Opini Ahli tentang Farmakoterapi

ISSN: 1465-6566 (Cetak) 1744-7666 (Online) Halaman muka jurnal: https://www.tandfonline.com/loi/ieop20

Farmakoterapi untuk hipertensi pada pasien hamil:

pertimbangan khusus

Juan Tamargo, Ricardo Caballero & Eva Delpón

Mengutip artikel ini: Juan Tamargo, Ricardo Caballero & Eva Delpón (2019): Farmakoterapi untuk hipertensi pada pasien
hamil: pertimbangan khusus, Pendapat Ahli tentang Farmakoterapi, DOI : 10.1080 / 14656566.2019.1594773
Untuk menautkan ke artikel ini: https://doi.org/10.1080/14656566.2019.1594773

Diterbitkan online: 03 Apr 2019.

Kirimkan artikel Anda ke jurnal ini

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journalCode=ieop20
PENDAPAT AHLI MENGENAI PHARMACOTHERAPY
https : //doi.org/10.1080/14656566.2019.1594773
TINJAUAN Farmakoterapi untuk hipertensi pada pasien hamil:
pertimbangan khusus Juan Tamargo, Ricardo Caballero dan Eva Delpón
Departemen Farmakologi dan Toksikologi, Sekolah Kedokteran, Instituto de Investigación Sanitaria Gregorio Marañón,
Universidad Complutense, CIBERCV, Madrid, Spanyol
ABSTRAK
Pendahuluan: Gangguan hipertensi kehamilan (HDP) merupakan
penyebab utama morbiditas dan mortalitas ibu, janin dan neonatal dan
mengidentifikasi wanita yang berisiko terkena penyakit kardiovaskular
dan kronis lainnya di kemudian hari. Jika obat antihipertensi digunakan
selama kehamilan, manfaat dan bahayanya bagi ibu dan janin harus
dievaluasi.
Area yang dicakup: Ulasan ini merangkum karakteristik farmakologis
dari obat antihipertensi yang direkomendasikan dan dampaknya pada
ibu dan janin bila diberikan selama kehamilan dan / atau pasca
melahirkan. Obat diidentifikasi menggunakan MEDLINE dan Pedoman
internasional utama untuk pengelolaan HDP.
Pendapat ahli: Meskipun ada konsensus bahwa hipertensi berat harus
diobati, pengobatan hipertensi ringan tanpa kerusakan organ akhir
(140–159 / 90–109 mmHg) tetap kontroversial dan tidak ada
kesepakatan kapan harus memulai terapi, target tekanan darah atau
merekomendasikan obat-obatan jika tidak ada bukti kuat untuk
keunggulan satu obat di atas yang lain. Lebih lanjut, hasil jangka
panjang dari paparan antihipertensi dalam rahim tetap tidak pasti. Oleh
karena itu, data berbasis bukti mengenai pengobatan HDP masih
kurang dan uji klinis acak yang dirancang dengan baik diperlukan
untuk menyelesaikan semua masalah kontroversial yang terkait
dengan pengelolaan HDP.
ARTICLE HISTORY
Diterima 25 Juli 2018 Diterima 11 Maret 2019
KEYWORDS
Kehamilan; hipertensi; kehamilan; pre-eklamsia; hipertensi postpartum; obat
antihipertensi; pengobatan
1. Pendahuluan
Gangguan hipertensi selama kehamilan (HDP) adalah komplikasi
medis yang paling umum dalam praktik kebidanan,
mempengaruhi 5-10% kehamilan dan merupakan penyebab
utama morbiditas dan mortalitas ibu, janin dan neonatal [1-5].
Terlepas dari kemajuan dalam kedokteran kebidanan, kejadian
HDP di masyarakat dua negara telah meningkat sebesar 25%
dalam 20 tahun terakhir, yang terkait dengan peningkatan
prevalensi hipertensi, obesitas, dan diabetes pada wanita usia
subur dan ibu lanjut usia. [1-3,5-12].
Ada data klinis berbasis bukti yang menunjukkan bahwa
wanita yang mengembangkan HDP selama kehamilan dan / atau
pascapersalinan dibandingkan dengan wanita tanpa HDP berada
pada peningkatan risiko perkembangan di masa dewasa
KONTAK Juan Tamargo jtamargo@med.ucm.es Departemen Farmakologi dan Toksikologi, Fakultas Kedokteran, Instituto de Investigación Sanitaria
Gregorio Marañón, Universidad Complutense, CIBERCV, Madrid, Spanyol
© 2019 Informa UK Limited, berdagang sebagai Taylor & Francis Group
2 J. TAMARGO ET AL .
selanjutnya dari:
(1) Hipertensi gestasional (16-47%) dan preeklamsia (PE, 2-
7%) pada kehamilan mendatang [8-15]. Semakin awal
timbulnya hipertensi pada kehamilan pertama, semakin
tinggi risiko kekambuhan pada kehamilan berikutnya [16].
Memang, wanita dengan PE sebelum minggu ke-30
kehamilan memiliki kemungkinan 10–15% untuk kambuh
dan 15% risiko lebih lanjut untuk hipertensi gestasional,
sementara wanita yang memiliki hipertensi gestasional
memiliki risiko 4% untuk mengembangkan PE dan 16–47
lebih lanjut. % risiko hipertensi gestasional di masa depan
kehamilan [1,4,12,17].
(2) Solusio plasenta dan hasil perinatal yang merugikan,
termasuk kematian intrauterin, prematuritas,intrauterin,
bayi
retardasi pertumbuhankecil untuk usia kehamilan (SGA),
sindrom gangguan pernapasan dan penerimaan unit
perawatan intensif neonatal (NICU) yang lebih lama
[1,10,11,18-25].
(3) Kejadian kardiovaskular (hipertensi kronis, penyakit
serebrovaskular, penyakit jantung iskemik, gagal jantung,
dan penyakit arteri perifer) dan gagal organ multipel,
edema paru, tromboemboli vena, penyakit ginjal kronis,
diabetes tipe 2, hipotiroidisme, koagulasi intravaskular
diseminata dan kematian [2,3,5,12,13,15,26-35].
Selain itu, wanita dengan PE secara signifikan melaporkan lebih
banyak kegagalan kognitif harian, penurunan kualitas hidup
terkait penglihatan yang terganggu dan peningkatan disfungsi
emosional, yang semuanya tampaknya setidaknya sebagian
terkait dengan adanya lesi materi putih otak menggunakan
pencitraan resonansi magnetik bertahun-tahun setelahnya.
indeks kehamilan dibandingkan dengan wanita parous sehat [36-
38].
Oleh karena itu, HDP berfungsi sebagai penanda sentinel bagi
wanita yang cenderung mengalami penyakit kardiovaskular dan
pembuluh darah otak prematur dan penyakit kronis lainnya [8,39].
Namun, ada kemungkinan juga bahwa hubungan positif ini
mungkin sebagian besar disebabkan oleh faktor risiko sebelum
kehamilan daripada mencerminkan pengaruh langsung dari
gangguan hipertensi pada kehamilan [40].
Karena banyak kehamilan yang tidak direncanakan, semua
wanita dengan hipertensi kronis dan gangguan hipertensi selama
kehamilan atau nifas harus mendapat manfaat dari konseling dan
penilaian pra-konsepsi oleh seorang dokter dengan keahlian
dalam manajemen HDP untuk mendiskusikan kemungkinan
jangka panjang.
Sorotan artikel

● Gangguan hipertensi selama kehamilan (HDP) tetap menjadi

komplikasi medis paling umum dalam praktik kebidanan dan
penyebab utama morbiditas dan mortalitas ibu, janin, dan
neonatal di seluruh dunia.
● Tujuan terapeutik adalah untuk mengurangi morbiditas ibu dan
janin, dan mortalitas serta meningkatkan hasil klinis jangka
panjang yang terkait dengan hipertensi yang tidak terkontrol
menggunakan obat antihipertensi yang efektif dan aman
● Terapi rumit karena HPD bukan merupakan satu kesatuan
tetapi terdiri dari kronis dan de-novo bentuk hipertensi ●
Pengobatan hipertensi ringan tanpa kerusakan organ akhir
masih kontroversial dan tidak ada kesepakatan mengenai
ambang batas untuk memulai terapi, target TD, atau obat yang
direkomendasikan.
● Beberapa uji klinis acak yang cukup bertenaga (RCT) telah
menganalisis langsung keefektifan dan keamanan obat
antihipertensi pada wanita dengan HDP.
● Risiko teratogenik obat antihipertensi belum cukup dipelajari.
● Kami membutuhkan RCT yang dirancang dengan baik yang
menentukan target TD optimal, kemanjuran, dan keamanan
obat antihipertensi dan regimen obat yang optimal untuk
meningkatkan hasil jangka panjang ibu dan janin pada wanita
dengan HDP

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Risiko utama CHTN adalah perkembangan PE yang dilapiskan 2.2. Hipertensi gestasional (GH)
yang terjadi di 13-25% wanita menyajikan faktor risiko
PE(Tabel2)[21,22,41-46].. Insidensinya meningkat seiring dengan gestasi (~ 50% kasus
terjadi dalam waktu dekat) dan biasanya sembuh pascapartum.
Dengan tidak adanya PE, hasil akhir ibu dan janin biasanya
2.1.1 White-coat hypertension (WCH) normal. Namun, 25% dari wanita, terutama mereka yang
mengembangkan GH di <32 minggu
WCH didiagnosis dengan 24 h ambulator y Pemantauan BP
(ABPM) dapat terjadi pada sebanyak 30% wanita hamil dengan
HDP. Wanita dengan WCH menunjukkan hasil tes laboratorium Tabel 2. Faktor risiko, tanda-tanda dan gejala untuk pra-eklampsia[1,16,22,41-
yang kurang abnormal (gangguan enzim hati, kreatinin serum 44,46,60].Faktor risiko klinis ibu untuk mengembangkan pre-eklamsia
protein urin 24 jam, dan nilai asam urat) dan hasil kehamilan • Penyakit hipertensi pada kehamilan sebelumnya *
yang lebih baik (pre-eklamsia, hambatan pertumbuhan intrau • Penyakit ginjal kronis *
PENDAPAT AHLI TENTANG FARMAKOTERAPI 3
terine dan persalinan prematur dan pemberian NICU)
dibandingkan wanita dengan CHTN atau hipertensi gestasional
[44,47-50]. Namun, WCH bukanlah kondisi yang jinak. Memang, kehamilan, dapat berkembang menjadi PE atau hasil akhir
hipertensi jas putih dapat bertahan pada 50% wanita dengan kehamilan yang merugikan [1,45,54-58]. Wanita yang awalnya
hasil kehamilan yang baik, sedangkan 40% mengembangkan didiagnosis dengan GH harus dipelajari setelah melahirkan. Jika
hipertensi gestasional jinak dan memiliki hasil kehamilan yang mereka hadir kadar BP meningkat melampaui 12 minggu, post-
baik, dengan hanya 8-12% yang mengembangkan PE proteinurik partum hipertensi akan diklasifikasikan sebagai
(22-57% di antara wanita dengan hipertensi dikonfirmasi. oleh CHTN[9,16,24,41-44].Oleh karena itu, wanita dengan GH
ABPM) [47-51]. memerlukan pemantauan TD ekstra selama kehamilan dan post
partum, idealnya melakukan pengukuran TD di rumah [1,41-
2.1.2. Hipertensi 44,58].
terselubung hadir pada pasien yang memiliki TD normal di kantor
(≤140 / 90 mmHg) tetapi BP siang hari meningkat pada ABPM atau 2.3. Preeklamsia / eklamsia
pemantauan BP rumah otomatis [51,52]. Hipertensi terselubung
terkait dengan peningkatan risiko kerusakan organ target dan Risiko utama CHTN dalam kehamilan adalah perkembangan PE,
kejadian CV, stroke dan mortalitas dibandingkan dengan individu kelainan progresif kompleks yang berkembang dengan
normotensi dan mereka dengan WCH dan mendekati atau lebih kecepatan yang tidak dapat diprediksi jika kehamilan berlanjut.
besar daripada hipertensi berkelanjutan [51-53]. Faktor dan kondisi risiko yang terkait dengan PE diringkas dalam
Tabel 2 [20,24,43,44,46,59,60]. PE onset dini (<34 minggu)
mewakili 5-20% dari semua kasus, sedangkan PE onset lambat
 (80%) dapat terjadi selama kehamilan, intra-partum atau post-
partum, terutama pada wanita dengan komorbiditas
[46,59,61,62]. PE adalah kondisi yang berpotensi berbahaya bagi
janin dan ibu, mewakili sepertiga dari kasus morbiditas obstetrik
yang parah [4]. PE meningkatkan risiko kelahiran prematur,
pembatasan pertumbuhan intrauterin, placental abruption,
kematian perinatal dan neonatal sindrom pernafasan
distress[1,4,16,24,41-44].PE dan eklampsia menyebabkan 9%
kematian ibu di Amerika Serikat [46] dan stroke hemoragik
bertanggung jawab atas ~ 60% dari semua kematian terkait
eklamsia [2,63,64]. Wanita dengan PE harus dinilai di rumah sakit
ketika pertama kali didiagnosis karena peningkatan risiko janin
ibu, terutama ketika PE mengembangkan ditumpangkan pada
CHTN, tetapi mereka dapat dikelola dalam pengaturan rawat
jalan setelah itu ditetapkan bahwa kondisi mereka stabil[41-44].
Pengobatan definitif PE adalah persalinan, sedangkan terapi
farmakologis diarahkan untuk mengelola hipertensi [1,16,24,41-
44]. Wanita dengan risiko tinggi harus menerima aspirin dosis
rendah (75–162 mg / hari) dari 12 minggu sampai lahir, dan
mereka yang menjalani diet rendah kalsium harus menerima
suplementasi kalsium (1,5-2 g / hari) untuk mencegah PE
[1,16,22,24,41- 44,65-67].

