MAKALAH KELOMPOK

CRITICAL ANALISIS PRAKTIK KEBIDANAN

“TELAAH JURNAL ANAK, BAYI ATAU BALITA”

Disusun Oleh :
Kelompok 9

1. Anjar Arum Siti M (P27824620005)

2. Asri Hartutika (P27824620006)
3. Ernawati (P27824620015)
4. Indri Puspitorini (P27824620023)
5. Raras Amaranggana (P27824620037)

KEMENTERIAN KESEHATAN REPUBLIK INDONESIA

BADAN PENGEMBANGAN DAN PEMBERDAYAAN SUMBER DAYA MANUSIA KESEHATAN
POLITEKNIK KESEHATAN KEMENKES SURABAYA
JURUSAN KEBIDANAN
PROGRAM STUDI PROFESI BIDAN
2020
 KATA PENGANTAR

Dengan memanjatkan puji syukur kehadirat Allah SWT, yang telah memberikan
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Analisis Praktik Kebidanan” dengan lancar.
Kami berharap makalah ini dapat memberikan informasi kepada kita
semua tentang critical analisis praktik kebidanan. Dalam hal ini pun penyusun
masih dalam tahapan belajar, oleh karena itu kritik dan saran yang bersifat
membangun selalu kami harapkan demi kesempurnaan makalah ini.
Akhir kata kami sampaikan terima kasih kepada semua pihak yang telah
berperan serta dalam penyusunan makalah ini. Semoga makalah ini bermanfaat
bagi penyusun maupun pembaca.

Surabaya, September 2020

Penyusun
 JURNAL BAYI
Nama jurnal : Association between enteropathogens and malnutrition
in children aged 6–23 mo in Bangladesh: a case-
control study

Penulis : James A Platts-Mills, Mami Taniuchi, Md Jashim

Uddin, Shihab Uddin Sobuz, Mustafa Mahfuz, SM
Abdul Gaffar, Dinesh Mondal,5 Md Iqbal Hossain, M
Munirul Islam, AM Shamsir Ahmed, William A Petri,

CLARITY Rashidul Haque, Eric R Houpt, and Tahmeed Ahmed

Tahun : 2017
1. Mampu Kekurangan gizi pada anak tetap menjadi faktor
mengelaborasi risiko penting untuk kematian dan gangguan
masalah perkembangan jangka panjang. Paparan dini
enteropatogen telah dikaitkan dengan pertumbuhan
anak yang buruk.

2. Mampu dengan Tujuan utama untuk mengidentifikasi

cepat enteropatogen yang terkait dengan malnutrisi di
menemukan jalan Bangladesh.
keluarnya

3. Mampu Patogen merupakan kontributor yang diduga

memberikan untuk pertumbuhan dan perkembangan yang buruk
Ilustrasi pada anak-anak di rangkaian sumber daya rendah.

4. Mampu Sebagian besar penelitian sebelumnya telah

memberikan mengevaluasi sejumlah patogen dan telah
contoh mengungkapkan kaitannya dengan Shigella dan
penghasil enterotoksin tahan panas Escherichia coli,
enteroaggregative E. Coli
 1. Apakah hal itu American journal of clinical nutrition
benar?
2. Bagaimana dapat 2020
melalukan /cek

ACCURACY bahwa itu akurat?

3. Bagaimana Q1
menentukan itu
benar?
1. Mampu Artikel ini mampu memberikan informasi lebih
membrikan
detail. Dalam artikel ini terdapat abstrak, latar
informasi lebih
detail. belakang, metode penelitian,hasil, pembahasan dan
PRECISION kesimpulan.

2. Mampu Artikel ini mampu memberikan informasi lebih

memberikan spesifik. Dalam artikel ini terdapat tabel untuk
informasi lebih menjelaskan hasil penelitian
spesifik

1. Bagaimana Relevan karena dalam artikel ini menghubungkan

menghubungkan enteropatogen dan malnutrisi pada anak usia 6-23
ide dengan bulan
pertanyaan yang
timbul?

RELEVANCE
2. Bagaimana Jurnal ini merupakan penelitian yang terupdate
menghubungkan
dengan isu?
3. Bagaimana Pada jurnal ini mempunyai relasi yang baik pada ide
relasinya satu ide penelitian.
dengan ide
lainnya?
1. Jumlah problem Pathogen dan malnutrisi pada anak berusia 6-23 bulan
yang muncul
DEPTH
 2. Mengurai factor – 1. Kriteria inklusi :
factor yang  Anak dengan malnutrisi
bermakna  Anak yang berusia 6-23 bulan
 Anak yang mengalami gejala diare
2. Kriteria eksklusi :
 Anak dengan diare yang parah

BREADTH 1. Pandangan Anak-anak dengan Campylobacter, EAEC, LT-

terhadap hasil ETEC, Shigella / EIEC, norovirus genogroup II, dan
pengamatan hasil Giardia lebih mungkin mengalami malnutrisi saat
pengamatan dan deteksi patogen
jawaban
terhadap
pertanyaan/masa
lah
1. Berpikir logis, Infeksi dengan patogen terkait malnutrisi ini tetap
membuat berhubungan kuat dengan malnutrisi setelah
pengertian, mengendalikan potensi perancu oleh faktor
menemukan sosiodemografi. Ukuran efek secara jelas dikurangi
LOGICALNESS
fakta/ bukti/ dengan menyesuaikan faktor-faktor ini, menunjukkan
petunjuk bahwa mereka secara independen terkait dengan
infeksi enteropatogen dan malnutrisi. Untuk setiap
patogen individu, tidak ada hubungan yang signifikan
antara deteksi kuantitatif dan kasus malnutrisi

1. Informasi yang Hasil penelitian tidak sesuai dengan hipotesa

dibutuhkan karena deteksi dari patogen ini dikaitkan dengan
malnutrisi dengan faktor sosiodemografi

2. Factor yang Tidak ada faktor yang lebih penting

SIGNIFICANCE penting
3. Pertanyaan mana Adakah Hubungan antara enteropatogen dan malnutrisi
yang lebih pada anak usia 6-23 bulan?
signifikan?
FAIRNESS Menurut saya, jurnal ini telah memenuhi kaidah penulisan yang benar.
Didalamnya terdapat table sehingga mudah untuk dipahami oleh pembaca.
Informasi yang dipaparkan inovatif dan kreatif dan bisa disosialisasikan untuk
menambah wawasan

BELAJAR ABSTRAK Sudah baik karena sudah memuat latar belakang,

AKTIF metode, hasil, dan kesimpulan yang informatif

METODE Metode dijelaskan dengan jelas
HASIL Dijelaskan dengan jelas dan terdapat tabel yang
memberikan informasi lebih spesifik
PEMBAHASAN Pada pembahasan hasil penelitian dibandingkan
dengan penelitian sebelumnya dan teori teori
KESIMPULAN Pada kesimpulan sudah cukup menggambarkan hasil
Association between enteropathogens and malnutrition in children
aged 6–23 mo in Bangladesh: a case-control study1–3
James A Platts-Mills,4,6* Mami Taniuchi,4,6 Md Jashim Uddin,5 Shihab Uddin Sobuz,5 Mustafa Mahfuz,5 SM Abdul Gaffar,5
Dinesh Mondal,5 Md Iqbal Hossain,5 M Munirul Islam,5 AM Shamsir Ahmed,5 William A Petri,4 Rashidul Haque,5
Eric R Houpt,4,6 and Tahmeed Ahmed5,6
4
Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA; and 5International Center for Diarrhoeal Disease
Research, Bangladesh, Dhaka, Bangladesh
ABSTRACT
Background: Early exposure to enteropathogens has been associated
with malnutrition in children in low-resource settings. However, the
contribution of individual enteropathogens remains poorly defined.
Molecular diagnostics offer an increase in sensitivity for detecting
enteropathogens but have not been comprehensively applied to stud-
ies of malnutrition.
Objective: We sought to identify enteropathogens associated with
malnutrition in Bangladesh.
Design: Malnourished children [weight-for-age z score (WAZ)
,22] aged 6–23 mo in Dhaka, Bangladesh, and identified by
active community surveillance were enrolled as cases, and normal-
weight children (WAZ .21) of the same age and from the same
community were enrolled as controls. Stools were collected at enroll-
ment and, for cases, after a 5-mo nutritional intervention. Enrollment
and follow-up stools were tested by quantitative polymerase chain
reaction for 32 enteropathogens with the use of a custom-developed
TaqMan Array Card.
Results: Enteropathogen testing was performed on 486 cases and
442 controls upon enrollment and 365 cases at follow-up. At en-
rollment, the detection of enteroaggregative Escherichia coli (OR:
1.39; 95% CI: 1.05, 1.83), Campylobacter spp. (OR: 1.46; 95% CI:
1.11, 1.91), heat-labile enterotoxin-producing E. coli (OR: 1.55;
95% CI: 1.04, 2.33), Shigella/enteroinvasive E. coli (OR: 1.65;
95% CI: 1.10, 2.46), norovirus genogroup I (OR: 1.66; 95% CI:
1.23, 2.25), and Giardia (OR: 1.73; 95% CI: 1.20, 2.49) were as-
sociated with malnourished cases, and the total burden of these
pathogens remained associated with malnutrition after adjusting
for sociodemographic factors. The number of these pathogens at
follow-up was negatively associated with the change in WAZ during
the intervention (20.10 change in WAZ per pathogen detected;
95% CI: 20.14, 20.06), whereas the number at enrollment was
positively associated with the change in WAZ (0.05 change in
WAZ per pathogen detected; 95% CI: 0.00, 0.10).
Conclusions: A subset of enteropathogens was associated with
malnutrition in this setting. Broad interventions designed to reduce
the burden of infection with these pathogens are needed. This trial
was registered at clinicaltrials.gov as NCT02441426. Am J
Clin Nutr 2017;105:1132–8.
Keywords: children, enteropathogens, malnutrition, PCR, low-
resource settings, diarrhea
1132
INTRODUCTION
Child undernutrition remains an important risk factor for
both mortality and impaired long-term development in low-
resource settings (1, 2). Early exposure to enteropathogens
has been associated with poor child growth in these settings;
however, the role of specific enteropathogens has not been
comprehensively evaluated. Most prior studies have evaluated a
limited number of pathogens and have revealed associations
with Shigella and heat-labile enterotoxin-producing Escherichia
coli (LT-ETEC)7 (3, 4), enteroaggregative E. coli (EAEC) (5),
Campylobacter (4, 6), Cryptosporidium (7–9), Giardia (10–12),
and Ascaris (13). Furthermore, interventional studies designed
to reduce enteropathogen exposure have primarily used di-
arrhea and growth as outcomes because, to our knowledge,
appropriate enteropathogen-specific outcomes have not been
established.
The development of highly sensitive molecular diagnostics for a
wide range of enteropathogens has provided new insight into the
etiology of diarrhea in children in low-resource settings (14–16). In
this study (NCT02441426), we sought to use a broad molecular
diagnostic approach to identify enteropathogens associated with
malnutrition in a case-control study of children aged 6–23 mo in
Dhaka, Bangladesh.
1
Supported by the Bill & Melinda Gates Foundation and NIH grant
K23AI114888 (to JAP-M). This is an open access article distributed under
the CC-BY license (http://creativecommons.org/licenses/by/3.0/).
2
The supporting agencies had no role in the design or conduct of the
study, the collection, analysis, or interpretation of the data, or the preparation
or approval of the manuscript.
3
Supplemental Tables 1–3 are available from the “Online Supporting
Material” link in the online posting of the article and from the same link in
the online table of contents at http://ajcn.nutrition.org.
6
These authors contributed equally to this work.
*To whom correspondence should be addressed. E-mail: jp5t@virginia.
edu.
7
Abbreviations used: Cq, quantification cycle; EAEC, enteroaggregative
E. coli; EIA, enzyme immunoassay; EIEC, enteroinvasive E. coli; LT-ETEC,
heat-labile enterotoxin-producing E. coli; PCR, polymerase chain reaction;
qPCR, quantitative polymerase chain reaction; WAZ, weight-for-age z score.
Received May 20, 2016. Accepted for publication March 2, 2017.
First published online April 5, 2017; doi: 10.3945/ajcn.116.138800.
Am J Clin Nutr 2017;105:1132–8. Printed in USA.
 ENTEROPATHOGENS AND MALNUTRITION IN BANGLADESH
METHODS
Study design and sample collection
The study was conducted in Mirpur, a subdistrict of Dhaka,
Bangladesh. The study site has been described in detail (17), and
the results of the nutritional intervention have been reported
elsewhere (18). Briefly, children aged 6–23 mo presenting to a
community malnutrition clinic with a weight-for-age z score
(WAZ) ,22 were eligible for inclusion as a case. Children were
eligible if they had diarrheal symptoms upon presentation;
however, children with diarrhea that was severe (defined as
needing intravenuous hydration or hospitalization) or persistent
(defined as a duration .14 d) were excluded. Contemporaneous
controls, frequency matched by age, sex, and area of residence,
and a WAZ .21 were actively enrolled from the same neigh-
borhood (the Bauniabadh area of Mirpur). Enrollment was
performed from November 2009 to December 2012. After en-
rollment, cases were given 2 daily macronutrient supplements
[Pushti packets (18, 19)] for 5 mo or until reaching a WAZ
.21; severely malnourished cases (WAZ ,23) were given an
additional packet each day. Both cases and controls received a
micronutrient powder (MoniMix; Renata Limited) for $2 mo
(children enrolled after August 2010 were given the micro-
nutrient powder for 4 mo). The contents of both supplements are
described in Supplemental Table 1. All children aged $1 y
were given 200 mg albendazole at enrollment, and all diarrheal
episodes at enrollment and during follow-up were treated with
an oral rehydration solution and zinc. Weights were obtained
both at enrollment and after the completion of the intervention
with the use of digital scales. Data on household food insecurity,
income, water access and treatment, personal hygiene, latrine
access, and feeding practices were obtained at enrollment via a
maternal questionnaire. Insufficient food in the home was de-
fined as a maternal report of concern that there was not enough
food in the home during the month before enrollment. The age
of cessation of exclusive breastfeeding was defined as the age in
months at which the mother reported sustained introduction of
nonbreastmilk liquid or food into the diet. Approval was ob-
tained from the institutional ethics review boards at the In-
ternational Center for Diarrheal Disease Research, Bangladesh,
and the University of Virginia.
Stool testing
A quantitative polymerase chain reaction (qPCR) of stools was
performed with the use of a custom-developed TaqMan Array
Card that compartmentalized probe-based real-time PCR assays
for 32 enteropathogens. This was performed in 2015 on all
available archived stools from the enrollment as well as from
cases after the completion of the 5-mo intervention. First, nucleic
acid was extracted from specimens with the QIAamp Fast DNA
Stool mini kit (Qiagen). Two external controls, MS2 bacterio-
phage and Phocine herpesvirus, were added to the stools during
extraction to confirm nucleic acid extraction and amplification
efficiency. The analytic cutoff of each pathogen was a quanti-
fication cycle (Cq) of 35; thus, a Cq . 35 was considered neg-
ative, as described previously (14). Pathogen quantities were
reported on a log scale on which each Cq value decrease
represented a 2-fold increase in pathogen quantity. Enrollment
stools were also tested for bacteria by culture and protozoa with
1133
the use of an enzyme immunoassay (EIA) as described pre-
viously (20). Specifically, EIA was performed for Campylobac-
ter (ProSpecT) and E. histolytica, Giardia, and Cryptosporidium
(TechLab). Testing for diarrheagenic E. coli was performed by
pooling 5 lactose-fermenting colonies for multiplex PCR for shiga
toxin 1 (stx1), shiga toxin 2 (stx2), heat-stabile enterotoxin (ST),
heat-labile enterotoxin (LT), intimin (eae), bundle-forming pilus
(bfpA), invasion plasmid antigen H (ipaH), AggR-activated Trans-
porter (gene A) (aatA), and AggR-activated Island (gene C) (aaiC).
Statistical analysis
We used univariable logistic regression to describe the associa-
tion between sociodemographic factors and case-control status. To
identify relations between enteropathogen detection and case-control
status, we fit a logistic regression model by dichotomously detecting
pathogens by either the original microbiological workup or PCR and
adjusting for age at enrollment, sex, and diarrhea at enrollment. To
estimate the association between the number of malnutrition-
associated pathogens detected and case-control status, we fit a
logistic regression model, adjusting for age at enrollment, sex, and
diarrhea at enrollment, as well as sociodemographic factors of
interest identified by regression as described previously.
To describe the association between pathogen presence at en-
rollment and follow-up and the change in WAZ in cases, we fit a
multivariable linear regression model for each pathogen, with the
change in WAZ from enrollment until the end of the intervention as
the outcome and the baseline WAZ, sex, enrollment age, socio-
demographic factors, and presence of the pathogen at both enrollment
and follow-up as predictors. All statistical analyses were performed
with the use of R version 3.2.2 (R Foundation for Statistical
Computing).
RESULTS
A total of 500 cases and 480 controls were enrolled, of whom
95% (928/980) had an enrollment stool available, and 73%
(365/500) of cases had both repeat anthropometry and qPCR
performed on a follow-up stool (Figure 1). First, we identified
sociodemographic characteristics at enrollment associated with
malnutrition (Table 1). Cases were slightly older than controls,
were breastfed for a shorter duration, and came from families
with a lower monthly income. Mothers of case children were
more likely to describe food insecurity and have a primary
drinking water source outside the home than those of control
children and were less likely to routinely treat their drinking
water. Malnourished children were not more likely to have di-
arrhea at the time of enrollment. The prevalence of stunting and
wasting was strikingly higher in cases.
qPCR detection of EAEC (OR: 1.39; 95% CI: 1.05, 1.83),
Campylobacter spp. (OR: 1.46; 95% CI: 1.11, 1.91), LT-ETEC
(OR: 1.55; 95% CI: 1.04, 2.33), Shigella/enteroinvasive E. coli
(EIEC) (OR: 1.65; 95% CI: 1.10, 2.46), norovirus genogroup II
(OR: 1.66; 95% CI: 1.23, 2.25), and Giardia (OR: 1.73;
95% CI: 1.20, 2.49) was associated with malnutrition at enrollment
after adjusting for enrollment age, sex, and the presence of
diarrhea at enrollment (Table 2). After further adjusting for
sociodemographic factors, the association remained statisti-
cally significant for EAEC, norovirus genogroup II, and
Giardia. Mixed infection with these malnutrition-associated
1134 PLATTS-MILLS ET AL.

FIGURE 1 Study flow diagram. qPCR, quantitative polymerase chain reaction; WAZ, weight-for-age z score.

pathogens was common (mean 6 SD for cases: 1.86 6 0.93;
mean 6 SD for controls: 1.45 6 0.97; Mann-Whitney test;
P , 0.001), and the detection of these pathogens was associated
with malnutrition in a dose-dependent fashion, an association that
persisted after adjusting for sociodemographic factors (Table 3).
For all pathogens, there was no statistically significant difference
in the quantity detected between cases and controls (Figure 2).
Culture- and EIA-based diagnostics did not reveal any statistically
significant associations (Supplemental Table 2). Similar associ-
ations as those between qPCR pathogen detection and low WAZ
were observed between qPCR pathogen detection and stunted
compared with nonstunted children (Supplemental Table 3).
The 5-mo nutritional intervention did not substantially in-
crease the WAZ of the malnourished cases (mean 6 SD change
in WAZ: 0.09 6 0.50). For most pathogens, there was no cor-
relation between detection at enrollment and follow-up in the
same individual, with the exception of Campylobacter (OR:
1.70; 95% CI: 1.07, 2.71; P = 0.019), C. difficile (OR: 11.34;
95% CI: 1.00, 74.89; P = 0.025), Giardia (OR: 3.46; 95% CI:
1.94, 6.18; P , 0.001), and Trichuris (OR: 14.08; 95% CI: 3.58,
50.65; P , 0.001) (all Fisher’s exact tests). We then examined
the enrollment stools of cases to identify whether these patho-
gens were associated with the change in WAZ during follow-up
(Figure 3). Although children with Campylobacter, EAEC,
LT-ETEC, Shigella/EIEC, norovirus genogroup II, and Giardia
were more likely to be malnourished, the detection of these
pathogens at enrollment was not associated with a lower
change in WAZ during follow-up. In fact, the detection of Cam-
pylobacter, as well as the total number of these pathogens detected
at enrollment (0.05 change in WAZ per pathogen detected; 95% CI:
0.00, 0.10; P = 0.040), were marginally positively associated with
the change in WAZ during the follow-up period.
Finally, we examined follow-up stools from cases to identify
pathogens associated with a lower change in WAZ over the
5-mo follow-up period (Figure 3). The detection of norovirus
genogroup II, LT-ETEC, Giardia, EAEC, and Campylobacter

TABLE 1
Study population characteristics1
Cases Controls
Sociodemographic factors (n = 486)2 (n = 442)3 ORs (95% CIs) P values

Age, mo 14 4
(9–19) 11 (8–15) 1.09 (1.06, 1.11) ,0.001
Females, n (%) 232 (47.7) 218 (49.3) 0.94 (0.73, 1.21) 0.630
Wasted at enrollment (WLZ ,22), n (%) 187 (38.5) 1 (0.2) 275.81 (38.48, 1976.97) ,0.001
Stunted an enrollment (LAZ ,22), n (%) 342 (70.4) 22 (5.0) 45.34 (28.31, 72.60) ,0.001
Diarrhea at enrollment, n (%) 14 (2.9) 22 (5.0) 0.57 (0.29, 1.12) 0.103
Insufficient food in the home, n (%) 228 (46.9) 154 (34.8) 1.65 (1.27, 2.15) ,0.001
Monthly income (thousand taka), n (%) 7 (5–9) 8 (6–12) 0.92 (0.90, 0.95) ,0.001
Primary drinking water source outside the home, n (%) 443 (91.2) 356 (80.5) 2.49 (1.68, 3.68) ,0.001
Routine treatment of drinking water, n (%) 292 (60.1) 322 (72.9) 0.56 (0.43, 0.74) ,0.001
Handwashing after using toilet, n (%) 129 (26.5) 94 (21.3) 1.34 (0.99, 1.81) 0.061
Access to flushing toilet, n (%) 162 (33.3) 157 (35.5) 0.91 (0.69, 1.19) 0.484
Current exclusive or partial breastfeeding, n (%) 452 (93.0) 416 (94.1) 0.83 (0.49, 1.41) 0.491
Age of cessation of exclusive breastfeeding, mo 3 (0–5) 4 (0–6) 0.96 (0.91, 1.01) 0.154
1
Univariate logistic regression was used to estimate the ORs (95% CIs) and P values. LAZ, length-for-age z score;
WAZ, weight-for-age z score; WLZ, weight-for-length z score.
2
WAZ ,22.
3
WAZ .21.
4
Median; IQR in parentheses (all such values).
 ENTEROPATHOGENS AND MALNUTRITION IN BANGLADESH 1135
TABLE 2
Pathogen detection by TaqMan Array Card in cases and controls1
Crude2 Adjusted3

Cases Controls ORs ORs

(n = 486) (n = 442) (95% CIs) P values (95% CIs) P values

Bacteria, n (%)
Aeromonas spp. 8 (1.6) 9 (2.0) 0.92 (0.34, 2.48) 0.874 0.77 (0.28, 2.11) 0.606
Campylobacter jejuni/coli 149 (30.7) 101 (22.9) 1.46 (1.08, 1.97) 0.014 1.26 (0.92, 1.72) 0.149
Campylobacter spp. 218 (44.9) 153 (34.6) 1.46 (1.11, 1.91) 0.007 1.22 (0.92, 1.63) 0.165
Clostridium difficile 18 (3.7) 15 (3.4) 1.36 (0.66, 2.78) 0.401 1.57 (0.74, 3.32) 0.237
EAEC 311 (64) 264 (59.7) 1.39 (1.05, 1.83) 0.020 1.36 (1.02, 1.82) 0.035
aEPEC 128 (26.3) 118 (26.7) 0.92 (0.68, 1.24) 0.580 0.95 (0.69, 1.30) 0.744
tEPEC 83 (17.1) 79 (17.9) 1.01 (0.71, 1.42) 0.967 0.93 (0.65, 1.34) 0.699
LT-ETEC 73 (15.0) 45 (10.2) 1.55 (1.04, 2.33) 0.033 1.43 (0.94, 2.17) 0.098
ST-ETEC 141 (29) 105 (23.8) 1.26 (0.94, 1.71) 0.127 1.27 (0.93, 1.75) 0.135
Shigella/EIEC 93 (19.1) 46 (10.4) 1.65 (1.10, 2.46) 0.014 1.47 (0.97, 2.23) 0.070
Viruses, n (%)
Adenovirus 40/41 99 (20.4) 86 (19.5) 1.14 (0.82, 1.58) 0.451 1.18 (0.83, 1.66) 0.358
Astrovirus 46 (9.5) 40 (9.0) 1.10 (0.70, 1.73) 0.681 1.03 (0.64, 1.63) 0.912
Norovirus GI 50 (10.3) 35 (7.9) 1.31 (0.83, 2.09) 0.247 1.37 (0.84, 2.22) 0.204
Norovirus GII 148 (30.5) 98 (22.2) 1.66 (1.23, 2.25) 0.001 1.73 (1.26, 2.37) 0.001
Rotavirus 48 (9.9) 52 (11.8) 0.99 (0.65, 1.52) 0.976 1.07 (0.69, 1.67) 0.758
Sapovirus 149 (30.7) 128 (29.0) 1.09 (0.82, 1.45) 0.567 1.07 (0.79, 1.44) 0.680
Parasites, n (%)
Ascaris lumbricoides 14 (2.9) 5 (1.1) 1.88 (0.66, 5.36) 0.239 1.79 (0.61, 5.31) 0.292
Cryptosporidium 44 (9.1) 39 (8.8) 0.93 (0.59, 1.48) 0.768 0.89 (0.55, 1.45) 0.651
Enterocytozoon bieneusi 54 (11.1) 34 (7.7) 1.20 (0.76, 1.91) 0.433 1.00 (0.62, 1.62) 0.998
Giardia 109 (22.4) 55 (12.4) 1.73 (1.20, 2.49) 0.003 1.51 (1.04, 2.20) 0.031
Trichuris trichiura 21 (4.3) 14 (3.2) 0.99 (0.49, 2.01) 0.981 0.90 (0.43, 1.89) 0.787
1
All pathogens detected in $1% of stools are shown. aEPEC, atypical enteropathogenic E. coli; EAEC, enteroag-
gregative E. coli; EIEC, enteroinvasive E. coli; GI, genogroup I; GII, genogroup II; LT-ETEC, heat-labile enterotoxin-
producing E. coli; ST-ETEC, heat-stable enterotoxin-producing E. coli; tEPEC, typical enteropathogenic E. coli.
2
Estimated with the use of multivariable logistic regression and adjusted for enrollment age, sex, and diarrhea at
enrollment.
3
Estimated with the use of multivariable logistic regression and adjusted for enrollment age, sex, diarrhea at enroll-
ment, insufficient food in the home, income, location of primary water source, routine treatment of drinking water, and age
of cessation of exclusive breastfeeding.

were again associated with a lower change in WAZ during pathogens detected in follow-up stools was also negatively
follow-up, whereas Shigella/EIEC detection was not associ- associated with the change in WAZ (20.10 change in WAZ
ated with the change in WAZ. The total number of these per pathogen detected; 95% CI: 20.14, 20.06; P , 0.001).

