Epilepsy Research 159 (2020) 106259

Contents lists available at ScienceDirect

Epilepsy Research
journal homepage: www.elsevier.com/locate/epilepsyres

Antiseizure drugs use during pregnancy and congenital malformations: A T

retrospective review from the United Arab Emirates
Taoufik Alsaadia, Seada Kassiea,*, Fathima Farookb, Wassim Nasreddinec, Saleema Wanib,
Bashir Salehb
a
Department of Neurology, American Center for Psychiatry and Neurology, Abu Dhabi, United Arab Emirates
b
Department of Obstetric Medicine, Corniche Hospital, Abu Dhabi, United Arab Emirates
c
Department of Neurology, American University of Beirut, Beirut, Lebanon

A R T I C LE I N FO A B S T R A C T

Keywords: Objective: To observe the incidence of congenital malformations occurring in foetuses exposed to antiseizure
Congenital malformations drugs (ASDs) during the first trimester and to identify individual drug associations in a population cohort from
Women with epilepsy the United Arab Emirates (UAE).
Consanguinity Methods: Pregnancy outcomes were observed and reported from women with epilepsy (WWE), attending the
Antiseizure drugs use during pregnancy
Obstetric Medicine Neurology Clinic at Corniche Hospital in Abu Dhabi, United Arab Emirates (UAE) from
United Arab Emirates
February 2008 to December 2015.
Results: Outcome data were available for 179 pregnancies in 112 WWE. There were 139 pregnancies who re-
ceived ASD treatment during the first trimester, of these 124 were on monotherapy. Thirteen (7.26 %) congenital
malformations (CMs) were observed in this cohort, seven were major ones and six were minor. Thirteen of the
CMs were from the group with ASDs while one had no ASD-exposure. From the ASD-group, we identified 32
(23.0 %) with poor pregnancy outcomes, including 13 (9.3 %) with CMs and 19 (13.7 %) miscarriages. These
figures were significantly higher than that of the no ASD-exposure group (7.9 %) (p = 0.04, Fisher test). The
most commonly used ASDs in monotherapy were levetiracetam (25.6 %), carbamazepine (16.2 %), valproate
(13.4 %), and lamotrigine (7.3 %). There were 57 (31.8 %) consanguineous marriages in this cohort; there was
no statistically significant difference in the CM rate within the consanguineous group between those with and
without exposure to ASD.
Conclusion: This study was the first to report pregnancy outcomes in a WWE cohort from the Middle East and
North Africa (MENA) region. It is the first step towards establishing a national / regional pregnancy registry to
create a database on ASD use and pregnancy outcomes among the WWE.

1. Introduction topiramate (TPM) increase chances of congenital malformations in

With around 50 million individuals affected globally, epilepsy is the
most common neurological disorder among women of childbearing age,
at 0.3 – 0.7 % prevalence rate during pregnancy (World Health
Organization, 2012; Borthen et al., 2009; Brosh et al., 2011). Pregnancy
among women with epilepsy (WWE) is complicated by the use of an-
tiseizure drugs (ASDs) during the first trimester. Studies have shown
that the teratogenicity of ASDs, as opposed to the underlying disorder
itself, plays a bigger role in the aetiology of congenital malformations
(CMs), both major and minor (Artama et al., 2005; Kulaga et al., 2011;
Veroniki et al., 2017). An increasing number of studies show that the
use of valproic acid (VPA), carbamazepine (CBZ), phenytoin (PHT), and
foetuses (Lammer et al., 1987; Matalon et al., 2002; Holmes et al., 2008;
Wide et al., 2004; Morrow et al., 2006; Vajda et al., 2016). On the other
hand, recent findings have shown that the newer generation ASDs, le-
vetiracetam (LEV) and lamotrigine (LTG), especially when used in
monotherapy, had significantly reduced teratogenic rates (Veroniki
et al., 2017; Vajda et al., 2016; Mawhinney et al., 2013).
The outcomes of pregnancies among WWE in national / interna-
tional registries and the documentation of ASD use during pregnancy as
well as the occurrence of congenital malformations is essential for en-
hancing evidence-based clinical practice and improving the overall
health-related quality of life for WWE / their offspring. Internationally,
pregnancy registries for epilepsy have been operational for more than

