Anti-Müllerian hormone and live birth in unexplained recurrent pregnancy loss.

RESEARCH QUESTION: Is anti-Müllerian hormone (AMH) associated with live birth rate (LBR) in women with unexplained recurrent pregnancy loss (RPL)? DESIGN: Cohort study of women with unexplained RPL attending the RPL Unit, Copenhagen University Hospital, Denmark, between 2015 and 2021. AMH concentration was assessed upon referral, and LBR in the next pregnancy. RPL was defined as three or more consecutive pregnancy losses. Regression analyses were adjusted for age, number of previous losses, body mass index, smoking, treatment with assisted reproductive technology (ART) and RPL treatments. RESULTS: A total of 629 women were included; 507 (80.6%) became pregnant after referral. Pregnancy rates were similar for women with low and high AMH compared to women with medium AMH (81.9, 80.3 and 79.7%, respectively) (low AMH: adjusted odds ratio [aOR] 1.44, 95% confidence interval [CI] 0.84-2.47, P = 0.18; high AMH: aOR 0.98, 95% CI 0.59-1.64, P = 0.95). AMH concentrations were not associated with live birth. LBR was 59.5% in women with low AMH, 66.1% with medium AMH and 65.1% with high AMH (low AMH: aOR 0.68, 95% CI 0.41-1.11, P = 0.12, high AMH: aOR 0.96, 95% CI 0.59-1.56, P = 0.87). Live birth was lower in ART pregnancies (aOR 0.57, 95% CI 0.33-0.97, P = 0.04) and with higher numbers of previous losses (aOR 0.81, 95% CI 0.68-0.95, P = 0.01). CONCLUSION: In women with unexplained RPL, AMH was not associated with the chances of live birth in the next pregnancy. Screening for AMH in all women with RPL is not supported by current evidence. The chance of live birth among women with unexplained RPL achieving pregnancy by ART was low and needs to be confirmed and explored in future studies.

A core outcome set for trials in miscarriage management and prevention: An international consensus development study.

OBJECTIVE: To develop core outcome sets (COS) for miscarriage management and prevention. DESIGN: Modified Delphi survey combined with a consensus development meeting. SETTING: International. POPULATION: Stakeholder groups included healthcare providers, international experts, researchers, charities and couples with lived experience of miscarriage from 15 countries: 129 stakeholders for miscarriage management and 437 for miscarriage prevention. METHODS: Modified Delphi method and modified nominal group technique. RESULTS: The final COS for miscarriage management comprises six outcomes: efficacy of treatment, heavy vaginal bleeding, pelvic infection, maternal death, treatment or procedure-related complications, and patient satisfaction. The final COS for miscarriage prevention comprises 12 outcomes: pregnancy loss <24 weeks' gestation, live birth, gestation at birth, pre-term birth, congenital abnormalities, fetal growth restriction, maternal (antenatal) complications, compliance with intervention, patient satisfaction, maternal hospitalisation, neonatal or infant hospitalisation, and neonatal or infant death. Other outcomes identified as important were mental health-related outcomes, future fertility and health economic outcomes. CONCLUSIONS: This study has developed two core outcome sets, through robust methodology, that should be implemented across future randomised trials and systematic reviews in miscarriage management and prevention. This work will help to standardise outcome selection, collection and reporting, and improve the quality and safety of future studies in miscarriage.

Increased risk of neonatal complications and infections in children of kidney-transplanted women: A nationwide controlled cohort study.

Information related to short- and long-term risks of children born to kidney-transplanted women remains limited. With the aim of investigating the risk of neonatal complications, and the short- and long-term risk of infections in offspring of kidney-transplanted women, all children born to kidney-transplanted women in Denmark from 1964 to 2016 were identified in a nationwide retrospective matched cohort study. A total of 124 children of kidney-transplanted women were identified and matched on gender, birth year, and number of siblings at birth 1:10 with children born to nontransplanted women identified in the Danish general population. Prevalence of low birth weight (37.9%, risk ratio [RR] = 12.61; 95% confidence interval [CI], 8.5-18.5), premature birth (46.0%, RR = 11.32; 95% CI, 8.1-15.7) and malformations (11.3%, RR = 1.98; 95% CI, 1.2-3.4) was increased in children of kidney-transplanted women compared with controls. Similarly, prevalence of hospitalization due to infection was increased during the first year of life (21.0%, RR = 1.94; 95% CI, 1.3-2.8), from age 1 to 5 (34.2%, RR = 1.89; 95% CI, 1.4-2.5), and overall (41.9%, RR = 1.67; 95% CI, 1.3-2.1). The risk of infection was also higher in children of kidney-transplanted mothers born preterm or with low birth weight compared with similar controls. In conclusion, risk of neonatal complications, malformations, and both early and late infection were increased in children born to kidney-transplanted women.