• Penyakit autoimun (lupus eritematosus sistemik atau sindrom antifosfolipid) *

• Hipertensi kronis *
• Diabetes tipe 1 atau tipe 2 *
• Riwayat hipertensi sebelumnya
• Usia ibu ≥40 tahun atau interval antar> 10 tahun
• Nulliparitas
kehamilan• Kehamilan multipel
• Riwayat keluarga pre-eklampsia
• Ibu kelebihan berat badan (BMI 25-29,9 kg / m2, obesitas BMI> 30 kg / m2)
• Afrika Amerika ras
• Sejarah trombofilia
• reproduksi dibantu
* resiko tinggi faktor
Tanda dan gejala
1. Hipertensi: SBP / DBP ≥ 160/110 mmHg
2. Proteinuria: ≥0,3 g / 24 jam, atau rasio albumin: kreatinin-ACR ≥30 mg / mmol, atau kadar protein dipstick urine ≥1 +
3. Tanda-tanda disfungsi organ akhir ibu, termasuk:
• Keterlibatan ginjal: cedera ginjal akut (kreatinin serum / plasma ≥90 μmol / L; 1,1 mg / dL), oliguria: <80 mL
• Keterlibatan hati: transaminase hati 2x lebih besar dari tingkat normal dengan atau tanpa nyeri perut kuadran atas atau
epigastrium yang parah • Keterlibatan hematologi: trombositopenia (<100.000 / μL), hemoly sis, koagulasi intravaskular diseminata
• Komplikasi neurologis: kejang (eklamsia), perubahan status mental, kebutaan, stroke, hiperrefleksia dengan klonus yang menetap, sakit kepala parah,
gangguan penglihatan persisten (fotopsia, skotomata, kebutaan kortikal, sindrom ensefalopati posterior reversibel, dan vasospasme retina) , stroke •
Edema paru
4. Disfungsi uterus-plasenta, seperti hambatan pertumbuhan janin, analisis bentuk gelombang Doppler arteri umbilikalis yang abnormal, atau lahir mati
4 J. TAMARGO ET AL. organ dan sistem ibu untuk memenuhi peningkatan kebutuhan
ibu dan janin (Tabel 3), yang dapat mengubah farmakoki netic
2.4. Preeklamsia yang ditumpangkan pada CHTN (penyerapan, distribusi, metabolisme, dan ekskresi) dan
farmakodinamik ( efek dari obat pada tubuh) sifat obat
Risiko utama CHTN dalam kehamilan adalah perkembangan PE antihipertensi[70-73].Perawatan medis HDP yang optimal
yang terjadi pada 13-40% wanita dengan CHTN, terutama pada membutuhkan pemahaman yang tepat tentang perubahan ini.
wanita dengan riwayat PE sebelumnya atau adanya satu atau Telah menunjukkan bahwa pada kehamilan normal BP
lebih faktor risiko lain (Tabel 2) [1,21,43,44]. Dalam kohort yang menurun 5-10 mmHg selama trimester pertama karena
terdiri dari 822 wanita dengan PE yang dilapiskan pada CHTN penurunan resistensi vaskular sistemik (SVR) dan terus menurun
menunjukkan tingkat kelahiran prematur yang lebih tinggi secara hingga 22-24 minggu, yang mengarah ke ketegangan hipo
signifikan <37/40 (51% vs 15%), SGA (48% vs 21%), berat badan fisiologis[74-76]. Akibatnya, beberapa wanita hipertensi menjadi
<2,5 kg (44% vs. 13%), seksio sesarea (70% vs 44%), kematian normotensi selama kehamilan, sementara mereka yang tetap
janin dan neonatal dan angka kematian ibu di rumah sakit hipertensi dapat mengurangi obat antihipertensi mereka.
dibandingkan dengan CHTN tanpa pelapis PE [21]. Wanita Kemudian, tekanan darah naik perlahan-lahan mencapai tingkat
dengan PE yang dilapiskan pada CHTN harus diperlakukan sebelum kehamilan [11,73]. Volume plasma dan curah jantung
sebagai risiko tinggi dengan pengawasan ibu dan janin yang mencapai maksimum 40-50% di atas nilai dasar pada usia
sesuai [68,69]. kehamilan 32 minggu. Peningkatan curah jantung dicapai dengan
peningkatan stroke volume pada paruh pertama kehamilan dan
setelahnya peningkatan denyut jantung secara bertahap. Karena
2.5. Hipertensi yang tidak dapat diklasifikasikan secara pada banyak wanita kadar TD sebelum kehamilan atau awal
antenatal trimester pertama tidak diketahui dan sangat jarang PE muncul
Istilah ini digunakan ketika TD pertama kali dicatat setelah 20 sebelum usia kehamilan 20 minggu, penurunan TD awal dapat
minggu kehamilan, dan tidak jelas apakah hipertensi sudah ada menutupi hipertensi yang sudah ada sebelumnya sampai nanti
sebelumnya. Penilaian ulang post-partum enam minggu akan dalam kehamilan. Namun, penelitian ini menggunakan
membantu membedakan yang sudah ada sebelumnya dari pengukuran trimester pertama akhir sebagai dasar, yang dapat
hipertensi gestasional [16]. memberikan perkiraan yang tidak dapat diandalkan tentang
perubahan fungsi kardiovaskular yang disebabkan kehamilan
normal. Analisis perubahan kardiovaskular ibu dari pra-kehamilan
3. Perubahan fisiologis selama kehamilan hingga sangat awal kehamilan menunjukkan bahwa perubahan
signifikan terjadi pada BP brakialis dan sentral, indeks
Kehamilan menginduksi adaptasi fisiologis penting di semua
augmentasi gelombang nadi dan PVR sekitar 6-7 minggu
kehamilan, yaitu jauh lebih awal dari yang diperkirakan [77], yang
mengkonfirmasi penelitian sebelumnya yang menunjukkan
bahwa SBP sentral lebih rendah pada wanita hamil dibandingkan
wanita tidak hamil [78,79]. Selain itu, data longitudinal yang
menggunakan pengukuran trimester pertama akhir sebagai
'baseline' menunjukkan bahwa SBP sentral menurun pada
pertengahan kehamilan dan lebih besar daripada SBP brakialis
[79].
Ini merupakan temuan penting karena TD aorta daripada
brakialis lebih erat kaitannya dengan tekanan arteri uterin, yang
pada gilirannya menentukan perfusi dasar uteroplasenta.
Hemodinamik ibu selama kehamilan dapat berdampak
langsung pada pertumbuhan janin mungkin karena efek pada
aliran darah uteroplasenta dan hipertensi menghasilkan
perubahan hemodinamik tambahan yang penting untuk
pertumbuhan janin dan dapat menentukan pilihan obat
antihipertensi. Peningkatan volume intravaskular dan penurunan
resistensi pembuluh darah perifer (PVR) memfasilitasi perfusi
plasenta, sistem tekanan rendah yang membutuhkan fluks tinggi
untuk mempertahankan aliran arah ke janin [80]. Sebaliknya,
penurunan curah jantung dan aliran darah uteroplasenta dan /
atau peningkatan SVR, yang mewakili bentuk hipertensi yang
lebih lanjut, dikaitkan dengan bayi yang lebih kecil.
Pada wanita hipertensi yang datang sebelum 28 minggu,
mereka yang ditandai dengan PVR tinggi dibandingkan dengan
mereka yang ditandai dengan curah jantung tinggi melahirkan
bayi dengan berat kurang dari 1058 g karena perbedaan usia
kehamilan 4 minggu dan dengan persentil berat lahir lebih
rendah (19 vs 39 ) [81,82].
Karakteristik farmakokinetik dari antihipertensi yang paling
umum digunakan selama kehamilan ditunjukkan pada Tabel 3
[71,73]. Ketersediaanhayati obat oral dapat berkurang selama
kehamilan karena pengosongan lambung yang tertunda, waktu
transit usus halus yang berkepanjangan dan mual dan muntah,
sehingga rute intravena (IV) mungkin diperlukan pada beberapa
wanita dengan hipertensi berat [44]. Perubahan volume plasma
dan pengikatan protein dapat mengubah volume distribusi (Vd)
dan waktu paruh obat antihipertensi. Bergantung pada apakah
obat diekskresikan tanpa perubahan oleh ginjal atau jalur
biotransformasi, perubahan frekuensi pemberian dosis mungkin
diperlukan. Aktivitas beberapa enzim isoform CYP (CYP2D6,
2C9, 3A4) dan glukuro nidasi (UDP-glukuronosiltransferase)
enzim meningkat selama kehamilan, sehingga kadar plasma dan
waktu paruh obat yang dimetabolisme melalui enzim ini menurun;
Oleh karena itu, wanita hamil mungkin memerlukan peningkatan
substansial dalam dosis untuk mencapai efek yang setara selama
kehamilan[70-73,83].Poli morfisme genetik dalam aktivitas P450
mungkin menjelaskan perbedaan individu dalam respon obat
antihipertensi [72,73,84]. Ekskresi obat yang tidak berubah
melalui ginjal meningkat selama kehamilan.
4. Teratogenisitas
Teratogenisitas adalah pusat keputusan terapeutik selama
kehamilan dan risikonya meningkat ketika obat diresepkan pada
trimester pertama kehamilan, periode penting untuk genesis
organ dan perkembangan plasenta termasuk invasi trofoblas,
remodeling vaskular, dan perkembangan vili korionik. Tetapi
meskipun HDP adalah masalah medis yang umum dan hipertensi
itu sendiri selama kehamilan dapat mempengaruhi janin dan
anak yang sedang berkembang, profil keamanan jangka pendek
dan jangka panjang dari agen antihipertensi dalam hal hasil ibu
dan janin sebagian besar masih belum diketahui [1,16,24,41-
44,72,85,86]. Baru-baru ini, Fitton et al. [87] meninjau 47
penelitian yang diterbitkan yang melaporkan efek paparan dalam
rahim terhadap obat antihipertensi pada janin dan anak. Hasil
anak yang merugikan, termasuk kelahiran prematur, Perina tal
kematian, berat badan lahir rendah, placental abruption, induksi
persalinan, risiko kelainan bawaan, ataulain
AHLI PENDAPAT TENTANG farmakoterapi 5

Tabel 3. perubahan fisiologis ibuselama kehamilan normal[70-73,83].

SISTEM KARDIOVASKULAR
• Kontraktilitas jantung, massa dinding ventrikel dan kepatuhan
• ↑ denyut jantung, volume stroke dan curah jantung (30-50%)
• ↓ resistensi vaskular sistemik dan parudarah
• ↑uterus (10 kali lipat) dan payudara (3 kali lipat) mengalir; aliran darah otak dan hati tetap tidak berubah
• ↑ volume plasma (40-50%), air tubuh total dan tekanan hidrostatik kapiler
• ↑ simpanan lemak ibu dan massa lemak (10 kali lipat)
- Vd obat hidrofilik dan obat lipofilik
- Vd yang lebih besar dapat menurunkan kadar plasma puncak: diperlukan dosis awal dan pemeliharaan yang lebih tinggi
• ↓ konsentrasi albumin serum dan tekanan osmotik koloid serum
- ↑ kadar obat dalam plasma bebas yang sangat terikat (99%) dengan protein plasma dan risiko efek samping terkait obat. Persyaratan dosis dapat diturunkan •
SISTEM PERNAPASAN
• ↑ volume tidal dan ventilasi menit (25-50%)
• ↓ kapasitas residu fungsional dan kapasitas total paru
• ↑ tekanan parsial arteri O2, ↓ tekanan parsial CO2
• Alkalosis pernapasan ringan: dapat mempengaruhi pengikatan protein beberapa obat
• FUNGSI GINJAL
• ↑ aliran darah ginjal dan laju filtrasi glomerulus (25-80%)
• ↑ aktivitas transporter tubulus ginjal (P-gp dan transporter ion organik
- ↑ ekskresi ginjal tingkat (20-50%) obat yang dibersihkan ginjal yang menyebabkan waktu paruh lebih pendek dan risiko kadar
plasma sub-terapeutik - Mungkin perlu untuk meningkatkan dosis
• ↓ konsentrasi kreatinin serum
• Retensi air dan natrium (hiponatremia pengenceran, ↓ serum osmolaritas)
• SISTEM GASTROINTESTINAL
• Pengosongan lambung yang tertunda, penurunan motilitas gastrointestinal (waktu transit usus halus yang berkepanjangan: 30-50%):
- ↓ Cmaks dan memperpanjang waktu hingga konsentrasi maksimum
• Mual dan muntah
- Kedua efek tersebut dapat mengurangi penyerapan obat
• ↑ pH lambung, meningkatkan ionisasi asam lemah yang mengurangi penyerapannya
• ↑ CYP3A4 (CYP2D6, 2C9 dan 3A4) dan UGT (1A4 dan 2B7) aktivitas
- Penurunan kadar obat dalam plasma yang dimetabolisme melalui isoform ini; peningkatan dosis mungkin diperlukan selama
kehamilan • ↓ Aktivitas CYPA12 dan 2C19: pengurangan dosis obat yang dimetabolisme melalui isoenzim ini mungkin
diperlukan
 • SISTEM HEMATOLOGI / KOAGULASI
• ↑ jumlah sel darah putih dan merah
• Anemia hemodilusional
• ↑ fibrinogen, faktor pembekuan (VII, VIII, IX, X, XII) dan faktor von Willebrand
- ↑ dosis heparin dengan berat molekul rendah
• ↓ tingkat aktivator plasminogen, ↑ tingkat inhibitor aktivator plasminogen (PAI-1) (2-3 kali lipat)
• ↑ risiko tromboemboli vena, stasis vena yang disebabkan oleh kompresi vena kava inferior oleh uterus yang sedang hamil •
Kehamilan adalah keadaan hiperkoagulasi yang berhubungan dengan peningkatan risiko tromboemboli.
• LAINNYA
• ↑ dalam konsentrasi serum kolesterol, globulin pengikat tiroid dan kortisol
P-gp: p-glikoprotein. Tmax: waktu untuk konsentrasi plasma puncak (C max). UGT: uridine difosfat glukuronosiltransferase. Vd: volume distribusi. ↑:
meningkat. ↓: menurun.

