Identical phalangeal defects induced by phenytoin and nifedipine suggest fetal hypoxia and vascular disruption behind phenytoin teratogenicity.
In previous experimental studies in rabbits, we have shown that vasodilating drugs (including nifedipine) cause distal digital defects. These defects were preceded by edema, hemorrhage, and finally necrosis of the developed cartilage in the phalanges. The underlying mechanism is most likely a fetal hypoxic response, secondary to maternal hypotension and decreased uteroplacental blood flow. Since phenytoin is known to cause distal digital defects both in man and rabbits, we decided to compare the defects provoked by oral administration of phenytoin (100 mg/kg) versus nifedipine (8.3 mg/kg) to New Zealand White rabbits on days 6-18 of gestation. In order to investigate phase-specificity, phenytoin (150 mg/kg) was given on days 14-17. The result of single dose administration on day 16 of phenytoin (300 mg/kg) versus nifedipine (33.2 mg/kg) was also studied. In this latter experiment maternal heart rate was measured up to 21 hours after phenytoin administration. Phenytoin induced digital defects identical with those produced by nifedipine and caused marked maternal cardiodepression. The defects consisted of a reduction, absence, or abnormal structure of the distal phalanges. The distal phalanx of the fourth digit on the hindpaw was the first to be affected, with inclusion of other phalanges, both on the hind- and forepaws, with increasing dose. The sensitive period for induction and histological appearance of these defects was identical for phenytoin and nifedipine. These results suggest that vascular disruption due to a fetal hypoxic response lies behind phenytoin teratogenicity, as has been shown for vasodilators. A cardiodepressive action on the maternal and fetal hearts, possibly in combination with decreased uteroplacental blood flow, is discussed as a probable factor behind phenytoin teratogenicity.
Danielsson
B R
BR
Department of Toxicology, Uppsala University, Sweden.
Danielson
M
M
Rundqvist
E
E
Reiland
S
S
D000014:Abnormalities, Drug-Induced; D000818:Animals; D001808:Blood Vessels / Q000187:drug effects / Q000196:embryology; D005260:Female; D005311:Fetal Hypoxia / Q000139:chemically induced*; D005865:Gestational Age; D006339:Heart Rate / Q000187:drug effects; D006801:Humans; D009543:Nifedipine / Q000633:toxicity*; D010672:Phenytoin / Q000633:toxicity*; D011247:Pregnancy; D011817:Rabbits; D014034:Toes / Q000002:abnormalities*
D010672:Phenytoin; D009543:Nifedipine