Search

Competing Interests: None Declared

Recurrent pregnancy loss (RPL) is one of the most challenging and difficult areas of reproductive treatment due to the immense emotional suffering inflicted on families and couples affected by RPL. As a result, it is predicted that couples experiencing recurrent pregnancy loss would have an increase in marital problems, stress levels, and anxiety, preventing them from achieving their family goals. The current cross-sectional study aimed to target pregnant women with thrombophilia with a history of RPL to observe their intimacy problems, stress levels, and couple satisfaction by completing a series of digital questionnaires. These patients were considered as the reference group, while the control group was formed by other women with thrombophilia and a history of RPL who eventually achieved pregnancy and gave birth. A total of 238 complete questionnaires were recorded (157 in the reference group and 81 in the control group). It was observed that women in the reference group who did not give birth had a significantly higher proportion of three or more pregnancy attempts (54.1% vs. 39.5%) and a significantly higher proportion of three more pregnancy losses (68.8% vs. 55.6%). It was observed that patients in the reference group were more likely to be emotion-oriented (42.7% vs. 27.2%). Also, women in the reference group had higher levels of dissatisfaction and lower levels of self-acceptance, pleasure, and marital quality scores. The total SII and DSCS scores were significantly lower than women with thrombophilia with a history of RPL who eventually gave birth. Women from the reference group had significantly greater intimacy problems and stress levels while having lower openness scores and self-esteem scores than women in the control group. It is possible that women with thrombophilia and recurrent pregnancy loss are more dissatisfied with their marriages than those who subsequently had one child. Since the financial status of those who achieved pregnancy was observed to be higher, it is likely that they achieved pregnancy by ART interventions, as they reported in questionnaires. It is important to target families afflicted by thrombophilia and other reasons for infertility to ease their access to ART therapies. By achieving their objectives, affected families will minimize dissatisfaction, divorce rates, and stress.

Chronic endometritis is a poorly understood infectious or inflammatory process, potentially disrupting the correct implantation of a human embryo (Puente et al., 2020). The exact prevalence is a subject of discussion and ranges across the available literature from 2% to almost 60%, with a higher suspicion of the condition being present in women with recurrent early pregnancy loss and recurrent implantation failure (Puente et al., 2020). The impact of chronic endometritis on reproductive outcomes following IVF remains questionable given the lack of proper data convincingly showing an improvement after diagnosis and treatment. This article aims to provide the reader with a critical appraisal of current diagnostic methods, treatments and patient populations to be tested for chronic endometritis., (Copyright © 2022 Reproductive Healthcare Ltd. Published by Elsevier Ltd. All rights reserved.)

Objective: The aim of this systematic review and meta-analysis was to analyze the reproductive outcomes of natural pregnancy after hysteroscopic septum resection in patients with recurrent miscarriage, primary infertility, or secondary infertility., Data Sources: The PubMed, Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure (CNKI), Wanfang Data Knowledge Service Platform, VIP Database, and Chinese Biomedical Literature Database (CBM) databases were electronically searched. The search time frame was from inception up to July 2021. The English search terms were (arcuate* and uter*), (sept* and uter*), (subseptate* and uter*), metroplast*, septoplast*, and resect*., Study Eligibility Criteria: Selection criteria included randomized controlled trials, cohort studies, and case series that explored reproductive outcomes after hysteroscopic septum resection in patients with recurrent miscarriage, primary infertility, or secondary infertility with or without a control group., Methods: The primary outcomes were the live birth rate and eventual postoperative live birth rate after hysteroscopic septum resection. The secondary outcomes were the clinical pregnancy rate, preterm birth rate, and miscarriage rate. Study-level proportions of outcomes were transformed using the Freeman-Tukey double-arcsine transformation to calculate pooled values for the postoperative rates; the counted data were analyzed using relative risk as the effect analysis statistic, and each effect size was provided with its 95% confidence interval. Heterogeneity between the results of the included studies was analyzed using the I 2 test., Results: Overall, 5 cohort studies and 22 case series involving 1506 patients were included. In patients with a septate uterus and recurrent miscarriage, hysteroscopic septum resection was associated with an increased live birth rate (relative risk, 1.77; 95% confidence interval, 1.26-2.49; P=.001; I 2 =0%), resulting in a postoperative live birth rate of 66% (95% confidence interval, 59-72), and septum resection was associated with a reduced preterm birth rate (relative risk, 0.15; 95% confidence interval, 0.04-0.53; P=.003; I 2 =0%) and miscarriage rate (relative risk, 0.36; 95% confidence interval, 0.20-0.66; P=.0009; I 2 =0%). In patients with a septate uterus and primary infertility, hysteroscopic septum resection was associated with an increased live birth rate (relative risk, 4.12; 95% confidence interval, 1.19-14.29; P=.03; I 2 =0%) and clinical pregnancy rate (relative risk, 2.28; 95% confidence interval, 1.04-4.98; P=.04; I 2 =0%). The postoperative live birth rate was 37% (95% confidence interval, 30-44), and the miscarriage rate of patients with primary infertility was reduced (relative risk, 0.19; 95% confidence interval, 0.06-0.56; P=.003). The efficacy of hysteroscopic septum resection in patients with secondary infertility was unclear. However, their postoperative live birth rate was found to be 41% (95% confidence interval, 2-88)., Conclusion: Hysteroscopic septum resection is associated with an increased live birth rate and a reduced miscarriage rate in patients with recurrent miscarriage or primary infertility, indicating that septum resection may improve the reproductive outcomes of these patients. The effectiveness of septum resection was unclear for patients with secondary infertility. These findings are limited by the quality of the included studies, warranting further randomized controlled trials, including only patients with recurrent miscarriage or primary infertility., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Thrombophilia is a group of disorders that result in a blood hypercoagulable state and induce thrombosis, which was found widely existed in recurrent pregnancy loss (RPL). More and more research about thrombophilia has been conducted but the association between thrombophilia and RPL remains uncertain. Thus, it's necessary to combine relevant literature to find the research hotspots and analyze the internal link between different study points, and then predict the development trend in RPL with thrombophilia., Methods: Relevant articles between 1970 and 2022 were obtained from the Web of Science (WoS) database. Software VOSviewer and CiteSpace were used to perform the analysis and conduct visualization of scientific productivity and emerging trends., Results: Seven hundred twenty-five articles published in recent 30 years by 3205 authors from 1139 organizations and 68 countries were analyzed. 37authors, 38 countries, and 53 organizations published papers ≥5. The United States was the most productive country and Univ Amsterdam was the most productive institution. Journal thrombosis and haemostasis had the most total citations. In keyword and clusters, factor-v-Leiden, inherited thrombophilia, activated protein-c, low-dose aspirin, molecular-weigh heparin, polymorphism had high-frequency focus on its etiology, diagnostics, and therapeutics. The strongest keyword bursts showed the research hotspots changed over time., Conclusions: There could be differences in the clinical relevance of different type of thrombophilia, as well as single and multiple thrombophilic factors. Anticoagulation and immunotherapy are currently the main treatment options. More clinical trials and basic research are expected and we should attach more attention to the whole management of in-vitro fertilization in the future., (© 2022. The Author(s).)

It is unknown whether depression and anxiety-related conditions associate with poor perinatal outcomes, especially live birth rates, among women diagnosed with recurrent pregnancy loss. We performed a retrospective cohort study using the Japanese Medical Data Centre Claims Database and identified women diagnosed with recurrent pregnancy loss. Live birth rates were compared as the primary outcome between patients with and without depression and/or anxiety-related disorders. A stabilised inverse probability of treatment weight analysis using propensity scores was also performed to assess the association. Among 5,517 eligible patients, there were 804 (14.6%) women who had depression and/or anxiety-related disorders during treatment for recurrent pregnancy loss during pregnancy. The overall live birth rates differed significantly between the groups according to the Kaplan-Meier method and log-rank test ( p  = 0.011). However, Cox proportional-hazards regression model and stabilised inverse probability of treatment weight analysis showed no statistically significant association between depressive disorders and live birth rates. The current study showed that approximately 15% of patients diagnosed with recurrent pregnancy loss develop depressive disorders. After accounting for variables, we found no independent association between depressive disorders after recurrent pregnancy losses and low live birth rates.

