We have previously written about studies which indicate that prenatal exposure to antiepileptic drugs (AEDs), particularly valproic acid, may adversely affect the developing fetus.  Numerous studies have documented long-term effects of antiepileptic exposure on cognitive functioning: prenatal exposure to AEDs has been associated with lower IQs, as well as lower scores on tests of executive functioning, memory, verbal and nonverbal abilities, in children at 6 yeas of age (Meador KJ et al, 2012).  These deficits were the most prominent in children exposed to valproic acid.

A recent study from Norway assesses the impact of prenatal antiepileptic drug exposure on development in younger children and, in addition, the impact of breastfeeding on these outcomes.  Mothers at 13 to 17 weeks of gestation were recruited in the population-based, prospective Norwegian Mother and Child Cohort Study. The mothers reported on their child’s motor and social skills, language, and behavior using items from standardized screening tools at 6 months (n=78,744), 18 months (n=61,351), and 36 months (n=44,147) of age. The mothers also provided detailed information on breastfeeding during the first year.

At 6 months, the infants with prenatal antiepileptic exposure (n=223) were more likely to have impaired fine motor skills compared to the unexposed control group (11.5% vs. 4.8%, respectively; odds ratio (OR)=2.1).  Results were similar for lamotrigine, carbamazepine, and valproic acid monotherapy.   Antiepileptic drug polytherapy was associated with worse outcomes for both fine motor skills (25.0% vs. 4.8%, respectively; odds ratio?=?4.3; 95% CI, 2.0-9.1) and social skills (22.5% vs. 10.2%, respectively; OR=2.6; 95% CI, 1.2-5.5).

At 18 and 36 months, the findings were similar, with the AED-exposed children demonstrating more autistic traits and deficits in motor development and communication skills than children in the control group.

Breastfeeding was not associated with adverse developmental outcomes in children of mothers using antiepileptic drugs. In fact, continuous breastfeeding in children of women using antiepileptic drugs was associated with less impaired development at ages 6 and 18 months compared with those with no breastfeeding or breastfeeding for less than 6 months.

Children of mothers with epilepsy who did not use antiepileptic drugs and children of fathers with epilepsy had normal development at 6 months, indicating that adverse effects in the drug-exposed group were not a result of genetic factors.

This study has many strengths, including its larger size and prospective design, and it is the first to systematically assess the impact of breastfeeding on outcomes.  While the study relied on mothers’ ratings of the children, which makes it difficult to precisely correlate the findings with medical diagnoses, these assessments were based on validated screening tools and were adequate information on the child’s development.

We have a fair amount of data regarding the risk of malformations in children exposed to AEDs in utero but much less information on the long-term developmental outcomes.  Consistent with previous reports on developmental outcomes, this study shows that the children exposed to AED polytherapy did worse than those exposed to AED monotherapy.  What is not so clear in this study is whether certain AEDs may be worse than others.  Outcomes were similar in infant exposed to monotherapy with lamotrigine, carbamazepine, and valproic acid; however, these comparison groups were relatively small.

Should Women on Antiepileptic Drugs Breastfeed?

One of the most interesting findings of this study is that outcomes were somewhat better in children in women who breastfed their children for more than 6 months.  We typically advise women taking AEDs not to breastfeed in order to reduce drug exposure; however, this study calls this practice into question.   Based on the findings of this study, the authors conclude that breastfeeding may be protective.  They state, “Women with epilepsy should be encouraged to breastfeed their children irrespective of antiepileptic drug treatment.”

While the children of breastfeeding women may do better, there are other factors that may be at play here.  The authors attempted to control for some of these factors, including socioeconomic status; however, women who breastfeed longer may be higher functioning or have more support at home, factors which may positively impact outcomes  It is also possible that babies with deficits in motor functioning might be less effective feeders and this may result in early discontinuation of breastfeeding.  Further studies are required to more fully delineate the benefits of breastfeeding in this population.

Ruta Nonacs, MD PhD

Veiby G, Engelsen BA, Gilhus N. Early Child Development and Exposure to Antiepileptic Drugs Prenatally and Through Breastfeeding: A Prospective Cohort Study on Children of Women With Epilepsy. JAMA Neurol. 2013.