hasil yang merugikan, setelah paparan antihipertensi dalam inhibitor ACE dan ARB dikaitkan dengan keguguran, kematian
rahim dilaporkan dalam literatur. Namun, 32 dari mereka yang janin dan kardiovaskular bawaan (defek septum atrium, paten
ditinjau memiliki kualitas yang buruk atau biasa-biasa saja, duc tus arteriosus, defek septum ventrikel, stenosis pulmonal),
dengan populasi penelitian yang kecil, dan penyesuaian yang sistem saraf pusat (hidrosefalus, spina bifida, mikro sefali),
tidak lengkap untuk perancu, dan kurangnya kekuatan statistik, muskuloskeletal (polydactyly, upper-limb defects, craniofacial
sehingga mencegah pengambilan kesimpulan yang tegas. Selain anomalies), gastrointestinal (pyloric stenosis, intestinal atresias),
itu, beberapa penelitian menyelidiki kemungkinan hasil jangka and renal (tubular dysplasia, oligohy dramnios, renal tubular
panjang dan penulis gagal menyebutkan keparahan hipertensi abnormalities, renal failure with oligo/anuria) malformations [103–
yang ada pada pasien, sehingga sulit untuk memastikan apakah 107]. Other adverse out comes thought to be secondary to
hasil kelahiran yang dilaporkan (kelahiran prematur, solusio reduced amniotic fluid volume included limb deformities, cranial
plasenta, induksi persalinan) mungkin terkait dengan hipertensi ossification deficits and lung hypoplasia [105]. Therefore, it is
yang mendasari atau tidak terkontrol secara memadai daripada recommended that in women who are planning a pregnancy
dengan terapi antihipertensi. Oleh karena itu, efek jangka RAASIs should be replaced by other recommended
panjang pada anak dari paparan in-utero agen antihipertensi antihypertensives (ie methyldopa, nifedipine, and/or labetalol)
masih belum pasti [87]. and then discon tinued immediately as soon as pregnancy is
Antihipertensi yang direkomendasikan, termasuk β-blocker, α / diagnosed [1,16,24,41–44,103–107]. If RAASIs are unavoidable
β-bloker atau terpusat bertindak agen adrenergik[88-93],kal cium or strongly indicated (eg proteinuric renal disease), women
channel blockers (CCBs)[89,90,94,95]dan metildopa[91,93,96- should be counseled regarding risks and effective contra ception
98] tidak terbukti teratogenik, tetapi kualitas informasi hanya adil recommended [1]. In the Registry On Pregnancy And Cardiac
untuk sebagian besar [16,24]. Namun demikian, informasi yang disease (ROPAC), fetal anomalies associated with the use of
berasal dari model hewan dapat menyesatkan. Secara umum, ACE inhibitors or ARBs occurred in 8% of pregnancies, which
obat yang tidak teratogenik pada hewan biasanya aman selama was more often than with any other type of drug, despite the fact
kehamilan; obat-obatan yang menghasilkan efek teratogenik that these drugs were stopped during the first trimester or were
pada hewan bila diberikan pada dosis tinggi dapat aman pada taken only for a short period of time [108]. Spironolactone causes
dosis terapeutik pada manusia; dan beberapa obat feminization in male animals, and endocrine dysfunction in both
menyebabkan malformasi pada hewan tetapi tidak pada manusia sexes and it is not recommended during pregnancy [109,110].
[73,86]. Eplerenone does not produce adverse effects in pregnant
Banyak wanita (32%) dengan penyakit kardiovaskular memiliki animals, so it can be an alternative to spironolactone in pregnant
kepatuhan yang rendah selama kehamilan karena ketakutan women with heart failure only when treatment with other diuretics
mereka terhadap kota teratogeni [99]. Kekhawatiran ibu tentang (such as furosemide) is ineffective [16].
kemungkinan bahaya antihipertensi pada janin bersama dengan Amiloride (former FDA category B) represents a safe and effective
penurunan TD awal selama paruh pertama kehamilan dapat alternative to spironolactone and eplerenone in patients with resistant
menyebabkan penurunan sementara atau penghentian terapi hypertension or when mineralocorti coid receptor antagonists are
pada wanita dengan hipertensi yang sudah ada sebelumnya contraindicated. Amiloride low ers BP and corrects the hypokalemia
sampai tekanan darah melebihi 150–160 / 100–110 mmHg pada and acidosis in pregnant women with Liddle, Battler or Gitelman
trimester ketiga [1,99]. Namun, hipertensi yang tidak diobati syndrome and is effective and well tolerated in a pregnant woman with
dikaitkan dengan beberapa malformasi kardiovaskular, hyper aldosteronism secondary to bilateral adrenal hyperplasia.
menunjukkan bahwa hipertensi mungkin memainkan peran However, amiloride should be restricted to patients with an eGFR ≥45
etiologi kunci, mungkin melalui gangguan perfusi uteroplasenta mL/min and a plasma potassium levels ≤4.5 mmol/L, because of the risk
[86,99-102]. Oleh karena itu, pentingnya terapi antihipertensi of hyperkalemia.
harus didiskusikan dengan ibu, menempatkan penekanan pada
risiko yang terkait dengan hipertensi yang tidak diobati untuk ibu
dan janin dan itu bisa menjadi pilihan yang lebih buruk daripada
menerima peningkatan kecil terkait risiko janin. ke meditasi [73]. 4.2. Antihypertensive drugs not recommended in
pregnancy
In animal models, diltiazem causes skeletal abnormalities and
4.1. Obat antihipertensi dikontraindikasikan pada kehamilan
both diltiazem and verapamil produce retarded fetal growth and
Penghambat renin-angiotensin-aldosteron (RAASI) termasuk development, hypotension and bradycardia [16]; thus, they are
penghambat enzim pengubah angiotensin (ACE), angiotensin not recommended in the treatment of HDP [16,90]. However,
6 J. TAMARGO ET AL. verapamil is recommended as a second-line drug (after β-
blockers) for rate control in atrial fibrillation [16].
penghambat reseptor (ARB), penghambat renin langsung, dan Atenolol crosses the placenta, is excreted in breast milk and
sakubi tril / valsartan bersifat fetotoksik. Paparan ibu terhadap produces adverse effects on uteroplacental hemodynamics
leading to low birth weights, prematurity, SGA babies, neonatal
hypoglycemia and bradycardia as compared to other antihy
pertensives [111–113]. Thus, it is not recommended during
pregnancy [16,43,114].
Thiazide and loop diuretics cross the placental barrier and
even when they are not teratogenic [115,116], they can pro duce
oligohydramnios, fetal and neonatal (thrombocytopenia,
hypoglycemia, and electrolyte imbalances) adverse effects (Table
4) [16,117,118]. Thiazide and loop diuretics are not
recommended during pregnancy because they may restrict the
physiologic plasma volume expansion, during PE because
plasma volume is already reduced or during breastfeeding,
because they produce excessive thirst and reduce/suppress
lactation [16,24,41,119,120], although the American Academy of
Pediatrics considers their use compatible with breastfeed ing
[121]. The ESC guidelines indicates that diuretic therapy is best
avoided [16]. However, they can have a role for women with salt-
sensitive hypertension and in the context of oliguria when low-
dose furosemide may be considered [16]. In preg nant women
with preexisting hypertension already treated with thiazide
diuretics, the treatment may be continued at low-doses through
pregnancy [122].
5. Impact of antihypertensive therapy on maternal and
fetal outcomes
Women treated with antihypertensive drugs during the second
and third trimesters of pregnancy have more adverse outcomes,
including increased risk of SGA and pre term birth
[86,89,111,123–125]. Two large meta-analyses sug gested that
/
antihypertensive drug use during pregnancy may be associated
with increased risk of SGA and lower birth weight, probably
because treatment-induced falls in maternal BP may adversely
affect fetal growth via placental hypoperfu sion [126,127]. As a
result, BP goals are higher during preg nancy than they are
outside pregnancy, they are often not specified in guidelines or
differ among guidelines [93] and antihypertensive drug dosages
may need to be adjusted downward to avoid a decrease in
fetoplacental perfusion.
In the ROPAC registry, β-blockers represent two-thirds of all
medications among women with hypertension, cardiac arrhyth
mias, angina, heart failure and Marfan syndrome [16,108]. They
cross the placenta and are excreted in breast milk, but are gen
erally considered safe for the mother and the fetus [72,128].
Nevertheless, maternal exposure to β-blockers increases the risk
of preterm birth, SGA newborns, bradycardia, hypotension,
respiratory distress syndrome, hypoglycemia, perinatal jaundice,
digestive system disorders, and feeding problems in the fetus and
newborn infants [88,90,93,127–131]. A register-based survey
from the Danish Fertility Database (4762 women) confirms that
exposure to β-blockers (including labetalol), methyldopa and
CCBs during pregnancy increases the risk of born SGA and pre
term birth (<37 weeks); β-blockers, but not methyldopa and
CCBs, also increase perinatal mortality [125]. In two case-control
studies using the Quebec Pregnancy Registry (59,033 women),
the use of selective β1-blockers, α/β-blockers or centrally-acting
adrenergic agents during the 2nd or 3rd trimesters of pregnancy
increases the risk of SGA newborn, but their use in the first
trimester of pregnancy does not increase the risk of major con
genital malformations compared with non-use [89]. These two
EXPERT OPINION ON PHARMACOTHERAPY 7
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of 13 population-based case–control or cohort studies, showed no increase in overall congenital malformations associated with first-
trimester exposure to β-blockers [92]. It is necessary to point out that there is limited evidence to suggest that the increased risk of
adverse fetal and maternal effects is due to the antihyper tensive drugs rather than the underlying hypertensive disease [87,108,132].
The uteroplacental circulation is characterized by the remodeling of spiral arteries into low resistance vessels by the invasion of
trophoblasts, leaving these arteries without auto regulatory capacity and directly dependent on maternal cardiac output [133,134]. β-
Blockers produce a vasoconstriction of pla cental vessels and reduce maternal cardiac output and uteropla cental circulation, which
can explain why these drugs may cause growth retardation, SGA newborns, premature deliveries and fetal death [73]. Nevertheless,
causality is difficult to establish given not only the heterogeneity of the studies but also that the indication for β-blocker therapy was not
always mentioned and that the underlying cardiovascular disease can be associated with adverse fetal and maternal effects as well.
HDP with or without treatment is an independent risk factor for adverse perinatal outcomes (SGA, intrauterine growth restriction,
prema turity, and increased mortality) as compared to birth outcomes in women without HDP and without exposure to antihypertensive
drugs [45,55,86,87]. In a metaregression analysis of 34 trials (2640 women), von Dadelszen et al. [124] reported a modest reduction in
birth weight (176 g/10 mmHg BP reduction) that was inde pendent of the drug used or the duration of therapy. Interestingly, only 19%
of the birth weight difference between trials could be explained by differential BP control. These findings suggest that the observed
adverse events are due to the hyper tension itself rather than to the selected antihypertensive agent and suggest that poorly controlled
hypertension may carry the same risks as untreated hypertension [82,86].
Interestingly, the risk increases in women with cardiovascular or congenital heart diseases where β-blockers are widely pre scribed so
that it is possible that the reduction in birth weight might depend on the maternal underlying disease rather than the effect of the β-
blocker [9,16,20,73,88,89,111,129,132]. Indeed, no effect, or a small effect, is observed in hypertensive women with aortic disease,
whereas a pronounced effect is evident in women with valvular disease or severe arrhythmias [73,132]. Thus, there is no reason to
withhold β-blocker therapy in the first half of pregnancy when considered beneficial to the mother [135,136], although it is
recommended to monitor placental blood flow and fetal growth closely; after birth, monitor the newborn for the signs and symptoms of
β-blockade, during the first 3 days.
6. Treatment of hypertension in pregnant patients 6.1. General principles
Treatment of HDP concerns both the mother and the fetus and depends on BP level, gestational age, and presence of associated
maternal and fetal risk factors [1,16,24,41–44]. The goal of therapy is to reduce maternal and fetal morbidity and mortality associated
with uncontrolled hypertension and prolong pregnancy safety as
long as possible to allow the fetus more time to mature before
delivery [16,64,137,138]. However, the pharmacological
treatment of HDP remains controversial and understudied
because rando mized clinical trials (RCTs) are limited in size and
scope and the information is quite frequently derived from meta-
analysis and administrative databases [82]. Furthermore, there
are limited data supporting one drug over another and
therapeutic classes are not recommended because potential
toxicity differs among agents within classes [138]. Until better
evidence is available, the choice of an antihypertensive drug
should depend on the characteristics of the patient (ie CCBs in
black women), pre-existing treatment, drug efficacy and safety,
clinician's experience and familiarity with a particular drug and
women´s preferences [16,41,139]. However, drug selection is
less complex than in the general population, because as already
mentioned some antihypertensives are not recommended during
pregnancy [93,140]. The pharmacodynamic and pharmacokinetic
characteristics of the antihypertensives recommended in the six
most frequently consulted guides from around the world for the
treatment of mild and acute-onset severe hypertension in
pregnancy are summarized in Table 4–6 [1,16,24,41–44]. Other
CCBs and β-blockers are widely used during pregnancy for the
treatment of cardiovascular diseases other than hypertension.
CHTN is best managed on an outpatient setting but tightly
controlling maternal BP, monitoring fetal growth and repeat edly
assessing the development of PE. Monotherapy is insuffi cient to
control BP in patients with SBP/DBP values >20/10 mmHg above
target, so that drug combinations are frequently needed.
Interestingly, a recent retrospective cohort study in 81,231
women with severe PE, the use of multiple antihyper tensive
agents reduces the risk for maternal stroke rates [137].
6.2. Pharmacological management of mild hypertension in
pregnancy
Treatment of mild hypertension (140–159/90–109 mmHg) and no
end-organ damage during pregnancy remains controver sial and
there is no agreement among clinical guidelines about when to
initiate antihypertensive therapy, optimal BP targets or
recommended drugs [1,16,24,41–44]. Despite the paucity of
evidence, the 2018 ESC guidelines recommend to initiate
antihypertensive treatment in all women with persis tent elevation of BP
≥150/95 mmHg and at values ≥140/90 mmHg in women with
gestational hypertension (with or with out proteinuria), pre-existing
hypertension with the superim position of gestational hypertension or
hypertension with asymptomatic organ damage or symptoms at any time
during pregnancy [16]. There is no evidence that tighter control to
<140/90 mmHg results in better outcomes, although outside
pregnancy <130/80 mmHg is specified for diabetic patients but to
achieve risk reduction over a longer timeframe [24,52].
Methyldopa, labetalol, and CCBs are the drugs of choice in many
guidelines [Table 5].
In contrast, the American College of Obstetricians and
Gynecologists [1] recommends that women with mild gestational
hypertension or PE and no evidence of end-organ damage
should not be treated with antihypertensive drugs, while others
argue that pregnant women should be treated as not-pregnant
ones
EXPERT OPINION ON PHARMACOTHERAPY 9
(Table 5). Arguments against treatment include that: a) since
most women with pre-existing non severe hypertension and
normal renal function are at low risk of cardiovascular
complications because of the physiological fall in BP during the
first half of pregnancy, in some of them it is possible to withdraw
or tempor ary decrease the antihypertensive medication during
most of pregnancy [9,16,20,128]. b) Fetal perfusion is dependent
upon adequate maternal BP and lowering BP may compromise
utero placental perfusion, increasing the risk of PE, SGA and
lower birth weight [123–126]. c) Few adequately powered RCTs
have assessed drug efficacy and safety and timing of treatment
initiation in pregnancy [133]; the only trial of treatment of
hypertension in pregnancy with adequate infant follow-up (7.5
years) was per formed 40 years ago with methyldopa [96]. d)
Treatment of mild hypertension reduces progression to severe
hypertension but does not improve adverse maternal and
perinatal outcomes nor does it prevent superimposed PE later in
gestation, while it increases the likelihood of intrauterine growth
restriction, SGA and preterm delivery
[1,9,11,20,86,124,132,141,142]. Thus, in the absence of
compelling evidence, it remains unclear whether treat ment of
mild hypertension should be considered an option.
Three Cochrane reviews analyze the treatment of mild
hypertension during pregnancy. In a review of 29 RCTs (2,900
women), oral β-blockers decrease the risk of severe
hypertension, the need for additional antihypertensives and
respiratory distress syndrome, but their use seems to be asso
ciated with SGA and neonatal bradycardia [88]. In another review
of 46 RCTs (4,282 women), antihypertensive therapy decreases
by half the risk of progression to severe hyperten sion compared
with placebo [number needed to treat (NNT) 10] but does not
improve adverse maternal (placental abrup tion) and perinatal
outcomes (death, SGA babies and preterm delivery) nor does it
prevent superimposed PE later in gesta tion. β-blockers seem
better than methyldopa for reducing the risk of severe
hypertension, but there is no clear difference between any of the
alternative drugs in the risk of developing proteinuria/PE [141].
Another review of two studies recruiting 256 pregnant women
with non-severe pre-existing or non proteinuric gestational
hypertension concluded that there is insufficient evidence to
determine how tight-control of hyper tension should be achieved
to improve maternal and fetal neonatal outcomes [143].
The Control of Hypertension in Pregnancy Study (CHIPS)
compared tight (target DBP 85 mmHg) versus less tight (target
DBP 100 mmHg) BP control on maternal and neonatal outcomes
in 961 pregnant women enrolled at 14–33 weeks of gestation with
non-severe, chronic (75%) or gestational (25%) non proteinuric
hypertension [144]. The composite primary outcome of pregnancy
loss or high-level neonatal care for >48 h during the first 28 days did not
differ between groups. Less-tight control was associated with a higher
frequency of severe maternal hypertension (40.6% vs 27.5%), but other
adverse perinatal out comes and serious maternal complications were
unaffected by the intensity of treatment. However, in a post-hoc analysis
of the study, women developing severe hypertension had higher rates of
adverse maternal (PE, thrombocytopenia, elevated liver enzymes with
symptoms, and maternal length of hospital stay ≥10 days) and primary
perinatal outcomes (perinatal death, high level neonatal care for >48 h,
 birth weight <10th percentile, PE
10 J. TAMARGO ET AL.