TABLE 3
Adjusted association between the number of malnutrition-associated pathogens detected and a WAZ ,221
Crude3 Adjusted4
Pathogens Cases Controls
detected2 (n = 486) (n = 442) ORs (95% CIs) P values ORs (95% CIs) P values

0 40 (8.2) 79 (17.9) Reference — Reference —

1 130 (26.7) 159 (36.0) 1.70 (1.08, 2.69) 0.023 1.55 (0.96, 2.49) 0.073
2 177 (36.4) 131 (29.6) 2.70 (1.71, 4.26) ,0.001 2.32 (1.44, 3.72) ,0.001
$3 139 (28.6) 73 (16.5) 3.82 (2.35, 6.22) ,0.001 3.02 (1.82, 5.01) ,0.001
1
WAZ, weight-for-age z score.
2
Defined as the number of detections of Campylobacter, enteroaggregative E. coli, heat-labile enterotoxin-producing
E. coli, Shigella/enteroinvasive E. coli, norovirus genogroup II, and Giardia with the use of polymerase chain reaction from
the stool collected at enrollment.
3
Estimated with the use of multivariable logistic regression and adjusted for enrollment age, sex, and diarrhea at
enrollment.
4
Estimated with the use of multivariable logistic regression and adjusted for enrollment age, sex, diarrhea at enroll-
ment, insufficient food in the home, income, location of primary water source, routine treatment of drinking water, and age
of cessation of exclusive breastfeeding.
1136 PLATTS-MILLS ET AL.

FIGURE 2 Pathogen quantity when detected with the use of quantitative polymerase chain reaction in cases and controls. Box-and-whisker plots
are shown with the use of Tukey’s method, in which the bottom and top of the box represent the first and third quartiles, respectively, the line within
the box represents the median, the whiskers extend from the box to all values within 1.5 times the IQR, and points beyond the whiskers represent
outliers. For all pathogens, there was no statistically significant difference in the quantity between cases and controls (Mann-Whitney test; P . 0.05).
aEPEC, atypical enteropathogenic E. coli; EAEC, enteroaggregative E. coli; EIEC, enteroinvasive E. coli; GI, genogroup I; GII, genogroup II; LT-
ETEC, heat-labile enterotoxin-producing E. coli; ST-ETEC, heat-stable enterotoxin-producing E. coli; tEPEC, typical enteropathogenic E. coli.

DISCUSSION these children. Shigella, Campylobacter, and EAEC are invasive

In this case-control study of malnourished children aged ,2 y in
Dhaka, Bangladesh, molecular diagnostics increased the sensitivity
and breadth of enteropathogen detection and identified associa-
tions between enteropathogen infection and malnutrition. Infection
with Campylobacter, EAEC, LT-ETEC, Shigella/EIEC, norovirus
genogroup II, and Giardia was associated with malnourished cases
(defined herein as WAZ ,22). Furthermore, infection with these
malnutrition-associated pathogens remained strongly associated
with malnutrition after controlling for potential confounding by
sociodemographic factors. The effect sizes were clearly reduced by
adjusting for these factors, suggesting that they are independently
associated with both enteropathogen infection and malnutrition. For
each individual pathogen, there was no significant association be-
tween quantitative detection and malnourished cases. We presume
that this is because with high quantities of most of these pathogens
diarrhea becomes likely (14), and children with severe and per-
sistent diarrhea were excluded, whereas less severe diarrhea was
rare at enrollment in this study. That is, the detection of high
quantities of these pathogens in the absence of diarrhea is un-
common. We did, however, observe that the detection of these
pathogens was associated with malnutrition. This observation
supports the link between these enteropathogen infections and
malnutrition in these settings. Plausible mechanisms exist for the
relation between many of these pathogens and malnutrition, in-
cluding increases in intestinal inflammation and permeability, that
are characteristic of environmental enteric dysfunction (21, 22).
The association with malnutrition was predominantly seen for
bacterial enteropathogens, some of which were highly prevalent in
enteropathogens that have clearly been associated with in-
flammation and gut barrier disruption (5, 23, 24). Enterotoxigenic
E. coli has also been associated with poor growth in several
studies (3, 4), and it has been postulated that heat-labile toxin
serves as a marker of the presence of certain colonization factors
that may mediate the association with malnutrition (25). The
recent application of culture-independent diagnostic tests for
Campylobacter has revealed a substantially higher prevalence
than previously appreciated, with a substantial burden of disease
(26). The strength of the association with cases was similar for
detecting Campylobacter jejuni/coli as well the Campylobacter
genus in general. Additional work is needed to identify the bur-
den and impact of diverse Campylobacter spp. in these settings
(27). Giardia has also been associated with poor growth (11). The
finding of an association between norovirus infection and mal-
nutrition is new to our knowledge. Immune dysfunction is a risk
factor for norovirus infection and is associated with persistent
shedding of this organism (28–30). One could speculate that the
increased detection of norovirus in cases may be a sequela of
impaired mucosal immunity. A strength of this work is the
testing for a broad range of pathogens so that prevalence and
effect sizes could be compared side by side. It is striking that
multiple pathogens were associated with malnutrition, and that
infection with many of these pathogens was common. In-
terventions aimed to broadly reduce the exposure to multiple
pathogens will be needed to affect growth improvements.
Although malnourished cases were more likely to have in-
fections with these pathogens than were normal-weight controls,
 ENTEROPATHOGENS AND MALNUTRITION IN BANGLADESH 1137

FIGURE 3 Association between pathogen detection at both enrollment and follow-up and change in weight during follow-up derived from a multivariable
linear regression model for each pathogen, with the change in WAZ from enrollment until the end of the intervention as the outcome and the baseline WAZ,
enrollment age, sex, diarrhea at enrollment, insufficient food in the home, income, location of primary water source, routine treatment of drinking water, and
age of cessation of exclusive breastfeeding as well as the presence of the pathogen at both enrollment and follow-up as predictors. The x axis in panel A shows
the difference in the change in WAZ from enrollment to the completion of a 5-mo nutritional intervention for cases in which each pathogen was detected
compared with not being detected at enrollment (black) and after the completion of the intervention (gray); panel B shows the proportion of stools in which
these pathogens were detected at enrollment (black) and follow-up (gray). EAEC, enteroaggregative E. coli; EIEC, enteroinvasive E. coli; GII, genogroup II;
LT-ETEC, heat-labile enterotoxin-producing E. coli; WAZ, weight-for-age z score.

enteropathogen infection at enrollment in cases did not predict
lower weight gain over the course of the intervention. Indeed, the
detection of Campylobacter and a higher pathogen burden at
enrollment were associated with a higher change in WAZ during
follow-up. This supports the notion that enteric infections can
cause weight loss but that recovery is possible. Meanwhile, in-
fections after enrollment and thus detected at follow-up were
associated with a lower change in WAZ, suggesting cycles of
subclinical enteropathogen infection with negative impacts on
weight and interludes of catch-up growth, as has been clearly
described with overt diarrhea (31). Campylobacter and Giardia
detection upon enrollment was associated with detection at
follow-up, suggesting either that these pathogens may be per-
sistently carried for months or that repeated exposure is com-
mon, or both. If the former is the case, then targeted treatment
interventions for these pathogens may be more likely to have an
enduring effect. Higher-resolution prospective studies with both
frequent stool collection and genotyping are needed to distin-
guish reinfection from persistence with these pathogens.
Studies of environmental interventions, including water treat-
ment, the promotion of exclusive breastfeeding, and improved
sanitation and hygiene have generally used diarrhea and occa-
sionally linear and ponderal growth as the primary outcomes for
assessing the efficacy of the intervention. However, it has been
proposed that enteropathogen infection may be a more proximal
outcome measure (32). In this study, we identified a subset of
enteropathogens that are associated with malnutrition and thus
might form the basis for such an outcome. Validating a single
metric of enteropathogen burden would best be performed in
a prospective cohort study.
This study has several limitations. First, the definition of
malnutrition (WAZ ,22) used in this study, although widely
endorsed, is broad and may limit the specificity of the identified
associations. Second, a case-control study does not allow for an
elucidation of the temporal relation between enteropathogen
infection and malnutrition. Malnutrition has a well-established
association with immunosuppression (33), and thus the increase
in enteropathogen carriage seen herein may be a sequela of
malnutrition rather than a cause. However, a case-control design
is an efficient way to broadly identify pathogens that are asso-
ciated with malnutrition in these children. In addition, this was
an exploratory analysis of a broad range of pathogens designed
1138 PLATTS-MILLS ET AL.
to broadly screen for pathogens that may be associated with
malnutrition. These findings should be confirmed in subsequent
studies that ideally would allow for some causal inference as to the
role of these pathogens in the development of malnutrition. Finally,
these findings may not be generalizable to other settings, although
many of the pathogens identified herein have been associated with
malnutrition in other studies.
In summary, screening for enteropathogens directly from stool
specimens with highly sensitive molecular assays revealed associ-
ations between several prevalent enteropathogens and malnutrition.
The association between the burden of these enteropathogens and
malnutrition persisted after adjusting for sociodemographic factors.
This study provides a list of specific pathogens that are putative
contributors to poor growth and development in children in low-
resource settings and provides a potential target for future
interventions.
We thank the staff and participants of the MAL-ED Network Project for
their important contributions.
The authors’ responsibilities were as follows—JAP-M, MT, WAP, RH,
ERH, and TA: designed the research; SUS, MM, SMAG, DM, MIH, MMI,
and AMSA: carried out the study and collected the data; MT and MJU:
performed the molecular diagnostic testing; JAP-M: performed the statistical
analyses; JAP-M, MT, and ERH: wrote the manuscript; and all authors: read
and approved the final manuscript. None of the authors reported a conflict of
interest related to the study.
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 TELAAH JURNAL

Jurnal Anak

No Nilai Berfikir Kritis Pembahasan

1 Clarity (Kejelasan)
Judul : A home-based exercise program for
children with congenital heart disease following
interventional cardiac catheterization: study
protocol for a randomized controlled trial)
Nama Penulis : Qing Du, Yasser Salem, Hao
(Howe) Liu, Xuan Zhou, Sun Chen, Nan Chen,
Xiaoyan Yang, Juping Liang and Kun Sun
Tahun : 2017
1.1 Masalah : Kateterisasi jantung telah
membuka bidang pengobatan inovatif untuk
penyakit jantung; pengobatan ini menjadi
pendekatan yang paling populer untuk
penyakit jantung bawaan pediatrik dan telah
menyebabkan pertumbuhan yang signifikan
pada jumlah anak dengan kateterisasi jantung.
Tujuan penelitian untuk mengidentifikasi
kemanjuran program latihan rumahan untuk
meningkatkan fungsi motorik anak dengan
penyakit jantung koroner dengan kateterisasi
jantung dan untuk mengurangi kecemasan
orang tua dan beban pengasuhan anak serta
untuk meningkatkan kualitas hidup orang tua
yang anaknya terdiagnosis PJB melalui
program kateterisasi jantung.
1.2 Jalan Keluar : Untuk mengidentifikasi
kemanjuran program latihan rumahan untuk
meningkatkan fungsi motorik anak dengan
 penyakit jantung koroner dengan kateterisasi
jantung, untuk mengurangi kecemasan orang
tua dan beban pengasuhan anak serta untuk
meningkatkan kualitas hidup orang tua yang
anaknya terdiagnosis PJB melalui program
kateterisasi jantung.
1.3 Ilustrasi : Program latihan berbasis rumah
dapat mewakili intervensi yang berharga dan
efisien untuk anak-anak dengan kelainan
jantung bawaan dan keluarganya.
1.4 Contoh : Penelitian telah menunjukkan
bahwa hemodinamik abnormal selama
kehamilan janin dan hipoksia dalam rahim
mungkin memainkan peran penting dalam
risiko hasil neurologis yang merugikan
jangka panjang pada anak-anak dengan
penyakit jantung koroner kritis. Beberapa
penelitian mengungkapkan bahwa program
pelatihan berbasis rumahan dapat
meningkatkan kemampuan motorik dan
meningkatkan kemampuan anak.
Accuracy 2.1 Apakah Benar : Trials
(Keakuratan) 2.2 Cek akurasi : 2017
2.3 Menentukan benar : Q1
3. Precision 3.1 Artikel ini memberikan informasi kurang
(Ketepatan) lengkap, di dalam artikel terdapat judul,
abstrak, pendahuluan, metode, hasil,
pembahasan.
3.2 Artikel ini kurang menyajikan informasi yang
spesifik yaitu di dalam pembahasan belum
 ada tabel atau gambar.
4. Relevance 4.1 Ide yang ada pada latar belakang telah
(Relevansi) menunjukkan adanya keterkaitan dengan
rumusan masalah yaitu program latihan
berbasih rumah terkait dengan penyakit
jantung koroner dan kateterisasi jantung
untuk meningkatkan fungsi motorik anak.
4.2 Artikel ini termasuk up to date, karena
permasalahan penyakit jantung bawaan masih
ada hingga sekarang.
4.3 Adanya penelitian terbaru pada latar belakang
menujukkan bahwa adanya keterkaitan.
5. Depth (Kedalaman) 5.1 Jumlah masalah : Jumlah masalah yang
muncul 2 yaitu latihan berbasis rumah dan
pendidikan berbasis rumah
5.2 Kriteria inklusi/ekslusi :
Kriteria inklusi
 Diagnosis ekokardiografi PJB sederhana dengan
paten duktus arteriosus, Stenosis paru, Defek
septum ventrikel atau defek septum atrium
 Usia 0 sampai 5 tahun
 Berencana menjalani kateterisasi jantung.
Kriteria eksklusi :
 Aritmia
 PJB dikombinasikan dengan kelainan genetik
lainnya
 Kelainan bawaan lainnya
 Penyakit hati atau ginjal
 Gagal jantung dengan skor Ross yang
dimodifikasi 3 poin atau lebih
  Riwayat operasi jantung kecuali kateterisasi
jantung
 Operasi pada organ lain
 Perawatan rehabilitasi sebelumnya
 Penyakit yang mungkin menghalangi anak untuk
berpartisipasi dalam penelitian seperti yang
diidentifikasi oleh dokter penelitian.
6. Breadht (Keluasan) Program latihan berbasis di rumah tidak hanya
berkontribusi pada peningkatan kinerja motorik
anak-anak ketika orang tua diikutsertakan, tetapi
juga dapat mengurangi kekhawatiran/kecemasan
yang tidak perlu pada orangtua.
7. Logicalness Penyakit Jantung Bawaan (PJB) adalah salah satu
(Alasan yang logis) kelainan struktural yang paling umum, terjadi pada
9 dari setiap 1000 kelahiran hidup. Kateterisasi
jantung terapeutik memiliki beberapa keunggulan,
lebih sederhana dan aman, dan dikaitkan dengan
hasil yang lebih baik dibandingkan dengan
prosedur bedah jantung tradisional (bedah jantung
terbuka). Kateterisasi jantung terapeutik pediatrik
baru-baru ini telah meningkat karena banyaknya
teknik kateter yang inovatif. Penelitian telah
menunjukkan bahwa hemodinamik abnormal
selama kehamilan janin dan hipoksia dalam rahim
mungkin memainkan peran penting dalam risiko
hasil neurologis yang merugikan jangka panjang
pada anak-anak dengan penyakit jantung koroner
kritis. Pola khas gangguan perkembangan saraf
ditandai dengan perkembangan motorik yang
tertunda, gangguan kognitif, dan pertumbuhan
 abnormal lainnya. Keterlambatan motorik sering
terjadi pada anak dengan penyakit jantung koroner
karena berbagai alasan. Sikap dan kecemasan orang
tua yang terlalu protektif ini mungkin membatasi
aktivitas fisik anak-anak mereka dan mengurangi
anak-anak mereka.
8. Significance 8.1 Artikel ini menujukkan adanya bukti yang
(Bermakna) sejalan dengan hipotesa yaitu program latihan
berbasis rumah dapat digunakan sebagai
intervensi yang berharga dan efisien untuk
anak-anak dengan kelainan jantung bawaan.
8.2 Faktor penting : tidak ada faktor yang lebih
penting dalam artikel ini
8.3 Bagaimana program latihan berbasis rumahan
dan intervensi pada kelainan jantung bawaan?
8.4 -
9 Fairness (Keadilan) Menurut saya artikel sudah memaparkan dengan
baik analisisnya, berdasarkan susunan penulisan
artikel telah memenuhi kaidah penulisan yang
benar
10. Berfikir Kritis Artikel ini sudah bagus, namun di bagian abtrak
dan pembahasan informasi yang disajikan belum
cukup detail, di pembahasan hanya memaparkan
hasil dalam bentuk narasi saja.
Du et al. Trials (2017) 18:38
DOI 10.1186/s13063-016-1773-7

STUDY PROTOCOL Open Access

A home-based exercise program for

children with congenital heart disease
following interventional cardiac
catheterization: study protocol for a
randomized controlled trial
Qing Du1†, Yasser Salem2†, Hao (Howe) Liu2†, Xuan Zhou1, Sun Chen3, Nan Chen1, Xiaoyan Yang1,
Juping Liang1 and Kun Sun3*

Abstract
Background: Cardiac catheterization has opened an innovative treatment field for cardiac disease; this treatment is
becoming the most popular approach for pediatric congenital heart disease (CHD) and has led to a significant
growth in the number of children with cardiac catheterization. Unfortunately, based on evidence, it has been
demonstrated that the majority of children with CHD are at an increased risk of “non-cardiac” problems. Effective
exercise therapy could improve their functional status significantly. As studies identifying the efficacy of exercise
therapy are rare in this field, the aims of this study are to (1) identify the efficacy of a home-based exercise
program to improve the motor function of children with CHD with cardiac catheterization, (2) reduce parental
anxiety and parenting burden, and (3) improve the quality of life for parents whose children are diagnosed with
CHD with cardiac catheterization through the program.
Methods/design: A total of 300 children who will perform a cardiac catheterization will be randomly assigned to
two groups: a home-based intervention group and a control group. The home-based intervention group will carry out
a home-based exercise program, and the control group will receive only home-based exercise education. Assessments
will be undertaken before catheterization and at 1, 3, and 6 months after catheterization. Motor ability quotients will be
assessed as the primary outcomes. The modified Ross score, cardiac function, speed of sound at the tibia, functional
independence of the children, anxiety, quality of life, and caregiver burden of their parents or the main caregivers will
be the secondary outcome measurements.
Discussion: The proposed prospective randomized controlled trial will evaluate the efficiency of a home-based
exercise program for children with CHD with cardiac catheterization. We anticipate that the home-based exercise
program may represent a valuable and efficient intervention for children with CHD and their families.
Trial registration: http://www.chictr.org.cn/ on: ChiCTR-IOR-16007762. Registered on 13 January 2016.
Keywords: Congenital heart disease, Cardiac catheterization, Children, Motor development, Home-based exercise

* Correspondence: sunkunxh@126.com
†
Equal contributors
3
Department of Pediatric Cardiology, Xin Hua Hospital Affiliated to Shanghai
Jiao Tong University School of Medicine, Shanghai 200092, China
Full list of author information is available at the end of the article

© The Author(s). 2017 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Du et al. Trials (2017) 18:38
Background
Congenital heart disease (CHD) is one of the most com-
mon structural abnormalities, occurring in 9 of every 1000
live births [1, 2]. Over the last three decades, dramatic
changes have occurred in pediatric cardiac catheterization,
and cardiac catheterization is now the main procedure for
pediatric cardiac disease. In comparison with traditional
cardiac surgical procedures (open heart surgery), thera-
peutic cardiac catheterization has several advantages, in-
cluding being simpler and safer, and it is associated with
an improved outcome [3]. Hence, pediatric therapeutic
cardiac catheterization has increased recently because of
numerous innovative catheter techniques, the increased
number of persons and centers using these techniques,
and the increased number of lesion types thought to be
amenable to catheter therapy. It has been considered as
the regular procedure clinically in dealing with patent
ductus arteriosus, pulmonary stenosis, ventricular septal
defect, and atrial septal defect [4].
Progress in medical diagnosis and new surgical tech-
niques imply that the majority of children with complex
CHD (80%) now enter adulthood successfully [5–7].
With increased survival rates, emerging evidence has
highlighted that “non-cardiac” problems have increased
rapidly in survivors [6, 8]. Studies have demonstrated
that abnormal hemodynamics during fetal gestation and
hypoxia in utero might play an important role in the risk
of long-term adverse neurological outcomes in children
with critical CHD [9, 10]. A distinctive pattern of neuro-
developmental and behavioral impairments has been no-
ticed over the years; these are characterized by delayed
motor development, cognitive impairments, and other ab-
normal growth [11, 12]. Many school-aged survivors adapt
poorly to their school life because of low physical activity
levels and poor academic performance, and these prob-
lems may persist into young adulthood, leading to a low
quality of life for these children and their families [13].
Motor delays are common in children with CHD be-
cause of various reasons. Studies demonstrate that car-
diac problems are not the only reason responsible for
development delays [11, 14–16]; overprotection of par-
ents or main caregivers is also a factor. Parents are the
most concerned caregivers for their children, and over-
protection of children with CHD has been observed with
most parents and teachers. These attitudes and the anx-
iety of overprotective parents might restrict the physical
activity of their children and reduce their children’s ex-
posure to their peers, and this, in turn, might influence
the social competence and motor development of these
children. As a result, children may develop a sedentary
lifestyle, and this may lead to increased risks of add-
itional cardiovascular diseases and complications [17].
Without intervention, these development deficits may
persist into adolescence and adulthood [18]. Mothers of
Page 2 of 9
children with CHD are more concerned and anxious
about their children’s behaviors than parents of children
without such health issues [19]. They often exaggerate
the risk of adverse events or medical prognoses of CHD,
and they may underestimate the adaptability of their
children. The consequence of such overprotection may
be reduced physical, emotional, psychosocial, or cogni-
tive functioning in their children [11, 20].
A few studies have developed interventions to improve
growth development in children with CHD, but there is
still limited evidence in the literature to support the poten-
tial benefits of rehabilitation for these children [21–25].
Only one study implemented a home-based training pro-
gram for 20 toddlers, aged 12 to 26 months, after either a
superior cardiopulmonary connection procedure or an ar-
terial switch operation. The study revealed that a home-
based training program could improve motor abilities and
increase children’s rates of development to age-appropriate
norms [25]. But these studies focus on complex CHD. Even
though cardiac catheterization is a minimally invasive
procedure, it causes damage to the body; moreover, the
patients are very young, with poor psychology and
compliance, which make post-surgery management dif-
ficult. It is reported that a better inpatient environment
with enough emotional support for the parents during
the pre- and post-procedure phase, as well as exercise
therapy for the children post-procedure, could relieve
pain and reduce complications [26]. Overall, little research
relates to growth in the development of therapeutic inter-
vention for CHD with cardiac catheterization.
This parallel randomized controlled trial aims to
evaluate the efficacy of a home-based exercise program
and whether it could improve the motor abilities of chil-
dren with CHD with cardiac catheterization, reduce par-
ental anxiety and parenting burden, and improve the
quality of life for the children’s parents through the pro-
gram, which may represent a valuable and efficient inter-
vention for children with CHD and their families.
Methods/design
Aims
The aims of this research study are as follows:
1. To evaluate whether a home-based exercise program
may improve motor abilities in CHD children with
cardiac catheterization
2. To identify whether a home-based exercise program
may reduce parental anxiety and caregiver burden
and promote parents’ quality of life.
Study design
Children with CHD who are planning to perform a car-
diac catheterization procedure will be recruited from the
Department of Pediatric Cardiology, Xinhua Hospital
Du et al. Trials (2017) 18:38
affiliated to Shanghai Jiao Tong University School of
Medicine, China.
The study will be implemented at the Shanghai Jiao
Tong University School of Medicine. Before participation
in the study, parents/legal guardians will be asked to sign
a written informed consent. First, patients who meet the
inclusion criteria will be recruited for the study through
echocardiography results. Second, patients will undergo
baseline evaluations including motor abilities, cardiac
function, modified Ross score, sound of speed at the tibia,
and functional independence level, and their parents will
complete three questionnaires about their anxiety levels,
quality of life, and caregivers’ burden. Children with CHD
will be allocated by a physician using computer-generated
block randomization into two groups: an intervention
group and a control group after the catheterization
process. The allocations will be concealed in sequentially
numbered, opaque, sealed envelopes through a signature
Fig. 1 Flow diagram showing home-based exercise program for children with CHD following interventional cardiac catheterization
Page 3 of 9
across the sealing point. A trained research assistant, who
will be blinded to the allocation, will enroll patients and
assign them to interventions. All evaluations will be car-
ried out by the evaluation team. Another team, composed
of experienced pediatric physiotherapists, will teach par-
ents the home-based exercises, remind them to perform
the exercises, and provide valuable information about the
details of the exercises. The evaluation team will be
blinded in this program; however, the intervention team
will not be blinded, as they must communicate with par-
ents and offer informed consent in order to obtain the
parents’ signatures. The intervention group will receive a
home-based exercise program, while the control group
will only receive home-based education (see Fig. 1). All
children and parents will be evaluated by the trained
evaluation team before the procedure and 1, 3, and
6 months after the cardiac catheterization. Micro Message
Public Platform dissemination and collaboration with staff
Du et al. Trials (2017) 18:38 Page 4 of 9

of the Department of Pediatric Cardiology was established
to facilitate enrollment to reach the target sample size. All
parents will be added into a CHD group of the Micro
Message Platform created by the intervention team to re-
mind them to bring their children for clinic visits in order
to promote patient retention.
The intervention group will implement a home-based
exercise program, while the control group will receive
home-based exercise education. Both groups will con-
tinue with their routine activities, but they will not be
able to attend any other formal exercise program.
This study design follows the SPIRIT guidelines (see
Fig. 2 and Additional files 1 and 2).
arrhythmia; (2) CHD combined with other genetic disor-
ders; (3) other congenital deformities; (4) liver or kidney
diseases; (5) heart failure with a modified Ross score of 3
points or more; (6) history of heart surgery except car-
diac catheterization; (7) operation on other organs; (8)
previous rehabilitation treatment; (9) illnesses that may
preclude the child from participation in the study as
identified by the study physician.
Withdrawal criteria and management
Children with CHD and their families will be allowed or
be asked to withdraw from the study in the event of the
following:

Participants 1. The child and his/her family make such a request.

