Objective: To assess the relative risk of major congenital malformation (MCM) from in utero exposure to antiepileptic drug (AEDs). Methods: Prospective data collected by the UK Epilepsy and Pregnancy Register were analysed. The presence of MCMs recorded within the first three months of life was the main outcome measure. Results: Full outcome data were collected on 3607 cases. The overall MCM rate for all AED exposed cases was 4.2% (95% confidence interval (CI), 3.6% to 5.0%). The MCM rate was higher for polytherapy (6.0%) (n = 770) than for monotherapy (3.7%) (n = 2598) (crude odds ratio (OR) = 1.63 (p = 0.010), adjusted OR = 1.83 (p = 0.002)). The MCM rate for women with epilepsy who had not taken AEDs during pregnancy (n = 239) was 3.5% (1.8% to 6.8%). The MCM rate was greater for pregnancies exposed only to valproate (6.2% (95% CI, 4.6% to 8.2%) than only to carbamazepine (2.2% (1.4% to 3.4%) (OR = 2.78 (p,0.001); adjusted OR = 2.97 (p,0.001)). There were fewer MCMs for pregnancies exposed only to lamotrigine than only to valproate. A positive dose response for MCMs was found for lamotrigine (p = 0.006). Polytherapy combinations containing valproate carried a higher risk of MCM than combinations not containing valproate (OR = 2.49 (1.31 to 4.70)). Conclusions: Only 4.2% of live births to women with epilepsy had an MCM. The MCM rate for polytherapy exposure was greater than for monotherapy exposure. Polytherapy regimens containing valproate had significantly more MCMs than those not containing valproate. For monotherapy exposures, carbamazepine was associated with the lowest risk of MCM.

In utero exposure to valproate carries a significantly higher MCM risk than lamotrigine (p=0.0001) and carbamazepine (p=0.0001) monotherapy. In contrast to prior findings, high-dose lamotrigine was associated with fewer MCMs than all doses of valproate. While lamotrigine has a favourable profile compared with valproate for adverse pregnancy outcomes, the requirements for seizure control should not be overlooked.

The number of outcomes of human pregnancies exposed to topiramate is low, but the major congenital malformation rate for topiramate polytherapy raises some concerns. Overall, the rate of oral clefts observed was 11 times the background rate. Although the present data provide new information, they should be interpreted with caution due to the sample size and wide confidence intervals.

Preconception counseling should include discussion of neurodevelopmental outcomes for specific treatments and their doses and women should be made aware of the limited nature of the evidence base for newer antiepileptic drugs.

Children exposed to LEV in utero are not at an increased risk of delayed early cognitive development under the age of 24 months. LEV may therefore be a preferable drug choice, where appropriate, for WWE prior to and of childbearing age.

This study, in a meaningful number of exposed pregnancies, confirms a low risk for MCM with levetiracetam monotherapy use in pregnancy. MCM risk is higher when levetiracetam is taken as part of a polytherapy regimen, although further work is required to determine the risks of particular combinations. With respect to MCM, levetiracetam taken in monotherapy can be considered a safer alternative to valproate for women with epilepsy of childbearing age.

The study supports the view that extrapolation from studies carried out in the general population to groups of women with epilepsy may be questionable. It may be that the increased risk of MCM recorded in this group occurs through mechanisms other than that of folic acid metabolism.

The current study indicates that children exposed to LEV in utero were superior in their language and motor development in comparison to children exposed to VPA. This information should be used collaboratively between health care professionals and WWE when deciding on women's preferred choice of antiepileptic drug.