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Miscarriage is generally defined as the loss of a pregnancy before viability. An estimated 23 million miscarriages occur every year worldwide, translating to 44 pregnancy losses each minute. The pooled risk of miscarriage is 15·3% (95% CI 12·5–18·7%) of all recognised pregnancies. The population prevalence of women who have had one miscarriage is 10·8% (10·3–11·4%), two miscarriages is 1·9% (1·8–2·1%), and three or more miscarriages is 0·7% (0·5–0·8%). Risk factors for miscarriage include very young or older female age (younger than 20 years and older than 35 years), older male age (older than 40 years), very low or very high body-mass index, Black ethnicity, previous miscarriages, smoking, alcohol, stress, working night shifts, air pollution, and exposure to pesticides. The consequences of miscarriage are both physical, such as bleeding or infection, and psychological. Psychological consequences include increases in the risk of anxiety, depression, post-traumatic stress disorder, and suicide. Miscarriage, and especially recurrent miscarriage, is also a sentinel risk marker for obstetric complications, including preterm birth, fetal growth restriction, placental abruption, and stillbirth in future pregnancies, and a predictor of longer-term health problems, such as cardiovascular disease and venous thromboembolism. The costs of miscarriage affect individuals, health-care systems, and society. The short-term national economic cost of miscarriage is estimated to be £471 million per year in the UK. As recurrent miscarriage is a sentinel marker for various obstetric risks in future pregnancies, women should receive care in preconception and obstetric clinics specialising in patients at high risk. As psychological morbidity is common after pregnancy loss, effective screening instruments and treatment options for mental health consequences of miscarriage need to be available. We recommend that miscarriage data are gathered and reported to facilitate comparison of rates among countries, to accelerate research, and to improve patient care and policy development.

Intrahepatic cholestasis of pregnancy, characterised by maternal pruritus and increased serum bile acid concentrations, is associated with increased rates of stillbirth, preterm birth, and neonatal unit admission. Ursodeoxycholic acid is widely used as a treatment without an adequate evidence base. We aimed to evaluate whether ursodeoxycholic acid reduces adverse perinatal outcomes in women with intrahepatic cholestasis of pregnancy. We did a double-blind, multicentre, randomised placebo-controlled trial at 33 hospital maternity units in England and Wales. We recruited women with intrahepatic cholestasis of pregnancy, who were aged 18 years or older and with a gestational age between 20 weeks and 40 weeks and 6 days, with a singleton or twin pregnancy and no known lethal fetal anomaly. Participants were randomly assigned 1:1 to ursodeoxycholic acid or placebo, given as two oral tablets a day at an equivalent dose of 500 mg twice a day. The dose could be increased or decreased at the clinician's discretion, to a maximum of four tablets and a minimum of one tablet a day. We recommended that treatment should be continued from enrolment until the infant's birth. The primary outcome was a composite of perinatal death (in-utero fetal death after randomisation or known neonatal death up to 7 days after birth), preterm delivery (<37 weeks' gestation), or neonatal unit admission for at least 4 h (from birth until hospital discharge). Each infant was counted once within this composite. All analyses were done according to the intention-to-treat principle. The trial was prospectively registered with the ISRCTN registry, number 91918806. Between Dec 23, 2015, and Aug 7, 2018, 605 women were enrolled and randomly allocated to receive ursodeoxycholic acid (n=305) or placebo (n=300). The primary outcome analysis included 304 women and 322 infants in the ursodeoxycholic acid group, and 300 women and 318 infants in the placebo group (consent to use data was withdrawn for 1 woman and 2 infants). The primary composite outcome occurred in 74 (23%) of 322 infants in the ursodeoxycholic acid group and 85 (27%) of 318 infants in the placebo group (adjusted risk ratio 0·85 [95% CI 0·62–1·15]). Two serious adverse events were reported in the ursodeoxycholic acid group and six serious adverse events were reported in the placebo group; no serious adverse events were regarded as being related to treatment. Treatment with ursodeoxycholic acid does not reduce adverse perinatal outcomes in women with intrahepatic cholestasis of pregnancy. Therefore, its routine use for this condition should be reconsidered. National Institute for Health Research Efficacy and Mechanism Evaluation Programme.

