Using antiepileptic drugs during pregnancy may harm IQ of newborns

Prenatal exposure to antiepileptic drugs (AEDs), particularly valproate, was associated with an excess risk of intellectual disability as well as delayed childhood milestones in the offspring, a study has shown.

“These findings suggest that women of childbearing potential may need to be counselled on [the] use of AEDs,” said the researchers.

After more than 10.2 million person-years of follow-up, the researchers identified 6,958 children (0.8 percent) as having intellectual disability and 14,967 (1.6 percent) as having intellectual disabilities combined with delayed childhood milestones. Participants were 913,302 children (51.3 percent boys, mean age 10.3 years) born as singletons from the Danish national healthcare registries. [JAMA Netw Open 2020;doi:10.1001/jamanetworkopen.2020.25570]

Compared with offspring with no exposure to valproate prenatally, children whose mothers used valproate during pregnancy were almost fivefold more likely to have intellectual disability (adjusted hazard ratio [aHR], 4.48, 95 percent confidence interval [CI], 2.97– 6.76).

Similarly, the combined risk of both intellectual disability and delayed childhood milestones were also significantly higher in offspring exposed to valproate prenatally than those who were not (aHR, 6.07, 95 percent CI, 4.67–7.89).

“The association persisted after adjusting for a range of potential confounders [ie, maternal psychiatric disorders, maternal epilepsy and diabetes status, maternal age, sex of child, year of birth of child, and parity] and showed an association with high-dose exposure but not with low-dose exposure,” the researchers noted.

“[Moreover,] increased risk of intellectual disability and combined outcome remained significant after excluding all children diagnosed with congenital malformations, suggesting that the risk was not confined to children with valproate-induced congenital malformations,” they pointed out.

When restricting the analyses to mothers with epilepsy, prenatal exposure to valproate remained associated with excess risk of intellectual disability (aHR, 1.95, 95 percent CI, 1.21–3.14) as well as intellectual disability with delayed childhood milestones (aHR, 3.07, 95 percent CI, 2.24-4.20).

In addition, sensitivity analyses suggest that the association was dose dependent. The risk of intellectual disability was increased with prenatal exposure to high-dose valproate monotherapy (>750 mg/day; aHR, 7.96, 95 percent CI, 4.80–13.19), but not with exposure at low dose (≤750 mg/day).   

Furthermore, use of other AEDs during pregnancy was also associated with a greater risk of intellectual disability in exposed offspring compared with nonexposed offspring. These drugs included carbamazepine (aHR, 3.84, 95 percent CI, 2.32–6.38), oxcarbazepine (aHR, 3.70, 95 percent CI, 2.11–6.51), and clonazepam (aHR, 2.41, 95 percent CI, 1.09–5.35), but not lamotrigine (aHR, 1.33, 95 percent CI, 0.71–2.48).

Compared with lamotrigene, prenatal exposure of all AEDs studied, except clonazepam, were associated with significant excess risk of intellectual disability (aHR, 4.91 for valproate; aHR, 3.30 for carbamazepine; and aHR, 3.53 for oxcarbazepine).

These associations between prenatal exposure to AEDs other than valproate and intellectual disabilities in offspring have not been reported previously, according to the researchers, who said these findings hold “clear implications for women of childbearing potential.”