Abstract
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. 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. 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. Prenatal exposure to maternal valproate and other AEDs. 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. 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). 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.
Highlights
Intellectual disability is a severe neurodevelopmental disorder, characterized by inhibited mental development and impairment of cognitive abilities with an IQ usually less than 70.1,2 The use of antiepileptic drugs (AEDs), including valproate, by pregnant women has been associated with adverse neurodevelopment in their children.[3]
Compared with offspring not exposed to valproate prenatally, offspring of women who used valproate during pregnancy had increased risk of intellectual disability and intellectual disability with delayed childhood milestones
Among mothers with epilepsy, offspring exposed prenatally to valproate had increased risk of intellectual disability and intellectual disability with delayed childhood milestones compared with offspring without prenatal exposure
Summary
Intellectual disability is a severe neurodevelopmental disorder, characterized by inhibited mental development and impairment of cognitive abilities with an IQ usually less than 70.1,2 The use of antiepileptic drugs (AEDs), including valproate, by pregnant women has been associated with adverse neurodevelopment in their children.[3]. A 2019 study[4] assessed neurodevelopment in offspring of women who had epilepsy and used valproate while pregnant, comparing the associated risk of adverse neurodevelopment with that among offspring of women with epilepsy who used other AEDs while pregnant. No studies to our knowledge have compared the risk of intellectual disability among children exposed to AEDs before birth with that of children not exposed to AEDs before birth, and we assessed this risk in a large, nationwide study in Denmark. To give a fuller description of adverse events that may be associated with prenatal exposure to AEDs, we included delayed development in childhood milestones in our risk assessment
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