Pregnancy-Associated Bleeding and Genetics: Five Sequence Variants in the Myometrium and Progesterone Signaling Pathway are associated with postpartum hemorrhage.

Bleeding in early pregnancy and postpartum hemorrhage (PPH) bear substantial risks, with the former closely associated with pregnancy loss and the latter being the foremost cause of maternal death, underscoring the severity of these complications in maternal-fetal health. Here, we investigated the genetic variation underlying aspects of pregnancy-associated bleeding and identified five loci associated with PPH through a meta-analysis of 21,512 cases and 259,500 controls. Functional annotation analysis indicated candidate genes, HAND2, TBX3, and RAP2C/FRMD7, at three loci and showed that at each locus, associated variants were located within binding sites for progesterone receptors (PGR). Furthermore, there were strong genetic correlations with birth weight, gestational duration, and uterine fibroids. Early bleeding during pregnancy (28,898 cases and 302,894 controls) yielded no genome-wide association signals, but showed strong genetic correlation with a variety of human traits, indicative of polygenic and pleiotropic effects. Our results suggest that postpartum bleeding is related to myometrium dysregulation, whereas early bleeding is a complex trait related to underlying health and possibly socioeconomic status.

Pregnancy Loss and the Risk of Myocardial Infarction, Stroke, and All-Cause Mortality: A Nationwide Partner Comparison Cohort Study.

Background Pregnancy loss has been associated with myocardial infarction, stroke, and all-cause mortality in women through unknown mechanisms. The aim of this study was to examine these associations in women and their male partners. Methods and Results In this register-based cohort study, all people born between 1957 and 1997, residing in Denmark between 1977 and 2017, and with a registered partner of the opposite sex were eligible for inclusion. Male partners through cohabitation, marriage, or paternity constituted the male cohort. Exposure to pregnancy loss was categorized as follows: 0, 1, 2, or ≥3 pregnancy losses. The outcomes of interest were myocardial infarction, stroke, and all-cause mortality. The Cox proportional hazards model estimated hazard ratios (HRs), adjusted for age, calendar year, parity, and parental history of myocardial infarction or stroke. During follow-up, 1 112 507 women experienced 4463 events of myocardial infarction compared with 13 838 events among 1 120 029 male partners. With the no pregnancy loss group as reference, the adjusted HRs of myocardial infarction in the female cohort after 1, 2, and ≥3 pregnancy losses were as follows: 1.1 (95% CI, 1.0-1.2), 1.3 (95% CI, 1.1-1.5), and 1.4 (95% CI, 1.1-1.8), respectively. In the male partner cohort, the corresponding estimates were 1.0 (95% CI, 1.0-1.1), 1.1 (95% CI, 1.0-1.2), and 1.0 (95% CI, 0.8-1.2), respectively. The outcome of stroke showed similar results. Pregnancy loss was not significantly associated with increased mortality in either sex. Conclusions Pregnancy loss or stillbirth was significantly associated with myocardial infarction and stroke in women but not their male partners. Pregnancy loss or stillbirth was not significantly associated with all-cause mortality in women or male partners.

Biopsy-free profiling of the uterine immune system in patients with recurrent pregnancy loss and unexplained infertility.

RESEARCH QUESTION: What are the differences in menstrual blood lymphocytes between controls, patients with recurrent pregnancy loss (RPL) and patients with unexplained infertility (uINF)? DESIGN: Prospective study including 46 healthy controls, 28 RPL and 11 uINF patients. A feasibility study compared lymphocyte compositions of endometrial biopsies and menstrual blood collected during the first 48 h of menstruation in seven controls. In all patients, peripheral and menstrual blood from the first and subsequent 24 h were analysed separately by flow cytometry, focusing on the main lymphocyte populations and natural killer (NK) cell subsets. RESULTS: The first 24 h of menstrual blood resembles the uterine immune milieu as tested by endometrial biopsy. RPL patients showed significantly higher menstrual blood CD56+ NK cell numbers than controls (mean ± SD: 31.13 ± 7.52% versus 36.73 ± 5.4%, P = 0.002). Menstrual blood CD56dimCD16bright NK cells within the CD56+ NK cell population were decreased in RPL (16.34 ± 14.65%, P = 0.011) and uINF (15.7 ± 5.91%, P = 0.02) patients versus control (20.42 ± 11.53%). uINF patients had the lowest menstrual blood CD3+ T cell counts (38.81 ± 5.04%, control versus uINF: P = 0.01) and cytotoxicity receptors NKp46 and NKG2D on CD56brightCD16dim cells were higher in uINF (68.12 ± 11.84%, P = 0.006; 45.99 ± 13.83%, P = 0.01, respectively) and RPL (NKp46: 66.21 ± 15.36%, P = 0.009) patients versus controls. RPL and uINF patients had higher peripheral CD56+ NK cell counts versus controls (11.42 ± 4.05%, P = 0.021; 12.86 ± 4.29%, P = 0.009 versus 8.4 ± 3.5%). CONCLUSIONS: Compared with controls, RPL and uINF patients had a different menstrual blood-NK-subtype profile, indicating an altered cytotoxicity. In future studies, this non-invasive analysis might enable identification and monitoring of patients receiving immunomodulatory medications.