Table 5. Antihypertensives recommended in different guidelines for the treatment of mild-to-moderate and acute-severe hypertension in
pregnancy. Guideline [reference] Mild-Moderate hypertension Severe hypertension
ACOG [1] 1. Target: 140-159/90-109 mmHg 1. Definition: ≥160/110 mm Hg 2. Treatment: not recommended 2. Treatment:
• 1st line: Labetalol (IV, oral), hydralazine (IV), nifedipine (IR oral)
• 2nd line: nicardipine or esmolol by infusion pump
NICE [41] 1. Target: <150/80-100 mmHg for uncomplicated 1. Definition: ≥160/110 mmHg
• <140/90 mmHg with target-organ damage
• <130/80 mmHg in diabetic women
2. Treatment: 2. Trea tment:
• β-blockers (labetalol), hydralazine, nifedipine, methyldopa • 1st line: Labetalol (IV, oral), methyldopa (IV), nifedipine (IR oral)
CANADIAN [42] 1. Target: 130-155/90-105 mmHg 1. Definition: ≥160/110 mmHg
• Without comorbidities: 130-155/80-105 mmHg
• With comorbidities: <140/90 mmHg
• Diabetes: <130/80 mmHg
2. Treatment: 2. Treatment:
• Labetalol, methyldopa, nifedipine, other beta-blockers (acebutolol, • 2nd line: clonidine (oral), labetalol (oral), nitroglycerin (IV), methyldopa (oral);
metoprolol, pindolol, propranolol) captopril (oral) only post-partum
• 1st line: Labetalol (IV), hydralazine (IV), nifedipine (IR oral)
SOMANZ [43] 1. Definition: ≥160/110 mmHg 1. Definition: ≥170/110 mmHg
2. Treatment: 2. Treatment:
• β-blockers (labetalol, oxprenolol), methyldopa • 1st line: Labetalol (IV, oral)
• 2nd line: clonidine, hydralazine, nifedipine, prazosin • 2nd line: diazoxide, hydralazine, nifedipine (IR oral)
ISSHP [44] 1. Target: 1. Definition: ≥160/110 mm Hg
• 110–140/80-85 mmHg for uncomplicated
2. Treatment: 2. Treatment:
• β-blockers (labetalol, oxprenolol), methyldopa, nifedipine • 1st line: Nfedipine (oral), hydralazine (IV), labetalol (IV) •
2nd choice: hydralazine, prazosin
ESC [16] 1. Target: ≤150/95 mmHg 1. Definition: ≥170/110 mmHg is an emergency • <140/90 mmHg with target-organ damage
2. Treatment: 2. Treatment:
• CCBs, labetalol, methyldopa • 1st line: Labetalol (IV; or possibly hydralazine), methyldopa (oral), nifedipine (IR, oral)
• Hypertensive crisis: Nitroglycerin (IV), nitroprusside (IV)
* The 2017 ACC/AHA guidelines for hypertension in adults reco mmend to reduce SBP/DBP to <130/80 mmHg [138].
Drugs are presented in alphabetic order. Treatment of mild-moderate hypertension: drugs are administered orally.
ACOG: American College of Obstetricians and Gynecologists. CANADIAN: Canadian Hypertensive Disorders of Pregnancy Working Group. CCBs:
calcium channel blockers. ESC: 2018 ESC Guidelines for the management of cardiovascular diseases during pregnancy. IR: immediate release. ISSHP:
International Society for the Study of Hypertension in Pregnancy. IV: intravenous. NICE: National Institute for Health and Care Excellence in the United
Kingdom. SOMANZ: Society of Obstetric Medicine of Australia and New Zealand.

and prematurity) [144]. These findings confirmed that severe
hypertension is a risk marker for adverse maternal and perinatal
outcomes, independent of BP control or presence or not of PE
[145]. However, the results of this trial are not generalizable to
the treatment of mild CHTN because only 35% of women were
enrolled <20 weeks of gestation, over half of the women in each
group, stayed on their antihypertensive medications at randomi
zation and the trial was underpowered to examine subgroup
differences in some key pregnancy outcomes that are likely to be
influenced by treatment. Moreover, the CHIPS trial only provided
short-term outcomes; thus, the potential long-term benefits and
risks of tight BP control during pregnancy remain unknown.
6.3. Treatment of acute-onset severe hypertension
Severe hypertension is defined as Severe hypertension is defined as
SBP/DBP ≥160/110 mmHg [1,24,41–43] or ≥170/110 mmHg [16,43]
recorded at rest on two separate occasions at least 4 h apart.
However, there is also no agreed definition of severe
hypertension, with values ranging between 160 and 180/>110
mmHg (Table 5). The ESC guidelines considers an SBP/DBP
≥170/110 mmHg persistent for 15 min an emergency and hospi
talization, and immediate treatment (within 15–60 min of
confirmation) with rapid-onset antihypertensive drugs is indicated
and delivery needs to be considered after the maternal condition
has stabilized [16,114]. If severe hypertension is detected in the
office setting, an oral antihypertensive drug may be useful during
transport to hospital for further evaluation and treatment. Severe
hypertension can occur during pregnancy, intrapartum, or post
partum and is associated with increased risk of adverse
outcomes for both the fetus (low birth weight, prematurity, death,
and NICU care) and the mother [45,64,146–148].
Cerebral autoregulation, the process by which blood flow to
the brain is maintained at an appropriate level despite changes in
blood pressure, is impaired in PE [149,150] and severe systolic
hypertension (>160 mmHg) increases the risk of maternal stroke
and hypertensive encephalopathy, even when severe systolic
hypertension can also be caused by stroke. Indeed, many
maternal deaths from HDP (38.7%) are due to cerebrovascular
complications [1,16,24,41–44,146–151]. Thus, even when the risk
of a stroke during pregnancy is low, the poor outcomes in terms
of morbidity and mortality and varia tions in care highlight the
importance of such women receiv ing specialist stroke care [152].
Severe diastolic hypertension (>110 mmHg) increases the risk of
placental abruption and intrauterine growth restriction [64,146–
148]. In severe
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EXPERT OPINION ON PHARMACOTHERAPY 11

hypertension the goal is to red uce SBP to <160/105 mmHg over minutes to hours and then to achieve a sustained BP of 140–150/90–
100 mm Hg in order to: a) prevent prolonged exposure to severe systolic hypertension in the mother and the subsequent loss of
cerebral vasculature autoregulation; and b) protect the pregnant woman from stroke and other end-organ damages [1,16,24,41–
44,63,64,114,146–148]. There is no evidence that lowering BP to 'normal' ranges (<140/90 mmHg) confer additional benefit and there
is a concern that the rapid reduction of >25% in mean BP might lead to mater nal end-organ hypoperfusion or may affect placental
perfusion and fetal growth [1,11,153]. Thus, we must keep in mind the principle 'not to reduce BP too rapidly and too far'. In hyper tensive
urgencies, characterized by very high BP levels (≥180/ ≥110 mmHg) with minimal or no signs or symptoms of end organ damage the goal is to
reduce BP to ≤160/≤100 mmHg over a period of hours using antihypertensive drugs reaching peak effects in 1–2 h.
The IV administration of magnesium sulfate should not be delayed in women with acute severe hypertension because it is the drug of
choice for the prevention and treatment of seizures in women with GH and PE with severe features and eclampsia during pregnancy
and/or the postpartum period [154]. It reduces the risk of eclampsia by half and decreases maternal morbidity and mortality without
deleterious effects on the fetus [67,139,155,156]. However, magnesium sulfate is not primarily an antihypertensive agent and should
not be used as such.
Most guidelines recommend initiating the treatment with labetalol, methyldopa or nifedipine (Table 5) [1,16,22,40– 44,114,157–159].
These drugs do not reduce uteroplacental blood flow or require cardiac monitoring and both IV and oral agents can be combined to
lower BP if needed [41– 44,160–163]. A Cochrane review of 35 drug trials recruiting 3573 women with severe hypertension during
pregnancy found no significant differences regarding either efficacy or safety between hydralazine and labetalol or between
hydralazine and any CCB [139]. More recently, a systematic review and meta-analysis of 51 studies suggest similar effi cacy between
nifedipine, hydralazine, and labetalol in the treatment of severe hypertension in pregnancy, although subtle differences may exist in
their safety profile [164]. Thus, the selection of the antihypertensive drug, dose, and route of administration depends on the clinician's
experi ence with a particular drug, the onset of drug action and the expected time of delivery [16]. Second-line drugs differ according to
guidelines.
Close maternal and fetal monitoring are advised during the treatment of hypertensive emergencies and urgencies, parti cularly after
dosing (every 20 min) or when there is evidence of an existing fetal compromise. Once target BP levels are achieved, BP
measurements should be performed every 10 min for 1 h, then every 15 min for 1 h, then every 30 min for 1 h, and then every hour for
4 h [1]. If severe hypertension persists after repeated doses of antihypertensive agents in monotherapy or following their combination,
emergent con sultation with an anesthesiologist, maternal–fetal or critical care subspecialists to discuss second-line intervention is
recommended [1,146].
12 J. TAMARGO ET AL. hypertensive emergencies, particularly when IV access is not
available or not yet obtained [1]. When this preparation is not
6.4. Antihypertensive drugs used for the treatment of available, labetalol (200 mg) can be administered orally; this dose
hypertension can be repeated in 30 min if needed [146]. However, immediate-
release nifedipine lowers BP faster than either IV labetalol or
6.4.1. Calcium channel blockers hydralazine [157,164]. This sudden (within 15 min) and potent fall
Nifedipine is the most commonly used CCB. The ACOG guide in BP can lead in pregnant women that are volume depleted to
lines recommends short-acting nifedipine as first-line therapy in
severe symptomatic hypotension that can compromise cerebral
and myocardial perfusion, leading to myocardial ischemia or
infarction, cerebrovascular accidents, and fetal distress [165–
167]. Therefore, the use of immediate release nifedipine is not
recommended [16,43].
Extended-release oral nifedipine produces minimal changes
on fetal or uteroplacental vessels [160,161], increases urine
output [157,168], is as effective as IV labetalol and hydralazine in
the acute control of severe hypertension [157,159,169] and
produces maternal and perinatal outcomes similar to these drugs
[139]. In a meta-analysis of 35 RCTs, women with severe
hypertension during pregnancy treated with CCBs were less likely
to have persistent high BP compared to those allocated on
hydralazine [139]. CCBs are considered safe during preg nancy,
and the use of nifedipine in the first trimester does not represent
a major teratogenic risk [94]. However, CCBs can increase
prematurity and cesarean delivery and produce intrauterine
growth retardation; additionally, exposure to CCBs during the
third trimester increases the risk of neonatal seizures and
perinatal jaundice [90,94,170,171]. Nifedipine is a tocolytic agent
and at the high doses used (up to 160 mg/ day) can cause
maternal hypotension and placental hypoper fusion [172]. CCBs
are metabolized via CYP3A4 and are highly bound to plasma
proteins. During pregnancy, CYP3A4 activity increases so that
oral bioavailability, peak plasma levels and half-life of CCBs
decrease [70,72]. Thus, higher doses might be necessary.
In women treated with nifedipine the IV administration of
magnesium can result in an excessive hypotension due to
potential synergism, hypocalcemia and neuromuscular block ade
that mandate more intensive monitoring of maternal
hemodynamic status [173–175]. However, a retrospective review
based on limited data concluded that this combination does not
increase the risk of serious magnesium-related effects [176]. At
the present time, the 2018 ESC guidelines recommended that IV
magnesium sulfate should not be given concomitantly with
nifedipine [16] and the 2017 ACOG Committee Opinion
recommended careful monitoring of women receiving this
combination [139], while the Canadian guidelines support the
combination [24]. Other guidelines did not mention this interaction
[93].
meta-analysis of 35 RCTs found no statistical significant
differences between parenteral labetalol and hydralazine, but
labetalol was associated with a lower risk of hypotension
compared to diazoxide [139], and a systematic review of 15 trials
reported that labetalol, nifedipine, and hydralazine achieved
similar treatment success in most women, with no differences in
adverse maternal or fetal outcomes [62].
One RCT [96] and two cohort studies [180,181] investigated
the effects of in-utero exposure of labetalol and methyldopa on
later childhood development. Cockburn et al. [96] and Chan et al.
[180] reported that exposure to methyldopa or labetalol in
offspring followed up to 7 years of age was not associated with
differences in health outcomes as compared with untreated
hypertensive women. Similar results were reported in another
study that compared the effects of methyldopa or labetalol with a
hypertensive control group treated with bed rest [181]. However,
these studies presented important methodological problems [87].
In a small comparative study of metoprolol and hydrala zine,
alone or in combination, perinatal mortality and fetal growth
retardations were lower in the metoprolol group (2.0% vs 8.0%
and 11.7% and 16.3%, respectively) and no abnormal fetal
effects were reported [182].
6.4.3. Hydralazine
Hydralazine crosses the placenta and appears in small amounts
in breast milk, but it does not alter the uteroplacental blood flow
[162] and maternal and perinatal outcomes are similar for
hydralazine and labetalol [139]. The antihyperten sive effects of
hydralazine are more pronounced in women with PE than with
GH, leading to more cases of fetal distress [153]. Intravenous
hydralazine may be less effective than CCBs, but more effective
than labetalol [127,158,162,168,178,183]. However, a meta-
analysis which compared hydralazine with labetalol and
nifedipine for treatment of severe hypertension in pregnancy
revealed that parenteral hydralazine was more often associated
with maternal hypotension, cesarean sec tions, placental
abruption and oliguria, adverse effects on the fetal heart, and low
Apgar scores at 1 min [127]. Because of this adverse safety
profile and the unpredictability of the

