a
protective effect against the development of allergy in pre-
term infants; however, the same RCT reports a protective
effect of DHM against eczema in preterm infants at high risk
for allergy.
CONCERNS AND UNCERTAINTIES
Safety
Microbiological Safety
DHM should be obtained from established HMBs that follow
specific guidelines for screening, storage, and handling procedures to
optimize its composition while ensuring its safety for the recipient
(32). Many countries now have their own HMB guidelines (8–11,33).
The first HMB was established as early as 1909 in Vienna, Austria.
Many banks have been established since then, and some closed
following the early years of the HIV pandemic in the 1980s.
Pasteurization of the milk minimizes the risk of disease
transmission via HM, inactivating most of the viral and bacterial
contaminants. In addition, donors are screened in a similar way as
for blood donation. No report has been published showing transfer
of diseases through pasteurized DHM, although milk may contain
microorganisms (34). Nevertheless, HMBs, like blood banks,
should be aware of the threat of emerging (milk transmissible)
pathogens that are not included in contemporary screening proto-
cols. There is concern that growth of Bacillus sp during the heating
537
 Arslanoglu et al
process may be increased (35); however, although spore-forming
Bacillus sp may survive pasteurization, this is thought to be a rare
contaminant of human breast milk in contrast to cow’s milk (36).
Regardless, this type of contamination can be controlled by proper
storage and handling after pasteurization, which should prevent any
Bacillus sp from growing. HMBs should have policies for micro-
biological quality control.
Chemical Pollutants, Including Drugs of Abuse
Environmental pollutants such as mercury, dioxins, and
polychlorinated biphenyls (PCBs) are taken up via food and stored
in fatty tissue. There are no specific studies conducted with DHM.
Some of the pollutants can act as endocrine disruptors involving
thyroid, hypothalamus, and gonads (37,38). Prenatal exposure to an
organochlorine compound has been reported to result in impaired
neurodevelopment at 4 years (39), whereas perinatal exposure to
high PCB levels has been associated with neurotoxicity (40), and
perinatal dioxin exposure has been associated with persistent
hematologic and immunologic disturbances (41). Theoretically,
these substances can be excreted in breast milk. The concentration
of PCBs and dioxins in breast milk of European women has
decreased during the last decade as a consequence of measures
against environmental pollution. Furthermore, as suggested in the
study, monitoring the effect of PCBs in colostral milk on the visual
function in infants (42), HM may be offsetting potential deleterious
effects of these pollutants through its various biofactors. Future
studies should address the presence of these pollutants in DHM and
their possible effects on infant health.
Besides environmental pollutants, other unwanted substances
such as medication, alcohol, nicotine, and drugs of abuse are also
excreted into the milk. Presently, no internationally accepted list of
medicines that can safely be used by milk donors exists. HMBs are
therefore expected to compile their own list based on available
literature and pharmacological properties. Because DHM is generally
intended for sick and premature infants, and infants are often exposed
to milk from >1 donor, guidelines for medication use in HM donors
should be more strict than those for women who are solely feeding
their own healthy infants. The safety of DHM relies heavily on the
accurate reporting of nicotine, alcohol, or drug abuse of potential
donors because it is not feasible to routinely test all milk for a wide
range of harmful substances. Special attention should also be paid to
the use of herbal remedies and herbal teas because some contain
harmful substances, for example, fennel tea can contain substantial
amounts of estragole (43).
Conclusion and Comments on Safety
 DHM should be pasteurized.
 Donors should be screened in a similar way as for blood
donation, and should be asked about their use of alcohol,
nicotine, and drugs.
 HM does not meet the high nutrient requirements of the
Studies are needed to address the presence and possible health
consequences of pollutants in DHM.
Alterations in Nutritional and Biological Quality
of DHM
Some significant concerns are related to the possible altera-
tions in the nutritional and biological quality of DHM because of its
handling and storage, but particularly because of the heat treatment.
Holder pasteurization (62.58C, 30 minutes) is the most commonly
538
Copyright 2013 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
JPGN  Volume 57, Number 4, October 2013
used method. It results in the loss of the quantity and/or activity of
some biologically functional milk components to varying degrees:
1. Mild to moderate decrease in IgA and secretory IgA
concentrations (20%–30%, range 0%–60%) and activity
(33%–39%) (44–53).