Purpose: To explore the association between recurrent pregnancy loss (RPL) and incident arthritis in midlife women., Methods: We analyzed the U.S. Study of Women's Health Across the Nation, a multi-ethnic cohort following pre- or peri‑menopausal women, using data from baseline up to the tenth annual follow-up visit. Discrete survival analysis was used to estimate adjusted hazard ratios and 95% confidence intervals for risk of incident arthritis at annual intervals in women with versus without RPL., Results: Of the 2159 participants analyzed, 8.5% reported a history of RPL. Cumulative incidence of arthritis was 43.3% in women with RPL and 40.1% in women without RPL, though differences between groups varied over time. Significant associations were observed only at visits three to seven, with the strongest associations at visits four to six. The adjusted hazard ratios (95% confidence intervals) were 1.80 (1.30-2.50) at visit 4 (median age = 50 years), 1.95 (1.38-2.75) at visit 5 (median age = 51 years), and 1.82 (1.28-2.58) at visit 6 (median age = 52 years)., Conclusions: Women with previous RPL may have elevated risk of arthritis specifically when entering their 50s, on average. Additional research is needed to determine whether women with a history of RPL may benefit from early detection of arthritis in midlife., (Copyright © 2022. Published by Elsevier Inc.)

Aim: The biology of recurrent pregnancy loss and recurrent implantation failure (RPL-RIF) is complex with multi-factorial etiology, with defective thrombosis being one of the most important and highly prevalent causes. The role of several thrombophilia related genes and variants associated with RPL-RIF is widely reported, and this study aimed to identify the risk associated with these genes in the Indian population., Methods: Next generation sequencing (NGS) was employed for the current study. NGS enables sequencing of multiple genes, identification of new variants, and establishment of genetic correlations with reproductive failure in diverse population groups. The present NGS based study evaluates association of twenty-nine genotypes of ten coagulation pathway genes ( F2 , F5 , F13 , MTR , MTRR , MTHFR , ANXA5 , PROZ , SERPINE1 and VEGFA ) with RPL-RIF in 540 female subjects - 474 patients with early recurrent pregnancy loss, late pregnancy loss, pregnancy complications in late gestation and recurrent implantation failure, with 66 controls., Results: The results emphasize inclusion of genotypes of seven thrombophilia genes ( MTHFR , MTRR , MTR , ANXA5 , PROZ , SERPINE1 , VEGFA ) for diagnosis of inherited thrombophilia risk for RPL-RIF in Indian population, as against the common practice of testing limited to F2, F5 and MTHFR genes., Conclusion: Deriving risk magnitude from Combined Risk Analysis and interpretation of high-risk haplotypes are crucial components for evidence based personalized management such as selection of drugs and dosage, and prenatal or pre-implantation recommendations, for high-risk patients in fertility and obstetric clinics.

Purpose: To assess perinatal outcomes and placental findings in in vitro fertilization (IVF) patients with previous recurrent pregnancy loss (RPL)., Methods: This was a retrospective cohort of live singleton births following IVF at a single university-affiliated center between 2009 and 2017. Outcomes were compared between patients with previous RPL, defined as two miscarriages (RPL group), and patients without RPL (control group). Placental examination was performed for all deliveries irrelevant of complications, and findings categorized according to the Amsterdam Placental Workshop Consensus., Results: One hundred seventy-two deliveries of women with previous RPL (RPL group) were compared to 885 controls. Maternal age, 36.2 ± 4.2 vs. 35.4 ± 4.2 years, p = 0.02, and rate of uterine fibroids, 12.7% vs. 7.3%, p = 0.01, were higher in the RPL group. The rate of nulliparity was lower in the RPL group, 63.3% vs. 74.1%, p = 0.003. Unexplained infertility and diminished ovarian reserve were more common in the RPL group and male factor infertility in controls. There was a lower rate of fresh embryo transfer in the RPL group, 50.5% vs. 64.7%, p < 0.001, and reduced endometrial thickness. Similar obstetric outcomes were noted in the groups after adjustment for confounders. Placental examinations were notable for lower placental thickness, β - 0.17 cm, 95%CI - 0.30-(- 0.0), a lower rate of velamentous cord insertion, aOR 0.44, 95%CI 0.20-0.95, and a higher rate of villous infarction, aOR 2.82, 95%CI 1.28-6.20 in the RPL group., Conclusion: In IVF patients with a history of RPL, subsequent deliveries were associated with a limited number of placental lesions, yet with similar obstetric outcomes., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Chromosomal abnormalities are more common in first trimester recurrent miscarriages (RM). Chromosomal anomalies affect approximately 2%-8% of couples with RM., Objectives: Evaluate the spectrum and the frequencies of chromosomal anomalies in RM., Design: A retrospective hospital record-based descriptive study., Setting: A tertiary care center in Turkey., Patients and Methods: We studied couples with RM between October 2020 and January 2022. Relevant family and medical history, clinical examination and the results of karyotype were statistically analyzed., Main Outcome Measures: Prevalence and types of chromosomal aberrations in couples with RM. SAMPLE SİZE: 362 couples with a history of RM RESULTS: Among the 362 couples, 14 cases (3.86%) had chromosome abnormalities. Eight cases (57.14%) were structural anomalies and six cases (42.86%) were numerical chromosomal aberrations. We found five balanced translocations (67.5%) and three Robertsonian translocations (37.5%). The prevalence of polymorphic variants was 51/362 (14.1%)., Conclusions: This study supports the conclusion that clinicians should understand the importance of chromosome analysis in these couples and direct them to karyotyping after two abortions in order to exclude the possibility of a genetic cause of RM., Limitations: Single-center study and retrospective., Conflict of Interest: None.

Background: The incidence of uterine anomalies is approximately 0.5-4.7%. In infertile women, this rises to 6.3%. T-shaped uterine anomalies have been associated with infertility, recurrent implantation failure (RIF), and recurrent miscarriage (RM). Hysteroscopic metroplasty (HM) may improve the reproductive outcomes of such cases., Study Objective: We assessed the effects of hysteroscopic metroplasty on the reproductive and in vitro fertilization (IVF) outcomes in women with T-shaped uteri., Design: A prospective controlled study., Setting: A teaching hospital., Patients: The reproductive outcomes of 182 patients with primary infertility (PI), RIF, or RM who underwent hysteroscopic metroplasty to treat T-shaped uteri were prospectively analyzed., Interventions: Between January 2017 and April 2021, hysteroscopic metroplasty was performed by a single experienced surgeon. The primary outcome was the live birth rate (either spontaneous or assisted)., Measurements and Principal Results: In all, 182 patients who underwent bilateral, longitudinal, uterine-lateral wall incisions without complications were included. The clinical pregnancy rates after metroplasty were 50.9% (primary infertility group), 71.4% (RM group), and 39.5% (RIF group). During the 1-year follow-up, 25.5% of patients conceived spontaneously (all groups)., Conclusion: Hysteroscopic metroplasty should be considered for women with primary infertility, RIF, and RM with T-shaped uteri., Competing Interests: Declaration of Competing Interest The authors do not have any potential conflicts of interest to report., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

The objective of this study was to evaluate prevalence of chronic endometritis in a cohort of patients with retained pregnancy tissue (RPT) following miscarriage, with and without a history of recurrent pregnancy loss (RPL). In a cohort of our single academic fertility centre, we evaluated women with unexplained RPL (two or more losses) without evidence of RPT and women undergoing hysteroscopic resection of RPT following miscarriage. Endometrial samples underwent staining with H and E and CD138. A pathologist blinded to patient history recorded the number of plasma cells per 10 high power fields (HPF) and the presence or absence of endometrial stromal changes. Our main outcome measure was to measure the prevalence of chronic endometritis. Endometrial samples from 50 women with RPT following miscarriage and 50 women with unexplained RPL without evidence of RPT were reviewed. The prevalence of chronic endometritis was significantly higher in the RPT cohort (62% versus 30%). A multivariable regression demonstrated significantly higher odds of chronic endometritis in the RPT cohort, aOR 7.3 (95% CI 2.1, 25.5). We conclude that women with RPT following pregnancy loss have a high rate of chronic endometritis, suggesting that RPT is a risk factor for this disorder. Impact Statement What is already known on this subject? Known risk factors for chronic endometritis include a history of pelvic inflammatory disease, intrauterine polyps and fibroids. The aetiology for increased chronic endometritis among women with RPL is unknown. What do the results of this study add? The prevalence of chronic endometritis is significantly higher among women with retained pregnancy tissue (RPT) following miscarriage compared to women with RPL. These data presented suggest that RPT is associated with chronic endometritis among women with a history of miscarriage. What are the implications of these findings for clinical practice and/or further research? We suggest a pathologic evaluation for chronic endometritis be performed on all patients who undergo hysteroscopic resection of RPT following miscarriage. Our findings also suggest that a uterine cavity evaluation with hysteroscopy to evaluate for RPT may be reasonable in women with a history of miscarriage who are found to have chronic endometritis on endometrial biopsy. Further research is needed to determine if resection of retained tissue is sufficient to treat RPOC associated chronic endometritis, or if additional antibiotic treatment is necessary.

