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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.

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.

In this multicenter, double-blind, placebo-controlled, randomized trial involving women with recurrent miscarriages, treatment with progesterone, administered vaginally during the first trimester, did not increase the rate of live births. Recurrent miscarriage, defined as the loss of three or more pregnancies, affects approximately 1% of couples who attempt to have a child. 1 Even after comprehensive investigations, a cause for recurrent miscarriage is identified in less than half of these couples. 1 , 2 Unexplained recurrent miscarriage is associated with substantial adverse clinical and psychological consequences for the women and their families. Various therapeutic strategies to increase the rate of live births among these women have been evaluated, but no effective treatment has been identified. Progesterone is essential to achieve and maintain a healthy pregnancy. It is secreted naturally by the corpus luteum . . .

Recurrent spontaneous abortion (RSA), characterized by the loss of two or more pregnancies, impacts approximately 1–2% of couples and poses a significant challenge for individuals of childbearing age. The precise mechanisms underlying RSA remain incompletely understood. Concurrently, the global prevalence of obesity is on the rise, with obesity being closely associated with female reproductive disorders and infertility. This study initially examines the pathways through which obesity contributes to RSA, encompassing factors such as embryonic euploid miscarriage, endometrial development, immune function, among others. Furthermore, adipokines and the fat mass and obesity-related (FTO) are identified as potential contributors to RSA. The study also explores the enhancement of pregnancy outcomes through various weight management strategies, with a particular focus on the roles of dietary interventions, physical activity, and weight control during pregnancy. Obesity is closely related to RSA in multiple aspects. Additional clinical prospective and experimental studies are required to explore its precise pathogenesis. Through this review, we aim to provide strategies for improvement and treatment approaches for RSA related to obesity. Through this review, we suggest potential clinical management strategies and research avenues aimed at offering enhancements and therapeutic insights for miscarriages linked to obesity and its associated risk factors.

The etiology of recurrent pregnancy loss (RPL) is complex and multifactorial and in half of patients it remains unexplained (U-RPL). Recently, low-molecular-weight heparin (LMWH) has gained increasing relevance for its therapeutic potential. On this regard, the aim of this systematic review and meta-analysis is to analyze the efficacy of low molecular weight heparin (LMWH) from the beginning of pregnancy in terms of live birth rates (LBR) in U-RPL. Registered randomized controlled trials (RCTs) were included. We stratified findings based on relevant clinical factors including number of previous miscarriages, treatment type and control type. Intervention or exposure was defined as the administration of LMWH alone or in combination with low-dose aspirin (LDA). A total of 6 studies involving 1016 patients were included. The meta-analysis results showed that LMWH used in the treatment of U-RPL was not associated with an increase in LBR with a pooled OR of 1.01, a medium heterogeneity (26.42%) and no publication bias. Results of other sub-analyses according to country, treatment type, and control type showed no significant effect of LMWH on LBR in all subgroups, with a high heterogeneity. The results highlight a non-significant effect of LMWH in U-RPL on LBR based on moderate quality evidence. Registration number: PROSPERO: ( https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022326433 ).

Aspirin and low-molecular-weight heparin are often prescribed to women with unexplained recurrent miscarriage, but their benefit is unclear. In this randomized trial involving women with a history of unexplained recurrent miscarriage, treatment with 80 mg of aspirin and open-label nadroparin (at a dose of 2850 IU) or aspirin alone did not improve live-birth rates or other pregnancy outcomes, as compared with placebo. In women with a history of unexplained recurrent miscarriage, treatment with aspirin and nadroparin or aspirin alone did not improve live-birth rates or other pregnancy outcomes, as compared with placebo. Approximately 1% of all women trying to conceive have recurrent miscarriage, defined as three previous miscarriages; when recurrent miscarriage is defined as two previous miscarriages, the proportion rises to 5%. 1 In half of such patients, no underlying cause of miscarriage can be identified. 2 , 3 Although various interventions have been suggested to improve rates of live birth in such cases, no effective treatment has been identified. It has been suggested that in women with recurrent miscarriage and a diagnosis of the antiphospholipid syndrome, treatment with aspirin and heparin may improve the pregnancy outcome, although findings from available randomized trials have been . . .

