The epilepsy and pregnancy registries have been operational for some 25 years and have made major contributions to our understanding of the comparative safety of different ASMs and of other related aspects. As already mentioned, the outcome of primary interest in these registries is MCMs, and the prevalence of MCMs after exposure to monotherapy of the eight most frequently used ASMs has been published [8,9,10,11,12]. The absolute risk in terms of prevalence of MCMs with specific ASMs may differ slightly between the registries presumably mainly due to differences in methodologies, but the overall pattern is very similar across registries when it comes to comparisons between ASMs. Valproate is consistently associated with the highest prevalence of MCMs, whereas lamotrigine, levetiracetam, and possibly oxcarbazepine are associated with the lowest risks (Table 1).

The registries have also shown that for some ASMs the risk of MCMs is dose dependent. The EURAP registry reported a higher prevalence of MCMs with increasing doses at the time of conception for valproate, phenobarbital, carbamazepine, and lamotrigine [15]. In a subsequent publication, EURAP provided comparisons of MCM risk between different ASMs at different dose levels to assist in the individual risk assessments and evidence-based treatment selection [12].

Being multinational, EURAP has the opportunity to compare ASM use during pregnancy between the participating countries, and an early publication revealed significant differences with regard to proportion using polytherapy as well as using first-generation ASMs [16]. Furthermore, changes in ASM selection over time have been analyzed. Over a 14-year period, the use of valproate and carbamazepine during pregnancy decreased markedly whereas the proportion of treatments with lamotrigine and levetiracetam increased [17]. In parallel with this shift in ASM use, the prevalence of MCMs declined by approximately 25%, indicating the benefits associated with the use of these newer-generation ASMs [17]. Interestingly, there was no indication of a higher rate of pregnancies with uncontrolled tonic–clonic seizures associated with this change in drug selection. However, the impact on seizure control may be different if switches or withdrawals are carried out during pregnancy rather than being completed well in advance of conception. A EURAP analysis of pregnancies where valproate was withdrawn or switched to another ASM during the first trimester showed that, compared with those who continued on valproate, the risk of major convulsive seizures was doubled (33% among withdrawals, 29% among switchers, vs. 16% among those with maintained use of valproate; [18]).

Most of the data from the pregnancy registries are on ASM monotherapies. An analysis of data from NAAPR, the UK Ireland Pregnancy Register, and the International Lamotrigine Pregnancy Registry demonstrated the importance of considering the type of ASMs included in polytherapy rather than just the number of drugs [19]. It appeared from this analysis that it was the inclusion of valproate in the combination therapy that was driving the higher prevalence of MCMs in polytherapy. The risk was much higher when carbamazepine or lamotrigine was combined with valproate compared with a combination of lamotrigine and carbamazepine or lamotrigine with any non-valproate ASM [19]. A more detailed analysis of MCM risks with valproate in monotherapy and in combination with lamotrigine or with other ASMs was carried out based on EURAP data [20]. Whether in monotherapy or combination therapy, the MCM risk increased with the dose of valproate. Interestingly, the prevalence of MCM when valproate at the lowest dose category (< 700 mg/day) was combined with lamotrigine (7.0%) or with any other ASM (5.4%) appeared to be lower than with valproate in monotherapy at a higher dose level (11% at doses 700–1500/day; and 24% at > 1500 mg/day; [20]).

EURAP and some other specific epilepsy and pregnancy registries prospectively collect information on seizures during pregnancy. In a first report [21] of 1956 pregnancies of 1882 women with epilepsy, 58% were seizure-free throughout pregnancy. There were 36 cases of status epilepticus (12 convulsive), which resulted in stillbirth in one case, but no cases of miscarriage or maternal mortality. A subsequent report focused on 3806 pregnancies of 3451 women on ASM monotherapy for their epilepsy [22]. Of all cases, 67% remained seizure-free throughout pregnancy. Generalized tonic–clonic seizures occurred in 15% of the pregnancies. Women with idiopathic generalized epilepsies were more likely to remain seizure-free (74%) than women with localization-related epilepsy (60%). There were 21 cases of status epilepticus (10 convulsive): none with maternal mortality and only one with a subsequent stillbirth.