Introduction: Recurrent pregnancy loss (RPL) is defined as the loss of two or more conceptions before 24 weeks gestation. Despite extensive diagnostic workup, in only 25%-40% an underlying cause is identified. Several factors may increase the risk for miscarriage, but the chance of a successful pregnancy is still high. Prognostic counselling plays a significant role in supportive care. The main limitation in current prediction models is the lack of a sufficiently large cohort, adjustment for relevant risk factors, and separation between cumulative live birth rate and the success chance in the next conception. In this project, we aim to make an individualised prognosis for the future chance of pregnancy success, which could lead to improved well-being and the ability managing reproductive choices., Methods and Analysis: In this multicentre study, we will include both a prospective and a retrospective cohort of at least 931 and 1000 couples with RPL, respectively. Couples who have visited one of the three participating university hospitals in the Netherlands for intake are eligible for the study participation, with a follow-up duration of 5 years. General medical and obstetric history and reports of pregnancies after the initial consultation will be collected. Multiple imputation will be performed to cope for missing data. A Cox proportional hazards model for time to pregnancy will be developed to estimate the cumulative chance of a live birth within 3 years after intake. To dynamically estimate the chance of an ongoing pregnancy, given the outcome of earlier pregnancies after intake, a logistic regression model will be developed., Ethics and Dissemination: The Medical Ethical Research Committee of the Leiden University Medical Center approved this study protocol (N22.025). There are no risks or burden associated with this study. Participant written informed consent is required for both cohorts. Findings will be published in peer-reviewed journals and presentations at international conferences., Trial Registration Number: NCT05167812., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Women with asthma appear to have an increased risk of pregnancy loss (PL). The impact of asthma on recurrent pregnancy loss (RPL), defined as 3 consecutive losses, is, however, unknown., Objective: The aim of this study was to investigate whether having asthma before or during the fertile age is associated with PL and RPL., Methods: Based on Danish national health registers, we identified all women aged 6 to 45 years with at least 2 filled prescriptions of an antiasthma drug during the period 1977 to 2019. Women with asthma were compared with women without asthma. Pregnancy outcomes were retrieved for both groups from national health registers. Logistic regression with adjustment for the year of birth and educational level provided odds ratios (ORs) for the number of PLs. Subgroup analyses were conducted for early-onset (age 6-15 years), adult-onset (age 16-39 years), and late-onset (age 40-45 years) asthma. Lastly, we compared uncontrolled asthma (defined as ≥ 400 doses of a short-acting beta-2 agonist in a year) to controlled asthma (defined as < 400 doses of a short-acting beta-2 agonist in a year)., Results: In a population of 1,309,786 women, we identified 128,553 women with asthma and 1,297,233 women without asthma. Compared with nonasthmatic women, women with asthma had ORs for 1, 2, and 3 or more PLs of 1.05 (95% CI 1.03-1.07), 1.09 (95% CI 1.05-1.13), and 1.18 (95% CI1.11-1.24), respectively, and for RPL of 1.19 (95% CI 1.12-1.27). In women with early-onset asthma, the OR of 3 or more PLs was 1.47 (95% CI 1.24-1.72). For women classified as having uncontrolled asthma compared with controlled asthma, we found a significant OR of 1.60 (95% CI 1.16-2.16) for 3 or more PLs., Conclusions: We found a significant positive association between asthma and number of PLs and RPLs. Early-onset asthma and uncontrolled asthma were more strongly associated with PL than adult-onset and late-onset asthma and controlled asthma., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Problem: Previous studies had shown that there might be an association between serum vitamin D concentrations and the occurrence of recurrent spontaneous abortion (RSA). However, the conclusions remained controversial. The objective of this study was to systematically review the evidence for an epidemiological association between vitamin D and RSA., Method of Study: The literature search was performed in the following databases: PubMed, Web of Science, Embase and Chinese databases. The I 2 statistic was used to evaluate heterogeneity. Effect sizes were calculated using fixed or random effects models, including standardized mean difference (SMD), odds ratios (OR) and their 95% confidence intervals (95% CI). Then, we performed subgroup analysis, sensitivity analysis and publication bias analysis., Results: Fourteen studies from five countries were included. Based on the results, patients with RSA had lower vitamin D levels than controls (SMD = -1.48, 95% CI: -2.01, -.94, P < .001), and pregnant women with vitamin D deficiency (VDD) had a higher risk of developing RSA (OR = 4.02, 95% CI: 2.23, 7.25, P < .001). There was remarkable heterogeneity between studies (I 2 SMD  = 97.3%, P < .001; I 2 OR  = 82.2%, P < .001). The results of the subgroup analysis suggested that heterogeneity may be caused by the assay method, age and region. Sensitivity analysis showed the analysis results were robust., Conclusion: Patients with RSA had lower serum vitamin D levels than normal pregnant women, and pregnant women with VDD might be at higher risk for RSA., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The incidence of recurrent pregnancy loss (RPL) in fertile women ranges from 1% to 5%, of which about 50% of them are due to unknown causes. The possible pathogenesis of RPL is an urgent problem to be solved in the clinical. Mutations or polymorphisms of certain genes in the coagulation mechanism are associated with susceptibility to thrombotic diseases and are one of the main reasons for the occurrence of RPL. Among them, the ANXA5 gene was newly studied and some single nucleotide polymorphisms (SNPs) in the promoter region of ANXA5 have been reported to be associated with RPL in multiple races. In this review, we summarized the research progress on the correlation between the SNPs in ANXA5 and RPL, hoping to provide some valuable guidance for the future studies., Competing Interests: Declaration of Competing Interest The authors declare that we have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier B.V.)

Background: Unexplained recurrent spontaneous abortion is a serious reproductive problem of unknown etiology. Thyroid peroxidase antibodies (TPO-Ab) may be associated with pregnancy outcomes in unexplained recurrent spontaneous abortion with normal thyroid function., Objective: This study aimed to investigate the relationship between TPO-Ab and the first trimester miscarriage rate/live birth rate in women of unexplained recurrent spontaneous abortion with normal thyroid function., Methods: We retrospectively analyzed the clinical data of 297 women who met our strict inclusion criteria, comparing the first trimester miscarriage rate/live birth rate between the TPO-Ab positive and TPO-Ab negative groups. For the same purpose, we also performed subgroup analysis., Results: Of the included women, 76 (25.6%) were TPO-Ab positive, and 221 (74.4%) were negative. First trimester miscarriage rate differed between the two groups (36.8% vs 24.0%, RR = 1.54, 95% CI: 1.05-2.24, P = 0.030). In the younger subgroup (<35 years) and the primary RSA subgroup, First trimester miscarriage rate was also higher in the TPO-Ab positive group (33.3% vs 19.0%, RR = 1.75, 95% CI: 1.07-2.87, P = 0.030; 36.5% vs 21.7%, RR = 1.69, 95% CI: 1.10-2.58, P = 0.020). While the live birth rate was lower in women with TPO-Ab positive, the difference did not reach statistical significance, even in the subgroup analysis., Conclusion: Our results suggest that TPO-Ab is associated with first trimester miscarriage rate in euthyroid women with unexplained recurrent spontaneous abortion., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Liu, Wang, Zhu, Yin, Ji, Zhong, Gao, Zhang, Liu, Zhang and Chen.)

