Comparative Risk for Major Congenital Malformations With High-Dose Antiepileptic Drugs

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An adjusted multivariable analysis demonstrated a significantly higher risk for major congenital malformations for all carbamazepine and valproate doses compared with lamotrigine ≤325 mg/day.
An adjusted multivariable analysis demonstrated a significantly higher risk for major congenital malformations for all carbamazepine and valproate doses compared with lamotrigine ≤325 mg/day.

The prevalence of major congenital malformations in offspring who are prenatally exposed to antiepileptic drugs is highest among those exposed to carbamazepine, phenobarbital doses of >80 mg/day, valproate of ≤650 mg/day, and levetiracetam at 250 to 4000 mg/day, according to a study published in Lancet Neurology. Prevalence rates also increase with specific drug doses at time of conception.

In this longitudinal, prospective analysis of patients in the EURAP international registry, investigators assessed the risk for major congenital malformations in offspring at 1 year who were prenatally exposed to 1 of 8 commonly prescribed antiepileptic drugs. The drugs assessed in the analysis included carbamazepine (n=1957), lamotrigine (n=2514), levetiracetam (n=599), oxcarbazepine (n=333), phenobarbital (n=294), phenytoin (n=125), topiramate (n=152), and valproate (n=1381). Investigators also compared risks associated with different antiepileptic dose ranges when dose dependency was detected.

A total of 7355 pregnancies with exposure to antiepileptic drug monotherapy were analyzed. For valproate, phenobarbital, phenytoin, carbamazepine, topiramate, oxcarbazepine, lamotrigine, and levetiracetam, the prevalence rates of major congenital malformations in offspring at 1 year were 10.3%, 6.5%, 6.4%, 5.5%, 3.9%, 3.0%, 2.9%, and 2.8%, respectively.

The major congenital malformation prevalence rate increased with drug dose at time of conception for carbamazepine (≤700 mg/day vs >700 mg/day, 4.5% [95% CI, 3.5-5.8] vs 7.2% [95% CI, 5.4-9.4]; P =.0140), lamotrigine (≤325 mg/day vs >325 mg/day, 2.5% [95% CI, 1.8-3.3] vs 4.3% [95% CI, 2.9-6.2]; P =.0145), phenobarbital (≤80 mg/day vs >80 to ≤130 mg/day vs >130 mg/day, 2.7% [95% CI, 0.3-9.5] vs 6.2% [95% CI, 3.0-11.1] vs 11.7% [95% CI, 4.8-22.6]; P =.0390), and valproate (≤650 mg/day vs >650 to ≤1450 mg/day vs >1450 mg/day, 6.3% [95% CI, 4.5-8.6] vs 11.3% [95% CI, 9.0-13.9] vs 25.2% [95% CI, 17.6-34.2]; P <.0001).

An adjusted multivariable analysis demonstrated a significantly higher risk for major congenital malformations for all carbamazepine (P =.0002 and P =.0143) and valproate (P =.0002, P =.0002, and P =.0002) doses compared with lamotrigine of ≤325 mg/day. In addition, there were significantly higher prevalence rates for phenobarbital doses of >80 mg/day than for lamotrigine at doses of ≤325 mg/day (P =.0196). Valproate of ≤650 mg/day also correlated with an increased risk for major congenital malformations vs levetiracetam at 250 to 4000 mg/day (odds ratio [OR] 2.43; 95% CI, 1.30-4.55; P =.0069), as did carbamazepine of >700 mg/day (OR 2.41; 95% CI, 1.33-4.38; P =.0055) and oxcarbazepine of 75 to 4500 mg/day (OR 2.37; 95% CI, 1.17-4.80; P =.0169).

A limitation of this analysis includes the absence of a control group to represent pregnancies without antiepileptic drug exposure.

Results from the study provide “physicians with vital information when they consider different treatment alternatives for women who are of childbearing potential.”

Reference

Tomson T, Battino D, Bonizzoni E, et al; for the EURAP Study Group. Comparative risk of major congenital malformations with eight different antiepileptic drugs: a prospective cohort study of the EURAP registry [published online April 18, 2018]. doi: 10.1016/S1474-4422(18)30107-8

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