2·6 million pregnancies were estimated to have ended in stillbirth in 2015. The aim of the AFFIRM study was to test the hypothesis that introduction of a reduced fetal movement (RFM), care package for pregnant women and clinicians that increased women's awareness of the need for prompt reporting of RFM and that standardised management, including timely delivery, would alter the incidence of stillbirth. This stepped wedge, cluster-randomised trial was done in the UK and Ireland. Participating maternity hospitals were grouped and randomised, using a computer-generated allocation scheme, to one of nine intervention implementation dates (at 3 month intervals). This date was concealed from clusters and the trial team until 3 months before the implementation date. Each participating hospital had three observation periods: a control period from Jan 1, 2014, until randomised date of intervention initiation; a washout period from the implementation date and for 2 months; and the intervention period from the end of the washout period until Dec 31, 2016. Treatment allocation was not concealed from participating women and caregivers. Data were derived from observational maternity data. The primary outcome was incidence of stillbirth. The primary analysis was done according to the intention-to-treat principle, with births analysed according to whether they took place during the control or intervention periods, irrespective of whether the intervention had been implemented as planned. This study is registered with www.ClinicalTrials.gov, number NCT01777022. 37 hospitals were enrolled in the study. Four hospitals declined participation, and 33 hospitals were randomly assigned to an intervention implementation date. Between Jan 1, 2014, and Dec, 31, 2016, data were collected from 409 175 pregnancies (157 692 deliveries during the control period, 23 623 deliveries in the washout period, and 227 860 deliveries in the intervention period). The incidence of stillbirth was 4·40 per 1000 births during the control period and 4·06 per 1000 births in the intervention period (adjusted odds ratio [aOR] 0·90, 95% CI 0·75–1·07; p=0·23). The RFM care package did not reduce the risk of stillbirths. The benefits of a policy that promotes awareness of RFM remains unproven. Chief Scientist Office, Scottish Government (CZH/4/882), Tommy's Centre for Maternal and Fetal Health, Sands.

The use of azithromycin reduces maternal infection in women during unplanned cesarean delivery, but its effect on those with planned vaginal delivery is unknown. Data are needed on whether an intrapartum oral dose of azithromycin would reduce maternal and offspring sepsis or death. In this multicountry, placebo-controlled, randomized trial, we assigned women who were in labor at 28 weeks' gestation or more and who were planning a vaginal delivery to receive a single 2-g oral dose of azithromycin or placebo. The two primary outcomes were a composite of maternal sepsis or death and a composite of stillbirth or neonatal death or sepsis. During an interim analysis, the data and safety monitoring committee recommended stopping the trial for maternal benefit. A total of 29,278 women underwent randomization. The incidence of maternal sepsis or death was lower in the azithromycin group than in the placebo group (1.6% vs. 2.4%), with a relative risk of 0.67 (95% confidence interval [CI], 0.56 to 0.79; P<0.001), but the incidence of stillbirth or neonatal death or sepsis was similar (10.5% vs. 10.3%), with a relative risk of 1.02 (95% CI, 0.95 to 1.09; P = 0.56). The difference in the maternal primary outcome appeared to be driven mainly by the incidence of sepsis (1.5% in the azithromycin group and 2.3% in the placebo group), with a relative risk of 0.65 (95% CI, 0.55 to 0.77); the incidence of death from any cause was 0.1% in the two groups (relative risk, 1.23; 95% CI, 0.51 to 2.97). Neonatal sepsis occurred in 9.8% and 9.6% of the infants, respectively (relative risk, 1.03; 95% CI, 0.96 to 1.10). The incidence of stillbirth was 0.4% in the two groups (relative risk, 1.06; 95% CI, 0.74 to 1.53); neonatal death within 4 weeks after birth occurred in 1.5% in both groups (relative risk, 1.03; 95% CI, 0.86 to 1.24). Azithromycin was not associated with a higher incidence in adverse events. Among women planning a vaginal delivery, a single oral dose of azithromycin resulted in a significantly lower risk of maternal sepsis or death than placebo but had little effect on newborn sepsis or death. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others; A-PLUS ClinicalTrials.gov number, NCT03871491.).

