Abstract
Early Child Development and Exposure to Antiepileptic Drugs Prenatally and through Breastfeeding: A Prospective Cohort Study on Children of Women with Epilepsy
Veiby G, Engelsen BA, Gilhus NE. JAMA Neurol 2013;70:1367–1374.
IMPORTANCE: Exposure to antiepileptic drugs during pregnancy is associated with adverse effects on psychomotor development. OBJECTIVES: To determine whether signs of impaired development appear already during the first months of life in children exposed prenatally to antiepileptic drugs, and to explore potential adverse effects of antiepileptic drug exposure through breastfeeding. DESIGN, SETTING, AND PARTICIPANTS: Mothers at 13 to 17 weeks of pregnancy were recruited in the population-based, prospective Norwegian Mother and Child Cohort Study from 1999 to 2009. 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. MAIN OUTCOMES AND MEASURES: The risk of adverse development in children according to maternal or paternal epilepsy was estimated as the odds ratio with corresponding 95% confidence interval, adjusted for maternal age, parity, education, smoking, breastfeeding, depression/anxiety, folate supplementation, and congenital malformation in the child. RESULTS: At age 6 months, infants of mothers using antiepileptic drugs (n = 223) had a higher risk of impaired fine motor skills compared with the reference group (11.5% vs 4.8%, respectively; odds ratio = 2.1; 95%CI, 1.3–3.2). Use of multiple antiepileptic drugs compared with the reference group was associated with adverse outcome 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; odds ratio = 2.6; 95%CI, 1.2–5.5). 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. At 36 months, prenatal antiepileptic drug exposure was associated with adverse development regardless of breastfeeding status during the first year. Children of women with epilepsy who did not use antiepileptic drugs and children of fathers with epilepsy had normal development at 6 months. CONCLUSIONS AND RELEVANCE: Prenatal exposure to antiepileptic drugs was associated with impaired fine motor skills already at age 6 months, especially when the child was exposed to multiple drugs. There were no harmful effects of breastfeeding. Women with epilepsy should be encouraged to breast-feed their children irrespective of antiepileptic drug treatment.
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 (i.e., 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
The clinical management of women with epilepsy who choose to have children requires balancing the health of the mother and potential harm to the child. Over the past 15 years, multiple worldwide pregnancy registries have tracked the safety (or adverse effects) of prenatal AED exposure. From recent data from the North American AED Pregnancy Registry (Fall 2014), the prevalence of malformations at birth is highest in infants exposed to valproate (9.0%, with the 95% confidence interval (CI) of 6.2 – 12.6%) but lower in infants exposed to lamotrigine (2.0%, 95%CI: 1.4 to 2.8%), phenytoin (2.9%, 95%CI: 1.5 to 5.0%), and carbamazepine (3.1%, 95%CI: 2.1 to 4.3%) (1). Long-term behavioral studies have indicated that in utero valproate exposure leads to developmental delay, intellectual disability, and behavioral and social disorders, including autism (1–3). Long-term effects of other AEDs are less clear and require further study. The difficult situation requires strategies to prevent or reduce the adverse consequences of prenatal AED treatment.
The benefits of breastfeeding continue to be discovered. The current guidelines of the American Academy of Pediatrics recommend breast milk as the primary source of nutrition for the first 6 months and as a supplement for at least the first year (4). Breastfeeding has been shown to reduce the incidence of infections, autoimmune disorders, sudden infant death syndrome (SIDS), and infant mortality. The greatest benefits were observed in children breastfed for more than 6 months, but any human milk is beneficial. Multiple studies associate breast-feeding with increased cognition, specifically verbal cognition, in preschool and school-age children. However, breastfeeding can be contraindicated in some cases, such as an infant with a metabolic disorder or maternal infections, or maternal medications that may be harmful.