6.4.2. Beta-adrenergic blockers antihypertensive response, hydralazine is no longer the first

Labetalol and metoprolol are the preferred β-blockers in preg choice drug for acute treatment in many patients [16], although it
nant women with non-severe HTN. In a meta-analysis of 19 is still used when other treatments fail to achieve adequate BP
RCTs (1282 women) comparing one antihypertensive drug control, hypertension carries serious risks for the mother or the
fetus or maternal heart rate is <60 bpm [16,158,178,184]. There
is a possible association between first trimester hydralazine use
with another, β-blockers seem better than methyldopa for and hypospadias, third-trimester use and neonatal
reducing the risk of severe hypertension, but there was no clear thrombocytopenia, and maternal or neonatal lupus-like syndrome
difference concerning drugs in the risk of developing PE [141]. [4].
Labetalol does not alter the uteroplacental blood flow and is safe
during pregnancy [127,162,177]; However, the idea that labetalol 6.4.4. Central α2-receptor agonists
is safer than other β-blockers for the treatment of HDP has not Methyldopa and clonidine stimulate α2-receptors in the brain
been confirmed [125]. If posterior reversible encephalopathy stem and reduce central sympathetic output. Methyldopa is
syndrome is suspected, labetalol may be a good choice, as it widely used for the treatment of HDP because it produces a
does not cerebrally vasodilate [4]. Labetalol is preferred to gradual BP control over 6–8 h, it does not affect uteropla cental
methyldopa because of its onset of effect is faster, more efficient and fetal hemodynamics or exert teratogenic effects, and there is
at controlling BP, produces less rates of intervention (cesarean an absence of long-term adverse effects on development in
delivery or induction of labor) and is better tolerated [97]. In children with in utero exposures followed up to 7.5 years
women with severe hyperten sion, IV labetalol close to delivery [91,93,96,97,185]. In a secondary analysis of the CHIPS trial,
produces less maternal symptoms (hypotension, palpitations, there was no evidence that women treated with methyldopa
cesareans) than IV hydralazine/diazoxide, but produces more versus labetalol had worse outcomes [186]. Exposure to
maternal and fetal bradycardia that may require intervention methyldopa (or clonidine) during the second and third trimesters
[88,127,158,164,178,179]. In women with severe hypertension a may increase the risk of SGA babies, but not perinatal mortality
[89,125], although methyldopa increases the risk of PE and antihypertensive treatment during pregnancy, the antenatal
preterm delivery compared to β-blockers [86]. Methyldopa and treatment should be continued after delivery unless
clonidine cause neonatal hypotension, and maternal depression contraindicated in breastfeeding and tapered slowly only after
and should be avoided beyond the second day postpartum [41]. days 3–6 post-partum; consider reducing antihypertensive
treatment if their BP falls <130/80 mmHg [44,196]. Women with
6.4.5. Sodium nitroprusside co-morbidities should be treated according to standard guidelines
produces a very rapid and potent arterial and venous vasodi for their specific medical condition when not pregnant.
latation and should be administered under intra-arterial BP A recent meta-analysis of 39 RCTs concludes that although
monitoring to women with severe PE or hypertensive emer there are no reliable data to guide the management [199],
gencies when other treatments have failed to control BP or when nifedipine, labetalol, hydralazine, captopril or enalapril are
pregnancy is complicated by left ventricular failure and pulmonary appropriate for the treatment of post-partum hypertension
edema refractory to hydralazine [1,16,24,41–44]. It should be [198,199]. Methyldopa and clonidine can produce depression and
used for the shortest time possible due to the risk of fetal (it postural hypertension and should be avoided beyond the second
crosses the placenta), maternal and neonatal cyanide and day postpartum [41,140]. Nevertheless, data on antihypertensive
thiocyanate toxicity resulting from nitroprusside biotrans formation drugs for postpartum use are limited and recommendations are
[187]. based on common usage rather than good quality evidence [196].
So, based on non-pregnancy data, in women without co-
6.4.6. Glyceryl trinitrate morbidities, antihypertensive ther apy should be considered to
Glyceryl trinitrate (nitroglycerin) is the drug of choice when PE is treat non-severe postpartum hypertension to keep BP <140/90
associated with pulmonary edema and/or coronary artery dis mmHg; in women with co morbidities, BP should be treated
ease [16,41–44,188–190]. Infused nitroglycerin is as effective as according to standard guidelines for their specific medical
oral nifedipine, but without adverse effects [164,189,190]. condition [16,43]. Acute onset, severe post-partum hypertension
requires the same therapeutic approach as during pregnancy
[1,16,24,41– 44,196].
6.5. Racial differences in treatment Guidelines recommend monitoring BP within 6 h of deliv ery in
“Hypertension is more prevalent among the black population all normotensive women without complications of preg nancy in
living in the USA [138] or in Europe have a disproportionately the hospital (or with an equivalent level of outpatient surveillance)
high prevalence of hypertension and risk of BP-related CVD and for 72 h after birth and 5–7 days post partum to identify a late PE
renal disease than white women probably related to excess [1,41,43,196]. In women with post-partum hypertension/PE, it is
cases of prepregnancy hypertension [16,191–194]. Hypertension recommended to monitor BP every 4
14 J. TAMARGO ET AL.
epidemiology, diagnosis, and treatment have been thoroughly
studied in black (ie African Americans) US patients [138], while
information available for European black people is less available h while in-hospital, at least once between days 3 and 5, every 1–
[16,52]. Thus, we extrapolate from US data, despite there are 2 days for 2 weeks to ensure adequate BP control. After this, a
important differences between the weekly BP check will allow their medications to be titrated
EXPERT OPINION ON PHARMACOTHERAPY 13 appropriately based on BP recordings. All women should be
reviewed 6–8 weeks post-partum because at this time BP,
North American and the European black population exist, urinalysis, and all laboratory tests should have normalized
especially with regard to socioeconomic status, CV risk and the [41,44,184]. Beyond this period, if the patient still requires
response to antihypertensive drug treatment [52,138]. Among antihypertensive therapy and urinalysis and blood tests are
black women in whom plasma renin may be low, thiazide abnormal, she should be investigated for secondary causes of
diuretics or CCBs are the drugs of choice, while RAASIs or β- hypertension, before establishing a diagnosis of essential chronic
blockers are less effective in lowering BP [16,52,138,193]. hypertension.
Patients respond to the combination of thia zide diuretics and/or Nonsteroidal anti-inflammatory drugs, often self administered
CCBs with each other or with a RAASI, making the latter more as analgesics, inhibit prostaglandin synthesis and produce salt
effective [138]. and fluid retention and vasoconstriction. Thus, most Guidelines
[1,16,41–44,154,193] did not recom mended their use because
they can increase BP and counter act the effect of some
6.6. Post-partum hypertension antihypertensives and cause or exacerbate acute kidney injury
[200,201]. Indeed, they were not recommended postpartum in
BP usually decreases within 48 h following delivery, but it
women with resistant hypertension, high serum creatinine or
increases again 3–6 days postpartum. Thus, most women can be
thrombocytopenia, unless other analgesics are not working
discharged by day 5 postpartum, especially when they are able to
[1,184,196,200,201]. However, two recent retrospective trials
monitor their BP at home [44]. GH usually resolves by 6 weeks
[202,203] and one RCT [204] concluded that in women with PE
postpartum, while the hypertension of severe PE may take 3–6
who remained hypertensive after delivery, NSAID exposure did
months [24,195]. However, HDP (including PE/ eclampsia) often
not appear to increase the average postpartum MAP, the
persist following delivery, and sometimes arise de novo post-
requirement for anti-hypertensive medications at discharge or the
partum, particularly in women with CHTN, gestational
rate of adverse postpartum events and did not extend hospital
hypertension, PE, previous cardiac or renal disease or a difficulty
stay for BP control or increase the risk for readmission after
to control BP [61,140,196–198].
hospital discharge. These results support the safe use of NSAIDs
Women with postpartum hypertension/PE should be fol lowed up
in postpartum patients with BP issues [154].
and medication adjusted as needed. Women with pre-existing
hypertension who did not require treatment dur ing pregnancy may
require antihypertensive therapy early in the puerperium if SBP/DBP 7. Antihypertensive drugs and breastfeeding
≥150/100 mmHg [1,41,62,196]. In hypertensive women on
Most antihypertensives taken by the nursing mother are excreted
into breast milk and can be absorbed by the new born, but levels
are generally lower than in maternal plasma [16,72,117,119,121].
Labetalol and nifedipine have little or no effect on breastfed
neonates, while atenolol and metoprolol reach high
concentrations in the milk with potential unwanted effects on the
newborn; therefore, both drugs should also be avoided
[72,119,140]. Some ACEIs (captopril, enalapril, and quinapril)
can be used safely during breastfeeding [24,72,119,140,196].
Methyldopa and clonidine can produce or exacerbate depression
and diuretics have the potential to reduce/suppress lactation.
Therefore, they are not recom mended during breastfeeding
[1,16,24,41–44,198].
8. Expert opinion
Despite advances in obstetric medicine HDP complicate 5–10%
of pregnancies worldwide and remain a leading cause of
maternal, fetal and neonatal morbidity and mortality. Furthermore,
HDP serves as a sentinel marker for women who are likely to
experience premature cardiovascular, cerebrovascular diseases
and other chronic illnesses later in life. Therefore, the therapeutic
goal is to reduce maternal and fetal morbidity and mortality and
improve long-term clinical outcomes associated with uncontrolled
hyper tension using effective and safe antihypertensive drugs for
both mother and fetus. However, the treatment of HDP is
complicated
for several reasons. First, HPD is not a single disorder but
comprises a wide spectrum of chronic and de-novo forms of
hypertension with different underlying pathophysiological
mechanisms, risk fac tors, and outcomes. Second, pregnancy
produces important phy siologic changes in virtually every organ
which may alter the pharmacokinetic and/or pharmacodynamic
properties of antihy pertensive drugs. Third, hypertension
produces maternal hemody namic changes that may influence
the developing fetus and child, the efficacy of antihypertensive
agents in terms of maternal and fetal outcomes and the possible
long-term effects of in-utero antihypertensive exposure. HDP with
or without treatment is an independent risk factor for adverse
perinatal outcomes, suggest ing that hypertension itself, rather
than the selected antihyperten sive agent, may play a key role in
these adverse outcomes, perhaps via compromised
uteroplacental perfusion. Additionally, severe hypertension can
also be caused by stroke. Therefore, causality of the
hypertension is not per se, and it can be suggested that
hypertension serves as a marker of underlying endothelial
damage, that remains present even in treated pregnant women.
However, obviously, it requires due treatment because at even
higher levels autoregulation may be a separate issue. In fact, on
page 20 line 50 and further, there is a chance to say this also.
Finally, many antihypertensives have the potential to cross the
placenta, so that the benefit and harm of the selected drug(s) to
both mother and fetus need to be carefully evaluated and
discussed.
Interestingly, although there is a general consensus that
severe hypertension in pregnancy should be treated, at the
present time the treatment of mild hypertension without end
organ damage remains controversial and there is no agree ment
among clinical guidelines on the threshold to initiate
antihypertensive therapy, the BP targets or the recommended
drugs; discrepancies among guidelines do not provide ade quate
guidance to clinicians and increase their confusion. The lack of
consensus is not a surprise but the logical consequence of the
limited number of adequately powered, head-to-head RCTs that
have compared the efficacy and safety of antihyper tensive
medications in pregnancy and, therefore, there is insufficient
evidence to recommend one drug over another. Moreover, it is
uncertain whether there are significant differ ences in the rates of
major adverse perinatal outcomes or overall serious maternal
complications in association with less tight versus tight control of
BP, although a less tight control is associated with more severe
hypertension.
In general, BP goals are higher in pregnant than in nonpreg
nant women without end-organ damage because of the concern
that a marked decrease in maternal BP might affect feto-placental
perfusion. However, an unanswered question is how comorbid
ities (diabetes mellitus, chronic kidney disease, other cardiovascu
lar diseases) may influence the ideal range for BP in women with
HDP. Even if it is accepted that the appropriate BP target may be
lower than for women without such complications, there are
insufficient data to state whether this provides benefit either to the
mother or the fetus. The extrapolation from nonpregnant
population (mainly derived from older and often male popula
tions) may or may not be a valid option and the decision to
maintain SBP/DBP levels between 130 and 140 mmHg and 80–
90 mmHg, respectively, in diabetic pregnant women must be
weighed individually. Similarly, data on the optimum BP
EXPERT OPINION ON PHARMACOTHERAPY 15

Table 7. Gaps in evidence.

