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Observational Study
. 2014 Aug;168(8):729-36.
doi: 10.1001/jamapediatrics.2014.118.

Breastfeeding in children of women taking antiepileptic drugs: cognitive outcomes at age 6 years

Kimford J Meador  1 , Gus A Baker  2 , Nancy Browning  3 , Morris J Cohen  4 , Rebecca L Bromley  5 , Jill Clayton-Smith  5 , Laura A Kalayjian  6 , Andres Kanner  7 , Joyce D Liporace  8 , Page B Pennell  9 , Michael Privitera  10 , David W Loring  11 ; Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) Study Group
Collaborators, Affiliations
Observational Study

Breastfeeding in children of women taking antiepileptic drugs: cognitive outcomes at age 6 years

Kimford J Meador et al. JAMA Pediatr. 2014 Aug.

Abstract

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.

Trial registration: clinicaltrials.gov Identifier: NCT00021866.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Meador reported serving on the editorial boards of Neurology, Behavior & Neurology, Epilepsy & Behavior, Epilepsy.com, and the Journal of Clinical Neurophysiology and on the professional advisory board for the Epilepsy Foundation; receiving travel support from sanofi-aventis; and receiving research support from GlaxoSmithKline, Eisai Inc, Marinus Pharmaceuticals Inc, Myriad Genetics Inc, NeuroPace Inc, Pfizer Inc, SAM Technology Inc, UCB Pharma, the National Institutes of Health (National Institute of Neurological Disorders and Stroke 2R01-NS38455 [principal investigator], 2U01-NS038455 [multi-principal investigator], and 1R01-NS076665 [consultant]), the Patient-Centered Outcomes Research Institute (527 [co-principal investigator]), and the Epilepsy Foundation. Dr Meador reported having consulted for the Epilepsy Study Consortium and receiving money from multiple pharmaceutical companies (in relation to his work for Eisai Inc, NeuroPace Inc, Novartis, Supernus, Upsher Smith Laboratories, UCB Pharma, and Vivus Pharmaceuticals). The funds for consulting for the Epilepsy Study Consortium were paid to Emory University. Dr Baker reported serving on a scientific advisory board for sanofi-aventis; serving on the editorial board of Epilepsy and Behavior; having received speaker honoraria from Eisai Inc, UCB Pharma, and Janssen; receiving research support from UCB Pharma, sanofi-aventis, Pfizer Inc, Epilepsy Research United Kingdom, Medical Research Council, and Epilepsy Action United Kingdom; and having served as an expert witness in litigation related to neurodevelopmental effects of antiepileptic drugs. Dr Browning reported receiving research support from the National Institutes of Health, including National Institute of Neurological Disorders and Stroke R01-NS050659 (statistician and data center principal investigator), grant 2U01NS038455-11A1, Maternal Outcomes and Neurodevelopmental Effects of Antiepileptic Drugs grant, National Institute of Neurological Disorders and Stroke and National Institute of Child Health and Human Development contract N01-A1-80013, and the Statistical and Data Coordinating Center Clinical Research in Infectious Disease contract for Division of Microbiology and Infectious Diseases/National Institute of Allergy and Infectious Diseases HHSN272200800013C. Dr Cohen reported serving on the editorial board of Developmental Neuropsychology and receiving royalties from the publication of Children’s Memory Scale (Psychological Corporation, 1997). Dr Bromley reported receiving lecture fees from sanofi-aventis (2 occasions), receiving conference travel support from UCB Pharma, and providing expert testimony pertaining to fetal anticonvulsant syndrome. Dr Clayton-Smith is the journal editor for Clinical Dysmorphology and reported having served as an expert witness in litigation related to neurodevelopmental effects of antiepileptic drugs. Dr Kalayjian reported receiving funding from the National Institutes of Health. Dr Kanner is a member of the data safety board for Vertex Laboratories and reported having served as a consultant for NeuroPace Inc. Dr Liporace reported receiving royalties from the publication of Crash Course Neurology (Elsevier, 2006) and having served on speakers’ bureaus for and received speaker honoraria from UCB Pharma and GlaxoSmithKline. Dr Pennell reported receiving research funding toward salary support from the Epilepsy Therapy Project, the Epilepsy Foundation, and the National Institutes of Health; receiving travel support and honoraria from the American Epilepsy Society and the American Academy of Neurology; and receiving travel support from the Tbilisi State Medical University and the Indian Academy of Neurology. She also reported serving as a volunteer member of the board of directors of the American Epilepsy Society and of the professional advisory board of the Epilepsy Foundation. Dr Privitera reported serving on scientific advisory boards or as a consultant on the data and safety monitoring boards for Upsher Smith Laboratories, GlaxoSmithKline, Lilly, and Astellas; receiving funding for travel and speaker honoraria from UCB Pharma; serving on speakers’ bureau for UCB Pharma; and receiving research support from UCB Pharma, Neuren, Eisai Inc, the National Institutes of Health (K23 NS052468 [co-mentor]), the American Epilepsy Society, the Food and Drug Administration, and the Shor Foundation for Epilepsy Research. Dr Loring reported serving on scientific advisory boards for the Epilepsy Foundation, serving as an associate editor for Epilepsia and is on the editorial board of Neuropsychology Review and Epilepsy Research, serving as a consultant for NeuroPace Inc, receiving royalties from the publication of the fourth edition of Neuropsychological Assessment (Oxford University Press, 2004) and INS Dictionary of Neuropsychology (Oxford University Press, 1999), estimating that 50% of his clinical effort involves neuropsychological testing, and receiving research support from the National Institutes of Health (National Institute of Neurological Disorders and Stroke R01038455 [coinvestigator] and R01 NS035929 [coinvestigator]) and the Patient-Centered Outcomes Research Institute (527 [principal investigator]). No other disclosures were reported.

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