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N Engl J Med. 2015 Nov 26;373(22):2141-8. doi: 10.1056/NEJMoa1504927.

A Randomized Trial of Progesterone in Women with Recurrent Miscarriages.

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From the College of Medical and Dental Sciences, University of Birmingham (A.C., H.W., E.T., J.J.C., A. Eapen, M.D.K.), Heart of England NHS Foundation Trust (R.S., P.G.), and Sandwell and West Birmingham Hospitals NHS Teaching Trust (A. Ewies), Birmingham, King's College London and King's Health Partners at St. Thomas' Hospital (P.T.S.), Women's Health Research Center, Imperial College at St. Mary's Hospital Campus (R.B., R.C., L.S., L.R., R.R.), King's Health Partners at St. Thomas' Hospital (A.L.B.), King's College Hospital NHS Foundation Trust (J.A.R.), and Assisted Conception Unit, Guy's and St. Thomas' Foundation Trust (Y.K.), London, Biomedical Research Unit in Reproductive Health, University of Warwick, Warwick (S.Q.), Liverpool Women's NHS Foundation Trust (F.D., R.G.F.), Liverpool, The Miscarriage Association, Wakefield (R.B.A.), University of Southampton Faculty of Medicine, Princess Anne Hospital, Southampton (Y.C.C.), Royal Hallamshire Hospital, Sheffield (T.-C.L.), Ayrshire Maternity Unit, University Hospital of Crosshouse, Kilmarnock (M.M.), Nottingham University Hospitals NHS Trust, Nottingham (J.M.), Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne (J.S.), and Portsmouth Hospitals NHS Trust, Portsmouth (N.V.) - all in the United Kingdom; the Department of Reproductive Medicine, University Medical Center Utrecht, Utrecht (Y.E.M.K.), the Department of Obstetrics, Leiden University Medical Center, Leiden (K.W.M.B.), the Department of Reproductive Medicine and Gynecology, University of Groningen, Groningen (A.H.), the Department of Obstetrics and Gynecology, Onze Lieve Vrouwe Gasthuis (E.M.K.), and Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Academic Medical Center (M.G.), Amsterdam, and the Department of Obstetrics and Gynecology, Maxima Medical Center Veldhoven, Veldhoven (C.A.M.K.) - all in the Netherlands; and the Robinson Institute, School of Pediatrics and Reproductive Health, University of Adelaide, Ade



Progesterone is essential for the maintenance of pregnancy. However, whether progesterone supplementation in the first trimester of pregnancy would increase the rate of live births among women with a history of unexplained recurrent miscarriages is uncertain.


We conducted a multicenter, double-blind, placebo-controlled, randomized trial to investigate whether treatment with progesterone would increase the rates of live births and newborn survival among women with unexplained recurrent miscarriage. We randomly assigned women with recurrent miscarriages to receive twice-daily vaginal suppositories containing either 400 mg of micronized progesterone or matched placebo from a time soon after a positive urinary pregnancy test (and no later than 6 weeks of gestation) through 12 weeks of gestation. The primary outcome was live birth after 24 weeks of gestation.


A total of 1568 women were assessed for eligibility, and 836 of these women who conceived naturally within 1 year and remained willing to participate in the trial were randomly assigned to receive either progesterone (404 women) or placebo (432 women). The follow-up rate for the primary outcome was 98.8% (826 of 836 women). In an intention-to-treat analysis, the rate of live births was 65.8% (262 of 398 women) in the progesterone group and 63.3% (271 of 428 women) in the placebo group (relative rate, 1.04; 95% confidence interval [CI], 0.94 to 1.15; rate difference, 2.5 percentage points; 95% CI, -4.0 to 9.0). There were no significant between-group differences in the rate of adverse events.


Progesterone therapy in the first trimester of pregnancy did not result in a significantly higher rate of live births among women with a history of unexplained recurrent miscarriages. (Funded by the United Kingdom National Institute of Health Research; PROMISE Current Controlled Trials number, ISRCTN92644181.).

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