Inclusion criteria 2. The child has an adverse effect/event related to
Children will be selected to participate in this study ac- participation in the study.
cording to the following inclusion criteria: (1) echocardi-
ography diagnosis of simple CHD with patent ductus Intervention
arteriosus, pulmonary stenosis, ventricular septal defect, The home-based exercise program will consist of home-
or atrial septal defect; (2) age 0 to 5 years; and (3) based exercise education, home-based exercise, and
planned to undergo cardiac catheterization. home-based exercise supervision.

Exclusion criteria 1. Home-based exercise education: The intervention

Children will be excluded from participation in this team will explain the results of the developmental
study according to the following exclusion criteria: (1) tests of their children to each family and emphasize
the importance of home-based exercise for their
STUDY PERIOD
children. Then, parents will receive a home-based
Enrolment Allocation Post-allocation Close-out physical activity brochure, and follow a Micro Mes-
TIMEPOINT Day-7 to -1 Day 0 Mo 1 Mo 3 Mo 6 sage Public Platform that will share various forms of
ENROLMENT: CHD knowledge twice monthly including exercise,
Eligibility screen X
education materials, and general care of children
Cardiac
with CHD. It will also provide the exercise guide
catheterization X
and tools for outpatient appointments. Parents will
Informed consent X be asked to take their children to perform daily out-
Allocation X door activities.
INTERVENTIONS: 2. Home-based exercise: The home-based exercise pro-
gram will be adopted from the motor activities pro-
Education

Home-based
gram of Peabody Motor Development [27]. The
exercise home-based exercise program will be designed by
ASSESSMENTS: the pediatric cardiologist, rehabilitation physician,
Peabody
Developmental X X X X
and intervention team with input from the parents.
Motor Scales
Modified Ross
The home-based exercise program will be individual-
Heart Failure
Classification
X X X X ized to each child’s developmental age, severity, and
X X X X
degree of developmental delay. The baseline assess-
Echocardiography
Quantitative ment results will be used to identify age-appropriate
Ultrasound X X X X
measurements skills that the children have not yet mastered. The ex-
Functional
Independence X X X X ercise program will be designed so that parents can
Measure
choose how to incorporate these activities into their
Self-Rating Anxiety X X X X
Sale daily schedules and preferred behaviors. First, a mem-
Short Form 36
X X X X ber of the intervention team will provide the parents
Zarit Caregiver
Burden Scale
X X X X with one-on-one rehabilitation program training until
the parents master the skills. In addition, the parents
Fig. 2 Time schedule of enrollment, assessments, and interventions
will be given a home-based game reader and the
Du et al. Trials (2017) 18:38
Micro Message Public Platform to guide them. At
least one of the children’s parents will be asked to
complete the entire exercise program, and the rest of
the family members must agree and support the
home-based exercise program. The intervention team
will maintain contact with the parents by phone to
provide the exercise guide.
Outline of the home-based exercise program
The outline of the home-based exercise program will
differ by developmental age:
1. Age 0–6 months
(a). Developmental activities: activities/games with
different postures, such as head lifting, support in
prone position, hand, or elbow support, etc. For
example, the infant could lie on the mother’s leg
in a prone position; the mother could shake a
soundtoy over the infant’s head to induce the
infant to lift his/her head or hand; the infant can
also lie on a big ball in a prone position
(b). Passive exercise: stretching the infant’s limbs and
shoulder, and wrist and leg manipulation by the
parents, such as clapping or nudging the infant’s
feet.
Parents will implement the rehabilitation program at
home over a 6-month period; the total daily time re-
quest will be 30 minutes for no less than 5 days per
week.
2. Age 7–12 months
(a). Developmental activities: activities in different
positions (prone, sitting, crawling, creeping,
kneeling, and standing)
(b). Passive exercise: stretching the infant’s limbs and
shoulder, and wrist and leg manipulation by the
parents, like the baby’s feet touching the mother’s
feet with bending and extending movements, and
stepping on a bicycle.
Parents will implement the rehabilitation program at
home over a 6-month period; the total daily time
request will be 30 minutes for no less than 5 days
per week.
3. 13–24 months
(a). Postural training: kneeling and standing
(b). Flexibility training: active stretching of the upper
and lower limbs, chest expansion, and shoulder,
wrist, and leg movement
(c). Breathing exercises: abdominal respiration,
resisted breathing, deep breathing, and blowing
bubbles and pinwheels
(d). Developmental activities: walking, stair activities,
stepping activities, and throwing a ball
(e). Aerobic endurance training: swimming, riding a
bike, and walking.
Page 5 of 9
Parents will implement the rehabilitation program at
home over a 6-month period; the total daily time
request will be 30 minutes for no less than 5 days
per week.
4. 25–60 months
(a). Postural training: single-leg standing, standing on
tiptoe, single-leg jumping, such as jumping fol-
lowing a rope with snake shapes, rope skipping,
or standing on a soft cushion
(b). Flexibility training: active stretching of the upper
and lower limbs, chest expansions, and shoulder,
wrist, and leg movements
(c). Breathing training: abdominal respiration,
resistant breathing, deep breathing, and blowing
bubbles and pinwheels
(d). Muscle strength training: pulling elastic bands
with the upper limbs, squatting down and
standing up, straight-leg raising movements, and
gluteus training, like hiding in a big box, and in-
ducing the child out with preferred toys
(e). Developmental activities: climbing upstairs and
coming downstairs, stepping activities, and
throwing and kicking a ball
(f ). Aerobic endurance training: swimming, riding a
bike, walking, jogging, and running to catch
things with a crossing obstacle.
Parents will implement the rehabilitation program at
home over a 6-month period; the total daily time re-
quest will be 30 minutes for no less than 5 days per
week.
Safety supervision of home-based exercise training
Researchers will provide a portable device to parents
that can be used to detect the blood oxygen saturation
and heart rates of children with CHD. The heart rates of
children with CHD will be maintained in a targeted
range (60–80% of maximum heart rate) throughout the
training. The training will stop if the child exceeds the
maximum heart rate. The maximum heart rate will be
calculated by a physiatrist according to the child’s age.
Compliance supervision
The intervention team will remind parents to carry out
the exercise program and monitor each child’s progress
through a Micro Message Public Platform or phone call
one or two times weekly, and will also help them sched-
ule rehabilitation evaluation appointments.
Control group
The intervention team will explain the children’s evalu-
ation results and share home-based exercise education
with parents at baseline assessments. Home-based phys-
ical activity education will be given to the parents, but
they will not receive the rehabilitation guide.
Du et al. Trials (2017) 18:38
Outcome measures
All assessments will be undertaken before the procedure
and at 1, 3, and 6 months after the procedure.
Primary outcome measures
Motor ability quotient
The Peabody Developmental Motor Scales, 2nd edition
(PDMS-2) [28] will be used to assess each child’s motor
development. The PDMS-2 is a performance-based tool
used to assess motor development in both clinical and
research settings. The PDMS-2 measures development
in two domains, gross motor and fine motor, and it in-
corporates both quantitative and qualitative rating cri-
teria. It consists of six sub-tests: reflexes, stationary,
locomotion, object manipulation, grasping, and visual-
motor integration. Sub-test scores are standardized by
age and combined to calculate gross, fine, and total
motor quotients. The raw scores for each of the sub-
tests will be converted to age-equivalent scores, percent-
ile ranks, standard scores, and composite scores. The
PDMS-2 is a valid and reliable tool to assess motor de-
velopment in children, and has excellent intra-rater
reliability.
Secondary outcome measurements
Ross score
The Modified Ross Heart Failure Classification will be
used to assess children’s cardiac functions [29]. It is used
to assess the cardiac functioning of children aged 0–14
years, including their history (diaphoresis, tachypnea)
and physical examination (respiratory rate, heart rate,
hepatomegaly size); the total scores range from 0 to 12
as follows: 0–2 (no congestive heart failure), 3–6 (mild
congestive heart failure), 7–9 (moderate congestive heart
failure), and 10–12 (severe congestive heart failure).
Index of echocardiography
The left ventricular diastolic diameter, left ventricular
systolic diameter, and left ventricular wall thickness will
be measured before and after the procedure to monitor
the inner diameter changes in cardiac chamber. Function
change of left and right ventricles, pulmonary artery sys-
tolic pressure, and pulmonary valve pressure difference
will also be tested. The left ventricular end-systolic vol-
ume, left ventricular end-diastolic volume, and left ven-
tricular short axis shortening rate are used to evaluate
the left ventricular function. The tricuspid valve systolic
peak velocity is used to check the right ventricular func-
tion. Measurements of highest velocity and defect size
will be recorded before the procedure, and correct loca-
tion and residual shunt will be verified by a cardiologist
using echocardiography [4].
Page 6 of 9
Speed of sound at the tibia
Speed of sound (SOS) will be evaluated using Quantita-
tive Ultrasound measurements (Sunlight Omnisense
TM7000, Petah Tikva, Israel) by the same trained re-
habilitation physician. Each subject is seated close to the
examination table and the patient’s non-dominant leg is
rested. After introducing the water-soluble coupling gel,
the probe moves across the tibia plane, searching for the
site with a maximal reading. The measurement site is
defined as the distal one-third of the tibia. The SOS is
influenced by the bone minerals (major factor), bone
thickness, microstructure, and skeletal elasticity [30].
Functional independence level
The WeeFIM (functional independence measure) instru-
ment is a useful pediatric functional independence assess-
ment tool for children aged 6 months to 7 years and for
children with developmental disabilities aged 6 months to
21 years. It is an 18-item, 3-domain questionnaire that
measures a child’s consistent performance in essential
daily functional skills. Three main domains (self-care, mo-
bility, and cognition) are assessed by interviewing or by
observing a child’s performance of a task to criterion
standards. Each item is rated on a 7-point ordinal
scale ranging from 7 (complete independence) to 1
(total assistance). The WeeFIM is a psychometrically
sound instrument in terms of its reliability, validity,
and responsiveness [31]. Studies have already demon-
strated that the WeeFIM can be used as a functional
independence measure for Chinese children [32].
Anxiety
The Self-Rating Anxiety Sale (SAS) will be used to assess
parents’ anxiety status. The SAS is a popular subject
scale to measure anxiety. It has 20 items, scored as 1, 2,
3, or 4. Lower total scores mean lower anxiety: <50 (no
anxiety); 51–60 (mild anxiety); 61–70 (moderate anx-
iety); >70 (severe anxiety) [33].
Quality of life
The Short Form 36 (SF-36) is used to evaluate parents’
quality of life; it is a widely used health status survey de-
signed to assess quality of life by measuring the individ-
ual’s self-perception of his/her own health status with 8
multi-item scales, including physical functioning, phys-
ical role functioning, bodily pain, general health, vitality,
social functioning, emotional role functioning, and men-
tal health, and one single item of health transition. It
can be used to assess the quality of life for patients with
various diseases or people in general. The reliability, val-
idity, and sensitivity of the Chinese (simple) SF-36v2
have been verified [34].
Du et al. Trials (2017) 18:38
Caregiver burden
The Zarit Caregiver Burden Scale (ZCBS) is a widely
used and valued assessment tool for caregiver burden,
which was designed in line with Zarit’s Caregiver Burden
measurement theory [35]. The ZCBS has two dimen-
sions: personal strain and role strain, with a total of 22
items. Each item is rated on a 4-point scale, and higher
scores represent a more serious burden: 0–20 (little or
no burden); 21–40 (mild to moderate burden); 41–60
(moderate to severe burden); 61–88 (severe burden),
corresponding to the subjective feeling.
Sample measurement
GPower 3.1.9.2 will be used to perform the power calcu-
lations. The motor quotient of the PDMS-2 will be our
primary outcome measurement.
The results of our pilot study showed that after
6 months of intervention, the motor quotient of the
intervention group with patent ductus arteriosus on
average was (94.33 ± 11.29), and that of the control
group was (84.67 ± 6.11); therefore, the effect size was
1.06. Thus, as the α will be 0.05 and the β will be 0.05,
each group should recruit 24 patients. Considering 10%
potential attrition, 27 patients in each group with patent
ductus arteriosus will be recruited.
The motor quotient of the intervention group with
pulmonary stenosis on average after 6 months of inter-
vention was (101.00 ± 9.90), and that of the control
group was (89.00 ± 1.41); therefore, the effect size was
1.70. Thus, as the α will be 0.05 and the β will be 0.05,
each group should recruit 11 patients. Considering 10%
potential attrition, 13 patients in each group with pul-
monary stenosis will be recruited.
The motor quotient of the intervention group with
ventricular septal defect on average after 6 months of
intervention was (95.00 ± 8.54), and that of the control
group was (90.50 ± 7.78); therefore, the effect size was
0.55. Thus, as the α will be 0.05 and the β will be 0.05,
each group should recruit 87 patients. Considering 10%
potential attrition, 96 patients in each group with ven-
tricular septal defect will be recruited.
The motor quotient of the intervention group with
atrial septal defect on average after 6 months of inter-
vention was (99.67 ± 5.43), and that of the control group
was (90.80 ± 5.72); therefore, the effect size was 1.59.
Thus, as the α will be 0.05 and the β will be 0.05, each
group should recruit 12 patients. Considering 10% po-
tential attrition, 14 patients in each group with atrial
septal defect will be recruited.
Data collection, management, and analysis
Data will be entered using EpiData software designed for
this study. All data will be collected, typed, and analyzed
by a statistician, who will be blinded during the trial.
Page 7 of 9
The main investigators will check the data every 2 weeks
to ensure the quality. All statistical analyses will be per-
formed using SPSS 20.0. Descriptive data will be pre-
sented as mean ± standard deviation. Considering that
age may be a potential factor influencing the outcome
measurement, a covariance analysis will be used to com-
pare the effects between two groups. A t test will be
used to compare changes in parent outcome measures
in the two groups. Multiple linear mixed models will be
used to analyze the relationships between the risk factors
and the outcome measures. An intention-to-treat ana-
lysis will be used if participants are lost to follow-up. All
statistical tests will be performed at a significance level
of 0.05.
The parents will also be informed of this crucial as-
pect, and a member of the intervention team will be
available any time the parents may need further informa-
tion or clarification during the study period.
An interim analysis will be performed by the statisti-
cian on the primary endpoint; the statistician will be
blinded for treatment allocation and will report to the
main investigators. The main investigators will discuss
the results of the interim analysis with the monitoring
board. However, the trial will be terminated in case of
harm. The criterion for stopping the trial for harm is as
follows: a statistically significant difference in the pri-
mary outcome between the intervention group and a
reasonable suspected causal relationship between the
intervention and adverse events.
Harms
If there is a reasonable suspected causal relationship
with the intervention, the adverse events will be reported
to the Ethics Committee to guarantee the safety of the
participants. We consider that there will be no risks for
either group (patients with or without intervention).
Data monitoring and auditing
A monitoring board, including independent assessors
(not involved in the study) from the Shanghai Jiao Tong
University School of Medicine, will review all data and
can conduct an audit of the trial at any time.
Confidentiality
Only the main investigators will be allowed back-end
EpiData software entry with passwords. All children with
CHD will be identified by sex, birth date, and evaluation
date, and will be assigned a trial number during and
after the trial in accordance with personal data protec-
tion laws.
Access to data
The main investigators will have the right to enter the
final and complete trial dataset, and there is no
Du et al. Trials (2017) 18:38
contractual agreement to limit such access to all the
investigators.
Ancillary and post-trial care
After completing the trial, we will continue to evaluate
and treat the patients in the future according to their
parents’ wishes.
Dissemination policy
The final results of the trial are planned to be published
in a scientific journal and presented at medical confer-
ences. The final reporting will follow the Consolidated
Standards of Reporting Trials (CONSORT) Statement
guidelines (http://www.consort-statement.org).
Discussion
The home-based exercise program may not only con-
tribute to an increase in the motor performance of chil-
dren when the parents are included; it may also reduce
unnecessary concerns [20, 25]. We will implement ap-
propriate guidelines and supervision for the home-based
exercise program; for example, we will call the parents
to remind them to carry out the rehabilitation program
weekly and to answer any questions or concerns. In
addition, we will hand out brochures and disks to share
exercise education materials. Our study may provide
replicable evidence that a home-based exercise program
can improve motor abilities in children with CHD and
improve parental anxiety, caregiver burden, and the
overall quality of life.
Strengths and limitations
The first strength of our study is that it will be the first
randomized controlled trial that focuses on home-based
exercise for young children with CHD and cardiac
catheterization. Second, except for the important ele-
ments of cardiac function, our study focuses more on
growth development at an early stage for children with
CHD. Third, we used GPower 3.1.9.2 software for the
sample calculation to ensure its scientific validity.
Fourth, our study will last for 6 months, with three re-
evaluations, in order to update the patients’ recovery
and development status in time. Fifth, our study de-
velops a detailed and individual home-based exercise
program for each patient, and provides a one-on-one
guide for the parents, until they master the skills. More-
over, there is a close home-based monitoring process,
which could ensure the quality of implementation of the
home-based exercise program to a certain extent. Sixth,
our intervention will not solely focus on the children, as
their parents will also be educated in home-based exer-
cise and other appropriate educational and care guide-
lines for children with CHD.
Page 8 of 9
Several limitations exist in our trial: (1) the age of sub-
jects is limited to 0 to 5 years; (2) we only recruit pa-
tients with cardiac catheterization for our trial; we will
not group the children according to their specific CHD
subtypes or the treatment approach to CHD; (3) we will
not evaluate language and speech development or cogni-
tive development directly, only motor development;
thus, our trial cannot be used as a comprehensive evalu-
ation of all types of home-based exercise programs for
CHD children with cardiac catheterization; and (4) our
study includes a short follow-up duration of 6 months.
In conclusion, our study design for delayed motor devel-
opment of CHD children with cardiac catheterization de-
veloped a home-based exercise program as the main
intervention approach after the procedure. It is crucial to
address whether a home-based exercise program could
improve the patients’ motor abilities and improve parental
anxiety, burden, and quality of life. The findings will be
beneficial for children with CHD and their families, re-
search collaborators, physicians, and the general public.
Trial status
Patient recruitment is ongoing. Recruitment of study
participants commenced on 10 January 2016.
Additional files
Additional file 1: SPIRIT 2013 checklist: Recommended items to address
in a clinical trial protocol and related documents.* (DOC 132 kb)
Additional file 2: Table S1. World Health Organization Trial
Registration Data Set. (DOC 45 kb)
Abbreviations
CHD: Congenital heart disease; PDMS-2: Peabody Developmental Motor
Scales-2; SOS: Speed of sound; WeeFIM: Functional independence measure
instrument
Acknowledgements
Not applicable.
Funding
This work was supported by the Xin Hua Hospital affiliated to the Shanghai Jiao
Tong University School of Medicine and the Clinical Research Unit of Xin Hua
Hospital. It was funded by the One Thousand Days project of Xin Hua Hospital
affiliated to the Shanghai Jiao Tong University School of Medicine (15QT17), the
key developing disciplines of Shanghai Municipal Commission of Health and
Family Planning (2015ZB0406), and a project of the Shanghai Municipal
Commission of Health and Family Planning (201640067).
Availability of data and materials
Data sharing is not applicable to this article, as no datasets are generated or
analyzed during the current study.
Authors’ contributions
KS, QD, YS, and HL conceived and designed the trial. QD, XZ, SC, and XY
participated in the trial registration, evaluation, and monitoring. NC
performed the exercises. QD, XZ, and JL participated in the design of the
statistical analysis. All authors read and approved the final manuscript.
Du et al. Trials (2017) 18:38
Authors’ information
Qing Du, M.D., Ph.D.; Yasser Salem, P.T., Ph.D.; Hao (Howe) Liu, M.D., Ph.D.;
Xuan Zhou, M.M.; Sun Chen, M.D.; Xiaoyan Yang, M.M.; Nan Chen, P.T.; Juping
Liang, M.S. and Kun Sun, M.D., Ph.D.
Competing interests
The authors declare that they have no competing interests.
Consent for publication
Not applicable.
Ethics approval and consent to participate
This study has been approved by the Xin Hua Hospital Ethics Committee
affiliated to the Shanghai Jiao Tong University School of Medicine (approval
no. XHEC-C-2015-047-2). Before participation in the study, parents/legal guard-
ians will be asked by the intervention team to sign a written informed consent.
Author details
1
Department of Rehabilitation Medicine, Xin Hua Hospital Affiliated to
Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China.
2
Department of Physical Therapy, University of North Texas Health Science
Center, Fort Worth, TX, USA. 3Department of Pediatric Cardiology, Xin Hua
Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,
Shanghai 200092, China.
Received: 18 March 2016 Accepted: 28 December 2016
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 Children 2019, 6, 131 3 of 25
TELAAH JURNAL

