The treatment of epilepsy in pregnancy: The neurodevelopmental risks associated with exposure to antiepileptic drugs
Introduction
The need to optimize seizure control whilst limiting the potential risk to the fetus can be a challenge. Given the nature of the condition pharmacological treatment during pregnancy is typically required and it is estimated that 0.5–2.5% of pregnancies are exposed to antiepileptic drugs (AEDs) for epilepsy and other indications [1], [2], [3], [4]. Prescription patterns in women with epilepsy have changed over the last two decades, with a decrease in the older AEDs such as phenytoin, phenobarbital, carbamazepine and valproate, and an increase in ‘newer’ therapies such as lamotrigine and levetiracetam in women of childbearing age [2], [3], [5].
The older AEDs have been demonstrated to be associated with a significant increase in risk of major congenital malformation. Valproate is reported as the AED with the highest level of teratogenicity [6] and is associated with neural tube [7], [8], [9], cardiac [9], [10], orofacial clefts [9], [11], [12] and skeletal or limb malformations [9], [11]; with levels of risk being clearly dose dependent [6], [13], [14]. Carbamazepine has been associated with an increased risk of major malformation [6], with a higher rate of spina bifida and cardiac malformations reported [6], [13], [14]. Phenobarbital has been associated with an increased overall rate of malformations [6], [15], and specifically with cardiac malformations [6], [16] and oral clefts [17]. Finally, phenytoin is also reportedly associated with an increased rate of malformations [15], [18].
Prenatal exposure to lamotrigine has been found by the majority of pregnancies registers and population-based studies to not be associated with an increased risk of malformation [16], [19], [20], [21], [22]. To date no specific pattern of malformations have been reported following exposure to lamotrigine [6]. A previously reported association with oral clefts in data from the North American Pregnancy Register [23] has not been maintained with increased study population [16]. Although the majority of studies have not documented a dose response, the largest study to date does find an association between dose of lamotrigine and prevalence of malformations [6]. Data is more limited pertaining to exposure to levetiracetam. Pregnancy register data from UK, US and Australia failed to find an association with malformation status of the child [16], [20], [24] as did a population based study [21]. There is consistent evidence of a specific risk of oral clefts following in utero exposure to topiramate [25], [26]. There is no evidence of an increased rate of malformation in children exposed to gabapentin [21], [27], oxcarbazepine [21] or zonisamide [16], however data is too limited for conclusions to be drawn.
There is therefore increased risk to the physical development of the fetus following exposure to certain AEDs. Additionally, there are further risks that should be considered, which convey lifelong impact to the fetus and the later child. Early reports of malformations following prenatal exposure to an AED often also reported neurodevelopmental difficulties [28], [29], [30], [31], [32], however it took until the turn of the century to see an increased international interest on neurodevelopment as a primary outcome [33], [34], [35], [36], [37], [38], [39] and also the utilization of the already established epilepsy and pregnancy registers for the ascertainment of neurodevelopmental data [38], [40], [41], [42]. Neurodevelopmental outcomes when affected can be substantial and therefore a comprehensive understanding of any association between a drug exposure and impaired neurodevelopmental outcome should be sought as quickly as possible. Below, the evidence pertaining to the neurodevelopment in children exposed to AEDs is reviewed and the approaches taken to understanding these risks are discussed.
Section snippets
Neurodevelopment
With the interchangeable terminology of neurodevelopment, neurobehavioral, intelligence and cognitive development, the term neurodevelopment is utilized here to refer to the functional outputs of the brain ranging from motor performance, intelligence, speed of information processing, social functioning as well as to other cognitive skills. The brain is a complex organ, its functional outcomes diverse and therefore the measurements employed to test cognitive functioning are numerous. The
Discussion
For both malformations and neurodevelopmental outcomes exposure to valproate presents the highest teratogenic risk of the AEDs and has led to a number of regulatory decisions and guidelines pertaining to the avoidance of valproate treatment in the childbearing years, where safe to do so [86], [87]. This presents a difficult decision for women requiring AED treatment during pregnancy. Valproate is an efficacious AED [85] and therefore harms to the fetus need to be considered alongside the
Conclusions
Given the magnitude of neurodevelopmental impairment which can be found following prenatal exposure to a teratogen such as valproate the cognitive functioning of exposed children should not be considered as a secondary feature or as a milder outcome but, given their lifelong impact and potential severity, should be considered as a central feature of teratological research.
Funding
This report is independent research supported by the National Institute for Health Research (Post Doctoral Fellowship, Dr Rebecca Bromley, PDF-2013-06-041). The views expressed in this publication are those of the author(s) and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health.
Conflict of interests
RB has contributed to studies funded by Sanofi Aventis and UCB Pharma and has received consultancy payment (one occasion) from UCB Pharma for work on an unrelated matter.
Transparency document
Acknowledgement
RB would like to acknowledge the very useful input on aspects of this manuscript from Dr Laura Yates, UK Teratology Information Service, Newcastle Upon-Tyne, UK.
References (93)
- et al.
Dose-dependent risk of malformations with antiepileptic drugs: an analysis of data from the EURAP epilepsy and pregnancy registry
Lancet Neurol.
(2011) - et al.
In-utero exposure to valproate and neural tube defects
Lancet
(1986) - et al.
Fetal growth, major malformations and minor anomalies in infants born to women receiving valproic acid
J. Pediatr.
(1986) - et al.
Pregnancy outcomes in women with epilepsy: a systematic review and meta-analysis of published pregnancy registries and cohorts
Epilepsy Res.
(2008) - et al.
First trimester exposure to topiramate and the risk of oral clefts in the offspring: a systematic review and meta-analysis
Reprod. Toxicol.
(2015) - et al.
Possible teratogenic effect of valproic acid
J. Pediatr.
(1981) - et al.
Four siblings with similar malformations after exposure to phenytoin and primidone
J. Pediatr.
(1984) - et al.
Motor and mental development of infants exposed to antiepileptic drugs in utero
Epilepsy Behav.
(2008) - et al.
Behavioral outcomes in children exposed prenatally to lamotrigine, valproate, or carbamazepine
Neurotoxicol. Teratol.
(2016) - et al.
Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study
Lancet Neurol.
(2013)