The anti-progesterone drug mifepristone and the prostaglandin misoprostol can be used to treat missed miscarriage. However, it is unclear whether a combination of mifepristone and misoprostol is more effective than administering misoprostol alone. We investigated whether treatment with mifepristone plus misoprostol would result in a higher rate of completion of missed miscarriage compared with misoprostol alone. MifeMiso was a multicentre, double-blind, placebo-controlled, randomised trial in 28 UK hospitals. Women were eligible for enrolment if they were aged 16 years and older, diagnosed with a missed miscarriage by pelvic ultrasound scan in the first 14 weeks of pregnancy, chose to have medical management of miscarriage, and were willing and able to give informed consent. Participants were randomly assigned (1:1) to a single dose of oral mifepristone 200 mg or an oral placebo tablet, both followed by a single dose of vaginal, oral, or sublingual misoprostol 800 μg 2 days later. Randomisation was managed via a secure web-based randomisation program, with minimisation to balance study group assignments according to maternal age (<30 years vs ≥30 years), body-mass index (<35 kg/m2vs ≥35 kg/m2), previous parity (nulliparous women vs parous women), gestational age (<70 days vs ≥70 days), amount of bleeding (Pictorial Blood Assessment Chart score; ≤2 vs ≥3), and randomising centre. Participants, clinicians, pharmacists, trial nurses, and midwives were masked to study group assignment throughout the trial. The primary outcome was failure to spontaneously pass the gestational sac within 7 days after random assignment. Primary analyses were done according to intention-to-treat principles. The trial is registered with the ISRCTN registry, ISRCTN17405024. Between Oct 3, 2017, and July 22, 2019, 2595 women were identified as being eligible for the MifeMiso trial. 711 women were randomly assigned to receive either mifepristone and misoprostol (357 women) or placebo and misoprostol (354 women). 696 (98%) of 711 women had available data for the primary outcome. 59 (17%) of 348 women in the mifepristone plus misoprostol group did not pass the gestational sac spontaneously within 7 days versus 82 (24%) of 348 women in the placebo plus misoprostol group (risk ratio [RR] 0·73, 95% CI 0·54–0·99; p=0·043). 62 (17%) of 355 women in the mifepristone plus misoprostol group required surgical intervention to complete the miscarriage versus 87 (25%) of 353 women in the placebo plus misoprostol group (0·71, 0·53–0·95; p=0·021). We found no difference in incidence of adverse events between the study groups. Treatment with mifepristone plus misoprostol was more effective than misoprostol alone in the management of missed miscarriage. Women with missed miscarriage should be offered mifepristone pretreatment before misoprostol to increase the chance of successful miscarriage management, while reducing the need for miscarriage surgery. UK National Institute for Health Research Health Technology Assessment Programme.

An understanding of the causes of postpartum haemorrhage is needed to provide appropriate treatment and services. Knowledge of the risk factors for postpartum haemorrhage can help address modifiable risk factors. We did a systematic review and meta-analysis to identify and quantify the various causes and risk factors for postpartum haemorrhage. In this systematic review and meta-analysis, we did a systematic literature search in MEDLINE, Embase, Web of Science, Cochrane Library, and Google Scholar for cohort studies of postpartum haemorrhage from Jan 1, 1960, to Nov 30, 2024 without language restrictions. At least two authors independently undertook study selection, data extraction, and quality assessment. Population-based cohort studies available in English were eligible. Rates of postpartum haemorrhage causes as well as crude and adjusted odds ratios (ORs) for risk factors were pooled using a random-effects model. Risk factors were classified as having weak, moderate, or strong association based on the pooled ORs: weak (OR >1 to 1·5), moderate (OR >1·5 to 2), and strong (OR >2). This study is registered with PROSPERO, CRD42023479686. We synthesised data from 327 studies, including 847 413 451 women with no restriction on age, race, or ethnicity. Most studies were of high methodological quality. The pooled rates of the five commonly reported causes of postpartum haemorrhage were uterine atony (70·6% [95% CI 63·9-77·3]; n=834 707 women, 14 studies), genital tract trauma (16·9% [9·3-24·6]; n=18 449 women, six studies), retained placenta (16·4% [12·3-20·5]; n=235 021 women, nine studies), abnormal placentation (3·9% [0·1-7·6]; n=29 638 women, two studies), and coagulopathy (2·7% [0·8-4·5]; n=236 261, nine studies). The pooled rate of women with multiple postpartum haemorrhage causes was 7·8% (95% CI 4·7-10·8; n=666, two studies). Risk factors with a strong association with postpartum haemorrhage included anaemia, previous postpartum haemorrhage, caesarean birth, female genital mutilation, sepsis, no antenatal care, multiple pregnancy, placenta praevia, assisted reproductive technology use, macrosomia with a birthweight of more than 4500 g, and shoulder dystocia. Risk factors with moderate association with postpartum haemorrhage included BMI ≥30 kg/m², COVID-19 infection, gestational diabetes, polyhydramnios, pre-eclampsia, and antepartum haemorrhage. Risk factors with weak association with postpartum haemorrhage included Black and Asian ethnicity, BMI 25-29·9 kg/m², asthma, thrombocytopenia, uterine fibroids, antidepressant use, induction of labour, instrumental birth, and premature rupture of membranes. The finding that uterine atony is the commonest cause of postpartum haemorrhage supports the WHO recommendation for all women giving birth to be given prophylactic uterotonics. Knowledge of risk factors with a strong association with postpartum haemorrhage can help to identify women at high risk of postpartum haemorrhage who could benefit from enhanced prophylaxis and treatment. The importance of multiple concurrent causes of postpartum haemorrhage supports the use of treatment bundles. Gates Foundation.