1. Jurnal Bayi
Critical Thinking
No. Didasarkan Pada Nilai Pembahasan
Intelektual Universal
1. Clarity (Kejelasan) Judul : Short- and Long-Term Neurodevelopmental
Outcomes of Very Preterm Infants with Neonatal Sepsis:
A Systematic Review and Meta-Analysis
Nama Penulis : Shirley Cai, Deanne K. Thompson, Peter
J. Anderson, and Joseph Yuan-Mou Yang
Tahun : 2019
1.1 Elaborasi Masalah : Sepsis merupakan salah satu
kejadian yang dapat terjadi pada saat masuk
perawatan intensif neonatal (NICU) dan
berkontribusi secara signifikan terhadap morbiditas
sangat prematur (VP: <32 minggu usia kehamilan)
dan / atau sangat BBLR (VLBW: <1500 g).
Penelitian telah melaporkan tingkat sepsis
berbanding terbalik sebanding dengan usia
kehamilan, dengan 33% bayi yang lahir kurang dari
28 minggu mengalami sepsis dibandingkan dengan
60% bayi lahir kurang dari 25 minggu. Selama
periode neonatal, komplikasi seperti sepsis dapat
berdampak dramatis pada pertumbuhan dan
perkembangan anak, terutama pada anak yang lahir
sangat prematur. Mekanismenya tentang bagaimana
sepsis menyebabkan kerusakan otak telah
dihipotesiskan.
1.2 Jalan Keluar : Untuk memberikan tinjauan terbaru
dari semua studi kohort VP, yang mengevaluasi hasil
perkembangan saraf jangka panjang di atas usia 18
bulan pada bayi yang memiliki sepsis neonatal
positif kultur dibandingkan dengan bayi VP tanpa
sepsis.
1.3 Ilustrasi : Sepsis neonatal pada bayi yang sangat
Children 2019, 6, 131 3 of 25
prematur dikaitkan dengan peningkatan risiko cacat
perkembangan saraf. Karena kurangnya data tindak
lanjut longitudinal setelah 36 bulan, efek kognitif
jangka panjang dari sepsis neonatal pada bayi yang
sangat prematur tidak bisa ditentukan secara
meyakinkan. Efek pada perkembangan gangguan
minor tidak dapat dinilai, karena sedikitnya jumlah
bayi yang dimasukkan dalam penelitian.
1.4 Contoh : Selama periode neonatal, komplikasi
seperti sepsis dapat berdampak dramatis pada
pertumbuhan dan perkembangan anak, terutama
pada anak yang lahir sangat prematur.
Mekanismenya tentang bagaimana sepsis
menyebabkan kerusakan otak telah
dihipotesiskan. . Penelitian menunjukkan otak
berkembang rentan terhadap karakteristik
lingkungan inflamasi sistematis sepsis, serta
sitotoksik dan cedera iskemik akibat hipotensi dan
berkurangnya aliran darah otak
2. Accuracy (Keakuratan) 2.1 Nama Jurnal : MDPI Children
2.2 Tahun terbit jurnal : 2019
2.3 Akreditasi : Q1
3. Precision (Ketepatan) 3.1 Artikel ini telah menyajikan pendahuluan hingga
kesimpulan dalam pembahasan seperti informasi secara
detail
3.2 Dalam artikel ini terdapat tabel, gambar dan diagram
dalam pembahasan
4. Relevance (Keterkaitan) 4.1 Ide yang ada pada pendahuluan terutama latar
belakang tidak menunjukkan adanya
keterkaitan/hubungan dengan rumusan masalah
yaitu penelitian ini tidak dapat diekstrapolasikan ke
semua bayi VP yang selamat dari sepsis neonatus karena
kurangnya penelitian melaporkan hasil kognitif
menggunakan variabel non-diskrit dan kontinu. Studi
yang diterbitkan saat ini kurang data tindak lanjut
longitudinal jangka panjang
Children 2019, 6, 131
5. Depth (Kedalaman)
6. Breadth (Keluasan)
3 of 25
.4.2 Artikel ini termasuk berkembang (up to date) adalah
masih dalam penelitian lagi yang lebih akurat dan pasti
untuk ke depannya
4.3 Tidak adanya penelitian terbaru pada latar belakang
yang menunjukkan bahwa adanya keterkaitan
5.1 Jumlah masalah : Apakah postnatal
sepsis pada bayi VP berdampak buruk pada hasil
perkembangan saraf jangka panjang dibandingkan
dengan bayi VP tanpa pajanan sepsis?
5.2. kriteria seleksi berikut untuk dimasukkan: (1)
Peserta terdiri dari bayi yang lahir dengan usia kehamilan
<32 minggu dan / atau <1500 g berat lahir tanpa genetik
atau kongenital mayor kelainan; (2) sepsis yang
dibuktikan dengan kultur darah selama masuk NICU,
dengan tambahan opsional kriteria untuk definisi sepsis
sesuai penelitian; dan (3) durasi tindak lanjut setidaknya
18 bulan penilaian perkembangan saraf.
Kriteria inklusi dan ekslusi :
Kriteria inklusi studi tambahan termasuk: (1) Studi
melaporkan data asli; (2) jika ada studi yang
menggunakan data hasil yang sama dari institusi yang
sama, yang memiliki informasi lebih banyak sudah
termasuk; (3) penelitian yang memasukkan bayi VP
dengan sepsis sebagai bagian dari kelompok prematur
yang lebih besar dan berisi informasi hasil yang
memadai; (4) studi yang diterbitkan dalam bahasa Inggris
atau telah diterjemahkan ke bahasa Inggris
Kriteria eksklusi studi meliputi: (1) Review artikel, studi
nonanalytical dan pakar artikel opini; (2) studi di mana
hasil tidak dilaporkan; (3) studi di mana hasil dari sepsis
kelompok paparan tidak bisa dipisahkan dari kelompok
paparan non-sepsis
6.1 Hasil penelitian : Dua puluh empat studi telah
diidentifikasi, 19 di antaranya menggunakan definisi
perkembangan saraf yang telah ditentukan sebelumnya
gangguan dan lima hasil perkembangan saraf yang
Children 2019, 6, 131 3 of 25
dilaporkan sebagai variabel continue. Analisisis
dilakukan dengan menggunakan 14 studi dengan
gangguan perkembangan saraf dan ditunjukkan bahwa
bayi yang sangat prematur dengan sepsis neonatal
berisiko lebih tinggi mengalami gangguan, seperti
serebral kelumpuhan dan defisit neurosensori,
dibandingkan dengan bayi tanpa sepsis (OR 3,18; 95%
CI 2,29-4,41). Heterogenitas substansial ada di seluruh
studi (I 2 = 83,1, 95% CI 73-89). Lima studi itu hasil
yang dilaporkan sebagai variabel continue tidak
menunjukkan perbedaan yang signifikan dalam kinerja
kognitif antara kelompok sepsis dan non-sepsis.
7. Logicalness (Alasan yang 7.1 Sepsis adalah kondisi klinis yang ditandai dengan
Logis) bakteremia dan tanda klinis infeksi sistemik. Hal tersebut
merupakan salah satu kejadian yang dapat terjadi pada
saat masuk unit perawatan intensif neonatal (NICU) dan
berkontribusi secara signifikan terhadap morbiditas
sangat premature. Selama periode neonatal, komplikasi
seperti sepsis dapat berdampak dramatis pada
pertumbuhan dan perkembangan anak, terutama pada
anak yang lahir sangat premature. Morbiditas semacam
itu kompleks dan dapat berkisar dari gangguan mayor,
seperti otak palsy, ke defisit yang lebih halus seperti
kesulitan dengan memori dan perhatian. Terlepas dari itu,
mereka semua punya potensi untuk mempengaruhi
fungsi akademik, sosial dan emosional
anak. Perkembangan saraf tindak lanjut pada VP bayi
dengan sepsis sangat penting untuk identifikasi dini
sehingga keterlambatan perkembangan intervensi yang
ditargetkan dapat diresepkan untuk meminimalkan
gangguan jangka panjang
8. Significance (Bermakna) 8.1 Hasil penelitian ini telah menjawab dari pertanyaan
yang dimunculkan oleh peneliti, dimana Ulasan ini
menunjukkan bahwa bayi VP yang paling rusak yang
selamat dari sepsis neonatal mungkin pada risiko yang
lebih tinggi untuk cacat perkembangan saraf jangka
Children 2019, 6, 131 3 of 25
panjang dibandingkan dengan bayi VP tanpa sepsis.
Namun, bukti saat ini dibatasi oleh heterogenitas statistik
yang signifikan dan bias publikasi untuk perbedaan yang
signifikan dalam desain studi yang disertakan dan
definisi yang digunakan untuk NDI. Apalagi ini temuan
tidak dapat diekstrapolasikan ke semua bayi VP yang
selamat dari sepsis neonatus karena kurangnya penelitian
melaporkan hasil kognitif menggunakan variabel non-
diskrit dan kontinu. Studi yang diterbitkan saat ini kurang
data tindak lanjut longitudinal jangka panjang. Hasil ini
menyoroti perlunya longitudinal di masa depan studi
untuk menggunakan hasil berkelanjutan yang dilakukan
di usia yang lebih tua untuk membedakan yang halus dan
yang lebih spesifik risiko kognitif jangka panjang untuk
VP anak dengan sepsis neonatal.
8.2 Partisipan yang termasuk dalam penelitian ini adalah
Protokol tinjauan terdiri dari pertanyaan penelitian rinci,
strategi pencarian, penyaringan awal kriteria dan kriteria
penyaringan teks lengkap. Menggunakan PICOS
(populasi, intervensi, pembanding, outcome, study
design)
9. Fainess (Keadilan) Menurut saya, jurnal ini telah memenuhi kaidah
penulisan yang benar. Didalamnya terdapat tabel
sehingga mudah untuk dipahami oleh pembaca
10. Belajar Aktif Pada abstrak jurnal sudah lengkap menyajikan latar
belakang, tujuan, bahan dan metode, hasil dan
kesimpulan namun pada bahan dan metode tidak
disebutkan teknik sampling serta analisis yang digunakan
dalam penelitian tersebut. Pada pendahuluan tidak
dijabarkan mengenai solusi atau penyelesaian terkait
hipotesis yang diangkat. Pada hasil sudah disajikan tabel
dilengkapi dengan narasi untuk memudahkan pembaca
menyerap informasi yang disampaikan oleh penulis
Children 2019, 6, 131 3 of 25

children
Review

Short- and Long-Term Neurodevelopmental

Outcomes of Very Preterm Infants with Neonatal
Sepsis: A Systematic Review and Meta-Analysis
Shirley Cai 1,2,3, Deanne K. Thompson 1,2,4,5,* , Peter J. Anderson 1,6 and

Joseph Yuan-Mou Yang 2,4,7,8

1
Victorian Infant Brain Study, Murdoch Children’s Research Institute, Royal Children’s Hospital, Flemington Road,
Parkville, VIC 3052, Australia; shirleycai6894@gmail.com (S.C.); peter.j.anderson@monash.edu (P.J.A.)
2
Developmental Imaging, Murdoch Children’s Research Institute, Parkville, VIC 3052, Australia;
Joseph.Yang4@rch.org.au
3
Melbourne Medicine School, Faculty of Medicine, Dentistry and Health Sciences, The University of
Melbourne, Parkville, VIC 3052, Australia
4
Department of Paediatrics, The University of Melbourne, Parkville, VIC 3052, Australia
5
Florey Institute of Neuroscience and Mental Health, Parkville, VIC 3052, Australia
6
Turner Institute for Brain and Mental Health, School of Psychological Sciences, Monash University, Clayton, VIC 3800,
Australia
7
Neuroscience Research, Murdoch Children’s Research Institute, Parkville, VIC 3052, Australia
8
Department of Neurosurgery, Royal Children’s Hospital, Parkville, VIC 3052, Australia
* Correspondence: deanne.thompson@mcri.edu.au

Received: 7 November 2019; Accepted: 23 November 2019; Published: 1 December 2019

Abstract: Sepsis is commonly experienced by infants born very preterm (<32 weeks gestational age and/or <1500 g
birthweight), but the long-term functional outcomes are unclear. The objective of this systematic review was to identify
observational studies comparing neurodevelopmental outcomes in very preterm infants who had blood culture-proven
neonatal sepsis with those without sepsis. Twenty-four studies were identified, of which 19 used prespecified definitions of
neurodevelopmental impairment and five reported neurodevelopmental outcomes as continuous variables. Meta-
analysis was conducted using 14 studies with defined neurodevelopmental impairment and demonstrated that very
preterm infants with neonatal sepsis were at higher risk of impairments, such as cerebral palsy and neurosensory
deficits, compared with infants without sepsis (OR 3.18; 95% CI 2.29–4.41). Substantial heterogeneity existed across the
studies (I2 = 83.1, 95% CI 73–89). The five studies that reported outcomes as continuous variables showed no significant
difference in cognitive performance between sepsis and non-sepsis groups. Neonatal sepsis in very preterm infants is
associated with increased risk of neurodevelopmental disability. Due to the paucity of longitudinal follow-up data
beyond 36 months, the long-term cognitive effect of neonatal sepsis in very preterm infants could not be conclusively
determined. Effects on the development of minor impairment could not be assessed, due to the small numbers of
infants included in the studies.

Keywords: premature; brain; infection; infant; development; cognition

1. Introduction
Sepsis is a clinical condition characterised by bacteraemia and clinical signs of systemic infection [1]. It is one of the
events that can occur during neonatal intensive care unit (NICU) admission and contributes significantly to the morbidity
of very preterm (VP: <32 weeks gestational age) and/or very low birthweight (VLBW: <1500 g) infants [2–4]. Studies
have reported rates of sepsis are inversely

Children 2019, 6, 131; doi:10.3390/children6120131 www.mdpi.com/journal/children

Children 2019, 6, 131 3 of 25
proportional to gestational age, with 33% of infants born less than 28 weeks acquiring sepsis compared with 60% of infants
born less than 25 weeks [5].
During the neonatal period, complications such as sepsis can have dramatic effects on the growth
and development of the child, especially in children born very prematurely [6,7]. The mechanism of how sepsis inflicts
brain damage has been hypothesised. Research suggests the developing brain is vulnerable to the systematic
inflammatory milieu characteristic of sepsis, as well as cytotoxic and ischaemic injury from hypotension and reduced
cerebral blood flow [7]. Together, these factors may result in white matter abnormalities and diffuse injury to
premyelinating oligodendrocytes, which have been shown to be closely associated with increased risk for impaired
cognitive and motor functioning [8,9]. Such morbidities are complex and can range from major impairments, such as cerebral
palsy, to more subtle deficits such as difficulties with memory and attention. Regardless, they all have the potential to
affect a child’s academic, social and emotional functioning. Neurodevelopmental follow-up in VP infants with sepsis is
crucial for the early identification of developmental delay so that targeted interventions can be prescribed to minimise
long-lasting impairments.
The short-term cognitive impact of sepsis in VP infants has been studied. A systematic review of 17 studies on
VLBW infants with neonatal sepsis concluded these infants are at twice the risk of neurodevelopmental impairment
compared with their non-sepsis counterparts [10]. The follow-up duration of studies included in this review ranged from
6 to 60 months; 11 of the 17 studies had a follow-up duration of less than 36 months. Many studies focused on serious
disabilities, such as cerebral palsy and neurosensory impairment, using dichotomised definitions of neurodevelopmental
impairment (NDI) that were study-specific. Little is known about NDI beyond 36 months and whether they impact other
cognitive domains.
A comprehensive analysis of the long-term consequences of sepsis in children born VP is needed to better inform
parents and health professionals of the long-term cognitive risks and to guide targeted and age-specific interventions in
high-risk infants to achieve optimal function.
The objective of this systematic review was to provide an updated review of all VP cohort studies, which evaluated
long-term neurodevelopmental outcomes beyond 18 months of age in infants who had culture-positive neonatal sepsis
compared with VP infants without sepsis.

2. Materials and Methods

The review protocol consisted of a detailed research question, search strategy, initial screening criteria
and full-text screening criteria. Using the PICOS (population, intervention, comparator, outcome, study
design) approach, the research question was formulated as follows: “Does postnatal sepsis in VP infants
adversely impact long-term neurodevelopmental outcomes compared with VP infants without sepsis
exposure?”.

2.1. Literature Search Strategy

An electronic search strategy was used to identify relevant studies in the following databases by one reviewer
(S.C.): Medline (using Ovid, 1966–present), Embase (using Ovid, 1980–present) and PubMed (1966–present). The search
strategy for the Medline database comprised the following Medical Subject Headings (MeSH) or keywords, using Boolean
terms ‘or’ then combined with ‘and’:
(1) infant, premature or infant, low birthweight; (2) and sepsis; (3) and neurodevelopmental disorders or developmental
disabilities or intellectual disability or learning disorders or motor skills disorders. The search was then adapted for each
database and the last search was conducted on 24 February 2018, see Table S1 for the full search strategy. Additional article
screening was performed by hand search of the reference lists of selected articles.

2.2. Study Selection Criteria

After removing duplicated studies, the search results were screened using titles and abstracts. Full texts of the
selected articles were then reviewed independently by one reviewer (S.C.). The articles
Children 2019, 6, 131 3 of 25

were included if they were full-text academic journal articles that reported quantitative information on our PICOS
parameters in observational clinical studies.
Studies had to meet the following selection criteria for inclusion: (1) Participants comprised of infants born <32
weeks’ gestational age and/or <1500 g birth weight with no major genetic or congenital abnormalities; (2) blood culture-
proven sepsis during the NICU admission, with optional additional criteria for sepsis definition as per study; and (3)
follow-up duration of at least 18 months assessing neurodevelopment. We intended to include studies with a longer
follow-up duration, starting at 18 months, and had no restriction on the upper limit of follow-up duration.
Additional study inclusion criteria included: (1) Studies reporting original data; (2) if there were studies that used
the same outcome data from the same institution, the one with greater information was included; (3) studies that
included VP infants with sepsis as part of a larger preterm cohort and contained sufficient outcome information; (4)
studies published in English or had been translated into English. Study exclusion criteria included: (1) Review articles,
nonanalytical studies and expert opinion articles; (2) studies where outcomes were not reported; (3) studies where
outcomes of the sepsis exposure group could not be separated from those of the non-sepsis exposure group. No restriction
on publication or publication status was applied.

2.3. Data Extraction

The information extracted from studies included: study design (single vs multi-centre; case-control vs. case-cohort
studies), year of birth, number of infants with and without sepsis, micro-organism isolated from blood cultures, age at
follow-up and blinding status of outcome assessors. This review only included infants with sepsis and excluded any cases with
suspected sepsis or necrotising enterocolitis. For each study, data from neurodevelopmental assessment tools and
relevant NDI definitions were tabulated. For studies with defined dichotomous outcomes as per study NDI definition, the
number of infants with NDI in the sepsis and the non-sepsis groups were calculated. In studies where the odds ratio (OR)
for association was reported, individual numbers were calculated using the 2 × 2 contingency tables. For individual
studies with reported neurodevelopmental outcome assessments as continuous variables, the mean values and standard
deviations (SD) for the sepsis and non-sepsis group were recorded. All numbers used were unadjusted.

2.4. Assess Risk of Bias in Individual Studies

Each study was assessed for the risk of bias using a modified version of the Cochrane Collaboration’s tool for
assessing risk of bias, as seen in Table S2 [11]. Each study was examined for selection bias, performance bias, attrition bias,
detection bias and reporting bias and ranked as ‘low risk’ or ‘high risk’. It was marked ‘unclear’ if there was insufficient
information to make an assessment.

2.5. Data Synthesis and Analysis

STATAversion 15 (Stata, College Station, TX, USA) and the STATAmeta-analysis software package ‘metan’ were used for
all statistical analysis. The meta-analysis was conducted using a random-effect model based on the DerSimonian & Laid
method [12,13]. Results were reported only from the random-effect model, given the data from the literature was
expected to have variable effect size. For studies reporting dichotomous outcome variables (i.e., NDI vs. no NDI),
estimates for OR and their corresponding 95% confidence interval (CI) and percentage weight contributing to the overall
meta-analysis from each study were calculated. The impact of missing outcome data was explored using a variety of
scenarios including available case analysis, best-case scenario, worst-case scenario and the informative missingness model
[14]. For studies reporting continuous outcome variables, the mean and SD were compared. Due to the diversity of
neurocognitive tools and domains assessed, the results of studies reporting continuous outcome variables were unable to
be pooled for meta-analysis. The inconsistency of effects across studies was measured by estimating statistical
heterogeneity across included studies using the I2 calculation along with the associated 95% CI [15,16]. The advantage
Children 2019, 6, 131 3 of 25

of this measure of inconsistency is that it does not depend on the number of studies and is accompanied by an uncertainty
interval—the predictive interval—which shows the predictive distribution of a future trial, based on the extent of
heterogeneity [17]. p < 0.05 defined statistical significance in the heterogeneity analysis.
To assess the possibility of publication bias, the log transform of the effect size was plotted against
the inverse of its standard error to generate a contour-enhanced funnel plot [18]. The plots were visually inspected for
asymmetry of data points, which may represent publication bias. Egger’s meta-regression test was performed to
examine small study effect to see if the effect decreased with increasing sample size [19]. A subgroup analysis of studies
with a follow-up duration of 36 months or greater was performed to investigate long-term NDI.

3. Results

3.1. Study Selection

The study selection process is summarised in Figure 1. Database searching identified 1165 articles. After removing
duplicates, 727 articles were available for screening. A total of 680 were excluded as they did not meet the initial
selection criteria. After full-text assessment of the remaining 47 articles, another 23 were excluded [20–42]. The
remaining 24 articles were eligible for data analysis and synthesis. Of these, 14 were eligible for quantitative synthesis.
The remaining ten studies were analysed via qualitative synthesis. Hand searching through the reference lists of the
included articles yielded one additional study which was later excluded during full-text analysis [42].

3.2. Study Characteristics

Twenty-four studies met the study selection criteria. The details of the study design and study population are
summarised in Table 1. Eight studies were multicentre cohort studies [43–50], 12 were single-centre cohort studies [51–62]
and four were single-centre case-control studies [63–66]. All studies were retrospective in design. Ten studies used
retrospectively collected data [51–53,56,59,60,63–65] and 13 studies used prospectively collected data [44–
50,55,57,58,61,62,66]. Publications years were between 1994 and 2019.
Children 2019, 6, 131 5 of 25

Figure 1. Flow diagram of the study selection process.

Children 2019, 6, 131 5 of 25

Table 1. Summary of the study design and study population characteristics of all included studies.
No. of No. of No. of Age at Blinding of
Follow-Up Total No. Organism
Author Year Study Design Population Birth Year Survivors at Confirmed Non-sepsis Assessment Outcome
Rate Followed Up Isolated
Follow-Up Sepsis Comparators (Months) Assessors
Msall [51] 1994 SC, cohort GA 23–28 1983–1986 153 97% 149 18 131 NS 52–62 Yes

Lee [63] 1998 SC, case control BW < 1250 1990–1995 35 N/A N/A 14 21 Candida 9–50 NS

Friedman [52] 2000 SC, cohort ELBW 1988–1996 334 90% 299 27 272 Candida 21–24 NS

Hack [53] 2000 SC, cohort ELBW 1992–1995 241 92% 221 109 112 NS 20 NS

Hoekstra [54] 2004 SC, cohort GA 23–26 1986–2000 778 87% 675 NS NS NS 36–60 No
Shows
Stoll [43] 2004 MC, cohort ELBW 1993–2001 7892 80% 6314 1922 2161 breakdown 18–22 NS

Shah [55] 2008 SC, cohort GA < 30 2001–2003 204 94% 192 64 119 NS 24 NS

Kono [44] 2011 MC, cohort VLBW 2003–2004 2847 64% 1826 113 1714 NS 36–42 NS

Jang [56] 2011 SC, cohort VLBW 1989–2007 967 N/A N/A NS NS NS 18–24 NS
Shows
Schlapbach [45] 2011 MC, cohort GA 24–27 2000–2007 482 77% 372 136 236 18–24 NS
breakdown
GA < 32 or Shows
Van der Ree [64] 2011 SC, case-control 2000–2001 50 N/A N/A 32 18 72–108 NS
VLBW breakdown

Adams-Chapman Candida and

2013 MC, cohort ELBW 2004–2007 1966 71% 1391 474 917 18–22 NS
[46]
other
GN and 24 NS
De Haan [65] 2013 SC, case-control GA < 30 1997–2007 168 90% 152 50 102
Candida

Dilli [66] 2013 SC, case control VLBW 2008–2009 33 N/A N/A 13 20 NS 18–24 NS

Mitha [47] 2013 MC, cohort GA 22–32 1997 2277 78% 1769 688 1081 NS 60 NS
Alshaikh [57] 2014 SC, cohort GA < 29 1995–2008 383 87% 332 105 227 CONS 30–42 Yes

GA < 32 or 2003–2010 291 78% 226 62 164

Shows
Hentges [58] 2014 SC, cohort 18–24 Yes
VLBW
breakdown

Yang [59] 2015 SC, cohort VLBW 1996–1999 111 55% 61 26 35 NS 144–180 NS

Maruyama [60] 2016 SC, cohort VLBW 2005–2012 200 78% 155 N/A N/A NS 36–42 NS

Synnes [48] 2016 MC, cohort GA < 29 2009–2011 2340 80% 1870 NS NS NS 18–21 NS

Young [61] 2016 SC, cohort GA < 32 2008–2010 100 N/A N/A 17 33 NS 24, 48 NS

Bright [49] 2017 MC, cohort GA < 28 2002–2004 966 92% 889 223 532 NS 120 Yes

Bolisetty [50] 2018 MC, cohort GA 23–28 2007–2012 1897 80% 1514 526 988 NS 24–36 NS
 GA < 32 or Shows breakdown
Zonnenberg [62] 2019 SC, cohort 2008–2014 104 87% 90 68 22
Children 2019, 6, 131 24 Yes 5 of 25
VLBW
Abbreviations: SC—single-centre, MC—multicentre, GA—gestational age (weeks), BW—birth weight (grams), ELBW—extremely low birth weight (<1000 g), VLBW—very low birth weight (<1500 g), GN—
Gram-negative organisms, CONS—coagulase negative Staphylococci, N/A—not applicable, NS—not specified.
Children 2019, 6, 131 7 of 25

Overall, the total number of survivors at follow-up ranged from 33 to 7892, with the number of confirmedsepsis ranging
from 13 to 1922 and the number of non-sepsis comparators ranging from 18 to 2161. Birth years were between 1983 and 2014.
Overall, the median attrition rate of all studies was 20% (range 3%–45%). Fourteen studies specifically analysed the impact of
sepsis [45–47,49,52,55,57,58,62–66], whereas the other ten studied perinatal variables more generally with sepsis as a factor
[44,48,50,51,53,56,59–61]. Fourteen studies did not report the prevalence of each micro-organism [44,47–51,53–56,59–
61,66]. Seven analysed the prevalence of each microorganism [43,45,46,58,62,64,65], of which four included fungal infections
[43,46,58,65]. Two studies restricted their studies to Candidaemia only [52,63] and one restricted to coagulase-negative
Staphylocci sepsis only [57]. Follow-up duration ranged from nine to 180 months. Four studies had a follow-up duration of
more than or equal to 36 months [47,51,59,60]. Five studies had blinded outcome assessors [49,51,57,58,62], one reported no
blinding was performed [54] and the rest did not specify [43–46,48,50,52,53,55,56,59–61,63–66]. Age of assessment ranged
from 18 months to 15 years. All studies contained information on the neurodevelopmental assessment tools used and details
of neurodevelopmental outcomes assessed as summarised in Table 2. Nineteen studies reported dichotomised outcomes
using a definition for NDI [43–54,56,57,59,60,63,65,66], whereas the other five reported outcomes as continuous variables
[55,58,61,62,64].

