Luteal phase progesterone to prevent recurrent miscarriage and improve live birth: A systematic review

Objective: Preventing recurrent miscarriage is a top research priority, for which luteal phase progesterone is a potential treatment. A systematic review was conducted to investigate the available evidence on luteal phase progesterone supplementation to reduce miscarriage, increase live birth rate and improve pregnancy outcomes in women and birthing people with a history of unexplained recurrent miscarriage. Evidence review: Pubmed, Cochrane Library, Ovid MEDLINE, Ovid EMBASE, CINAHL and ClinicalTrials.gov were systematically searched in 05/2025 to identify English-language, peer-reviewed, randomised-controlled trials and observational studies involving human participants published from the year 2000 onwards. This study adhered to PRISMA guidelines. Participants had a history of unexplained recurrent miscarriage who were prescribed luteal phase progesterone or placebo/usual care. Primary outcomes were miscarriage and live birth. Additional outcomes were informed by the miscarriage prevention core outcome set. Two independent reviewers conducted screening and study selection. Our protocol was pre-registered (PROSPERO CRD:420250653486). Results: A systematic search yielded 6722 studies. None of the 47 articles that underwent full text review met eligibility criteria. Three observational studies were identified however, due to differences in population characteristics or study design, none were eligible for inclusion. This highlights a significant gap in evidence. Conclusion: No evidence was identified linking luteal phase progesterone treatment to a reduction in miscarriage or increase in live births in women and birthing people with a history of unexplained recurrent miscarriage. A feasibility trial investigating treatment acceptability and adherence is proposed. This will subsequently support a definitive trial assessing clinical effectiveness, providing high quality evidence on luteal progesterone supplementation in recurrent miscarriage care.