2. Considerable loss in concentration/activity of lactoferrin
(50%–75%) (46,47,49–51,54,55), lysozyme (24%–74%)
(44–48,50–52,54), IgG (34%–76%) (45,47), some cytokines
(interleukin-10, tumor necrosis factor-a) (56,57), growth factors,
and hormones (insulin-like growth factor 1, adinopectin, insulin,
and leptin) (58–60), and antioxidant capacity of HM (61).
3. Almost complete loss of lipase activity (44,49), IgM
(concentrations) (45,46), and white blood cells (62,63).
Other nutritional and biological components, such as oligo-
saccharides (64), lactose, glucose (65,66), long-chain polyunsatu-
rated fatty acids, gangliosides (57,67,68), vitamins A, D, E, B12, folic
acid (44,69), some cytokines (interleukin-2, -4, -5, -8, -13) (57), and
some growth factors (EGF and TGF-b1), are preserved (56,58).
Holder pasteurization maintains the bactericidal activity of
the milk against Escherichia coli better than high-temperature
short-term pasteurization (70). It has been also shown that despite
the reduction in IgA concentrations, remaining molecules in the
Holder-pasteurized HM effectively inhibit bacterial (enteropatho-
genic E coli) adhesion (71). Similarly, in an earlier study, although
Holder pasteurization decreased the activities of specific antibody
to E coli and lactoferrin, pasteurized milk remained effective at
inhibiting in vitro growth of E coli (54).
New methods to improve the biological quality and safety of
DHM are under investigation (72). High-temperature short-term
pasteurization (flash pasteurization, 728C for 5–15 seconds)
(44,49,55,58,70) and its homemade low-tech variant for developing
countries (flash-heat treatment) (73–75), thermoultrasonic treat-
ment (50), high-pressure processing (76,77), and Ohmic heat
treatment (72) are the alternative methods on which present studies
are focused.
Conclusion and Comments on Nutritional and
Biological Quality of DHM
 Holder pasteurization, the most commonly used procedure, is
safe but reduces the nutritional/biological quality of DHM.
 Pasteurization should be optimized to maintain microbiolo-
gical safety while preserving the highest amount and activity
of the bioactive milk components.
Slow Growth
Slow Growth Because of Inadequate Nutrient
Content of DHM
VLBW infant. Standard multicomponent fortification of HM
designed to optimize nutritional intakes (78) often falls short of this
goal with regard to protein (79,80). This problem may be amplified
with DHM, which is most often provided by the mothers of term
infants beyond 1 month postpartum and which is likely to have lower
protein content than preterm mothers’ milk (66,81–83). A recent
observational study indicates that using standard fortification, weight
gain is faster in preterm infants fed OMM than in those fed DHM,
whereas there is no difference in terms of linear growth (84).
The systematic reviews of Quigley (12) and Boyd (2)
reported that preterm or low-birth-weight infants who received
formula regained birth weight earlier and had higher short-term
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 JPGN  Volume 57, Number 4, October 2013
rates of weight gain, linear growth, and head growth than infants
who received DHM; however, of 8 trials included, only 1 (18)
compared fortified DHM with PF. In this trial, infants fed DHM had
a slower rate of weight gain compared with PF (17.1 vs 20.1
g  kg1  day1; P ¼ 0.001). Length and head circumference incre-
ments were similar in the 2 groups.