AbstractObjectiveTo evaluate if induction of labour at 41 weeks improves perinatal and maternal outcomes in women with a low risk pregnancy compared with expectant management and induction of labour at 42 weeks.DesignMulticentre, open label, randomised controlled superiority trial.Setting14 hospitals in Sweden, 2016-18.Participants2760 women with a low risk uncomplicated singleton pregnancy randomised (1:1) by the Swedish Pregnancy Register. 1381 women were assigned to the induction group and 1379 were assigned to the expectant management group.InterventionsInduction of labour at 41 weeks and expectant management and induction of labour at 42 weeks.Main outcome measuresThe primary outcome was a composite perinatal outcome including one or more of stillbirth, neonatal mortality, Apgar score less than 7 at five minutes, pH less than 7.00 or metabolic acidosis (pH <7.05 and base deficit >12 mmol/L) in the umbilical artery, hypoxic ischaemic encephalopathy, intracranial haemorrhage, convulsions, meconium aspiration syndrome, mechanical ventilation within 72 hours, or obstetric brachial plexus injury. Primary analysis was by intention to treat.ResultsThe study was stopped early owing to a significantly higher rate of perinatal mortality in the expectant management group. The composite primary perinatal outcome did not differ between the groups: 2.4% (33/1381) in the induction group and 2.2% (31/1379) in the expectant management group (relative risk 1.06, 95% confidence interval 0.65 to 1.73; P=0.90). No perinatal deaths occurred in the induction group but six (five stillbirths and one early neonatal death) occurred in the expectant management group (P=0.03). The proportion of caesarean delivery, instrumental vaginal delivery, or any major maternal morbidity did not differ between the groups.ConclusionsThis study comparing induction of labour at 41 weeks with expectant management and induction at 42 weeks does not show any significant difference in the primary composite adverse perinatal outcome. However, a reduction of the secondary outcome perinatal mortality is observed without increasing adverse maternal outcomes. Although these results should be interpreted cautiously, induction of labour ought to be offered to women no later than at 41 weeks and could be one (of few) interventions that reduces the rate of stillbirths.Trial registrationCurrent Controlled Trials ISRCTN26113652.

In this multicountry, randomized trial involving women in low-resource countries who were at risk for early preterm birth, the risks of neonatal death and stillbirth or neonatal death were significantly lower among women who received antenatal dexamethasone than among those who received placebo, and dexamethasone was noninferior with respect to possible maternal bacterial infection.

AbstractObjectiveTo examine the associations of infertility, recurrent miscarriage, and stillbirth with the risk of first non-fatal and fatal stroke, further stratified by stroke subtypes.DesignIndividual participant pooled analysis of eight prospective cohort studies.SettingCohort studies across seven countries (Australia, China, Japan, Netherlands, Sweden, the United Kingdom, and the United States) participating in the InterLACE (International Collaboration for a Life Course Approach to Reproductive Health and Chronic Disease Events) consortium, which was established in June 2012.Participants618 851 women aged 32.0-73.0 years at baseline with data on infertility, miscarriage, or stillbirth, at least one outcome event (non-fatal or fatal stroke), and information on covariates were included; 93 119 women were excluded. Of the participants, 275 863 had data on non-fatal and fatal stroke, 54 716 only had data on non-fatal stroke, and 288 272 only had data on fatal stroke.Main outcome and measuresNon-fatal strokes were identified through self-reported questionnaires, linked hospital data, or national patient registers. Fatal strokes were identified through death registry data.ResultsThe median follow-up for non-fatal stroke and fatal stroke was 13.0 years (interquartile range 12.0-14.0) and 9.4 years (7.6-13.0), respectively. A first non-fatal stroke was experienced by 9265 (2.8%) women and 4003 (0.7%) experienced a fatal stroke. Hazard ratios for non-fatal or fatal stroke were stratified by hypertension and adjusted for race or ethnicity, body mass index, smoking status, education level, and study. Infertility was associated with an increased risk of non-fatal stroke (hazard ratio 1.14, 95% confidence interval 1.08 to 1.20). Recurrent miscarriage (at least three) was associated with higher risk of non-fatal and fatal stroke (1.35, 1.27 to 1.44, and 1.82, 1.58 to 2.10, respectively). Women with stillbirth were at 31% higher risk of non-fatal stroke (1.31, 1.10 to 1.57) and women with recurrent stillbirth were at 26% higher risk of fatal stroke (1.26, 1.15 to 1.39). The increased risk of stroke (non-fatal or fatal) associated with infertility or recurrent stillbirths was mainly driven by a single stroke subtype (non-fatal ischaemic stroke and fatal haemorrhagic stroke), while the increased risk of stroke (non-fatal or fatal) associated with recurrent miscarriages was driven by both subtypes.ConclusionA history of recurrent miscarriages and death or loss of a baby before or during birth could be considered a female specific risk factor for stroke, with differences in risk according to stroke subtypes. These findings could contribute to improved monitoring and stroke prevention for women with such a history.