1. A better understanding of the pathophysiological mechanisms, risk factors and heterogeneity in outcomes for all types of hypertensive
disorders. 2. Large, well-designed, randomized and adequately powered comparative RCTs are needed to:
● Determine both the optimal BP targets and drug regimens for pregnant women during pregnancy and in the post-partum period ● Better
define the benefits and risks of antihypertensive drugs for both the mother and the fetus in women with mildly pregnancy hypertension ●
Directly compare different antihypertensive agents on fetal, perinatal and maternal morbidity and mortality
● Determine the long-term outcomes of children born from women who were treated or not for their hypertension
● Provide more specific information on how best to manage formerly pre-eclamptic women
● How changes in baseline hemodynamic conditions may impact the choice of pharmacological agent
● Identify effective preventive strategies that might reduce the long-term incidence of cardiovascular and cerebrovascular diseases in women with HPD
3. Studies investigating the pharmacokinetic changes that may affect antihypertensive dru g efficacy and safety during pregnancy are required ●
Hypertensive conditions of pregnancy are associated with changes in baseline hemodynamic conditions that may impact the choice of the
pharmacological agent.
4. The teratogenic risk of the most commonly used medications has not been adequately studied in human pregnancy, limiting the opportunity for
informed clinical decisions about the best management of acute and chronic disorders during pregnancy
5. Determine the safety profile of antihypertensive drugs for breastfeeding women
BP: blood pressure. HDP: hypertensive disorders of pregnancy. RCTs: randomized clinical trials