The fat and protein content of HM is extremely variable, and
protein decreases with lactation duration. In recent years, it has
become evident that preterm infants fed fortified HM (OMM or
DHM) receive less protein than assumed (85) and continue to grow
more slowly in the short term, even with standard HM fortification,
compared with PF-fed infants. Although there is some uncertainty
about the optimal growth, postnatal growth failure has not been
solved with HM fortification in standard fashion (79). Thus, HM
fortification should be optimized to achieve better short-term
growth, which is associated with improved neurocognitive out-
come. Individualized fortification has been shown to be effective in
improving protein intake, weight gain, and head circumference gain
(86,87). There are 2 ways to individualize HM fortification:
‘‘adjustable fortification’’ (individualization based on blood urea
nitrogen measurements) (86) and ‘‘targeted fortification’’ (indivi-
dualization based on milk analysis) (87). Improvement of the
quality of HMF is a further issue, and HM-based fortifier may
offer benefits compared with cow’s-milk–based fortifiers as shown
in the multicentric study using Prolact þ H2MF (HM concentrate
with minerals and vitamins) (20). Earlier studies showed that infants
fed exclusively HM proteins (HM þ HM protein supplement) have
plasma amino acid concentrations that differ significantly from
those fed either whey-predominant or casein-predominant formulas
at similar protein intakes. The amino acid pattern of low-birth-
weight infants fed exclusively HM proteins is similar to the pattern
found in growing breast-fed term infants (88,89).
Potential Slow Growth Because of Alterations in
the Nutritional Quality of DHM
As mentioned before, lipase activity is almost completely
lost following Holder pasteurization. It has also been shown that
heat induces alterations of the milk fat globule surface removing the
glycoprotein filaments (90). These heat-induced changes can
explain the reduced milk fat absorption reported in pasteurized
HM-fed preterm infants (91,92). Optimizing the heat processing
and determining the best method of pasteurization for maintaining
the nutritional and biological quality of DHM are essential.
Conclusion and Comments on Growth
 HM- and DHM-fed preterm infants have slower early growth
than PF-fed infants.
 Inadequacy of standard HM fortification, particularly with
regard to protein, and decreased fat absorption owing to the
loss of lipase activity following pasteurization and loss of fat
during handling are the main factors explaining the slower
growth seen in infants who receive DHM.
 Individualized fortification (adjustable or targeted) may help
to ensure adequate nutrient intakes.

Studies on the quality of fortifiers and different heat treatment
strategies are needed.
Does the Presence of an HMB Compete With
Breast-feeding?
The purpose of HM banking is to provide a HM supply for
infants (mainly preterm). Promotion of breast-feeding and use of
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Donor Human Milk for Preterm Infants
OMM come first. When OMM is not available or is insufficient,
DHM is used along with the ongoing efforts to promote lactation. In
fact, the European Milk Bank Association, in its constitution, states
the first 3 objectives of the Association as follows:
1. To promote breast-feeding
2. To promote the donation of HM to HMBs
3. To promote the use of DHM for premature infants and
other infants with specific needs who do not have access
to OMM
Some concerns have been raised that the presence of an HMB
and the use of DHM may attenuate the efforts to promote lactation
resulting in decreased breast-feeding rates.
No RCT could be identified addressing this concern, but
recently some reports showed the opposite: A report from Australia
(93) cites the breast-feeding rates in the 3 years following the
establishment of an HMB. Despite a marked increase in DHM use in
the NICU, opening an HMB did not reduce the rate of milk
expression, and breast-feeding rates at discharge increased.
In an attempt to improve HM availability for preterm infants,
health care providers of a NICU in UT designed an integrated
approach: ‘‘Breast Milk Early Saves Trouble Program’’ (94). This
program consisted of using exclusively HM (OMM and/or DHM) in
the NICU. Its implementation for 12 months increased HM and
DHM use in NICU, and breast-feeding rates at discharge tended to
increase compared with the situation before the implementation
period (53% vs 44%; P ¼ 0.09)
A Spanish study conducted in Madrid (95) directly
addressed this concern and evaluated the effect of opening an
HMB in a NICU on the rates of exclusive breast-feeding at
discharge and formula use in the NICU. The researchers concluded
that presence of an HMB in a neonatal unit did not reduce the rate of
exclusive breast-feeding at discharge, but did reduce the use of
infant formula during the first 4 weeks of life (37% vs 60%;
P ¼ 0.01). The availability of having DHM also enabled earlier
initiation of enteral feeding.
Conclusion and Comment on the Relation of HMBs
and Rates of Breast-feeding
The existing data show that the presence of an HMB and use of
DHM in the NICU do not decrease the breast-feeding rates at
discharge, but decrease formula use during the first weeks
of life.
