Foetal valproate syndrome is a foetopathy likely to occur when a pregnant woman takes valproic acid/valproate for epileptic seizures. Approximately 2% of women giving birth are epileptic and valproic acid is prescribed to 5 to 20% of these patients, with differences between countries (the figure is around 20% in France). Studies have shown that for women treated with valproic acid during the first trimester of their pregnancy the risk of giving birth to infants with spina bifida is 30 higher than that for the general population. More recent studies have since confirmed the risk and highlighted other teratogenic effects specific to valproic acid: hypospadias, malformations of the thumb and hallux, and a dysmorphic syndrome called foetal valproate syndrome. This syndrome is similar to foetal hydantoin syndrome; it is mainly marked by facial dysmorphism (hypoplasic middle part of the face), and a mild growth disorder, although the latter has not been clearly been established. Sporadic cases of malformation have been reported in one or two children (omphalocele, gastroschisis, cardiopathy, diaphragmatic hernia), but a link with valproic acid has not been established. Maternal seizures multiply the global risk of foetal malformation by five. In rare cases, neonatal liver cell necrosis has been described, resulting sometimes in neonatal death. The risk of behavioural problems also needs to be considered: a clinical study was reported, describing 46 children with anticonvulsant syndrome who had been exposed to valproic acid in utero. Thirty-seven of these children had attention deficit and hyperactivity disorder, autistic features, or Asperger's syndrome. Valproic acid serum concentrations at birth seem to correlate with the degree of neonatal hyperexcitability and neurologic dysfunction at the age of 6. In addition, there seems to be a genetic susceptibility to the teratogenic effects of valproic acid. A woman who has had an affected child should be informed of anincreased risk of malformation following exposure to the drug during subsequent pregnancies. Women on valproate who are of childbearing age and planning a pregnancy should be referred to their epileptologist for reconsideration of their treatment: if the indication of a treatment is confirmed, a change for other drugs (particularly lamotrigine) should be tried before conception. Daily supplementation with 5mg of folic acid should be prescribed before conception, and if it appears that only valproic acid is able to prevent seizures, then the pregnancy should be carefully monitored by level II ultrasound examinations. Surveillance of the newborn should include searching for withdrawal symptoms at birth. Long-term follow-up of the child should allow early management of any potential behavioural effects.
Last update: February 2006
- Dr Elisabeth ROBERT-GNANSIA