Background: Women who have had miscarriages or stillbirths are known to have a high risk for enduring grief. However, the course and frequency of enduring grief in this subgroup are not fully understood. Objective: Our aims were to assess the intensity of grief and its course in women with miscarriages or stillbirths and to estimate the frequency of severe grief reactions in this population. Additionally, we compared subgroups with miscarriages versus stillbirths and with single versus recurrent pregnancy loss. Method: A systematic literature search of the databases MEDLINE, psycINFO and PSYNDEX was conducted to consider all studies published between 2000 and 31 March 2022 in English or German on the prevalence and intensity of grief in women who had miscarriages or stillbirths. Studies that used validated assessment methods were included in this systematic review. The PRISMA guidelines were followed. Results: Study characteristics and grief data were extracted independently by two investigators from 13 cross-sectional and eight longitudinal studies from 11 countries ( N  = 2597). All studies used self-reporting instruments. According to 17 of 21 studies (81%), grief is markedly elevated in women after miscarriages or stillbirths. The studies are very heterogeneous regarding the samples, the length of pregnancies and the time of assessment regarding grief after miscarriages. Most studies document intense grief and frequent severe grief reactions - with a decrease over time - in women who have had miscarriages or stillbirths. Clear conclusions regarding corresponding differences between women with miscarriages and stillbirths or single and recurrent pregnancy losses cannot be drawn. Conclusions: Pronounced grief is frequent in women who had miscarriages or stillbirths. More longitudinal studies are needed to examine the course of grief in this group and to identify those women who develop prolonged grief disorder, depression or other mental-health problems., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2022 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

The aim of this study was to analyse the risk factors of pregnancy loss of patients with recurrent spontaneous abortion (RSA) and develop a scoring system to predict RSA. Clinical data of 242 cases, with RSA who were treated at Fujian Provincial Maternity and Children's Hospital, were selected. The factors of pregnancy loss for RSA patients were evaluated by univariate and multivariate analyses. There were 242 RSA patients, of whom 34 (14.0%) developed pregnancy loss. A multivariate analysis showed the following adverse risk factors for RSA: antinuclear antibody spectrum, protein s deficiency and antiphospholipid antibodies. The pregnancy loss rates of antinuclear antibody spectrum group, protein S deficiency group and antiphospholipid antibodies group were 25.0%, 22.5% and 19.4%, respectively. Each of these factors contributed 1 point to the risk score. The pregnancy loss rates were 6.3%, 24.6%, 50% for the low-, intermediate- and high-risk categories, respectively ( p  < .001). The area under the receiver operating characteristic curve for the score of RSA was .733. Our findings suggest that this validated and simple scoring system could accurately predict the risk of pregnancy loss of RSA patients. The score might be helpful in the selection of risk-adapted interventions to decrease the incidence. Impact Statement What is already known on this subject? The live birth rate increases to 80%-90% after anticoagulant and/or immunosuppressive treatment in patients with RSA. However, there is still a high rate of re-abortion even after active treatment. What do the results of this study add? Antinuclear antibody spectrum, protein s deficiency and antiphospholipid antibodies were independent risk factors for pregnancy loss. A novel predictive model based on these factors was then established and validated. What are the implications of these findings for clinical practice and/or further research? The newly developed score might be helpful in the selection of risk-adapted interventions to decrease the incidence. For patients in the intermediate-risk and high-risk groups, we should conduct more targeted studies and formulate corresponding therapies to improve the success rate of treatment.

There are a limited number of studies in which the depression status was followed up throughout pregnancy and postpartum to 1 year after delivery though 8.6-33% of women with recurrent pregnancy loss (RPL) and 10-25% of women who undergo in vitro fertilization and embryo transfer (IVF-ET) suffer from depression. We examined whether RPL and IVF-ET affect depressive symptoms during pregnancy and postpartum. A nationwide large-scale birth cohort study known as the "Japan Environment and Children's Study (JECS)" was conducted. The subjects consisted of 99,202 pregnant women recruited between January 2011 and March 2014. The Kessler Psychological Distress Scale was used for the 1st trimester, 2nd/3rd trimester and 1 year postpartum. The Edinburgh Postnatal Depression Scale was used for the first and the sixth month postpartum. The screening instruments were used to quantify depressive symptoms. Women with no live births had a significantly higher prevalence of elevated depressive symptoms throughout pregnancy and postpartum. The prevalence of elevated depressive symptoms was significantly higher in the second/third trimester among women with three or more pregnancy losses with no live births. IVF-ET was associated with reduced risk of developing depressive symptoms during all pregnancies and at 1 and 6 months after delivery in women with no live births. RPL and IVF-ET did not affect postpartum depressive symptoms, and IVF-ET rather reduced the risk of depression throughout pregnancy and postpartum. Psychological support for RPL women would be necessary., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: There are numerous studies reporting a disproportionally high prevalence of thrombophilia in women with a history of recurrent miscarriage (RM), which has led to overdiagnosis and treatment without an improvement in clinical outcomes. The objective of our study was to assess the prevalence of inherited and acquired thrombophilia in a large cohort of women with a history of early RM using internationally agreed diagnostic criteria and inclusion parameters and compare it to the meta-analysis results of existing literature., Methods: DESIGN: Retrospective cohort study and systematic review of literature., Setting: This is a retrospective cohort study set-up in two dedicated tertiary centres for women with RM in Southwest London and Surrey. We reviewed all the available literature related to causes of RMs. We ascertained the prevalence of thrombophilia in the study population and compared it with historical and published prevalence in the general population., Participants: 1155 women between 2012 and 2017. All patients had three or more first trimester miscarriages and a full thrombophilia screen., Results: The overall prevalence of thrombophilia in our study population is 9.2% (106/1155) with 8.1% (94/1155) of cases positive for inherited thrombophilia, which is similar to the general population; Factor V Leiden (4.9%; 57/1155) and prothrombin gene mutation (2.9%; 34/1155) were the most common inherited thrombophilias, while only 1% (12/1155) tested positive for acquired thrombophilia. Persistent positive lupus anticoagulant (LA) was found in 0.5% (6/1155) and persistent positive anticardiolipin (ACL) antibodies with a value ≥40 U/mL was found in 0.5% (6/1155) of patients. Tests for LA/ACL were performed a minimum of 12 weeks apart thus meeting the revised Sapporo criteria for a diagnosis of antiphospholipid syndrome., Conclusion: The findings of our study demonstrate that the prevalence of inherited thrombophilia is similar in women with RM to that in the general population. Similarly, the prevalence of acquired thrombophilia, using the revised Sapporo criteria, in the cohort of RMs is similar to that in the general population. Therefore, we do not recommend investigation or treatment of inherited or acquired thrombophilia in women with RM., Prospero Registration Number: CRD42020223554., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Annexin A5 (ANXA5) haplotypes can increase the risk of recurrent pregnancy loss (RPL). This study aimed to investigate the effect of ANXA5 haplotypes on ANXA5 expression in patients with RPL., Methods: Female subjects with RPL, parous controls (those who intentionally aborted without medical conditions or complications), and population controls (normal delivery) were studied. Real-time polymerase chain reaction was carried out to evaluate ANXA5 expression in the placenta and peripheral blood. Western blotting and immunohistochemistry were used to assess ANXA5 protein expression. The luciferase assay was performed to detect the effect of M1 and M2 haplotypes on transcription efficiency of the ANXA5 promoter., Results: We found that the percentage of the M2 carrier was highest in the RPL group. ANXA5 expression in the placenta and peripheral blood in subjects with RPL was significantly inhibited. Furthermore, ANXA5 expression in subjects carrying the M2 haplotype was remarkably suppressed compared with that in carriers of other haplotypes. Finally, the M2 haplotype decreased the transcription efficiency of the ANXA5 promoter., Conclusion: Our findings show that ANXA5 expression is decreased in carriers of the M2 haplotype and that M1/M2 haplotypes in the ANXA5 gene are associated with an increased risk of RPL.

