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Women who have had repeated miscarriages often have uncertainties about the cause, the likelihood of recurrence, the investigations they need, and the treatments that might help. Health-care policy makers and providers have uncertainties about the optimal ways to organise and provide care. For this Series paper, we have developed recommendations for practice from literature reviews, appraisal of guidelines, and a UK-wide consensus conference that was held in December, 2019. Caregivers should individualise care according to the clinical needs and preferences of women and their partners. We define a minimum set of investigations and treatments to be offered to couples who have had recurrent miscarriages, and urge health-care policy makers and providers to make them universally available. The essential investigations include measurements of lupus anticoagulant, anticardiolipin antibodies, thyroid function, and a transvaginal pelvic ultrasound scan. The key treatments to consider are first trimester progesterone administration, levothyroxine in women with subclinical hypothyroidism, and the combination of aspirin and heparin in women with antiphospholipid antibodies. Appropriate screening and care for mental health issues and future obstetric risks, particularly preterm birth, fetal growth restriction, and stillbirth, will need to be incorporated into the care pathway for couples with a history of recurrent miscarriage. We suggest health-care services structure care using a graded model in which women are offered online health-care advice and support, care in a nurse or midwifery-led clinic, and care in a medical consultant-led clinic, according to clinical needs. [ABSTRACT FROM AUTHOR]

The physical and psychological effect of miscarriage is commonly underappreciated. The journey from diagnosis of miscarriage, through clinical management, to supportive aftercare can be challenging for women, their partners, and caregivers. Diagnostic challenges can lead to delayed or ineffective care and increased anxiety. Inaccurate diagnosis of a miscarriage can result in the unintended termination of a wanted pregnancy. Uncertainty about the therapeutic effects of interventions can lead to suboptimal care, with variations across facilities and countries. For this Series paper, we have developed recommendations for practice from a literature review, appraisal of guidelines, and expert group discussions. The recommendations are grouped into three categories: (1) diagnosis of miscarriage, (2) prevention of miscarriage in women with early pregnancy bleeding, and (3) management of miscarriage. We recommend that every country reports annual aggregate miscarriage data, similarly to the reporting of stillbirth. Early pregnancy services need to focus on providing an effective ultrasound service, as it is central to the diagnosis of miscarriage, and be able to provide expectant management of miscarriage, medical management with mifepristone and misoprostol, and surgical management with manual vacuum aspiration. Women with the dual risk factors of early pregnancy bleeding and a history of previous miscarriage can be recommended vaginal micronised progesterone to improve the prospects of livebirth. We urge health-care funders and providers to invest in early pregnancy care, with specific focus on training for clinical nurse specialists and doctors to provide comprehensive miscarriage care within the setting of dedicated early pregnancy units. [ABSTRACT FROM AUTHOR]

Anticoagulant therapy might reduce the number of miscarriages and adverse pregnancy outcomes in women with recurrent pregnancy loss and inherited thrombophilia. We aimed to assess use of low-molecular-weight heparin (LMWH) versus standard care in this population. The ALIFE2 trial was an international open-label, randomised controlled trial undertaken in hospitals in the UK (n=26), the Netherlands (n=10), the USA (n=2), Belgium (n=1), and Slovenia (n=1). Women aged 18–42 years who had two or more pregnancy losses and confirmed inherited thrombophilia, and who were trying to conceive or were already pregnant (≤7 weeks' gestation), were eligible for inclusion. Women were randomly assigned (1:1) to use low-dose LMWH or not (alongside standard care in both groups) once they had a positive urine pregnancy test. LMWH was started at or before 7 weeks' gestation and continued until the end of pregnancy. The primary outcome measure was livebirth rate, assessed in all women with available data. Safety outcomes included bleeding episodes, thrombocytopenia, and skin reactions, and were assessed in all randomly assigned women who reported a safety event. The trial was registered within the Dutch Trial Register (NTR3361) and EudraCT (UK: 2015-002357-35). Between Aug 1, 2012, and Jan 30, 2021, 10 625 women were assessed for eligibility, 428 were registered, and 326 conceived and were randomly assigned (164 to LMWH and 162 to standard care). 116 (72%) of 162 women with primary outcome data in the LMWH group and 112 (71%) of 158 in the standard care group had livebirths (adjusted odds ratio 1·08, 95% CI 0·65 to 1·78; absolute risk difference, 0·7%, 95% CI –9·2% to 10·6%). 39 (24%) of 164 women in the LMWH group and 37 (23%) of 162 women in the standard care group reported adverse events. LMWH did not result in higher livebirth rates in women who had two or more pregnancy losses and confirmed inherited thrombophilia. We do not advise use of LMWH in women with recurrent pregnancy loss and inherited thrombophilia, and we advise against screening for inherited thrombophilia in women with recurrent pregnancy loss. National Institute for Health and Care Research and the Netherlands Organization for Health Research and Development. [ABSTRACT FROM AUTHOR]

