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 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 databases 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
epileptic pregnant women than in non-epileptic women [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
& Hongling Peng
[email protected] & Bing Peng
[email protected] Daijuan Chen
[email protected] Lisha Hou
[email protected] Xia Duan
[email protected] 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
West China School of Public Health, Sichuan University, Chengdu 610041, Sichuan, China
4
The Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu 610041, Sichuan, China
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 possible seizure types and syndromes, diverse etiologies, and variable prognoses [2]. And it can trigger seizures with neurobiological, cognitive, psychological, and social consequences [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 ten times higher in women with epilepsy compared with those without epilepsy [8]. Thus, growing interests focus on exploring maternal complications and pregnancy outcomes. Epilepsy is one of the most common brain disorders; 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 epilepsy 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 secondmost 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 cardiovascular 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 population 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 metaanalyses (i.e., PRISMA). Initially, regardless of publication language or regional restrictions, the identified and collected studies included those targeting FGR and pregnancy outcomes in patients with epilepsy. Sources included BIOSIS, Medline, Embase, and PubMed databases and paper documents 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 outcomes’’. 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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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 observational 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 possible. 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 different definitions were used in enrolled studies, then primary 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 determine original literature included while abiding by principles of retrieval and assessment of relevant text citations. Second, when reviewers disagreed about the included literature, 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 incidences 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
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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.
Results From the conducted search of electronic databases, paper 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 pregnancies, 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 pregnant women without epilepsy (Table 1) [13, 15–22]. Six studies (n = 900,093 patients) presented data for incidence 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 studies. STATA 10.0 statistical software was used to analyze data and to obtain statistical analysis results.
Fig. 1 Selection process for the systematic review
Table 1 The data of FGR for pregnant women with epilepsy compared with non-epilepsy women
Q statistic was used to assess the between-study heterogeneity 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. Combination of forest and funnel plots were used to graphically represent statistical data and to determine whether publication 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.
References
Year
Total
Test
Control
OR (95% CI)
Hvas et al. [13]
2000
24,287
193
24,094
1.90 (1.30–2.70)
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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Arch Gynecol Obstet Table 2 Subgroup analysis for FGR between antiepileptic drugs exposed for pregnancies with epilepsy compared with women without epilepsy
References
Year
Total
Test
Control
OR (95%CI)
Hvas.et al. [13]
2000
24,181
87
24,094
2.30 (1.30–4.00)
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 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.
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.
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Risk of bias in included studies Funnel plot was used to describe publication bias of studies. 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 significantly 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 quantitative 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.
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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 limitations. First, as reported previously, the present study shows significant between-study heterogeneity. Heterogeneity existed between pregnant women with epilepsy and pregnant 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 variability in definitions, statistical methods, measurements, experimental procedures, and outcomes [39]. Third, documents included in this study provided types of AED, with most common kinds being lmino glycosides (such as carbamazepine) and double-chain fatty acids (such as valproate), 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. Clinically, 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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Author contributions HLP, BP: Project development, manuscript editing. DJC: Data collection, manuscript writing. XD: Data collection. 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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