LAPORAN PRAKTIK JURNAL READING

ANTIEPILEPTIC DRUG USE AMONG PREGNANCY WOMEN

Disusun Oleh :

Gebby Febrina

PROGRAM STUDI PENDIDIKAN PROFESI BIDAN

JURUSAN KEBIDANAN POLTEKKES KEMENKES BANDUNG
2022

i
 HALAMAN PENGESAHAN

LAPORAN PRAKTIK JURNAL READING

Oleh:
Gebby Febrina
NIM. P17324121514

Menyetujui,

Pembimbing Klinik
Kokon Wiartin Lestari, SST (.......................................)
NIP. 196903051990122001

Pembimbing Akademik (.......................................)

Bd.Ferina, SST., M.Keb__
NIP.198102282002122001

Mengetahui,

Ketua Program Studi Pendidikan Profesi Bidan

Bd. Diyan I, SST.,M.Keb

NIP.198106092002122001

ii
 DAFTAR ISI

Halaman

HALAMAN JUDUL ..................................................................................... i

HALAMAN PENGESAHAN ....................................................................... ii
KATA PENGANTAR ................................................................................... iii
DAFTAR ISI.................................................................................................. iv

BAB 1 PENDAHULUAN ............................................................................ 1

1.1 LatarBelakang .................................................................................... 1
1.2 Tujuan ................................................................................................ 2
1.3 Manfaat .............................................................................................. 2

BAB 2 METODOLOGI............................................................................... 3
2.1 Hasil Telaah Jurnal ............................................................................ 3
2.2 Pembahasan........................................................................................ 6

BAB 3 KESIMPULAN DAN SARAN ........................................................ 8

3.1 Kesimpulan ........................................................................................ 8
3.2 Saran .................................................................................................. 9

DAFTAR PUSTAKA ................................................................................... 10

LAMPIRAN
 KATA PENGANTAR

Puji syukur kepada Allah SWT penulis ucapkan atas rahmat dan karunia-Nya sehingga
penulis dapat menyelesaikan Journal Reading yang berjudul “Antiepileptic drug use among
women from the Taiwanese Registry of Epilepsy and Pregnancy : Obstetric complications and
fetal malformation outcomes” Untuk memenuhi salah satu persyaratan untuk menyelesaikan
Praktik Stase Prakonsepsi pada Prodi Profesi Bidan Poltekkes Bandung.
Terima kasih penulis ucapkan kepada pembimbing akademik yaitu ibu Bd.Ferina, SST.,
M.Keb dan pembimbing lahan yaitu ibu Kokon Wiartin Lestari, SST yang telah bersedia
memberikan ilmu dan nasihat kepada penulis sehingga penulis bisa menyelesaikan Journal
Reading ini.
Mohon maaf penulis ucapkan jika terdapat kesalahan dalam Journal Reading ini. Kritik
dan saran penulis perlukan demi perbaikan serta tambahan ilmu dalam penyelesaian Journal
Reading ini.
Akhir kata penulis berharap semoga Journal Reading ini dapat memberikan manfaat dan
menambah ilmu pengetahuan di bidang kebidanan.

Bandung, Februari 2022

Penulis

iii
 1

BAB I

PENDAHULUAN

1.1 Latar Belakang

A. Latar belakang
Epilepsi adalah salah satu penyebab neurologis utama beban bagi individu dan
masyarakat, dengan tingkat kejadian tahunan 40-70 per 100.000 orang per
tahun. Wanita dengan Epilepsi yang hamil membuat sekitar 0,3-0,7% dari
semua kehamilan di negara maju Epilepsi umum dikaitkan dengan lebih
banyak komplikasi pada kehamilan dan persalinan. Bukti lebih lanjut dari
komplikasi dalam persalinan, wanita dengn epilepsi memiliki insiden induksi
yang lebih tinggi persalinan (43,8%) dibandingkan dengan populasi umum
(17,1%), sedangkan kejadian Caesar bagian (CS) lebih tinggi di wanita dengn
epilepsi (65,6%), dibandingkan pada kelompok kontrol (37,1%). Jandhavet al.,
juga menemukan hasil kesehatan ibu lainnya serupa antara wanita dengn
epilepsi dan wanita hamil non-epilepsi (yaitu perdarahan postpartum, aborsi,
persalinan pervaginam operatif, persalinan prematur, dan anemia).

Obat antiepilepsi (AED) adalah pengobatan kejang yang umum dan efektif
pada epilepsi, meskipun dapat menimbulkan peningkatan risiko malformasi
kongenital pada kehamilan, serta komplikasi kebidanan. Bukti menunjukkan
bahwa monoterapi (hanya menggunakan 1 AED) dan AED yang lebih baru
(AED Generasi ke-2) lebih aman dalam hal komplikasi kebidanan dan bayi
malformasi. Meskipun temuan terbaru dari data tingkat populasi di Swedia
telah menemukan bukti bahwa AED aman. Konsensus apakah terpapar AED
atau kejang menimbulkan risiko yang lebih besar belum tercapai, karena
penelitian yang menyelidiki efek AED individu pada perkembangan janin dan
kesehatan ibu tidak cukup untuk membuat temuan konklusif. Upaya terbaru
dalam mengembangkan pendaftar untuk wanita hamil dengan epilepsi telah
menghasilkan pemahaman yang lebih baik tentang hubungan antara AED,
malformasi, dan komplikasi kehamilan. Borthen dkk. serangan epilepsi yang
diamati kurang berbahaya, karena wanita dengan epilepsi aktif yang
 2

melakukannya tidak menggunakan AED tidak memiliki risiko yang

berlebihan. Sebaliknya, Chen et al. kejang yang diamati dikaitkan dengan
sejumlah hasil kehamilan yang buruk pada wanita hamil dengan epilepsi di
pengaturan Taiwan menggunakan Data Riset Jaminan Kesehatan Nasional
(NHIRD). Demikian pula, Lin et al. melaporkan bahwa wanita dengan epilepsi
yang tidak menggunakan AED memiliki risiko lebih tinggi untuk memiliki
hasil kelahiran yang buruk. Kedua studi memberikan data tentang kehamilan
hingga tahun 2003. Penggunaan AED WWE dan hasil obstetrik di Taiwan
dapat diperbarui untuk secara akurat mencerminkan tren saat ini di wilayah
tersebut.

B. Tujuan
Tujuan dari penelitian ini adalah untuk menganalisis Daftar Epilepsi dan
Kehamilan Taiwan (TREP) dari tahun 2004–2015. Data dari registri
menyajikan tampilan unik pada kehamilan obat antiepilepsi yang memiliki
kejang terperinci, penggunaan obat antiepilepsi, dan catatan hasil kehamilan.
Pembaruan studi tren terbaru dalam penggunaan obat antiepilepsi di antara
wanita dengan epilepsi di negara Asia dengan aksesibilitas perawatan
kesehatan yang tinggi. Selain itu, kami berharap dapat membedakan antara
efek serangan epilepsi, paparan obat antiepilepsi, dan komplikasi obstetrik
yang buruk.

C. Metodologi

Jurnal Judul Populasi Intervensi Comparasion Outcome Time

1. Yeh CC, Antiepilepti Wanita Obat Manajemen Epilepsi menganalisis
Lussier EC, c drug use hamil Antiepilepsi data Taiwanese
Sun Y, Lan among dengan Registry of
T. Epilepsy and
women Epilepsi
Antiepileptic Pregnancy
drug use from the
(TREP) dari
among Taiwanese tahun 2004-2015
women from Registry of
the Epilepsy
Taiwanese and
Registry of Pregnancy
Epilepsy and
Pregnancy :
 3