⁎
Corresponding author at: P.O. Box – 108699, Abu Dhabi, United Arab Emirates.
E-mail address: research.officer@americancenteruae.com (S. Kassie).

https://doi.org/10.1016/j.eplepsyres.2019.106259
Received 1 October 2019; Received in revised form 21 November 2019; Accepted 20 December 2019
Available online 20 December 2019
0920-1211/ © 2019 Published by Elsevier B.V.
T. Alsaadi, et al.
20 years, including the three major registries in the Western world: the
UK Epilepsy and Pregnancy Registry, the North American AED
Pregnancy Registry (NAAPR), and the European and International
Registry of Antiepileptic Drugs in Pregnancy (EURAP). However, there
is no regional database available for comparison in the Middle East and
North Africa (MENA) region. This study is the first step towards for-
mulating such a regional registry. The aim was to report pregnancy
outcomes and the incidence of major and minor CMs, occurring in
foetuses exposed to ASDs during the first trimester, and to identify in-
dividual drug associations.
2. Methodology
2.1. Subjects
This was a retrospective review of pregnancy outcomes in women
with epilepsy who attended the Obstetric Medicine Neurology Clinic at
Corniche Hospital in Abu Dhabi, United Arab Emirates (UAE) from
February 2008 to August 2015. Corniche Hospital is a major maternity
hospital with 8000 deliveries per year. In February 2008, Obstetric
Medicine Neurology Clinic was established in Corniche Hospital to
provide multidisciplinary care for patients with Epilepsy. The clinic is
managed by a Consultant Neurologist, Consultant Obstetrician and
Consultant Obstetric Medicine Physician.
2.2. Data collection
Pregnant women with a confirmed diagnosis of epilepsy were in-
cluded in the study. Demographic variables were collected for all WWE
which included age, ethnicity, epilepsy syndrome and parity. ASD ex-
posure, its type before conception and during the first trimester, and the
use of folic acid before and during pregnancy were also collected.
Consanguinity status was recorded. Patients who were not taking ASDs
during the first trimester of pregnancy were analyzed separately and
considered to be in the no-ASD (during pregnancy) group. Fig. 1 shows
a flow-chart of the studied population and the retrospective recruitment
process.
2.3. Procedure
As per the clinical protocol, information about the epilepsy syn-
drome and seizure frequency was recorded at each clinic visit. The
Fig. 1. Flow-chart of the studied population and pregnancy outcomes.
2
Epilepsy Research 159 (2020) 106259
underlying epilepsy syndrome was identified and recorded following
the 2010 ILAE classification and organization of seizures and epilepsies
(International League Against Epilepsy, 2019). The treating neurologist
routinely reviewed each patient chart including the underlying seizure
types, and additional diagnostic testing was carried out before the un-
derlying epilepsy syndrome was recorded. Patients were seen at a two-
month interval as per the clinical protocol, or sooner, if deemed ne-
cessary by the team. ASD exposure pre- pregnancy and at conception
until registered at the clinic was recorded. Information about pre-con-
ception folic acid use and alterations made to ASDs during pregnancy
were collected. Foetal anomaly scans were requested from all patients.
Pregnancy outcomes in the form of miscarriage, live birth and still birth
were documented. All neonates were examined by a neonatologist at
birth for malformations. Pregnancy outcome was stratified as live birth,
miscarriage, and the presence of CM as documented by a neonatologist
who examined all new-borns. For each new-born, the birth gestation
and weight as well as the mode of delivery were documented. This
series followed the EUROCAT instruction for the registration of con-
genital anomalies (EUROCAT, 2013).
2.4. Analysis
Demographic characteristics of patients were compared between
WWE on ASDs and those in the no-ASD group. In addition, the occur-
rence of congenital malformations was tabulated and compared be-
tween those on ASDs and the non-exposed group. Finally, the frequency
of congenital malformations was calculated for specific ASDs on
monotherapy. For continuous variables, descriptive statistics including
mean and standard deviation were calculated while for categorical
variables frequencies and confidence intervals were used. Statistical
analysis was performed using chi-square test for categorical variables
and the student t-test for continuous variables. Significant p-values
were set at < 0.05.
3. Results
During the period of 2008 and 2015, a total of 179 pregnancies
among 112 WWE were included in this study, with mean age at con-
ception of 29.4 years (SD = 5.21). One-hundred-thirty-nine were on
ASD treatment with mean age at conception of 29.4 years (SD = 5.13):
124 were receiving monotherapy treatment with mean age of 29.4
years (SD = 5.22) at conception, 13 on dual therapy with mean age at
conception of 29.1 years (SD = 4.7) and two on polytherapy (three
ASDs, specifically) with mean age of 29.0 years (SD = 4.24) at con-
ception. A sub-group of 40 WWE were not receiving ASD treatment
with mean age of 29.55 years (SD = 5.57) at conception. This cohort
included a diverse group of WWE from the UAE (61.5 %) and from
around the Middle East and North Africa region (14.7 %) which in-
cluded Algeria, Egypt, Jordan, Lebanon, Morocco, Palestine, Somalia,
Sudan, and Syria, as well as from India (16.5 %), Pakistan (4.6 %), the
United Kingdom (1.8 %), and Bangladesh (0.9 %). Other demographic
and clinical details are displayed in Table 1.
3.1. Consanguinity rate
Consanguinity status was recorded in 57 (31.8 %) marriages in this
WWE cohort. The difference in malformation rates between those with
ASD treatment (33.81 %) and those without (25.0 %) within the con-
sanguineous group did not reach statistical significance (P = 0.3).
Consanguinity was not significantly associated with the presence of
abnormal pregnancy outcome, albeit the consanguineous group had a
higher rate of malformations and miscarriage occurrence (23.2 %)
when compared with the non-consanguineous (18.3 %), p = 0.44).
T. Alsaadi, et al. Epilepsy Research 159 (2020) 106259