Endometrial cancer does not increase the 30-day risk of venous thromboembolism following hysterectomy compared to benign disease. A Danish National Cohort Study.

OBJECTIVES: We aimed to clarify if endometrial cancer patients are at higher risk of venous thromboembolism (VTE) following hysterectomy, compared to patients undergoing hysterectomy for benign gynecological disease. METHODS: In a nationwide registry-based cohort study, patients undergoing hysterectomy for endometrial cancer or benign disease were followed 30 days after surgery. The Danish Gynecological Cancer Database (DGCD) and the Danish National Patient Register (DNPR) were linked with four other administrative registries to describe the population and retrieve data on venous thromboembolism and mortality. Multivariable logistic regression models were used to estimate odds ratios (ORs) for 30-day postoperative VTE. RESULTS: We identified 5513 patients with endometrial cancer, and 45,825 patients with benign disease undergoing hysterectomy in the period 2005-2014. The overall incidence of 30-day VTE following hysterectomy was 0.2% (103/51,338). Thirty (0.5%) patients with endometrial cancer and 73 (0.16%) patients with benign disease developed VTE. In a multivariable logistic regression analysis, significant predictors of 30-day OR for VTE were open surgery (minimally invasive surgery vs. open: OR = 0.46; 95% CI, 0.30-0.71; p < 0.001), lymphadenectomy (OR = 4.00; 95% CI, 1.89-8.46; p < 0.001), BMI > 40 (OR = 2.34;95% CI, 1.10-5.01; p = 0.03) and previous VTE (OR = 34; 95% CI, 22.7-51.3; p < 0.001). There was no statistically significant difference in the 30-day OR for VTE in endometrial cancer compared to benign disease (OR = 1.47; 95% CI, 0.74-2.91; p = 0.27). CONCLUSIONS: This study did not identify endometrial cancer to be an independent risk factor for VTE following hysterectomy compared to benign disease. We identified open surgery, lymphadenectomy, BMI above 40 and previous VTE as independent risk factors for 30-day postoperative VTE.

Venous Thromboembolic Complications to Hysterectomy for Benign Disease: A Nationwide Cohort Study.

STUDY OBJECTIVE: To estimate the risk of venous thromboembolic complications after abdominal, laparoscopic, and vaginal hysterectomy when performed for benign disorders. DESIGN: A nationwide cohort study (Canadian Task Force classification II-2). SETTING: Data from Danish national registers on all women undergoing hysterectomy for benign conditions from 1996 to 2015. PATIENTS: Women aged 18 years and older who underwent hysterectomy for benign disease were stratified into 3 groups according to the hysterectomy approach: abdominal, laparoscopic, or vaginal. INTERVENTIONS: Hysterectomy. MEASUREMENTS AND MAIN RESULTS: Eighty-nine thousand nine hundred thirty-one women met the inclusion criteria. Venous thromboembolism (VTE) as a diagnosis or cause of death was identified. The risk of postoperative VTE was examined with Cox proportional hazard models adjusting for age, surgical approach, and relevant comorbidities. The mean age was 49.9, 47.9, and 54.3 years for women with abdominal, laparoscopic, and vaginal hysterectomy, respectively. The crude incidences of VTE within 30 days after hysterectomy were 0.24% (n = 142), 0.13% (n = 12), and 0.10% (n = 21). The most important predictors of VTE were the approach to hysterectomy and a history of thromboembolic disease. In the multivariable analysis, the risk of VTE was significantly reduced with laparoscopic hysterectomy (hazard ratio [HR] = 0.51; 95% confidence interval [CI], 0.28-0.92; p = .03) and vaginal hysterectomy (HR = 0.39; 95% CI, 0.24-0.63; p < .001) when compared with the abdominal procedure. Data on postoperative heparin thromboprophylaxis were available in 53 566 patients, and the adjusted HR was 0.63 (95% CI, 0.42-0.96; p = .03) in patients receiving heparin thromboprophylaxis. CONCLUSION: The 30-day cumulative incidence of VTE after hysterectomy for benign conditions was low overall (0.19%). Laparoscopic hysterectomy and vaginal hysterectomy carry a lower risk than the abdominal procedure. Postoperative heparin thromboprophylaxis significantly reduces the risk of VTE and should be considered, especially if risk factors are present.

