Abstract
Breastfeeding in Children of Women Taking Antiepileptic Drugs: Cognitive Outcomes at Age 6 Years
Meador KJ, Baker GA, Browning N, Cohen MJ, Bromley RL, Clayton-Smith J, Kalayjian LA, Kanner A, Liporace JD, Pennell PB, Privitera M, Loring DW; for the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) Study Group. JAMA Pediatr 2014;168:729–736.
IMPORTANCE: Breastfeeding is known to have beneficial effects, but concern exists that breastfeeding during maternal antiepileptic drug (AED) therapy may be harmful. We previously noted no adverse effects of breastfeeding associated with AED use on IQ at age 3 years, but IQ at age 6 years is more predictive of school performance and adult abilities. OBJECTIVES: To examine the effects of AED exposure via breastfeeding on cognitive functions at age 6 years. DESIGN, SETTING, AND PARTICIPANTS: Prospective observational multicenter study of long-term neurodevelopmental effects of AED use. Pregnant women with epilepsy receiving monotherapy (ie, carbamazepine, lamotrigine, phenytoin, or valproate) were enrolled from October 14, 1999, through April 14, 2004, in the United States and the United Kingdom. At age 6 years, 181 children were assessed for whom we had both breastfeeding and IQ data. All mothers in this analysis continued taking the drug after delivery. MAIN OUTCOMES AND MEASURES: Differential Ability Scales IQ was the primary outcome. Secondary measures included measures of verbal, nonverbal, memory, and executive functions. For our primary analysis, we used a linear regression model with IQ at age 6 years as the dependent variable, comparing children who breastfed with those who did not. Similar secondary analyses were performed for the other cognitive measures. RESULTS: In total, 42.9% of children were breastfed a mean of 7.2 months. Breastfeeding rates and duration did not differ across drug groups. The IQ at age 6 years was related to drug group (P < .001 [adjusted IQ worse by 7–13 IQ points for valproate compared to other drugs]), drug dosage (regression coefficient, −0.1; 95% CI, −0.2 to 0.0; P = .01 [higher dosage worse]), maternal IQ (regression coefficient, 0.2; 95% CI, 0.0 to 0.4; P = .01 [higher child IQ with higher maternal IQ]), periconception folate use (adjusted IQ 6 [95% CI, 2–10] points higher for folate, P = .005), and breastfeeding (adjusted IQ 4 [95% CI, 0–8] points higher for breastfeeding, P = .045). For the other cognitive domains, only verbal abilities differed between the breastfed and nonbreastfed groups (adjusted verbal index 4 [95% CI, 0–7] points higher for breastfed children, P = .03). CONCLUSIONS AND RELEVANCE: No adverse effects of AED exposure via breast milk were observed at age 6 years, consistent with another recent study at age 3 years. In our study, breastfed children exhibited higher IQ and enhanced verbal abilities. Additional studies are needed to fully delineate the effects of all AEDs.
Commentary
Engaging in prepregnancy counseling for women with epilepsy is a critical yet delicate endeavor. More than perhaps at any other time, the patient wants to know and understand the specific risks of antiepileptic medications (AEDs), advocating on behalf of their developing children. These sessions typically focus on the risk–benefit ratio of taking AEDs during pregnancy, in which it is clear that in most cases, the risk of maternal seizure outweighs the risk of fetal exposure. In that sense, in utero AED exposure, optimally with lower risk AEDs, can usually be viewed as necessary. In contrast, discussions of breastfeeding have been more difficult. While the American Academy of Pediatrics recommends breastfeeding as the primary source of nutrition for the first 6 months (1), the risk–benefit ratio of breastfeeding benefit versus continued exposure to AEDs is less certain. In fact, as recently as 2009, a practice parameter from the American Academy of Neurology stated: “The clinical consequences for the newborn of ingesting AEDs via breast milk remain sorely underexplored and will continue to produce anxiety in women with epilepsy bearing children and all who care for these clinical dyads” (2).
Happily, the landscape has changed significantly since 2009, with an expanding body of evidence examining developmental outcomes after AED exposure through breastfeeding (3, 4). In this article derived from the Neurodevelopmental Effects of Antiepileptic Drugs Study (NEAD), Meador et al. present the age-6 outcome results for children exposed to AEDs during breastfeeding (5). NEAD is a prospective observational study that follows a cohort of women with epilepsy recruited during a pregnancy between 1999 and 2004 in the United States and the U.K. These women were taking a single AED in monotherapy during pregnancy, including carbamazepine, lamotrigine, phenytoin, or valproate. The longitudinal follow-up from the children of this cohort has contributed valuable evidence toward fetal exposure and breastfeeding exposure outcomes related to AED use in pregnant women with epilepsy.
