Arch Gynecol Obstet

DOI 10.1007/s00404-017-4404-y

REVIEW

Effect of epilepsy in pregnancy on fetal growth restriction:

a systematic review and meta-analysis
Daijuan Chen1,2 • Lisha Hou3 • Xia Duan1,2 • Hongling Peng1,4 • Bing Peng1,4

Received: 4 March 2017 / Accepted: 16 May 2017

Ó Springer-Verlag Berlin Heidelberg 2017

Abstract epileptic pregnant women than in non-epileptic women

Purpose Epilepsy is one of the most common neurological
diseases during pregnancy. However, the influence of
epilepsy on fetal growth is not understood. Thus, this study
conducted a meta-analysis to determine the influence of
epilepsy during pregnancy on fetal growth restriction
(FGR).
Methods BIOSIS, Medline, Embase, and PubMed data-
bases were searched between January 2000 and January
2016. Without imposing language or regional restrictions,
referenced articles were selected.
Results Final analysis included 684 citations from 11
studies. Estimated risk of FGR was 1.28-fold higher in
& Hongling Peng
m13508302272@163.com
& Bing Peng
pengbin-a111@163.com
Daijuan Chen
m15528309193@163.com
Lisha Hou
1561531710@qq.com
Xia Duan
1742687985@qq.com
1
Department of Obstetrics and Gynecology, West China
Second University Hospital, Sichuan University, No. 20,
Section 3, RenminNanlu Road, Chengdu 610041, Sichuan,
China
2
West China School of Medicine, Sichuan University,
Chengdu 610041, Sichuan, China
3 ten times higher in women with epilepsy compared with
West China School of Public Health, Sichuan University,
Chengdu 610041, Sichuan, China
4 on exploring maternal complications and pregnancy out-
The Key Laboratory of Birth Defects and Related Diseases of
Women and Children (Sichuan University), Ministry of
Education, Chengdu 610041, Sichuan, China
[95% confidence interval (95% CI) 1.09–1.50, p \ 0.05].
Given the course of previous studies, hierarchical analysis
of pregnant women who use antiepileptic drugs (AEDs)
was conducted. Results show that FGR rate is significantly
increased even if AEDs were taken [odds ratio 1.26, 95%
CI 1.13–1.41, p \ 0.05].
Conclusions Although modest bias cannot be avoided, our
meta-analysis indicated that epilepsy participates in fetal
development as an unfavorable factor, and AEDs seemed
to be useless in decreasing the occurrence rate of FGR.
Keywords Epilepsy
Antiepileptic drug (AED)
Fetal
growth restriction (FGR)
Pregnancy
Meta-analysis
Introduction
Epilepsy is defined as a disorder of the brain characterized
by an enduring predisposition to epileptic seizures [1]. It is
a heterogenous condition characterized by multiple possi-
ble seizure types and syndromes, diverse etiologies, and
variable prognoses [2]. And it can trigger seizures with
neurobiological, cognitive, psychological, and social con-
sequences [3]. Epilepsy is a rare neurological disorder in
pregnant women, with incidence rate of 0.3–0.7%. Despite
its rarity, epilepsy can cause different clinical problems
during pregnancy [4–6]. However, epilepsy is also one of
the common chronic disorders, which affects the women of
reproductive age [7], and the rate of maternal mortality is
those without epilepsy [8]. Thus, growing interests focus
comes. Epilepsy is one of the most common brain disor-
ders; it requires medical treatment in pregnant women with

