Embryo-fetal toxicity signals for 17α-hydroxyprogesterone caproate in high-risk pregnancies:: A review of the non-clinical literature for embryo-fetal toxicity with progestins

Objective. A large National Institutes of Health (NIH) study showed that pharmacy-compounded 17 alpha-hydroxyprogesterone caproate (17-OHP-C) reduced the incidence of preterm birth. The study results included a signal that 17-OHP-C may be associated with an increase in the rate of miscarriages and stillbirths. The most probable cause of an increased incidence of miscarriage/stillbirths may be the use of 17-OHP-C in high-risk patients. The current search of the non-clinical literature was performed to identify whether there were any signals from studies in animals that might suggest concerns for the safe use of progestins generally, and 17-OHP-C specifically, in the prevention of preterm birth in humans. Methods. An extensive literature search was performed for progesterone, 17-hydroxyprogesterone, and 17-OHP-C, using Medline and Toxline databases, textbooks, and then the obtained publications. Because 17-OHP-C does not have a standardized clinical formulation or optimal route of administration identified, all formulations, vehicles, routes and doses were included in the search, as well as treatment during any stage of pregnancy. All publications obtained were reviewed for relevancy; those in German, French, Italian or Russian were translated. Results. None of the relevant non-clinical studies conducted in mice, rats, rabbits, guinea pigs, horses or non-human primates met current standards for determining reproductive and developmental effects as part of the process of drug development. Most studies focused on the potential of 17-OHP-C for teratogenicity. Many studies used suprapharmacologic and/or high multiples of human exposure in their study design. Overall, 17-OHP-C was consistently shown to be less potent than progesterone, and neither progesterone nor 17-OHP-C consistently adversely affected maternal weight, embryo-fetal viability or caused malformations. One study in rhesus monkeys raises concerns because resorption/abortion occurred at the human equivalent dose of 17-OHP-C, 10 mg/kg; this finding did not occur in cynomolgus monkeys. The absence of information regarding the serum levels of both progesterone and 17-OHP-C in the animal studies and in humans, as well as presumed inter-species metabolic differences, make it difficult to conclude that the findings with 17-OHP-C in rhesus monkeys and the signal in the NIH trial are related. A few studies in rats raised questions regarding potential effects on postnatal development, but in the absence of better study designs, the relevancy of these findings to human risk are also questionable at best. Conclusion. There is a signal for embryo-fetal toxicity associated with 17-OHP-C in the two largest clinical trials conducted to date; there is also a signal for embryo-fetal toxicity with 17-OHP-C in rhesus monkeys and possibly one in rodent species. The relationship between these signals is unclear given the absence of state-of-the-art reproductive toxicology studies and human pharmacokinetic studies.