Introduction Clinical practice guidelines provide inconsistent recommendations regarding progestogen supplementation for threatened and recurrent miscarriage. We conducted a systematic review and meta‐analysis to assess the effectiveness and safety of progestogens for these patients. Material and methods We searched Medline, Embase, and Cochrane Central Registry of Controlled Trials up to October 6, 2023 for randomized control trials (RCTs) comparing progestogen supplementation to placebo or no treatment for pregnant women with threatened or recurrent miscarriage. We assessed the risk of bias using a modified version of the Cochrane risk‐of‐bias tool and the certainty of evidence using the GRADE approach. Results Of 15 RCTs (6616 pregnancies) reporting on threatened or recurrent miscarriage, 12 (5610 pregnancies) reported on threatened miscarriage with or without a prior history of miscarriage. Results indicated that progesterone probably increases live births (relative risk (RR) 1.04, 95% confidence interval (CI) 0.99–1.10, absolute increase 3.1%, moderate certainty). Of these RCTs, three (1973 pregnancies) reporting on threatened miscarriage with a prior history of miscarriage indicated that progesterone possibly increases live births (RR 1.06, 95% CI: 0.97–1.16, absolute increase 4.4%; low certainty), while four (2540 pregnancies) reporting on threatened miscarriage and no prior miscarriage left the effect very uncertain (RR 1.02, 95% CI: 0.96–1.10, absolute increase 1.7%; very low certainty). Three trials reporting on 1006 patients with a history of two or more prior miscarriages indicated progesterone probably increases live births (RR 1.08, 95% CI: 0.98–1.19, absolute increase 5.7%, moderate certainty). Six RCTs that reported on 2979 patients with at least one prior miscarriage indicated that progesterone probably increases live births (RR 1.07, 95% CI: 1.01–1.13, absolute increase 5.0%; moderate certainty). Progesterone probably has little or no effect on congenital anomalies (RR 1.06, 95% CI: 0.76–1.48, absolute increase 0.1%; moderate certainty), and other serious adverse pregnancy events (RR 1.07, 95% CI: 0.83–1.40, absolute increase 0.2%, moderate certainty). Conclusions In women at increased risk of pregnancy loss, progestogens probably increase live births without increasing adverse maternal and neonatal events. It remains possible that the benefit is restricted to those with prior miscarriages. Previous meta‐analyses have generated inconsistent summary estimates for progestogen supplementation effects on live birth for women with threatened or recurrent miscarriage. To assess this, we conducted a meta‐analysis and found an increase in the likelihood of a live birth with progestogen supplementation, most convincing in those with prior miscarriage

The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. In an accompanying research study in PLOS Medicine, Landman and colleagues report on a randomised controlled trial designed to assess the effectiveness of low-dose aspirin in the prevention of preterm birth in women at high risk of preterm birth [5]. The sample size calculation for the APRIL trial was based on a potential 35% relative reduction in the rate of preterm birth (which the authors state was based on the average risk reduction in preterm birth seen in secondary analyses of other trials of aspirin), from a background rate of 36%. Evaluation of low-dose aspirin in the prevention of recurrent spontaneous preterm labour (the APRIL study): A multicentre, randomised, double-blinded, placebo-controlled trial.

The risk of pregnancy loss prior to 24 weeks gestation has been found to be 15.3% of all pregnancies, around 23 million losses each year. Recurrent pregnancy loss (RPL) - two or more pregnancy losses - are now presumed to affect 5% of couples. Clinical guidelines for health professionals for RPL are conflicting, lacking in good quality evidence and fail to involve those who experience RPL, especially the male partner. Despite folate being recommended for preconception support, no mention of folate exists in RPL guidelines. A national cross-sectional survey which assessed health professionals’ recommendations, testing, prescribing and referral practices when providing care for couples in preconception and RPL was conducted. Clinical guidelines for RPL were found to be critically important for health professionals to provide care to couples experiencing RPL, however health professionals ( n  = 175) require stronger clinical guidance and more specialised training (47.3%), education (62.8%) and funding to better assist couples with RPL. Only 34% of health professionals reported having the necessary resources to support couples with RPL. Health professionals are aware of how important folate is to support preconception in females but are unaware of the critical role it plays in male fertility and as a result males are largely ignored in preconception care. Given the importance of folate supplementation in preconception and pregnancy, the guidelines for RPL fail to include dosing recommendations or variations in the type of folate that should be prescribed. Improved clinical guidelines, better resourcing and funding are required for health professionals to better support couples with RPL. Male partners need to be included in the preconception care and folate form and dosing must be considered.

Recurrent miscarriage is a distressing condition with limited therapeutic options. Chronic histiocytic intervillositis of unknown etiology (CIUE) is a rare inflammatory placental disorder characterized by maternal immune cell infiltration of the intervillous space, fibrin deposition, and ischemic tissue damage, leading to pregnancy loss. The condition likely reflects an immune response against paternal alloantigens, with histopathological features resembling antibody-mediated rejection in solid organ transplantation. We investigated two women with recurrent CIUE-related pregnancy losses. Detailed immunological profiling included anti-human leukocyte antigen (HLA) antibody characterization, compatibility testing, and histopathological examination of previous placentas, as well as screening for other causes of recurrent pregnancy losses. Based on evidence of antibody-mediated alloimmune injury, we implemented a targeted immunosuppressive regimen derived from transplantation medicine, combining intravenous immunoglobulins (IVIG), tacrolimus, corticosteroids, and hydroxychloroquine, with close pregnancy monitoring. The first patient, after six consecutive CIUE-related pregnancy losses, underwent preconception desensitization and continued treatment throughout pregnancy. Early signs of placental dysfunction prompted therapy intensification, leading to delivery of a viable infant at 33 + 2 weeks. Placental histology showed only minor residual CIUE lesions. The second patient, with two pregnancy losses and a fetal demise from CIUE, began treatment at 6 weeks’ gestation and delivered a healthy infant at 36 weeks. In both cases, therapy was generally well tolerated, with gestational diabetes as the main complication, and no major maternal or neonatal adverse events. These cases support the concept that CIUE represents a breakdown of maternal immune tolerance toward paternal antigens, mediated by fetal-specific anti-HLA antibodies—akin to solid organ graft rejection. An immunosuppressive protocol adapted from transplantation medicine achieved two successful live births after multiple CIUE-related pregnancy losses. Targeting antibody-mediated alloimmunity may represent a promising therapeutic strategy for selected patients with recurrent miscarriages due to CIUE. Further studies are warranted to define optimal regimens and identify predictors of response.