Tubal ectopic pregnancies can cause substantial morbidity or even death. Current treatment is with methotrexate or surgery. Methotrexate treatment fails in approximately 30% of women who subsequently require rescue surgery. Gefitinib, an epidermal growth factor receptor inhibitor, might improve the effects of methotrexate. We assessed the efficacy of oral gefitinib with methotrexate, versus methotrexate alone, to treat tubal ectopic pregnancy. We performed a multicentre, randomised, double-blind, placebo-controlled trial across 50 UK hospitals. Participants diagnosed with tubal ectopic pregnancy were administered a single dose of intramuscular methotrexate (50 mg/m2) and randomised (1:1 ratio) to 7 days of additional oral gefitinib (250 mg daily) or placebo. The primary outcome, analysed by intention to treat, was surgical intervention to resolve the ectopic pregnancy. Secondary outcomes included time to resolution of ectopic pregnancy and serious adverse events. This trial is registered at the ISRCTN registry, ISCRTN 67795930. Between Nov 2, 2016, and Oct 6, 2021, 328 participants were allocated to methotrexate and gefitinib (n=165) or methotrexate and placebo (n=163). Three participants in the placebo group withdrew. Surgical intervention occurred in 50 (30%) of 165 participants in the gefitinib group and in 47 (29%) of 160 participants in the placebo group (adjusted risk ratio 1·15, 95% CI 0·85 to 1·58; adjusted risk difference –0·01, 95% CI –0·10 to 0·09; p=0·37). Without surgical intervention, median time to resolution was 28·0 days in the gefitinib group and 28·0 days in the placebo group (subdistribution hazard ratio 1·03, 95% CI 0·75 to 1·40). Serious adverse events occurred in five (3%) of 165 participants in the gefitinib group and in six (4%) of 162 participants in the placebo group. Diarrhoea and rash were more common in the gefitinib group. In women with a tubal ectopic pregnancy, adding oral gefitinib to parenteral methotrexate does not offer clinical benefit over methotrexate and increases minor adverse reactions. National Institute of Health Research. [ABSTRACT FROM AUTHOR]

Background: Sperm selection strategies aimed at improving success rates of intracytoplasmic sperm injection (ICSI) include binding to hyaluronic acid (herein termed hyaluronan). Hyaluronan-selected sperm have reduced levels of DNA damage and aneuploidy. Use of hyaluronan-based sperm selection for ICSI (so-called physiological ICSI [PICSI]) is reported to reduce the proportion of pregnancies that end in miscarriage. However, the effect of PICSI on livebirth rates is uncertain. We aimed to investigate the efficacy of PICSI versus standard ICSI for improving livebirth rates among couples undergoing fertility treatment.Methods: This parallel, two-group, randomised trial included couples undergoing an ICSI procedure with fresh embryo transfer at 16 assisted conception units in the UK. Eligible women (aged 18-43 years) had a body-mass index of 19-35 kg/m2 and a follicle-stimulating hormone (FSH) concentration of 3·0-20·0 mIU/mL or, if no FSH measurement was available, an anti-müllerian hormone concentration of at least 1·5 pmol/L. Eligible men (aged 18-55 years) had not had a vasovasostomy or been treated for cancer in the 24 months before recruitment and were able, after at least 3 days of sexual abstinence, to produce freshly ejaculated sperm for the treatment cycle. Couples were randomly assigned (1:1) with an online system to receive either PICSI or a standard ICSI procedure. The primary outcome was full-term (≥37 weeks' gestational age) livebirth, which was assessed in all eligible couples who completed follow-up. This trial is registered, number ISRCTN99214271.Findings: Between Feb 1, 2014, and Aug 31, 2016, 2772 couples were randomly assigned to receive PICSI (n=1387) or ICSI (n=1385), of whom 2752 (1381 in the PICSI group and 1371 in the ICSI group) were included in the primary analysis. The term livebirth rate did not differ significantly between PICSI (27·4% [379/1381]) and ICSI (25·2% [346/1371]) groups (odds ratio 1·12, 95% CI 0·95-1·34; p=0·18). There were 56 serious adverse events in total, including 31 in the PICSI group and 25 in the ICSI group; most were congenital abnormalities and none were attributed to treatment.Interpretation: Compared with ICSI, PICSI does not significantly improve term livebirth rates. The wider use of PICSI, therefore, is not recommended at present.Funding: National Institute for Health Research Efficacy and Mechanism Evaluation Programme. [ABSTRACT FROM AUTHOR]