3.3. Risk of Bias within Studies

Figure 2 summarises the risk of bias from all studies; see Table S3 for detail assessment from each study. Overall, six
studies were ranked high risk and 18 studies were ranked low risk for selection bias. All studies were ranked low risk for
performance bias. Eleven studies were ranked high risk and 13 studies were ranked low risk for attrition bias. Two studies
were ranked high risk and four studies were ranked low risk for detection bias, with the remaining 18 marked as unclear.
Four studies were ranked high risk and 20 studies were ranked low risk for reporting bias.

Assessment of risk of bias of the 24 included studies

Selection bias

Low risk
Attrition bias
High risk
Detection bias Unclear

Reporting bias

0% 10% 20% 30% 40% 50% 60% 70% 80% 90% 100%

Figure 2. Assessment of risk of bias of the 24 included studies. The risk of bias was assessed using a modified version
of the Cochrane Collaboration’s tool for assessing risk of bias; see Table S2.
Children 2019, 6, 131 8 of 25

Table 2. Neurodevelopmental outcome scales used by the included studies and their respective neurodevelopmental impairment definitions.

Study Scale Used NDI Definitions

Studies Which Reported Dichotomised Outcomes

One or more of the following:

- CP defined as early onset, nonprogressive motor and postural delay (hemiplegia,

McCarthy Scales of Children’s Abilities, Cattell Infant Intelligence diplegia or quadriplegia)

Msall [51] Test or the Clinical Linguistic Auditory Milestone Scale (for children
with a mental age < 30 months) - IQ: Mild 52–67, Moderate 36–51, Severe 20–35 on McCarthy instrument
- Blindness defined as legal blindness or corrected vision worse than 20/200
- Deafness defined as bilateral hearing impairment of more than 85 dB

One or more of the following:

- CP of all types of severity

BSID-II (<24 months), Stanford–Binet Intelligence Scale,
Lee [63]
Peabody Developmental Motor Scales

Friedman [52] BSID-II

Hack [53] BSID-II

BSID-II (<36 mo)

Hoekstra [54]

3–6 years: Denver Developmental Screening Test, Early

Language Milestone Scale, Zimmerman Preschool
Articulation Test

School children: University of Vermont Achenbach Child

Behaviour Checklist and the Teacher’s Report form
 - Legal blindness (corrected visual acuity of the better eye, <20/200) Mild–moderate: isolated muscle tone abnormalities, unilateral blindness, hyperactivity, scores 1–2 SD
- 2019,
Children 6, 131loss (neurosensory hearing loss in the better ear, >30 dB)
Hearing below mean 9 of 25
- Cognitive delay (MDI, >3 SD below the mean)
Severe: spasticity, severe hypotonia, blindness, deafness, scores >2 SD below mean
Mild-moderate: mild-moderate CP, moderate cognitive delay (MDI 70–82)
Mild–moderate: minor abnormalities, developmental assessments 6 –12 months below
Severe: severe CP (not sitting by 2 years of age, non-ambulatory), bilateral chronological age
blindness, aided sensorineural hearing loss, severe cognitive delay (MDI < 70),
shunted hydrocephalus Severe: severe physical and neurologic examinations, developmental assessments >1 year

One or more of the following: below chronological age

- CP (spastic diplegia, hemiplegia, hemiplegia, or quadriplegia), hypertonia, Mild–moderate: below grade average in >1 subject, but not far below in >1 subject, or had
hypotonia and shunt-dependent hydrocephalus below-normal Achenbach scores
- Blindness unilateral or bilateral
Severe: spasticity, severe hypotonia, blindness, hearing loss, repeated a grade, require special
- Deafness unilateral or bilateral
education, far below grade average in >1 subject or Achenbach scores far below normal
- MDI < 70
Children 2019, 6, 131 10 of 25

Table 2. Cont.

Study Scale Used NDI Definitions

One or more of the following:

- CP

Stoll [43] BSID-II - MDI < 70 or PDI < 70

- Bilateral blindness
- Bilateral hearing impairment

One or more of the following:

- CP (nonprogressive CNS disorder characterised by abnormal muscle tone in at least one

extremity and abnormal control of movement and posture)
Kono [44] KPSD - Unilateral or bilateral blindness
- Hearing impairment requiring hearing aids
- KPSD < 70 or judged by physicians (i.e., ability to say any meaningful words, ability to say own
name or age, able to build using several small bricks, able to distinguish size of circles with a
diameter of 4 cm and 6 cm)

One or more of the following:

- CP (permanent, but no unchanging, disorder of movement and/or posture and of motor

Jang [56] BSID or Denver Developmental Screening Test function caused by a nonprogressive interference, lesion, or abnormality of the developing
immature brain)
- >6 months delay of motor and/or mental development including cognitive impairment,
psychomotor impairment and neurosensory impairment

One or more of the following:

- CP (nonprogressive motor disorder characterised by abnormal tone in at least one

Schlapbach [45] BSID-II, GMFCS extremity and abnormal control of movement and posture)
- MDI < 70 or PDI < 70
- Bilateral blindness
- Hearing impairment requiring amplification
Children 2019, 6, 131 11 of 25

Table 2. Cont.

Study Scale Used NDI Definitions

BSID-II (Epoch 1)

- Moderate–severe CP with GMFCS ≥ 2

- MDI < 70 or PDI < 70
- Bilateral blindness with no functional vision
- Bilateral amplification for permanent hearing loss
Adams-Chapman [46] BSID-II, BSID-III, GMFCS BSID-III (Epoch 2)

- Moderate to severe CP with GMFCS ≥ 2

- BSID-III cognitive < 70
- Visual acuity < 20/200 bilateral
- Permanent hearing loss that does not permit the child to understand directions of
examiner and communicate despite amplification

One or more of the following:

De Haan [65] BSID-II-NL
- CP ± clinical hearing loss or visual handicaps
- MDI < 85 or PDI < 85

One or more of the following:

Dilli [66] BSID-II, GMFCS - Moderate–severe CP

- MDI < 70, PDI < 70

- Bilateral deafness
- Bilateral blindness

- CP (at least two of the following: abnormal posture or movement, increased tone,
hyperreflexia)
Mitha [47] Kaufman Assessment Battery for Children
- MPC < 70

One or more of the following:

- CP (non-progressive motor impairment characterised by abnormal muscle tone in at least one

extremity and decreased range or control of movements)
- Cognitive delay >2 SD below mean on standardised assessment (WPPSI-Revised, BSID-II or
Alshaikh [57] BSID-II, WPPSI-Revised, Stanford–Binet IV
Stanford–Binet IV)
- Sensorineural hearing loss requiring amplification
- Visual acuity <20/200 following refractive correction

CBCL, “Current Status Survey”, WISC-IV, MINI-KID (for ADHD,
Yang [59]
anxiety/mood disorders), DSM-IV-TR (for ASD)
“Disabled” = when parents disclosed that the child received a handicap status as issued by the Ministry
of the Interior of Taiwan. Handicap is defined as disadvantaged condition, deriving from impairment or
disability limiting a person performing a role considered normal in respect of their age, sex and social
and cultural factors.
Children 2019, 6, 131 12 of 25

Table 2. Cont.

Study Scale Used NDI Definitions

One or more of the following:

- CP
Maruyama [60] KPSD - Unilateral or bilateral blindness
- Severe hearing impairment
- Developmental delay: DQ < 70

Severe NDI
- CP with GMFCS III, IV or V
- Bayley-III motor composite < 70, cognitive composite < 70, language composite < 70
- Hearing aid or cochlear implant
- Bilateral visual impairment
Synnes [48] BSID-III, GMFCS NDI
- CP with GMFCS I
- Bayley-III motor composite < 85, cognitive < 85, language composite < 85
- Sensorineural/mixed hearing loss
- Unilateral or bilateral visual impairment
- Parent-reported legally blind—severe visual impairment
GMFCS, DAS-II, OWLS, NEPSY-II, WIAT-III, Manual Ability - Severe auditory impairment—parent-reported child has hearing aids or cochlear plant and/or
Bright [49]
receives special services for the hearing-impaired
Classification Test
Moderate

- BSID-III 2–3 SD below mean

- Moderate CP GMFCS level 2 or 3 (able to walk with the assistance of aids)
- Bilateral deafness (requiring amplification with hearing aids or unilateral/bilateral
cochlear implants)

Bolisetty [50] BSID-III, GMFCS Severe

- BSID-III >3 SD below mean

- Severe CP GMFCS level 4 or 5 (unable to walk with the assistance of aids)
- Bilateral blindness (visual acuity of <6/60 in better eye)
Children 2019, 6, 131 13 of 25
Studies Which Reported Continuous Outcomes

Shah [55] BSID-II N/A

Bax’ criteria, GMFCS, Movement ABC, WISC-III-NL,

Van der Ree [64] NEPSY-II, AVLT, TEA-Ch, ADHD questionnaire, BRIEF, CBCL N/A
Children 2019, 6, 131 14 of 25

Table 2. Cont.

Study Scale Used NDI Definitions

Hentges [58] BSID-II N/A

At 2 years: BSID-III

At 4 years: WPPI-III, CLEF-2, Beery-Buktenica Test of Visual

Young [61] Motor Integration, the Behaviour Assessment System for N/A
Children Parent Rating Scales, Behavioural Rating Inventory of
Executive Functioning-Preschool

Zonnenberg [62] BSID-II, Lexilijst (lexical development questionnaire), CBCL N/A

Abbreviations: NDI—neurodevelopmental impairment; CP—cerebral palsy; BSID-II—Bayley Scales of Infant Development, Second Edition; MDI—Mental Development Index; PDI—Psychomotor
Development Index; KPSD—Kyoto Scale of Psychological Development; DQ—Development Quotient; GMFCS—Gross Motor Function Classification System; Bayley-III—Bayley Scales of Infant and
Toddler Development, Third Edition; MPC—Mental Processing Composite score; WPPSI-Revised—Wechsler Preschool and Primary Scales of Intelligence, Revised; CBCL—Child Behaviour Checklist;
WISC-IV—Wechsler Intelligence Scale for Children-IV; MINI-KID—Mini-International Neuropsychiatric Interview for Children and Adolescents; DAS-II—School-Age Differential Ability Scales, Second
Edition; OWLS—Oral Written Language Scales; NEPSY-II—Neuropsychological Assessment, Second Edition; WIAT-III—Wechsler Individual Achievement Test, Third Edition; M-ABC—Movement
Assessment Battery for Children; WISC-III—Wechsler Intelligence Scale for Children, Third edition; AVLT—Rey’s Auditory Verbal Learning Test; TEA-Ch—Test of Everyday Attention for Children; BRIEF—
Behavior Rating Inventory of Executive Function; WPPSI-III—Wechsler Preschool and Primary Scales of Intelligence, Third edition; CELF-2—Clinical Evaluation of Language Fundamentals—Preschool,
Second Edition; WASI—Wechsler Abbreviated Scale of Intelligence; M-ABC2—Movement Assessment Battery for Children, Second Edition; CELF-4—Clinical Evaluation of Language Fundamentals, Fourth
Edition; CLI—Core Language Index; WMTB-C—Working Memory Test Battery for Children; SD—standard deviation(s); N/A—not applicable.
Children 2019, 6, 131 13 of 25

3.4. Quantitative Synthesis

Fourteen out of the 19 studies reporting dichotomised neurodevelopmental outcomes contained adequate
information for meta-analysis. Table 3 details the number of NDI identified in the sepsis and non-sepsis groups in each
study. Overall, 35% of the individuals with culture-proven sepsis had NDI compared with 17% in the non-sepsis group. The
median attrition rate in these studies was 18% (range 3%–45%). Figure 3 demonstrates the OR forest plot based on
available case analysis and a random effect model. Repeated analyses examining the impact of missing data
demonstrated similar outcome trends. The forest plot demonstrated that VP infants with neonatal sepsis had more adverse
long-term NDI compared with those without sepsis (OR 3.18, 95% CI 2.29–4.41), as seen in Figure 3. Substantial
heterogeneity existed across the studies (I2 = 83.1, 95% CI 73–89). The estimated predictive value was 1.02–9.89.

Figure 3. Forest plot showing the results of random effects meta-analysis of the 14 studies comparing
neurodevelopmental outcomes in very premature infants with and without neonatal sepsis exposure
(Outcome: number of participants with neurodevelopmental impairment). NDI—neurodevelopmental
impairment; OR—odds ratio; CI—confidence interval.

The contour-enhanced funnel plot shown in Figure 4 demonstrates a high likelihood of publication bias, as reflected by
high degrees of plot asymmetry with a lack of negative studies. There was a predominance of studies showing statistically
significant positive effect. However, on visual assessment of the plot, the publication bias was unlikely due to small study
effects. The studies which demonstrated statistically significant findings (i.e., those lying outside the 1% line (p < 0.01))
were not restricted to studies with small sample size. This was confirmed quantitatively using the Egger’s meta-
regression test. This test demonstrated that smaller studies did not give different results when compared with larger
studies as the 95% CI of the intercept did include the zero value (coefficient 1.33, 95% CI
−0.76–3.42, p = 0.190).
Children 2019, 6, 131 14 of 25

Table 3. Summary of the 19 studies with reported dichotomised neurodevelopmental outcomes.

Number of Infants with NDI

Study Sepsis Group No Sepsis Group Attrition Rate Comments
Msall [51] 9/18 (50%) 22/131 (17%) 3% N/A
Lee [63] 4/14 (29%) 3/21 (14%) N/A N/A
Friedman [52] 11/27 (41%) 32/272 (12%) 10% N/A
Hack [53] 43/93 (46%) 62/112 (55%) 8% N/A
At 47.5 months (range 36–60), there was no statistically significant association between primary
Hoekstra [54] # NS NS 13%
or secondary sepsis and NDI.
Stoll [43] 861/1778 (48%) 576/1976 (29%) 20% N/A
At 36–42 months, there was an association between sepsis and cerebral palsy or death (OR 2.6, 95% CI
Kono [44] # NS NS 36%

1.4–4.8) as well as sepsis and NDI or death (OR 2.8, 95% CI 1.6–4.8).
palsy (OR 1.653, 95% CI 0.849–3.215).
At 18–24 months, univariate analysis showed weak association between sepsis and cerebral
Jang [56] #[45]
Schlapbach NS(34%)
46/134 NS(23%)
55/235 23%
N/A N/A
Adams-Chapman [46] 148/474 (31%) 153/917 (17%) 16% N/A
De Haan [65] 28/50 (56%) 16/102 (17%) 10% N/A
Dilli [66] 8/13 (62%) 4/20 (20%) N/A N/A
Mitha [47] 84/643 (14%) 73/1126 (6%) 22% N/A
Alshaikh [57] 26/105 (25%) 34/227 (15%) 13% N/A
Yang [59] 13/26 (50%) 7/35 (20%) 45% N/A
Maruyama [60] 3/4 (75%) 37/153 (24%) 28% N/A

At 18–21 months, there was significant association between sepsis and significant NDI (OR 1.50, 95% CI
Synnes [48] # NS NS 20%

1.05–1.86), but no information was reported on association between sepsis and NDI.

At 10 years of age, children who had confirmed bacteraemia were associated with lower

Bright [49] # NS NS 8% z-scores in verbal and nonverbal IQ, oral expression, academic achievement, executive function and
visual impairment. They were also more likely to have visual and auditory impairment but not motor
deficits. After adjusting for IQ, many of these associations were lost.

Bolisetty [50] 138/526 (26%) 29/988 (3%) 20% N/A

Total 1422/3905 (36%) 1103/6315 (17%) Median: 18%

 #: studies did not report absolute numbers for NDI for each study group. NS—not specified; N/A—not applicable.
Children 2019, 6, 131 15 of 25
Children 2019, 6, 131 16 of 25

Figure 4. Contour-enhanced funnel plot of the 14 studies with reported dichotomised neurodevelopmental
outcomes.

Results of subanalysis based on the four studies with a follow-up duration of 36 months or greater showed similar
association between neonatal sepsis and NDI (OR 3.07, 95% CI 1.79–5.28; Figure 5), as compared to the primary meta-
analysis conducted from all 14 studies (OR 3.18, 95% CI 2.29–4.41), as seen in Figure 3.

Figure 5. Forest plot of the subanalysis of studies which had a follow-up duration of 36 months or greater.
The plot shows the results of random effects meta-analysis of the four studies comparing
neurodevelopmental outcomes in very premature infants with and without neonatal sepsis exposure
(Outcome: number of participants with neurodevelopmental impairment).
Children 2019, 6, 131 16 of 25

3.5. Qualitative Synthesis

The qualitative synthesis included five studies which reported dichotomised outcomes [44,48,49,54,56]
but did not have adequate information for meta-analysis, and five studies which reported continuous outcomes
[55,58,61,62,64].
Table 3 summarises the five studies which reported dichotomised outcomes. They revealed conflicting findings, as
some studies demonstrated no or minimal association between sepsis and NDI [54,56], whilst others showed an
association between sepsis and NDI [44,48]. One study showed an association between sepsis and NDI which they argued
was attributable to the effect of IQ [49]. Table 4 summarises the five studies which reported continuous outcomes
[55,58,61,62,64]. Four of the studies demonstrated no or minimal association [55,58,61,62,64] and only one found
significant association between sepsis and cognitive function in the studied VP children [62].

Table 4. Summary of the five studies with reported continuous neurodevelopmental outcomes.

Sepsis Group Non-sepsis Group

Study Assessment Tool Attrition Rate Comments

Mean (SD) Mean (SD)

MDI (BSID-II) 79.7 (21.2) 86.5 (18.7)
Shah [55] 6% N/A
PDI (BSID-II) 84.2 (21.4) 89.9 (14.5)

Movement ABC Total

13 (10) 8 (6)
(M-ABC2)—raw score
Van der Ree [64] N/A N/A
Total intelligence
(WISC-II)—IQ
89 (13) 98 (8)
Total behavioural problems
(CBCL)—t-scores
53 (12) 56 (9)

MDI (BSID-II) 85.9 (10.8) 86.1 (11.59)

Hentges [58] 22% N /A

PDI (BSID-II) 89.8 (13.3) 91.7 (14.02)

At 2 years: BSID-III

At 4 years: WPPI-III, CLEF-2, Sepsis was not significant

with 2-year or 4-year
Beery–Buktenica Test of Visual cognitive measures, but
Young [61] # NS NS N/A
Motor Integration, the significant with 4-year
Behaviour Assessment System behavioural measures.
for Children Parent Rating
Scales, Behavioural Rating
Inventory of Executive
Functioning – Preschool

MDI (BSID-II) 100 (9.0) 98 (13.9)

PDI (BSID-II) 100 (9.4) 99 (12.3)

Zonnenberg [62] 23% N/A
Lexiquotient (Lexilijst) 91 (16.1) 88 (18.2)

Total behavioural score

26 (14.9) 30 (21.2)
(CBCL)
Total internalising score
(CBCL) 5 (4.3) 8 (7.9)

Total externalising score

(CBCL) 12 (7.5) 12 (7.6)
Median: 22%

#: Studies did not report group mean and SD for sepsis and non-sepsis group. NS—not specified.

The following sections provide detailed accounts of each study included in this qualitative synthesis.

3.5.1. Studies Reporting Dichotomised Outcomes

Hoekstra et al. [54] retrospectively analysed results from 675 out of 778 (87% follow-up rate) children born at 23–
26 weeks gestational age and assessed them between 36 and 60 months of age. The association between sepsis and NDI
at a mean age of 47.5 months (range 36–60 months) was not statistically significant. No detailed psychometric testing
was done at school age.
Jang et al. [56] retrospectively reviewed medical records of VLBW infants admitted from 1998 to 2007 and
compared with those admitted from 1989 to 1997. There was a total of 967 survivors. Univariate analysis showed sepsis
was a weak risk factor for cerebral palsy (OR 1.653, 95% CI 0.849–3.215) assessed at 18–24 months. No information was
reported on sepsis and noncerebral palsy NDI.
Children 2019, 6, 131 17 of 25

Kono et al. [44] evaluated a prospective cohort of 2847 VLBW survivors. A total of 1826 (64%) completed follow-up
at 36–42 months of age. Of the 1826, 113 survivors had neonatal sepsis. An association was found between sepsis and a
combined measure of cerebral palsy or death (OR 2.6, 95% CI 1.4–4.8) as well as sepsis and a combined measure of NDI or
death (OR 2.8, 95% CI 1.6–4.8). No information was reported between sepsis and NDI only.
Synnes et al. [48] evaluated a prospective national cohort of children born at less than 29 weeks gestational age at
18–21 months. Eighty percent (1870 out of 2340) of the infants completed follow-up. Outcomes were differentiated into
NDI and significant NDI based on a prespecified criterion, as seen in Table 2. They found a statistically significant
association between sepsis and significant NDI (OR 1.50, 95% CI 1.05–1.86), but no information was reported on
association between sepsis andNDI.
Bright et al. [49] reviewed a multicentre prospective study of extremely preterm infants born before 28 weeks
gestational age. Ninety-two percent of infants were followed up (889 out of 966) with cognitive assessments at ten years
of age, of which 233 infants had neonatal bacteraemia. A wide variety of outcomes were assessed. Confirmed
bacteraemia was associated with lower z-scores in outcomes assessing verbal and nonverbal IQ, oral expression,
academic achievement, executive function and visual perception. Children with confirmed bacteraemia were more likely
to have visual or auditory impairment, but not motor impairment. However, after adjusting for IQ, many of these
associations were lost, suggesting IQ may be a mediator between bacteraemia and cognitive deficits.

3.5.2. Studies Reporting Continuous Outcomes

Shah et al. [55], Hentges et al. [58] and Zonnenberg et al. [62] assessed mental development index (MDI) and
psychomotor development index (PDI) outcomes of VP infants at 24 months. Shah et al. [55] reported an unadjusted mean
difference of 6.8 (95% CI 0.8–12.8, p = 0.02) in MDI and 5.6 (95% CI 0.4–10.9, p = 0.04) in PDI between VP infants with
and without sepsis. After adjusting for potential confounders and white matter abnormalities, group differences
decreased and there was no statistical significance, suggesting white matter abnormalities may mediate functional
impairment. Hentges et al. [58] and Zonnenberg et al. [62] reported no significant mean difference in MDI and PDI between
the two study populations. Zonnenberg et al. [62] found no significant difference in lexical development or behaviour
scores between the two groups.
Young et al. [61] reviewed 100 infants born before 32 weeks gestational age at 24 months and 48 months. Using
bootstrap ratios of predictors and partial least square regression to draw relationships, they found sepsis was not
significantly associated with 2-year or 4-year cognitive measures but was significantly associated with 4-year behavioural
measures.
Van der Ree et al. [64] evaluated 50 VP infants (of which 32 had neonatal sepsis) at 6–9 years of age using an
extensive list of motor, cognitive and behavioural outcomes. The study demonstrated 68% of the proven sepsis cohort had
abnormal or borderline motor skills (OR 3.30, 95% CI 0.98–11.07, p
< 0.10), particularly poorer fine motor skills (OR 5.46, 95% CI 1.52–1.58, p < 0.01). Their total IQ was 89
(14 SD, range 55–118) compared with 98 (8 SD, range 82–110) in VP infants without sepsis, giving an OR of 13.22 (95% CI
1.57–111.75, p < 0.05). Verbal memory and attention were significantly affected in those with proven sepsis compared
with VP infants without sepsis (0.61 SD, 95% CI 0.04–1.17, p =
0.033 and 0.94 SD, 95% CI 0.32–1.62, p = 0.011, respectively). There were no significant differences in total behavioural
problems between the groups (OR 0.86, 95% CI 0.25–3.00).

4. Discussion
This review provides an updated literature synthesis on the long-term neurodevelopmental impact of neonatal
sepsis in VP infants compared to those without sepsis. The conducted meta-analysis demonstrated statistically significant
association between sepsis and NDI, but was limited by the substantial heterogeneity that existed between studies. On
the contrary, qualitative synthesis of the remaining studies revealed less clear associations between sepsis and long-term
neurocognitive deficits.
Children 2019, 6, 131 18 of 25

There were limited studies examining continuous outcomes of NDI after sepsis. The included studies in this review offer
valuable insight, but will need to be interpreted in the context of the study limitations.

4.1. Study Designs

All studies were observational studies, as randomised control trials were not ethically possible given the nature of
the topic. In case-control studies, controls were generally matched for admission period, gestational age and/or birth
weight. These studies may have suffered from selection bias and reporting bias. One case-control study reported they
selected controls by randomly selecting every fifth subject admitted to the NICU within a specific time-frame [65]. Case-
cohort studies used either retrospectively collected data or prospectively collected data. Prospective data collection is
dependent on the proportion of infants successfully followed up which determines attrition bias. Retrospective data
collection can be limited as not all information for the study may be collected at the time, which can result in reporting bias.
In addition, all retrospective reviews rely on accurate data entries and recordings.
In retrospective studies, increasing sample size results in increasing statistical power. Some studies included in this
review had much smaller study populations compared with other studies (i.e., the sample size in all includedstudies ranged
from 33 to 7892). This would contribute to the overall statistical heterogeneity and impede the validity and interpretation of
study outcome. Adams-Chapman et al. [46] reported that the non-sepsis group in the Candida study was not
representative of the homogeneous extremely low birthweight population and thus performed a secondary analysis
using additional non-sepsis infants enrolled in the registry by the Neonatal Research Network (NRN) of the Eunice
Kennedy Shriver National Institute of Child Health and Health Development (NICHD). Although this increases statistical
power, it also increases the risk of selection and reporting bias.
Similarly, several of the included studies consisted of disproportionate sample size in the sepsis versus the non-
sepsis group, with up to ten times greater numbers in the non-sepsis group compared to the sepsis group in one study
[51,52]. For example, Msall et al. [51] investigated sepsis as a perinatal factor and of the 149 participants followed up,
only 18 had confirmed sepsis. Van der Ree et al. [64] compared 32 infants with sepsis to 18 non-sepsis infants. Due to the
disparity in group numbers, with much smaller numbers in the sepsis group, there is a higher chance of over-representing
infants developing NDI in the sepsis group as compared to the much larger non-sepsis group. This overestimation can
result in publication bias as studies are more inclined to publish results with significant findings.