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.

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.).

Pregnancy loss and risk of multiple sclerosis and autoimmune neurological disorder: A nationwide cohort study.

BACKGROUND: The loss of one or more pregnancies before viability (i.e. pregnancy loss or miscarriage), has been linked to an increased risk of diseases later in life such as myocardial infarction and stroke. Recurrent pregnancy loss (i.e. three consecutive pregnancy losses) and multiple sclerosis have both been linked to immunological traits, which could predispose to both occurrences. The objective of the current study was to investigate if pregnancy loss is associated with later autoimmune neurological disease. METHODS: This register-based cohort study, included the Danish female population age 12 or older between 1977-2017. Women were grouped hierarchically: 0, 1, 2, ≥3 pregnancy losses, primary recurrent pregnancy loss (i.e. not preceded by a delivery), and secondary recurrent pregnancy loss (i.e. preceded by a delivery). The main outcome was multiple sclerosis and additional outcomes were amyotrophic lateral sclerosis, Guillain-Barré syndrome, and myasthenia gravis. Bayesian Poisson regression estimated incidence rate ratios [IRR] and 95% credible intervals [CI] adjusted for year, age, live births, family history of an outcome, and education. RESULTS: After 40,380,194 years of follow-up, multiple sclerosis was diagnosed among 7,667 out of 1,513,544 included women (0.5%), median age at diagnosis 34.2 years (IQR 27.4-41.4 years), and median age at symptom onset 31.2 years (IQR 24.8-38.2). The adjusted IRR of multiple sclerosis after 1 pregnancy loss was: 1.03 (95% CI 0.95-1.11), 2 losses: 1.02 (95% CI 0.86-1.20), ≥3 non-consecutive losses: 0.81 (95% CI 0.51-1.24), primary recurrent pregnancy loss: 1.18 (95% CI 0.84-1.60), secondary recurrent pregnancy loss: 1.16 (95% CI 0.81-1.63), as compared to women with no pregnancy losses. Seven sensitivity analyses and analyses for additional outcomes did not show significantly elevated adjusted risk estimates. CONCLUSIONS: In this nationwide study, pregnancy loss was not significantly associated with autoimmune neurological disorder.

Feelings of guilt and loss of control dominate in stress and depression inventories from women with recurrent pregnancy loss.

PURPOSE: Which feelings on the major depression inventory (MDI) and the perceived stress scale (PSS) are predominant among women with recurrent pregnancy loss (RPL)? MATERIALS AND METHODS: Prospective cohort study of women with RPL referred to the tertiary RPL Unit at Copenhagen University Hospital, Rigshospitalet, Denmark, from 2010-2013. All women answered the MDI and PSS at time of referral. RESULTS: In total, 298 women completed the MDI and the PSS, of which 162 had primary RPL and 136 secondary RPL. The most common feelings were low in energy (42%), loss of interest (35%), sadness (35%), and guilt (29%). Twenty-six (8.6%) women fulfilled the criteria for moderate to severe depression. Of the remaining 272 women, nine felt that life was not worth living. Among all women feeling angered of things outside their control (35%) and unable to control important things (27%) were predominant. Women with primary RPL compared to secondary RPL more often felt less self-confident and that life wasn't worth living (p = 0.007 and p = 0.002). CONCLUSIONS: Feelings of guilt and loss of control were predominant in women with RPL. Women with primary RPL could represent a particularly sensitive group. Addressing these specific feelings could help treating the psychological aspects of RPL.

Meditation and mindfulness reduce perceived stress in women with recurrent pregnancy loss: a randomized controlled trial.