For the case of AEDs, the safety of breastfeeding has been unclear, and the option was often discouraged by primary care physicians and pediatricians. The main concern is the level of AED(s) in the breast milk and the overall dose the infant will receive. Unlike in utero exposure, in which the fetal levels are similar to maternal plasma concentrations, AEDs are differentially secreted into human milk. Phenytoin and valproate are considered safe due to very low concentrations found in milk (5). By contrast, the levels of levetiracetam in breast milk are high and may be equivalent to a therapeutic dose. Therefore, a mother with epilepsy and her health care team are faced with the conundrum of whether the benefits of breastfeeding will overcome the potential harm due to the possible AED exposure.
New data from two independent studies support breastfeeding in mothers using AEDs but also confirm the adverse effects of prenatal AED exposure. Using the Norwegian mother and child cohort, Veiby, Engelsen and Gilhus assessed multiple developmental outcomes at birth through 36 months of age. The study evaluated 974 children of mothers or fathers with epilepsy, compared to a reference group of >77,000 children. The effects of three AEDs (lamotrigine, carbamazepine, and valproate, administered as monotherapy), along with polytherapy were measured. In general, breastfeeding was less common in mothers taking AEDs. The children who were not breastfeeding had higher rates of low body weight at 6 weeks, most marked in the AED polytherapy group, but there were no differences by age 6 months old.
At 6 months, children exposed in utero to the AED monotherapy regimens showed a marginal increased risk of fine motor skill impairment, while the children with in utero AED polytherapy exposure had a particularly high risk for fine motor impairment and for social impairment, compared to the reference control reference group of 77,770 children, in agreement with the literature. Children of mothers with epilepsy who did not use AEDs during the pregnancy and children of fathers with epilepsy exhibited normal development, providing evidence that the observed impaired fine motor and social skills were due to AED exposure and not genetic factors. The most important findings were that in no cases did maternal AED use during breastfeeding adversely affect child development, providing strong support that breastfeeding is safe for this population. Trends for improvements in outcomes in fine motor, gross motor, and social skills were observed in children who were breastfeed for >6 months compared to <6 months, suggesting longer times can be beneficial. Additional assessment at 18 months for communication skills and at 36 months for autistic traits, sentence skills, symptoms of attentional deficit hyperactivity disorder (ADHD), or aggression found no adverse effects of breastfeeding. The risk of developing autistic traits was significantly greater in the non-breastfed AED-exposed group at 18 months but not at 36 months. The study was limited by potential bias present in the maternal reports used for the behavioral assessments. Additional studies and data may lead to a positive correlation with breastfeeding duration and decreased risk of adverse developmental scores.
The finding that breastfeeding has no adverse effects on cognition in the Norwegian cohort is supported by data from the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study of children in the United States and the United Kingdom. The NEAD study used intelligence quotient (IQ) as determined by blinded assessors as a measure of cognition. The NEAD study included four AEDs (carbamazepine, lamotrigine, phenytoin, and valproate) given as monotherapy, but this study did not include unexposed children. The newest data on children at 6 years of age show no adverse effects of breastfeeding, and most surprising that breastfeeding may reverse the cognitive impairment of prenatal AED exposure (6). Breastfed children exhibited significant impressive increases in IQ and verbal cognitive domain index scores. The effects of breastfeeding are beneficial and long lasting, leading to gains into school ages and perhaps longer.
For a mother prescribed an AED, the recommendation to breastfeed her children is supported by these two studies, which utilized different methodologies and different populations, yet the scientific details of the critical components of human milk are unknown. The few reports that examine the effects of AEDs on the early postnatal brain demonstrate neuron cell death, disruptions in synapse formation, and behavioral deficits (7, 8). However, animal studies use therapeutic doses, not the subtherapeutic levels expected to be present in milk, and they do not control for the non-nursing condition. With current data on the levels of AEDs in human milk, animal experiments can be designed to find the beneficial components of milk and develop testing platforms to find components (either dietary or pharmaceutical) that may reverse the effects of prenatal AED exposure.