Obstetric
complication
s and fetal
malformation
outcomes.
2017;1–14.
 4

BAB II
HASIL DAN PEMBAHASAN

2.1 Hasil Telaah Jurnal

No Jurnal Validity Important Aplicable

1 Yeh CC, • Penelitian ini • Penelitian ini • ukuran sampel yang
Lussier EC, secara retrospektif menggunakan kecil, kami tidak
Sun Y, Lan T. meninjau data dari cross-sectional dapat secara
Antiepileptic data Taiwanese dengan dipilih meyakinkan
drug use among Registry of Epi sampel wanita mengesampingkn
women from lepsy and hamil dengan efek AED atau
the Taiwanese Pregnancy epilepsi yang kejang tertentu pada
Registry of (TREP) yang menggunakan malformasi, dan
Epilepsy and dikumpulkan AED sebelum kemungkinan
Pregnancy : secara prospektif hamil dan komplikasi wanita
Obstetric penelitian TREP mencari dengan epilepsi
complications adalah pendataan perawatan dipengaruhi oleh
and fetal yang kesehatan dari AED atau kejang
malformation mengumpulkan ahli saraf. dan ini
outcomes. data dari wanita menghasilkan
2017;1–14. dengan epilepsi • Di antara 349 tingkat malformasi
yang: kehamilan, 318 yang lebih tinggi
(1) pernah hamil, (91,1%) telah
menyelesaikan • Penelitian kami
(2) terdiagnosis kuesioner secara memiliki
Epilepsy keseluruhan beberapa
(3) tidak memiliki sampai persalinan keterbatasan.
penyakit kronis lain berhasil, atau Pertama,
(4) bersedia mengikuti memiliki hasil pendaftar
Pendataan kehamilan yang adalah alat
(5) bersedia untuk tidak berhasil. penting dalam
mempertahankan usia rata-rata ibu mengumpulkan
asupan AED selama adalah 29,6 tahun informasi rinci
kehamilan seperti (SD = ±4,2), dengan terutama untuk
yang sebagian besar penyakit
ditentukan oleh dokter (73,4%) antara 26- dengan tingkat
terlatih. 35 tahun pada saat insiden rendah,
kehamilan. namun
• TREP diinisiasi Sebagian besar seringkali tidak
untuk berpartisipasi adalah nulipara mewakili
dalam International (67,7%). populasi umum
Registri Eropa Obat
Antiepilepsi dan • 94,7% pasien telah
Kehamilan diberi resep
(EURAP). EURAP setidaknya 1 AED
 5

adalah 42 dimana 69,0% dan

pendaftaran negara 25,7% masing-
yang menyediakan masing telah
informasi tentang menerima
kehamilan WWE, monoterapi AED,
resep AED, dan hasil atau politerapi.
obstetri. Registri Mayoritas
TREP adalah menerimaAED
registrasi kohort generasi kedua
prospektif sukarela (44,5%), dengan
yang mengumpulkan 32,9% AED
tanggapan kuesioner generasi pertama,
dari wanita dengan dan 17,2%
epilepsi pada 5 menerima resep
kunjungan. AED bersamaan
Kuesioner telah (AED generasi
digunakan dalam pertama dan kedua
studi pendahuluan bersama–sama.
sebelumnya.
Kunjungan dipilih Sekitar 47,6%
agar sesuai dengan pernah mengalami
jadwal pemeriksaan setidaknya 1
ibu rutin, untuk kejang selama
meningkatkan kehamilan,
kepatuhan. sedangkan
Kunjungan pertama dalam32,6 trimester
terjadi pada awal pertama
kehamilan, % pernah mengalami
kunjungan kedua beberapa bentuk
pada 12 dan 13 kejang. Kami
minggu usia mengamati tingkat
kehamilan (GA) kelahiran hidup 96,2%.
tindak lanjut, dan Lebih dari
kunjungan ke-3 semua malformasi
mencatat tanggapan ditemukan 5,0%.
pada 28-32 minggu Meskipun kasus-
GA. Setelah kasus tertentu
pengiriman, telah memiliki
tanggapan kuesioner malformasi yang
ke-4 dicatat 7 hari terdeteksi sebelum
setelahnya lahir, lahir, beberapa
sedangkan kuesioner kehamilan yang
terakhir dicatat 1 diaborsi (n = 4)
tahun setelah lahir. meninggalkan tingkat
Selama perjalanan malformasi 3,9% di
data koleksi, 50 ibu antara kelahiran hidup.
memiliki lebih dari Komplikasi obstetri
satu kehamilan. baik selama kehamilan
Kami memasukkan maupun persalinan
kehamilan ganda terjadi pada 4,4%
 6

karena profil wanita kasus. Pengiriman CS

(Usia, paritas, profil adalah metode
AED, pengiriman yang
kejadian/frekuensi paling umum (54,5%).
kejang, hasil
kelahiran) • Usia ibu di atas 35
cukup berbeda tahun (X2 = 4,347, p
untuk di = 0,046), kejang
pertimbangkan yang dialami
secara independen. selama kehamilan
(X2 = 4,977, p =
• Unit analisis adalah 0,026), dan
total kehamilan komplikasi
wanita dengan kebidanan (X2 =
epilepsi. Data 5,738, p = 0,017),
deskriptif dianalisis semuanya memiliki
menggunakan CS yang lebih
penghitungan tinggi secara
sederhana dan signifikan
persentase (%), dibandingkan
serta mean dan dengan kelompok
standar deviasi persalinan
untuk variabe pervaginam.
kontinu.
• Komplikasi
obstetrik
dikonfirmasi hanya
terkait dengan hasil
CS (OR = 5,11, CI
95% = 1,11-23,51,
p = 0,036).
Malformasi
ditemukan sangat
terkait dengan
komplikasi ibu
(OR = 20,46, CI
95% = 4,80-87,21,
p<0,001).
Politerapi AED dan
generasi paparan
pertama tidak
ditemukan terkait
dengan komplikasi
obstetrik atau
malformasi janin.
 7

2.1 Pembahasan
Kehamilan dengan epilepsi yang telah diresepkan AED sebelum hamil dari 2004-
2015 dan mencatat 318 kehamilan dengan epilepsi. Peningkatan kontrol kejang
adalah tujuan utama dari resep AED pada kehamilan, menemukan tingkat kontrol
kejang yang relatif sama selama trimester pertama dibandingkan dengan studi
EURAP. Di antara semua kehamilan, 95,7% telah menggunakan AED selama masa
kehamilan mereka. Dari sebuah studi oleh Lin et al. mereka menemukan bahwa data
NHI selama 2001-2003 memiliki 1182 wanita berkode epilepsi dan hamil.

Di antara mereka, hanya 165 (14%) yang memiliki catatan resep AED dan
diperkirakan setiap tahun ada 83 ibu hamil dengan epilepsi yang menggunakan AED.
Kehamilan tahunan di TREP berkisar antara 15 dan 47, yang merupakan 18%~55%
dari kehamilan dengan epilepsi yang menggunakan AED yang terdaftar dalam
registri TREP ini. Selanjutnya, tingkat kesuburan total di Taiwan tetap pada 1,0-1,1
baru-baru ini dan total populasi sekitar 23 juta. Ini dicirikan oleh tingkat kesuburan
total yang rendah dan paparan AED yang tinggi selama kehamilan yang merupakan
cerminan dari situasi nyata di Taiwan dan dengan demikian memberikan tampilan
yang menarik pada sampel dengan paparan tinggi terhadap penggunaan AED di
Taiwan.

Antara 2004–2015,AED generasi pertama berkurang drastis (dari 73% menjadi 8%).
Mulai tahun 1997 hingga 2007 penurunan bertahap dari resep AED lama dan
peningkatan AED generasi baru telah diamati. AED yang lebih baru telah dilaporkan
memiliki efek samping yang lebih sedikit dan tolerabilitas yang lebih baik dan
mungkin lebih aman dalam perkembangan janin.

Politerapi juga mengalami penurunan prevalensi selama kurun waktu yang sama
(dari 40% menjadi 20%). Bukti menunjukkan bahwa menggunakan beberapa AED
dikaitkan dengan risiko malformasi dan komplikasi kehamilan yang lebih tinggi.
Pengurangan politerapi selama masa studi mungkin disebabkan oleh peningkatan
pengetahuan tentang risiko politerapi. Pada tahun 2009, terjadi penyimpangan tren
resep jenis AED, dengan lonjakan besar pada resep politerapi (40,7%). Di Taiwan,
Chen dkk. dan Lin et al. keduanya menemukan AED aman, sementara mereka yang
tidak menggunakan AED dan mengalami kejang melihat risiko malformasi yang
 8

lebih tinggi. Kami berspekulasi bahwa makalah ini mungkin mengindikasikan

pergeseran dalam pandangan dan praktik klinis, dan WWE mungkin telah diresepkan
tingkat AED yang lebih tinggi. Hal ini juga dimungkinkan karena sifat observasional
dari penelitian ini, mungkin ada fluktuasi data pada tahun itu.

