NTP Research Report on the Scoping Review of Prenatal Exposure to Progestogens and Adverse Health Outcomes

Introduction:

Endogenous progesterone is a sex hormone, one role of which is to maintain the uterine lining to support pregnancy. Drugs that exert progesterone action, collectively called progestogens (or progestins), include bioidentical progesterone from plant sources and synthetic progestogens. Progestogens are administered to reproductive-aged women for a variety of reasons, including contraception, threatened miscarriage (or its prevention), and preterm birth (or its prevention), which create the potential for fetal exposure to these drugs. Case reports and case series of adverse reproductive development (e.g., virilization in female infants) have been documented after exposure to progestogens in the first trimester, and similar effects on reproductive development have been observed in nonhuman mammalian animal studies after in utero exposure to certain synthetic progestogens.

Objective:

The objective of the scoping activities was to identify and characterize the literature on the possible association between exposure to progestogens (bioidentical progesterone or synthetic progestogens) during pregnancy and adverse pregnancy outcomes, congenital malformations, neurologic effects, cancer, and other health outcomes in offspring related to prenatal exposure.

Methods:

The scoping review was conducted following the Office of Health Assessment and Translation’s method for systematic review through an abbreviated data extraction step. A literature search was performed up to September 13, 2019, in PubMed, Cochrane Library, and Database of Abstracts of Reviews of Effects (through 2015) for references reporting on adverse neonatal outcomes, congenital malformations, neurological effects, and cancer incidence following in utero exposure to progestogens. Relevant references were characterized by evidence stream (e.g., animal, human, in vitro study), study design, exposure, and outcome, and by the indication for administration of the drug. An interactive evidence map was prepared to enable researchers to explore the health outcome data by exposure. Tables were developed to describe the human data on congenital malformations and neurodevelopmental outcomes.

Results:

The literature search yielded 7,654 references of which 212 were relevant, including 123 epidemiological studies and 90 nonhuman animal studies and 1 that reported on both human and animal subjects. In these studies, 24 different progestogens were evaluated, and the most frequently reported exposures were bioidentical progesterone, 17-alpha-hydroxyprogesterone caproate (17OHPC), and medroxyprogesterone acetate. Congenital malformations were evaluated in 32 human studies with first-trimester exposure and in 32 animal studies. Genital organ malformations (e.g., hypospadias) were the most common congenital malformation evaluated. Exposures in studies reporting significantly higher rates of genital malformations primarily involved synthetic progestogens with known androgenic (e.g., allylestrenol, lynestrenol, norethindrone) or anti-androgenic (e.g., cyproterone acetate) activities. In contrast, 17OHPC did not appear to induce congenital malformations in either humans (five of five studies) or nonhuman mammalian animals (five of five studies) exposed during organogenesis. Anogenital distance (AGD) in animal studies followed a similar pattern with prenatal exposure to androgenic synthetic progestogens generally reported to be associated with a longer AGD in females (i.e., virilization), whereas prenatal exposures to anti-androgenic synthetic progestogens were associated with shorter AGD in males (i.e., demasculinization).

Discussion:

The literature reporting on neurological outcomes (n = 61 studies) had several limitations, including few studies assessing similar endpoints and exposures or inconsistent results. Studies evaluating sexually dimorphic behavior in animals reported the most consistent findings for neurological effects; 12 of 14 studies reported altered mating behavior following prenatal exposure to bioidentical progesterone, 17OHPC, cyproterone acetate, or allylestrenol. Other limitations in the body of evidence of this scoping review included inconsistently used nomenclature for bioidentical progesterone and the synthetic progestogens and an inability to evaluate the data across progestogens as a group because of the unique biological activities of the progestogens administered (e.g., androgenic, anti-androgenic).

This scoping review identified and characterized a limited body of evidence on potential adverse health effects associated with in utero exposure to progestogens. The evidence was not sufficient to recommend an evaluation by systematic review on the association of potential adverse health effects with prenatal exposure to progestogens due to limitations of the literature. These limitations included heterogeneity of the endpoints assessed within some outcome categories (e.g., neurological outcomes), inconsistent results, and inconsistently used nomenclature to identify bioidentical progesterone or the specific synthetic progestogens used. In addition, evaluating these exposures as a group was challenging because of the unique biological activities of the progestogens administered (e.g., androgenic, anti-androgenic). More research is needed to better understand the potential association of prenatal exposure to progestogens and adverse pregnancy outcomes, congenital malformation incidence, and longer-term health outcomes of prenatally exposed offspring (e.g., neurological effects and cancer).