RESEARCH QUESTION: Can participating in a tailored 7-week meditation and mindfulness programme with additional standard supportive care versus standard supportive care only reduce perceived stress for women with recurrent pregnancy loss (RPL)? DESIGN: A two-armed randomized controlled trial (RCT) with 12-month follow-up. In total 76 patients were enrolled and randomly assigned to either standard supportive care or to a 7-week meditation and mindfulness programme led by an instructor in addition to standard supportive care. RESULTS: At intervention completion (after 7 weeks), perceived stress decreased significantly both in the intervention group (P = 0.001) and in the control group (P = 0.006). The decrease in perceived stress in the intervention group was significantly larger (P = 0.027) compared with the control group. At the 12-month follow-up perceived stress was still significantly decreased in both groups compared with baseline (P < 0.0001 in the intervention group and P = 0.002 in the control group). CONCLUSION: This first RCT of a tailored meditation and mindfulness intervention for women with RPL documents that a 7-week daily at-home meditation and mindfulness programme combined with group sessions reduced perceived stress significantly more than a standard supportive care programme. Future studies should address the most effective format and the 'dose' needed for an impact on perceived stress levels.

Stress and depression among women and men who have experienced recurrent pregnancy loss: focusing on both sexes.

RESEARCH QUESTION: Are women and men suffering from recurrent pregnancy loss (RPL) more affected by psychological stress and depression than the general population? DESIGN: Cross-sectional study investigating the prevalence of stress and depression in women and men with RPL seen in the Danish national RPL Unit. Data were collected between 2015-2018. All newly referred couples were asked to complete the Major Depression Index (MDI) and Cohen's Perceived Stress Scale (PSS). The scores of both sexes were compared with scores from relevant cohorts of men and women from the general population. RESULTS: In total, 412 women with RPL (82% response rate) and 281 male partners (60% response rate) were included. Depression: 5/281 (1.8%) of men with RPL had moderate/severe depression vs. 5/253 (2.0%) of men in the comparison group (relative risk (RR) 0.90; 95% CI 0.26-3.07, p=0.99). Among women with RPL, 34/412 (8.3%) had a moderate/severe depression vs. 2.2% in the comparison group (RR 3.74; 95% CI 2.40-5.83, p<0.001). High stress levels were found in 30/281 men with RPL (10.7%) vs. 15.8% in the comparison group (co-habiting men) (RR 0.67; 95% CI 0.48-0.94, p=0.017). High stress level was found among 110/384 (28.6%) of RPL-women vs. 420/1813 (23.2%) of comparison women (RR 1.24; 95% CI 1.03-1.48, p=0.026). Both MDI and PSS scores, respectively, for a woman and a man in an RPL couple were significantly correlated. CONCLUSION: Male partners in RPL couples did not have increased prevalence of stress and depression compared with other men but we confirmed our previous finding of significantly increased frequencies among women with RPL.

Serum ferritin level is inversely related to number of previous pregnancy losses in women with recurrent pregnancy loss.

OBJECTIVE: To study whether low serum ferritin (s-ferritin) levels are associated with recurrent pregnancy loss (RPL), and whether low s-ferritin predicts the risk of another pregnancy loss or the ability to conceive. DESIGN: Cohort study. SETTING: Fertility clinic at a university hospital. PATIENT(S): Eighty-four women referred to the RPL Unit and 153 women of reproductive age with no known fertility problem. s-Ferritin levels were measured in serum samples taken before pregnancy attempt. INTERVENTION: None. MAIN OUTCOME MEASURE(S): s-Ferritin levels were correlated to pregnancy history, ability to conceive, and time to conception during the first 2 years after sampling. Furthermore, s-ferritin levels were correlated to outcome of the first pregnancy after referral for RPL. RESULT(S): Women with RPL had lower s-ferritin than the comparison group, 39.9 µg/L versus 62.2 µg/L, and had a higher prevalence of low iron stores (s-ferritin <30 µg/L), 35.7% versus 13.7%. We found an inverse relationship between s-ferritin level and number of pregnancy losses before referral. We did not find s-ferritin level to be associated with ability to conceive or time to pregnancy in either group. Nor did s-ferritin level predict the risk of losing the first pregnancy after referral for RPL. CONCLUSION(S): The inverse relationship between s-ferritin levels and previous pregnancy losses suggests that low s-ferritin is associated with a more severe reproductive disturbance in women with RPL. Whether low s-ferritin is causally related to RPL and if such women could benefit from iron supplementation to achieve a live birth warrants further investigation.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Antibodies at Delivery in Women, Partners, and Newborns.

