The use of antiepileptic drugs (AEDs) in women with epilepsy (WWE) of child-bearing potential is a delicate balance between seizure control and adverse effects of AEDs, which are both potentially harmful to the developing fetus. This balancing act leaves many neurologists feeling as though they are backed into a corner concerning the treatment of adverse effects and the risk of doing more harm than good. With regard to pregnancy, experience has taught us much, scientific evidence from clinical trials is lacking and observational studies are slowly increasing to fill the gap Citation[1]. Intrauterine growth retardation, microcephaly, neuropsychological dysfunction and fetal demise are the stakes for the fetus; however, future cognitive implications for childhood development are now also unfolding Citation[1]. It has become evident that there is a differential teratogenic effect between AEDs that stems primarily from the drug exposure as opposed to the underlying effects of the epilepsy Citation[1–3]. Today, a worldwide collaboration Citation[2] and recent guidelines Citation[3] have advanced our efforts to unfold the mystery of ‘what to do’ with pregnancy and treating WWE. A rational approach requires knowledge of such risks, as well as an understanding of the effects of pregnancy on seizure control and of gestational effects on AED disposition Citation[4].
Uncontrolled tonic–clonic seizures are potentially hazardous to the mother and, although strict evidence is lacking, are generally also assumed to be more harmful to the fetus than AEDs Citation[4]. Seizures increase during pregnancy in a minority of WWE, but convulsive seizures are most worrisome and even one generalized tonic–clonic seizure may cause fetal heart rate deceleration, periventricular hemorrhage, premature delivery or fetal demise Citation[2,4]. When more than five convulsions occur during pregnancy, the offspring can suffer a lower (verbal) IQ Citation[2]. The risks to the fetus with infrequent or brief nonconvulsive partial seizures are less clear. Less aggressive efforts to attempt complete seizure freedom with AED polytherapy or high-dose AEDs may be the optimal approach, with the likelihood of limited seizure freedom after two or more drugs have failed Citation[5]. Yet in 31 and 48% of WWE, serial seizures and status epilepticus occur, respectively, and may result in maternal or fetal mortality Citation[6]. Noncompliance and pharmacokinetic changes of the AED may occur with lower levels that result in breakthrough seizures and attendant risks Citation[2,4,6,7].
The risk to the fetus from AEDs is becoming clearer. The appearance of major congenital malformations (MCMs) in fetuses of WWE treated with AEDs is twice that of the general population, without a clear effect seen from the epilepsy itself Citation[2,4,6,7]. AED registries from North America, the UK, Australia, Finland, Sweden, Italy, The Netherlands and Japan have been reported, with results that clearly demonstrated a differential effect in the absence of an evidence-based outcome Citation[2]. The jury has weighed in on valproate (VPA; level B) Citation[1]; even in monotherapy, VPA probably reduces cognitive outcome at 3 years of age, and this is also possible for phenytoin (PHT) and phenobarbital, independent of maternal IQ Citation[1]. Higher AED doses may further compound the problem, as has been suggested for VPA and lamotrigine (LTG) Citation[2], although this might well occur with other AEDs yet to receive scrutiny. It is highly probable that intrauterine first-trimester VPA exposure does carry a higher risk of MCMs compared with carbamazepine, and possibly compared with PHT and LTG Citation[3]. Carbamazepine, which has long been a gold standard for the treatment of complex partial seizures, may carry specific risks of neural tube defects, yet the ‘total package’ appears to justify its use for the majority of case Citation[1]. Measuring serum concentrations is an emerging technique to assist in defining the optimal balance between risk and benefit for seizure control Citation[1]. Given the pronounced influence of pregnancy on LTG, possibly oxcarbazepine and others Citation[4], pharmacokinetics are rapidly becoming a standard in WWE that will help further our knowledge in other areas of epilepsy management Citation[1].
Postnatal complications for the child, at least from VPA, PHT and phenobarbital, do not appear to cease soon after birth, and the detrimental effects may extend into the developmental years by creating neuropsychiatric sequelae, including impaired IQ Citation[1,3]. Babies are likely to be small for their gestational age with a greater possibility of Apgar scores below 7 Citation[3]. Newer AEDs have received limited attention, but LTG appears to carry a difference of 9 IQ points in early childhood compared with VPA Citation[8]. Polytherapy consistently appears to carry a higher risk for MCM and reduced cognitive outcomes and is best avoided if possible Citation[9]. However, the newer promising AEDs may also exhibit the gestational downfall with time. Many questions remain. Is high-dose monotherapy safer than medium-dose dual therapy for certain AEDs? What combinations are optimal for those with refractory seizures? How long will the effects of drug treatment persist and to what extent will they impact activities of daily living? Further research from animal studies appears to be necessary to answer these questions in the absence of human clinical trials. The recent Practice Parameter statements add to our awareness of the risks of treatment for WWE during pregnancy Citation[3]. However, they purposely limit the much desired unified approach to treatment that all experts and nonexperts alike desire. Until more population studies become available, it seems advisable for WWE to continue taking AEDs during pregnancy in monotherapy at the lowest dose required to achieve seizure control.
Today we see AED embryonopathy shaping physical, mental and emotional development. In the future, the long-term effects on IQ, quality of life, personality and behavior remain important issues to answer. For example, with ‘optimal’ AED therapy for WWE do we gain seizure control (or not) at the expense of unique neuropsychological characteristics, thus negating possible advances from the likes of Napoleon Bonaparte, Vincent Van Gogh and Ernest Hemmingway? Still, we must caution ourselves with lists of ‘AEDs to avoid’ during pregnancy. Until further metrics for optimal balance become clear, the benefits of all AEDs must lie in the primary directive of seizure prevention for the individual mother–baby pair. Perhaps by improving AED mechanisms, defining pharmacokinetics and searching for drugs that ‘bypass’ the fetus Citation[2], we may prevent such modern day ‘thalamide eras’ for WWE. Additional research on AEDs or comedication might carry added benefit beyond the vitamin polypharmacy strategy that is now routine for inhibition of apoptotic and neuronal suppression effects from seizures to tip the balance in favor of aggressive AED therapy Citation[3]. However, there is not, and probably never will be, a ‘cook-book’ recipe where one approach fits all. Until the future provides a greater insight into the contributing risks to define the balance between seizures and their treatments, the art of epilepsy management should remain the purview of the practicing clinical neurologist.
Financial & competing interests disclosure
The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
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