Table 1 Types of CMs and their frequency are detailed in Tables 2 and 3
Demographic and clinical details of WWE. along with Folic Acid (FA) use, consanguinity status and ASD-types. A
N = 112 total of 112 (62.6 %) WWE were taking FA at the time of conception, of
which, 96 (85.7 %) were from the ASD-group. There was a significant
Demographics association between FA use and normal pregnancy outcomes (P = .005,
Age, Mean Years ± SD 29.37 ± 5.2 Fisher’s Exact Test).
Marital status, n (%)
Married 112 (100)
Of the 139 WWE in the ASD group, 124 (89.2 %) were receiving
Ethnicity, n (%) monotherapy, while 13 (9.3 %) were on dual therapy, and two (1.4 %)
Arab 86 (76.8) on polytherapy. The most commonly used ASDs in monotherapy were
Non-Arab 26 (23.1) LEV (25.6 %), CBZ (16.2 %), VPA (13.4 %), and LTG (7.3 %). ASD types
Clinical Features
used in pregnancies that ended with abnormal outcomes are mentioned
Epilepsy type, n (%) N = 112
Generalized 68 (60.4) in Tables 2 and 3.
Focal 29 (25.9)
Unspecified 15 (13.7) 3.4. Abnormal pregnancy outcome
Parity N = 179
0 37 (10.9)
1 45 (13.3) In WWE on ASDs, 32 (23.0 %) pregnancies had an outcome of CMs
2 40 (11.8) 13 (9.3 %) and miscarriage 19 (13.7 %). This frequency was sig-
>3 57 (64.0) nificantly higher than that of WWE on no ASDs (7.9 %) (p = 0.04,
Mode of delivery, n (%) N = 155
Fisher test). There was only one major malformation reported in the no-
Spontaneous vaginal delivery 100 (55.9)
Lower segment cesarean section 55 (30.7)
ASD group, compared to the monotherapy group which had a relatively
high rate of abnormal pregnancy outcomes, at 21.2 %. The numbers for
the groups on dual and polytherapy were too small to run comparative
3.2. Pregnancy outcome analysis. Frequencies of abnormal pregnancy outcomes according to the
number of ASDs is summarized in Table 4. When the outcomes were
Of the 179 pregnancies, 100 (55.9 %) were by spontaneous vaginal stratified by the types of ASDs for the monotherapy group, those on
delivery and 55 (30.7 %) by C-section. Twenty-one pregnancies (11.7 VPA had the highest number of major CMs at 8.3 %. Those on CBZ had
%) ended in miscarriage, while one couple terminated their pregnancy the highest minor CMS at 10.3 %. Further details on outcomes stratified
and two lost follow-ups with the hospital. For the remaining analysis, by specific ASDs for the monotherapy group is summarized in Table 5.
the terminated pregnancy and the two who lost to follow up were ex- We could not do the same for the other two groups due to their smaller
cluded from further results. sample size.
Miscarriage occurred in 19 of the WWE (13.7 %) on ASDs versus
two (5 %) in the no-ASD group (P = 0.25, fisher test). In pregnancies 4. Discussion
which did not end in miscarriage or termination, 73/119 (61.3 %) of
WWE exposed to ASDs during the first trimester were delivered through This retrospective review was the first of its kind from the MENA
a spontaneous vaginal delivery compared to 27/36 (75 %) of those who region, reporting the use of ASDs by WWE during pregnancy. In this
were not exposed, and the difference was not statistically significant series, LEV, LTG, CBZ, and VPA were the most commonly prescribed
(P = 0.13). ASDs in monotherapy use. Significantly higher rates of abnormal
One-hundred-fifty (96.8 %) of the 155 livebirths were delivered at pregnancy outcome were reported in the ASD-group versus the non-
term. Term delivery occurred in 115/119 WWE (96.6 %) on ASDs ASD group, although differences in CM rates alone between the two
compared to 35/36 (97.2 %) in those on no ASDs, which was not a groups did not reach statistical significance. These results are in partial
statistically significant difference (P = 0.3). Four WWE (3.3 %) on ASDs agreement with previously reported findings (Kulaga et al., 2011;
delivered between 24–33 weeks gestation while only one WWE (2.8 %) Borthen et al., 2010; Kilic et al., 2014).
in the no ASD group delivered at 26 weeks gestation. One intrauterine Consanguinity rate in this cohort was relatively high at 31.8 %,
foetal death from the ASD-group was reported at 34 weeks due to while the difference in abnormal pregnancy outcomes between the
abruption secondary to severe pre-eclampsia. consanguineous and non-consanguineous group was not significant. It
is highly probable that the non-significant results are due to limited
3.3. Congenital malformations power of the sample, seeing the clinical significance of one in three
WWE in the ASD group having abnormal pregnancy outcomes. In a
Thirteen (7.26 %) pregnancies ended with CMs, seven (4.5 %) were sample from the general population, a cohort study from Iran reported a
major and six (3.4 %) minor; twelve were from the group with ASDs 25 % consanguinity rate and significant association between con-
while one was from the no ASD-group. When pregnancies that ended in sanguineous marriages and congenital anomalies (Tayebi et al., 2010).
miscarriage were excluded, these translated to a frequency of 10.9 % in A review of the reproductive consequences of consanguinity (Oniya
WWE on ASDs (13/119) compared to 2.8 % (1/36) in the no-ASD et al., 2019) indicates that consanguinity is practiced by nearly 80.6 %
group, a difference that was not statistically significant (P = 0.2, Fisher of the population in certain provinces of the Middle East, and con-
Exact Test). genital anomalies are consistently reported to be higher in