A previous report from NEAD compared cognitive outcome of 199 children at age 3 years among breastfed and nonbreastfed children (3) and demonstrated no negative effects of breastfeeding on cognitive outcomes. The children of women who were still breastfeeding at 3 months after delivery were considered “breastfed” for the analysis. In this follow-up study, cognitive outcomes were again assessed in the breastfed versus nonbreastfed groups, now at age 6 and with a slightly smaller sample size of 181 children. The primary outcome was Differential Ability Scales IQ, and secondary measures included other cognitive domain indices. Forty-two percent of the children were breastfed, and the mean duration was 7.2 months.
The results are reassuring. In regression analysis, variables significantly associated with IQ included breastfeeding status (higher for breastfed group), AED group (lower for valproate), maternal IQ (higher for higher maternal IQ), periconceptual folate use (higher for positive use), and AED dosage (lower for higher valproate dose). Overall IQ at age 6 (adjusted for these other significant factors) was 108 in the breastfed group versus 104 in the nonbreastfed group, which was statistically significant. In the adjusted cognitive domain index analyses, verbal IQ was significantly higher in the breastfed group (mean IQ, 105) than the nonbreastfed group (mean IQ, 102), while the other indexes were not different.
It is important to examine these results in contrast to the 3-year outcome study. Both studies show no adverse cognitive outcomes associated with breastfeeding; this finding has also been reported in a large Norwegian cohort of children exposed to AEDs and examined out to 3 years (4). Since IQ at 6 years is a better predictor of school performance and beyond than IQ at 3 years, this finding is particularly welcome. Even more intriguing is the IQ advantage in the breastfed group noted at 6 years, which was not present at 3 years. While the authors present this data cautiously, given the challenges inherent in this evaluation, the results are certainly compatible with other reports linking breastfeeding and positive cognitive outcomes, including later cognition (6). Finally, although not specifically addressed by the authors, the mean adjusted IQs appear to have increased between the 3-year and 6-year evaluations for both the breastfed and nonbreastfed groups. This suggests the possibility that the IQ impact of prenatal AED exposure may recover to some degree by age 6, perhaps more robustly in the setting of having been breastfed. Certainly this is an avenue that should be further explored.
The article adds to the growing body of concern about perinatal valproate exposure and developmental outcome, which includes both fetal malformations and longer term behavioral and cognitive outcomes (7–9). In the NEAD studies previously published, prenatal valproate exposure was associated with a lower IQ at age 3 and 6 years (6, 7), which was not present for exposure to carbamazepine, lamotrigine, or phenytoin. In fact, the European Medical Agency's Pharmacovigilance and Risks Assessment Committee has recently strengthened the warning about valproate use in girls and women of childbearing age given the rate of adverse pregnancy outcomes, while acknowledging that at times the use of valproate is medically necessary (10). However, the data are not uniform regarding other AEDs, including breastfeeding data. For example, in the Norwegian study, Veiby et al. demonstrated impaired fine motor skills at age 6 months in infants prenatally exposed to AEDs, with similar results for lamotrigine, carbamazepine, and valproate exposure, and a breastfeeding advantage was noted in very early life but absent by age 36 months (4).
An important perspective on this and related studies is that these children have been exposed more directly to the same AEDs during the pregnancy, and the magnitude of AED exposure through breastmilk is typically considerably lower than in utero exposure (although this varies across AEDs owing to varying excretion and clearance rates). Assessing the incremental effects related to breastfeeding is therefore a particular challenge and was not accomplished in this study given the absence of a group who did not take AEDs during pregnancy. Other study limitations as discussed by the authors include the lack of randomization as well as the lack of reliable data regarding the exact duration of breastfeeding or any information regarding concentrations of the AEDs in breast milk. The most pressing limitation for clinical relevance may in fact be that the recruitment period ended in 2004, thus data regarding the newer AEDs is absent, yet some of these AEDs are now commonly used during pregnancy, such as levetiracetam. As an example, levetiracetam has been shown to be extensively excreted into breast milk but results in low measurable levels in the infant (11). An outcome study similar to NEAD would be very welcome.
The article presents compelling reassurance about the safety of breastfeeding in the setting of certain AED use for epilepsy, despite these limitations. The conclusion derived from this and other studies appears to be that maternal use of many AEDs for epilepsy does not worsen outcome and may in fact improve it. We await expanded prospective studies and similarly robust data for the newer AEDs.