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epilepsy [9]. Therefore, more and more scholars focused on
exploring the effects of AED. The earliest use of AED
therapy dates back to 1850; we put forward freedom from
seizures without significant adverse effects as goal of epi-
lepsy treatment. However, once epileptic women become
pregnant, continuing AED treatment may pose concerns.
Thus, at the time of initiating AED treatment, epilepsy
control and fetus development must be balanced [10].
Therefore, important considerations for epileptic women
include planning for pregnancy, prenatal counseling, and
management of delivery.
Many studies investigated association between epilepsy
and maternal and fetal complications. FGR is a condition
that can affect 5–10% of pregnancies and is the second-
most common cause of perinatal mortality [11]. Perinatal
mortality rate of FGR is 4–10 times than that of normal
fetuses with higher stillbirth or neonatal death rate. FGR
infants experience numerous long-term consequences, such
as neurological and developmental delays and cardiovas-
cular diseases or diabetes in later life [12]. Factors that can
be derived from maternal disease include genetic aspects,
seizures during pregnancy, and exposure to AED. Other
possible causes can also be associated with epilepsy; such
causes include environmental factors (e.g., maternal
smoking and alcohol) [13]. This study investigates and
assesses incidence of FGR in epileptic and general popu-
lation and whether the epileptic women who receive AED
treatment can decrease the occurrence rate of FGR.
Maternal and fetal characteristics were considered.
Materials and methods
Data sources and search strategy
To conduct systematic reviews, recommended methods, e.g.,
a combination of computer and manual retrieval, were used in
accordance with guidelines for systematic reviews and meta-
analyses (i.e., PRISMA). Initially, regardless of publication
language or regional restrictions, the identified and collected
studies included those targeting FGR and pregnancy out-
comes in patients with epilepsy. Sources included BIOSIS,
Medline, Embase, and PubMed databases and paper docu-
ments obtained from the library of Sichuan University dating
from January 2000 to January 2016. The following keywords
were used for database search: ‘‘epilepsy’’, ‘‘fetal growth
restriction (FGR) and intrauterine growth restriction
(IUGR)’’, ‘‘antiepileptic drug (AED)’’, and ‘‘pregnancy out-
comes’’. References of retrieved articles were also screened. A
total of 684 citations were retrieved. Based on the research
purpose and exclusion criteria, 11 studies were found to meet
the criteria, and total research objects included 1,910,042
cases. Among these studies, nine articles reported FGR
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Arch Gynecol Obstet
between pregnancies with and without epilepsy, and
1,009,949 cases were involved in these studies. Seven articles
reported on incidence of FGR between pregnant women with
epilepsy and were exposed to AED and normal pregnant ones;
900,093 cases were involved in these studies. In all included
articles, studies should be in strict accordance with observa-
tional study design and should provide relevant data on
experimental and control groups. Studies on epilepsy and
pregnant women were selected; these researches involved and
evaluated risk of FGR in antenatal, intrapartum, or postnatal
periods. Abstracts, case reports, and animal studies were
excluded. Studies with original data on FGR were included.
Definitions and standardizations
The main outcome of meta-analysis is FGR. Standard
definition of FGR positivity was utilized as much as pos-
sible. FGR positivity is defined as fetal birth weight \10th
percentile of weight for the same gestational age. This
definition was used in most enrolled studies. When dif-
ferent definitions were used in enrolled studies, then pri-
mary investigators were contacted.
Data extraction process and quality assessment
Newcastle–Ottawa Scale was used to evaluate quality of
methodology, selection bias, feasibility of research, and
outcomes [14]. In screening articles, two steps were used
for selection. First, two reviewers (i.e., Doctor Chen and
Doctor Peng) screened article titles and abstracts to deter-
mine original literature included while abiding by princi-
ples of retrieval and assessment of relevant text citations.
Second, when reviewers disagreed about the included lit-
erature, then a third reviewer (i.e., Professor Peng) was
included in discussion to resolve the issue regarding
inclusion of literature. After the screening of articles, two
independent investigators extracted data separately and
used unified standards on all items. Extracted data include
features of studies and patients, statistical methods, and
results. Each report particularly recorded country of origin,
year of publication, first author, indicators, statistical
methods, and number of patients analyzed (i.e., total
number and number of experimental and control groups).
Statistical data were tabulated, and tables showed inci-
dences of FGR between epileptic pregnant women and
healthy women and the rates of FGR between pregnant
women with epilepsy exposed to AED and non-epileptic
pregnant women.
Outcome indicator
Outcome indicator was defined as the incidence of FGR in
the neonatal periods between pregnant women with
Arch Gynecol Obstet

epilepsy and those without epilepsy. Thus, hierarchical
analysis was conducted for incidences of FGR between
pregnant women with epilepsy and who are exposed to
AED and normal healthy pregnant ones.
Data analysis
Standard data abstraction form was employed to abstract
the needed data. Observation focused on divergences
between included studies, quality assessments, and data
abstractions. Team members conducted more discussions.
Data analysis was conducted using STATA 10.0 statistical
software. For the synthesis of OR, fixed and random
effects models were used to combine data on predictive
ability of occurrence of FGR for pregnant women across
studies. OR shows rate of FGR in epilepsy group.
Q statistic was used to assess the between-study hetero-
geneity of OR (considered statistics for p \ 0.10; I2).
Similarly, evaluation was conducted on relationship of
FGR between the epileptic pregnant women exposed to
AEDs and the non-epileptic pregnant women. Combina-
tion of forest and funnel plots were used to graphically
represent statistical data and to determine whether publi-
cation bias exists. When funnel chart is symmetric, then
publication bias was less likely to exist and vice versa.
Mantel–Haenszel method was used to calculate and to
combine weighted OR values. Meta-analysis obtained
ORs and 95% CIs and assessed heterogeneity by means of
Q test/I2 statistic.
Results

