The Effects of Ribavirin on Development and Reproduction: A Critical Review of Published and Unpublished Studies in Experimental Animals

Abstract

The effects of the antiviral agent ribavirin on reproduction and development have been examined by several experimental means in multiple animal species. In studies designed primarily to explore its mechanism of action on in utero development, the incidence, nature, and patterns of effect were directly correlated to embryonic gestational age at the time of maternal treatment. In a detailed evaluation of the pattern of embryonic cell death, there was a clear relationship between tissue necrosis and the types of congenital defects produced at effective doses. At subthreshold treatment levels there were no abnormalities in the young or necrotic areas in the embryonic/fetal tissues examined. When the developmental toxicity of ribavirin was examined, few if any, developmental malformations were present that could be related with confidence to the test agent. Several malformed fetuses were present in the highest dose level tested in rats (10 mg/kg/day) treated by gavage from Days 6-15 of pregnancy, but none were reported in rabbits similarly treated with as much as 1.0 mg/kg per day (highest dose tested) from Days 6-18 of pregnancy. The treatment level in rats may have been associated with maternal toxicity, but this important point is not established clearly for either species. When evaluated for effects on reproduction and postnatal survival in rats, ribavirin at levels of 60 and 90 mg/kg/day produced statistically significantly and/or clearly dose-related increased incidences of fetal resorptions, abnormalities, and reduced postnatal survival. Pregnant baboons given ribavirin orally at submaternally toxic levels of 60 or 120 mg/kg per day during critical periods of differentiation and organogenesis were reported to have produced no adverse effects on in utero development.