4.2. Population
All studies adjusted for selected confounding factors such as age and sex. However, they adjusted differently with
various combinations of other factors such as multiple birth, mode of delivery, corticosteroid exposure, intrauterine growth
restriction, bronchopulmonary dysplasia, necrotising enterocolitis, chorioamnionitis, periventricular leukomalacia,
socioeconomic status and maternal education. As a result, we extracted unadjusted numerical data to pool, but were
unable to assess the impact of these confounding factors.
The median attrition rate was 20% and the range was wide (3%–45%). Loss through follow-up can be due to many
factors, such as unable to be contacted, parent refusal, or being too impaired to participate in tests [67]. Most studies
did not report the reason for loss to follow-up. Some studies compared patient demographics between infants who
completed follow-up with those who did not to identify attrition bias. As loss to follow-up increases, bias in the reported
outcome also increases [68]. Prevention of attrition bias is inherently difficult and best to be addressed in prospectively
designed studies.
One potential confounder may be related to the wide range in birth years of the infants, and different ages at
assessment. For instance, infants born in earlier eras may have received less advanced neonatal care as compared to more
recent eras. Furthermore, quality of neonatal care may vary across
Children 2019, 6, 131 19 of 25

regions and countries, potentially influencing the events experienced by the infant during the neonatal period and the
subsequent neurodevelopmental outcomes.

4.3. Assessment of Sepsis

One limitation of this review was the definition of neonatal sepsis as an appreciable portion of neonatal sepsis is
blood culture-negative or have positive cultures from other sterile sites. For a focused review, we defined sepsis as having a
blood culture-proven infection which has historically been the ‘gold standard’, but there was great variability amongst
studies [4,69]. Definitions included: positive blood culture only [44,46,48,49,52,54,56,59,60,62–64,66]; positive blood
culture and clinical signs of sepsis [50,53,58,65]; positive blood culture and antibiotic use [43,47,51,61]; positive blood
culture, clinical signs of sepsis and antibiotic use [57]; positive blood culture, antibiotic use and presence of raised
inflammatory markers [55]; and positive blood culture, clinical signs of sepsis, antibiotic use and presence of raised
inflammatory markers [45]. Other specific variations include time that the blood culture was taken, duration of antibiotic
use and type of infection laboratory markers examined. Some of these studies justified that using a blood culture only
definition has suboptimal sensitivity and specificity, as there is risk of contamination which could produce false positives
[55]. Infants who had clinically suspicious sepsis, but no positive blood culture may also be missed. The diversity in sepsis
definitions could contribute to the population heterogeneity and overall selection bias.
Selected studies that analysed the impact of specific micro-organisms may also contribute to selection bias. Lee et
al. [63], Friedman et al. [52], and Adams-Chapman et al. [46] focused on Candidaemia, De Haan et al. [65] examined
Candidaemia and Gram-negative organisms, whereas Alshaikh et al. [57] investigated coagulase-negative Staphylocci
specifically. In contrast, Stoll et al. [43], Schlapbach et al. [45], and Hentges et al. [58] did a micro-organism subtype
analysis and reported the association between predominant organisms and outcomes. For instance, Hentges et al. [58]
found no statistical difference between the two study groups, but upon further analysis, reported VLBW infants with Gram-
positive sepsis showed higher rates of motor deficit when compared to the non-sepsis group (68.8% and 29.3%
respectively). Similarly, Schlapbech et al. [45] did a subtype analysis and found infants who had Gram-positive sepsis had the
poorest outcomes. This suggests different organisms may cause different deficits which should be further explored in
future studies.

4.4. Assessment of Outcomes

Functional outcomes must be interpreted carefully given the variability between studies. Most studies focused on
early outcomes, with half of the included studies in this review performing assessments at or before the age of 24
months. Only five studies examined outcomes beyond 5 years of age [47,49,51,59,64], two of which investigated
outcomes beyond the age of ten [49,59]. No studies assessed outcomes in early adulthood or reported if difficulties
persisted into early adulthood. Cognitive skills are complex and may evolve overtime with brain maturation. Early
assessments may underestimate the full spectrum of outcomes, such as milder motor dysfunctions and specific learning
disorders, and be of less predictive value for long-term outcomes [45,66]. Most studies performed a single cross-
sectional follow-up, but outcomes may alter over time. Children who test within the normal range at early follow-up may
still remain at risk of developing significant problems later in life [43,54,57]. Conversely, children with early deficits may
improve or remain unchanged.
Eighteen out of the 24 included studies did not specify if outcome assessors were blinded to the infants’ neonatal
history [43–46,48,50,52,53,55,56,59–61,63–66]. Five studies reported blinding of outcome assessors [49,51,57,58,62] and
one reported no blinding was performed [54]. Without blinding, there is a high chance of detection and reporting bias as
assessors may perceive sepsis-affected infants to be at higher risk of functional deficits. Although the tests are
standardised, most studies did not note the experience level of outcome assessors, which may also contribute to the risk
of detection and reporting bias.
Children 2019, 6, 131 20 of 25

Two approaches were used to assess outcomes: using dichotomised (using a prespecified NDI definition) or
continuous (calculating mean and SD of groups) outcomes. In the former, variation in NDI definition was a significant
limitation. Most studies defined NDI as cerebral palsy or its components, cognitive and psychomotor scores of <70 or
more than two SD below the mean, visual impairment or hearing impairment. Lee et al. [63] defined cognitive delay as
more than three SD below the mean which would exclude children who scored between two and three SD below the
mean. In contrast, Yang et al. [59] utilised a different definition whereby the parent had to disclose that the child was
‘disabled’, a handicap status issued by the Ministry of the Interior of Taiwan, which is a subjective evaluation of disability.
Fifteen studies used BSID-II as an assessment tool where MDI and PDI was defined as a score of <70 or more than two SD
below the mean. BSID-II is useful for infants who are yet to enter preschool as it provides an indicator if the infant is at risk
of developmental delay, therefore the caregiver has the opportunity to seek early intervention to improve outcomes. The
2005 BSID revision saw a shift from BSID-II to Bayley-III. Four studies used Bayley-III for assessment [46,48,50,61]. However,
studies have reported that the Bayley-III detects lower rates of NDI in infants as compared to BSID-II using the same
population [70–72]. There is also limited data on the long-term predictive validity of Bayley-III [72]. Kono et al. [44], De
Haan et al. [65] and Maruyama et al. [60] looked at NDI and death together, which may overestimate the study effect of
sepsis in VP infants. Overall, dichotomised studies tended to focus on identifying the most impaired children, often at an
early age. This was reflected by the reporting of incomplete assessments in several studies due to reasons such as
distractions or limitations in the child’s ability to complete the assessment.
Accordingly, less focus was placed on less impaired children who may have more subtle cognitive difficulties. To
address this, studies using continuous outcomes can identify subtle impairments as a child grows older and begins
school. For instance, Van der Ree et al. [64] noted that out of the 18 children with neonatal sepsis exposure who had
normal full-scale IQs, nine of them had problems in attention or memory. Limited studies (n = 5) reported continuous
outcome variables, and the heterogeneity of the reporting cognitive domains in each study made it difficult to pool these
results. In these studies, the mean results were comparable between the sepsis group and non-sepsis group. One
potential factor contributing to the conflicting results may be the Zonnenberg et al. [62] study, as they compared proven
sepsis versus no proven sepsis in a cohort that all had an episode of suspicious infection, which questions the incorporation
of clinically suspicious infants into our analysis and introduces selection bias. Only one study used a wide variety of
assessments in a continuous manner to extensively study the neurocognitive deficits a child may be experiencing [64].

4.5. Review Limitations

This review has several limitations. Data screening, extraction, and analysis were performed by one reviewer (S.C.),
instead of consensus reached by at least two independent reviewers. However, data synthesis was discussed with, and
consensus was reached with the senior author (J.Y.-M.Y). The reviewer did not attempt to contact the included study
authors for missing data. Thus, this systematic review did not strictly adhere to the recommended Preferred Reporting
Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines [73]. Secondly, sensitivity analyses were not
performed to examine the influence of attrition bias and the contribution of different micro-organisms. Given that
substantial disagreement remains in the definition of sepsis, selecting a sepsis definition also subjects our review to this
methodological limitation. Our review did not address the impact of neonatal meningitis and urinary tract infection
separately, which are both common in the NICU setting.

4.6. Recommendations for Future Research

Based on the results of this systematic review, we recommend future studies examining cognitive outcomes of VP
infants with neonatal sepsis. Longitudinal studies of prospectively collected data would be the most appropriate study
design. Larger cohorts and high rates of follow-up would increase statistical power and reduce attrition bias. If follow-up
rates are low, assessment of the characteristics
Children 2019, 6, 131 21 of 25

between infants who do complete follow-up and those who do not would be needed. There is much evidence to support
the risk of major NDI, but little research has been done in identifying more subtle difficulties in less impaired children
which may be significant during activities of daily living. To dissect the specific cognitive impairments, a range of
assessment tools should be used to measure motor function, cognitive skills and behaviour as continuous variables.
Participants should be assessed later in life, ideally once they have entered the education curriculum, as there is a higher
predictive value in dissecting long-term outcomes.

5. Conclusions
Neonatal sepsis can have a profound impact on neurodevelopment of VP infants. This systematic review found 24
published studies and performed meta-analysis in 14 studies using prespecified NDI definitions. This review suggests that
the most impaired VP infants surviving neonatal sepsis may be at higher risk for long-term neurodevelopmental disability
compared with VP infants without sepsis. However, current evidence is limited by significant statistical heterogeneity and
publication bias due to significant differences in the included study design and definitions used for NDI. Moreover, this
finding could not be extrapolated to all VP infants surviving neonatal sepsis due to lack of studies reporting cognitive
outcomes using non-discrete, continuous variables. Current published studies lack long-term longitudinal follow-up data.
These results highlight the necessity for future longitudinal studies to use continuous outcomes performed at a later age
to discern the subtle and more specific long-term cognitive risks for VP children with neonatal sepsis.

Supplementary Materials: The following are available online at http://www.mdpi.com/2227-9067/6/12/131/s1, Table S1.
Detailed literature search strategy, Table S2. The Cochrane Collaboration’s tool for assessing risk of bias, Table S3.
Assessment of risk of bias of the 24 included studies.
Author Contributions: Conceptualization, S.C., D.K.T., P.J.A. and J.Y.-M.Y.; Methodology, S.C. and J.Y.-M.Y.; Formal Analysis,
S.C. and J.Y.-M.Y.; Investigation, S.C., D.K.T., P.J.A. and J.Y.-M.Y.; Resources, D.K.T., P.J.A. and J.Y.-M.Y.; Writing-Original
Draft Preparation, S.C.; Writing-Review & Editing, S.C., D.K.T., P.J.A. and J.Y.-M.Y.; Supervision, D.K.T., P.J.A. and J.Y.-M.Y.;
Project Administration, J.Y.-M.Y.; Funding Acquisition, D.K.T., P.J.A. and J.Y.-M.Y.
Funding: This project was financially supported by the Australian National Health and Medical Research Council (NHMRC)
(Centre of Research Excellence Grant ID 1060733 and 1153176; Senior Research Fellowship ID 1081288 to P.J.A.; Career
Development Fellowship ID 1160003 to D.K.T.), the Royal Children’s Hospital Foundation (RCH 1000 to J.Y.-M.Y.), Murdoch
Children’s Research Institute, The University of Melbourne, Department of Paediatrics, and the Victorian Government’s
Operational Infrastructure Support Program.
Acknowledgments: We gratefully acknowledge support provided by the members of the Victorian Infant Brain Study
(VIBeS), Developmental Imaging and Neuroscience Research groups, located at the Murdoch Children’s Research
Institute, Melbourne, Victoria. We also thank Poh Chua at the Royal Children’s Hospital library for her advice and
assistance in performing the literature search.

Conflicts of Interest: The authors have no conflict of interest to declare.

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© 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article
distributed under the terms and conditions of the Creative Commons Attribution (CC BY)
license (http://creativecommons.org/licenses/by/4.0/).
 JURNAL BAYI
Nama jurnal : Prevalence of breastfeeding in a babyfriendly pediatric
practice: an experience in Trieste, Italy
Penulis : Mariarosa Milinco
Tahun : 2019
1. Mampu Enam belas tahun setelah akreditasi bayi pertama-
mengelaborasi rumah sakit ramah pada tahun 2001, praktek menyusui
masalah di Italia masih kurang dari rekomendasi. Sampai saat ini
(Maret 2018), hanya 26 dari 500 lebih rumah sakit
CLARITY bersalin ramah bayi dan hanya sekitar 7% kelahiran
yang terjadi di layanan persalinan yang ditunjuk
2. Mampu dengan Tujuan dari penelitian ini adalah untuk mengevaluasi
cepat pengaruh tindakan yang dilaksanakan, dalam kaitannya
menemukan jalan dengan prevalensi ASI eksklusif.
keluarnya

3. Mampu Penerapan praktik pediatrik ramah menyusui dan

memberikan penerapan santai pemberian ASI dapat meningkatkan
Ilustrasi kecepatan dan durasi pemberian ASI eksklusif
4. Mampu Untuk mendukung pemberian ASI dalam praktiknya,
memberikan media tricians mulai dengan menerapkan Akademi
contoh secara bertahap rekomendasi dari Breastfeeding
Medicine (ABM) untuk kantor dokter yang ramah
menyusui
1. Apakah hal itu International Breastfeeding Journal
benar?
2. Bagaimana dapat 2019
melalukan /cek
ACCURACY bahwa itu akurat?
3. Bagaimana Q1
menentukan itu
benar?
 1. Mampu Artikel ini mampu memberikan informasi lebih detail.
membrikan Dalam artikel ini terdapat abstrak, latar belakang,
PRECISION informasi lebih metode penelitian,hasil, pembahasan dan kesimpulan.
detail.
2. Mampu Artikel ini sudah memberikan informasi lebih spesifik.
memberikan Dalam artikel ini terdapat tabel dan grafik untuk
informasi lebih menjelaskan hasil penelitian
spesifik
1. Bagaimana Dalam artikel ini latar belakang berhubungan dengan
menghubungkan rumusan masalah
ide dengan
pertanyaan yang
RELEVANCE timbul?
2. Bagaimana Jika dihubungkan dengan isu saat ini artikel ini cukup
menghubungkan update dimana masih kita ketahui bahwa penerapan
dengan isu? untuk ASI eksklusif mungkin banyak di sebagian
negara yang angka pencapaiannya masih rendah
sehingga dari penelitian ini dapat mengetahui apa yang
dapat mempengaruhi keberhasilan pemberian ASI
eksklusif
3. Bagaimana Pada jurnal ini mempunyai relasi yang baik dan saling
relasinya satu ide berhubungan
dengan ide
lainnya?
1. Jumlah problem 1. Pemberian ASI eksklusif
DEPTH yang muncul
2. Mengurai factor – Populasi:Semua wanita yang melahirkan antara 1
factor yang Januari 2016 dan 31 Desember 2016 dan mendaftarkan
bermakna bayi mereka dengan praktek pediatrik termasuk dalam
kami analisis, hanya ibu dengan bayi baru lahir
prematur <30 minggu usia kehamilan dikeluarkan.
Sampel: 265 Bayi dengan usia kehamilan
lebih dari 30 minggu
BREADTH 1. Pandangan Sebanyak 265 bayi baru lahir dengan usia kehamilan
terhadap hasil lebih dari 30 minggu terdaftar di praktik dokter anak
pengamatan hasil selama masa studi, sekitar 18% dari semua bayi yang
pengamatan dan lahir di Trieste dalam periode tersebut. Data lengkap
jawaban terhadap tersedia untuk 252 di antaranya (95,1%). Angka
pertanyaan/masa pemberian ASI eksklusif pada usia lima bulan lebih
lah tinggi dibandingkan yang dilaporkan untuk seluruh
populasi bayi di Trieste dan di Wilayah Friuli Venezia
Giulia (62,3% vs. 42,9% vs. 30,3%) dalam periode yang
sama.

1. Berpikir logis, Pada tingkat lima bulan pemberian ASI eksklusif

membuat anak-anak yang ditindaklanjuti dalam praktik pediatrik
pengertian, adalah statistic secara signifikan lebih tinggi daripada
LOGICALNESS menemukan yang dilaporkan di periode yang sama untuk seluruh
fakta/ bukti/ populasi bayi di Trieste dan FVG (62,3% vs.
petunjuk 42,9%, p <0,0001 dan vs. 30,3%, p <0,0001, masing-
masing).
1. Informasi yang Penelitian ini menunjukkan bahwa ada pengaruh
dibutuhkan tindakan yang dilaksanakan, dalam kaitannya dengan
prevalensi ASI eksklusif.
2. Factor yang Factor Tindakan
SIGNIFICANCE penting
3. Pertanyaan mana Apakah pengaruh tindakan yang dilaksanakan, dalam
yang lebih kaitannya dengan prevalensi ASI eksklusif.
signifikan?
FAIRNESS Menurut pendapat saya isi dari jurnal ini cukup bagus dimana dalam jurnal ini
menjelaskan tingginya pemberian ASI eksklusif dibandingkan dengan yang
tidak
BELAJAR AKTIF ABSTRAK Sudah baik karena sudah memuat latar belakang,
metode, hasil, dan kesimpulan yang informatif
METODE Metode dijelaskan dengan jelas
HASIL Dijelaskan dengan jelas dan terdapat tabel serta grafik
yang memberikan informasi lebih spesifik
PEMBAHASAN Pada pembahasan penjelasannya sudah cukup jelas dan
mudah dimengerti
KESIMPULAN Pada kesimpulan sudah cukup menggambarkan hasil
Milinco et al. International Breastfeeding Journal (2019) 14:44
https://doi.org/10.1186/s13006-019-0239-4

RESEARCH Open Access

Prevalence of breastfeeding in a baby-

friendly pediatric practice: an experience in
Trieste, Italy
Mariarosa Milinco1, Adriano Cattaneo1, Anna Macaluso2, Paola Materassi2, Nicola Di Toro2 and Luca Ronfani1*

Abstract
Background: In a pediatric practice in Italy, actions were undertaken to apply the recommendations for a
breastfeeding-friendly physician’s office and to promote the adoption of a semi-reclined or laid-back maternal
position in breastfeeding. The aim of this study is to evaluate the effect of the actions implemented, in terms of
prevalence of exclusive breastfeeding.
Methods: A historical cohort study was carried out using administrative data routinely collected. All women who
gave birth in 2016 and registered their newborns with the pediatric practice were included, only mothers of
preterm newborns < 30 weeks gestational age were excluded. The main actions undertaken were: employment of a
breastfeeding peer supporter; ensuring unlimited daily access in case of breastfeeding difficulties; provision of
individual support to breastfeeding mothers in a dedicated room and advice on the laid-back position; scheduling
of weekly meetings of small groups for breastfeeding support. Each infant was followed up for five months. The
main study outcomes were duration of exclusive breastfeeding (only breast milk and no other liquids or solids,
except for drops of syrups with nutritional supplements or medicines) and prevalence at five months.
Results: A total of 265 newborn infants with a gestational age greater than 30 weeks were registered with the
pediatric practice during the study period, about 18% of all infants born in Trieste in that period. Complete data
were available for 252 of these (95.1%). The rate of exclusive breastfeeding at five months of age was higher than
the one reported for the whole infant population of Trieste and of the Friuli Venezia Giulia Region (62.3% vs. 42.9%
vs. 30.3%) in the same period.
Conclusions: The implementation of breastfeeding-friendly pediatric practice and the application of laid-back
breastfeeding may improve the rate and duration of exclusive breastfeeding.
Keywords: Breastfeeding-friendly physician’s office, Laid-back breastfeeding, Exclusive breastfeeding prevalence

Background
Sixteen years after the accreditation of the first baby-
friendly hospital in 2001, breastfeeding practices in Italy
still fall short of recommendations [1]. To date (March
2018), only 26 out of more than 500 maternity hospitals
are baby-friendly and only about 7% of births take place
in designated maternities services [2]. The rate of initi-
ation of breastfeeding increased from 81.1 to 85.5%
between 2000 and 2013, but the mean duration was only
* Correspondence: luca.ronfani@burlo.trieste.it
1
Clinical Epidemiology and Public Health Research Unit, Institute for Maternal
and Child Health - IRCCS “Burlo Garofolo”, Trieste, Italy
Full list of author information is available at the end of the article
8.3 months and the percentage of infants less than six
months of age exclusively breastfed was 42.7% (48.7% at
0–1, 43.9% at 2–3, and 38.6% at 4–5 months) [3]. These
national figures conceal regional variations, with higher
breastfeeding rates in the north than in the south. But
even where breastfeeding rates and practices are better,
the situation is far from ideal and fails to comply with
the national policy recommendations of exclusive breast-
feeding up to six months [1].
It is not easy to identify the causes of this gap between
policy and practices. Improving hospital practices (i.e.
promoting the Baby Friendly Hospital Initiative) helps
increase breastfeeding rates, but not to recommended

© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Milinco et al. International Breastfeeding Journal (2019) 14:44
levels [4]. Even the Baby Friendly Community Initiative,
introduced in Italy in 2006 [5], seems to be unable to
produce the expected improvements in terms of exclu-
sive breastfeeding rates at six months [6]. Among the
many health system and social determinants of breast-
feeding, research has often focused on the organization
of services, on training of staff, and on support to effective
latching on to the mother’s breast. Better health services
and staff training, as promoted by the above-mentioned
Baby Friendly initiatives (Hospital and Community), have
an important but limited effect. Interventions aimed at
improving positioning and latching, a core element of staff
training within Baby Friendly initiatives [7], have shown to
be equally ineffective [8, 9]. Some evidence is available
of a possible effect on exclusive breastfeeding initiation
and duration of the implementation of breastfeeding-
friendly physician’s office, particularly if associated with
extra care provided by a lactation consultant or by a
peer counsellor [10–13].
Based on the above considerations, at the beginning of
2016 two family pediatricians (PM and AM) decided to
improve the environment and the support for breast-
feeding in their Trieste practice. In Trieste, a city located
in the north-east Italian Region of Friuli Venezia Giulia
(FVG), the Local Health Authority was accredited as
Baby Friendly in 2015. Data from a cohort study carried
out between 2007 and 2008 in this area showed that, at
hospital discharge, 69% of infants were exclusively breast-
fed according to World Health Organization (WHO) defi-
nitions, and that the rate dropped to 6% by the time the
infants were six months old [14]. More recently, data rou-
tinely collected by the Regional Health Authority of FVG
using the same definitions [15], showed that in 2015 ex-
clusive breastfeeding in Trieste was 43.5% at five months;
factoring in also 1.7% of predominant breastfeeding, full
breastfeeding amounted to 45.3%. Complementary feeding
was 27.7% and formula feeding 27.0%.
To support breastfeeding in their practice, the pedia-
tricians started by progressively applying the Academy
of Breastfeeding Medicine (ABM) recommendations for
a breastfeeding-friendly physician’s office [16]. They then
decided to reduce the attention paid to correct position-
ing and latching, typical of Baby Friendly initiatives
training and evaluation, and to adopt the biological nurt-
uring method. This neurobehavioral approach to breast-
feeding encourages mothers to breastfeed in a relaxed,
laidback position. In this position the baby lies prone on
the mother’s chest, ensuring the largest possible contact
between the baby’s body and the mother’s chest and
abdomen. This position opens up the mother’s body and
promotes the baby’s movements through the activation
of 20 primitive neonatal reflexes that stimulate breast-
feeding [17–19]. The results of a small, unpublished ran-
domized trial [20], show that, compared to standard
Page 2 of 8
care, the biological nurturing approach reduces the need
for supplementation and the number of women who
stop breastfeeding. The biological nurturing approach is
simple and requires no specific position or particular
procedure. To promote it, the pediatricians placed a re-
clining armchair in a small room and employed full-time
a breastfeeding peer supporter (MM) whose role was to
advise mothers on the laid-back position and to encour-
age them to breastfeed with no further interference,
unless help was requested. This paper reports the results
of that experience in terms of rate of exclusive breast-
feeding and of variables associated to exclusive breast-
feeding at five months.
Methods
Design
This historical cohort study used data routinely collected
during child health visits. Data collection followed Italian
regulations and laws: parents sign a standard privacy
form in which they give consent to the collection and
storage of child health data. The study was approved by
the Regional Ethics Committee of Friuli Venezia Giulia.
Setting
The study was carried out in a single pediatric practice
located in Trieste. The practice cares for about 2000
children. Trieste is served by a third level hospital in
which the mean newborn hospital stay is about three
days for vaginal and five days for caesarean section deliv-
eries. About 20 pediatric practices are present in Trieste.
Sample
All the women who gave birth between 1 January 2016
and 31 December 2016 and registered their newborn in-
fants with the pediatric practice were included in our
analysis, only mothers of preterm newborns < 30 weeks
gestational age were excluded.
According to the regulations of the Italian National
Health System, new mothers choose their family
pediatrician around the time their infant is born, usu-
ally in the first few days after delivery, but sometimes
even before giving birth. In the absence of health prob-
lems and of breastfeeding difficulties, mothers book the
first child health visit when the infant is about 30 days
old, and subsequent visits are usually scheduled at three
and six months. Mothers can, however, book a visit any
time after registering with the pediatrician, should they
have any health problem. The first child health visit
normally lasts about 30 min.
In the pediatric practice where the study was perfor-
mede, visits can be very frequent, even daily, in the case
of breastfeeding difficulties, and can last as much as the
mother wishes and needs. Mothers and infants are cared
for individually in the pediatric office for clinical issues,
Milinco et al. International Breastfeeding Journal (2019) 14:44
and in the small breastfeeding room, equipped with a re-
clining armchair, for individual breastfeeding support
provided by both the pediatricians and the peer sup-
porter. In addition to individual care, the peer supporter
meets small groups of mothers once a week in the wait-
ing area, to discuss common concerns and share positive
and negative experiences. In Italy, breastfeeding peer sup-
porters are women with experience in breastfeeding who
volunteer their time to help women with breastfeeding
problems and who have attended at least a short training
course, usually based on the WHO 40-h course [21]. They
are not officially recognized within the national healthcare
system, however, peer support for breastfeeding can be of-
fered in hospital and outpatient settings through specific
initiatives and projects. This is the case of the present
study, in which the pediatric practice employed a breast-
feeding peer supporter with specific training (the 20-h
course on Breastfeeding Management and Promotion in a
Baby Friendly Hospital, and the 40-h course on Breast-
feeding Counselling, among others) and with more than
20 years of experience in supporting breastfeeding
women.
Table 1 summarizes the steps recommended by the
American Academy of Pediatrics for Breastfeeding
Table 1 Summary of Breastfeeding Supportive Office Practicesa
and steps implemented at the pediatric practice in Trieste
Steps Steps implemented
Have a written breastfeeding-friendly office policy No
Train staff in breastfeeding support skills Yes
Discuss breastfeeding during prenatal visits and Yes
at each well-child visit
Encourage exclusive breastfeeding for ∼6 months Yes
Provide appropriate anticipatory guidance that Yes
supports the continuation of breastfeeding as
long as desired
Incorporate breastfeeding observation into Yes
routine care
Educate mothers on breast-milk expression Yes
and return to work
Provide noncommercial breastfeeding educational No
resources for parents
Encourage breastfeeding in the waiting room, Yes
but provide private space on request
Eliminate the distribution of free formula Yes
Train staff to follow telephone triage protocols Yes
to address breastfeeding concerns
Collaborate with the local hospital or birthing Yes
center and obstetric community regarding
breastfeeding-friendly care
Link with breastfeeding community resources Yes
Monitor breastfeeding rates in your practice Yes
a
Adapted from: Meek JY, Hatcher AJ, AAP Section on Breastfeeding. The
breastfeeding-friendly pediatric office practice. Pediatrics.
2017;139:e20170647 [22]
Page 3 of 8
Supportive Office Practices [22], in accordance with
those proposed by ABM [16], and the steps imple-
mented in the Trieste pediatric practice. In particular,
all the staff of the pediatric office is trained in breast-
feeding support skills with the 40-h course [21];
breastfeeding is routinely discussed with mothers at
each child-health visit and women are encouraged to
exclusively breastfed for six months and to continue
breastfeeding as long as desired; mothers are educated
on breast-milk expression before they return to work;
the staff of the pediatric office collaborates with the
local hospital and the community health services for
matters regarding breastfeeding; the prevalence of
breastfeeding is periodically monitored using routinely
collected data.
In the study pediatric practice, breastfeeding mothers,
whether they have difficulties or not, are invited to lay
back in a comfortable posture, with the baby on their
chest in ventral position, after a brief explanation on the
primitive maternal and neonatal reflexes that facilitate a
good latch and on the positive use of gravity. Mothers
are then left undisturbed in order to avoid any interfer-
ence with their instinctual behaviors. In particular, both
the pediatricians and the peer supporter avoid any form
of teaching on how to breastfeed using a hands-off ap-
proach. When the result of this initial phase is success-
ful, mothers are discharged with the recommendation to
apply the same laid-back position at home, when they
consider it helpful. In case of difficulties, mothers are
given additional advice and support and are referred for
a further session of laid-back breastfeeding one or two
days later, and again subsequently, until a good latch is
established.
Outcomes
The main outcome of interest was the prevalence of ex-
clusive breastfeeding at five months, defined according
to the WHO as infants receiving only breast milk, from
their mother or from a wet nurse, through breastfeeding
or breast milk expression, and no other liquids or solids,
except for drops of syrups with nutritional supplements
or medicines; according to WHO, the “complementary
feeding” category includes infants receiving breast milk
and other food or liquid, including non-human milk and
formula [23]. The 24-h recall period recommended by
WHO was used [24]. Breastfeeding rates were evaluated
also at discharge from the maternity ward, and at one
and three months of age.
To study the association between possible explanatory
factors and exclusive breastfeeding at five months, the
following variables were considered: mother’s nationality
(Italian vs. non-Italian), age (< 29; 30–39; ≥ 40 years),
education (primary/intermediate vs. secondary/higher),
occupation (employed vs. non-employed), type of delivery
Milinco et al. International Breastfeeding Journal (2019) 14:44
(vaginal vs. caesarean section), parity (primiparity vs. mul-
tiparity), gestational age at delivery (< 37 vs. ≥ 37 weeks),
single pregnancy (yes vs. no), birthweight (< 2500 vs. ≥
2500), time at first visit (≤ 30 vs. > 30 days), and breast-
feeding at discharge from the maternity ward (exclusive
vs. other).
Data on parents and infants were recorded during rou-
tine child health visits using the custom software and
database employed by all family pediatricians in the re-
gion. Each infant was followed up to at least five months
of age. Data on breastfeeding in the maternity hospitals
were derived from the discharge letters. The remaining
data on breastfeeding were collected during the routine
child health visits at one, three and five months of age.
The prevalence of exclusive breastfeeding at five months
in the pediatric practice was compared with the one re-
ported in the same period by the FVG health information
system for the whole infant population in Trieste and in
FVG. In FVG data on prevalence of exclusive breastfeed-
ing were routinely collected at birth and at five months of
infant’s age (second immunization visit) using the same
definitions and methods recommended by the WHO [15].
Statistical analysis
Continuous variables are reported as median and interquar-
tile range (IQR); categorical data as number and percentage.
To compare the descriptive data and the prevalence of ex-
clusive breastfeeding at five months between the sample of
children of the pediatric practice and the general popula-
tion of Trieste and of the FVG Region, the binomial prob-
ability test was used. Chi-square (or the Fisher’s exact
test when appropriate) was used to test the bivariate
association between possible explanatory variables and
exclusive breastfeeding at five months. Variables associ-
ated with p < 0.05 were subsequently entered into a logis-
tic regression model (forward stepwise). The statistical
analysis was performed using IBM SPSS Statistics for
Windows, Version 23.0. Armonk, NY: IBM Corp.
Results
A total of 265 newborn infants with gestational age
greater than 30 weeks were registered with the two fam-
ily practice pediatricians in 2016. This amounts to about
18% of all the infants born in Trieste in that period.
Table 2 shows some characteristics of the 252 (95.1%)
mother and baby dyads with complete data, and the
comparison with the last official data available for the
general population of newborns of the FVG region
(2011–2013 period) [25]. A statistically significant differ-
ence between the two population was seen for: the pro-
portion of non-Italian mothers and fathers, the proportion
of primiparity, the proportion of mothers between 20 and
29 years of age and 40 years or older, and the proportion
of children with birthweight ≥4000 g. Most infants, 67.5%,
Page 4 of 8
were seen for the first time when they were less than one
month of age. In particular, 28.2% were seen during their
first two weeks of life, in most cases because of mothers
reporting breastfeeding difficulties.
Figure 1 shows the rates of exclusive breastfeeding and
of other types of feeding at discharge and at one, three
and five months for the 252 mother and baby dyads with
complete data. Data on the age of the infants at the
three collection points are shown in Table 3. Some
mothers, who were discharged from the maternity hos-
pital with complementary feeding, recovered exclusive
breastfeeding at one month. Exclusive breastfeeding
remained high at three months and started dropping at
five. Up to the age of three months, complementary
feeding is a combination of breastmilk and formula,
from the age of five months it includes also complemen-
tary foods.
At five months the rate of exclusive breastfeeding of
children followed up in the pediatric practice was statis-
tically significantly higher than the one reported in the
same period for the whole infant population of Trieste
and of FVG (62.3% vs. 42.9%, p < 0.0001 and vs. 30.3%,
p < 0.0001, respectively).
At bivariate statistical analysis, a non-statistically sig-
nificant higher rate of exclusive breastfeeding at five
months was seen in non-Italian mothers (65.4% vs.
60.8%), in women with higher education (63.7% vs.
56.3%), in non-working women (65.5% vs. 60.7%), in
mothers who had a vaginal delivery (63.6% vs. 57.4%),
and in multipara (66.2% vs. 60.8%). A statistically signifi-
cant associations with exclusive breastfeeding at five
months was seen for mothers aged 30–39 years compared
to those < 29 years and ≥ 40 years (69.0% vs. 56.3% vs.
48.8, respectively; p = 0.04), infants 37–42 weeks of gesta-
tional age compared to those less than 37 weeks (65.2% vs.
26.3%; p = 0.001), singletons compared to twins (64.4% vs.
23.1%; p = 0.006, Fisher’s exact test), infants with birth-
weight greater than 2500 g compared to those with lower
birthweight (66.8% vs. 17.4%; p < 0.0001), infants seen for
the first time after 30 days of age compared to those seen
earlier (74.4% vs. 56.5%; p = 0.006), and exclusive breast-
feeding vs. other at discharge from the maternity ward
(76.6% vs 32.1%, p < 0.001).
The logistic regression model shows that three variables
have a positive association with exclusive breastfeeding at
five months: birthweight 2500 g or more (Odds Ratio
[OR] 7.8; 95% Confidence Interval [CI] 2.1, 28.2), exclusive
breastfeeding at discharge from the maternity hospital
(OR 5.4; 95% CI 2.9, 10.0), and first visit after 30 days of
age (OR 3.4; 95% CI 1.6–7.0), meaning that infants in
these categories have almost 8, more than 5 and more
than 3 times, respectively, higher odds of being exclusively
breastfed at five months compared to the infants with
birthweight less than 2500 g, non-exclusive breastfeeding
Milinco et al. International Breastfeeding Journal (2019) 14:44 Page 5 of 8

Table 2 Characteristics of the study population (N = 252) and comparison with the last official data available for the general
population of newborns of the FVG region
Characteristic n (%) Trieste pediatric practice FVG Region 2011–2013 p value*
(n = 252) (number of births = 28,916)
Mother not Italian 81 (32.1) 6762 (23.4) 0.002
(32 missing)
Father not Italian 72 (28.7) 5527 (19.4) < 0.001
(1 missing) (443 missing)
Maternal education
Primary/intermediate 48 (19.0) 6496 (22.5) 0.20
Secondary/higher 204 (81.0) 22,404 (77.5)
(16 missing)
Paternal education
Primary/intermediate 65 (25.9) 8198 (29.8) 0.17
Secondary/higher 186 (74.1) 19,334 (70.2)
(1 missing) (1384 missing)
Mother employed 168 (66.7) 19,493 (67.4) 0.79
(16 missing)
Maternal age
Less than 20 years 2 (0.8) 315 (1.1) 1.00
20–29 years 62 (24.6) 8867 (30.7) 0.04
30–39 years 145 (57.5) 17,476 (60.5) 0.33
40 years and more 43 (17.1) 2242 (7.8) < 0.001
(16 missing)
First child 181 (71.8) 15,205 (52.6) < 0.001
Cesarean-section 54 (21.4) 6735 (23.3) 0.55
Gestational age
< 31 weeks – 233 (0.8) Na
31–36 weeks 19 (7.5) 1706 (5.9) 0.28
37–42 weeks 233 (92.5) 26,974 (93.3) 0.61
> 42 weeks 0 3 (0.01) 0.1
Twin delivery 6 (2.4) 469 (1.6) 0.31
Birthweight§
Less than 2500 g 23 (9.1) 1991 (6.8) 0.17
2500–3999 g 221 (87.7) 25,422 (86.5) 0.65
4000 g and more 8 (3.2) 1978 (6.7) 0.02
(2 missing)
Age first visit
15 days or less 71 (28.2) Not available
16–30 days 99 (39.3)
More than 30 days 82 (32.5)
* binomial probability test, two sided
§
Data for the FVG Region are referred to newborns (n = 29,393)

at discharge from the maternity hospital, and seen for the
first time before 30 days of age.
Discussion
The data gathered during the implementation of the
protocol for a baby-friendly pediatric practice and of the
support of breastfeeding using the biological nurturing
approach, show that the rate of exclusive breastfeeding
that can be achieved at five months of age is much
higher than the one reported in the same period for the
whole infant population of Trieste and of FVG by the
Regional Health Authority (unpublished) using the same
definitions and methods recommended by WHO (62.3%
vs. 42.9 and 30.3%, respectively). It is higher than the
Milinco et al. International Breastfeeding Journal (2019) 14:44
Fig. 1 Types of feeding at different ages
27% (range among Local Health Authorities: 10 - 45%)
recorded in 2012 in Lombardia, where the rate of exclu-
sive breastfeeding at discharge was similar (67.3%) [26].
It is higher than the rate of full breastfeeding reported
from Emilia Romagna in 2015: 33% (range among Local
Health Authorities: 26 - 46%), of which only 27% was ex-
clusive [27]. It is also higher than the rate estimated for
the whole of Italy, which is probably close to the 38.6%
reported at 4–5 months of age in 2013, as mentioned in
the introduction. In fact, our exclusive breastfeeding rate
at five months, based on WHO definitions and 24-h
recall, is probably one of the highest recorded in the
European Region of WHO; a compilation of national
data published in 2016 reports a figure of 49.3% at six
months from Slovakia, while reports from all the other
member states range from 1 to 43.9% [28].
It is obviously difficult to establish a cause and effect
relationship between our intervention and the observed
high rate of exclusive breastfeeding, as is assessing the
individual contribution of the actions implemented by
the two pediatricians in their practice: promotion of the
baby-friendly pediatric practice protocol, and the
Table 3 Infants’ age in days, at routine child health visits
Child health visit Median (interquartile range)
First month 31.0 (26.0–35.8)
Third month 92.0 (87.0–100.0)
Fifth month 159.0 (153.0–164.8)
Page 6 of 8
adoption of the biological nurturing approach, including
the extra care provided by the peer supporter. Our study
is purely observational and was carried out using data
routinely collected by the two pediatricians. We did,
however, include a non-selected population of mother-
infant pairs: only preterm newborns < 30 weeks, which
account for about 1% of all births in Trieste, were ex-
cluded. This exclusion does not explain the higher rates
of exclusive breastfeeding found in our population. In-
deed, the comparison with the last available administra-
tive data on births in FVG (Table 2) shows that the
prevalence data of low birthweight, of births 31 to 36
weeks of gestational age, and of twin deliveries, condi-
tions usually associated with reduced rates of exclusive
breastfeeding, were higher in our population [25].
There is some evidence from similar studies that a
breastfeeding friendly pediatric practice may have a posi-
tive effect, regardless of the presence of a lactation con-
sultant or of a peer supporter. In Rio de Janeiro, Brazil,
the prevalence of exclusive breastfeeding among infants
aged four to six months rose from 41 to 82% between
2001 and 2004, after a basic health center was accredited
as breastfeeding friendly [10]. The application of the
ABM protocol for a breastfeeding-friendly physician’s
office in two community practices in Northern Virginia,
USA, resulted in statistically significant increases in the
rates of exclusive breastfeeding at two, four and six
months in a before-and-after comparison [11]. Baby-
friendly changes in a pediatric practice with a lactation
Milinco et al. International Breastfeeding Journal (2019) 14:44
consultant helping mothers with breastfeeding difficulties,
led to an increase in non-formula feeding in Cleveland,
Ohio, USA, between 2007 and 2009 [12]. It is well known
that peer support effectively improves the rates of breast-
feeding initiation, duration, and exclusivity [13]. The three
studies cited above and the review on peer counselling
lend support to the hypothesis that a breastfeeding-
friendly pediatric practice may help increase breastfeeding
rates, especially when extra care is provided by a lactation
consultant or by a peer counsellor [10–13].
What is more difficult to support with convincing evi-
dence is the hypothesis that the adoption of the bio-
logical nurturing approach may yield further benefits in
terms of exclusive breastfeeding. Most of the available
evidence derives from the observation of the physiology
of breastfeeding, i.e. of the presence in all healthy
mother and newborn dyads of innate reflexes aimed at
initiating and establishing breastfeeding, if left undis-
turbed in a comfortable semi-reclined position, with the
baby placed ventrally on the mother’s chest [18, 19].
There is very little literature, if any, on the effect of the
biological nurturing approach on breastfeeding rates. Re-
cently, a small, unpublished, randomized controlled trial
was carried out in France for a doctorate in human lac-
tation [20]. In this study, 32 mother and infant dyads
with latch-on problems in the first two days after birth
were randomized to laid-back breastfeeding or standard
support. Infants in the laid-back breastfeeding group had
significantly fewer formula supplements (19% vs. 26%)
and none of the mothers in this group stopped breast-
feeding during the first week compared with nine in the
standard support group.
As expected, a birthweight of 2500 g or more and
exclusive breastfeeding at discharge from the mater-
nity hospital, were associated with a higher prevalence
of exclusive breastfeeding at five months. The third
variable associated with exclusive breastfeeding at five
months was the time of first visit > 30 days after birth.
A possible explanation for this result is that mothers
who weren’t experiencing problems with breastfeed-
ing, rarely scheduled the first child health visit before
30 days after birth.
Furthermore, we cannot exclude a selection bias due
to the fact that our pediatric practice may have attracted
women with an interest in breastfeeding, given the sup-
port offered by the pediatricians and the peer supporter.
However, this seems unlikely for the following reasons:
in Italy, families choose to enroll with a pediatric prac-
tice mostly based on the catchment area and on the
number of patients already registered; the presence of a
peer supporter was not advertised; the socioeconomic
characteristics of the study population (maternal and pa-
ternal education and employment) were comparable
with those of the general population of the FVG Region,
Page 7 of 8
except for a higher proportion of foreign families in our
practice.
Conclusions
Our study contributes some evidence to the already well
established recommendations of the ABM for implement-
ing breastfeeding-friendly pediatric practice [16]. More
research is needed to support the hypothesis that the ap-
plication of laid-back breastfeeding may contribute to in-
creasing rate and duration of exclusive breastfeeding.
Abbreviations
ABM: Academy of Breastfeeding Medicine; FVG: Friuli Venezia Giulia Region;
IQR: Interquartile range; OR: Odds Ratio; WHO: World Health Organization
Acknowledgments
We acknowledge Alessandra Knowles for the English language supervision.
The study was supported by the Institute for Maternal and Child Health -
IRCCS “Burlo Garofolo”, Trieste, Italy (RC 28/18).
Authors’ contributions
MM, AM, PM, NDT conceived the study and contributed to data collection
and interpretation. AC conceived the study, contributed to data interpretation
and drafted the manuscript. LR analyzed the data, contributed to data
interpretation and drafted the manuscript. All authors read and approved the
final manuscript.
Funding
None
Availability of data and materials
The dataset used during the current study is available from the
corresponding author on reasonable request.
Ethics approval and consent to participate
The study was approved by the Regional Ethics Committee of Friuli Venezia
Giulia (02/04/2019 - odg 5.9). Data were collected following Italian
regulations and laws: parents sign a standard privacy form in which they
give consent to the collection and storage of child health data.
Consent for publication
Not applicable
Competing interests
The authors declare that they have no competing interests.
Author details
1
Clinical Epidemiology and Public Health Research Unit, Institute for Maternal
and Child Health - IRCCS “Burlo Garofolo”, Trieste, Italy. 2Pediatric practice,
Trieste, Italy.
Received: 26 April 2019 Accepted: 30 September 2019
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 TELAAH JURNAL

1. Jurnal Bayi Baru lahir

Critical Thinking
No. Didasarkan Pada Nilai Pembahasan
Intelektual Universal
1. Clarity (Kejelasan) Judul : Hypothermia and the newborn’s bath
in the first hours of life
Nama Penulis : Luma Maiara Ruschela,b Diane
Bressan Pedrinia Maria Luzia Chollopetz da Cunhaa
Tahun : 2018
1.1 Elaborasi Masalah : Ada kontroversi dalam
literatur tentang momen untuk mandi pertama
bayi yang baru lahir. Di setting sedang dibahas,
mandi dilakukan di dua yang pertama jam hidup
bayi baru lahir, meskipun ada rekomendasi
pengobatan untuk menunda prosedur selama 6
jam setelahnya kelahiran , atau bahkan 24 jam ,
untuk menghindari risiko hipotermia mia, hadir
dalam masa transisi dari lahir ke neonatal
kehidupan. Diyakini bahwa penelitian
metodologis diperlukan untuk mengisi
kesenjangan pengetahuan ilmiah ini, dan itu
adalah proposal penelitian ini.
1.2 Jalan Keluar : Menganalisis terjadinya
hipotermia pada neonatus sebelum dan sesudah
mandi pada jam-jam pertama kehidupan
1.3 Ilustrasi : Disimpulkan bahwa mandi pertama
dapat ditunda untuk mendukung adaptasi
neonatus ke lingkungan ekstrauterin. ment,
mencegah terjadinya hipotermia neonatal
 1.4 Contoh : Menurut pedoman untuk sistematisasi
perawatan integral untuk bayi baru lahir di
Persatuan Brasil Sistem Kesehatan (SUS), kulit
langsung dan terus meneruskontak dengan kulit
harus dipastikan, menyusui harus didorong pada
jam pertama kehidupan dan prosedur rutin dures
harus ditunda (seperti mandi, misalnya) untuk
bayi cukup bulan dengan ritme pernapasan
normal, atau tonus otot mal dan tanpa cairan
mekonium. Itu kehadiran dan kontak ibu / bayi
program binomial memberikan beberapa
manfaat bagi keduanya, seperti pencegahan
hipotermia neonatal dan stimulasi mamenyusui
ternal
2. Accuracy (Keakuratan) 2.1 Nama Jurnal : Revista gaucha de enfermagem
2.2 Tahun terbit jurnal : 2018
2.3 Akreditasi : Q3
3. Precision (Ketepatan) 3.1 Artikel ini telah menyajikan, pendahuluan,
metode, hasil penelitan, pembahasan, dan kesimpulan
informasi detail
3.2 Dalam artikel ini terdapat tabel maupun grafik
pada hasil penelitian yang spefisik dan mudah
dipahami
4. Relevance (Keterkaitan) 4.1 Ide yang ada pada pendahuluan terutama latar
belakang cukup menunjukkan adanya
keterkaitan/hubungan dengan rumusan masalah
meyatakan bahwa hipotermia berepengaruh pada
neonatus sebelum dan sesudah mandi pada jam-jam
pertama kehidupan, Sehingga hal tersebut
berhubungan dengan rumusan masalah
4.2 Artikel ini termasuk berkembang (up to date)
karena untuk memperbarui bukti yang dipublikasikan
 tentang hipotermia pada neonatus sebelum dan
sesudah mandi pada jam-jam pertama kehidupan
4.3 Adanya penelitian terbaru pada latar belakang
yang menunjukkan bahwa adanya keterkaitan
5. Depth (Kedalaman) 5.1 Jumlah masalah : dalam artikel ini membagi
praktek mandi bayi pada jam pertama : 1 dan 2 jam
kehidupan, antara 2 dan 3 jam, dan antara 3 jam dan
4 jam kehidupan
5.2. Kriteria inklusi : bayi baru lahir yang
pengiriman terjadi di rumah sakit tersebut di atas.
Barulahir dalam kondisi umum baik, dengan usia
kehamilan ≥ 35 minggu dan berat ≥2000g
5.3. Sampel: 149 bayi baru lahir
6. Breadth (Keluasan) Sebanyak 149 bayi baru lahir dilibatkan dalam penelitian
ini, menunjukkan prevalensi hipotermia neonatal pada
40,3% kasus, dengan hubungan yang signifikan secara
statistik (p <0,001) antara kejadian hipotermia neonatal
pada semua suhu aksila penilaian. Korelasi yang signifikan
secara statistik ditemukan antara variabel: suhu kamar dan
verifikasi suhu 60 menit setelah mandi (p = 0,032).
7. Logicalness (Alasan 7.1 Berpikir logis: Mandi pertama merupakan
yang Logis) tantangan bagi bayi yang baru lahir untuk menjaga
suhu tubuh yang memadai, karena sebagai tambahan
paparan terhadap variasi termal lingkungan, prosedur
ini membuat bayi baru lahir kehilangan panas akibat
air konduksi dan penguapan sehingga rentan
mengakibatkan hipotermi. penundaannya mandi
pertama menawarkan beberapa manfaat seperti
inisiasi menyusui dini . Karena itu, tunda pun prosedur
rutin selama jam-jam pertama kehidupan (seperti
mandi pertama) menghindari pemisahan binomial ibu
/ bayi, memungkinkan kulitnyakontak dengan kulit,
mendukung adaptasi bayi baru lahir ke
 ekstralingkungan rahim dan mempromosikan inisiasi
menyusui dini.
8. Significance (Bermakna) 8.1 Penelitian ini menunjukkan adanya bukti yang
sejalan dengan hipotesa yaitu ada pengaruh
hipotermia pada neonatus sebelum dan sesudah mandi
pada jam-jam pertama kehidupan,
8.2 Hasil penelitian menunjukkan tidak ada hubungan
antara termoregulasi dan variabel baru lahir seperti
berat badan dan usia kehamilan. Itu tidak adanya
signifikansi statistik dikaitkan dengan fakta bahwa itu
adalah sampel neonatus yang sehat.
9. Fainess (Keadilan) Menurut saya, jurnal ini telah memenuhi kaidah
penulisan yang benar. Didalamnya terdapat tabel dan
grafik sehingga mudah untuk dipahami.
10. Belajar Aktif Pada abstrak jurnal sudah lengkap menyediakan latar
belakang, tujuan, bahan, dan metode, hasil, dan
kesimpulan. Namun tidak disebutkan jumlah populasi
pada metode. Pada pendahuluan sudah dilengkapi
penelitian terdahulu dengan kasus yang serupa dan
solusi. Pada hasil juga sudah disajikan tabel dan
penjelasan dibawahnya, sehingga pembaca dengan
mudah memahami jurnal.