Temuan dari sampel TREP menunjukkan tingkat kelahiran CS yang lebih tinggi
(54,5%) dibandingkan dengan penelitian sebelumnya yang menyelidikil wanita hamil
dengan epilepsi: 37,6%, 54,3%, dan 19,8% Tingkat CS di antara populasi umum di
Taiwan juga lebih rendah daripada dalam penelitian kami (36,7%). Kebanyakan
wanita tidak pernah melakukan CS sebelumnya. Meskipun epilepsi tidak dianggap
sebagai risiko CS, kecuali terjadi selama persalinan, dokter mungkin telah memilih
untuk melakukan persalinan CS untuk menghindari wanita mengalami kejang dalam
persalinan, meningkatkan kejadian dalam sampel kami. Investigasi CS kami
menemukan bahwa usia ibu di atas 35 tahun, epilepsi umum dan komplikasi
kebidanan semuanya lebih mungkin menghasilkan kelahiran CS. Temuan ini sesuai
dengan pengalaman klinis dan penelitian sebelumnya, dengan usia dan komplikasi
obstetrik, lebih mungkin mengarah ke CS. Pengalaman keseluruhan dari setidaknya
satu serangan epilepsi berkorelasi dengan tingkat CS yang lebih tinggi. Penelitian
sebelumnya mendukung temuan kami tentang paparan kejang dan risiko komplikasi
kehamilan.
 9

BAB III
KESIMPULAN DAN SARAN

3.1 Kesimpulan

Kemunculan wanita hamil dengan epilepsy relatif rendah dan kasus-kasus yang

menggunakan AED selama kehamilan bahkan lebih rendah, diperlukan untuk mengumpulkan

data yang cukup. Terlepas dari keterbatasan bias dalam mengumpulkan sample, sampel

masih merupakan pengamatan yang menarik di wanita dengn epilepsi yang memiliki

penggunaan AED yang tinggisepanjang kehamilan. Selain itu, meskipun termasuk kehamilan

berkerumun sebagai independenkasus dapat menimbulkan risiko bias, banyak kehamilan dari

ibu yang sama berbeda pada nomor faktor (yaitu usia, paritas, profil AED, frekuensi kejang,

hasil kehamilan dan kelahiran, dll.)dan dengan demikian diperlakukan sebagai unit analisis

independen. Kedua, registri TREP memiliki accumenghasilkan 349 kehamilan dalam 11

tahun. Alasan untuk nomor registri kecil termasuk: rendah tingkat kesuburan, kesenjangan

pengobatan wanita dengan epilepsi selama kehamilan, kesalahpahaman atau penyembunyian

pasien. Ketiga, kami hanya melihat wanita yang telah hamil. Wanita-wanita ini kemungkinan

akan berbeda dari wanita dengan epilepsi yang memilih untuk tidak hamil dalam tingkat

keparahan epilepsi, akan memilih sendiri untuk menghindari kehamilan, dan mungkin tidak

mewakili spektrum penuh risiko epilepsi. Oleh karena itu, hasilnya harus digeneralisasikan ke

populasi wanita dengan epilepsi yang lebih besar dengan hati-hati. Keempat, kuesioner

dikelola sendiri, oleh karena itu tanggapan mungkin bias dalam pelaporan diri untuk

karakteristik tertentu seperti kejang yang dialami selama kehamilan dan jenis epilepsi. Karena

potensi kesenjangan pengetahuan pasien, beberapa pertanyaan mungkin tidak ada telah

dijawab secara akurat.

 10

Terlepas dari keterbatasan ini, penelitian kami memberikan pandangan yang menarik pada

sampel Taiwan yang memiliki tingkat resep AED yang tinggi. Hasil menunjukkan AED

generasi pertama dan poliester resep secara bertahap menurun selama masa studi. CS

dikaitkan dengan kehamilan yang mengalami komplikasi obstetri. Meskipun memiliki resep

AED tinggi, tingkat malformasi tetap rendah dan tidak terkait dengan faktor risiko AED yang

khas. Selain itu, CS dikaitkan dengan komplikasi kebidanan, dan komplikasi kebidanan

dikaitkan dengan malformasi. Faktor risiko AED tipikal tidak terkait dengan risiko

malformasi atau komplikasi. Penelitian tingkat populasi lebih lanjut diperlukan untuk

mengeksplorasi hubungan antara kejang, AED, komplikasi kebidanan dan hasil kelahiran.

3.2 Saran

Literatur yang digunakan sudah tepat. Semua bahan acuan dalam bentuk jurnal ataupun

naskah ilmiah yang digunakan sebagai referensi atau acuan ditulis pada bagian ini. Referensi

yang dirujuk haruslah yang benar benar mempunyai kontribusi nyata dalam penelitian

tersebut.
 11

DAFTAR PUSTAKA

1. Yeh CC, Lussier EC, Sun Y, Lan T. Antiepileptic drug use among women from the
Taiwanese Registry of Epilepsy and Pregnancy : Obstetric complications and fetal
malformation outcomes. 2017;1–14.
 RESEARCH ARTICLE

Antiepileptic drug use among women from

the Taiwanese Registry of Epilepsy and
Pregnancy: Obstetric complications and fetal
malformation outcomes
Chang Ching Yeh1,2,3☯, Eric C. Lussier4☯, Yi-Ting Sun4‡, Tzuo-Yun Lan5,6‡, Hsiang-
Yu Yu7,8‡, Tung-Yao Chang4‡*
a1111111111 1 Department of Obstetrics & Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan, 2 Institute of
a1111111111 Clinical Medicine, National Yang-Ming University, Taipei, Taiwan, 3 Department of Obstetrics and
a1111111111 Gynecology, National Yang-Ming University, Taipei, Taiwan, 4 Taiji Clinic, Taipei, Taiwan, 5 Institute of
a1111111111 Hospital and Health Care Administration, National Yang-Ming University, Taipei, Taiwan, 6 Department of
Public Health, China Medical University, Taichung, Taiwan, 7 Neurology Department, Taipei Veterans
a1111111111
General Hospital, Taipei, Taiwan, 8 Neurology Department, National Yang-Ming University, Taipei, Taiwan

☯ These authors contributed equally to this work.

‡ These authors also contributed equally to this work.
* tychang@fetalmedicine.tw
OPEN ACCESS

Citation: Yeh CC, Lussier EC, Sun Y-T, Lan T-Y, Yu

H-Y, Chang T-Y (2017) Antiepileptic drug use Abstract
among women from the Taiwanese Registry of
Epilepsy and Pregnancy: Obstetric complications To investigate antiepileptic drugs (AEDs) prescription and pregnancy outcomes in pregnan-
and fetal malformation outcomes. PLoS ONE 12 cies with epilepsy in Taiwan between 2004 and 2015. We retrospectively reviewed data
(12): e0189497. https://doi.org/10.1371/journal.
pone.0189497
from the Taiwanese Registry of Epilepsy and Pregnancy (TREP). The TREP registry is a
voluntary prospective cohort registry, which tracks pregnant women with epilepsy and AED
Editor: Giuseppe Biagini, University of Modena and
Reggio Emilia, ITALY
prescription throughout pregnancy, delivery, and early childhood development. All TREP
pregnancies (n = 318) that had completed questionnaires up until delivery or had had an
Received: August 18, 2017
unsuccessful pregnancy were analyzed. Over 94.7% of women had been prescribed AEDs
Accepted: November 28, 2017 during pregnancy, with 69.0% and 25.7% having received monotherapy, or polytherapy,
Published: December 18, 2017 respectively. Among live births, 12 (3.9%) reported malformation. Cesarean section rate
Copyright: © 2017 Yeh et al. This is an open access was reported higher than usual (54.5%). In 2004, 73.3% of AEDs prescribed were 1st gener-
article distributed under the terms of the Creative ation, with 1st generation prescription rates falling to only 8.3% of total prescribed in 2015.
Commons Attribution License, which permits AED polytherapy also fell during the study period (40.0% to 20.0%). Cesarean sections
unrestricted use, distribution, and reproduction in
any medium, provided the original author and
were found to be higher for women over 35 years, who had generalized epilepsy, or had
source are credited. experienced an obstetric complication during pregnancy term. Binary logistic regression
Data Availability Statement: Data are available via
revealed that Cesarean section was associated with maternal complications (OR = 5.11, CI
the Harvard Dataverse Network at: https:// 95% = 1.11–23.51, p = 0.036), while malformations were associated with obstetric complica-
dataverse.harvard.edu/dataset.xhtml?persistentId= tion (OR = 20.46, CI 95% = 4.80–87.21, p<0.001). Both AED risk types were not associated
doi:10.7910/DVN/T9PWQQ (DOI: 10.7910/DVN/
with complications or malformations. Our sample provides a unique insight into the women
T9PWQQ).
with epilepsy with AED use during pregnancy. Cesarean section rate was observed to be
Funding: The authors received no specific funding
higher than usual, but malformation rates remained low. Results indicate a decrease in both
for this work.
1st generation AEDs and proportion of patients receiving polytherapy over the study period.
Competing interests: The authors had no
Obstetric complications were associated with Cesarean section. Fetal malformations were
competing interests at the time of writing the
manuscript.

