The effects of repeated doses of indomethacin on fetal rabbit mortality and on the patency of the ductus arteriosus

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Abstract
The effects on fetal mortality and on the patency of the ductus arteriosus of several doses of indomethacin administered at different frequencies to pregnant rabbits were studied. The data show that the number of intrauterine deaths was related to both the dose and frequency of indomethacin administration. However, the degree of constriction of the ductus arteriosus of the dead fetuses was approximately the same, regardless of the dose or the frequency of drug administration. Therefore, the smaller doses may have caused constriction of the ductus for a sufficiently short period of time as not to be lethal in all cases whereas the constriction produced by the larger doses would be of greater duration and more likely to cause death. Although both maternal and fetal plasma concentrations of drug were elevated, there were litters in which no fetal deaths occurred. As the Cesarean sections were performed at various times after the last maternal injecion of drug, there was no evidence of a relationship between the dose of drug and the plasma concentrations. However, the fetal plasma concentrations of indomethacin were consistently higher than that of the doe, suggesting that the monitoring of only maternal plasma concentrations of some drugs may be a poor index of the amount of drug in the fetal circulation.