CONCLUSIONS, RECOMMENDATIONS,
FUTURE RESEARCH DIRECTIONS
Conclusions
Based on the evidence presented in this commentary, the
European Society for Pediatric Gastroenterology, Hepatology, and
Nutrition Committee on Nutrition concludes the following:
1. DHM is associated with reduced NEC rates compared with
cow’s-milk–based formula.
2. Unfortified DHM, like HM, is associated with slower neonatal
growth when compared with PF.
3. Appropriately handled and pasteurized DHM is microbio-
logically safe.
4. Presence of an HMB does not decrease the breast-feeding rates
at discharge, but may decrease formula use during the first
weeks of life.
539
 Arslanoglu et al
Recommendations
1. OMM is the first choice in preterm infant feeding, and strong
efforts should be made to promote lactation.
2. When mother’s milk is not available, DHM is the preferred
choice. When mother’s milk and DHM are not available, PF
should be used.
3. No DHM should be provided outside the organization of an
established HMB.
4. Adequate screening of donors and pasteurization of the donor
milk should be performed.
5. DHM should be fortified to meet early nutrient requirements
and achieve better short-term growth, which is associated with
improved neurocognitive outcome. Individualized fortification
is advised.
Research Directions
1. Randomized clinical trials comparing
a. The impact of feeding with PF versus fortified DHM on
short-term clinical outcomes: growth, NEC, sepsis and other
infections, retinopathy of prematurity, BPD, feeding
tolerance, and mortality
b. The impact of feeding with PF versus fortified DHM on
long-term clinical outcomes: allergy, neurodevelopmental
outcomes, obesity, metabolic syndrome, and other cardio-
vascular risk factors
c. The impact of feeding with DHM with bovine fortifier
versus HM diet (OMM/DHM þ HM-based fortifier) on
short-term and long-term clinical outcomes
2. Development and evaluation of different pasteurization
techniques to optimize microbiological safety, and to maintain
the biological and nutritional quality of HM
3. Development of systems to ensure the lowest possible level of
toxic products and pollutants in the donor HM
REFERENCES
1. Agostoni C, Braegger C, Decsi T, et al. Breast-feeding: a commentary
by the ESPGHAN Committee on Nutrition. J Pediatr Gastroenterol
Nutr 2009;49:112–25.
2. Boyd CA, Quigley MA, Brocklehurst P. Donor breast milk versus infant
formula for preterm infants: systematic review and meta-analysis. Arch
Dis Child Fetal Neonatal Ed 2007;92:F169–75.
3. Sisk PM, Lovelady CA, Dillard RG, et al. Early human milk feeding is
associated with a lower risk of necrotizing enterocolitis in very low birth
weight infants. J Perinatol 2007;27:428–33.
4. Meinzen-Derr J, Poindexter B, Wrage L, et al. Role of human milk in
extremely low birth weight infants’ risk of necrotizing enterocolitis or
death. J Perinatol 2009;29:57–62.
5. WHO/UNICEF. Global strategy for infant and young child
feeding. http://whqlibdoc.who.int/publications/2003/9241562218.pdf.
Published 2003. Accessed September 5, 2013.
6. American Academy of Pediatrics. Section on Breastfeeding. Breast-
feeding and the use of human milk. Pediatrics 2012;129:e827–41.
7. Arnold LD. Global health policies that support the use of banked donor
human milk: a human rights issue. Int Breastfeed J 2006;1:26.
8. Hartmann BT, Pang WW, Keil AD, et al. Best practice guidelines for the
operation of a donor human milk bank in an Australian NICU. Early
Hum Dev 2007;83:667–73.
9. Arslanoglu S, Bertino E, Tonetto P, et al. Guidelines for the establish-
ment and operation of a donor human milk bank. J Matern Fetal
Neonatal Med 2010;23(suppl 2):1–20.
540
Copyright 2013 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
JPGN  Volume 57, Number 4, October 2013
10. HMBANA. Guidelines for the establishment and operation of a donor
human milk bank. https://www.hmbana.org/products/publications. Pub-
lished 2011. Accessed September 5, 2013.
11. National Institute for Health and Clinical Excellence (NICE). Donor
Breast Milk Banks: The Operation of Donor Milk Bank Services. http://
www.ncbi.nlm.nih.gov/pubmed/22319806. Accessed September 5,
2013.