Revista Gaúcha
de Enfermagem
How to cite this article:
Ruschel LM, Pedrini DB, Cunha MLC.
Hypothermia and the newborn’s bath in
the first hours of life. Rev Gaúcha Enferm.
2018;39:e20170263. doi: https://doi.
org/10.1590/1983-1447.2018.20170263.
Universidade Federal do Rio Grande do Sul (UFRGS).
a
Escola de Enfermagem. Porto Alegre, Rio Grande do
Sul, Brasil.
b
Universidade Federal do Rio Grande do Sul (UFRGS).
Programa de Pós-graduação em Enfermagem. Porto
Alegre, Rio Grande do Sul, Brasil.
Online Version Portuguese/English: www.scielo.br/rgenf
www.seer.ufrgs.br/revistagauchadeenfermagem
„ Original Article
doi: https://doi.org/10.1590/1983-1447.2018.20170263
Hypothermia and the newborn’s bath
in the first hours of life
Hipotermia e banho do recém-nascido nas primeiras horas de vida
Hipotermia y el baño del recién nascido en las primeras horas de vida
Luma Maiara Ruschela,b
Diane Bressan Pedrinia
Maria Luzia Chollopetz da Cunhaa,b
ABSTRACT
Objective: to analyze the occurrence of hypothermia in neonates before and after bathing in the first hours of life.
Method: a cross-sectional study in which the axillary temperature of newborns before bathing, after bathing, 30 and 60 minutes
after bathing was verified at an Obstetric Center. In the statistical analysis, the Chi-Square, Student’s t and Mann-Whitney tests were
used, with α = 0.05.
Results: A total of 149 newborns were included in the study, showing the prevalence of neonatal hypothermia in 40.3% of the cases,
with a statistically significant association (p <0.001) between the occurrence of neonatal hypothermia at all axillary temperature
assessments. A statistically significant correlation was found between the variables: room temperature and temperature verification
60 minutes after bath (p = 0.032).
Conclusions: It is concluded that the first bath can be postponed to favor the adaptation of the neonate to the extrauterine environ-
ment, preventing the occurrence of neonatal hypothermia.
Keywords: Infant, newborn. Baths. Hypothermia.
RESUMO
Objetivo: analisar a ocorrência de hipotermia em recém-nascidos antes e após o banho nas primeiras horas de vida.
Método: estudo transversal, no qual se verificou a temperatura axilar de recém-nascidos antes do banho, após o banho, 30 minutos
após o banho e 60 minutos, no Centro Obstétrico. Na análise estatística utilizou-se os Testes Qui-Quadrado, t de Student e Mann-
-Whitney, com α = 0,05.
Resultados: Foram incluídos 149 recém-nascidos no estudo, evidenciando-se a prevalência de hipotermia neonatal em 40,3% dos
casos, tendo associação com significância estatística (p< 0,001) entre a ocorrência de hipotermia neonatal em todos os momentos de
verificação de temperatura axilar. Constatou-se correlação estatística significativa entre as variáveis: temperatura da sala de parto e a
verificação da temperatura 60 minutos após o banho (p= 0,032).
Conclusões: Conclui-se que o primeiro banho pode ser adiado para favorecer a adaptação do neonato ao ambiente extrauterino,
prevenindo a ocorrência de hipotermia neonatal.
Palavras-chave: Recém-nascido. Banhos. Hipotermia.
ABSTRACT
RESUMEN
Objetivo: analizar la ocurrencia de hipotermia en recién nacidos antes y después del baño en las primeras horas de vida.
Método: estudio transversal, en el cual se verificó la temperatura axilar de recién nacidos antes del baño, después del baño, 30
minutos después del baño y 60 minutos, en el Centro Obstétrico. En el análisis estadístico se utilizaron las pruebas Qui-cuadrado, t de
Student y Mann-Whitney, con α = 0,05.
Resultados: Se incluyeron 149 recién nacidos en el estudio, evidenciándose la prevalencia de hipotermia neonatal en el 40,3% de los
casos, teniendo asociación con significancia estadística (p <0,001) entre la ocurrencia de hipotermia neonatal en todos los momentos
de verificación de temperatura axilar. Se constató correlación estadística significativa entre las variables: temperatura de la sala de
parto y la verificación de la temperatura 60 minutos después del baño (p = 0,032).
Conclusiones: Se concluye que el primer baño puede ser pospuesto para favorecer la adaptación del neonato al ambiente extraute-
rino, previniendo la ocurrencia de hipotermia neonatal.
Palabras clave: Recién nacido. Baños. Hipotermia.
Rev Gaúcha Enferm. 2018;39:e20170263 1
„ Ruschel LM, Pedrini DB, Cunha MLC
„ INTRODUCTION
Newborns baths are routine procedures that follow
cultural tradition and aim to remove residues of the skin
and reduce its colonization. This procedure needs to be
recommended when there are evidences, to avoid injur-
ing the skin of the newborn, as it changes rapidly during
the adaptive process from the intrauterine to the extra-
uterine environment(1).
The first bath of the newborn is a controverse type of
care. A study suggests that the first bath should be delayed
for at least 24 hours, without removing the vernix caseosa,
which would bring a number of benefits to the newborn,
like: adequate thermoregulation, hydration of the skin, ab-
sence of skin peeling, reduction of neonatal toxic erythe-
ma, improved wound healing and protection from coloni-
zation of the skin by non-pathogenic bacteria(2).
When considering such benefits, it is recommended
to avoid the separation of the mother and the newborn in
the first hours of life, thus favoring skin-to-skin contact. This
practice helps in several mechanisms of self-regulation of
the newborn, among which the maintenance of body tem-
perature. Therefore, early care procedures can interrupt the
process of adaptation to the extrauterine environment(3).
According to guidelines for the systematization of
integral care for the newborn in the Brazilian Unified
Health System (SUS), immediate and continuous skin-
to-skin contact should be ensured, breastfeeding should
be encouraged in the first hour of life and routine proce-
dures should be postponed (like the bath, for example)
for full-term infants with normal respiratory rhythm, nor-
mal muscular tonus and without meconium fluid(4). The
presence and contact of the mother/baby binomial pro-
vides several benefits to both, such as the prevention of
neonatal hypothermia and the stimulation of early ma-
ternal breastfeeding(5-6).
The importance of the study is due to the fact that
there are controversies in the literature regarding the ideal
moment for the first bath of the newborn. In the setting
being discussed, the bath is carried out in the first two
hours of life of the newborn, though there are recom-
mendations to postpone the procedure for 6 hours after
birth(7), or even 24 hours(2), to avoid the risk for hypother-
mia, present in the transition period from birth to neonatal
life. It is believed that a methodological research is neces-
sary to fill this gap of scientific knowledge, and that is the
proposal of this study.
Consequently, considering the information about bath-
ing in the first hours of life, this study proposes the following
question: “What is the effect of the first bath on the axillary
2 Rev Gaúcha Enferm. 2018;39:e20170263
temperature of the newborn in the first hours of life?”. There-
fore, its objective is to analyze the occurrence of hypothermia
in newborns before and after bathing in the first hours of life.
„ METHODS
This is a cross-sectional study. This research belongs to
a dissertation project linked to the Postgraduate Program
in Nursing of the Federal University of Rio Grande do Sul
(UFRGS)(8). It took place in the delivery and newborn admis-
sion rooms of the Obstetric Center Unit (UCO), in a univer-
sity hospital located in the city of Porto Alegre, Rio Grande
do Sul, Brazil. The sample consisted of newborns whose
delivery took place at the aforementioned hospital. New-
borns in ​​good general conditions, with a gestational age ≥
35 weeks and weight ≥2000g were included in the study.
Newborns who needed to be admitted to the neonatal in-
tensive care unit (NICU), newborns born to mothers with
HIV and children of mothers with any STORCH infections
were excluded. To calculate the sample, a 10% proportion
was considered, with 80% power and significance index of
5%. Thus, the number of participants to compose the pres-
ent study was of 149 newborns. The calculation was carried
out using the WINPEPI software.
Data were collected in the delivery rooms and in the
admission room of the Obstetric Unit of a university hos-
pital, from April to October 2017, and stratified into four
moments. Initially, the axillary temperature was checked
with a “Medlevenson®” clinical thermometer for one min-
ute before the baby’s bath (moment 1). This occurred in
the newborn admission room, with them under the cradle
of radiant heat. After the bath, the axillary temperature was
verified (moment 2), with the body of the newborn dry af-
ter the procedure. The axillary temperature was also veri-
fied 30 minutes (moment 3) and 60 minutes after the bath
(moment 4). It should be noted that moments 1, 2 and 3 of
axillary temperature verification occurred in the Admission
Room, while the fourth moment took place in the Recov-
ery Room, where the newborn returned to his mother.
The data collected, as well as the clinical and sociode-
mographic data of the mother and the newborn were tak-
en from electronic nursing records. The present study used
the definition of hypothermia of the American Association
of Pediatricians(9), in which axillary temperatures ≤ 36.4°C
correspond to neonatal hypothermia and the thermal
range between 36.5° and 37.5°C corresponds to a normal
temperature. The Brazilian norms and guidelines of Res-
olution 466 of 2012(10) on human research were followed.
The present study was approved by the Research Ethics
Committee of the Institution, under protocol 160026. All

parents responsible for the newborn signed the Free and
Informed Consent Form.
According to the routine of the hospital where the
study was performed, the infant is born in the delivery and/
or cesarean delivery rooms at the Obstetric Center Unit. In
normal situations, it is placed on the chest/abdomen of the
mother (after pediatrician evaluation and weighing) and
remains in skin-to-skin contact for at least one hour, being
stimulated breastfeeding in the first hour of life with the aid
of the assistant team.
At the end of the skin-to-skin contact period, the moth-
er is taken to the recovery room and the newborn is taken
to the Admission Room to receive the first routine care,
such as physical examination and bathing.
For this study, the first assessment of axillary temperature
before bathing, with the newborn naked and under the radi-
ant heat cradle, lasted for one minute with a “Medlevenson®”
clinical thermometer. The routines of the institution recom-
mend that, for the bath to take place, the axillary tempera-
ture of the neonate should be 36.8°C, the bath water tem-
perature, 38°C, and the ambient temperature, between 25°C
and 27°. The temperature of the water and ambient was
checked by a digital thermometer of the brand “Incoterm®”.
The second moment of verification was immediately
after the bath (where the newborn was dry and under the
cradle of radiant heat). The third time was 30 minutes af-
ter the bath ended, when the infant was still in the Admis-
sion Room (already dressed) and under an external source
of heat. The fourth time, after 60 minutes of the end of the
bath, the temperature was checked, when the baby was in
the recovery room (accompanied by his mother), in skin-to-
skin contact or in a crib (dressed) next to the mother’s bed.
Statistical software SPSS version 18.0 was used to ana-
lyze the data. Initially, the data were treated descriptively
through frequencies, mean, standard deviation, median
and interquartile range. For the statistical analysis, the Chi-
square test was used to verify the association between the
hypothermia categories and the factors studied, such as
the variables of duration of the first bath and of the period
of the first bath. Student’s t-Test and the Mann-Whitney test
were used according to the distribution of the quantitative
variables, to compare the means or distributions of the
studied covariates, such as: gestational age, birth weight
and assessments of axillary temperature. Spearman’s cor-
relation was used and the correlation degree of the quan-
titative variables was verified, such as: the temperature of
the delivery room, the temperature of the admission room
and the temperature of the water in the moments of axil-
lary temperature verification. The accepted level of statisti-
cal significance was α = 0.05.
Hypothermia and the newborn’s bath in the first hours of life
„ RESULTS
A total of 149 newborns were included in the study.
There were no losses and/or refuses to participate. Regard-
ing the demographic data of the mothers, it was found that
63 (42.3%) of them were from 18 to 24 years, 56 (37.6%) had
completed their high school, 98 (65.8%) were primiparous,
and normal labors were the most common 93 (62.4%).
Sixty newborns (40.3%) had hypothermia in at least one
of the four axillary temperature verification assessments.
The prevalence of hypothermia was observed in 12% of
the assessments before the bath, 11% immediately after
the bath, 6% in 30 minutes after the end of the bath and
11.4% in 60 minutes after the bath.
To improve the analysis, data were stratified into two
groups, the hypothermia group and the normothermia one.
We sought to investigate the association between weight,
gestational age and temperature verification moments, but
no statistical significance was observed (Table 1).
Regarding the independent variables cited, the asso-
ciation between the four axillary temperature assements
and the occurrence or not of neonatal hypothermia was
verified, and statistical significance was evident at all mo-
ments (Table 2).
When analyzing the temperatures of the delivery
rooms, a median of 23.9ºC (22.5-24.8°C) was observed, that
is, about 80% of the newborns were exposed to an ambi-
ent temperature below 25ºC. Regarding the newborn ad-
mission room, a median of 25.8°C (24.9-26.4°C) was found.
It was observed that the admission room had higher tem-
peratures than the delivery rooms, even so, about 20% of
the newborns were exposed to an ambient temperature of
less than 25°C during the first admission care.
When considering the characteristics of the first bath of
the newborn, the temperature of the water, the moment in
which the first bath was conducted and the duration of the
bath were evaluated. Considering the temperature of the
bath water, most of the verifications found values that were
correct or close to the recommended by the institution
where the present research was carried out, that is, 38ºC.
The moment of the first bath was stratified in: between
1 and 2 hours of life, between 2 and 3h, and between 3
and 4h of life. It was found that most newborn received
the first bath between 1 and 2 hours of life. The infants
who received the first bath in this time frame account
for 91.7% of the 60 cases of neonatal hypothermia due
to bath observed in this study. We sought to investigate
associations between the moment of the first bath and
the occurrence or not of hypothermia, but no statistically
significant associations were found.
Rev Gaúcha Enferm. 2018;39:e20170263 3
„ Ruschel LM, Pedrini DB, Cunha MLC

Table 1 – Data of the newborns related to the variables of the research (n = 149). Porto Alegre, RS, 2017

Characteristics Normothermia n=89 Hypothermia n=60 p*

39+2 (38+5- 40+2); 40 (38+2 - 41);
Gestational Age (weeks) 0.616
[36-41] [35-42]
3365(3052-3647); 3332 (3047-3601);
Weight (g) 0.500
[2515-4595] [2115-4065]
37 (36.8 – 37.1); 36.5 (36.2 – 36.9);
Moment 1 (°C) 0.200
[36.5-38.1] [35.2-37.8]
36.9 (36.7- 37.1); 36.6(36.4 – 37);
Moment 2 (°C) 0.200
[36.5-37.8] [35.6-37.2]
37 (36.8 – 37.2); 36.7 (36.5-36.9);
Moment 3 (°C) 0.200
[37-38] [36-38]
37 (36.8-37.1); 36.6 (36.4-36.9);
Moment 4 (°C) 0.200
[36.5-38.2] [35.7-38.4]
Source: Research data, 2017.
Median (interquartile range: P25 and P75) and [minimum and maximum].
* Student’s t-test.

Table 2 - Prevalence of Hypothermia in moments of axillary temperature verification of the newborn. Porto Alegre, RS,
2017

Hypothermia n = 60 Normothermia n = 89 p*
36,7 (36.2 -36.9); 37 (36.8 – 37.1);
Moment 1 <0.001
[35.2 -37.8] [36.5-38.1]
36.7 (36.4 – 37); 36.9 (36.7-37.1);
Moment 2 0.001
[35.6-37.6] [36.5-37.8]
36.8(36.5 -37); 37 (36.8-37.2);
Moment 3 <0.001
[36-38] [37-38]
36.6 (36.4 -36.9); 37 (36.8 – 37.1);
Moment 4 <0.001
[35.7-38.4] [36.5-38.2]
Source: Research data, 2017.
Median (interquartile range: P25 and P75) and [minimum and maximum].
* Mann-Whitney test.

The duration of the bath was stratified in: 1 to 2 min- We attempted to evaluate possible associations between
utes, 2 to 3 min, 3 to 4 min, 4 to 5 min or 5 min or more. It bath time and hypothermia, but associations with statisti-
was observed that most baths lasted from 2 to 3 minutes. cal significance were not found (Table 3).

Table 3 – Duration of the first bath of the newborn (n = 149). Porto Alegre, RS, 2017

Interval Hypothermia % Normothermia % Total % p*

1→2min 10 45.5 12 54.5 22 100
2→3min 15 36.6 26 63.4 41 100
3→4min 13 37.1 22 62.9 35 100 0,472
4→5min 11 34.4 21 65.6 32 100
5min or more 11 57.9 8 42.1 19 100
Source: Research Data, 2017.
* Chi-square test (Pearson’s test).

4 Rev Gaúcha Enferm. 2018;39:e20170263


Other possible associations between variables were
analyzed, like: room temperature, admission room tem-
perature and water temperature with axillary tempera-
ture verification moments. A significant but weak cor-
relation was found between the variable of the delivery
Table 4 – Correlation between variables of the newborn (n = 149). Porto Alegre, RS, 2017
Variables Moment 1
r P R p
Delivery Room -0.100 (0.223) -0.088
Admission Room -0.067 (0.414) 0.175
Water temperature 0.060 (0.464) 0.249
Source: Research Data, 2017.
r (p): Spearman correlation.
„ DISCUSSION
Through the present study it was possible to analyze
the occurrence of hypothermia in newborns before and
after bathing in the first hours of life. The prevalence of
neonatal hypothermia among the newborns in the sample
was 40.3%. Newborns baths are controversial, and discus-
sions about how to perform the procedure and the most
appropriate time to do it in the first days of life are still pres-
ent in neonatal care routine(11). In order to prevent neonatal
hypothermia, the first bath is recommended to take place
six hours after the newborn’s birth(7).
In a study carried out in four regions of Ethiopia,
through interviews done in home visits by health profes-
sionals, it was demonstrated that postponing the first bath
contributed to the maintenance of the body temperature
of the newborn, in addition to keeping them alive due to
the longer period of contact with the mother(12). In a study
conducted in the United States, it was shown that post-
poning the infant’s first bath for 12 hours contributes to
reducing the risk of neonatal hypothermia due to the sep-
aration of the mother/baby binomial, thus bringing several
benefits for both(5).
In this study, it was observed that the temperatures of
the delivery room were below the range recommended
by the literature, and a large number of newborns in the
study were exposed to temperatures below 25°C at birth,
while keeping a skin-to-skin contact with their mothers. In
the admission room, on the other hand, the temperatures
found were higher, and were in agreement with the rec-
ommendations for the newborn care(13).
Hypothermia and the newborn’s bath in the first hours of life
room temperature and the fourth moment of axillary
temperature check, that is, after 60 minutes of the end of
the first bath, when the newborn was again in the com-
pany of his mother in the Recovery Room. Such data can
be seen in Table 4.
Moment 2 Moment 3 Moment 4
r P r p
(0.288) 0.021 (0.797) 0.175 (0.032)
(0.033) 0.118 (0.151) 0.114 (0.167)
(0.002) 0.018 (0.824) -0.108 (0.191)
The lower delivery room temperatures raise the risk of
heat loss by conduction and convection of the newborn, a
study has shown that when newborns are exposed to low-
er temperatures (approximately 23°C), they tend to present
hypothermia of moderate to severe intensity in admission
care. Thus, it is recommended to increase the temperature
of such rooms at the time of the procedure, in order to pre-
vent maternal and neonatal hypothermia(14).
Regarding the characteristics of the newborn bath, it
was observed that the water temperature used for the
first bath remained within the range recommended by
the hospital where the study happened, that is, 38°C. With
similar findings, a randomized clinical trial (conducted in
Canada) showed that the immersion bath, with a water
temperature range of 37.8°C to 38.8°C, can reduce the
heat losses of healthy full-term infants. In addition, such
care helps newborns to maintain higher body tempera-
tures after the procedure(15).
The first bath should be performed when the newborn
reaches thermal and cardiorespiratory stability, and thus it
is ideal to wait at least two hours to perform the proce-
dure. One study suggests that bathing immediately after
birth may compromise the thermal and cardiorespiratory
stability of the newborn during the period of transition to
extrauterine life. When measures of thermal control of the
environment are adopted, the occurrence of such events
is potentially reduced. Regarding the duration of the bath,
the procedure is recommended to be as fast as possible,
lasting from five to ten minutes. Limiting the bath to five
minutes prevents stress from cold and reduces the expo-
sure time of neonates to cleaning agents(13,15).
Rev Gaúcha Enferm. 2018;39:e20170263 5
„ Ruschel LM, Pedrini DB, Cunha MLC
In this study, hypothermia was found in 60 cases. How-
ever, there was no association between thermoregulation
and newborn variables like weight and gestational age. The
absence of statistical significance was attributed to the fact
that it was a sample of healthy neonates. The median ges-
tational age of both groups was greater than 39 weeks and
the median weight was greater than 3.300 g., which shows
good adaptation to extrauterine life. Considering the oc-
currence of hypothermia in the assessments of the present
study, an association with statistical significance was found
between the occurrence of hypothermia and all moments
when the assessments were conducted. Such association
could be understood as a result of the lower temperatures
of the delivery rooms and the baths that were mostly per-
formed between one and two hours of life(7).
The first bath represents a challenge for the newborns
to maintain adequate body temperature, because in addi-
tion to exposure to thermal variations of the environment,
the procedure exposes newborns to heat losses by water
conduction and evaporation. In this sense, care with the
reheating of the newborn after bathing is important. A
study conducted at a school hospital in the United States
of America has shown that skin-to-skin contact after bath-
ing may be a more effective technique in reheating the
newborn than using the radiant heat cradle, as long as the
staff provides attention to the correct positioning of the
newborn over his mother(13,16).
Finally, assessments of the statistical correlations be-
tween the thermal variables to which the newborn was
exposed (delivery room, admission room and water tem-
perature) and the four axillary temperature verification
moments showed a statistical significance, with a weak
correlation result, between the variable delivery room tem-
perature and the fourth moment of assessment, that is, 60
minutes after the end of the bath. This finding can also be
explained by the low temperatures of the neonate in the
delivery room, since neonatal hypothermia is an event that
may occur late (after bathing or hours after birth) if thermal
admission care has not been efficient(16).
Although studies have shown that the maintenance of
infant body temperature can occur even when the first bath
is carried out within a few hours of life, its postponement
offers several benefits such as the early initiation of breast-
feeding (11). Therefore, delaying any routine procedures
during the first hours of life (such as the first bath) avoids the
separation of the mother/baby binomial, allows their skin-
to-skin contact, favors the newborn adaptation to the extra-
uterine environment and promotes the initiation of breast-
feeding. Such care should be recommended, especially in
places with few resources to care for the newborn(17).
6 Rev Gaúcha Enferm. 2018;39:e20170263
„ CONCLUSION
The present study found 60 cases of neonatal hypo-
thermia among the 149 newborns included in the study.
Protective factors of the thermal care provided to the
newborn were observed, such as the existence of a nurs-
ing care routine for the performance of the procedure,
whose guidelines address the initial care of the newborn
for their care during admission, including the control of
the axillary temperature, of the temperature of the bath
water and the temperature of the room where the proce-
dure is performed.
This study brings, as contributions for nursing care
practice, evidences regarding the thermoregulation of
the newborn at full-term and the practice of the first bath
performed with few hours of life. The results suggest that
a bath in the first hours of life can interfere with thermo-
regulation and should be postponed for a few hours. It is
also worth mentioning the need for greater regulation and
supervision of the temperature of the newborn’s admis-
sion environment, considering this as one of the pillars of
the attendance during the Golden Hour. Thus, this study
suggests that the temperature of the newborn and their
environment must be considered with greater care during
the first bath. This should be recommended as a protective
action in order to reduce the instances of neonatal hypo-
thermia in the first hours of life.
Studies comparing the bath in the first hours of life and
the bath postponed for a few hours are recommended, to
evaluate the thermal stabilization of the newborn and the
promotion of contact and permanence with the mother.
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Corresponding author:
Luma Maiara Ruschel
E-mail: luma.m.ruschel@gmail.com
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Received: 12.20.2017
Approved: 07.02.2018
Rev Gaúcha Enferm. 2018;39:e20170263 7