Is the incidence of recurrent pregnancy loss increasing? A retrospective register-based study in Sweden.

INTRODUCTION: The aim of this study was to estimate the incidence of recurrent pregnancy loss (RPL). The prevalence of RPL defined as three or more consecutive miscarriages before gestation week 22, is often stated to be 1%. To our knowledge no study has estimated the incidence of RPL, which might be more informative and clinically relevant than the prevalence. MATERIAL AND METHODS: This retrospective register-based study was conducted from 2003 until 2012 in Sweden with data provided by the Swedish National Board of Health and Welfare. In all, 6852 women were registered with the diagnoses of RPL in the National Patient Register. The incidence of RPL is the number of new women receiving the RPL diagnosis per year in the numerator and population at risk in the denominator. RESULTS: For each year, from 2003 to 2012, the incidence was calculated in two different risk populations: [1] all women aged 18-42 years, and [2] all women registered as being pregnant (deliveries or miscarriages). The average incidence in the study period was 53 per 100 000 (0.05%) in women aged 18-42 years and 650 per 100 000 (0.65%) in women who had achieved pregnancy in the period. The incidence of RPL in the two risk populations increased by 74 and 58%, respectively, during the study period. CONCLUSION: This study suggests that the incidence of RPL increased during the 10-year period studied. Causes can only be speculated upon in this study design, but might be associated with environmental changes, as the increase was fairly rapid.

Recurrence rates after abdominal and vaginal cerclages in women with cervical insufficiency: a validated cohort study.

PURPOSE: To estimate the incidence of cervical insufficiency and compare recurrence rates of second trimester miscarriage/delivery in second and third pregnancies after prophylactic vaginal cerclage, abdominal cerclage, or no cerclage. METHODS: Retrospective chart review of a representative register-based sample of 621 women with a spontaneous second trimester miscarriage/delivery in the first pregnancy in Denmark (1997-2012). We used strict criteria for the diagnosis of cervical insufficiency. The outcome of subsequent pregnancies was described by treatment with prophylactic vaginal cerclage, abdominal cerclage, or no prophylactic cerclage. Women were followed until June 2015. RESULTS: Of 621 women, 149 (24%) fulfilled the strict criteria of cervical insufficiency. Prophylactic treatment with abdominal cerclage (n = 20), vaginal cerclage (n = 59), and no prophylactic cerclage (n = 61) resulted in a second pregnancy ending before 28 weeks in 5, 30, and 72% (p < 0.001) and before 34 weeks in 10, 46, and 84% (p < 0.001), respectively. Take-home baby rate was 95% after abdominal cerclage, 73% after vaginal cerclage, and 33% after no cerclage. In a third pregnancy, abdominal cerclage (n = 47), vaginal cerclage (n = 38), and no cerclage (n = 8) resulted in pregnancy ending before 34 weeks of gestation in 2, 21, and 25%, respectively (p = 0.01). CONCLUSIONS: Cervical insufficiency was diagnosed in 24% of women with an initial second trimester spontaneous miscarriage/delivery. In second and third pregnancies, recurrence rates were significantly lower after prophylactic vaginal or abdominal cerclage compared with no cerclage.

Polymorphisms in Genes Coding for Cytokines, Mannose-Binding Lectin, Collagen Metabolism and Thrombophilia in Women with Cervical Insufficiency.