Objective: To investigate whether a significant association between vitamin D status and the risk of miscarriage or recurrent miscarriage (RM) exists., Design: Systematic review and meta-analysis., Setting: Not applicable., Patient(s): Women with miscarriage and RM., Intervention(s): We searched the Ovid MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature, and Cochrane Central Register of Controlled Trials from database inception to May 2021. Randomized and observational studies investigating the association between maternal vitamin D status and miscarriage and/or vitamin D treatment and miscarriage were included., Main Outcome Measure(s): The primary outcome was miscarriage or RM, with vitamin D status used as the predictor of risk. Whether vitamin D treatment reduces the risk of miscarriage and RM was also assessed., Result(s): Of 902 studies identified, 10 (n = 7,663 women) were included: 4 randomized controlled trials (n = 666 women) and 6 observational studies (n = 6,997 women). Women diagnosed with vitamin D deficiency (<50 nmol/L) had an increased risk of miscarriage compared with women who were vitamin D replete (>75 nmol/L) (odds ratio, 1.94; 95% confidence interval, 1.25-3.02; 4 studies; n = 3,674; I 2 = 18%). Combined analysis, including women who were vitamin D insufficient (50-75 nmol/L) and deficient (<50 nmol/L) compared with women who were replete (>75 nmol/L), found an association with miscarriage (odds ratio, 1.60; 95% confidence interval, 1.11-2.30; 6 studies; n = 6,338; I 2 = 35%). Although 4 randomized controlled trials assessed the effect of vitamin D treatment on miscarriage, study heterogeneity, data quality, and reporting bias precluded direct comparison and meta-analysis. The overall study quality was "low" or "very low" using the Grading of Recommendations, Assessment, Development and Evaluations approach., Conclusion(s): Vitamin D deficiency and insufficiency are associated with miscarriage. Whether preconception treatment of vitamin D deficiency protects against pregnancy loss in women at risk of miscarriage remains unknown., Registration Number: CRD42021259899., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objective: To examine the associations of infertility, recurrent miscarriage, and stillbirth with the risk of first non-fatal and fatal stroke, further stratified by stroke subtypes., Design: Individual participant pooled analysis of eight prospective cohort studies., Setting: Cohort 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., Participants: 618 851 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 Measures: Non-fatal strokes were identified through self-reported questionnaires, linked hospital data, or national patient registers. Fatal strokes were identified through death registry data., Results: The 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., Conclusion: A 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., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at https://www.icmje.org/disclosure-of-interest/ and declare: support from the Australian National Health and Medical Research Council Centres of Research Excellence for the submitted work; no financial relationships with any organizations that might have an interest in the submitted work in the previous three years; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: This study aimed to assess whether the use of levothyroxine was beneficial in pregnant women with subclinical hypothyroidism (SCH) or women who were positive for thyroid peroxidase antibody (TPOAb + ). Study design: This was a randomized clinical trial involving 1736 populations of pregnant women. Our study was conducted into two groups: normal pregnant group and recurrent pregnancy loss (RPL) pregnant group. Both patients were divided into SCH and TPOAb + groups, respectively; the patients of four groups were randomized into either the L-T4 treatment or control groups. Results: There was no significant difference between the two groups in the prevalence of SCH and TPOAb + ( p  > .05); The live births rate of normal pregnant group was higher than that of the RPL pregnant Group (79.5% vs. 70.8%, p  < .05); Considering normal pregnant women, whether women who were TPOAb  +  or SCH, there was no significant difference between the treatment and control group in the live birth rate and the pregnancy loss rate. In RPL group, whether women who were TPOAb  +  or SCH, L-T4 treatment can obtain higher live birth rate and lower abortion rate compared to the control. Conclusion: There was no significant difference between normal and RPL pregnant women in the prevalence of SCH and TPOAb + .Treatment with L-T4 decreased the risk of pregnancy loss and increased the live birth rate in RPL pregnant women who were positive for TPOAb or subclinical hypothyroidism. Levothyroxine therapy is recommended for SCH and TPOAb  +  women in pregnant women with recurrent pregnancy loss.

Purpose: Recurrent Miscarriages (RM) commonly complicates the reproductive outcome where prominently chromosomal aberrations and molecular factors lead to recurrent miscarriages. We investigated couples with RM for cytogenetic abnormalities and Y chromosome microdeletions in males along with detection of aneuploidies de novo in the product of conception from a highly ethnic consanguineous population (Kashmir, North India) ., Study Design: Chromosomal analysis was done by Karyotyping on peripheral blood lymphocyte cultures and analyzed by Cytovision software Version 3.9. Microdeletion in Y chromosome was performed by STS-PCR and QF-PCR was used to detect aneuploidy in the product of conception., Results: Of the 380 samples (190 couples) screened for cytogenetic analysis, 50 (13.1%) chromosomal aberrations were detected in both couples. Numerical aberrations were detected in 16.0%, inversions 22%, duplications 16.0% and translocations were found in 26.0% with three unique reciprocal translocations in males. The couples bonded consanguineously had 32% chromosomal changes with a significant difference in chromosomal inversions (37.5% vs. 14.7%) and translocations (37.5% vs. 20.6%) for consanguineous and non-consanguineous group, respectively (p < 0.05). Further, translocations and inversions (44.5% and 33.3%) were significantly implicated in couples with a positive family history of RM (p < 0.05). Y chromosome deletions were found in 2.1% cases of males., Conclusion: We conclude 15.2% couples affected either by chromosomal or Y chromosome deletions contribute hugely in the diagnosis and management of repeated pregnancy losses. It is recommended that couples that belong to consanguineous and multigenerational group of RM should be considered for cytogenetic and molecular testing after two abortions for successful pregnancy outcomes and management of RM., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

The purpose of this study is to characterise the sexual and reproductive health risks associated with mental illness among women. This was a retrospective cohort study of 2,680,149 women aged 14 to 45 years in the Clinical Practice Research Datalink, a UK primary care register, linked to 1,702,211 pregnancies that ended between the 1st January 1990 and 31st December 2017. Mental illness was identified in primary care and categorised into the following: common mental illness (depression/anxiety); addiction (alcohol/drug misuse); serious mental illness (affective/non-affective psychosis); other mental illness (eating/personality disorders). Logistic regression estimated the association between mental illness and subsequent risk of recurrent miscarriage and termination. Cox proportional hazards estimated the association between mental illness and time to gynaecological diseases, sexually transmitted infections, reproductive cancers, cervical screen, contraception and emergency contraception. Models were adjusted for calendar year, year of birth, smoking status and ethnicity, region and index of socioeconomic status. Compared to women without mental illness, exposed women were more likely to experience recurrent miscarriage (adjOR = 1.50, 95%CI 1.41 to 1.60), termination (adjOR = 1.48, 95%CI 1.45 to 1.50), gynaecological diseases (adjHR = 1.39, 95%CI 1.37 to 1.40), sexually transmitted infections (adjHR = 1.47, 95%CI 1.43 to 1.51), reproductive cancers (adjHR = 1.10, 95%CI 1.02 to 1.19), contraception (adjHR = 1.28 95%CI 1.26 to 1.29) and emergency contraception (adjHR = 2.30, 95%CI 2.26 to 2.34), and less likely to attend for cervical screening (adjHR = 0.91, 95%CI 0.90 to 0.92). Currently, the sexual and reproductive health needs of women with mental illness are unmet representing significant health inequalities. Clinicians must create opportunities to engage with women in primary care and mental health services to address this gap., (© 2022. The Author(s).)

