Anti‐epileptic drug exposure and risk of foetal death in utero

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Since 1964, there has been intermittent interest in the question of whether anti‐epileptic drug (AED) exposure during pregnancy is associated with increased risks of spontaneous abortion or stillbirth.1 A recent meta‐analysis based on 39 relevant studies published between 1990 and 2015 was carried out by Viale et al2 These authors found that there was a statistically significantly increased hazard of spontaneous abortion but not of stillbirth in the pregnancies of women with epilepsy, as compared with the pregnancies of untreated normal women. The rate of intrauterine foetal death (spontaneous abortion plus stillbirth) was not significantly higher in AED‐treated pregnancies, but was statistically significantly so in series where over 30% of the pregnancies in the series had been exposed to AEDs, as compared with series with lower rates of pregnancy AED exposure. AED polytherapy was not associated with increased spontaneous abortion or stillbirth rates.
The Viale et al2 paper did not include the recent large study of Tomson et al3 that was based on 7055 pregnancies from the EURAP Pregnancy Register. That study found very similar rates of intrauterine foetal death (spontaneous abortion plus stillbirth) for women taking various more commonly employed AEDs (lamotrigine, carbamazepine, valproate, levetiracetam, oxcarbazepine, phenobarbitone) and no correlations with AED dosage. Unfortunately, this study did not include a control group of pregnant women with epilepsy that was not treated with an AED. In contrast to the Vaile et al2 study, AED polytherapy in the Tomson et al study was found to be associated with a statistically significantly higher rate of intrauterine foetal death.
As the findings of these two studies differed in some regards, we have utilized data from the Australian Register of AEDs in Pregnancy (APR) to investigate the association of AED use during pregnancy with intrauterine foetal deaths. The APR contains a subset of pregnancies unexposed to AEDs, in at least the earlier half of pregnancy, in women with epilepsy, and this subset can provide a comparator for the Register's AED‐exposed pregnancies. Data from this work have also been provided for the EURAP data set in collaboration with the International Register, chaired by T. Tomson.

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