PLOS ONE | https://doi.org/10.1371/journal.pone.0189497 December 18, 2017 1 / 14

 Antiepileptic drug use among pregnancy Taiwanese women

significantly associated with obstetric complications. AED risk factors were not significantly
associated with either complications or malformations.

Introduction
Epilepsy is one of the leading neurological causes of burden to the individuals and community,
with an annual incidence rate of 40–70 per 100,000 persons per year [1]. Women with Epilepsy
(WWE) who are pregnant make up roughly 0.3–0.7% of all pregnancies in developed countries
[2]. Generalized epilepsy is associated with more complications in pregnancy and delivery [3].
Further evidence of complications in delivery, WWE had a higher incidence of induction of
labor (43.8%) compared to the general populations (17.1%), while the incidence of Cesarean
section (CS) was higher in WWE (65.6%), than in the control group (37.1%) [4]. Jandhav
et al., also found other maternal health outcomes were similar between WWE and non-epilep-
tic pregnant women (i.e. postpartum hemorrhage, abortion, operative vaginal delivery, pre-
term delivery, and anemia) [4].
Antiepileptic drugs (AEDs) are a common and effective treatment of seizures in epilepsy,
although may pose an increased risk of congenital malformations in pregnancies [5], as well as
obstetric complications [6]. Evidence suggests that monotherapy (only taking 1 AED) and
newer AEDs (2nd Generation AEDs) are safer in terms of obstetric complications and infant
malformations, [7,8]. Although recent findings from population level data in Sweden have
found evidence that AEDs are safe.[9] Consensus on whether exposure to AEDs or seizures
pose a greater risk has yet to be reached, since studies investigating individual AEDs’ effect on
fetal development and maternal health are insufficient to make conclusive findings [10].
Recent efforts in developing registries for pregnant WWE has led to a better understanding in
the link between AEDs, malformations, and pregnancy complications [5,11,12]. Borthen et al.
[2] observed epileptic seizures were less harmful, since women with active epilepsy who did
not take AEDs had no excessive risk. In contrast, Chen et al. [13] observed seizures were asso-
ciated with a number of poor pregnancy outcomes in pregnant WWE in the Taiwan setting
using the National Health Insurance Research Data (NHIRD). Similarly, Lin et al. [14]
reported that WWE who had not taken AEDs had a higher risk of having poor birth outcomes.
Both studies provided data on pregnancies up until 2003. WWE’s AED use and obstetrical out-
comes in Taiwan could be updated to accurately reflect current trends in the region.
The objective of the study was to analyze the Taiwanese Registry of Epilepsy and Pregnancy
(TREP) data from 2004–2015. Data from the registry presents a unique look at WWE pregnan-
cies that had detailed seizure, AED use and pregnancy outcomes records. The study updates
the latest trends in AED use among WWE in an Asian country with high healthcare accessibil-
ity. In addition, we hope to distinguish between the effects of epileptic seizures, AED exposure,
and poor obstetric complications.

Methods
Design
We retrospectively reviewed data from the prospectively collected Taiwanese Registry of Epi-
lepsy and Pregnancy (TREP) data. The TREP was initiated to participate in the International
European Registry of Antiepileptic Drugs and Pregnancy (EURAP) [15]. The EURAP is a 42
country registry that provides information on WWE pregnancies, AED prescription, and
obstetrical outcomes. The TREP registry is a voluntary prospective cohort registry that collects

PLOS ONE | https://doi.org/10.1371/journal.pone.0189497 December 18, 2017 2 / 14

 Antiepileptic drug use among pregnancy Taiwanese women

questionnaire responses from WWE upon 5 visits. The questionnaire has been used in a previ-
ous preliminary study [16]. Visits were selected to match regular maternal check-up schedules,
in order to increase compliance. The 1st visit occurred in early pregnancy, the 2nd visit was at
12 and 13 weeks of gestational age (GA) follow-up, and the 3rd visits recorded responses at 28–
32 weeks GA. Following delivery, the 4th questionnaire responses was recorded 7 days after
birth, while the last questionnaire was recorded 1 year after birth. During the course of data
collection, 50 mothers had more than one pregnancy. We included multiple pregnancies
because women’s profile (Age, parity, AED profile, seizure event/frequency, birth outcomes)
differed enough to be considered independently.

Study sample
TREP is a registry collecting data from WWE who: (1) had a pregnancy, (2) were diagnosed
with epilepsy, (3) did not have other chronic diseases, (4) were willing to participate in the reg-
istry, and (5) were willing to maintain AED intake during the course of the pregnancy as pre-
scribed by a trained physician. Cases with chronic diseases that were excluded included: past
history of hypertension, cardiovascular disease or diabetes, women who had history of psychi-
atric issues. All women that were given a questionnaire also signed an informed consent form.
The total TREP pregnancies entered into the registry from 2004 to 2015 was 349. There were
50 women that entered into the analysis more than once. Although TREP questionnaires
recorded all follow-ups until 1 year after birth (5th visit), we chose to include any cases that had
at least been followed-up to the 4th questionnaires or had an unsuccessful pregnancy, since we
were only interested in maternal health outcomes, and did not focus on child development
until 1 year. An additional 30 cases had failed to complete up to the 4th wave, or had incom-
plete questionnaire information, and were also excluded from the analysis, leaving 319 cases.
Four cases that had malformations were aborted early, 1 case reported Trisomy 21 (S1 Table).
Since it is not seen to be clinically linked with epilepsy or AED pharmacologically, we chose to
delete the case as including this case may have overestimated malformation outcome. Since
many cases were excluded due to missing information, we conducted a sensitivity analysis
comparing baseline characteristics between included and excluded samples. No significant dif-
ferences were observed and thus was not presented here. The final WWE sample was 318 preg-
nancies. The study was approved by the Research Ethics Committee of Taipei Veterans
General Hospital with IRB number 2017-07-017CC.

Primary measures and covariates

Variables selected from the questionnaire items and responses included: maternal age (contin-
uous and categorical {15–20, 21–25, 26–35, 36–40, 41]}, type of epilepsy (Generalized, Local-
ization-related, and Unknown), and maternal history (parity). We also looked at the number
of AEDs patients were prescribed (none, monotherapy (1), and polytherapy (2)). Previously
established categorization of AED by generation were employed [5,17]. 1st generation are
AEDs which were developed before 1993, while 2nd generation were developed after 1993.
Since some patients had been prescribed both 1st and 2nd generation AEDs, they were coded as
having a concurrent prescription. In the analytical stage, in order to isolate exposure to a 1st
generation AED we assigned a binary code for those who were exposed to 1st generation and
those who were not. Overall seizure frequency was reported for any seizure experienced
throughout the pregnancy (Y/N). We also looked more closely at seizures in the first trimester,
as previous research indicates that seizures in this trimester are associated with malformations
[18]. Three levels of seizures were categorized as: no seizures experienced, <1 seizure/month,
1 seizure/month. Gestational age at birth was coded along with normal birth timing: Aborted

PLOS ONE | https://doi.org/10.1371/journal.pone.0189497 December 18, 2017 3 / 14

 Antiepileptic drug use among pregnancy Taiwanese women

(20 weeks), Preterm Birth (21–36 weeks), Term Birth (37–42 weeks), Post-term Birth (>42
weeks), and late abortion. Having a live birth was coded as a binary category (Y/N). Overall
malformations, which included in utero malformations for those with early abortions, were
identified. Malformations included any congenital physical deformity to external limbs or
organ structure, confirmed by physician or ultrasound technician if aborted early or con-
firmed by pediatrician in post-partum period. For a complete list of malformations detected
see S1 Table. Obstetric complications (Y/N) were defined as any WWE who had developed an
obstetrical complication in the perinatal period as diagnosed by an obstetrician. For a full list
of obstetrical complications see S2 Table. Delivery methods (vaginal delivery, Cesarean (CS),
aborted) were also recorded. Cases that had CS were defined into two categories: primary CS
(having never had a CS performed previously) or previous CS (having had a CS operation in a
previous pregnancy).

