Evaluating the clinical efficacy and safety of progestogens in the management of threatened and recurrent miscarriage in early pregnancy-A review of the literature

Background Progestogens have been considered as a viable therapeutic option for the treatment of miscarriage for more than half a century. Aim: The aim of the present review is to provide a comprehensive view of the literature regarding the clinical efficacy and safety effects of progestogens for preventing recurrent miscarriages and managing threatened miscarriage during early pregnancy. Methods: A literature search was performed using electronic databases like Pubmed/ Medline to identify from 1953 to 2015. The search yielded around 27 original studies and review articles. Results: Dydrogesterone (oral) and various micronized progesterone (MCP) given orally, vaginally and intramuscularly are the most commonly used progestogens for the treatment of recurrent and threatened miscarriages. Pharmacokinetic profile of dydrogesterone exhibits better bioavailability, receptor affinity, quick onset of action and a better half-life imparting long and stable effect. Dydrogesterone exhibits 47% and 29% statistically significant reduction in odds ratio of threatened and recurrent miscarriage when compared to standard of care. While, literature supports use of MCP (vaginal), recent findings suggest no statistically significant difference in live birth rate when compared to placebo (65.8% vs. 63.3%). MCP (vaginal) is associated with vaginal discharge and irritation whereas dydrogesterone (oral) avoids vaginal discharge and no birth defects have been associated with its use. Conclusion: Treatment with dydrogesterone and other progestogens in general suggest dydrogesterone has number of advantages over other progestogens in terms of pharmacokinetic parameter clinical efficacy and safety profile. However, further studies are warranted to establish and promote the role of these progestogens in management of threatened and recurrent miscarriage. Key Words: Progestogens, Recurrent miscarriage, Threatened miscarriage Key Messages: Bioavailability ·         Oral bioavailability of dydrogesterone is approximately 5.6 times better than oral MCP.32,37,82 ·         Dydrogesterone is selective for progesterone receptor with 1.5 times better affinity than oral MCP.32 ·         Dydrogesterone exhibits quick onset of action reaching peak absorption levels within 30 minutes with a half-life of 5-7 hours imparting long and stable effect.37 Efficacy and safety ·         Based on PROMISE study data vaginal MCP therapy did not significantly improve live birth rate in women with unexplained recurrent miscarriage compared to placebo.57 ·         Dydrogesterone leads to a 47% statistically significant  reduction in the odds of a threatened miscarriage.38 ·         Dydrogesterone leads to 29% statistically significant reduction in the odds of a recurrent miscarriage.39 ·         Clinical experience with dydrogesterone does not provide evidence of a causal link between maternal dydrogesterone use during pregnancy and birth defects.41 ·         Use of medroxyprogesterone and hydroxyprogesterone in the management of miscarriages has not been supported in literature. They are indicated as contraceptive and for preventing preterm labor; respectively.61,62,73 Recommendations ·         Dydrogesterone has been approved for pregnancy indication including threatened miscarriage, habitual miscarriage, and infertility.81 ·         Dydrogesterone has been recommended for the treatment of threatened and recurrent miscarriage by FOGSI and EPC guideline.79,80 Oral MCP is not indicated for threatened and/or recurrent miscarriages.81