12th June 2021, Dr Chee L Khoo
More than 50 years ago, there were reports of association between anti-epileptic drugs (AEDs) and birth defects (1). We now have newer AEDs including carbamazepine, lamotrigine, phenytoin and levetiracetam. In 2016, the UK banned valproate use in women who are not in a pregnancy prevention programme. Despite that, sodium valproate is still widely prescribed in many countries to women of childbearing age. But these drugs are also use as a mood stabiliser in bipolar disorder and occasionally, for migraine prophylaxis. Although the initial focus was on anatomical teratogenicity, the focus is now more on adverse effect on the neurodevelopment of the offspring. As primary care physicians, we have more than a few women of childbearing age who may be on these drugs for various reasons. How do we navigate this minefield?
NEAD was a landmark prospective, observational, assessor-masked, multicentre study trial which looked at children of pregnant women with epilepsy on monotherapy AEDs, carbamazepine, lamotrigine, phenytoin, or valproate (2). Meador et al showed that exposure to high doses of valproate was associated with lower IQ in children at 6 years of age compared with children whose mothers had been treated with phenytoin, carbamazepine or lamotrigine.
The results were confirmed in other similar studies subsequently (3). In nation-wide population based studies, valproate exposure has also been associated with a 2-5 X increased risk of autism and autism spectrum disorders (4,5), a 1.5- 1.7 X increased risk of attention-deficit/hyperactivity disorder (5, 6), a 4-5 X increased risk of intellectual disabilities (7) and a 3-5 X increased risk of early neurodevelopmental disorders (8).
Many second generation AEDs that have been introduced during the past 30 years. However, in addition to the fact that the efficacy of second-generation AEDs may not be comparable to that of valproate for the treatment of generalized epilepsy, the assessment of their safety during pregnancy is far from complete. Although epilepsy and pregnancy registers have shown that lamotrigine and levetiracetam are relatively safe with respect to major congenital malformations, with lower rates than first-generation AEDs, the information on neurodevelopmental outcomes has been insufficient even for these frequently prescribed second-generation AEDs (9,10). The reason for this discrepancy is that compared with birth defects, assessment of cognitive functions and other neuro-developmental outcomes requires longer-term, expert follow-up and is therefore demanding of resources.
In a follow up study to NEAD, Meador et al looked at children of pregnant women exposed to newer AEDs in the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs (MONEAD) (11). This time, a new cohort of children born to pregnant women on lamotrigine monotherapy, levetiracetam monotherapy, other monotherapy, lamotrigine plus levetiracetam polytherapy, and other polytherapy were compared children from with healthy women.
The primary outcomes for this analysis were the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III) language domain score at 2 years of age in children of women with epilepsy (WWE) vs healthy women. Exposure to AEDs during the third trimester was used for the primary analysis because AEDs associations with the immature animal brain are similar to those of alcohol, and foetal alcohol effects are primarily due to exposure during the third trimester (1,10).
Potential confounding maternal variables included age, IQ score, gestational age in weeks at enrolment, educational level, employment status at enrolment, household income, planned/welcomed pregnancy, major depressive episode during pregnancy, smoking, alcohol use, and illicit substance use.
There was no significant difference in cognitive outcomes at 2 years of age between children of WWE and children of healthy women. Analyses comparing monotherapy vs polytherapy at enrolment were not significant for the language domain. The authors cautioned that neuropsychological assessments conducted at 2 years of age are not as strongly associated with adolescent/adult functioning as assessments performed in older children. MONEAD is ongoing and subsequent assessment will be conducted till the children reached 6 years old.
Although there was no difference between WWE and healthy women, there were some interesting findings unrelated to the exposure to AEDs. The mean scores for most domains were higher for children who were receiving folate or breastfeeding. Postpartum maternal depression, post-partum anxiety and poorer post-partum sleep were associated with a lower language domain score.