Objective: To evaluate the impact of recurrent pregnancy loss (RPL) on the risk of preterm birth (PTB) in subsequent pregnancies., Design: Systematic review and meta-analysis., Setting: Not applicable., Patient(s): Pregnant women with and without a history of RPL., Intervention(s): PubMed, Embase, Google Scholar and Cochrane trial registry were used to identify relevant studies., Main Outcome Measure(s): The odds ratios (ORs) for the association between RPL and PTB across included studies were evaluated. Effect estimates were pooled using a DerSimonian and Laird random-effects meta-analysis model., Result(s): Eighteen studies met the inclusion criteria. A total of 58,766 women with a history of RPL and 2,949,222 women without a history of RPL were included. A pooled OR of 1.60 (95% confidence interval [CI], 1.45-1.78; 18 observational studies; I 2 = 85.6%) was observed in our random-effects meta-analysis. A trend toward higher odds of PTB is observed with the increasing number of pregnancy losses: 2 RPLs (pooled OR, 1.31; 95% CI, 1.09-1.57; I 2 = 88.9%); ≥2 RPLs (pooled OR, 1.58; 95% CI, 1.27-1.96; I 2 = 71.7%); and ≥3 RPLs (pooled OR, 1.81; 95% CI, 1.58-2.07; I 2 = 73.6%). The analysis of the risk of PTB for patients with unexplained RPL demonstrated a significantly heightened risk of PTB in this subgroup (pooled OR, 2.05; 95% CI, 1.46-2.89; I 2 = 21.0%). Inconsistent adjustment for confounders and significant between-study heterogeneity were noted in this study., Conclusion(s): Despite significant heterogeneity among studies, we found that women with a history of RPL had significantly higher odds of delivering preterm infants in subsequent pregnancies., Clinical Trial Registration Number: CRD 224763., (Copyright © 2022 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Objective: To compare the prevalence of chromosomal abnormalities detected in products of conception (POCs) between recurrent pregnancy loss and sporadic pregnancy loss., Methods: A systematic search was performed in the PubMed and Embase databases from inception to December 31, 2020. Relevant studies analysing the association between the number of pregnancy losses and the incidence of chromosomal abnormalities were included. Independent data extraction was conducted and study quality was assessed. Meta-analyses were carried out to calculate odds ratios by using fixed- or random-effects models according to statistical homogeneity., Results: A total of 8320 POCs in 19 studies were identified for the meta-analyses. The incidence of chromosomal abnormalities in sporadic pregnancy loss was significantly higher than that in recurrent pregnancy loss. In subgroup analyses, the following studies reported a high incidence of abnormal outcomes of sporadic pregnancy loss: studies with ≥ 300 samples, studies published before 2014, studies conducted in European and American countries, and studies with analyses using conventional karyotype techniques. Moreover, the incidence of chromosomal abnormalities in women with two pregnancy losses was significantly higher than that in women with three or more pregnancy losses. However, there was no difference in the distribution of abnormal types between sporadic and recurrent pregnancy loss or between two and three or more pregnancy losses., Conclusions: The prevalence of chromosomal abnormalities detected in POCs was lower in recurrent pregnancy loss than in sporadic pregnancy loss, and decreased with an increasing number of pregnancy losses., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Parental chromosomal aberrations are important causes of recurrent pregnancy loss (RPL). Some immunological factors such as antiphospholipid antibodies and interleukin-6 (IL-6) also contribute to this complication. The aim of this study was to determine the frequency of chromosomal abnormalities and to evaluate some of the immunological factors in couples with RPL from different cities in Iraq., Methods: This study was conducted on 25 couples (50 individuals) who had more than two first trimester abortions in the past and 25 healthy females as controls. Karyotyping was performed on peripheral blood of all participants. Anticardiolipin (IgG and IgM), antiphosopholipid (IgG and IgM), lupus anticoagulant, and IL-6 were assayed. Data were analyzed using appropriate statistical tests., Results: Chromosomal abnormalities were found in 28.0% ( n = 7/25) of RPL couples. Of these five (10.0%) were female and two (4.0%) were male. The types of structural abnormalities were as follows: 45, XX, t(21; 21); 45, XX, rob (14, 15); 46, XX, add (21) (p13); 46 XY, add (21)(p13); 46, XX, 21ps+; 46, XY, per inv (9) (p11q12) and 45, XX, t(13q, 13q). No chromosomal abnormalities were found in the control group. Also, no significant differences were found in the immunological parameters of the couples with RPL and the control group., Conclusion: In this study, karyotyping revealed a high number of chromosomal abnormalities associated with the RPL in Iraqi couples. Since identification of genetic causes of miscarriage is important for genetic counseling and educating couples about the risk of future pregnancies, it is recommended that conventional karyotyping be investigated in patients with RPL., Competing Interests: The authors declare that they have no competing interests., (© 2022 Khamees and Al-Ouqaili.)

Objectives: To measure pregnancy outcome following attendance at a recurrent miscarriage service and identify factors that influence outcome., Design: Prospective, observational electronic cohort study., Setting: Participants attending a specialist recurrent miscarriage clinic, with a history of two or more pregnancy losses. 857 new patients attended over a 30-month period and were invited to participate. Participant data were recorded on a bespoke study database, 'Tommy's Net'., Participants: 777 women consented to participate (90.7% of new patients). 639 (82%) women continued within the cohort, and 138 were lost to follow-up. Mean age of active participants was 34 years for women and 37 years for partners, with a mean of 3.5 (1-19) previous pregnancy losses. Rates of obesity (maternal: 23.8%, paternal: 22.4%), smoking (maternal:7.4%, paternal: 19.4%) and alcohol consumption (maternal: 50%, paternal: 79.2%) were high and 55% of participants were not taking folic acid., Outcome Measures: Biannual collection of pregnancy outcomes, either through prompted self-reporting, or existing hospital systems., Results: 639 (82%) women were followed up. 404 (83.4%) reported conception and 106 (16.6%) reported no pregnancy, at least 6 months following registration. Of those that conceived, 72.8% (294/404) had a viable pregnancy. Maternal smoking and body mass index (BMI) over 30 were significantly higher in those who did not conceive (p=0.001) CONCLUSIONS: Tommy's Net provides a secure electronic repository on data for couples with recurrent pregnancy loss and associated outcomes. The study identified that subfertility, as well as repeated miscarriage, maternal BMI and smoking status, contributed to failure to achieve live birth. Study findings may enable comparison of clinic outcomes and inform the development of a personalised holistic care package., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

There are a plethora of publications on the role of miRNA gene polymorphism and its association with recurrent pregnancy loss (RPL), but a lack of uniformity in the studies available due to the variable subject population, heterogeneity and contrary results of significance. Rigorous data mining was done through PubMed, SCOPUS, Cochrane library, Elsevier and Google Scholar to extract the studies of interest published until June 2021. A total of eight SNPs of miRNAs have been included, where ≥2 studies per SNPs were available. Analysis was done on the basis of pooled odds ratios and 95% CI. This is the first meta-analysis on miRNA SNPs in RPL that suggests that rs11614913, rs3746444 and rs2292832 biomarkers may decrease the risk of RPL under different genetic models.

Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: SJS is an academic editor for PLOS Medicine. SJS has received grant funding (paid to her institution) from National Institute of Healthcare Research, Scottish Chief Scientist Office, Wellcome Trust and Tommy’s Charity. SJS has received fees (paid to institution) for consultancy to Natera; and received honoraria (paid to institution) from Hologic for talks. VHM has received a honoraria from Hologic for a talk.

Objective: To identify, besides maternal age and the number of previous pregnancy losses, additional characteristics of couples with unexplained recurrent pregnancy loss (RPL) that improve the prediction of an ongoing pregnancy., Design: Hospital-based cohort study in couples who visited specialized RPL units of two academic centers between 2012 and 2020., Setting: Two academic centers in the Netherlands., Patients: Clinical data from 526 couples with unexplained RPL were used in this study., Intervention(s): None., Main Outcome Measures: The final model to estimate the chance of a subsequent ongoing pregnancy was determined using a backward selection process and internally validated using bootstrapping. Model performance was assessed in terms of calibration and discrimination (area under the receiver operating characteristic curve)., Results: Subsequent ongoing pregnancy was achieved in 345 of 526 couples (66%). The number of previous pregnancy losses, maternal age, paternal age, maternal body mass index, paternal body mass index, maternal smoking status, and previous in vitro fertilization/intracytoplasmic sperm injection treatment were predictive of the outcome. The optimism-corrected area under the receiver operating characteristic curve was 0.63 compared with 0.57 when using only the number of previous pregnancy losses and maternal age., Conclusions: The identification of additional predictors of a subsequent ongoing pregnancy after RPL, including male characteristics, is significant for both clinicians and couples with RPL. At the same time, we showed that the predictive ability of the current model is still limited and more research is warranted to develop a model that can be used in clinical practice., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Progesterone supplementation is widely performed in women with threatened miscarriage or a history of recurrent miscarriage; however, the effects of early progesterone supplementation on pregnancy-related complications and perinatal outcomes in later gestational weeks remain unknown., Methods: Ovid MEDLINE, the Cochrane Library, Embase and ClinicalTrials.gov were searched until April 3rd, 2021. Randomized controlled trials regarding spontaneously achieved singleton pregnancies who were treated with progestogen before 20 weeks of pregnancy and were compared with those women in unexposed control groups were selected for inclusion. We performed pairwise meta-analyses with the random-effects model. The risk of bias was assessed according to the Cochrane Collaboration tool. The primary outcomes included preeclampsia (PE), and gestational diabetes mellitus (GDM), with the results presented as odds ratios (ORs) with 95% confidence intervals (CIs)., Results: We identified nine eligible studies involving 6439 participants. The pooled OR of subsequent PE following early progestogen supplementation was 0.64 (95% CI 0.42-0.98, moderate quality of evidence). A lower OR for PE was observed in the progestogen group when the subgroup analysis was performed in the vaginal subgroup (OR 0.62, 95%CI 0.40-0.96). There was insufficient evidence of a difference in the rate of GDM between pregnant women with early progestogen supplementation and unexposed pregnant women (OR 1.02, 95% CI 0.79-1.32, low quality of evidence). The pooled OR of low birth weight (LBW) following oral dydrogesterone was 0.57 (95% CI 0.34-0.95, moderate quality of evidence). The results were affected by a single study and the total sample size of enrolled women did not reach the required information size., Conclusion: Use of vaginal micronized progesterone (Utrogestan) in spontaneously achieved singleton pregnancies with threatened miscarriage before 20 weeks of pregnancy may reduce the risk of PE in later gestational weeks. Among spontaneously achieved singleton pregnancies with threatened miscarriage or a history of recurrent miscarriage, use of oral dydrogesterone before 20 weeks of pregnancy may result in a lower risk of LBW in later gestational weeks. However, the available data were not sufficient to reach definitive conclusions, which highlighted the need for future studies., (© 2021. The Author(s).)

