Fetal Valproate Syndrome (FVS) through the USF Teratogen Information Service (TIS)

Abstract

Between January 2, 1988 and December 31, 1997 through the TIS program and genetics clinics at USF there were 168 requests for information/evaluations about valproic acid exposure. Fifty-four of these were for valproic acid as monotherapy. Among them, 7 were for information only, 3 women were not pregnant, 3 have not delivered yet and 2 were for paternal exposure. Of the remaining 39 pregnancies, there is no outcome information on 19. Of the 20 referrals with reported outcome, there are 13 full term normal infants, 1 premature without abnormalities, 1 hydropic premature stillborn and 5 with anomalies: 1 case each of hypoplastic left heart, hypospadias, club feet, single umbilical artery and anisocoria. Among the 114 referrals for combination therapy there were 6 pregnancies with fetal anomalies; 2/6 had open neural tube defect (ONTD) with hydrocephaly and one of them had polysyndactyly as well. The latter had normal karyotype and the mother took 750 mg valproic acid/day and paroxetine 25 mg/day. The other mother was on valproic acid, haloperidol and chlorpromazine (dosage unknown) for chronic schizophrenia with seizures. The third abnormal outcome was a term boy with trigonocephaly, right hand preaxial polydactyly, right inguinal hernia and pyloric stenosis. The mother took valproic acid 2500 mg/day and Phenobarbital 120 mg/day for seizures since infancy. The remaining three infants had VSD, polydactyly and sacral teratoma respectively. These data support the valproate teratogenieity in humans by showing ONTD in 2/168, polysyndactyly in 3, congenital heart defects in 2, inguinal hernia in 1 and hypospadias in 1. Trigonocephaly, pyloric stenosis, hypoplastic left heart, anisocoria and sacral teratoma suggest an expanded FVS phenotype. In 1 of the 2 infants with ONTD the mother had seizures due to MVA so epilepsy was excluded as a possible teratogen. Also the combination therapy in both mothers did not consist of two anticonvulsants; valproic acid was combined with paroxetine in one and with haloperidol and chlorpromazine in the other. As to TIS as an adjunct in addressing/recording/managing birth defects, important outcome information can be lost without an active follow-up component. However, a TIS program is invaluable for obtaining data regarding prenatal exposures.