Statistical analysis
The unit of analysis was total pregnancies of WWE. Descriptive data were analyzed using sim-
ple counts and percentages (%), and mean and standard deviation for continuous variables.
We compared the proportion of number of AEDs prescribed in each year and were plotted
with a bar graph. Pearson’s Chi-square (X2) analysis was run between cases that had experi-
enced CS and those who hadn’t. Polytherapy, 1st generation AEDs and CS were coded into
binary variables (having exposure/experience or not) for analysis. A binary logistic regression
compared factors associated with obstetric complications rate and malformation rate. Factors
investigated for obstetric complications included: maternal age (above or below 35 years),
overall seizure exposure throughout pregnancy, exposure to polytherapy, exposure to 1st gen-
eration AEDs and CS outcome. Factors investigated for fetal malformations included: seizures
experienced in 1st Trimester, exposure to polytherapy, exposure to 1st generation AEDs, as
well as CS outcome. Both models were adjusted for variables and additionally controlled for
epilepsy type and parity. Odds ratios with confidence intervals were reported. A 2-sided p-
value of p < .05 was used as a cut-off for significance. All data were analyzed using SPSS version
21.0.

Results
Among the 349 pregnancies, 318 (91.1%) had completed a questionnaire in its entirety up
until successful delivery, or had had an unsuccessful pregnancy outcomes. Table 1 shows aver-
age maternal age was 29.6 years (SD = ±4.2), with the large majority (73.4%) between 26–35
years at time of pregnancy. The large majority were nulliparous (67.7%). We observed a high
prescription rate of AEDs, with 94.7% of patients having been prescribed at least 1 AEDs of
which 69.0% and 25.7% had received AED monotherapy, or polytherapy, respectively. The
majority received 2nd generation AEDs (44.5%), with 32.9% 1st generation AEDs, and 17.2%
receiving concurrent AED prescriptions (1st and 2nd generation AEDs together). Around
47.6% had experienced at least 1 seizure throughout the pregnancy, while within the 1st trimes-
ter, 32.6% had experienced some form of seizure. We observed a live birth rate of 96.2%. Over-
all malformations were found to be 5.0%. Although certain cases had had malformations
detected prenatally, some aborted pregnancies (n = 4) left a malformation rate of 3.9% among
live births. Obstetric complications, either during pregnancy or in delivery occurred in 4.4% of
cases. CS delivery was the most common delivery method (54.5%).
Rates of monotherapy and polytherapy in pregnancy were observed throughout TREP data
collection (Fig 1). Trends over the course of the study indicate that exposure to polytherapy
had steadily decreased, while over the study period from 40% to 20%, while monotherapy had

PLOS ONE | https://doi.org/10.1371/journal.pone.0189497 December 18, 2017 4 / 14

 Antiepileptic drug use among pregnancy Taiwanese women

Table 1. Descriptives of TREP WWE pregnancies (N = 318c).

Variables Categories Count/Mean %/SD
Age (years) 29.6 4.2
Age Group 15–20 6 1.9%
21–25 45 14.2%
26–35 233 73.3%
36–40 33 10.4%
41 1 .3%
Epilepsy Type Generalized 181 56.9%
Localization-related 119 37.4%
Unknown or Not Ascertained 18 5.7%
Parity Nulliparous 215 67.6%
Primiparous 85 26.7%
Multiparous 18 5.7%
No. of AEDsa prescribed None 17 5.3%
Monotherapy (1) 219 68.9%
Polytherapy ( 2) 82 25.8%
AED Type 1st Generation 104 32.7%
2nd Generation 142 44.7%
Cocurrent Prescription 55 17.3%
No AEDs Prescribed 17 5.3%
Seizure in Overall Pregnancy No 167 52.5%
Yes 151 47.5%
Seizure Events (1st Trimester) No Seizures 214 67.3%
<1 Seizure/month 56 17.6%
>1 Seizure/month 48 15.1%
Mean Gestational Age (weeks) 38.1 4.3
Gestational Age at birth (weeks) Aborted (20 weeks) 10 3.1%
Preterm Birth (21–36) 34 10.7%
Term Birth (37–42) 272 85.5%
Post-term Birth (>42) 2 .6%
Live Birth No 11 3.5%
Yes 307 96.5%
Overall Malformation rate Normal 303 95.3%
Abnormal 15 4.7%
Maternal Complications Absent 304 95.6%
Present 14 4.4%
Delivery Method Vaginal Delivery 133 41.8%
CSb 174 54.7%
Aborted or Stillborn 11 4.4%
Overall CS (N = 174) Previous CS 46 26.4%
Primary CS 80 46.0%
Not Indicated 48 27.6%

Notes
a.
AEDs—antiepileptic drug
b.
CS—ceserean section
c.Trisomy 21 case (n = 1) was excluded, since these malformations are not clinically linked to seizures nor AEDs

https://doi.org/10.1371/journal.pone.0189497.t001

PLOS ONE | https://doi.org/10.1371/journal.pone.0189497 December 18, 2017 5 / 14

 Antiepileptic drug use among pregnancy Taiwanese women

Fig 1. AED monotherapy, polytherapy, and no prescription rates among TREP WWE pregnancies (n = 318).
https://doi.org/10.1371/journal.pone.0189497.g001

risen from 50% to 80%. Among all AEDs prescribed between 2004 and 2015 (n = 412), varia-
tions between 1st generation and 2nd generation AEDs were observed (Fig 2). In 2004, 73.3%
of AEDs prescribed were 1st generation AEDs, with the 1st generation AED rate steadily fall-
ing to 8.3% in 2015.
Next, we categorized pregnancies as either having experienced CS or having experienced a
vaginal delivery among those that had a live birth (n = 307) in Table 2. Maternal age above 35
years (X2 = 4.347, p = 0.046), seizure experienced throughout pregnancy (X2 = 4.977, p =
0.026), and obstetric complications (X2 = 5.738, p = 0.017), all had significantly higher CS rates
compared to the vaginal delivery groups.

Fig 2. AED prescription by year (2004–2015) and AED generation (1st vs. 2nd) (Total AEDs prescribed: n = 411).
https://doi.org/10.1371/journal.pone.0189497.g002

PLOS ONE | https://doi.org/10.1371/journal.pone.0189497 December 18, 2017 6 / 14

 Antiepileptic drug use among pregnancy Taiwanese women

Table 2. WWE related factors by delivery group (N = 307; aborted: n = 11 excluded).

Vaginal Delivery Cesarean Section
(VD) (C/S)
Variables Categories Count % Count % Chi-Square (X2) p-value Sig.
Maternal Age (years) 4.347 0.046 *
<35 120 90.2% 143 82.2%
35 13 9.8% 31 17.8%
Epilepsy Type 5.697 0.058
Generalized 69 51.9% 104 59.8%
Localization-related 51 38.3% 65 37.4%
Unknown or Not Ascertained 13 9.8% 5 2.9%
st
Seizure Events (1 Trimester) 4.915 0.086
No Seizures 82 61.7% 126 72.4%
<1 Seizure/month 31 23.3% 24 13.8%
>1 Seizure/month 20 15.0% 24 13.8%
Overall Seizures in Pregnancy 4.977 0.026 *
No 65 48.9% 101 58.0%
Yes 68 51.1% 73 42.0%
Exposure to AEDa polytherapy 0.198 0.657
No 96 72.2% 131 75.3%
Yes 37 27.8% 43 24.7%
Exposure to 1st Generation AED 1.13 0.288
No 77 53.1% 82 47.1%
Yes 68 46.9% 92 52.9%
Malformations 3.614 0.057
Normal 131 98.5% 164 94.3%
Abnormal 2 1.5% 10 5.7%
Maternal Complications 5.738 0.017 *
Present 131 98.5% 164 94.3%
Absent 2 1.5% 10 5.7%

Notes
a
AEDs—antiepileptic drug
*p = 0.05

https://doi.org/10.1371/journal.pone.0189497.t002

Factors associated with obstetric complications (Table 3) and fetal malformations among
live births (Table 4) were analyzed using a binary logistic regression. Obstetric complications
were confirmed to only be associated with CS outcome (OR = 5.11, CI 95% = 1.11–23.51,
p = 0.036). Malformations were found to be strongly associated with maternal complications
(OR = 20.46, CI 95% = 4.80–87.21, p<0.001). AED polytherapy and 1st generation exposure
were not found to be associated with either obstetric complications or fetal malformations.

