Two children born with birth defects after intrauterine exposure to valproic acid are reported from the Dept Pediatrics Hopital Sainte-Justine, University of Montreal, Quebec, Canada. The drug was taken by the mothers throughout pregnancy as monotherapy for primary generalized epilepsy. One baby had facial dysmorphism, hypertelorism, anti-mongoloid palpebral fissures, a naevus flammeus on the forehead, portwine palpebral and nasal angiomas, arachnodactyly, triphalangeal thumbs, syndactyly, and a septum pellucidum cyst and dilated veluticles on CT scan. The second baby had facial dysmorphism, laryngeal hypoplasia, tracheomalacia, aberrant innominate artery and hydronephrosis. The authors concluded that valproic acid has probable teratogenic potential in humans but the spectrum of anomalies is broad and a definite fetal valproate syndrome is difficult to delineate. [1]

Comment. Approximately 50 malformed babies born to epileptic mothers taking valproate monotherapy have been reported. Contrary to the above opinion, Diliberti et al [2] have recognized a “fetal valproate syndrome”, and the frequency of reports of valproate-induced congenital malformations together with other side-effects (liver failure, pancreatitis, endocrine abnormalities, weight gain) tend to contraindicate its use in pregnancy.

Portwine angioma noted in the first baby in this study of valproic acid toxicity may also be induced by thalidomide and alcohol ingestion during pregnancy [3, 4]. Dilated ventricles, defined by CT in the first baby, are reported as a reversible cerebral pseudoatrophy for the first time as a side-effect of valproic acid monotherapy in a 17-year-old with epilepsy [5].

For an update of antiepileptic drugs and teratogenicity [6]. According to this report, the frequency of congenital malformations among children of epileptic mothers is twice that in the general population, genetic factors play a major role, and generally the teratogenic potential of antiepileptic drugs is low and does not contraindicate pregnancy in epileptic women. Many neurologists and certainly geneticists would advise stricter selectivity and caution in the choice of anticonvulsant for epileptic women contemplating pregnancy. Drugs with especially high or relatively frequent tetratogenic potential (e.g. trimethadione, phenytoin) are usually contraindicated, those with moderate or unknown degrees of propensity (primidone, valproic acid, carbamazepine, clonazapam) are avoided when possible, and the drug of choice, least likely to induce malformations and most often recommended, is probably phenobarbital.