targets and antihypertensive agents for post-partum hyperten RCTs. Therefore, it should not be a surprise that the recent guide
sion are quite limited and choices came largely from expert lines of the ESC [16] recognized that evidence-based data regard
opinions and they are based on common usage rather than on ing treatment of hypertension in pregnancy are lacking and that
no antihypertensive drug received a 'class IA' recommendation. 2. Lo JO, Mission JF, Caughey AB. Hypertensive disease of pregnancy and
maternal mortality. Curr Opin Obstet Gynecol. 2013;25:124–132. 3. Leffert LR,
A specific characteristic of HDP is that many antihyperten sive Clancy CR, Bateman BT, et al. Hypertensive disorders and pregnancy-related
drugs have the potential to cross the placenta, but the benefits stroke: frequency, trends, risk factors, and outcomes. Obstet Gynecol.
and risks of the selected drug(s) for both mother and fetus need 2015;125:124–131.
to be better defined. In-utero exposure to antihy pertensive drugs 4. Vest AR, Cho LS. Hypertension in pregnancy. Curr Atheroscler Rep.
2014;16:395.
is associated with adverse child outcomes, such as preterm birth, • Very comprehensive review of hypertensive disorders in pregnancy.
perinatal mortality, low birth weight or risk of congenital 5. Bateman BT, Bansil P, Hernandez-Diaz S, et al. Prevalence, trends, and
abnormalities. However, most published studies present outcomes of chronic hypertension: a nationwide sample of delivery
methodological weaknesses and/or lacked sta tistical power thus admissions. Am J Obstet Gynecol. 2012;206:e1–134.e8.
6. Say L, Chou D, Gemmill A, et al. Global causes of maternal death: a WHO
preventing to draw any firm conclusions [87]. Furthermore, systematic analysis. Lancet Glob Health. 2014;2:e323–e333. 7. Lindheimer
assessing the potential risks of treating HDP to the offspring is MD, Taler SJ, Cunningham FG. ASH position paper: hyper tension in
further complicated by the underlying dis ease and there is pregnancy. J Clin Hypertens (Greenwich). 2009;11:214–225.
evidence that untreated hypertension also results in preterm birth, 16 J. TAMARGO ET AL.
low birth weight, and increased mor tality so that it can be
suggested that poorly controlled hyper tension may carry the 8. Ananth CV, Keyes KM, Wapner RJ. Pre-eclampsia rates in the United
same risks as untreated hypertension. Similarly, the safety profile States, 1980–2010: age-period-cohort analysis. BMJ. 2013;347:f6564. 9.
Brown MC, Best KE, Pearce MS, et al. Cardiovascular disease risk in women
of antihypertensive drugs in breast feeding women remains with pre-eclampsia: systematic review and meta-analysis. Eur J Epidemiol.
uncertain. 2013;28:1–19.
In the near future, further research is needed to better 10. Hutcheon JA, Lisonkova S, Joseph KS. Epidemiology of pre-eclampsia and
the other hypertensive disorders of pregnancy. Best Pract Res Clin Obstet
understand the pathophysiological mechanisms underlying HDP. Gynaecol. 2011;25:391–403.
This is the first step to identify effective preventive strategies and 11. Ahmad AS, Samuelsen SO. Hypertensive disorders in pregnancy and fetal
new therapeutic targets that might allow improving maternal and death at different gestational lengths: a population study of 2 121 371
fetal outcomes and reduce the risk of cardiovascular and pregnancies. BJOG. 2012;119:1521–1528.
12. Seely EW, Ecker J. Chronic hypertension in pregnancy. Sirkulasi.
cerebrovascular diseases in women with HPD later in life. High- 2014;129:1254–1261.
quality RCTs are urgently needed to determine the threshold to 13. Sibai BM. Chronic hypertension in pregnancy. Obstet Gynecol.
initiate antihypertensive therapy, the ideal range for BP to 2002;100:369–377.
optimize the health of the mother, fetus, and neonate, the efficacy 14. Zhang J, Meikle S, Trumble A. Severe maternal morbidity asso ciated with
hypertensive disorders in pregnancy in the United States. Hypertens
and safety of antihypertensive agents, and the most effective and Pregnancy. 2003;22:203–212.
safest drug combinations to improve long-term maternal and fetal 15. Bellamy L, Casas JP, Hingorani AD, et al. Pre-eclampsia and risk of
outcomes in women with HDP and other comorbidities. It is cardiovascular disease and cancer in later life: systematic review and meta-
important that these studies be undertaken and funded. The main analysis. BMJ. 2007;335:974.
16. Regitz-Zagrosek V, Roos-Hesselink JW, Bauersachs J, et al. ESC
research ques tions and controversial issues related to the guidelines for the management of cardiovascular diseases during
management of arterial hypertension in pregnant and child- pregnancy. Eur Heart J. 2018;2018(39):3165–3241.
bearing age women for which answers are currently unavailable 17. van Oostwaard MF, Langenveld J, Schuit E, et al. Recurrence of
are sum marized in Table 7. Finally, management of the pregnant hypertensive disorders of pregnancy: an individual patient data
metaanalysis. Am J Obstet Gynecol. 2015;212:624.e1–624.17.
woman should be individualized. Women at moderate- and 18. Zeitlin J, El AM, Jarreau PH, et al. Impact of foetal growth restriction on
high-risk of complications during pregnancy, pre-pregnancy mortality and morbidity in a very preterm birth cohort. J Pediatr.
counseling, and management during pregnancy and post delivery 2010;157:733e9.
should be managed in specialized centers by a multidisciplinary 19. preeclampsia
Habli M, Levine RJ, Qian C, et al. Neonatal outcomes in pregnancies with
or gestational hypertension and in normoten sive pregnancies
expert team. that delivered at 35, 36, or 37 weeks of gestation. Am J Obstet Gynecol.
2007;197:406.e1–7.
20. Sibai BM, Stella CL. Diagnosis and management of atypical preeclampsia-
Funding eclampsia. Am J Obstet Gynecol. 2009;200:481.e1– 481.e7.
21. Chappell LC, Enye S, Seed P, et al. Adverse perinatal outcomes and risk
This work was supported by grants from the Ministry of Science, Innovation and factors for preeclampsia in women with chronic hypertension: a prospective
Universities (SAF2017-88116-P), Carlos III Institute of Health [PI16/00398, CIBER- study. Hipertensi. 2008;51:1002–1009.
Cardiovascular (CB16/11/00303)] and the Comunidad de Madrid [B2017/BMD- 22. Duley L. The Global Impact of pre-eclampsia and eclampsia. Semin
3738]. Perinatol. 2009;33:130–137.
23. Langenveld J, Ravelli ACJ, van Kaam AH, et al. Neonatal outcome of
pregnancies complicated by hypertensive disorders between 34 and 37
Declaration of interest weeks of gestation: a 7 year retrospective analysis of a national registry. Am
J Obstet Gynecol. 2011;205:540.e1–7.
The authors have no other relevant affiliations or financial involvement with any 24. Behrens I, Basit S, Melbye M, et al. Risk of post-pregnancy hyper tension in
organization or entity with a financial interest in or financial conflict with the subject women with a history of hypertensive disorders of pregnancy: nationwide
matter or materials discussed in the manuscript apart from those disclosed. cohort study. BMJ. 2017;358:j3078.
25. Harmon QE, Huang L, Umbach DM, et al. Risk of fetal death with
preeclampsia. Obstet Gynecol. 2015;125:628–635.
Reviewer disclosures 26. Black MH, Zhou H, Sacks DA, et al. Hypertensive disorders first identified in
pregnancy increase risk for incident prehypertension and hypertension in
Peer reviewers on this manuscript have no relevant financial or other relationships the year after delivery. J Hypertens. 2016;34:728–735.
to disclose. 27. Grandi SM, Filion KB, Yoon S, et al. Cardiovascular disease-related
morbidity and mortality in women with a history of pregnancy complications.
Sirkulasi. 2019;139:1069–1079.
References 28. Stuart JJ, Tanz LJ, Missmer SA, et al. Hypertensive disorders of pregnancy
and maternal cardiovascular disease risk factor development: an obser
Papers of special note have been highlighted as either of interest (•) or of vational cohort study. Ann Intern Med. 2018;169:224–232.
considerable interest (••) to readers. 29. Wikström AK, Haglund B, Olovsson M, et al. The risk of maternal ischaemic
1. American College of Obstetricians and Gynecologists. Task force on heart disease after gestational hypertensive disease. BJOG.
hypertension in pregnancy. Hypertension in pregnancy. Report of the 2005;112:1486–1491.
American college of obstetricians and gynecologists' task force on 30. Ronsmans C, Graham WJ. Maternal mortality: who, when, where, and why.
hypertension in pregnancy. Obstet Gynecol. 2013;122:1122–1131. Lanset. 2006;368:1189–1200.
 31. Lykke JA, Langhoff-Roos J, Sibai BM, et al. Hypertensive pregnancy 58. Lee-Ann Hawkins T, Brown MA, Mangos GJ, et al. Transient gesta tional
disorders and subsequent cardiovascular morbidity and type 2 dia betes hypertension: not always a benign event. Pregnancy Hypertens. 2012;2:22–
mellitus in the mother. Hipertensi. 2009;53: 944–951. 27.
59. Huppertz B. Placental origins of preeclampsia: challenging the current
hypothesis. Hipertensi. 2008;51:970–975.
60. Snydal S. Major changes in diagnosis and management of preeclampsia. J
32. Magnussen EB, Vatten LJ, Smith GD, et al. Hypertensive disorders in MidwiferyWomens Health. 2014;59:596–605. 61. August P, Malha L. Postpartum
pregnancy and subsequently measured cardiovascular risk factors. Obstet hypertension: “it ain't over 'til it's over”. Sirkulasi. 2015;132:1690–1692.
Gynecol. 2009;114:961–970. 62. Firoz T, Magee LA, MacDonell K, et al. Oral antihypertensive therapy for
33. Kajantie E, Eriksson JG, Osmond C, et al. Pre-eclampsia is associated with severe hypertension in pregnancy and postpartum: a systematic review.
increased risk of stroke in the adult offspring: the Helsinki Birth Cohort BJOG. 2014;121:1210–1218.
Study. Stroke. 2009;40:1176–1180. 63. Clark SL, Belfort MA, Dildy GA, et al. Maternal death in the 21st century:
34. Theilen LH, Fraser A, Hollingshaus MS, et al. All-cause and cause-specific causes, prevention, and relationship to cesarean delivery. Am J Obstet
mortality after hypertensive disease of pregnancy. Obstet Gynecol. Gynecol. 2008;199:36.e1–5.
2016;128:238–244. 64. Martin JN Jr, Thigpen BD, Moore RC, et al. Stroke and severe preeclampsia
35. Tooher J, Thornton C, Makris A, et al. Hypertension in pregnancy and long- and eclampsia: a paradigm shift focusing on systolic blood pressure. Obstet
term cardiovascular mortality: a retrospective cohort study. Am J Obstet Gynecol. 2005;105:246–254.
Gynecol. 2016;214:722e1–e726. 65. Hofmeyr GJ, Lawrie TA, Atallah AN, et al. Calcium supplementation during
36. Aukes AM, De Groot JC, Aarnoudse JG, et al. Brain lesions several years pregnancy for preventing hypertensive disorders and related problems.
after eclampsia. Am J Obstet Gynecol. 2009;200:504e1–5. 37. Wiegman MJ, Cochrane Database Syst Rev. 2014 Jun 24;(6): CD001059. doi:
de Groot JC, Jansonius NM, et al. Long-term visual functioning after eclampsia. 10.1002/14651858.CD001059.pub4
Obstet Gynecol. 2012;119:959–966. 38. Aukes AM, de Groot JC, Wiegman MJ, 66. Bujold E, Roberge S, Lacasse Y, et al. Prevention of preeclampsia and
et al. Long-term cerebral intrauterine growth restriction with aspirin started in early pregnancy: a
imaging after preeclampsia. BJOG. 2012;119:1117–1122. 39. Robbins CL, metaanalysis. Obstet Gynecol. 2010;116:402–414.
Dietz PM, Bombard J, et al. Gestational hypertension: a neglected 67. WHO Recommendations for Prevention and Treatment of Pre Eclampsia and
cardiovascular disease risk marker. Am J Obstet Gynecol. 2011;204:336.e1–9. Eclampsia. Jenewa: Organisasi Kesehatan Dunia; 2011. ISBN-13: 978-92-4-
40. Romundstad PR, Magnussen EB, Smith GD, et al. Hypertension in 154833-5.
pregnancy and later cardiovascular risk: common antecedents? Sirkulasi. 68. Sibai BM, Koch MA, Freire S, et al. The impact of prior preeclampsia on the
2010;122:579–584. risk of superimposed preeclampsia and other adverse preg nancy outcomes
41. National Institute for Health and Clinical Excellence. (CG107) hyper tension in patients with chronic hypertension. Am J Obstet Gynecol.
in pregnancy: the management of hypertensive disorders during pregnancy. 2011;204:345e1–345.e6.
London: RCOG Press; 2011. 69. Gilbert WM, Young AL, Danielsen B. Pregnancy outcomes in women with
42. Magee LA, Pels A, Helewa M, et al. Canadian Hypertensive Disorders of chronic hypertension: a population-based study. J Reprod Med.
Pregnancy Working Group. Diagnosis, evaluation, and management of the 2007;52:1046–1051.
hypertensive disorders of pregnancy: executive summary. J Obstet 70. Anderson GD, Carr DB. Effect of pregnancy on the pharmacoki netics of
Gynaecol Can. 2014;36: 416–441. antihypertensive drugs. Clin Pharmacokinet. 2009;48:159–168.
43. Lowe SA, Bowyer L, Lust K, et al. The SOMANZ guidelines for the 71. Costantine MM. Physiologic and pharmacokinetic changes in pregnancy.
management of hypertensive disorders of pregnancy 2014. Aust NZJ Pharmacol depan. 2014;5:65.
Obstet Gynaecol. 2015;55:e1–29. • This comprehensive review analyzes how the physiologic changes in
44. Brown MA, Magee LA, Kenny LC, et al. International Society for the Study pregnancy induce profound alterations to the phar macokinetic properties of
of Hypertension in Pregnancy (ISSHP). Hypertensive disor ders of many medications.
pregnancy: ISSHP classification, diagnosis, and manage ment 72. Ke AB, Rostami-Hodjegan A, Zhao P, et al. Pharmacometrics in preg nancy:
recommendations for international practice. Hipertensi. 2018;72:24–43. an unmet need. Annu Rev Pharmacol Toxicol. 2014;54:53–69. 73. Pieper PG.
45. Buchbinder A, Sibai BM, Caritis S, et al. Adverse perinatal outcomes are Use of medication for cardiovascular disease during pregnancy. Nat Rev Cardiol.
significantly higher in severe gestational hypertension than in mild 2015;12:718–729.
preeclampsia. Am J Obstet Gynecol. 2002;186:66–71. •• Excellent overview of the pharmacokinetic changes in medica tions for CVD
46. Gulati M. Early identification of pregnant women at risk for preeclamp sia: during pregnancy and the safety of these drugs for the fetus.
USPSTF recommendations on screening for preeclampsia. JAMA Cardio. 74. Robson SC, Hunter S, Boys RJ, et al. Serial study of factors influen cing
2017;2:593–595. changes in cardiac output during human pregnancy. Am J Physiol.
47. Bellomo G, Narducci PL, Rondoni F, et al. Prognostic value of 24-hour 1989;256:H1060–H1065.
blood pressure in pregnancy. JAMA. 1999;282:1447–1452. 48. Bar J, Maymon 75. Capeless EL, Clapp JF. Cardiovascular changes in early phase of
R, Padoa A, et al. White coat hypertension and pregnancy. Am J Obstet Gynecol. 1989;161:1449–1453. 76. Chapman AB,
pregnancy outcome. J Hum Hypertens. 1999;13:541–545. 49. Rodrigues A, Abraham WT, Zamudio S, et al. Temporal relation ships between hormonal and
Barata C, Marques I, et al. Diagnosis of white coat hypertension and pregnancy hemodynamic changes in early human pregnancy. Kidney Int. 1998;54:2056–
outcomes. Pregnancy Hypertens. 2018;14:121–124. 2063.
50. Brown MA, Mangos G, Davis G, et al. The natural history of white coat 77. Mahendru AA, Everett TR, Wilkinson IB, et al. Maternal cardiovas cular
hypertension during pregnancy. BJOG. 2005;112:601–606. 51. O'Brien E, changes from pre-pregnancy to very early pregnancy. J Hypertens.
Parati G, Stergiou G, et al. European society of hyperten 2012;30:2168–2172.
sion working group on blood pressure monitoring. European society of EXPERT OPINION ON PHARMACOTHERAPY 17
hypertension position paper on ambulatory blood pres sure monitoring. J
Hypertens. 2013;31:1731–1768.
52. Williams B, Mancia G, Spiering W, et al. ESC/ESH guidelines for the •• The authors demonstrated that significant changes occur in brachial and
management of arterial hypertension. Eur Heart J. 2018;39:3021–3104. 53. central BP, augmentation index and PVR in ongoing pregnancies by about
Banegas JR, Ruilope LM, de la Sierra A, et al. Relationship between clinic and 6–7 weeks gestation, ie much earlier than has hitherto been assumed.
ambulatory blood-pressure measurements and mortality. N Engl J Med. 78. Macedo ML, Luminoso D, Savvidou MD, et al. Maternal wave reflections and
2018;378:1509–1520. arterial stiffness in normal pregnancy as assessed by applanation tonometry.
54. Gofton EN, Capewell V, Natale R, et al. Obstetrical intervention rates and Hipertensi. 2008;51:1047–1051.
maternal and neonatal outcomes of women with gestational hypertension. 79. Fujime M, Tomimatsu T, Okaue Y, et al. Central aortic blood pres sure and
Am J Obstet Gynecol. 2001;185:798–803. augmentation index during normal pregnancy. Hypertens Res. 2012;35:633–
55. Steer PJ, Little MP, Kold-Jensen T, et al. Maternal blood pressure in 638.
pregnancy, birth weight, and perinatal mortality in first births: prospective 80. Yoder SR, Thornburg LL, Bisognano JD. Hypertension in pregnancy and
study. BMJ. 2004;329:1312. women of childbearing age. Am J Med. 2009;122:890–895. 81. Easterling TR,
Benedetti TJ, Carlson KC, et al. The effect of maternal
hemodynamics on fetal growth in hypertensive pregnancies. Am J Obstet
Gynecol. 1991;165:902–906.
56. Davis GK, Mackenzie C, Brown MA, et al. Predicting transformation from 82. Easterling TR. Pharmacological management of hypertension in pregnancy.
gestational hypertension to preeclampsia in clinical practice: a possible role Seminars Perinatol. 2014;38:487–495.
for 24 hour ambulatory blood pressure monitoring. Hypertens Pregnancy. 83. Rosano GM, Lewis B, Agewall S, et al. Gender differences in the effect of
2007;26:77–87. cardiovascular drugs: a position document of the working group on
57. Anumba DO, Lincoln K, Robson SC. Predictive value of clinical and pharmacology and drug therapy of the ESC. Eur Heart J. 2015;36:2677–
laboratory indices at first assessment in women referred with suspected 2680.
gestational hypertension. Hypertens Pregnancy. 2010;29:163–179. 84. Haas DM, D'Alton M. Pharmacogenetics and other reasons why drugs can
 fail in pregnancy: higher dose or different drug? Obstet Gynecol.
2012;120:1176–1179.
85. Thorpe PG, Gilboa SM, Hernandez-Diaz S, et al. Medications in the first
trimester of pregnancy: most common exposures and critical gaps in
understanding fetal risk. Pharmacoepidemiol Drug Saf. 2013;22:1013–1101.
86. Orbach H, Matok I, Gorodischer R, et al. Hypertension and antihy pertensive
drugs in pregnancy and perinatal outcomes. Am J Obstet Gynecol.
2013;208:301–306.
87. Fitton CA, Steiner M, Aucott L, et al. In-utero exposure to antihy
pertensivemedication and neonatal and child health outcomes: a systematic
review. J Hypertens. 2017;35:2123–2137.
•• Excellent review of the primary literature reporting child out comes following
exposure in utero to one or more antihyper tensive medications compared
with unexposed children.
88. Magee LA, Duley L. Oral beta-blockers for mild to moderate hyper tension
during pregnancy. Cochrane Database Syst Rev. 2003;3: CD002863.
89. Nakhai-Pour HR, Rey E, Berard A. Antihypertensive medication use during
pregnancy and the risk of major congenital malformations or small-for-
gestational-age newborns. Birth Defects Res B Dev Reprod Toxicol.
2010;89:147–154.
90. Davis RL, Eastman D, McPhillips H, et al. Risks of congenital mal formations
and perinatal events among infants exposed to calcium channel and beta-
blockers during pregnancy. Pharmacoepidemiol Drug Saf. 2011;20:138–145.
91. Molvi SN, Mir S, Rana VS, et al. Role of antihypertensive therapy in mild to
moderate pregnancy-induced hypertension: a prospective randomized study
comparing labetalol with alpha methyldopa. Arch Gynecol Obstet.
2012;285:1553–1562.
92. Yakoob MY, Bateman BT, Ho E, et al. The risk of congenital mal formations
associated with exposure to beta-blockers early in preg nancy: a meta-
analysis. Hipertensi. 2013;62:375–381.
93. Al Khaja KA, Sequeira RP, Alkhaja AK, et al. Drug treatment of hypertension
in pregnancy: a critical review of adult guideline recommendations. J
Hypertens. 2014;32:454–463.
•• This excellent review evaluates the recommendations for the management of
hypertension in pregnancy as presented by 25 national/international
guidelines
94. Magee LA, Schick B, Donnenfeld AE, et al. The safety of calcium channel
blockers in human pregnancy: a prospective, multicenter cohort study. Am J
Obstet Gynecol. 1996;174:823–828.
95. Weber-Schoendorfer C, Hannemann D, Meister R, et al. The safety of
calcium channel blockers during pregnancy: a prospective, mul ticenter,
observational study. Reprod Toxicol. 2008;26:24–30.
96. Cockburn J, Moar VA, Ounsted M, et al. Final report of study on hypertension
during pregnancy: the effects of specific treatment
18 J. TAMARGO ET AL.
on the growth and development of the children. Lanset. 1982;1:647–649
97. el-Qarmalawi AM, Morsy AH, al-Fadly A, et al. Labetalol vs. methyl dopa in
the treatment of pregnancy-induced hypertension. Int J Gynaecol Obstet.
1995;49:125–130.
98. Fidler J, Smith V, Fayers P, et al. Randomized controlled compara tive
study of methyldopa and oxprenolol in treatment of hyperten sion in
pregnancy. BMJ. 1983;286:1927–1930.
99. Lupattelli A, Spigset O, Nordeng H. Adherence to medication for chronic
disorders during pregnancy: results from a multinational study. Int J Clin
Pharm. 2014;36:145–153.
100. Caton AR, Bell EM, Druschel CM, et al. National birth defects pre vention
study. Antihypertensive medication use during pregnancy and the risk of
cardiovascular malformations. Hipertensi. 2009;54:63–70.
101. Lennestal R, Otterblad OP, Kallen B. Maternal use of antihyperten sive
drugs in early pregnancy and delivery outcome, notably the presence of
congenital heart defects in the infants. Eur J Clin Pharmacol. 2009;65:615–
625.
102. Caton AR, Bell EM, Druschel CM, et al. National birth defects pre vention
study. Maternal hypertension, antihypertensive medication use, and the risk
of severe hypospadias. Birth Defects Res A Clin Mol Teratol. 2008;82:34–
40.
103. Tabacova S, Little R, Tsong Y, et al. Adverse pregnancy outcomes
associated with maternal enalapril antihypertensive treatment.
Pharmacoepidemiol Drug Saf. 2003;12:633–646.
104. Cooper WO, Hernandez-Diaz S, Arbogast PG, et al. Major congenital
malformations after first-trimester exposure to ACE inhibitors. N Engl J
Med. 2006;354:2443–2451.
105. Quan A. Fetopathy associated with exposure to angiotensin con verting
enzyme inhibitors and angiotensin receptor antagonists. Early Human Dev.
2006;82:23–28.
106. Moretti ME, Caprara D, Drehuta I, et al. The fetal safety of angio tensin
converting enzyme inhibitors and angiotensin II receptor blockers. Obstet
Gynecol Int. 2012;2012:658310.
107. Pucci M, Sarween N, Knox E, et al. Angiotensin-converting enzyme
inhibitors and angiotensin receptor blockers in women of child bearing age:
risks versus benefits. Expert Rev Clin Pharmacol. 2015;8:221–231.
108. Ruys TP, Maggioni A, Johnson MR, et al. Cardiac medication during
pregnancy, data from the ROPAC. Int J Cardiol. 2014;177:124–128. 109. Hecker
A, Hasan SH, Neumann F. Disturbances in sexual differentia tion of rat fetuses
following spironolactone treatment. Acta Enodcrinol (Copenh). 1980;95:540–
545.
110. Groves TD, Corenblum B. Spironolactone therapy during human
pregnancy. Am J Obstet Gynecol. 1995;172:1655–1656.
111. Lydakis C, Lip G, Beevers M, et al. Atenolol and fetal growth in pregnancies
complicated by hypertension. Am J Hypertens. 1999;12:541–547.
112. Reynolds B, Butters L, Evans J, et al. First year of life after the use of
atenolol in pregnancy associated hypertension. Arch Dis Child.
1984;59:1061–1063.
113. Butters L, Kennedy S, Rubin PC. Atenolol in essential hypertension during
pregnancy. BMJ. 1990;301:587–859.
114. Committee on Obstetric Practice. Emergent therapy for acuteonset, severe
hypertension during pregnancy and the postpartum period. Committee
Opinion No. 623. American college of obstetricians and gynecologists.
Obstet Gynecol. 2015;125:521–525.
115. Collins R, Yusuf S, Peto R. Overview of randomized trials of diuretics in
pregnancy. BMJ. 1985;290:17–23.
116. Churchill D, Beevers GDG, Meher S, et al. Diuretics for preventing pre-
eclampsia. Cochrane Database Syst Rev. 2007;(1):CD004451. doi:
10.1002/14651858.CD004451.pub2
117. Briggs G, Freeman R, Yaffe S. Drugs in pregnancy and lactation: reference
guide to fetal and neonatal risk. Philadelphia: Lippincott Williams dan
Wilkins; 2002.
118. Ferrer RL, Sibai BM, Mulrow CD, et al. Management of mild chronic
hypertension during pregnancy: a review. Obstet Gynecol. 2000;96:849–
860.
119. Beardmore KS, Morris JM, Gallery ED Excretion of antihypertensive
medication into human breast milk: a systematic review. Hypertens
Pregnancy. 2002;21:85–95.
120. Sibai B, Grossman RA, Grossman HG. Effects of diuretics on plasma
volume in pregnancies with long-term hypertension. Am J Obstet Gynecol.
1984;150:831–835.
121. American Academy of Pediatrics. Committee on Drugs. The transfer of
drugs and other chemicals into human milk. Pediatrics. 2001;108:776–789.
122. Williams B, Poulter NR, Brown MJ, et al. Masyarakat. Guidelines for
management of hypertension: report of the fourth working party of the
british hypertension society, – BHS IV. J Hum Hypertens. 2004;18:139–185.
123. Magee L. Treating hypertension in women of child-bearing age and during
pregnancy. Drug Saf. 2001;24:457–474.
124. von Dadelszen P, Magee LA. Fall in mean arterial pressure and fetal
growth restriction in pregnancy hypertension: an updated meta-regression
analysis. J Obstet Gynaecol Can. 2002;24:941–945.
125. Meidahl Petersen K, Jimenez-Solem E, Andersen JT, et al. β-Blocker
treatment during pregnancy and adverse pregnancy outcomes: a
nationwide population-based cohort study. BMJ Open. 2002 Jul 19;2(4). pii:
e001185. doi: 10.1136/bmjopen-2012-001185
126. von Dadelszen P, Ornstein MP, Bull SB, et al. Fall in mean arterial pressure
and fetal growth restriction in pregnancy hypertension: a meta-analysis.
Lanset. 2000;355:87–92.
127. Magee LA, Elran E, Bull SB, et al. Risks and benefits of beta-receptor
blockers for pregnancy hypertension: overview of the randomized trials. Eur
J Obstet Gynecol Reprod Biol. 2000;88:15–26.
128. Magee LA, Ornstein MP, von Dadelszen P. Fortnightly review: man
agement of hypertension in pregnancy. BMJ. 1999;318:1332–1336. 129. Ersbøll
AS, Hedegaard M, Søndergaard L, et al. Treatment with oral beta-blockers
during pregnancy complicated by maternal heart disease increases the risk of
fetal growth restriction. BJOG. 2014;121(5):618–626.
130. Klarr JM, Bhatt-Mehta V, Donn SM. Neonatal adrenergic blockade following
single dose maternal labetalol administration. Am J Perinatol. 1994;11:91–
93.
131. Bateman BT, Patorno E, Desai RJ, et al. Late pregnancy β blocker
exposure and risks of neonatal hypoglycemia and bradycardia. Pediatrics.
2016;138:e20160731.
132. Gelson E, Curry R, Gatzoulis MA, et al. Effect of maternal heart disease on
fetal growth. Obstet Gynecol. 2011;117:886–891. 133. Prefumo F, Sebire NJ,
Thilaganathan B. Decreased endovascular trophoblast invasion in first trimester
pregnancies with high-resistance uterine artery Doppler indices. Hum Reprod.
2004;19:206–209.
134. Osol G, Mandala M. Maternal uterine vascular remodeling during
pregnancy. Physiology (Bethesda). 2009;24:58–71.
135. Kramer MS, Platt R, Yang H, et al. Are all growth-restricted new borns
created equal(ly). Pediatrics. 1999;103:599–602.
136. Nakhai-Pour HR, Rey E, Bérard A. Discontinuation of antihyperten sive
drug use during pregnancy and the risk of pre-eclampsia and eclampsia
among women with chronic hypertension. Am J Obstet Gynecol.
 2009;180:e1–8.
137. Cleary KL, Siddiq Z, Ananth CV, et al. Use of antihypertensive medications
during delivery hospitalizations complicated by preeclampsia. Obstet
Gynecol. 2018;131:441–450.
138. Whelton PK, Carey RM, Aronow WS, et al. ACC/-AHA/AAPA/ABC/
ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the preven tion,
detection, evaluation, and management of high blood pres sure in adults: a
report of the American college of cardiology/ American Heart Association
task force on clinical practice guidelines. J Am Coll Cardiol.
2017;2018(71):e127–248.
139. Duley L, Meher S, Jones L. Drugs for treatment of very high blood pressure
during pregnancy. Cochrane Database Syst Rev. 2013;(7): CD001449. doi:
10.1002/14651858.CD001449.pub3
• Women with severe hypertension during pregnancy treated with CCBs were
less likely to have persistent high BP compared to those allocated
hydralazine.
140. Podymow T, August P. Update on the use of antihypertensive drugs in
pregnancy. Hipertensi. 2008;51:960–969.
141. Abalos E, Duley L, Steyn DW, et al. Antihypertensive drug therapy for mild to
moderate hypertension during pregnancy. Cochrane Database Syst Rev.
2018;(10):CD002252. doi: 10.1002/14651858. CD002252.pub4
•• Treatment with any antihypertensive drugs halved the risk for severe
hypertension, but does not prevent PE or the asso ciated adverse perinatal
outcomes (stillbirth, preterm birth or SGA babies).
142. von Dadelszen P, Menzies JM, Payne B, et al. Predicting adverse outcomes
in women with severe preeclampsia. Semin Perinatol. 2011;33:152–157.
143. Nabhan AF, Elsedawy MM. Tight control of mild-moderate pre-existing or
non-proteinuric gestational hypertension. Cochrane Database Syst Rev.
2011;(7):CD006907. doi: 10.1002/ 14651858.CD006907.pub2
144. Magee LA, von Dadelszen P, Rey E, et al. Less-tight versus tight control of
hypertension in pregnancy. N Engl J Med. 2015;372:407–417.
•• This seminal clinical trial analyzed less-tight control of mater nal hypertension
in pregnancy as compared with tight control in the risk of adverse perinatal
outcomes.
145. Magee LA, von Dadelszen P, Singer J, et al. The CHIPS randomized
controlled trial (control of hypertension in pregnancy study): is severe
hypertension just an elevated blood pressure? Hipertensi. 2016;68:1153–
1159.
146. Committee on Obstetric Practice. Committee opinion No. 767: emergent
therapy for acute-onset, severe hypertension during pregnancy and the
postpartum period. Obstet Gynecol. 2019;133: e174–e180.
147. Cantwell R, Clutton-Brock T, Cooper G, et al. Saving Mothers' Lives:
reviewing maternal deaths to make motherhood safer: 2006–2008. The
eighth report of the confidential enquiries into maternal deaths in the United
Kingdom. BJOG. 2011;118 ((suppl1)):1–203.
148. Bernstein PS, Martin JN, Barton JR Jr, et al. Consensus bundle on severe
hypertension during pregnancy and the postpartum period. J
MidwiferyWomens Health. 2017;62:493–501.
149. Cipolla MJ. Cerebrovascular function in pregnancy and eclampsia.
Hipertensi. 2007;50:14–24.
150. van Veen TR, Panerai RB, Haeri S, et al. Cerebral autoregulation in normal
pregnancy and preeclampsia. Obstet Gynecol. 2013;122:1064–1069. 151.
Schutte JM, Schuitemaker NEW, van Roosmalen J, et al. Dutch maternal
mortality committee. Substandard care in maternal mor tality due to hypertensive
disease in pregnancy in the Netherlands. BJOG. 2008;115:732–736.
152. Scott CA, Bewley S, Rudd A, et al. Incidence, risk factors, manage ment,
and outcomes of stroke in pregnancy. Obstet Gynecol. 2012;120:318–324.
153. Foo L, Tay J, Lees CC, et al. Hypertension in pregnancy: natural history and
treatment options. Curr Hypertens Rep. 2015;17:36. 154. Practice Bulletin ACOG.
Clinical management guidelines for obstetrician-gynecologist, number 202.
gestational hypertension and preeclampsia. Obstet Gynecol. 2019;133:e1–e25.
155. Altman D, Carroli G, Duley L, et al. Magpie Trial Collaboration Group. Do
women with pre-eclampsia, and their babies, benefit from magnesium
sulphate? The magpie trial: a randomised placebo-controlled trial. Lanset.
2002;359:1877–1890.
156. Livingston JC, Livingston LW, Ramsey R, et al. Magnesium sulfate in women
with mild preeclampsia: a randomized controlled trial. Obstet Gynecol.
2003;101:217–220.
157. Vermillion ST, Scardo JA, Newman RB, et al. A randomized, double-blind
trial of oral nifedipine and intravenous labetalol in hypertensive emergencies
of pregnancy. Am J Obstet Gynecol. 1999;181:858–861.
158. Vigil-De Gracia P, Ruiz E, Lopez JC, et al. Management of severe
hypertension in the postpartum period with intravenous hydrala zine or
labetalol: a randomized clinical trial. Hypertens Preg. 2007;26:163–171.
EXPERT OPINION ON PHARMACOTHERAPY 19
159. Raheem IA, Saaid R, Omar SZ, et al. Oral nifedipine versus intravenous
labetalol for acute blood pressure control in hypertensive emergencies of
pregnancy: a randomised trial. BJOG. 2012;119:78–85.
160. Moretti MM, Fairlie FM, Akl S, et al. The effect of nifedipine therapy on fetal
and placental Doppler waveforms in preeclampsia remote from term. Am J
Obstet Gynecol. 1990;163:1844–1848.
161. Scardo JA, Vermillion ST, Hogg BB, et al. Hemodynamic effects of oral
nifedipine in preeclamptic hypertensive emergencies. Am J Obstet Gynecol.
1996;175:336–338.
162. Baggio MR, Martins WP, Calderon AC, et al. Changes in fetal and maternal
Doppler parameters observed during acute severe hyper tension treatment
with hydralazine or labetalol: a randomized con trolled trial. Ultrasound Med
Biol. 2011;37:53–58.
163. Tuffnell DJ, Jankowicz D, Lindow SW, et al. Outcomes of severe pre-
eclampsia/eclampsia in Yorkshire 1999/2003. Yorkshire obste tric critical
care group. BJOG. 2005;112:875–880.
164. Sridharan K, Sequeira RP. Drugs for treating severe hypertension in
pregnancy: a network meta-analysis and trial sequential analysis of
randomized clinical trials. Br J Cin Pharmacol. 2018;84:1906–1916.
•• This excellent network meta-analysis and trial sequential ana lysis of RCTs
suggests similar efficacy between nifedipine, hydralazine and labetalol in the
treatment of severe hyperten sion in pregnancy.
165. Impey L. Severe hypotension and fetal distress following sublingual
administration of nifedipine to a patient with severe pregnancy induced
hypertension at 33 weeks. Br J Obstet Gynaecol. 1993;100:959–961.
166. Papatsonis DN, Lok CA, Bos JM, et al. Calcium channel blockers in
themanagement of preterm labor and hypertension in pregnancy. Eur J
Obstet Gynecol Reprod Biol. 2001;97:122–140.
167. Brown MA, Buddle ML, Farrell T, et al. Efficacy and safety of nifedi pine
tablets for the acute treatment of severe hypertension in pregnancy. Am J
Obstet Gynecol. 2002;187:1046–1050.
168. Rezaei Z, Sharbaf FR, Pourmojieb M, et al. Comparison of the efficacy of
nifedipine and hydralazine in hypertensive crisis in pregnancy. Acta Med
Iran. 2011;49:701–706.
169. Martins Costa S, Ramos JG, Barros E, et al. Randomized, controlled trial of
hydralazine versos nifedipine in preeclamptic women with acute
hypertension. Clin Exp Hypertens B. 1992;11:25–44.
170. Sørensen HT, Steffensen FH, Olesen C, et al. Pregnancy outcome in women
exposed to calcium channel blockers. Reprod Toxicol. 1998;12:383–384.
171. Gruppo di Studio Ipertensione in Gravidanza. Nifedipine versus expectant
management in mild to moderate hypertension in pregnancy. Br J Obstet
Gynaecol. 1998;105:718–722.
172. Hubinont C, Debieve F. Prevention of preterm labour: 2011 update on
tocolysis. J Pregnancy. 2011;2011:941057.
173. Waisman GD, Mayorga LM, Camera MI, et al. Magnesium plus nifedipine:
potentiation of hypotensive effect in preeclampsia? Am J Obstet Gynecol.
1988;159:308–309.
174. Snyder SW, Cardwell MS. Neuromuscular blockade with magne sium sulfate
and nifedipine. Am J Obstet Gynecol. 1989;161:35–36. 175. Koontz SL, Friedman
SA, Schwartz ML. Symptomatic hypocalcemia after tocolytic therapy with
magnesium sulfate and nifedipine. Am J Obstet Gynecol. 2004;190:1773–1776.
176. Magee LA, Miremadi S, Li J, et al. Therapy with both magnesium sulfate and
nifedipine does not increase the risk of serious magnesium-related maternal
side effects in women with preeclampsia. Am J Obstet Gynecol.
2005;193:153–163.
177. Sibai BM, Mabie WC, Shamsa F, et al. A comparison of no medica tion
versus methyldopa or labetalol in chronic hypertension during pregnancy.
Am J Obstet Gynecol. 1990;162:960–967.
178. Vigil-De Gracia P, Lasso M, Ruiz E, et al. Severe hypertension in pregnancy:
hydralazine or labetalol. A randomized clinical trial. Eur J Obstet Gynecol
Reprod Biol. 2006;128:157–162.
179. Garden A, Davey DA, Dommisse J. Intravenous labetalol and intra venous
dihydralazine in severe hypertension in regnancy. Clin Exp Hypertens B.
1982;1:371–383.
180. Chan WS, Koren G, Barrera M, et al. Neurocognitive development of children
following in-utero exposure to labetalol for maternal
20 J. TAMARGO ET AL.
hypertension: a cohort study using a prospectively collected database.
Hypertens Pregnancy. 2010;29:271–283.
181. Pasker-De Jong PC, Zielhuis GA, van Gelder MM, et al. Antihypertensive
treatment during pregnancy and functional development at primary school
age in a historical cohort study. BJOG. 2010;117:1080–1086.
182. Sandström B. Antihypertensive treatment with the adrenergic betare ceptor
blocker metoprolol during pregnancy. Gynecol Invest. 1978;9:195–204.
183. Mesquita MRDS, Atallah AN, Rocha NDSC, et al. The use of hydra lazine
and nifedipine in hypertensive emergencies in pregnancy. Rev Bras
Ginecol Obstet. 1995;17:103–111.
184. Moroz LA, Simpson LL, Rochelson B. Management of severe hyper tension
in pregnancy. Semin Perinatol. 2016;40:112–118. 185. Montan S, Anandakumar
C, Arulkumaran S, et al. Effects of methyldopa on uteroplacental and fetal
hemodynamics in pregnancy-induced hypertension. Am J Obstet Gynecol.
1993;168:152–156.
186. Magee LA, CHIPS Study Group, von Dadelszen P, et al. Do labetalol and
 methyldopa have different effects on pregnancy outcome? Analysis of data
from the control of hypertension in pregnancy study (CHIPS) trial. BJOG.
2016;123:1143–1151.
187. Sass N, Itamoto CH, Silva MP, et al. Does sodium nitroprusside kill babies?
Tinjauan sistematis. Sao Paulo Med J. 2007;125:108–111.
188. Neri I, Valensise H, Facchinetti F, et al. 24-hour ambulatory blood pressure
monitoring: a comparison between transdermal glyceryl-trinitrate and oral
nifedipine. Hypertens Pregnancy. 1999;18:107–113.
189. Cetin A, Yurtcu N, Guvenal T, et al. The effect of glyceryl trini trate on
hypertension in women with severe preeclampsia, HELLP syndrome, and
eclampsia. Hypertens Pregnancy. 2004;23:37–46.
190. Hernandez-Sierra JF, Rodriguez-Martinez M. Efficacy of nitroglycer ine
infusion versus sublingual nifedipine in severe preeclampsia: a randomized,
triple-blind, controlled trial. Clin Exp Pharmacol Physiol. 2008;35:580–585.
191. Samadi AR, Mayberry RM, Zaidi AA, et al. Maternal hypertension and
associated pregnancy complications among African-American and other
women in the United States. Obstet Gynecol. 1996;87:557–563.