Objective: To investigate the association of maternal body mass index (BMI) and recurrent pregnancy loss (RPL)., Design: Systematic review and meta-analysis., Setting: Not applicable., Patient(s): A total of 3,833 women with RPL and 4,083 women as controls., Intervention(s): Studies were identified through a search of PubMed, Embase, Scopus, and Cochrane., Main Outcome Measure(s): The primary outcome of interest was RPL using the mean differences in maternal BMI as the predictor variable. The results of the meta-analysis were reported as the mean difference with a 95% confidence interval., Result(s): In total, 892 studies were reviewed. Pooled data from 25 studies suggested that the maternal BMI of women with a history of recurrent pregnancy loss was significantly higher than the BMI of controls, mean difference 0.7 kg/m 2 [95% confidence interval 0.2-1.3]., Conclusion(s): These findings supported an association between maternal BMI and RPL. Large prospective studies are needed to evaluate the influence of maternal BMI on pregnancy outcomes in women with RPL., (Copyright © 2021 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Aim: Women with a history of recurrent miscarriage are a vulnerable population. This study aimed to examine changes and relationships among anxiety, depression and social support across three trimesters of pregnancy in women with a history of recurrent miscarriage., Methods: A prospective, longitudinal study was employed. A convenience sample of 166 pregnant women with a history of recurrent miscarriage completed the measures at their 6-12, 20-24 and 32-36 gestational weeks., Results: The prevalence of anxiety at early, middle and late pregnancy was 47.6%, 36.1% and 32.5%, respectively, whereas that of depression was 38%, 34.3% and 31.3%, respectively. Social support scores increased from early pregnancy to middle pregnancy then remained in late pregnancy. There were correlations among anxiety, depression and social support across pregnancy., Conclusions: Anxiety and depression were highly prevalent in pregnant women with a history of recurrent miscarriage, especially in early pregnancy when the level of social support was the lowest. Social support is an essential buffer against anxiety and depression throughout the pregnancy., (© 2021 John Wiley & Sons Australia, Ltd.)

Background: The interplay between female fertility and autoimmune diseases (AIDs) can involve HLA haplotypes and micronutrients. We analyzed the distribution of HLA-DQ2/-DQ8 in women with infertility or recurrent spontaneous abortion (RSA) and possible associations with AIDs and micronutrient status., Methods: Consecutive women ( n = 187) with infertility and RSA, and controls ( n = 350) were included. All women were genotyped for HLA-DQ2 (DQA1*0201, A1*05, and B1*02) and -DQ8 (DQA1*03 and DQB1*0302) alleles. Serum 25(OH)D, VB12, folate, and ferritin were evaluated., Results: DQA1*05/B1*02 and the occurrence of at least one DQ2 allele were more prevalent among RSA and infertile women than controls. Infertile women showed lower 25(OH)D and higher prevalence of AIDs than RSA women. In the multivariate analysis, DQA1*05/B1*02 was associated with a significantly higher risk of AIDs in infertile women, and DQA1*05 was independently associated with both 25(OH)D deficiency and AIDs. In RSA women, the presence of AIDs was associated with a significantly higher risk of 25(OH)D deficiency., Conclusion: Our findings showed, for the first time, a higher proportion of DQ2 alleles in infertile and RSA women as compared to controls. Predisposing DQ2 alleles are independent risk factors for AIDs and 25(OH)D deficiency in infertile women and could represent biomarkers for performing early detection of women requiring individually tailored management.

Objective: To develop diagnostic criteria for chronic endometritis and compare the prevalence of chronic endometritis between women with recurrent pregnancy loss (RPL) and controls., Design: Cohort study., Setting: Single academic fertility center., Patients: Women with unexplained RPL (two or more pregnancy losses) and prospectively recruited controls without a history of RPL or infertility., Interventions: Endometrial samples were stained with hematoxylin and eosin and CD138. A pathologist blinded to patient history recorded the number of plasma cells per 10 high-power fields (HPFs). In addition, the presence or absence of endometrial stromal changes was documented., Main Outcome Measure: Prevalence of chronic endometritis., Results: Endometrial samples from 50 women with unexplained RPL and 26 controls were evaluated. When chronic endometritis was defined as the presence of one or more plasma cells per 10 HPFs, 31% of controls and 56% of women with RPL met the criterion. When both endometrial stromal changes and plasma cells were required for a diagnosis of chronic endometritis, no controls and 30% of women with RPL met the criteria., Conclusions: Although rare plasma cells were found in biopsy samples from controls, the presence of both plasma cells and endometrial stromal changes was limited to the RPL cohort. We propose that chronic endometritis be defined as the presence of one or more plasma cells per 10 HPFs in the setting of endometrial stromal changes. With the use of these strict diagnostic criteria, women with RPL have a significantly higher rate of chronic endometritis, supporting an association between chronic endometritis and RPL., (Copyright © 2021 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.)

Introduction: Recurrent miscarriages are defined as three or more early miscarriages before 12 weeks of gestation. The aim of this study was to describe a cohort of women with unexplained recurrent miscarriages, evaluate several potential biomarkers of immune origin, and describe the outcome of pregnancies under immunomodulatory therapies., Methods: Women having a history of at least 3 early miscarriages without any etiology were recruited from 3 university hospitals., Results: Among 101 women with recurrent miscarriages, overall, 652 pregnancies have been included in the analysis. Women which experienced miscarriages were older (33.3 ± 5.4 versus 31.9 ± 6.7; p = 0.03), with history of more pregnancies (4 (2-6) versus 3.5 (1-5.75); p 0.0008), and less frequently the same partner (406 (74%) versus 79 (86%); p=0.01). There was no difference in the level and frequencies of biomarkers of immune origin (NK, lymphocyte, gamma globulins and blood cytokine levels and endometrial uNK activation status), except the higher rates of positive antinuclear antibodies in women with live birth (12 (13%) versus 36 (7%); p=0.03). Among the 652 pregnancies, 215 (33%) have been treated and received either aspirin/low weighted molecular heparin (LMWH) and/or combined to different lines of immunomodulatory treatment. Patients with pregnancy under treatment had a significantly higher rate of cumulative live birth rate than those with untreated ones (43.0% vs 34.8%; p = 0.04). When compared to patients with untreated pregnancies, patients with steroids during the pregnancy had twice more chances to obtain live birth (OR 2.0, CI95% 1.1 - 3.7, p = 0.02)., Conclusions: Unexplained recurrent miscarriages could have improved obstetrical outcome under immunomodulatory therapies and in particular steroids., (© 2021 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: The aim of this study was to evaluate whether the number of p16-positive cells in the functional layer of the endometrium could be a useful biomarker to identify women with recurrent implantation failure (RIF) undergoing in vitro fertilization (IVF) at risk of miscarriage., Methods: Immunohistochemical staining was performed in 311 endometrial biopsies taken during mid-luteal phase using antibody against p16 INK4A . The percentage of p16-positive cells was determined in luminal, glandular and stromal endometrial cells. After embryo transfer, women were divided into the following groups: unsuccessful embryo implantation (n = 151), miscarriage (n = 66) and live birth (n = 94). The percentage of p16-positive cells in all endometrial compartments was compared among these groups., Results: We found that the percentages of p16-positive glandular and luminal epithelial endometrial cells were significantly higher in patients with live births compared to women with miscarriage (9.3% vs. 2.9%, P < 0.001; and 35.2% vs. 11.7%, P = 0.001, respectively). This tendency was not confirmed in thе stroma. The cut-off values with p16-positive luminal cells lower than 12.5% and p16-positive glandular cells lower than 3.2% could be predictive factors for miscarriage (AUC 0.80 and 0.79; sensitivity 71.3% and 74.5%; specificity 74.2% and 71.2%, respectively)., Conclusion: A decreased number of senescent p16-positive cells could be involved in the implantation failures and aetiology of recurrent miscarriage. Women with history of RIF with reduced populations of p16-positive cells in the endometrial glandular and luminal epithelium may be at greater risk for unsuccessful implantation and miscarriage. The percentage of p16-positive luminal epithelial cells may be clinically useful as a biomarker of miscarriage., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: Early pregnancy loss leads to a devastating situation for many couples. Genetic disorders found in the pregnancy tissue are a frequent cause of miscarriages. It is unclear whether maternal age or previous miscarriages are associated with a higher chromosomal anomaly rate. This study aimed to determine the cytogenetical distribution of chromosomal disorders in couples after one or more previous miscarriages as well as the influence of maternal age., Methods: 406 fetal tissue samples obtained after spontaneous abortion between 2010 and 2014 were successfully karyotyped. This included 132 couples with at least two losses and 274 couples with sporadic miscarriage. Normal and abnormal karyotype rate was determined for age, parity, gravidity, gestational week and number of previous miscarriages by logistic regression analysis., Results: 145 (35.71%) fetal tissue samples had a normal karyotype, and 261 (64.8%) did not. After adjusting for age, older patients have a statistically significantly higher probability of genetic disorders in the pregnancy tissue (p < 0.001, OR 1.064, 95% CI 1.03-1.11). With each additional year, the probability of finding chromosomal abnormalities in a miscarriage increased by 6.4%. Patients younger than 35 years have a lower probability of having chromosomal disorders in the aborted material after two or more miscarriages than after sporadic miscarriages (50.7 vs. 58.9%) (p = 0.014, OR 0.67, 95% CI 0.48-0.914). Nevertheless, the risk of embryonic chromosomal disorders in patients aged 35 and above increased from 75.5% in sporadic miscarriages to 82.4% after more than one pregnancy losses (p = 0.59, OR 1.14, 95% CI  - 0.72 to 1.92)., Conclusion: Chromosomal disorders found after one or more previous miscarriages are related to patients' age. Couples suffering two or more miscarriages should be further researched, especially in younger patients.