12. Quigley MA, Henderson G, Anthony NY, et al. Formula milk versus
donor breast milk for feeding preterm or low birth weight infants.
Cochrane Database Syst Rev 2007:CD002971.
13. McGuire W, Anthony MY. Donor human milk versus formula for
preventing necrotising enterocolitis in preterm infants: systematic re-
view. Arch Dis Child Fetal Neonatal Ed 2003;88:F11–4.
14. Gross SJ. Growth and biochemical response of preterm infants fed
human milk or modified infant formula. N Engl J Med 1983;308:237–
41.
15. Lucas A, Gore SM, Cole TJ, et al. Multicentre trial on feeding low
birthweight infants: effects of diet on early growth. Arch Dis Child
1984;59:722–30.
16. Lucas A, Cole TJ. Breast milk and neonatal necrotising enterocolitis.
Lancet 1990;336:1519–23.
17. Tyson JE, Lasky RE, Mize CE, et al. Growth, metabolic response, and
development in very-low-birth-weight infants fed banked human milk or
enriched formula. I. Neonatal findings. J Pediatr 1983;103:95–104.
18. Schanler RJ, Lau C, Hurst NM, et al. Randomized trial of donor human
milk versus preterm formula as substitutes for mothers’ own milk in the
feeding of extremely premature infants. Pediatrics 2005;116:400–6.
19. Neu J, Walker WA. Necrotizing enterocolitis. N Engl J Med 2011;
364:255–64.
20. Sullivan S, Schanler RJ, Kim JH, et al. An exclusively human milk-
based diet is associated with a lower rate of necrotizing enterocolitis
than a diet of human milk and bovine milk-based products. J Pediatr
2010;156:562–7e1.
21. Lucas A. AIDS and human milk bank closures. Lancet 1987;1:1092–3.
22. Schultz K, Soltesz G, Mestyan J. The metabolic consequences of human
milk and formula feeding in premature infants. Acta Paediatr Scand
1980;69:647–52.
23. Fewtrell MS. Breast-feeding and later risk of CVD and obesity:
evidence from randomised trials. Proc Nutr Soc 2011;70:472–7.
24. Singhal A, Cole TJ, Lucas A. Early nutrition in preterm infants and later
blood pressure: two cohorts after randomised trials. Lancet 2001;
357:413–9.
25. Singhal A, Cole TJ, Fewtrell M, et al. Breastmilk feeding and lipopro-
tein profile in adolescents born preterm: follow-up of a prospective
randomised study. Lancet 2004;363:1571–8.
26. Lucas A, Morley R, Cole TJ, et al. A randomised multicentre study of
human milk versus formula and later development in preterm infants.
Arch Dis Child Fetal Neonatal Ed 1994;70:F141–6.
27. Bode L. Human milk oligosaccharides: prebiotics and beyond. Nutr Rev
2009;67(suppl 2):S183–91.
28. Gottrand F. Long-chain polyunsaturated fatty acids influence the im-
mune system of infants. J Nutr 2008;138:S1807–12.
29. Penttila IA. Milk-derived transforming growth factor-beta and the infant
immune response. J Pediatr 2010;156:S21–5.
30. Verhasselt V, Milcent V, Cazareth J, et al. Breast milk-mediated transfer
of an antigen induces tolerance and protection from allergic asthma. Nat
Med 2008;14:170–5.
31. Lucas A, Brooke OG, Morley R, et al. Early diet of preterm infants and
development of allergic or atopic disease: a randomised prospective
study. BMJ 1990;300:837–40.
32. Arslanoglu S, Ziegler EE, Moro GE. World Association of Perinatal
Medicine Working Group On Nutrition. Donor human milk in preterm
infant feeding: evidence and recommendations. J Perinat Med 2010;
38:347–51.
33. Décret No 2010-805 du 13 juillet 2010 relatif aux missions, à l’auto-
risation et aux conditions techniques d’organisation et de fonctionne-
ment des lactariums [in French]. http://sdp.perinat-france.org/ADLF/
textes_legislation_adlf.php. Accessed September 24, 2012.
