Progestogen supplementation to prevent miscarriage: Evidence and controversies

Progesterone plays a key role in the establishment and maintenance of pregnancy and its deficiency has been associated with early pregnancy loss. Progestogen supplementation has therefore been widely investigated as a preventive strategy against miscarriage, particularly in women with recurrent pregnancy loss or threatened miscarriage or after assisted reproductive technologies. However, the overall evidence remains inconclusive. Meta-analyses of randomized trials, including the large PROMISE and PRISM studies, have not demonstrated a significant overall benefit in live birth rates, although a possible advantage was observed in women with both early bleeding and prior miscarriages. The biological plausibility of supplementation lies in the luteal-placental shift, when the placenta assumes progesterone production after the first trimester. Yet, low progesterone levels in early pregnancy might often represent a marker of a non-viable gestation rather than the underlying cause of miscarriage. The optimal route and duration of treatment remain uncertain. Vaginal and subcutaneous progesterone offer comparable efficacy to intramuscular formulations, with better tolerability and compliance. Current evidence does not support universal progesterone supplementation in early pregnancy, but individualized treatment might be considered for women at increased risk, based on clinical history. Future research should focus on identifying reliable markers of luteal deficiency, refining patient selection and comparing different administration routes and serum thresholds.