OBJECTIVE: To study the association between cervical insufficiency and single nucleotide polymorphisms in seven genes coding for pro- and anti-inflammatory cytokine-related factors, mannose-binding lectin 2 (MBL2), collagen1α1 (COL1A1), factor II and factor V Leiden genes. METHODS: In a case-control study, potential maternal biomarkers for cervical insufficiency were investigated in 30 women with a history of second-trimester miscarriage or preterm birth due to cervical insufficiency and in 70 control women. RESULTS: Homozygous carriers of the interleukin 6 (IL6) -174 genotype GG had an odds ratio (OR) of 3.1 [95% confidence interval (95% CI) 1.3-7.4, p = 0.01] and MBL2 genotypes coding for low or intermediate levels of plasma MBL had an OR of 3.3 (95% CI 1.2-9.0, p = 0.01) for cervical insufficiency compared with controls. Serum MBL levels were lower in women with cervical insufficiency than in controls (median 408 and 1,985 ng/ml, respectively, p < 0.01). CONCLUSIONS: Single nucleotide polymorphisms in the IL6 gene and the MBL2 gene and low MBL levels related to the latter polymorphism may increase the risk of preterm birth due to cervical insufficiency.

Seminal Oxidative Stress and Sperm DNA Fragmentation in Men from Couples with Infertility or Unexplained Recurrent Pregnancy Loss.

(1) Background: This case-control study examined whether men from couples with unexplained recurrent pregnancy loss (RPL) or infertility exhibited higher seminal oxidative stress (OS) and sperm DNA fragmentation (SDF) compared to fertile controls. (2) Methods: The study included 30 participants from each group: unexplained RPL, unexplained infertility, and proven fertility. Data were collected at Aalborg University Hospital tertiary RPL and fertility treatment clinics (Aalborg, Denmark), excluding couples with mixed conditions for homogeneity. Semen samples were analyzed using computer-aided sperm analysis (CASA) for concentration, motility, and morphology. SDF was assessed via a CASA-based sperm chromatin dispersion test. OS was measured as static oxidation-reduction potential (sORP). (3) Results: The results showed no significant OS differences between groups. The RPL group had significantly lower SDF levels than the control group. A significant positive correlation between SDF and OS was observed in the infertility group. Overall, this study did not find significant differences in OS levels between men from couples with unexplained RPL or infertility and fertile controls, while SDF levels were lower in the RPL group compared to controls. (4) Conclusion: In conclusion, despite the existing literature suggesting that OS and SDF are negative prognostic factors, our findings suggest they may not be reliable diagnostic markers for RPL and infertility.

Prediction of large-for-gestational-age at birth using fetal biometry in type 1 and type 2 diabetes: A retrospective cohort study.

OBJECTIVE: To compare ultrasound-assessed fetal head circumference (HC), abdominal circumference (AC), HC/AC ratio, and estimated fetal weight (EFW) in prediction of large-for-gestational-age (LGA) at birth in pregnancies affected by type 1 (T1DM) and type 2 (T2DM) diabetes. METHODS: This retrospective cohort study included all women with T1DM and T2DM giving birth to singletons between 2010 and 2019 at Aalborg University Hospital, Denmark. Ultrasound scans were performed at 16, 20, 28 and 34 weeks of pregnancy. LGA was defined as birth weight deviation of 15% or greater from the expected for gestational age (≥90th centile). Prediction of LGA was assessed by logistic regression adjusted for maternal characteristics and glycated hemoglobin (HbA1c) and area under the receiver operating characteristics curve (AUC). RESULTS: Among 180 T1DM pregnancies, 118 (66%) had an LGA neonate at birth. At 28 weeks of pregnancy, they were predicted with AUCHC/AC = 0.67, AUCAC = 0.85, and AUCEFW = 0.86. The multivariate analysis did not improve the predictive performance of the HC/AC ratio or AC. Among 87 T2DM pregnancies, 36 (41%) had an LGA neonate at birth. At 28 weeks, they were predicted with AUCHC/AC = 0.73, AUCAC = 0.83, and AUCEFW = 0.87. In T2DM, the multivariate analysis significantly improved the predictive performance for both HC/AC ratio and AC from 20 weeks of pregnancy. CONCLUSION: In T1DM and T2DM pregnancies, LGA is characterized by a general fetal overgrowth including both AC and HC. Therefore, AC and EFW perform better than the HC/AC ratio in the prediction of LGA. In T2DM, as opposed to T1DM, the predictive performance was improved by the inclusion of maternal characteristics and HbA1c in the analysis.

New insights into mechanisms behind miscarriage.