In this randomized trial of treatment versus no treatment for mild gestational diabetes mellitus, rates of the primary outcome (a composite of stillbirth or perinatal death and neonatal hyperbilirubinemia, hypoglycemia, hyperinsulinemia, or birth trauma) did not differ significantly between groups. However, there were significant reductions with treatment in several secondary outcomes, including the frequency of large-for-gestational-age infants, shoulder dystocia, cesarean delivery, and hypertension in pregnancy. In this randomized trial of treatment versus no treatment for mild gestational diabetes mellitus, rates of the primary outcome (a composite of stillbirth or perinatal death and neonatal hyperbilirubinemia, hypoglycemia, hyperinsulinemia, or birth trauma) did not differ significantly between groups. However, there were significant reductions with treatment in several secondary outcomes. Gestational diabetes mellitus is defined as glucose intolerance that first occurs or is first identified during pregnancy. 1 The frequency of this condition is rising in the United States and occurs in 1 to 14% of all pregnancies, depending on varying characteristics of the population. 2 More than 40 years ago, O'Sullivan and Mahan developed glucose-tolerance-test criteria for the diagnosis of gestational diabetes mellitus. 3 The diagnostic thresholds that they developed were based on the subsequent development of adult-onset diabetes and were not predicated on any association between carbohydrate intolerance discovered during gestation and adverse pregnancy outcomes. Although gestational diabetes mellitus is a . . .