34. Landers S, Updegrove K. Bacteriological screening of donor human
milk before and after Holder pasteurization. Breastfeed Med 2010;
5:117–21.
www.jpgn.org
 JPGN  Volume 57, Number 4, October 2013
35. Hanson ML, Wendorff WL, Houck KB. Effect of heat treatment of milk
on activation of Bacillus spores. J Food Prot 2005;68:1484–6.
36. Crielly EM, Logan NA, Anderton A. Studies on the Bacillus flora of
milk and milk products. J Appl Bacteriol 1994;77:256–63.
37. Robins JC, Marsit CJ, Padbury JF, et al. Endocrine disruptors, environ-
mental oxygen, epigenetics and pregnancy. Front Biosci (Elite Ed)
2011;3:690–700Review.
38. Crofton KM. Thyroid disrupting chemicals: mechanisms and mixtures.
Int J Androl 2008;31:209–23.
39. Puertas R, Lopez-Espinosa MJ, Cruz F, et al. Prenatal exposure to mirex
impairs neurodevelopment at age of 4 years. Neurotoxicology 2010;
31:154–60.
40. Huisman M, Koopman-Esseboom C, Fidler V, et al. Perinatal exposure
to polychlorinated biphenyls and dioxins and its effect on neonatal
neurological development. Early Hum Dev 1995;41:111–27.
41. ten Tusscher GW, Steerenberg PA, van Loveren H, et al. Persistent
hematologic and immunologic disturbances in 8-year-old Dutch chil-
dren associated with perinatal dioxin exposure. Environ Health Perspect
2003;111:1519–23.
42. Riva E, Grandi F, Massetto N, et al. Polychlorinated biphenyls in
colostral milk and visual function at 12 months of life. Acta Paediatr
2004;93:1103–7.
43. Raffo A, Nicoli S, Leclercq C, et al. Quantification of estragole in fennel
herbal teas: implications on the assessment of dietary exposure to
estragole. Food Chem Toxicol 2011;49:370–5.
44. Hamprecht K, Maschmann J, Muller D, et al. Cytomegalovirus (CMV)
inactivation in breast milk: reassessment of pasteurization and freeze-
thawing. Pediatr Res 2004;56:529–35.
45. Koenig A, de Albuquerque Diniz EM, Barbosa SF, et al. Immunologic
factors in human milk: the effects of gestational age and pasteurization.
J Hum Lact 2005;21:439–43.
46. Ford JE, Law BA, Marshall VM, et al. Influence of the heat treatment of
human milk on some of its protective constituents. J Pediatr 1977;
90:29–35.
47. Evans TJ, Ryley HC, Neale LM, et al. Effect of storage and heat on
antimicrobial proteins in human milk. Arch Dis Child 1978;53:239–41.
48. Gibbs JH, Fisher C, Bhattacharya S, et al. Drip breast milk: it’s
composition, collection and pasteurization. Early Hum Dev 1977;1:
227–45.
49. Baro C, Giribaldi M, Arslanoglu S, et al. Effect of two pasteurization
methods on the protein content of human milk. Front Biosci (Elite Ed)
2011;3:818–29.
50. Czank C, Simmer K, Hartmann PE. Simultaneous pasteurization and
homogenization of human milk by combining heat and ultrasound:
effect on milk quality. J Dairy Res 2010;77:183–9.
51. Akinbi H, Meinzen-Derr J, Auer C, et al. Alterations in the host defense
properties of human milk following prolonged storage or pasteurization.
J Pediatr Gastroenterol Nutr 2010;51:347–52.
52. Wills ME, Han VE, Harris DA, et al. Short-time low-temperature
pasteurisation of human milk. Early Hum Dev 1982;7:71–80.
53. Chen HY, Allen JC. Human milk antibacterial factors: the effect of
temperature on defense systems. Adv Exp Med Biol 2001;501:341–8.
54. Eyres R, Elliott RB, Howie RN, et al. Low-temperature pasteurisation of
human milk. N Z Med J 1978;87:134–5.
55. Conesa C, Rota C, Castillo E, et al. Antibacterial activity of recombinant
human lactoferrin from rice: effect of heat treatment. Biosci Biotechnol
Biochem 2009;73:1301–7.