Sporadic miscarriage is the most common complication of early pregnancy. Two or three consecutive pregnancy losses is a less common phenomenon, and this is considered a distinct disease entity. Sporadic miscarriages are considered to primarily represent failure of abnormal embryos to progress to viability. Recurrent miscarriage is thought to have multiple etiologies, including parental chromosomal anomalies, maternal thrombophilic disorders, immune dysfunction and various endocrine disturbances. However, none of these conditions is specific to recurrent miscarriage or always associated with repeated early pregnancy loss. In recent years, new theories about the mechanisms behind sporadic and recurrent miscarriage have emerged. Epidemiological and genetic studies suggest a multifactorial background where immunological dysregulation in pregnancy may play a role, as well as lifestyle factors and changes in sperm DNA integrity. Recent experimental evidence has led to the concept that the decidualized endometrium acts as biosensor of embryo quality, which if disrupted, may lead to implantation of embryos destined to miscarry. These new insights into the mechanisms behind miscarriage offer the prospect of novel effective interventions that may prevent this distressing condition.

Changes in human fetal oxygenation during maternal hyperoxia as estimated by BOLD MRI.

OBJECTIVE: Changes in blood oxygen level dependent (BOLD) magnetic resonance imaging (MRI) signal are closely related to changes in fetal oxygenation. In this study, we aimed to investigate the changes in human fetal oxygenation during maternal hyperoxia by using the non-invasive BOLD MRI technique. METHOD: Eight healthy pregnant women in gestational week 28 to 34 were included. With the use of a facial oxygen mask, we induced maternal hyperoxia and measured changes in the BOLD MRI signal of selected fetal organs. RESULTS: In a number of fetal organs, the BOLD MRI signal increased significantly (P < 0.01) during maternal hyperoxia (mean change in % ± SEM): liver (14.3 ± 3.7%), spleen (15.2 ± 3.5%) and kidney (6.2 ± 1.8%) as well as the placenta (6.5 ± 1.6%). In the fetal brain, however, the BOLD MRI signal remained constant (0.3 ± 0.2%). CONCLUSION: During maternal hyperoxia, we demonstrated an increased oxygenation in a number of human fetal organs by using the non-invasive BOLD technique. The oxygenation of the fetal brain remained constant, thus a 'reversed' brain sparing mechanism could be considered in healthy fetuses subjected to hyperoxia.

A combination of the HLA-DRB1*03 phenotype and low plasma mannose-binding lectin predisposes to autoantibody formation in women with recurrent pregnancy loss.

Introduction: It is documented that a series of autoantibodies can be detected with increased frequency in women with recurrent pregnancy loss (RPL) and they may impact the pregnancy prognosis negatively. It is unknown whether the autoantibodies per se or the basic immune disturbances underlying autoantibody production, are the reason for this association. Our group has previously found that some genetically determined immunological biomarkers are associated with RPL and the same biomarkers are also in various degrees known to predispose to autoantibody production. The aim of this study was to clarify whether the RPL-associated immunogenetic biomarkers are associated with positivity for three major classes of autoantibodies associated with RPL. Methods: In 663 patients with RPL in whom we had results for HLA-DRB1 typing and plasma mannose-binding lectin (p-MBL) measurement, it was investigated whether there is a correlation between positivity for the autoantibodies: anticardiolipin antibodies, ß2 glycoprotein I antibodies, and lupus anticoagulant (jointly called antiphospholipid antibodies), thyroid-peroxidase antibodies, and antinuclear antibodies and each of the HLA-DRB1 alleles HLA-DRB1*03 or HLA-DRB1*07 either alone or in combination with low p-MBL defined as ≤500 µg/l. Results: Although slightly higher frequencies of positivity of two or more autoantibodies were seen in patients with either p-MBL ≤500 µg/l or being positive for HLA-DRB1*03, none were significantly associated. However, in patients with the combination of low p-MBL and HLA-DRB1*03, presence of at least one autoantibody was significantly more frequent than in patients with no such combination (OR= 2.4; 95% CI 1.2-5.0, p = 0.01). In an analysis of which autoantibodies were most strongly associated with the low p-MBL/HLA-DRB1*03 combination, antinuclear antibodies were significantly more frequent in these patients (OR 2.0; 95% CI 1.0-3.9, p=0.05) whereas the other autoantibodies were also positively but more weakly associated with this combination. Discussion: In conclusion, to clarify the pathogenetic background, underlying immunogenetic factors should be examined in autoantibody positive RPL patients (as well as other patients with autoimmune diseases) but the genetic background may be complex.

