Do the Results of Pregnancy Registries Contradict One Another?
Authors: Harden Cynthia L. 
Published: May 2006

Malformation Risks of Antiepileptic Drugs in Pregnancy: A Prospective Study from the UK Epilepsy and Pregnancy Register

J Morrow, A Russell, E Guthrie, L Parsons, I Robertson, R Waddell, B Irwin, R C, McGivern, P J Morrison, J Craig

J Neurol Neurosurg Psychiatry 2006;77;193–198

Objective

To assess the relative risk of major congenital malformation (MCM) from in utero exposure to antiepileptic drug (AED).

Methods

Prospective data collected by the UK Epilepsy and Pregnancy Register were analyzed. The presence of MCMs recorded within the first 3 months of life was the main outcome measure.

Results

Full outcome data were collected on 3,607 cases. The overall MCM rate for all AED exposed cases was 4.2% (95% confidence interval (CI): 3.6–5.0%). The MCM rate was higher for polytherapy (6.0%) ( n = 770) than for monotherapy (3.7%) ( n = 2,598) (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% (1.8–6.8%). The MCM rate was greater for pregnancies exposed only to valproate (6.2% (95% CI: 4.6–8.2)) than only to carbamazepine (2.2% (1.4–3.4%)) (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—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. Maternal Valproate Dosage and Foetal Malformations Vajda FJ, Eadie MJ Acta Neurol Scand 2005;112(3):137–143

Objective

To study the possible dose dependence of the foetal malformation rate after exposure to sodium valproate in pregnancy.

Methods

Analysis of records of all foetuses in the Australian Registry of Antiepileptic Drugs in Pregnancy exposed to valproate, to carbamazepine, lamotrigine or phenytoin in the absence of valproate, and to no antiepileptic drugs.

Results

The foetal malformation rate was higher ( p < 0.05) in the 110 foetuses exposed to valproate alone (17.1%), and in the 165 exposed to valproate, whether alone or together with the other antiepileptic drugs (15.2%), than in the 297 exposed to the other drugs without valproate (2.4%). It was also higher ( p < 0.10) than in the 40 not exposed to antiepileptic drugs (2.5%). Unlike the situation for the other drugs, the malformation rate in those exposed to valproate increased with increasing maternal drug dosage ( p < 0.05). The rate was not altered by simultaneous exposure to the other drugs. Valproate doses exceeding 1,400 mg per day seemed to be associated with a more steeply increasing malformation rate than at lower doses and with a different pattern of foetal malformations.

Conclusions

Foetal exposure to valproate during pregnancy is associated with particularly high, and dose-dependent risks of malformation compared with other antiepileptic drugs, and may possibly involve different teratogenetic mechanisms.