EMBRYOTOXIC EFFECTS OF MISOPROSTOL IN THE MOUSE

Misoprostol (MSP) is a synthetic prostaglandin E(1) methyl analogue in dicated for the prevention of gastric ulcers induced by non-steroidal anti-inflammatory drugs (NSAIDs). Because of its abortifacient propert ies, MSP has been extensively misused for abortion induction in Brazil . Since abortion induction with MSP very often fails and pregnancy con tinues to term, there has been increasing concern regarding the potent ial teratogenicity of this PGE(1) analogue in humans. The objective of the present study was to evaluate the embryotoxicity of MSP in mice. A single dose of MSP (20 or 30 mg/kg body weight) was administered to Han:NMRI mice (ca 60 days old) by gavage on day 10 of pregnancy. The n umber of treated mice was as follows: control, 19; MSP 20 mg/kg, 10; M SP 30 mg/kg, 28. Cesarean sections were performed on day 18 of pregnan cy and the number of resorptions and implantation sites were recorded. Fetuses were weighed, examined for external malformations, fixed, cle ared and stained with Alizarin Red S for skeleton evaluation. No evide nce of embryotoxicity was found at the lower dose tested. A slight and reversible deficit in pregnancy weight gain (day 10-11: control, 1.3 +/- 0.3 g; MSP 20 mg/kg, -0.9 +/- 0.9 g; MSP 30 mg/kg, -1.7 +/- 0.6 g) was the only sign of maternal toxicity noted in both groups of mice t reated with misoprostol. In the group treated with the higher dose of MSP, the ratio of resorptions per implantation site was as high as 42% , and an increased occurrence of cleft palate (control, 0.6%; MSP 30 m g/kg, 2.8%) as well as other skeletal abnormalities (e.g. whole skelet on poorly ossified: control, 0%; MSP 30 mg/kg, 4.4%) was observed in t he surviving fetuses. These findings indicate that misoprostol is embr yotoxic to mice at doses higher than 20 mg/kg body weight given by the oral route. This dose corresponds to approximately 1250 times the cli nical dose when misoprostol is prescribed for ulcers in patients.