Digital defects induced by vasodilating agents: relationship to reduction in uteroplacental blood flow

The effects of nifedipine (40-100 mumol/kg), nitrendipine (40 and 80 mumol/kg), hydralazine (381 and 763 mumol/kg), felodipine (12 mumol/kg), and the pharmacologically inactive first-step metabolite of felodipine, H152/37 (80 mumol/kg) were studied in rabbits (New Zeeland White) after oral administration on day 16 of gestation. The vasodilating drugs--nifedipine, nitrendipine, felodipine, and hydralazine--all induced digital defects in the fetuses. The defects consisted of a reduction, absence, or abnormal structure of the distal phalanx of especially the fourth digit on the hind paw(s). Histologically, a disturbed differentiation of the cartilage, and secondarily also of the ossification centre and joint structure of the distal phalanx, was observed. In contrast, no digital abnormalities were observed after administration of vehicle or H152/37. The findings that vasodilators with different structures, like dihydropyridines and hydralazine, induced the same type of digital defects strongly suggest that the observed phalangeal defects are secondary to pharmacological action, and not related to chemical structure. A decrease in uteroplacental blood flow, caused by excessive hypotension, is discussed as the most probable mechanism underlying the observed defects.