From the conducted search of electronic databases, paper

Fig. 1 Selection process for the systematic review
documents, and reference lists of selected articles, 684
studies were included in initial review. Of the 684
citations identified, 11 articles were selected for detailed
assessment; these articles included 1,910,042 pregnan-
cies, which met inclusion criteria. Selection process is
summarized in Fig. 1. Most of the studies were excluded
after initial screening of abstracts or titles mainly
because they were unrelated to research topic or were
repeated titles from different electronic databases or
paper documents. Finally, 11 studies (n = 1,910,042
patients) were available for meta-analysis. Overall, nine
studies (n = 1,009,949 patients) showed data for odds of
FGR between pregnant women with epilepsy and preg-
nant women without epilepsy (Table 1) [13, 15–22]. Six
studies (n = 900,093 patients) presented data for inci-
dence of FGR between pregnant women with epilepsy
who use AEDs and normal women (Table 2)
[10, 13, 16, 18, 22, 23]. As per collected data, all
available studies were observational retrospective stud-
ies. STATA 10.0 statistical software was used to analyze
data and to obtain statistical analysis results.

Table 1 The data of FGR for

References Year Total Test Control OR (95% CI)
pregnant women with epilepsy
compared with non-epilepsy Hvas et al. [13] 2000 24,287 193 24,094 1.90 (1.30–2.70)
women
Katz et al. [17] 2006 139,168 220 138,948 0.64 (0.20–2.00)
Kalviainen et al. [21] 2006 24,905 127 24,778 2.16 (1.34–3.47)
Chen et al. [22] 2009 9310 1182 8128 1.16 (0.98–1.41)
Cahill et al. [20] 2012 47,495 445 47,050 1.20 (0.94–1.65)
Jadhav et al. [19] 2013 67 32 35 2.00 (0.58–6.91)
McPherson et al. [18] 2013 47,118 440 46,678 1.11 (0.82–1.50)
Christensen et al. [15] 2014 676,759 65,524 611,235 1.06 (0.97–1.15)
Farmen et al. [16] 2015 40,840 287 40,553 1.41 (0.89–2.24)

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Table 2 Subgroup analysis for

References Year Total Test Control OR (95%CI)
FGR between antiepileptic
drugs exposed for pregnancies Hvas.et al. [13] 2000 24,181 87 24,094 2.30 (1.30–4.00)
with epilepsy compared with
women without epilepsy Chen et al. [22] 2009 8693 565 8128 1.33 (1.03–1.71)
Lin et al. [10] 2009 6076 166 5910 1.38 (0.94–2.02)
McPherson.et al. [18] 2013 46,934 256 46,678 0.97 (0.64–1.50)
Veiby et al. [23] 2014 773,498 2086 771,412 1.19 (1.03–1.60)
Farmen et al. [16] 2015 40,711 158 40,553 1.86 (1.04–3.31)

Fig. 2 Meta-analysis of risk of FGR for epileptic pregnant women compared with non-epileptic women

Outcome analysis: fetal growth restriction Data synthesis

Data synthesis
Risks of FGR for epileptic pregnant women compared
with non-epileptic women Nine studies were included,
with a total of 68,450 cases of exposed and 941,499
cases of unexposed women with epilepsy. The results of
meta-analysis showed that epilepsy was associated with
pregnancy outcomes regarding risk of FGR. Estimated
risk of FGR was 1.28-fold higher in epileptic pregnant
women than non-epileptic women (95% CI 1.09–1.50,
p \ 0.05; Fig. 2). Analysis for odds of FGR showed
significant effect, indicating that epilepsy is a risk factor
for FGR.
Risks of FGR for epileptic pregnant women who used AED are
compared with non-epileptic women Six assessed studies
included 3318 women who used AEDs during pregnancy and
896,775 healthy women. FGR was associated with use of
AEDs, and effect was statistically significant (OR 1.26, 95%
CI 1.13–1.41, p \ 0.05; Fig. 3). This finding indicated that
pregnant women with epilepsy who were exposed to AEDs
present higher risk of FGR than do normal pregnant ones.
Risk of bias in included studies
Funnel plot was used to describe publication bias of stud-
ies. Funnel plot shows that all plots fall in the funnel figure.