Recurrent pregnancy loss (RPL) represents one of the pregnancy complications affecting 1-3% of women. Sex hormones, progesterone and estrogen play a critical role in the maintenance of pregnancy; they are mediated by estrogen receptor 1 (ESR1) and progesterone receptor (PR) genes respectively. Polymorphisms of (ESR1) and (PR) genes are linked to RPL. We aimed to explore the association of single nucleotide polymorphisms (SNPs) of (ESR1) gene and (PR) gene with RPL in a cohort of Egyptian population (50 infertile Egyptian women who experienced RPL and 50 healthy women), using polymerase chain reaction-restriction fragment length polymorphism analysis (PCR-RFLP) of (ESR1) gene and DNA sequencing of exons 1 and 5 of (PR) gene. Genotyping of ESR1 gene SNP's: (rs2234693) and (rs9340799) revealed higher significance in cases compared to controls of p value (p = 0.006 and p = 0.001) respectively. However, the frequencies of the two variants in (PG) gene; S344T (rs3740753) (p = 0.0001) and H770H (rs1042839) (p = 0.001) were significantly higher in women compared to the healthy control women. New polymorphism P352Q was observed in 2% of cases (p = 0.0001). There was a significant association of SNP's of ESR1 and PR genes with recurrent pregnancy loss RPL. Further demographics studies should be carried on a larger number of women at risk of recurrent implantation to elucidate this SNP's association and its role in RPL women.

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., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: To evaluate the interaction of depression and anxiety with the development of recurrent pregnancy loss (RPL)., Methods: A nested case-control study involving 2558 participants was conducted with data from the prospective Miscarriage Woman Cohort study between 2017 and 2019 in the province of Gansu, China. The questionnaire data, self-rating anxiety scale and self-rating depression scale were collected after each participant's first miscarriage. Information on RPL outcomes was obtained from the medical records within the subsequent 2 years. All patients diagosed RPL were recruited as cases whilst a randomly selected group of women with only one miscarriage in the past were recruited as controls. The logistic regression and the interaction effects between anxiety and depression and RPL were analysed., Results: The prevalence of anxiety (n = 325, 28.7% vs. n = 278, 19.5%) and depression symptoms (n = 550, 48.6% vs. n = 589, 41.3%) for the 1132 RPL cases were higher than 1426 non-RPL controls (P < 0.001). After adjusting for possible confounding variables, the odds ratio (OR) value, reflecting the multiplicative interaction, was 1.91 (95% CI 1.50-2.44, P < 0.001) for cases with both anxiety and depression symptoms compared with the non-RPL group. The relative excess risk of interaction value, reflecting the additive interaction between anxiety and depression to RPL was 1.15 (95% CI 0.32-4.21). Moreover, the adjusted OR for RPL cases with mild anxiety and severe depression was 2.77 (95% CI 1.07-44.14, P < 0.001), for RPL cases with severe anxiety and mild depression was 4.23 (95% CI 1.01-22.21, P < 0.001), for RPL cases with severe anxiety and moderate depression was 4.34 (95% CI 1.03-21.28, P < 0.001) and for RPL cases with severe anxiety and severe depression was 5.95 (95% CI 1.09-45.09, P < 0.05)., Conclusions: Either depression or anxiety alone could increase the risk of subsequent RPL. Anxiety and depression had a synergistic effect after the first miscarriage which increased the development of subsequent RPL disease.

Problem: The association between subclinical hypothyroidism (SCH) and recurrent pregnancy loss (RPL) remains unclear. We evaluated whether SCH affects subsequent live births and whether levothyroxine is effective in improving the live birth rate in patients with RPL., Method of Study: This observational cohort study included 1418 pregnancies of 1014 patients with a history of 2 or more pregnancy losses, who were euthyroid or had hypothyroidism, and had at least one subsequent pregnancy outcome. Some patients with SCH, as defined as a TSH >2.5 mIU/L, were treated with levothyroxine, and these comprised the levothyroxine group. The prevalence of SCH, subsequent live birth rates per patient and per pregnancy were compared among patients with SCH treated with and without levothyroxine and patients with euthyroid., Results: The prevalence of SCH was 14.4%. Subsequent live birth rates were 75.0% for the levothyroxine group, 68.6% for the untreated SCH group, and 70.1% for the euthyroid group. After excluding miscarriages with abnormal karyotypes, live birth rates were 89.2%, 90.0%, and 91.1%. The adjusted odds ratio (95%CI) was 0.95 (0.23-3.83) after controlling covariables when comparing SCH patients with and without treatment. The live birth rates per pregnancy were 93.1%, 85.7%, and 90.9%, respectively. The adjusted OR was 0.95 (0.23-3.83)., Conclusion: Levothyroxine has no effect on improving the live birth rate in patients with RPL associated with SCH. Treatment in patients with RPL and SCH raised TSH levels (2.5-10mIU/L) might not be beneficial in improving the live birth rate., (© 2020 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Recurrent pregnancy loss (RPL) is defined as the loss of two or more pregnancies and is often multifactorial with the majority of miscarriages being due to aneuploidy and anatomic or physiological abnormalities. However, inherited or acquired thrombophilias have also been associated with RPL, albeit inconsistently. While inherited thrombophilias, such as factor V Leiden and prothrombin gene mutation, are relatively prevalent in women with RPL compared with the general population, a causal link has yet to be definitively established. Recently, systemic inflammation, as measured by high-sensitivity C-reactive protein, has also been hypothesized to play a role in infertility. Based on limited prospective trial data, antithrombotic therapy and antiplatelet agents have been proposed as possible tools for the prevention of RPL. Because of the multifactorial nature of RPL and infertility, various clinicians, as obstetricians and gynecologists, endocrinologists, hematologists, or vascular medicine specialists, may be requested to counsel these women. This, together with evidence gaps, frequently leads to distinctly different diagnostic and therapeutic recommendations, especially regarding thrombophilia testing and treatment. Using four case vignettes in this review, we critically appraise the literature and highlight how two clinicians from different subspecialties approach the relationship between RPL, inflammation, and thrombophilia., Competing Interests: Dr. Piazza has received research grant support from Bristol Myers Squibb/Pfizer Alliance, Janssen, Boston Scientific Corporation, Bayer, and Portola and consultant fees from Amgen and Agile Therapeutics. Dr. Grandone has received consultant fees from Italfarmaco and Sanofi., (Thieme. All rights reserved.)