Table 2
Types of minor congenital malformations and patient-specific associations.
CM Category ASD-exposure ASD-Type Consanguinity status FA use Count

Two-vessel cord Yes CBZ Yes Yes 1

Foetal hydrops + Micrognathism Yes LTG Yes Yes 1
Umbilical hernia Yes CBZ Yes Yes 1
Mild hydronephrosis Yes CBZ No No 1
Bilateral inguinal hernia Yes VPA+LEV No Yes 1
Spina bifida occulta Yes CBZ+VPA+TPM Yes Yes 1

3
T. Alsaadi, et al. Epilepsy Research 159 (2020) 106259

Table 3
Types of major congenital malformations and patient-specific associations.
CM Category ASD-exposure ASD-type Consanguinity status FA use Count

Pulmonary Stenosis Yes LEV No No 1

Atrial septal defect Yes VPA Yes No 1
Cleft lip Yes TPM Yes No 1
Small atrial septal defect, ventricular septal defect/patent ductus arteriosus, patent foramen ovale Yes VPA No Yes 1
Bilateral talipes equinovarus + multiple long bone fractures Yes CBZ Yes Yes 1
Holoprosencephaly + bilateral cleft lip and palate Yes CBZ+LTG No Yes 1
Coronary heart disease – Partial atrioventricular septal defect, small ventricular septal defect, large atrial No N/A Yes No 1
septal defect

consanguineous marriages (4.5 %) than the general population (1 %).
More studies are needed to further investigate the association between
consanguinity and congenital anomalies particularly among the WWE
population.
FA use during the first trimester was significantly associated with
pregnancy outcomes, indicating there were more counts of healthy
pregnancy outcomes in the FA-group than in the group without. Even
though our results on FA-use do not correlate with recent findings
(Mawhinney et al., 2013; Ban et al., 2015) which found no significant
association between FA-use and reduced risk of CMs, it is promising to
learn that the level and quality of care offered to WWE in this region
closely follows standard international guidelines which highlight the
importance of high dose folic acid throughout the whole periconcep-
tional period.
Findings from the EURAP registry estimate ASD use in monotherapy
varying between 3.5 % and 75 % across various countries worldwide
(Kulaga et al., 2011; Tomson et al., 2018). The high rate of ASD use in
monotherapy within this cohort (89.2 %) indicates that clinicians in the
MENA region recognize the importance of controlling symptoms of
epilepsy and minimizing risks of abnormal pregnancy outcomes in
WWE during their reproductive years. The need to minimize CM risk in
foetuses should not preclude the importance of controlling seizures
fully in WWE. The high percentage of WWE who received anti-seizure
drugs is a probable indication of the severity of their condition, ne-
cessitating treatment throughout pregnancy, and that could have po-
tentially confounded the high rate of abnormal pregnancy outcomes
within this group. However, as a general guideline, the neurologists
who consulted the WWE in this cohort had routinely advised these
patients to continue on ASD treatment regardless of their condition
such as pregnancy, so the group who opted out of ASD treatment during
pregnancy did so out of personal preference.
With just an 8.4 % rate, there is also a considerable decline in the
prescription of dual and polytherapy due to the increased awareness
that monotherapy, especially in the first trimester of pregnancy, is the
