Progesterone during early pregnancy to prevent miscarriage

Progesterone helps a narrow group: women bleeding in early pregnancy who have already lost at least one. For everyone else, the evidence is weak or absent.

The biggest trial, PRISM, gave vaginal progesterone 400 mg twice daily to 4,153 women with early bleeding. Overall live birth was 1,513 of 2,025 on progesterone versus 1,459 of 2,013 on placebo, a difference so small it barely cleared the line [1]. The benefit concentrated in women with prior losses. With one or more prior miscarriages, 689 of 914 versus 619 of 886 had a live birth, about 9 in 100 more, meaning roughly 20 women treated for one extra birth [1][4]. With three or more prior losses the gap widened to about 28 in 100 more, roughly 8 treated per extra birth [1].

PROMISE, 836 women with recurrent miscarriage, found no benefit at all: 262 of 398 versus 271 of 428 [1]. That contradiction matters. The positive signal comes from subgroup analyses, which are weaker than the main result.

Safety is the thin part. The trials tracked live birth, not childhood outcomes. One 136-woman trial could not record adverse outcomes or fetal outcomes at delivery [2]. A 2021 network meta-analysis of 59 trials ranked dydrogesterone highest for miscarriage but only 4 trials reported congenital abnormalities [3]. The Lancet review flags safety concerns for dydrogesterone specifically [4]. No retrieved record gives long-term child follow-up.

My call: reasonable for bleeding plus prior miscarriage, not justified as routine for a first pregnancy with no bleeding, and the long-term child safety data does not exist. Confidence: moderate on the narrow benefit, low on safety.