Discussion
Our study included WWE pregnancies that had been prescribed AEDs prior to becoming
pregnant from 2004–2015 and recorded 318 WWE pregnancies. Improved seizure control is
the primary aim of AED prescription in pregnancy, we found relatively similar rates of seizure
control during the first trimester compared to the EURAP study [18]. Among all pregnancies,
95.7% had taken AEDs throughout their pregnancy term. From a study by Lin et al. [14] they
found that NHI data during 2001–2003 had 1182 women coded as epileptic and pregnant.

PLOS ONE | https://doi.org/10.1371/journal.pone.0189497 December 18, 2017 7 / 14

 Antiepileptic drug use among pregnancy Taiwanese women

Table 3. Associated factors with maternal complications of WWEa pregnancies, n = 318.

Variables Category Complications Complication rate aOR P-value
/N (%) (CI 95%)d,e
Maternal Age (years)
<35 12/273 4.4% 1.00 (Ref.)
35 2/45 4.4% 1.05 (0.21–5.34) 0.954
Overall Seizures in Pregnancy
No 9/167 5.4% 1.00 (Ref.)
Yes 5/151 3.3% 0.53 (0.15–1.81) 0.31
Exposure to AEDb polytherapy
No 9/236 3.8% 1.00 (Ref.)
Yes 5/82 6.1% 2.14 (0.60–7.70) 0.242
Exposure to 1st Generation AED
No 6/159 3.8% 1.00 (Ref.)
Yes 8/159 5.0% 1.16 (0.36–3.78) 0.805
CSc outcome (n = 307)
No 2/133 1.5% 1.00 (Ref.)
Yes 12/174 6.9% 5.01 (1.07–23.41) 0.04 *

Notes.
*p0.05
a.
WWE = women with epilepsy
b.
AED = antiepileptic drug
c.
CS = cesarean section
d.
aOR = adjusted Odds Ratio, CI 95% = confidence interval
e.
Variables controlled for in model: epilepsy type, parity

https://doi.org/10.1371/journal.pone.0189497.t003

Among them, only 165 (14%) had a record of AEDs prescription and it was estimated that
every year there are 83 pregnant women with epilepsy taking AEDs [14]. The annual pregnan-
cies in the TREP ranged between 15 and 47, which accounted for 18%~55% of the WWE preg-
nancies taking AEDs who were enrolled in this TREP registry. Furthermore, total fertility rate
in Taiwan remained at 1.0–1.1 recently and the total population is around 23 million [19]. Our
data were characterized by a low total fertility rate and high AEDs exposure during pregnancy
which was a reflection of real situation in Taiwan and thus provided an interesting look into a
sample with a high exposure to AED use in Taiwan.
Between 2004–2015, 1st generation AEDs were drastically reduced (from 73% to 8%). Start-
ing in 1997 until 2007 a gradual decrease of older AEDs prescriptions and increase in newer
generation AEDs had already been observed [5,20,21]. Newer AEDs have been reported to
have less side-effects and better tolerability and may be safer in fetal development [22,23].
Polytherapy had also decreased in prevalence during the same timeline (from 40% to 20%).
Evidence shows that taking multiple AEDs is associated with a higher risk of malformations
and pregnancy complications [7,24]. The reduction of polytherapy over the study period may
have been due to improved knowledge of polytherapy risk. In 2009, there was a deviation in
AED type prescription trend, with a large spike in polytherapy prescription (40.7%). In Tai-
wan, Chen et al. [13] and Lin et al. [14] both found AEDs to be safe, while those without AED
taken and had seizures saw a higher risk of malformations. We speculate that these papers may
have indicated a shift in clinical views and practices, and WWE may have been prescribed
higher rates of AEDs. It also possible due to the observational nature of this study, there may
have been fluctuations in the data in that year.

PLOS ONE | https://doi.org/10.1371/journal.pone.0189497 December 18, 2017 8 / 14

 Antiepileptic drug use among pregnancy Taiwanese women

Table 4. Associated factors with malformation rate among WWE pregnancies, n = 318.
Variables Category Malformation Malformation aORc,d (CI95%) P-value
/N Rate
Seizures in 1st Trimester
None 9/214 4.2% 1.00 (ref.)
<1/month 2/56 3.6% 0.62 (0.10–3.90) 0.61
1/month 4/48 9.1% 0.49 (0.50–4.89) 0.54
Exposure to AEDa polytherapy
No 10/236 4.2% 1.00 (ref.)
Yes 5/82 6.1% 0.92 (0.20–4.25) 0.915
Exposure to 1st Generation AED
No 5/159 3.1% 1.00 (ref.)
Yes 10/159 6.3% 2.08 (0.49–8.78) 0.319
Maternal Complications
No 10/304 3.3% 1.00 (ref.)
Yes 5/14 35.7% 20.64 (5.15–99.59) <0.001 ***
CSb outcome (n = 307)
No 2/133 1.5% 1.00 (ref.)
Yes 10/174 5.7% 2.34 (0.46–12.00) 0.309

Notes.
***p0.001
a. AED = Antiepileptic drug
b. CS = cesarean section
c. aOR = adjusted Odds Ratio, CI 95% = confidence interval
d. Variables controlled for in model: epilepsy type, parity

https://doi.org/10.1371/journal.pone.0189497.t004

Malformation rates were around the average compared with past studies [18,25]. The latest
data from EURAP saw a 5.1% malformation rate [18]. In utero malformation rates (5.0%) and
malformations among live births (3.9%) differed, indicating that cases that had performed
advanced screening for severe malformation had been aborted due to early presence of malfor-
mations. Among the most recent 588 EURAP cases with major malformations, 110 were
detected by ultrasound examination. Out of these 110, there were 51 with induced abortions,
four stillbirths, four perinatal deaths and 51 live births. Detection of malformations in our
sample were observed in 56% of advanced screenings accurately detecting the presence of mal-
formations in the TREP sample (S1 Table).Seizures during the first trimester have previously
been associated with malformations in fetal development, with women with untreated epilepsy
having a higher risk of giving birth to children with growth retardation and cognitive dysfunc-
tion [26], malformations and live birth rate [23]. Recent improvements in screening methods
have allowed obstetricians to detect early malformations and enhance ability to remedy abnor-
malities or providing mothers with more accurate information to make informed obstetrical
decisions [6].
Findings from the TREP sample indicated a higher rate of CS deliveries (54.5%) compared
to those in previous studies investigating pregnant WWE: 37.6% [2], 54.3% [5], and 19.8%
[10]. CS rates among the general population in Taiwan were also lower than in our study
(36.7%) [27]. Most women had never had a previous CS performed. Despite epilepsy not being
considered a risk of CS, unless occurring during delivery [3], doctors may have preemptively
selected to perform a CS delivery in order to avoid women experiencing seizures in delivery,
increasing the occurrence in our sample. Investigating CS we found that maternal age over 35

