Objectives In utero exposure to antiepileptic drugs has previously been associated with adverse outcome among offspring, but evidence on longer term milestone development remains limited. We investigated the association between in utero exposure to antiepileptic drugs and learning disabilities in the first year of compulsory education among offspring and assessed which antiepileptic drugs carried the highest risk.
Methods This population-based case–cohort study used Danish nationwide register data from 2005 to 2008. Cases were offspring exposed to antiepileptic drugs in utero, and controls were unexposed offspring of mothers previously redeeming antiepileptic drug prescriptions. Offspring were followed from birth until the first year of compulsory education from 2011 to 2015. Learning disabilities were defined as mental retardation, specific developmental disorders, autism spectrum disorders, emotional/behavioural disorders or having special educational needs. Logistic regression was used to compute ORs with 95% CIs adjusted for potential confounding.
Results Of 117 475 incident singleton births, 636 cases and 434 controls were included (median age: 6.1 years, males: 55.7%). Learning disabilities were identified among 7.1% cases compared with 3.7% for controls. During any trimester, the adjusted OR of the association between in utero exposure to antiepileptic drugs and learning disabilities was 2.20 (95% CI 1.16 to 4.17). Among cases not exposed to polytherapy (n=556), in utero exposure to lamotrigine compared with another antiepileptic drug was associated with the lowest adjusted risk (OR 0.42, 95% CI 0.19 to 0.92), and valproate carried a higher risk (OR 4.67, 95% CI 1.73 to 12.59).
Conclusion In utero exposure to antiepileptic drugs was significantly associated with learning disabilities among offspring. Lamotrigine should preferentially be considered over, for example, valproate if clinically feasible.
- Antiepileptic drugs
- In utero exposure
- Learning disabilities
- Cognitive functioning
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Contributors LFB: study design, data management, data analysis, drafting of manuscript and manuscript preparation; CP: study design, data management, data analysis and manuscript revision; KK: study design, data management and manuscript revision; MPA: study design, data management and manuscript revision; CR, CT-P, JN and SH: manuscript revision.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests CP reported receiving speaker honorarium from Lundbeck. KK reported receiving speaker honorarium from Novartis and research grants from the Laerdal Foundation. CT-P reported receiving research grants from Bayer. JN reported receiving research grants from Lundbeck and Pfizer and speaker honoraria from Bristol-Myers Squibb, Lundbeck and Sunovion.
Patient consent Not required.
Ethics approval Statistics Denmark and the Danish Health Data Authority approved the use of data for this study. By Danish law, ethics approval is not required for register-based studies.
Provenance and peer review Not commissioned; externally peer reviewed.
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