OBJECTIVE: To investigate the frequency of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies in parturient women, their partners, and their newborns and the association of such antibodies with obstetric and neonatal outcomes. METHODS: From April 4 to July 3, 2020, in a single university hospital in Denmark, all parturient women and their partners were invited to participate in the study, along with their newborns. Participating women and partners had a pharyngeal swab and a blood sample taken at admission; immediately after delivery, a blood sample was drawn from the umbilical cord. The swabs were analyzed for SARS-CoV-2 RNA by polymerase chain reaction, and the blood samples were analyzed for SARS-CoV-2 antibodies. Full medical history and obstetric and neonatal information were available. RESULTS: A total of 1,313 parturient women (72.5.% of all women admitted for delivery at the hospital in the study period), 1,188 partners, and 1,206 newborns participated in the study. The adjusted serologic prevalence was 2.6% in women and 3.5% in partners. Seventeen newborns had SARS-CoV-2 immunoglobulin G (IgG) antibodies, and none had immunoglobulin M antibodies. No associations between SARS-CoV-2 antibodies and obstetric or neonatal complications were found (eg, preterm birth, preeclampsia, cesarean delivery, Apgar score, low birth weight, umbilical arterial pH, need for continuous positive airway pressure, or neonatal admission), but statistical power to detect such differences was low. Full serologic data from 1,051 families showed an absolute risk of maternal infection of 39% if the partner had antibodies. CONCLUSION: We found no association between SARS-CoV-2 infection and obstetric or neonatal complications. Sixty-seven percent of newborns delivered by mothers with antibodies had SARS-CoV-2 IgG antibodies. A limitation of our study is that we lacked statistical power to detect small but potentially meaningful differences between those with and without evidence of infection.

Pregnancy loss is associated with type 2 diabetes: a nationwide case-control study.

AIMS/HYPOTHESIS: Type 2 diabetes is killing more people than ever, and early-life predictors remain critical for the development of effective preventive strategies. Pregnancy loss is a common event associated with later atherosclerotic disease and ischaemic heart failure and might constitute a predictor for type 2 diabetes. The objective of this study was to investigate whether pregnancy loss is associated with later development of type 2 diabetes. METHODS: Using a Danish nationwide cohort, we identified all women born from 1957 through to 1997 and who had a diagnosis of type 2 diabetes during the period 1977 to 2017. The women were matched 1:10 on year of birth and educational level to women without diabetes in the general Danish population. Conditional logistic regression models provided odds ratios for type 2 diabetes with different numbers of pregnancy losses. RESULTS: We identified 24,774 women with type 2 diabetes and selected 247,740 controls without diabetes. Women who had ever been pregnant (ever-pregnant women) with 1, 2 and ≥ 3 pregnancy losses had ORs of type 2 diabetes of 1.18 (95% CI 1.13, 1.23), 1.38 (95% CI 1.27, 1.49) and 1.71 (95% CI 1.53, 1.92) compared with ever-pregnant women with no pregnancy losses, respectively. Women who never achieved a pregnancy had an OR of type 2 diabetes of 1.56 (95% CI 1.51, 1.61) compared with ever-pregnant women with any number of losses. Similar results were found after adjustment for obesity and gestational diabetes. CONCLUSIONS/INTERPRETATION: We found a significant and consistent association between pregnancy loss and later type 2 diabetes that increased with increasing number of losses. Thus, pregnancy loss and recurrent pregnancy loss are significant risk factors for later type 2 diabetes. Future studies should explore whether this association is due to common background factors or whether prediabetic metabolic conditions are responsible for this association. Graphical abstract.

Thyroid Peroxidase Antibodies and Prospective Live Birth Rate: A Cohort Study of Women with Recurrent Pregnancy Loss.