PLOS ONE | https://doi.org/10.1371/journal.pone.0189497 December 18, 2017 9 / 14

 Antiepileptic drug use among pregnancy Taiwanese women

years, generalized epilepsy and obstetric complications were all more likely to result in a CS
delivery. These findings are in accordance with clinical experience and past research, with age
[28] and obstetric complications [29], being more likely to lead to CS. Overall experience of at
least one epileptic seizure was correlated with higher rates of CS. Past research supports our
findings on seizure exposure and risks for pregnancy complications [3,24].
Obstetric complications were found to be significantly associated with CS rate. Complica-
tions ranged from early development in pregnancy (ie. Pregnancy induced hypertension) to
complications in delivery (ie. Epileptic seizures in delivery) (S2 Table). Obstetric complications
have been linked to higher chances of CS [29]. We speculate that since WWE also had an ad-
ditional complication during pregnancy, physicians may have taken greater precautions,
increasing the rate of CS among cases with obstetric complications. None of the TREP cases
that had suffered from a complication had resulted in an abortion. In a review by D’Alton
et al., improvements in fetal care were found to often be accompanied by improvements in
maternal healthcare access [30]. WWE pregnancies with complications in early terms would
potentially be more likely to attend to healthcare visits which may have prevented further neg-
ative effects on the fetal development.
The overall rate of polytherapy use in our cohort was similar to previous studies of AED use
in Taiwan (72% vs. 69%) [31]. In contrast to our findings, AED polytherapy and 1st generation
have previously been associated with malformations [7,24]. Despite our negative findings for
the number of AEDs, our study may have had sample size issues which may have underesti-
mated the effect. Fetal malformations were however highly associated with obstetric com-
plications. Obstetric complications were associated with higher CS rate, however the same
association between malformations and CS rate was not detected. Obstetric complication
seems to be the most important factor associated with both CS and malformations beyond the
effect of age, seizures and AEDs. Epilepsy and AEDs have both previously been found to be
risk factors for CS[2] and obstetric complications [8]. Women who had experienced a compli-
cation in their pregnancy or in the course of labor, are more likely to be candidates for CS
[32], thus potentially explaining the reason for our findings. Association between malforma-
tions and obstetric complications was unexpected, since obstetrical complications such as pre-
term premature rupture of membranes (PPROM) (S2 Table) are not usually associated with
malformations. Although recent findings in a large population data study in Sweden found
that pregnant WWE had a higher risk of adverse pregnancies or perinatal outcomes, while
AED use did not pose a risk, [9] the study pointed out that different AEDs had a range of tera-
togenic potential. Since we had a small sample size, we aren’t able to conclusively rule out the
effect of specific AEDs or seizures on malformations, and it’s possible that WWE complica-
tions were influenced by AEDs or seizures and this resulted in higher rate of malformations.
Yet it is an interesting finding which deserves further research to investigate the causal path-
way between seizures, AEDs, obstetric complications and malformations.
Our study had some limitations. First, registries are important tools in accumulating
detailed information especially for diseases with low incidence rates, however they often are
not representative of the general population. Our study was cross-sectional with a selected
sample of pregnant WWE who were taking AEDs previous to becoming pregnant and were
seeking healthcare from a neurologist. Due to selected nature of our sample, our results are not
generalizable to the overall population in Taiwan. However, since the occurrence of WWE is a
relatively low and those cases who use AEDs during pregnancy are even lower, a selected sam-
ple was necessary in order to collect sufficient data. Despite the limitation of bias in our sam-
ple, the sample still represents an interesting observation in WWE who had a high AED use
throughout pregnancy. Moreover, although including clustered pregnancies as independent
cases may pose a risk of biases, many pregnancies from the same mother differed on a number

PLOS ONE | https://doi.org/10.1371/journal.pone.0189497 December 18, 2017 10 / 14

 Antiepileptic drug use among pregnancy Taiwanese women

of factors (i.e. age, parity, AED profile, seizure frequency, pregnancy and birth outcomes, etc.)
and thus were treated as an independent units of analysis. Second, the TREP registry had accu-
mulated 349 pregnancies in 11 years. The reasons for a small registry number included: low
fertility rate, treatment gap of WWE during pregnancy, patient misunderstanding or conceal-
ment. [14,33,34]. Third, we only looked at women who had become pregnant. These women
would likely differ from WWE who chose not to become pregnant in the severity of epilepsy,
would self-select to avoid pregnancy, and may not represent the full spectrum of epilepsy risk.
Therefore the results should be generalized to the larger WWE population with caution.
Fourth, the questionnaires was self-administered, therefore responses may have been biased in
self-reporting for certain characteristics such as seizures experienced during pregnancy and
type of epilepsy. Due to patient’s potential gaps in knowledge, some questions may not have
been answered accurately.
Despite these limitations, our study provides an interesting look at the Taiwanese sample
that had a high rates of AED prescription. Results indicated 1st generation AEDs and polyther-
apy prescription gradually declining throughout the study period. CS was associated with
pregnancies that had suffered an obstetric complication. Despite having a high AED prescrip-
tion, malformation rates remained low and were not associated with typical AED risk factors.
Additionally, CS was associated with obstetric complications, and obstetric complications
were associated with malformations. Typical AED risk factors were not associated with higher
risks of malformations or complications. Further population level research is needed to
explore the links between seizures, AED, obstetric complications and birth outcomes.

Supporting information
S1 Fig. International European Registry of Antiepileptic Drugs and Pregnancy (EURAP)
questionnaire for pregnant women with epilepsy. In English.
(PDF)
S2 Fig. Taiwanese Registry of Epilepsy and Pregnancy (TREP) questionnaire for pregnant
women with epilepsy. Translated into Mandarin from the EURAP questionnaire (see S1 Fig).
(PDF)
S1 Table. Fetal malformation listed by cases (N = 16). Notes. a MCM = major congenital
malformation, b PDA = Patent Ductus Arteriosus, c DORV = Double outlet right ventricle. d.
Live Birth: Y = live birth, N = still birth, a = aborted. e. Ultrasound Screening Performed: Y = Yes,
N = No, n/a = not available. f. Positive Findings: 5/9 = 55.6% accuracy. g. Means reported for live
births only.  ,  ,  , †, ‡, indicate concurrent maternal complications (S2 Table).
(PDF)
S2 Table. Obstetric complications listed by cases (N = 14). Notes. a. CS = Cesarean section, b.
PPROM = Preterm premature rupture of the membranes, c. n/a = not applicable. d.Live Birth:
Y = live birth, N = still birth, a = aborted. e. CS rate 11/14 = 78.5%.  ,  ,  , †, ‡, indicate con-
current fetal malformations (Table 2).
(PDF)

Acknowledgments
We would like to acknowledge Dr. Lai Chi-Wan’s contributions in establishing the TREP reg-
istry in Taiwan. In addition, we would like to thank Dr. Lai for providing invaluable feedback
which helped to improve the quality of our submission.

PLOS ONE | https://doi.org/10.1371/journal.pone.0189497 December 18, 2017 11 / 14

 Antiepileptic drug use among pregnancy Taiwanese women

Author Contributions
Conceptualization: Chang Ching Yeh, Eric C. Lussier, Yi-Ting Sun, Tzuo-Yun Lan, Tung-
Yao Chang.
Data curation: Chang Ching Yeh, Eric C. Lussier, Yi-Ting Sun, Hsiang-Yu Yu, Tung-Yao
Chang.
Formal analysis: Eric C. Lussier.
Investigation: Chang Ching Yeh, Eric C. Lussier, Yi-Ting Sun, Tzuo-Yun Lan, Hsiang-Yu Yu,
Tung-Yao Chang.
Methodology: Chang Ching Yeh, Eric C. Lussier, Yi-Ting Sun, Tzuo-Yun Lan, Hsiang-Yu Yu,
Tung-Yao Chang.
Project administration: Chang Ching Yeh, Eric C. Lussier, Yi-Ting Sun, Tung-Yao Chang.
Resources: Chang Ching Yeh, Eric C. Lussier, Yi-Ting Sun, Tung-Yao Chang.
Software: Eric C. Lussier, Tung-Yao Chang.
Supervision: Chang Ching Yeh, Tzuo-Yun Lan, Hsiang-Yu Yu, Tung-Yao Chang.
Validation: Chang Ching Yeh, Eric C. Lussier, Yi-Ting Sun, Tzuo-Yun Lan, Hsiang-Yu Yu,
Tung-Yao Chang.
Visualization: Eric C. Lussier, Yi-Ting Sun.
Writing – original draft: Eric C. Lussier.
Writing – review & editing: Chang Ching Yeh, Eric C. Lussier, Tzuo-Yun Lan, Hsiang-Yu
Yu, Tung-Yao Chang.