56. Untalan PB, Keeney SE, Palkowetz KH, et al. Heat susceptibility of
interleukin-10 and other cytokines in donor human milk. Breastfeed
Med 2009;4:137–44.
57. Ewaschuk JB, Unger S, O’Connor DL, et al. Effect of pasteurization on
selected immune components of donated human breast milk. J Perinatol
2011;31:593–8.
58. Goelz R, Hihn E, Hamprecht K, et al. Effects of different CMV-heat-
inactivation-methods on growth factors in human breast milk. Pediatr
Res 2009;65:458–61.
59. Resto M, O’Connor D, Leef K, et al. Leptin levels in preterm human
breast milk and infant formula. Pediatrics 2001;108:E15.
60. Ley SH, Hanley AJ, Stone D, et al. Effects of pasteurization on
adiponectin and insulin concentrations in donor human milk. Pediatr
Res 2011;70:278–81.
www.jpgn.org
Copyright 2013 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
Donor Human Milk for Preterm Infants
61. Silvestre D, Miranda M, Muriach M, et al. Antioxidant capacity of
human milk: effect of thermal conditions for the pasteurization. Acta
Paediatr 2008;97:1070–4.
62. Tully DB, Jones F, Tully MR. Donor milk: what’s in it and what’s not.
J Hum Lact 2001;17:152–5.
63. Björkstén B, Burman LG, De Château P, et al. Collecting and banking
human milk: to heat or not to heat? BMJ 1980;281:765–9.
64. Bertino E, Coppa GV, Giuliani F, et al. Effects of Holder pasteurization
on human milk oligosaccharides. Int J Immunopathol Pharmacol
2008;21:381–5.
65. de Segura AG, Escuder D, Montilla A, et al. Heating-induced bacter-
iological and biochemical modifications in human donor milk after
holder pasteurisation. J Pediatr Gastroenterol Nutr 2012;54:197–
203.
66. Vieira AA, Soares FV, Pimenta HP, et al. Analysis of the influence of
pasteurization, freezing/thawing, and offer processes on human milk’s
macronutrient concentrations. Early Hum Dev 2011;87:577–80.
67. Henderson TR, Fay TN, Hamosh M. Effect of pasteurization on long
chain polyunsaturated fatty acid levels and enzyme activities of human
milk. J Pediatr 1998;132:876–8.
68. Fidler N, Sauerwald TU, Koletzko B, et al. Effects of human milk
pasteurization and sterilization on available fat content and fatty acid
composition. J Pediatr Gastroenterol Nutr 1998;27:317–22.
69. Van Zoeren-Grobben D, Schrijver J, Van den Berg H, et al. Human milk
vitamin content after pasteurisation, storage, or tube feeding. Arch Dis
Child 1987;62:161–5.
70. Silvestre D, Ruiz P, Martinez-Costa C, et al. Effect of pasteurization
on the bactericidal capacity of human milk. J Hum Lact 2008;24:
371–6.
71. Carbonare SB, Palmeira P, Silva ML, et al. Effect of microwave
radiation, pasteurization and lyophilization on the ability of human
milk to inhibit Escherichia coli adherence to HEp-2 cells. J Diarrhoeal
Dis Res 1996;14:90–4.
72. Moro GE, Arslanoglu S. Heat treatment of human milk. J Pediatr
Gastroenterol Nutr 2012;4:165–6.
73. Chantry CJ, Wiedeman J, Buehring G, et al. Effect of flash-heat
treatment on antimicrobial activity of breastmilk. Breastfeed Med
2011;6:111–6.
74. Volk ML, Hanson CV, Israel-Ballard K, et al. Inactivation of cell-
associated and cell-free HIV-1 by flash-heat treatment of breast milk.
J Acquir Immune Defic Syndr 2010;53:665–6.
75. Israel-Ballard K, Chantry C, Dewey K, et al. Viral, nutritional, and
bacterial safety of flash-heated and pretoria-pasteurized breast milk to
prevent mother-to-child transmission of HIV in resource-poor countries:
a pilot study. J Acquir Immune Defic Syndr 2005;40:175–81.