Background: Progesterone is essential for a healthy pregnancy. Several small trials have suggested that progesterone therapy may rescue a pregnancy in women with early pregnancy bleeding, which is a symptom that is strongly associated with miscarriage. Objectives: (1) To assess the effects of vaginal micronised progesterone in women with vaginal bleeding in the first 12 weeks of pregnancy. (2) To evaluate the cost-effectiveness of progesterone in women with early pregnancy bleeding. Design: A multicentre, double-blind, placebo-controlled, randomised trial of progesterone in women with early pregnancy vaginal bleeding. Setting: A total of 48 hospitals in the UK. Participants: Women aged 16–39 years with early pregnancy bleeding. Interventions: Women aged 16–39 years were randomly assigned to receive twice-daily vaginal suppositories containing either 400 mg of progesterone or a matched placebo from presentation to 16 weeks of gestation. Main outcome measures: The primary outcome was live birth at ≥ 34 weeks. In addition, a within-trial cost-effectiveness analysis was conducted from an NHS and NHS/Personal Social Services perspective. Results: A total of 4153 women from 48 hospitals in the UK received either progesterone (n = 2079) or placebo (n = 2074). The follow-up rate for the primary outcome was 97.2% (4038 out of 4153 participants). The live birth rate was 75% (1513 out of 2025 participants) in the progesterone group and 72% (1459 out of 2013 participants) in the placebo group (relative rate 1.03, 95% confidence interval 1.00 to 1.07; p = 0.08). A significant subgroup effect (interaction test p = 0.007) was identified for prespecified subgroups by the number of previous miscarriages: none (74% in the progesterone group vs. 75% in the placebo group; relative rate 0.99, 95% confidence interval 0.95 to 1.04; p = 0.72); one or two (76% in the progesterone group vs. 72% in the placebo group; relative rate 1.05, 95% confidence interval 1.00 to 1.12; p = 0.07); and three or more (72% in the progesterone group vs. 57% in the placebo group; relative rate 1.28, 95% confidence interval 1.08 to 1.51; p = 0.004). A significant post hoc subgroup effect (interaction test p = 0.01) was identified in the subgroup of participants with early pregnancy bleeding and any number of previous miscarriage(s) (75% in the progesterone group vs. 70% in the placebo group; relative rate 1.09, 95% confidence interval 1.03 to 1.15; p = 0.003). There were no significant differences in the rate of adverse events between the groups. The results of the health economics analysis show that progesterone was more costly than placebo (£7655 vs. £7572), with a mean cost difference of £83 (adjusted mean difference £76, 95% confidence interval –£559 to £711) between the two arms. Thus, the incremental cost-effectiveness ratio of progesterone compared with placebo was estimated as £3305 per additional live birth at ≥ 34 weeks of gestation. Conclusions: Progesterone therapy in the first trimester of pregnancy did not result in a significantly higher rate of live births among women with threatened miscarriage overall, but an important subgroup effect was identified. A conclusion on the cost-effectiveness of the PRISM trial would depend on the amount that society is willing to pay to increase the chances of an additional live birth at ≥ 34 weeks. For future work, we plan to conduct an individual participant data meta-analysis using all existing data sets. Trial registration: Current Controlled Trials ISRCTN14163439, EudraCT 2014-002348-42 and Integrated Research Application System (IRAS) 158326. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 33. See the NIHR Journals Library website for further project information.

The evidence on the association between diet and miscarriage risk is scant and conflicting. To summarize the evidence on the association between peri-conceptual diet and miscarriage risk in healthy women of reproductive age. Electronic databases were searched from inception to August 2022 without restriction of regions, publication types or languages. Experimental or observational studies were considered for inclusion. The population was healthy women of reproductive age. Exposure was peri-conception diet. Study quality was assessed using the modified Newcastle-Ottawa Scale. Summary effect sizes (odds ratio [OR] with 95% confidence interval [CI]) were calculated for each food category. Miscarriage rate (as defined by primary studies) RESULTS: We included 20 studies (11 cohort and 9 case-control), of which 6 presented data suitable for meta-analysis (2 cohort and 4 case-control, n = 13,183 women). Our primary analyses suggest a reduction in miscarriage odds with high intake of the following food groups: fruit (OR 0.39, 95% CI 0.33 to 0.46), vegetables (OR 0.59, 95% CI 0.46 to 0.76), fruit and vegetables (OR 0.63, 95% CI 0.50 to 0.81), seafood (OR 0.81, 95% CI 0.71 to 0.92), dairy products (OR 0.63, 95% CI 0.54 to 0.73), eggs (OR 0.81, 95% CI 0.72 to 0.90) and cereal (grains) (OR 0.67, 95% CI 0.52 to 0.87). The evidence was uncertain for meat, red meat, white meat, fat and oil, and sugar substitutes. We did not find evidence of an association between adherence to pre-defined dietary patterns and miscarriage risk. However, a whole diet containing healthy foods as perceived by the trialists, or with a high Dietary Antioxidant Index score (OR 0.43, 95% CI 0.20 to 0.91) may be associated with a reduction in miscarriage risk. In contrast, a diet rich in processed food was demonstrated to be associated with increased miscarriage risk (OR 1.97, 95% CI 1.36 to 3.34). A diet abundant in fruit, vegetables, seafood, dairy, eggs and grain may be associated with lower miscarriage odds. Further interventional studies are required to accurately assess the effectiveness of peri-conception dietary modifications on miscarriage risk.