The result from this study was consistent with previous AED studies. Excluding valproate and phenobarbital, several studies have found no differences comparing children of WWE with those of healthy women or with normative data from general populations but some studies have found impairments compared with children of healthy women, and another study found mixed results. Thus, the association of neurodevelopment with foetal exposure for most ASMs remain uncertain.
At least, in the short term, we can reassure women with epilepsy that lamotrigine and levetiracetam do not adversely affect the neurodevelopment of their children while we await longer term studies. Many of these women do not have a choice of whether to take their medications or not. Similarly, in women who are on either drugs for bipolar disorder or migraine prophylaxis, we can also reassure them that both drugs are safe. More importantly, we need to look after the post-partum mental health of these women.
While many of these women have a neurologist managing their epilepsy or migraines, they still require the reassurance from their family doctors. Similarly, women with bipolar disorder are co-managed by their psychiatrist but then the psychiatrist may not be as up to date as you are.
- Meadow SR. Anticonvulsant drugs and congenital abnormalities. Lancet. 1968;2(7581):1296. doi:10.1016/S0140-6736(68)91781-9
- Meador KJ, Baker GA, Browning N, et al; NEAD Study Group. Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurol. 2013;12(3):244-252. doi:10.1016/S1474-4422(12)70323-X
- Baker GA, Bromley RL, Briggs M, et al; Liverpool and Manchester Neurodevelopment Group. IQ at 6 years after in utero exposure to antiepileptic drugs: a controlled cohort study. Neurology. 2015;84(4):382-390. doi:10.1212/WNL.0000000000001182
- Christensen J, Grønborg TK, Sørensen MJ, et al. Prenatal valproate exposure and risk of autism spectrum disorders and childhood autism. JAMA. 2013;309(16):1696-1703. doi:10.1001/jama.2013.2270
- Wiggs KK, RickertME, Sujan AC, et al. Antiseizure medication use during pregnancy and risk of ASD and ADHD in children. Neurology. 2020;95(24):e3232-e3240. doi:10.1212/WNL.0000000000010993
- Christensen J, Pedersen L, Sun Y, Dreier JW,Brikell I, Dalsgaard S. Association of prenatal exposure to valproate and other antiepileptic drugs with risk for attention-deficit/hyperactivity disorder in offspring. JAMA Netw Open. 2019;2(1):e186606. doi:10.1001/jamanetworkopen.2018.6606
- Daugaard CA, Pedersen L, Sun Y, Dreier JW, Christensen J. Association of prenatal exposure to valproate and other antiepileptic drugs with intellectual disability and delayed childhood milestones. JAMA Netw Open. 2020;3(11):e2025570. doi:10.1001/jamanetworkopen.2020.25570
- Coste J, Blotiere PO, Miranda S, et al. Risk of early neurodevelopmental outcomes associated with prenatal exposure to the antiepileptic drugs most commonly used during pregnancy: a French nationwide population-based cohort study. Sci Rep. 2020;10(1):17362. doi:10.1038/s41598-020-74409-x
- Tomson T, Battino D, Bonizzoni E, et al; EURAP Study Group. Comparative risk of major congenital malformations with eight different antiepileptic drugs: a prospective cohort study of the EURAP registry. Lancet Neurol. 2018;17(6):530-538. doi:10. 1016/S1474-4422(18)30107-8
- European Medicines Agency. Assessment report: procedure under Article 31 of Directive 2001/83/EC resulting from pharmacovigilance data. Issued October 9, 2014. Accessed June 6, 2021. https://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Valproate_and_related_substances_31/Recommendation_provided_by_Pharmacovigilance_Risk_Assessment_Committee/WC500177352.pdf
- Meador KJ, Cohen MJ, Loring DW, et al; Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs Investigator Group. Two-year-old cognitive outcomes in children of pregnant women with epilepsy in the Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs Study. Published online June 7, 2021. JAMANeurol. doi:10.1001/jamaneurol.2021.1583