ESHRE guideline: recurrent pregnancy loss: an update in 2022.

STUDY QUESTION: What are the updates for the recommended management of women with recurrent pregnancy loss (RPL) based on the best available evidence in the literature from 2017 to 2022? SUMMARY ANSWER: The guideline development group (GDG) updated 11 existing recommendations on investigations and treatments for RPL, and how care should be organized, and added one new recommendation on adenomyosis investigation in women with RPL. WHAT IS KNOWN ALREADY: A previous ESHRE guideline on RPL was published in 2017 and needs to be updated. STUDY DESIGN SIZE DURATION: The guideline was developed and updated according to the structured methodology for development and update of ESHRE guidelines. The literature searches were updated, and assessments of relevant new evidence were performed. Relevant papers published between 31 March 2017 and 28 February 2022 and written in English were included. Cumulative live birth rate, live birth rate, and pregnancy loss rate (or miscarriage rate) were considered the critical outcomes. PARTICIPANTS/MATERIALS SETTING METHODS: Based on the collected evidence, recommendations were updated and discussed until consensus was reached within the GDG. A stakeholder review was organized after the updated draft was finalized. The final version was approved by the GDG and the ESHRE Executive Committee. MAIN RESULTS AND THE ROLE OF CHANCE: The new version of the guideline provides 39 recommendations on risk factors, prevention, and investigation in couples with RPL, and 38 recommendations on treatments. These includes 62 evidence-based recommendations-of which 33 were formulated as strong recommendations and 29 as conditional-and 15 good practice points. Of the evidence-based recommendations, 12 (19.4%) were supported by moderate-quality evidence. The remaining recommendations were supported by low (34 recommendations; 54.8%), or very low-quality evidence (16 recommendations; 25.8%). Owing to the lack of evidence-based investigations and treatments in RPL care, the guideline also clearly mentions those investigations and treatments that should not be used for couples with RPL. LIMITATIONS REASONS FOR CAUTION: The guidelines have been updated; however, several investigations and treatments currently offered to couples with RPL have not been well studied; for most of these investigations and treatments, a recommendation against using the intervention or treatment was formulated based on insufficient evidence. Future studies may require these recommendations to be revised. WIDER IMPLICATIONS OF THE FINDINGS: The guideline provides clinicians with clear advice on best practice in RPL, based on the best and most recent evidence available. In addition, a list of research recommendations is provided to stimulate further studies in RPL. Still, the absence of a unified definition of RPL is one of the most critical consequences of the limited scientific evidence in the field. STUDY FUNDING/COMPETING INTERESTS: The guideline was developed and funded by ESHRE, covering expenses associated with the guideline meetings, with the literature searches and with the dissemination of the guideline. The guideline group members did not receive payment.O.B.C. reports being a member of the executive board of the European Society for Reproductive Immunology and has received payment for honoraria for giving lectures about RPL in Australia in 2020. M.G. reports unconditional research and educational grant received by the Centre for Reproductive Medicine, Amsterdam UMC from Guerbet, Merck and Ferring, not related to the presented work. S.L. reports position funding from EXAMENLAB Ltd. and ownership interest by stock or partnership of EXAMENLAB Ltd (CEO). S.Q. reports being a deputy director of Tommy's National centre for miscarriage research, with payment received by the institution for research, staff time, and consumables for research. H.S.N. reports grants with payment to institution from Freya Biosciences ApS, Ferring Pharmaceuticals, BioInnovation Institute, the Danish ministry of Education, Novo Nordic Foundation, Augustinus Fonden, Oda og Hans Svenningsens Fond, Demant Fonden, Ole Kirks Fond, and Independent Research Fund Denmark and speakers' fees for lectures from Ferring Pharmaceuticals, Merck A/S, Astra Zeneca, IBSA Nordic and Cook Medical. She also reports to be an unpaid founder and chairman of a maternity foundation. M.-L.v.d.H. received small honoraria for lectures on RPL care. The other authors have no conflicts of interest to declare. DISCLAIMER: This guideline represents the views of ESHRE, which were achieved after careful consideration of the scientific evidence available at the time of preparation. In the absence of scientific evidence on certain aspects, a consensus between the relevant ESHRE stakeholders has been obtained.Adherence to these clinical practice guidelines does not guarantee a successful or specific outcome, nor does it establish a standard of care. Clinical practice guidelines do not replace the need for application of clinical judgment to each individual presentation, nor variations based on locality and facility type.ESHRE makes no warranty, express or implied, regarding the clinical practice guidelines and specifically excludes any warranties of merchantability and fitness for a particular use or purpose. (Full disclaimer available at www.eshre.eu/guidelines.).