Pre-eclampsia is a leading cause of maternal and perinatal mortality. Evidence regarding interventions in a low-income or middle-income setting is scarce. We aimed to evaluate whether planned delivery between 34+ 0 and 36+ 6 weeks’ gestation can reduce maternal mortality and morbidity without increasing perinatal complications in India and Zambia. In this parallel-group, multicentre, open-label, randomised controlled trial, we compared planned delivery versus expectant management in women with pre-eclampsia from 34+ 0 to 36+ 6 weeks’ gestation. Participants were recruited from nine hospitals and referral facilities in India and Zambia and randomly assigned to planned delivery or expectant management in a 1:1 ratio by a secure web-based randomisation facility hosted by MedSciNet. Randomisation was stratified by centre and minimised by parity, single-fetus pregnancy or multi-fetal pregnancy, and gestational age. The primary maternal outcome was a composite of maternal mortality or morbidity with a superiority hypothesis. The primary perinatal outcome was a composite of one or more of: stillbirth, neonatal death, or neonatal unit admission of more than 48 h with a non-inferiority hypothesis (margin of 10% difference). Analyses were by intention to treat, with an additional per-protocol analysis for the perinatal outcome. The trial was prospectively registered with ISRCTN, 10672137. The trial is closed to recruitment and all follow-up has been completed. Between Dec 19, 2019, and March 31, 2022, 565 women were enrolled. 284 women (282 women and 301 babies analysed) were allocated to planned delivery and 281 women (280 women and 300 babies analysed) were allocated to expectant management. The incidence of the primary maternal outcome was not significantly different in the planned delivery group (154 [55%]) compared with the expectant management group (168 [60%]; adjusted risk ratio [RR] 0·91, 95% CI 0·79 to 1·05). The incidence of the primary perinatal outcome by intention to treat was non-inferior in the planned delivery group (58 [19%]) compared with the expectant management group (67 [22%]; adjusted risk difference –3·39%, 90% CI –8·67 to 1·90; non-inferiority p<0·0001). The results from the per-protocol analysis were similar. There was a significant reduction in severe maternal hypertension (adjusted RR 0·83, 95% CI 0·70 to 0·99) and stillbirth (0·25, 0·07 to 0·87) associated with planned delivery. There were 12 serious adverse events in the planned delivery group and 21 in the expectant management group. Clinicians can safely offer planned delivery to women with late preterm pre-eclampsia, in a low-income or middle-income country. Planned delivery reduces stillbirth, with no increase in neonatal unit admissions or neonatal morbidity and reduces the risk of severe maternal hypertension. Planned delivery from 34 weeks’ gestation should therefore be considered as an intervention to reduce pre-eclampsia associated mortality and morbidity in these settings. UK Medical Research Council and Indian Department of Biotechnology.

Placental growth factor (PlGF)-based testing has high diagnostic accuracy for predicting pre-eclampsia needing delivery, significantly reducing time to diagnosis and severe maternal adverse outcomes. The clinical benefit of repeat PlGF-based testing is unclear. We aimed to determine whether repeat PlGF-based testing (using a clinical management algorithm and nationally recommended thresholds) reduces adverse perinatal outcomes in pregnant individuals with suspected preterm pre-eclampsia. In this multicentre, parallel-group, superiority, randomised controlled trial, done in 22 maternity units across England, Scotland, and Wales, we recruited women aged 18 years or older with suspected pre-eclampsia between 22 weeks and 0 days of gestation and 35 weeks and 6 days of gestation. Women were randomly assigned (1:1) to revealed repeat PlGF-based testing or concealed repeat testing with usual care. The intervention was not masked to women or partners, or clinicians or data collectors, due to the nature of the trial. The trial statistician was masked to intervention allocation. The primary outcome was a perinatal composite of stillbirth, early neonatal death, or neonatal unit admission. The primary analysis was by the intention-to-treat principle, with a per-protocol analysis restricted to women managed according to their allocation group. The trial was prospectively registered with the ISRCTN registry, ISRCTN 85912420. Between Dec 17, 2019, and Sept 30, 2022, 1253 pregnant women were recruited and randomly assigned treatment; one patient was excluded due to randomisation error. 625 women were allocated to revealed repeat PlGF-based testing and 627 women were allocated to usual care with concealed repeat PlGF-based testing (mean age 32·3 [SD 5·7] years; 879 [70%] white). One woman in the concealed repeat PlGF-based testing group was lost to follow-up. There was no significant difference in the primary perinatal composite outcome between the revealed repeat PlGF-based testing group (195 [31·2%]) of 625 women) compared with the concealed repeat PlGF-based testing group (174 [27·8%] of 626 women; relative risk 1·21 [95% CI 0·95–1·33]; p=0·18). The results from the per-protocol analysis were similar. There were four serious adverse events in the revealed repeat PlGF-based testing group and six in the concealed repeat PlGF-based testing group; all serious adverse events were deemed unrelated to the intervention by the site principal investigators and chief investigator. Repeat PlGF-based testing in pregnant women with suspected pre-eclampsia was not associated with improved perinatal outcomes. In a high-income setting with a low prevalence of adverse outcomes, universal, routine repeat PlGF-based testing of all individuals with suspected pre-eclampsia is not recommended. Tommy's Charity, Jon Moulton Charitable Trust, and National Institute for Health and Care Research Guy's and St Thomas' Biomedical Research Centre.