References
1. De Boer HM, Mula M, Sander JW (2008) The global burden and stigma of epilepsy. Epilepsy Behav 12:
540–546. https://doi.org/10.1016/j.yebeh.2007.12.019 PMID: 18280210
2. Borthen I, Eide M, Daltveit A, Gilhus N (2011) Obstetric outcome in women with epilepsy: a hospital-
based, retrospective study. BJOG 118: 956–965. https://doi.org/10.1111/j.1471-0528.2011.03004.x
PMID: 21557799
3. Sveberg L, Svalheim S, Taubøll E (2015) The impact of seizures on pregnancy and delivery. Seizure
28: 35–38. https://doi.org/10.1016/j.seizure.2015.02.020 PMID: 25746572
4. Jadhav SV, Jadhav VK (2013) Comparative Study of Obstetric Outcome in Epileptic and Non-epileptic
Pregnant Women. Ind Med Gaz: 352–355.
5. Bobo WV, Davis RL, Toh S, Li DK, Andrade SE, et al. (2012) Trends in the use of antiepileptic drugs
among pregnant women in the US, 2001–2007: a medication exposure in pregnancy risk evaluation
program study. Paediatr Perinat Ep 26: 578–588.
6. Kaplan PW, Norwitz ER, Ben-Menachem E, Pennell PB, Druzin M, et al. (2007) Obstetric risks for
women with epilepsy during pregnancy. Epilepsy Behav 11: 283–291. https://doi.org/10.1016/j.yebeh.
2007.08.012 PMID: 17996636
7. Kinney MO, Morrow J (2016) Epilepsy in pregnancy. BMJ 353.
8. Patel SI, Pennell PB (2016) Management of epilepsy during pregnancy: an update. Ther Adv Neurol
Disord 9: 118–129. https://doi.org/10.1177/1756285615623934 PMID: 27006699
9. Razaz N, Tomson T, Wikström A-K, Cnattingius S (2017) Association Between Pregnancy and Perina-
tal Outcomes Among Women With Epilepsy. JAMA Neurol 74: 983–991. https://doi.org/10.1001/
jamaneurol.2017.1310 PMID: 28672292
10. Viale L, Allotey J, Cheong-See F, Arroyo-Manzano D, Mccorry D, et al. (2015) Epilepsy in pregnancy
and reproductive outcomes: a systematic review and meta-analysis. Lancet 386: 1845–1852. https://
doi.org/10.1016/S0140-6736(15)00045-8 PMID: 26318519

PLOS ONE | https://doi.org/10.1371/journal.pone.0189497 December 18, 2017 12 / 14

 Antiepileptic drug use among pregnancy Taiwanese women

11. Meador K, Reynolds MW, Crean S, Fahrbach K, Probst C (2008) Pregnancy outcomes in women with
epilepsy: a systematic review and meta-analysis of published pregnancy registries and cohorts. Epi-
lepsy Res 81: 1–13. https://doi.org/10.1016/j.eplepsyres.2008.04.022 PMID: 18565732
12. Tomson T, Battino D, Craig J, Hernandez-Diaz S, Holmes LB, et al. (2010) Pregnancy registries: differ-
ences, similarities, and possible harmonization. Epilepsia 51: 909–915. https://doi.org/10.1111/j.1528-
1167.2010.02525.x PMID: 20196792
13. Chen Y-H, Chiou H-Y, Lin H-C, Lin H-L (2009) Affect of seizures during gestation on pregnancy out-
comes in women with epilepsy. Arch Neurol—Chicago 66: 979–984. https://doi.org/10.1001/
archneurol.2009.142 PMID: 19667219
14. Lin H-L, Chen Y-H, Lin H-C, Lin H-C (2009) No increase in adverse pregnancy outcomes for women
receiving antiepileptic drugs. Neurology 256: 1742–1749.
15. Tomson T, Battino D, Bonizzoni E, Craig J, Lindhout D, et al. (2004) EURAP: an international registry of
antiepileptic drugs and pregnancy. Epilepsia 45: 1463–1464. https://doi.org/10.1111/j.0013-9580.
2004.451101.x PMID: 15509250
16. Chang T-Y, Lai C-W, Yu H-Y, Hsu J-J, Shih Y-H, et al. (2007) Preliminary descriptive statistics of the
Taiwanese registry of epilepsy and pregnancy for the first 2 years. TJOG 46: 47–49.
17. Perucca E (2005) An introduction to antiepileptic drugs. Epilepsia 46: 31–37.
18. Battino D, Tomson T, Bonizzoni E, Craig J, Lindhout D, et al. (2013) Seizure control and treatment
changes in pregnancy: observations from the EURAP epilepsy pregnancy registry. Epilepsia 54: 1621–
1627. https://doi.org/10.1111/epi.12302 PMID: 23848605
19. Lee M-L (2010) Transition to below replacement fertility and policy response in Taiwan. Jpn J Popul 9:
1–43.
20. Nicholas JM, Ridsdale L, Richardson MP, Ashworth M, Gulliford MC (2012) Trends in antiepileptic drug
utilisation in UK primary care 1993–2008: cohort study using the General Practice Research Database.
Seizure 21: 466–470. https://doi.org/10.1016/j.seizure.2012.04.014 PMID: 22608976
21. Hsieh L-P, Huang C-Y (2011) Trends in the use of antiepileptic drugs in Taiwan from 2003 to 2007: a
population-based national health insurance study. Epilepsy Res 96: 81–88. https://doi.org/10.1016/j.
eplepsyres.2011.05.003 PMID: 21632214
22. Hernandez-Diaz S, Smith C, Shen A, Mittendorf R, Hauser W, et al. (2012) Comparative safety of anti-
epileptic drugs during pregnancy. Neurology 78: 1692–1699. https://doi.org/10.1212/WNL.
0b013e3182574f39 PMID: 22551726
23. Cassina M, Dilaghi A, Di Gianantonio E, Cesari E, De Santis M, et al. (2013) Pregnancy outcome in
women exposed to antiepileptic drugs: teratogenic role of maternal epilepsy and its pharmacologic
treatment. Reprod Toxicol 39: 50–57. https://doi.org/10.1016/j.reprotox.2013.04.002 PMID: 23591043
24. Thomas SV, Syam U, Devi JS (2012) Predictors of seizures during pregnancy in women with epilepsy.
Epilepsia 53: e85–e88. https://doi.org/10.1111/j.1528-1167.2012.03439.x PMID: 22429269
25. Tomson T, Battino D, Bonizzoni E, Craig J, Lindhout D, et al. (2011) Dose-dependent risk of malforma-
tions with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry. Lan-
cet Neurol 10: 609–617. https://doi.org/10.1016/S1474-4422(11)70107-7 PMID: 21652013
26. Bansal R, Jain G, Kharbanda P, Goyal M, Suri V (2016) Maternal and neonatal complications during
pregnancy in women with epilepsy. IJEP 3: 80–85.
27. Liu C-M, Lin Y-J, Su Y-Y, Chang S-D, Cheng P-J (2013) Impact of health policy based on the self-man-
agement program on Cesarean section rate at a tertiary hospital in Taiwan. J Formos Med Assoc 112:
93–98. https://doi.org/10.1016/j.jfma.2011.12.005 PMID: 23380611
28. Ecker JL, Chen KT, Cohen AP, Riley LE, Lieberman ES (2001) Increased risk of cesarean delivery with
advancing maternal age: indications and associated factors in nulliparous women. Am J Obstet Gynecol
185: 883–887. https://doi.org/10.1067/mob.2001.117364 PMID: 11641671
29. MacDonald SC, Bateman BT, McElrath TF, Hernández-Dı́az S (2015) Mortality and morbidity during
delivery hospitalization among pregnant women with epilepsy in the United States. JAMA Neurol 72:
981–988. https://doi.org/10.1001/jamaneurol.2015.1017 PMID: 26147878
30. D’Alton ME, Bonanno CA, Berkowitz RL, Brown HL, Copel JA, et al. (2013) Putting the “M” back in
maternal–fetal medicine. Am J Obstet Gynecol 208: 442–448. https://doi.org/10.1016/j.ajog.2012.11.
041 PMID: 23211544
31. Hsieh L-P, Huang C-Y (2008) Prevalence of treated epilepsy in western medicine among the adult pop-
ulation in Taiwan: a study conducted using antiepileptic drug prescription data. Epilepsy Res 80: 114–
118. https://doi.org/10.1016/j.eplepsyres.2008.03.016 PMID: 18541408
32. Nisenblat V, Barak S, Griness OB, Degani S, Ohel G, et al. (2006) Maternal complications associated
with multiple cesarean deliveries. Am J Obstet Gynecol 108: 21–26.

PLOS ONE | https://doi.org/10.1371/journal.pone.0189497 December 18, 2017 13 / 14

 Antiepileptic drug use among pregnancy Taiwanese women

33. Chung MY, Chang Yc, Lai YHC, Lai CW (1995) Survey of public awareness, understanding, and atti-
tudes toward epilepsy in Taiwan. Epilepsia 36: 488–493. PMID: 7614927
34. WHO (2015) 2015 World Population Data Sheet. Population Reference Bureau.

PLOS ONE | https://doi.org/10.1371/journal.pone.0189497 December 18, 2017 14 / 14