Antiepileptic drugs and teratogenesis in two consecutive cohorts: changes in prescription policy paralleled by changes in pattern of malformations.
We analyzed the influence of changes in the prescribing of antiepileptic drugs to pregnant women on frequency and pattern of malformations in their offspring by comparing two consecutive cohorts (1972 to 1979, cohort A; 1980 to 1985, cohort B). In cohort A, 15 (10%) of 151 exposed, live-born infants had one or more congenital anomalies, which consisted primarily of congenital heart defects, facial clefts, and syndromes of dysmorphia with developmental retardation, in association with polytherapy (carbamazepine plus phenobarbitone plus valproate, with or without phenytoin, or phenobarbitone plus phenytoin plus primidone). In cohort B, the prescribing of phenobarbitone, phenytoin, or primidone had dropped markedly, whereas monotherapy with valproate and carbamazepine had increased. Thirteen (7.6%) of 172 exposed, live-born infants had congenital anomalies. The most frequent anomalies were spinal defects (four) and glandular hypospadias (three), all in association with maternal therapy with valproate, carbamazepine, or both. The results underline the need for continuation of prospective studies to monitor the effect of change in prescribing policies and to evaluate the role of metabolic interactions between drugs prescribed in combination.
Lindhout
D
D
Department of Clinical Genetics, Erasmus University, Rotterdam, The Netherlands.
Meinardi
H
H
Meijer
J W
JW
Nau
H
H
D000014:Abnormalities, Drug-Induced / Q000453:epidemiology; D000927:Anticonvulsants / Q000008:administration & dosage / Q000009:adverse effects* / Q000097:blood; D002220:Carbamazepine / Q000009:adverse effects / Q000031:analogs & derivatives / Q000097:blood / Q000627:therapeutic use; D015331:Cohort Studies; D011307:Drug Prescriptions; D004827:Epilepsy / Q000188:drug therapy*; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D010634:Phenobarbital / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use; D010672:Phenytoin / Q000009:adverse effects / Q000097:blood / Q000627:therapeutic use; D011247:Pregnancy; D011248:Pregnancy Complications / Q000188:drug therapy*; D014635:Valproic Acid / Q000009:adverse effects / Q000097:blood / Q000378:metabolism / Q000627:therapeutic use
D000927:Anticonvulsants; D002220:Carbamazepine; D014635:Valproic Acid; D010672:Phenytoin; C012227:carbamazepine epoxide; D010634:Phenobarbital