Live Birth Rate in Women with Recurrent Pregnancy Loss after In Vitro Fertilization with Concomitant Intravenous Immunoglobulin and Prednisone.

Pregnancy loss after in vitro fertilization (IVF) is at least as common as after spontaneous conception. Recurrent pregnancy loss (RPL) may often have an immunological background, and it is therefore relevant to test immune-based interventions in these patients. The objective was to investigate the effect of immunotherapy with intravenous immunoglobulin (IvIg) and prednisone (PRS) as concomitant therapy to IVF in women with RPL after earlier IVF treatments. In a cohort study conducted at The Danish RPL Clinic, 41 women with three or more consecutive pregnancy losses after IVF underwent at least one further IVF cycle with concomitant immunotherapy from 2012 to 2017. The immunotherapy with IvIg and PRS was given before embryo transfer and repeatedly in the first trimester when pregnancy was achieved. Fourteen women (34.2%) achieved a live birth after the first embryo transfer with immunotherapy, and a total of 32/41 (78%) achieved a live birth after up to 4 embryo transfers. Baseline characteristics and the presence of autoantibodies were not significantly different among women achieving live birth or not. The observed 34% birth rate in women with RPL after IVF receiving immunotherapy appears higher than the expected 16-19% birth rate without immunotherapy and is similar to findings in a previous cohort from our clinic. Concomitant immunotherapy as described may be a promising intervention for women with RPL after IVF; however, the effect must be tested in a randomized controlled trial.

Intravenous immunoglobulin and prednisolone to women with unexplained recurrent pregnancy loss after assisted reproductive technology treatment: a protocol for a randomised, double-blind, placebo-controlled trial.

INTRODUCTION: Recurrent pregnancy loss (RPL), defined as two or more consecutive pregnancy losses in the first trimester, affects around 5% of fertile women. The underlying causes remain unknown in up to 60% of patients; however, most studies point at an immunological pathology in unexplained RPL, and therefore, an effective treatment may be immunomodulatory. This study aims to evaluate the effect of intravenous immunoglobulin (IVIg) and prednisolone on reproductive outcome and the immune system in women with unexplained RPL undergoing assisted reproductive technology treatment. METHODS AND ANALYSIS: This randomised, placebo-controlled trial with double-blinded randomisation to two parallel arms evaluate if immunomodulatory (active) treatment is superior to placebo in increasing the chance of ongoing pregnancy assessed at nuchal translucency scan in gestational weeks (GW) 11-13 after embryo transfer (ET) in 74 RPL patients with ≥2 pregnancy losses as its primary objective. The active treatment consists of IVIg (one infusion preferably 1-5 days before ET and in GW 5, 6 and 7) and prednisolone (5 mg/day from first day of menstrual bleeding until ET and 10 mg/day from ET to GW 8+0) while the comparator consists of intravenous human albumin (5%) and placebo tablets. Allocation is concealed for participants, caregivers, and investigators until trial termination and is performed in a 1:1 ratio. The secondary objective is to evaluate treatment safety, and the tertiary objective is exploration of the association between treatment, reproductive outcome after ET, and the lymphocyte subset distribution in peripheral blood collected before and after intravenous infusion(s). Excess biological material is stored in a biobank for future research. ETHICS AND DISSEMINATION: The North Denmark Region Committee on Health Research Ethics (N-20200066) approved this trial. The results will be published in peer-reviewed scientific journals and presented to relevant patient associations, at relevant academic conferences and to key stakeholders. TRIAL REGISTRATION NUMBER: NCT04701034.

Association of HY-restricting HLA class II alleles with pregnancy outcome in patients with recurrent miscarriage subsequent to a firstborn boy.