Background: Thyroid autoimmunity has been associated with pregnancy loss. Suggested mechanisms include thyroid function aberrations or an underlying breach of immunotolerance. We hypothesized that thyroid autoimmunity is a marker of the latter in women with recurrent pregnancy loss. This study investigated thyroid peroxidase antibody (TPOAb) status as a predictor of live birth in women with unexplained recurrent pregnancy loss. Methods: Cohort study of 825 consecutive women with recurrent pregnancy loss followed at the tertiary referral center for Recurrent Pregnancy Loss, Copenhagen University Hospital (Rigshospitalet), from 2011 to 2017. Recurrent pregnancy loss was defined as ≥3 consecutive losses, and as unexplained by absence of antiphospholipid syndrome, parental chromosome abnormality, or uterus malformation. Upon first visit, all women were screened for thyrotropin (TSH) and TPOAbs (TPOAb positivity: ≥60 kIU/L). Adjusted logistic regression analyses included as covariates the following: maternal age, TSH, previous number of losses, body mass index, smoking, pregnancy achieved by assisted reproductive technology, and thyroxine replacement (T4) treatment. Results: We included 825 women with a total of 3246 previous losses, of whom 139 (16.8%) were TPOAb positive. TPOAb positivity was not associated with the previous number of losses (p = 0.41). Women with unexplained recurrent pregnancy loss had a live birth rate in the first pregnancy after referral of 62.8% (285 of 454). TPOAb positivity was found in 78 of 454 (17.2%) women and was associated with a reduced live birth rate (51.3% vs. 65.2%, p = 0.02, adjusted odds ratio [aOR] 0.2 [0.1-0.6] p = 0.001). Treatment with T4 increased live birth rate significantly (aOR 3.7 [1.4-9.8], p = 0.007), and TPOAb-positive women receiving T4 had a live birth rate similar to that of TPOAb-negative women not receiving T4 (p = 0.70). Only 30% of TPOAb-positive women and 39% of women treated with T4 during pregnancy had known thyroid disease at referral. Conclusion: In a large cohort of women with unexplained recurrent pregnancy loss, TPOAb positivity was predictive of a reduced live birth rate. However, T4 treatment improved odds of live birth. The study supports screening for TPOAbs as a risk factor in women with unexplained recurrent pregnancy loss. The beneficial effect of T4 treatment in this high-risk group needs confirmation by randomized controlled trials. Close collaboration between fertility experts and endocrinologists is paramount.

ESHRE guideline: recurrent pregnancy loss.

STUDY QUESTION: What is the recommended management of women with recurrent pregnancy loss (RPL) based on the best available evidence in the literature? SUMMARY ANSWER: The guideline development group formulated 77 recommendations answering 18 key questions on investigations and treatments for RPL, and on how care should be organized. WHAT IS KNOWN ALREADY: A previous guideline for the investigation and medical treatment of recurrent miscarriage was published in 2006 and is in need of an update. STUDY DESIGN SIZE DURATION: The guideline was developed according to the structured methodology for development of ESHRE guidelines. After formulation of key questions by a group of experts, literature searches and assessments were performed. Papers published up to 31 March 2017 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 formulated and discussed until consensus was reached within the guideline group. A stakeholder review was organized after finalization of the draft. The final version was approved by the guideline group and the ESHRE Executive Committee. MAIN RESULTS AND THE ROLE OF CHANCE: The guideline provides 38 recommendations on risk factors, prevention and investigations in couples with RPL, and 39 recommendations on treatments. These include 60 evidence-based recommendations - of which 31 were formulated as strong recommendations and 29 as conditional - and 17 good practice points. The evidence supporting investigations and treatment of couples with RPL is limited and of moderate quality. Of the evidence-based recommendations, only 10 (16.3%) were supported by moderate quality evidence. The remaining recommendations were supported by low (35 recommendations: 57.4%), or very low quality evidence (16 recommendations: 26.2%). There were no recommendations based on high quality evidence. Owing to the lack of evidence-based investigations and treatments in RPL care, the guideline also clearly mentions investigations and treatments that should not be used for couples with RPL. LIMITATIONS REASONS FOR CAUTION: Several investigations and treatments are offered to couples with RPL, but most of them are not well studied. For most of these investigations and treatments, a recommendation against 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 evidence available. In addition, a list of research recommendations is provided to stimulate further studies in RPL. One of the most important consequences of the limited evidence is the absence of evidence for a definition of RPL. 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. J.E. reports position funding from CARE Fertility. S.L. reports position funding from SpermComet Ltd. S.M. reports research grants, consulting and speaker's fees from GSK, BMS/Pfizer, Sanquin, Aspen, Bayer and Daiichi Sankyo. S.Q. reports speaker's fees from Ferring. The other authors report no conflicts of interest.ESHRE Pages are not externally peer reviewed. This article has been approved by the Executive Committee of ESHRE.

[Recurrent pregnancy loss].