Background: The success rate of in-vitro fertilisation (IVF) remains low and many women undergo multiple treatment cycles. A previous meta-analysis suggested hysteroscopy could improve outcomes in women who have had recurrent implantation failure; however, studies were of poor quality and a definitive randomised trial was needed. In the TROPHY trial we aimed to assess whether hysteroscopy improves the livebirth rate following IVF treatment in women with recurrent failure of implantation.Methods: We did a multicentre, randomised controlled trial in eight hospitals in the UK, Belgium, Italy, and the Czech Republic. We recruited women younger than 38 years who had normal ultrasound of the uterine cavity and history of two to four unsuccessful IVF cycles. We used an independent web-based trial management system to randomly assign (1:1) women to receive outpatient hysteroscopy (hysteroscopy group) or no hysteroscopy (control group) in the month before starting a treatment cycle of IVF (with or without intracytoplasmic sperm injection). A computer-based algorithm minimised for key prognostic variables: age, body-mass index, basal follicle-stimulating hormone concentration, and the number of previous failed IVF cycles. The order of group assignment was masked to the researchers at the time of recruitment and randomisation. Embryologists involved in the embryo transfer were masked to group allocation, but physicians doing the procedure knew of group assignment and had hysteroscopy findings accessible. Participants were not masked to their group assignment. The primary outcome was the livebirth rate (proportion of women who had a live baby beyond 24 weeks of gestation) in the intention-to-treat population. The trial was registered with the ISRCTN Registry, ISRCTN35859078.Findings: Between Jan 1, 2010, and Dec 31, 2013, we randomly assigned 350 women to the hysteroscopy group and 352 women to the control group. 102 (29%) of women in the hysteroscopy group had a livebirth after IVF compared with 102 (29%) women in the control group (risk ratio 1·0, 95% CI 0·79-1·25; p=0·96). No hysteroscopy-related adverse events were reported.Interpretation: Outpatient hysteroscopy before IVF in women with a normal ultrasound of the uterine cavity and a history of unsuccessful IVF treatment cycles does not improve the livebirth rate. Further research into the effectiveness of surgical correction of specific uterine cavity abnormalities before IVF is warranted.Funding: European Society of Human Reproduction and Embryology, European Society for Gynaecological Endoscopy. [ABSTRACT FROM AUTHOR]

Background Maternal and neonatal mortality rates remain high in many low-income and middle-income countries. Different approaches for the improvement of birth outcomes have been used in community-based interventions, with heterogeneous effects on survival. We assessed the effects of women's groups practising participatory learning and action, compared with usual care, on birth outcomes in low-resource settings. Methods We did a systematic review and meta-analysis of randomised controlled trials undertaken in Bangladesh, India, Malawi, and Nepal in which the effects of women's groups practising participatory learning and action were assessed to identify population-level predictors of effect on maternal mortality, neonatal mortality, and stillbirths. We also reviewed the cost-effectiveness of the women's group intervention and estimated its potential effect at scale in Countdown countries. Findings Seven trials (119 428 births) met the inclusion criteria. Meta-analyses of all trials showed that exposure to women's groups was associated with a 37% reduction in maternal mortality (odds ratio 0.63, 95% CI 0.32-0.94), a 23% reduction in neonatal mortality (0.77, 0.65-0.90), and a 9% non-significant reduction in stillbirths (0.91, 0.79-1.03), with high heterogeneity for maternal (I²=58.8%, p=0.024) and neonatal results (I²=64.7%, p=0.009). In the meta-regression analyses, the proportion of pregnant women in groups was linearly associated with reduction in both maternal and neonatal mortality (p=0.026 and p=0.011, respectively). A subgroup analysis of the four studies in which at least 30% of pregnant women participated in groups showed a 55% reduction in maternal mortality (0.45, 0.17-0.73) and a 33% reduction in neonatal mortality (0.67, 0.59-0.74). The intervention was cost effective by WHO standards and could save an estimated 283 000 newborn infants and 41100 mothers per year if implemented in rural areas of 74 Countdown countries. Interpretation With the participation of at least a third of pregnant women and adequate population coverage, women's groups practising participatory learning and action are a cost-effective strategy to improve maternal and neonatal survival in low-resource settings. Funding Wellcome Trust, Ammalife, and National Institute for Health Research Collaboration for Leadership in Applied Health Research and Care for Birmingham and the Black Country programme. [ABSTRACT FROM AUTHOR]

An abstract of the article "Carbetocin Versus Oxytocin for Prevention of Postpartum Haemorrhage: A Randomised Controlled Trial" by Sergio Rosales-Ortiz et al. is presented.