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Fig. 3 Meta-analysis of risk of FGR for epileptic pregnant women who use AED compared with non-epileptic women
This finding indicates that risk of bias was not observed
during assessment of selected studies included in this
publication.
Discussion
In pregnant women, epilepsy can cause adverse pregnancy
outcomes, and women with epilepsy possess small but sig-
nificantly increased rate of adverse pregnancy outcomes
[24]. Our meta-analysis showed that FGR, as one of the
pregnancy outcomes, is associated with overall incidence in
patients with epilepsy. Increase in odds of FGR was observed
in epileptic women who use AEDs. Some studies also
hypothesized that epilepsy plays a significant role in risk of
fetal malformations in epileptic pregnant women, and recent
findings showed that AED therapy may be the main cause of
fetal birth defects [9, 25, 26]. Neural tube and cardiac defects
occur along with use of AEDs [27]. Meta-analysis of the
existing evidence-based research can provide precise quan-
titative and qualitative estimates for this study and shows that
small but significant increase in risk exists among epileptic
pregnant women compared with non-epileptic pregnant
women. Significant statistical difference was observed in
pregnant women with epilepsy who receive AED treatment
compared with pregnant women without epilepsy. Most
AEDs (e.g., carbamazepine, valproate, phenytoin,
oxcarbazepine, and primidone) are transferred through the
placenta to a certain extent [28–30]. Many studies described
that at the same range, fetal drug concentrations are close or
may even be higher than maternal drug concentrations
[31–37]. However, results should be interpreted cautiously
as epilepsy is one of the most common brain disorders
requiring medical treatment during pregnancy. Thus, when
conducting treatment, adverse drug effects of AEDs must be
considered [38]. AEDs are the most common and effective
drugs for treating epilepsy. Increased rate of FGR requires
further research to support the previously presented results.
When women with epilepsy become pregnant, continuing
AED treatment or not remains a dilemma [36]. Results of this
review can serve as guide for epileptic women and their
families during antepartum, intrapartum, and postpartum
periods.
Current observational studies provide evidence for risk
of FGR in pregnancy with epilepsy and pregnancy without
epilepsy. However, these studies did not provide strong
evidence and detailed description of incidence of FGR
between epileptic pregnant women who use AEDs and
non-epileptic pregnant women. This review involves a
large sample size of studies focused on pregnancy and
FGR. And results of meta-analysis show that epilepsy is a
risk factor for normal pregnancies in FGR, and pregnant
women with epilepsy who exposed to AEDs present higher
risk of FGR than normal pregnant ones.
123

This meta-analysis is based on analysis of 11 research
studies on outcomes of pregnancy. Results may help
determine risk of FGR for women with epilepsy who use
AEDs. 11 articles described relevant data on FGR. Details
are shown in Tables 1 and 2.
However, this meta-analysis also poses some limita-
tions. First, as reported previously, the present study shows
significant between-study heterogeneity. Heterogeneity
existed between pregnant women with epilepsy and preg-
nant women without the condition (p = 0.011,
I2 = 59.9%; Fig. 2). Statistically significant heterogeneity
was also observed between pregnancies with epilepsy
exposed to AEDs and pregnancies without epilepsy
(p = 0.125, I2 = 42.1%; Fig. 3). Limited studies involving
FGR were included. Although the authors attempted to
retrieve all related articles and to collect all relevant data
and information, some data may still be missing. Missing
data and information may reflect ‘‘negative’’ FGR with
epilepsy; this type of FGR can reduce effectiveness of
occurrence rate of FGR as outcome of pregnancy [13].
Second, in meta-analyses, several factors can cause
between-study heterogeneity; such factors include vari-
ability in definitions, statistical methods, measurements,
experimental procedures, and outcomes [39]. Third, doc-
uments included in this study provided types of AED, with
most common kinds being lmino glycosides (such as car-
bamazepine) and double-chain fatty acids (such as val-
proate), but details were incomplete and did not describe
information regarding dose, duration, and time of fetal
exposure to AED. Finally, collected data cannot be used to
check whether meta-analysis results may affect response to
specific therapeutic regimens.
Conclusion
In conclusion, through statistical methods, data on epilepsy
and FGR were obtained. Findings show that epileptic
women who receive AED treatment should be informed
regarding higher risk of FGR than normal persons. Clini-
cally, pregnancies with epilepsy do present increased rate
of FGR than pregnancies without epilepsy. Considering
these results and despite limitations of this study, epilepsy
and those who use AEDs may result in significant neonatal
pregnancy outcomes. Thus, women with epilepsy who
want to become pregnant should be fully prepared. Because
of the effects of AED on human placental perfusion,
potential reproductive risks of epilepsy and AED treatment
on mother and newborn should be considered. Further,
more studies with high methodological quality are needed
to confirm our conclusion.
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Arch Gynecol Obstet
Author contributions HLP, BP: Project development, manuscript
editing. DJC: Data collection, manuscript writing. XD: Data collec-
tion. LSH, HLP: Data analysis.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflicts of
interest.
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