Anti-epileptic drug exposure during pregnancy and neonatal birth weight outcomes: protocol for a systematic review and meta-analysis

Epilepsy is a neurological condition that affects 50 million people worldwide [1]. The prevalence of epilepsy in pregnant women is estimated at 0.3-1% [2, 3]. Anti-epileptic drug (AED) exposure in utero has been associated with various adverse health outcomes in neonates including congenital malformations, intrauterine growth restriction, neurological complications, and adverse birth weight outcomes [4‐7]. Previous reports suggests that any AED exposure during pregnancy is associated with an increased risk of infants having a low birth weight (LBW) and being small for gestational age (SGA) [5, 8, 9]. Infants with adverse birth weight outcomes like SGA are at a higher risk of stillbirth, impaired thermoregulation, and hypoglycemia at birth [10]. Studies have also linked SGA with various long-term health outcomes, including impaired neurodevelopment throughout childhood, as well as cardiovascular diseases and diabetes in adulthood [11‐16]. The safety profile of AEDs varies based on the molecule, generation/class, and dose used [17, 18]. AEDs have been broadly classified into old generation AEDs and new generation AEDs [19]. Old generation AEDs were the first introduced drugs to treat epilepsy during the early 1900s, whereas new generation AEDs were first used in the management of epilepsy in the 1970s [19]. Evidence on the perinatal risk of old generation AEDs are relatively established when compared to new generation AEDs [17]. First-generation AEDs have been strongly associated with SGA compared to new generation AEDs, specifically valproic acid exposure is associated with an increased risk of SGA compared to the new generation AED lamotrigine, which is believed to be safe [17, 18].

Systematic reviews summarizing the published evidence on AED’s safety in pregnancy have mainly focused on malformations and neurological outcomes [17, 20, 21]. A limited number of systematic reviews have been published on AEDs exposure during pregnancy and neonatal birth weight outcomes [22‐24]. The most common limitation observed in the previously published systematic review is using fetal growth restriction (FGR) and intrauterine growth restriction (IUGR) interchangeable with SGA. SGA is a term used to describe newborns who are smaller in size than the usual for their gestational age and is defined as birth weight less than 10th percentile for the same gestational age. FGR, also known as IUGR, implies that fetal growth is being inhibited and that the fetus does not attain its growth potential [25]. Therefore, it is to say, not all SGA infants have FGR and some larger infants can still be SGA [25]. Therefore, substituting SGA for FGR might potentially affect the results of any systematic review. One recent systematic review by Chen et al. in 2017 defined FGR using SGA definition; therefore, using FGR as a substitute for SGA might have potentially excluded some of the studies which used SGA exclusively in the manuscripts [23]. Another systematic review by Viale et al. published in 2015 defined FGR as having either SGA or LBW; by doing this, they failed to differentiate the risk of an infant being born SGA and LBW separately [22] Other published reviews are at least two decades old [26]. Moreover, several original reports were published on new generation AEDs in the past 20 years; hence, the need for an up-to-date review to summarize and evaluate the risks associated with the use of AEDs in pregnancy, specifically adverse birth weight outcomes.

This systematic review aims to summarize the evidence on the association between AEDs exposure during pregnancy and neonatal birth weight outcomes.

A systematic review protocol was developed and registered in the PROSPERO database (CRD42020192713) on 19 August 2020. Preparation of our systematic review protocol was done following the guidelines of Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols (PRISMA-P) checklist [27].

It is essential to understand how AEDs exposure in pregnancy affects birth weight outcomes in offspring. This is particularly important due to the increased prescribing rates of new-generation AEDs, and the limited evidence of their fetal safety. Cautious prescribing practices of AEDs in women of reproductive age are crucial, as more than 30% of pregnancies are not planned, and some AEDs can potentially reduce contraceptives’ efficacy [35, 36]. Therefore, placing women of childbearing age on AEDs should be based on recommended care, with sufficient evidence on neonates’ safety. Clinicians must make medication choices by balancing the risk of increased seizure frequency in mothers versus the potential of adverse fetal outcomes caused by AED exposure [37].

There is a need for a well-constructed systematic review focusing on an array of adverse birth weight outcomes potentially caused by AED exposure during pregnancy. We anticipate the presence of fewer published reports on new generation AEDs and new versus old generation AEDs. This review will locate reports from numerous sources including gray literature and will summarize, pool, and evaluate the methodological quality of the studies in a systematic approach.

This will help us expand the knowledge on how the safety of AED during pregnancy varies based on the type of AED and the combination of prescribed AEDs. It will also help physicians make a careful decision regarding the safety of AED use in pregnancy and choose the safest treatment regimen. The knowledge generated through this project will also help in the pre-counseling of women who plan to be pregnant and will help them make rational evidence-based choices along with their physicians.