Fetal valproate syndrome.

There is an increased incidence of major and minor congenital abnormalities in infants born to epileptic mothers (6 to 7% compared with 2 to 3% in the general population).' Factors which may contribute to this include the occurrence of seizures leading to periods of hypoxia during pregnancy, an inherited predisposition to malformations owing to intrinsic maternal factors, and the teratogenic effects of anticonvulsants. Congenital malformations following intrauterine exposure to phenytoin are well documented,2 but more recently a teratogenic effect has been observed in humans after maternal sodium valproate therapy.3-6 Sodium valproate is a salt of dipropyl acetic acid which is conjugated in the liver and has a short half life. It is thought to act either by inhibiting y-aminobutyric acid metabolism or by a direct effect on mitochondria, thereby impairing cellular energy metabolism.7 It is a popular drug because of its broad range of anticonvulsant effects and relative freedom from sedative and behavioural effects. It is 80 to 90% bound to plasma proteins and may displace other drugs ifused in combination, giving rise to toxicity. It may also interact with other drugs metabolised by the liver, for example, phenobarbitone. Long term valproate therapy may lead to carnitine depletion which impairs mitochondrial fatty acid metabolism and leads to hepatotoxicity.8 This effect is seen mainly in children. There is no clear relationship between serum concentrations and anticonvulsant effects, and although increasing doses are required during pregnancy to keep patients seizure free, it is generally accepted that the lowest dose at which the patient is seizure free should be used, even if this does not fall within the recommended therapeutic range of 50 to 100 ,ug/ml. Valproic acid crosses the placenta and is present in a higher concentration in the fetus than in the mother. Sodium valproate was licensed for use in 1978, and the first adverse report of a fetus exposed to the drug was published in 1980.9 Other reports have followed, documenting similar patterns ofminor and major malformations. Particular attention has been drawn to the occurrence of neural tube defects in infants exposed to valproate in utero.'0-'2 A summary of the clinical features of the "fetal valproate syndrome" (FVS) is documented below. Natural history Pregnancy usually proceeds uneventfully and there is no increased incidence of instrumental delivery or birth asphyxia; 10% of babies are small for gestational age. Withdrawal symptoms during the neonatal period are extremely common.'3 The most frequent of these are irritability, jitteriness, hypotonia, and seizures, typically occurring between 12 and 48 hours. They appear to be dose related. Feeding problems often ensue. Data on long term follow up of these infants are scanty but postnatal growth appears to be normal. Microcephaly tends only to occur in those infants also exposed to other anticonvulsants. General health is good and not all children with FVS will be drawn to the attention of the paediatrician during the first year of life. Ardinger et al,6 however, reviewed the clinical features in 15 cases of FVS presenting with dysmorphic features and found evidence of mild to moderate developmental delay or neurological abnormality in 10 (67%) on follow up. The association ofdevelopmental delay with valproate exposure has been confirmed in another report3 and also correlates with our own personal experience. Longer term effects have not yet been documented because ofthe relatively recent introduction ofthe drug.