76. Viazis S, Farkas BE, Jaykus LA. Inactivation of bacterial pathogens in
human milk by high-pressure processing. J Food Prot 2008;71:109–18.
77. Permanyer M, Castellote C, Ramirez-Santana C, et al. Maintenance of
breast milk immunoglobulin A after high-pressure processing. J Dairy
Sci 2010;93:877–83.
78. Kuschel CA, Harding JE. Multicomponent fortified human milk for
promoting growth in preterm infants. Cochrane Database Syst Rev
2004:CD000343.
79. Arslanoglu S, Moro GE, Ziegler EE. The World Association of Perinatal
Medicine Working Group On Nutrition. Optimization of human milk
fortification for preterm infants: new concepts and recommendations.
J Perinat Med 2010;38:233–8.
80. Ziegler EE. Meeting the nutritional needs of the low-birth-weight infant.
Ann Nutr Metab 2011;58(suppl 1):8–18.
81. Wojcik KY, Rechtman DJ, Lee ML, et al. Macronutrient analysis of a
nationwide sample of donor breast milk. J Am Diet Assoc 2009;
109:137–40.
82. Casadio YS, Williams TM, Lai CT, et al. Evaluation of a mid-infrared
analyzer for the determination of the macronutrient composition of
human milk. J Hum Lact 2010;26:376–83.
83. Michaelsen KF, Skafte L, Badsberg JH, et al. Variation in macronu-
trients in human bank milk: influencing factors and implications for
human milk banking. J Pediatr Gastroenterol Nutr 1990;11:229–39.
84. Montjaux-Regis N, Cristini C, Arnaud C, et al. Improved growth of
preterm infants receiving mother’s own raw milk compared with
pasteurized donor milk. Acta Paediatr 2011;100:1548–54.
541
 Arslanoglu et al
85. Arslanoglu S, Moro GE, Ziegler EE. Preterm infants fed fortified human
milk receive less protein than they need. J Perinatol 2009;29:489–92.
86. Arslanoglu S, Moro GE, Ziegler EE. Adjustable fortification of human
milk fed to preterm infants: does it make a difference? J Perinatol
2006;26:614–21.
87. Polberger S, Räihä NC, Juvonen P, et al. Individualized protein for-
tification of human milk for preterm infants: comparison of ultrafiltrated
human milk protein and a bovine whey fortifier. J Pediatr Gastroenterol
Nutr 1999;29:332–8.
88. Moro G, Fulconis F, Minoli I, et al. Growth and plasma amino acid
concentrations in very low birthweight infants fed either human milk
protein fortified human milk or a whey predominant formula. Acta
Paediatr Scand 1989;78:18–22.
89. Moro GE, Minoli I, Fulconis F, et al. Growth and metabolic responses in
low-birth-weight Infants fed human milk fortified with human milk
protein or with a bovine milk preparation. J Pediatr Gastroenterol Nutr
1991;13:150–4.
542
Copyright 2013 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
JPGN  Volume 57, Number 4, October 2013
90. Buchheim W, Welsch U, Huston GE, et al. Glycoprotein filament
removal from human milk fat globules by heat treatment. Pediatrics
1988;81:141–6.
91. Andersson Y, Savman K, Blackberg L, et al. Pasteurization of mother’s
own milk reduces fat absorption and growth in preterm infants. Acta
Paediatr 2007;96:1445–9.
92. Williamson S, Finucane E, Ellis H, et al. Effect of heat treatment of
human milk on absorption of nitrogen, fat, sodium, calcium, and
phosphorus by preterm infants. Arch Dis Child 1978;53:555–63.
93. Simmer K, Hartmann B. The knowns and unknowns of human milk
banking. Early Hum Dev 2009;85:701–4.
94. Montgomery D, Schmutz N, Baer VL, et al. Effects of instituting the
‘‘BEST Program’’ (Breast Milk Early Saves Trouble) in a level III
NICU. J Hum Lact 2008;24:248–51.
95. Utrera Torres MI, Medina Lopez C, et al. Does opening a milk bank in a
neonatal unit change infant feeding practices? A before and after study.
Int Breastfeed J 2010;5:4.
www.jpgn.org