Recurrent pregnancy loss (RPL) is defined as three or more consecutive pregnancy losses, and it affects 2-3% of couples trying to conceive. RPL is a multifactorial disorder, and only few evidence-based treatments are available. It is associated with an increased prevalence of stress and major depression, and also with immunogenetic markers, autoimmunity and an increase of the risk of cardiovascular disease in later life. Immunology seems to be a key element in RPL, and further research is needed to understand the pathogenesis of this heterogeneous condition in order to develop personalized treatment.

Maternal HY-restricting HLA class II alleles are associated with poor long-term outcome in recurrent pregnancy loss after a boy.

PROBLEM: Women with secondary recurrent pregnancy loss (RPL) after a boy have a reduced chance of live birth in the first pregnancy after referral if they carry HY-restricting HLA class II alleles, but long-term chance of live birth is unknown. METHODS OF STUDY: Live birth was compared for 540 women with unexplained secondary RPL according to firstborn's sex and maternal carriage of HLA-DRB3*03:01, HLA-DQB1*05:01/02, HLA-DRB1*15, and HLA-DRB1*07. The groups were compared by Cox proportional hazard ratios. RESULTS: For women with at firstborn boy, maternal carriage of HY-restricting HLA class II alleles decreased chance of live birth: 0 vs 1: hazard ratio 0.75 (95% CI 0.55-1.02); 0 vs 2: HR 0.62 (0.40-0.94). Carriage of HY-restricting HLA class II alleles decreased chance of live birth only if the firstborn was a boy: boy vs girl: HR 0.72 (95% CI 0.55-0.98). CONCLUSION: Maternal carriage of HY-restricting HLA class II alleles decreases long-term chance of live birth in women with RPL after a boy.

Immunomodulatory treatment with intravenous immunoglobulin and prednisone in patients with recurrent miscarriage and implantation failure after in vitro fertilization/intracytoplasmic sperm injection.

OBJECTIVE: To assess outcome in terms of live-birth rate after fresh or frozen IVF/intracytoplasmic sperm injection assisted reproductive technology (ART) cycles where immunomodulation was given to patients with recurrent pregnancy loss after prior ART treatments. DESIGN: Retrospective cohort study. SETTING: Tertiary care university hospital. PATIENT(S): Fifty-two patients with a history of at least three consecutive pregnancy losses after ART who underwent at least one further ART cycle with concurrent immunomodulation in 2003-2012. INTERVENTION(S): Immunomodulation with IV immunoglobulin and prednisone starting from before ET and continuing in the first trimester if pregnancy was established. MAIN OUTCOME MEASURE(S): Live-birth rate per ET and cumulative live-birth rate after up to five ETs. RESULT(S): Nineteen patients (36.5%) achieved a live birth after the first ET with immunomodulation, and a total of 32 patients achieved a live birth in the study period, resulting in a cumulative live-birth rate of 61.5%. There was no significant difference in baseline and immunological parameters between the patients achieving a live birth or not. The live-birth rate after the first immunomodulated ART cycle in our patients is higher than that reported in a previous study. CONCLUSION(S): Immunomodulation with a combination of IV immunoglobulin and prednisone is a promising treatment for recurrent pregnancy loss after ART, but randomized placebo-controlled trials are needed.

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.

A firstborn boy is suggestive of a strong prognostic factor in secondary recurrent miscarriage: a confirmatory study.

OBJECTIVE: To test our previously generated hypothesis that women with secondary recurrent miscarriages with a firstborn boy have a poorer pregnancy prognosis than those with a firstborn girl. DESIGN: A study of a retrospective and a prospective cohort. SETTING: The Danish recurrent miscarriage clinic. PATIENT(S): Two cohorts of 175 and 130 consecutive patients with unexplained secondary recurrent miscarriage referred from 1986 to 1999 (cohort 1) and 2000 to 2005 (cohort 2), respectively. MAIN OUTCOME MEASURE(S): The odds ratio (OR) for a live birth in the first pregnancy after referral in those with a firstborn boy compared with a firstborn girl in each of the two cohorts. The corresponding OR for a live birth adjusted for relevant prognostic variables in the combined group of patients. RESULT(S): The crude ORs for a live birth in those with a firstborn boy compared with a firstborn girl were very similar in cohorts 1 and 2 (OR = 0.35, 0.33). In the adjusted analysis only two of five included variables significantly predicted live birth: a firstborn boy and the number of previous miscarriages. CONCLUSION(S): Male sex of the firstborn child is a strong negative prognostic factor in women with secondary recurrent miscarriage. A possible explanation is an abnormal maternal immune response against male-specific minor histocompatibility (HY) antigens.