Association of Prenatal Exposure to Valproate and Other Antiepileptic Drugs With Intellectual Disability and Delayed Childhood Milestones.

Importance: There is concern about neurodevelopmental outcomes associated with prenatal exposure to valproate and other antiepileptic drugs (AEDs) among children of mothers with or without epilepsy. Objective: To study the risk of intellectual disability and delayed development in childhood milestones among children of women who used valproate or other AEDs during pregnancy. Design, Setting, and Participants: This population-based cohort study analyzed information on use of AEDs from the Danish National Prescription Registry and register diagnoses from the Danish Psychiatric Central Research Register and Danish National Patient Registry. The study included all live-born singletons in Denmark from January 1, 1997, to December 31, 2011. Data were analyzed in April 2020. Exposures: Prenatal exposure to maternal valproate and other AEDs. Main Outcomes and Measures: The main measures were adjusted Cox regression estimates of hazard ratios (aHRs) for intellectual disability and a combined outcome of intellectual disability with delayed childhood milestones. Results: A total of 913 302 children (468 708 [51.3%] boys; mean [SD] age, 10.3 [4.4] years and median [interquartile range] age, 10.1 [6.5-14.0] years at final follow-up) were identified and contributed more than 10.2 million person-years of observation, including 580 children exposed to valproate (302 [51.3%] boys). At end of follow-up, 6958 children (0.8%) were identified as having intellectual disability and 14 967 children (1.6%) were identified as having intellectual disability with delayed childhood milestones. Compared with offspring not exposed to valproate prenatally, offspring of women who used valproate during pregnancy had increased risk of intellectual disability (aHR, 4.48; 95% CI, 2.97-6.76) and intellectual disability with delayed childhood milestones (aHR, 6.07; 95% CI, 4.67-7.89). Among mothers with epilepsy, offspring exposed prenatally to valproate had increased risk of intellectual disability (aHR, 1.95; 95% CI, 1.21-3.14) and intellectual disability with delayed childhood milestones (aHR, 3.07; 95% CI, 2.24-4.20) compared with offspring without prenatal exposure. Compared with offspring without prenatal exposure to AEDs, increased risk of intellectual disability was identified in children with prenatal exposure to maternal monotherapy use of carbamazepine (aHR, 3.84; 95% CI, 2.32-6.38), clonazepam (aHR, 2.41; 95% CI, 1.09-5.35), and oxcarbazepine (aHR, 3.70; 95% CI, 2.11-6.51) but not lamotrigine (aHR, 1.33; 95% CI, 0.71-2.48). Conclusions and Relevance: These findings suggest that prenatal exposure to valproate was associated with increased risk of intellectual disability and delayed childhood milestones. Statistically significant associations were also found for prenatal exposure to other AEDs. These findings suggest that women of childbearing potential may need to be counseled on use of AEDs.

Use of antiepileptic drugs in women of fertile age.

INTRODUCTION: We studied the use of antiepileptic drugs (AEDs) in women of fertile age and pregnant women in a 16-year-period in Denmark. METHODS: We included all women of fertile age (age 18-44 years) and pregnant women from 2001 to 2016 identified from Danish registers. RESULTS: The median proportion of women of fertile age who took AEDs increased from 10.7‰ (95% confidence interval (CI): 10.5-10.9‰) in 2001 to 27.1‰ (95% CI: 26.8-27.4‰) in 2016. Lamotrigine, levetiracetam, gabapentin and pregabalin have been increasingly used over time and have been the main AEDs used in recent years. The use of valproate in women of fertile age decreased slightly from 2.1‰ (95% CI: 2.0-2.2‰) to 1.9‰ (95% CI: 1.8-2.0‰), which was explained by a decrease in the use after 2014 among women aged 18-24 years. The increased use of AEDs was likely owed to use for other indications than epilepsy. The overall use of AEDs in pregnant women increased from 3.8‰ (95% CI: 3.3-4.3‰) in 2001 to 6.9‰ (95% CI: 6.2-7.6‰) in 2016, and the use of valproate decreased from 0.6‰ (95% CI: 0.4-0.8‰) in 2001 to 0.2‰ (95% CI: 0.1-0.4‰) in 2016. CONCLUSIONS: The overall use of AEDs in women of fertile age and pregnant women has increased in the past 16 years, especially due to an increased use of lamotrigine. However, valproate use in pregnant women and in younger women of fertile age has become less frequent. FUNDING: This study received funding from the Lundbeck Foundation, the Danish Epilepsy Association, the Central Denmark Region and the Novo Nordisk Foundation (NNF16OC0019126). TRIAL REGISTRATION: none.