192. Healy AJ, Malone FD, Sullivan LM, et al. Early access to prenatal care:
implications for racial disparity in perinatal mortality. Obstet Gynecol.
2006;107:625–631.
193. Whelton PK, Einhorn PT, Muntner P, et al. Research needs to improve
hypertension treatment and control in African Americans. Hipertensi.
2016;68:1066–1072.
194. Modesti PA, Reboldi G, Cappuccio FP, et al. Panethnic differences in blood
pressure in Europe: a systematic review and meta-analysis. PLoS One.
2016;11:e0147601.
195. Report of the National High Blood Pressure Education Program Working
Group on High Blood Pressure in Pregnancy. Am J Obstet Gynecol.
2000;183:S1–S22.
196. Bramham K, Nelson-Piercy C, Brown MJ, et al. Postpartum manage ment
of hypertension. BMJ. 2013;346:f894.
•• Excellent review on postpartum management of hypertension 197. Goel A,
Maski MR, Bajracharya S, et al. Epidemiology and mechan isms of De Novo and
persistent hypertension in the postpartum period. Sirkulasi. 2015;132:1726–
1733.
198. Cairns AE, Pealing L, Duffy JMN, et al. Postpartum management of
hypertensive disorders of pregnancy: a systematic review. BMJ Open.
2017;7:e018696.
199. Magee L, von Dadelszen P. Prevention and treatment of postpartum
hypertension. Cochrane Database Syst Rev. 2013;(4):CD004351. doi:
10.1002/14651858.CD004351.pub3
200. Makris A, Thornton C, Hennessy A. Postpartum hypertension and
nonsteroidal analgesia. Am J Obstet Gynecol. 2004;190:577–578. 201.
Snowden S, Nelson R. The effects of nonsteroidal antiinflammatory drugs on
blood pressure in hypertensive patients. Cardiol Rev. 2011;19:184–191.
202. Wasden SW, Ragsdale ES, Chasen ST, et al. Impact of non-steroidal anti-
inflammatory drugs on hypertensive disorders of pregnancy. Pregnancy
Hypertens. 2014;4:259–263.
203. Viteri OA, England JA, Alrais MA, et al. Association of nonsteroidal
antiinflammatory drugs and postpartum hypertension in women with
preeclampsia with severe features. Obstet Gynecol. 2017;130:830–835.
204. Blue NR, Murray-Krezan C, Drake-Lavelle S, et al. Effect of ibuprofen vs
acetaminophen on postpartum hypertension in preeclampsia with severe
features: a double-masked, randomized controlled trial. Am J Obstet
Gynecol. 2018;218:616.e1–8.