safest mode of treatment for both the mother and her offspring. This is
in line with the recommendations provided by several diagnostic and
care management facilities (NICE Guidance, 2012; SIGN Guidance,
2015; Epilepsy in Pregnancy, 2016; Leach et al., 2017).
Levetiracetam was the most commonly used ASD in monotherapy,
accounting for just one major congenital malformation (MCM) in
monotherapy and another one in dual therapy use. These results cor-
relate with previous reports of reduced associated risk of MCMs in LEV
monotherapy (Vajda et al., 2016; Mawhinney et al., 2013; Hernandez-
Diaz et al., 2012; Montouris et al., 2010). We could not reach a similar
conclusion for LEV use in dual and polytherapy due to insufficient
number of registered cases that allow for meaningful statistical power.
The same can be said for the use of LTG in both mono and polytherapy
due to the small number of cases enrolled, despite previous findings
showing low risk of MCMs associated with its use (Morrow et al., 2006;
Holmes et al., 2011). Similarly, there are reports of topiramate use and
its increased risk of abnormal pregnancy outcomes (Vajda et al., 2016;
Keni et al., 2018), particularly when used in polytherapy, but we could
not corroborate such findings due to the small number of cases in this
series.
The relatively higher rate of VPA used in this cohort is a cause for
concern and needs to be addressed. Its use in monotherapy was 13.4 %,
a considerably high rate given its extensively reported dose-dependent
teratogenicity (Keni et al., 2018; European Medicines Agency, 2014;
Pennell, 2008; Vajda, 2010; Mawer et al., 2010; Tomson et al., 2015).
Four (2.9 %) of the 14 reported CMs in this cohort, two minor and two
major, were accounted for by VPA use at an average dose of 787.5
(+351) in monotherapy. Nevertheless, this high rate of use could be
related to the underlying epilepsy syndrome; it is established that VPA
is the first drug of choice in patients with generalized and unclassified
epilepsies (Marson et al., 2007). Recent findings indicate that VPA,
CBZ, and PB are dose-dependent teratogens and the prevalence of CMs
significantly increased for all doses of VPA and CBZ as well as for PB at
doses of more than 80 mg / day than for LTG at doses of 325 mg/day or
less (Tomson et al., 2018). Data collection for this series ended in 2015,
and we speculate that the use of VPA among pregnant WWE would have
since been significantly reduced.
4.1. Limitations
As a retrospective review, the study did not have a specific protocol,
and as such did not go through ethical review and approval process.
Nevertheless, the care and treatment provided to the WWE in this co-
hort followed strict clinical protocols to ensure patient safety, response,
and tolerability to ASD-treatment throughout their gestation period.
The number of WWE in the dual or polytherapy group was insufficient
to provide statistical power needed for robust interpretation of the re-
sults. As a result, generalizability of the findings, particularly the ones
related to specific ASD combinations and their dose-related effect in
dual and polytherapy, is limited and should further be analysed by
future researchers. Serum level of ASDs was also not routinely recorded,
lending to a considerable limitation of the study since actual rates of

