Occipitofrontal head circumference (OFC) of 172 neonates exposed prenatally to phenobarbital and phenytoin was compared to 168 control neonates, and the findings were studied in relation to a follow-up assessment of cognitive functioning in adulthood, at the University of Amsterdam, The Netherlands. Prenatally phenobarbital + phenytoin - exposed neonates had a significantly smaller OFC than those exposed to phenobarbital monotherapy and controls (0.7 cm mean difference, p=0.003). In follow-up as adults, no significant differences in cognitive functioning were determined in the three groups. However, persistent learning problems were evident in 12% of the exposed subjects versus 1% of the controls, and more of the exposed subjects were mentally retarded. Learning problems were not clearly related to small OFC, or maternal epilepsy. 
COMMENT. Neonates exposed prenatally to PB + PHT polytherapy for maternal epilepsy have smaller head sizes than neonates exposed to PB monotherapy and controls. As adults, a higher number of subjects exposed to anticonvulsants have learning problems, but these are not necessarily correlated with the head circumference at birth.
In a commentary, Hansen D and Lou HC  emphasize the frequency of conflicting results and methodological problems of studies of brain development and prenatal exposure to drugs. Women with seizures may have episodes of hypoxia that affect brain development, and those with refractory epilepsy are likely to receive polytherapies, more often complicated by fetal malformation.