BACKGROUNDProgesterone 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. METHODSWe 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 twicedaily 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. RESULTSA 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. CONCLUSIONSProgesterone 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.

Background and objectivesProgesterone is essential to maintain a healthy pregnancy. Guidance from the Royal College of Obstetricians and Gynaecologists and a Cochrane review called for a definitive trial to test whether or not progesterone therapy in the first trimester could reduce the risk of miscarriage in women with a history of unexplained recurrent miscarriage (RM). The PROMISE trial was conducted to answer this question. A concurrent cost-effectiveness analysis was conducted.Design and settingA randomised, double-blind, placebo-controlled, international multicentre study, with economic evaluation, conducted in hospital settings across the UK (36 sites) and in the Netherlands (nine sites).Participants and interventionsWomen with unexplained RM (three or more first-trimester losses), aged between 18 and 39 years at randomisation, conceiving naturally and giving informed consent, received either micronised progesterone (Utrogestan®, Besins Healthcare) at a dose of 400 mg (two vaginal capsules of 200 mg) or placebo vaginal capsules twice daily, administered vaginally from soon after a positive urinary pregnancy test (and no later than 6 weeks of gestation) until 12 completed weeks of gestation (or earlier if the pregnancy ended before 12 weeks).Main outcome measuresLive birth beyond 24 completed weeks of gestation (primary outcome), clinical pregnancy at 6–8 weeks, ongoing pregnancy at 12 weeks, miscarriage, gestation at delivery, neonatal survival at 28 days of life, congenital abnormalities and resource use.MethodsParticipants were randomised after confirmation of pregnancy. Randomisation was performed online via a secure internet facility. Data were collected on four occasions of outcome assessment after randomisation, up to 28 days after birth.ResultsA total of 1568 participants were screened for eligibility. Of the 836 women randomised between 2010 and 2013, 404 received progesterone and 432 received placebo. The baseline data (age, body mass index, maternal ethnicity, smoking status and parity) of the participants were comparable in the two arms of the trial. The follow-up rate to primary outcome was 826 out of 836 (98.8%). The live birth rate in the progesterone group was 65.8% (262/398) and in the placebo group it was 63.3% (271/428), giving a relative risk of 1.04 (95% confidence interval 0.94 to 1.15;p = 0.45). There was no evidence of a significant difference between the groups for any of the secondary outcomes. Economic analysis suggested a favourable incremental cost-effectiveness ratio for decision-making but wide confidence intervals indicated a high level of uncertainty in the health benefits. Additional sensitivity analysis suggested the probability that progesterone would fall within the National Institute for Health and Care Excellence’s threshold of £20,000–30,000 per quality-adjusted life-year as between 0.7145 and 0.7341.ConclusionsThere is no evidence that first-trimester progesterone therapy improves outcomes in women with a history of unexplained RM.LimitationsThis study did not explore the effect of treatment with other progesterone preparations or treatment during the luteal phase of the menstrual cycle.Future workFuture research could explore the efficacy of progesterone supplementation administered during the luteal phase of the menstrual cycle in women attempting natural conception despite a history of RM.Trial registrationCurrent Controlled Trials ISRCTN92644181; EudraCT 2009-011208-42; Research Ethics Committee 09/H1208/44.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 20, No. 41. See the NIHR Journals Library website for further project information.

Summary:Background: Iron-deficiency anaemia is common in pregnancy, with well-described maternal morbidities. When oral iron therapy has failed, intravenous (IV) preparations are considered. Ferric carboxymaltose (ferinject) is a new IV preparation which can be given quickly. There are no published data on Ferinject use in pregnancy. This study analyses historical data from women given Cosmofer, compared with those given Ferinject in pregnancy, to assess comparative efficacy and safety. Methods: Pregnant women treated with Cosmofer and Ferinject, were identified from pharmacy records. Records for all cases were reviewed and those which fulfilled inclusion criteria selected. The inclusion criteria included: symptomatic iron-deficient anaemia unresponsive to oral iron; age 18; second to third trimester; full blood count taken at least once at two, four and/or six weeks postinfusion. Data were collected on the pre-treatment Hb, ferritin, and same data collected at two, four and six weeks after the infusion. Side-effects or adverse reactions were noted for both the Cosmofer and Ferinject patients. Results: Results were obtained for 92 women (44 received Ferinject and 48 Cosmofer). Pre-infusion Hb and ferritin levels were comparable in the two groups. At two weeks, the mean Hb rise in the Ferinject group was 1.73 g/dL and 1.34 g/dL in the Cosmofer group. At four weeks, the total rise in Hb was 2.57 g/dL Ferinject, 2.34 g/dL Cosmofer. At six weeks the rise was 3.01 g/dL and 3.2 g/dL respectively. No serious adverse events were reported in either group. Conclusion: Both preparations appear effective and safe, with low risk of serious adverse effects and side-effects.

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Iron deficiency is the most common nutritional deficiency worldwide, in part due to the inherent low bioavailability of dietary iron (1) . Although dietary components such as vitamin C have been demonstrated to influence iron bioavailability, with the discovery of hepicidin as the hormone central regulator of iron homeostasis (2) , their significance has been questioned. Specifically, the Scientific Advisory Committee in the UK has stated that only the consumption of a healthy balanced diet is required for adequate iron status and the role of dietary enhancers is minimal (3) . Therefore, the aims of this systematic review and meta-analysis were to determine the effect of vitamin C on nonheme iron absorption and the effects of long term supplementation on iron status.The review was conducted by independent reviewers in accordance with PRISMA guidelines and is registered at Prospero (CRD42014010453). Medline, Scopus and Cochrane databases were searched from inception through to December 31 st 2016, with a basic search strategy of "(iron OR ferritin OR haemoglobin) AND (ascorbic acid OR ascorbate OR vitamin C)". Short-term (<4 weeks) and long-term trials (>4 weeks) reporting measures of iron absorption from isotopically labelled iron meals with and without vitamin C or changes to biomarkers of iron status with vitamin C supplementation in healthy adults were included. Meta-analyses were executed in Review Manager 5 software (version 5.3).From a total of 4830 identified records, 26 studies (20 short-term, 6 long-term) were included in qualitative synthesis and 22 were included in the meta-analysis (3 excluded as reported arithmetic not geometric means, 1 excluded for not reporting variance). All of the short-term studies were a 16-day crossover design, where the same iron test meals were labelled with different isotopes and consumed on consecutive mornings with and without ascorbic acid; with washout in between. The combined pooled effects showed a highly significant increase in % iron absorption when ascorbic acid was added to test meals and the l 2 statistic quantifying the level of heterogeneity, indicated a very low level of inconsistency (MD: 5·87; 95 % CI 4·43, 7·31; P = 0·00001; n = 315 total study participants; l 2 = 14 %). The effect of long-term ascorbic acid supplementation on haemoglobin status was assessed in 5 studies, arranged in descending order of haemoglobin (Hb) level (g/L) which ranged from 146 g/L-101 g/L (Fig. 1). These data show ascorbic acid supplementation increased haemoglobin value levels from baseline to follow-up significantly, (MD: 8·26; 95 % CI 3·00, 13·53; P = 0·002; n = 118 total study participants; l 2 = 58 %), with a moderate level of inconsistency between studies.We conclude, ascorbic acid enhances the absorption of nonheme iron and can increase biomarkers of iron status overtime. Increasing vitamin C intake from food or supplementation remains a practical measure to reduce the risk of iron deficiency and to moderate the incidence of iron deficiency anaemia.