Table 4
Frequency of pregnancy outcomes stratified by number of ASDs with 95 % confidence intervals.
Number of ASDs N Normal outcome (%) Major Malformations (%) Minor Malformations (%) Miscarriage (%)

0 38 92.1 (79.2–97.3) 2.6 (0.5–13.5) 0 5.3 % (1.5 %–17.3 %)

1 123 78.9 (70.8–85.1) 4.1 (1.7–9.2) 3.3 (1.3–8.1) 13.8 (8.8–21)
2 13 69.2 (42.4–87.3) 7.7 (1.4–33.3) 7.7 (1.4–33.3) 15.4 (4.3–42.2)
3 2 50.0 (9.5–90.5) 0 50.0 (9.5–90.5) 0
Total 176 142 7 6 21

4
T. Alsaadi, et al.
Table 5
Frequency of pregnancy outcomes stratified by type of ASDs in monotherapy with 95 % confidence intervals.
Name of ASD N Dose (Mean ± SD) Normal outcome (%)
CBZ 29 424.1 ± 172.5 65.5 (47.3–80.1)
LTG 13 287 ± 157.7 84.6 (57.8–95.7)
LEV 46 1694.4 ± 686.1 80.4 (66.8–89.3)
VPA 24 787.5 ± 351 87.5 (69.0–95.7)
adherence to prescribed ASDs cannot be entirely confirmed. Non-ad-
herence to ASDs in patients with epilepsy ranges between 30–50 %, and
it is likely that maternal recall bias is a limitation of this study.
Neonates were only examined at birth for CMs and the study design did
not include a post-partum follow-up period, limiting our ability to re-
port certain malformations which can only be detected at a much later
period after birth.
4.2. Conclusion
This study paves the way to establishing the first national / regional
registry for epilepsy in the Middle East and North Africa Region. We
have prospectively observed and reported pregnancy outcomes where
ASDs were used, primarily in monotherapy. Following the 2020 vision
template for optimal management of epilepsy in pregnancy (Epilepsy in
Pregnancy, 2016), the results of this study might encourage health-care
practitioners and policy makers in the MENA region to establish a na-
tional / regional registry and create a database on ASD use and preg-
nancy outcomes, reduce epilepsy-related risks to mothers and their
offspring, and minimize the unnecessary use of VPA during pregnancy.
Study funding
The study did not receive funding from any source.
Declaration of Competing Interest
The authors report no disclosures relevant to the manuscript and
declare there was no conflict of interest involved in the running and
completion of the manuscript.
Appendix A. Supplementary data
Supplementary material related to this article can be found, in the
online version, at doi:https://doi.org/10.1016/j.eplepsyres.2019.
106259.
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