Healthy females, pregnant with a boy, generate immune responses against male-specific minor histocompatibility (HY) antigens. The clinical importance of these responses is evident in stem cell transplantation. Birth of a boy prior to a series of miscarriages reduces the chance of a subsequent live birth. This study explores the putative impact of known HY-presenting HLA alleles on future pregnancy outcome in women with at least three consecutive miscarriages following a birth [secondary recurrent miscarriage (SRM)]. HLA-A, -B, -DRB1, DRB3-5 and DQB1 genotyping was performed in 358 SRM patients and in 203 of their children born prior to the miscarriages. The subsequent live birth in women with boys prior to the miscarriages compared with girls is lower in women with HY-restricting HLA class II alleles [odds ratio (OR): 0.17 (0.1-0.4), P = 0.0001]. One HY-restricting HLA class II allele in women with firstborn boys significantly reduces the chances of a live birth [OR: 0.46 (0.2-0.9), P = 0.02]. Two HY-restricting HLA class II alleles further reduced this chance [OR: 0.21 (0.1-0.7), P = 0.02]. HY-restricting HLA class II did not reduce the chances of a live birth in SRM women with firstborn girls. HY-restricting HLA class II alleles are associated with a decreased chance of a live birth in SRM women with firstborn boys. These findings strongly indicate an aberrant maternal immune reaction against fetal HY-antigens in SRM. The results may shed light on the as-yet unknown immunological causes of SRM and may help understand the successful maternal acceptance of the fetal semi-allograft.

Special Issue Recurrent Pregnancy Loss: Etiology, Diagnosis, and Therapy.

The definition of recurrent pregnancy losses (RPL) varies between guidelines from different national and international scientific societies, but overall, a history of two or more (or alternatively, three or more) confirmed pregnancy losses is required for the diagnosis [...].

Women with a History of Recurrent Pregnancy Loss Are a High-Risk Population for Adverse Obstetrical Outcome: A Retrospective Cohort Study.

Recurrent pregnancy loss (RPL), defined as three or more consecutive miscarriages, is hypothesized to share some of the same pathogenic factors as placenta-associated disorders. It has been hypothesized that a defect implantation causes pregnancy loss, while a partially impaired implantation may lead to late pregnancy complications. The aim of this retrospective register-based cohort study was to study the association between RPL and such disorders including pre-eclampsia, stillbirth, small for gestational age (SGA) birth, preterm birth and placental abruption. Women registered with childbirth(s) in the Swedish Medical Birth Register (MFR) were included in the cohort. Pregnancies of women diagnosed with RPL (exposed) in the National Patient Register (NPR), were compared with pregnancies of women without RPL (unexposed/reference). Obstetrical outcomes, in the first pregnancy subsequent to the diagnosis of RPL (n = 4971), were compared with outcomes in reference-pregnancies (n = 57,410). Associations between RPL and placental dysfunctional disorders were estimated by odds ratios (AORs) adjusting for confounders, with logistic regression. RPL women had an increased risk for pre-eclampsia (AOR 1.45; 95% CI; 1.24-1.69), stillbirth <37 gestational weeks (GWs) (AOR 1.92; 95% CI; 1.22-3.02), SGA birth (AOR 1.97; 95% CI; 1.42-2.74), preterm birth (AOR 1.46; 95% CI; 1.20-1.77), and placental abruption <37 GWs (AOR 2.47; 95% CI; 1.62-3.76) compared with pregnancies by women without RPL. Women with RPL had an increased risk of pregnancy complications associated with placental dysfunction. This risk population is, therefore, in need of improved antenatal surveillance.

Sex of prior children and risk of stillbirth in subsequent pregnancies.

BACKGROUND: Delivery of a boy has been reported to increase a woman's risk of recurrent miscarriage in subsequent pregnancies. We explored whether delivery of boys similarly increases the risk of a subsequent stillbirth. METHODS: We identified all Danish women delivering their first child (singleton) between 1980 and 1998 (n = 499,731) using the Danish Birth Registry. These women had subsequent singleton births through 2004 (n = 558,314). We assessed the risk of stillbirth conditional on sex of prior children. RESULTS: The risk of stillbirth was increased by 12% after deliver of boys compared with girls (relative risk = 1.12 [95% confidence interval = 1.02-1.23]). This association did not appear to be explained by maternal confounders. CONCLUSION: Stillbirth risk appears to be slightly higher among the pregnancies of women who have previously delivered a boy. One possible mechanism is maternal immune response to male-specific minor histocompatibility antigens initiated during pregnancies with boys.