The onset of large prospective studies designed to answer the question regarding the longer term outcome of children exposed to AEDs in utero
marks a large step forward in this area of research. The Kerala Registry of Epilepsy and Pregnancy (KREP) is a registry designed to examine the birth and later abilities of the child born to a mother with epilepsy. Recent published results from this registry report on the evaluation of 395 children under the age of 2 years [29••
]. They found that children exposed to monotherapy VPA (n
= 71) were significantly poorer in their motor abilities than those exposed to CBZ in utero
= 101). Children exposed to VPA in utero
also had the poorest mental development mean score and had the highest incidence of children falling within the impaired range (40.8%) among the other monotherapy groups (CBZ 29.7%, phenobarbital 26.8% and PHT 37.9%). These differences did not reach statistical significance, however, and the group exposed to PHT in utero
did not differ greatly from the VPA group. The incidence of impaired performance was higher but again not significantly different for the polytherapy-exposed children (48.7%) in comparison with the monotherapy-exposed children (33.7%). Maternal IQ, a strong correlate of child IQ, was not measured and a control group of children born to women without epilepsy was not included. These represent weaknesses in the methodology of this study.
Further research in this area has recently come from the multicentre Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study running in the USA and in the UK [30••
]. Preliminary results focus on the intellectual functioning of 258 children exposed to monotherapy CBZ (n
= 73), VPA (n
= 53), lamotrigine (LTG; n
= 84) and PHT (n
= 48). After adjusting for maternal IQ and other influential factors, children of 3 years of age and younger who were exposed to VPA in utero
were found to have a significantly lower level of intellectual functioning in comparison with children exposed to other AEDs [30••
]. More children exposed to VPA (13%) than the other monotherapy groups (CBZ = 3%, LTG = 2% PHT = 5%) fell within the impaired range (IQ<70). There was a significant dose–effect relationship with VPA and not with the other monotherapy drugs. This is the first report regarding the cognitive abilities of children exposed to LTG in utero
. As with the KREP study, the NEAD study does not have a control group to allow for comparison to be made between children exposed to an AED in utero
and those representative of the general population. Both the KREP study and the NEAD study have protocols to follow their cohorts to the age of 6 years to allow for a more reliable documentation of the possible longer term effects of exposure to AEDs in utero
There is recent evidence of the cognitive abilities of older children exposed to AEDs in utero
. In a Finnish study [32••
], the cognitive abilities of 154 children born to women with epilepsy with an IQ in the normal range were assessed along with 130 control children who were born to women without epilepsy. The cognitive domains assessed included attention, language, fine motor, visuospatial, memory and learning abilities. Analysis indicated no significant differences across any of the cognitive domains for the study group as a whole versus the control group. Interestingly, the children born to women without epilepsy who were not exposed to medication in utero
were found to perform significantly poorer on the memory for names task. When children exposed to AEDs and control children were compared, children exposed to AED monotherapy performed poorer on attentional tasks than control children. Further, the children exposed to AED polytherapy performed poorer on auditory attention, sentence repetition and the fine motor task. Children exposed to VPA in utero
(either as monotherapy or polytherapy; n
= 22) had a significantly lower score in attentional tasks and memory tasks. Although these results may be complicated by the inclusion of both monotherapy and polytherapy cases, they indicate that despite intelligence within the normal range, children exposed to VPA in utero
may show deficits in specific areas of cognition.
Another recent study has followed up adolescents of 10–20 years of age [33••
], whose cognitive abilities were originally reported on by Steinhausen et al.
]. In the previous assessment, children within this cohort were found to have a significantly poorer verbal and performance IQ if they had been exposed to medication in utero
. The most recent assessment included 34% of the previous cohort. This represents a dropout rate of 4% per year, which highlights the difficulties in completing research over such a long follow-up period. The results from 116 adolescents (67 born to women with epilepsy and 49 controls) showed that exposure to all AEDs in utero
with the exception of CBZ had a negative impact on later intellectual functioning. The number of participants in the follow-up study, however, was small and the lost to follow-up group was too big to allow drug comparisons. This study indicates the need for prospective studies to follow cohorts until adulthood.