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Emma Rasmark Roepke,1 Ole Bjarne Christiansen,2 Stefan R Hansson11Department of Obstetrics and Gynecology, Institute of Clinical Sciences Lund, Skåne University Hospital, Lund University, Lund, Sweden; 2Department of Obstetrics and Gynecology, Aalborg University Hospital, Clinical Institute at Aalborg University, Aalborg, DenmarkBackground: The Swedish National Patient Registry (NPR) is a nationwide registry that is used extensively for epidemiological research. Using the NPR, we recently found a recurrent pregnancy loss (RPL) incidence of 650/100,000 (0.65%) pregnant women in Sweden. It is of great importance that the quality of the coding is good and reliable in order to use NPR data for research. To specifically study RPL in Sweden, a general validation of this diagnosis in the NPR is needed.Objective: To validate the diagnosis of RPL, defined as ≥3 consecutive miscarriages before 22 gestational weeks, recorded in the NPR and assess how registered miscarriages were verified clinically (ultrasound or urine/serum hCG) by reviewing the medical records.Materials and methods: In a cohort of 6,852 women diagnosed with RPL in Sweden, during 2003–2012, a total of 238 complete medical records from 38 hospitals were reviewed. A power calculation estimated that 228 medical records had to be reviewed for a positive predictive value (PPV) of 85% (95% CI) with a power of 90%. The ICD-10 diagnoses used for RPL were N96.9 and O26.2.Results: The diagnosis of RPL was confirmed in 202 out of 238 medical records resulting in a PPV of 85% (95% CI 78–89%) out of which 59% were verified with ultrasound whereas 35% were verified only by urine/serum hCG.Conclusion: The Swedish NPR is a valuable tool for epidemiological research. We found a high PPV of RPL in the NPR, supporting the use of these data for future research.Keywords: abortius habitualis, recurrent pregnancy loss, validation study, registries, epidemiology

Kirstine Sneider,1 Jens Langhoff-Roos,2 Iben Blaabjerg Sundtoft,3 Ole Bjarne Christiansen4,5 1Department of Clinical Research, Vendsyssel Hospital, Hjørring, 2Department of Obstetrics, Rigshospitalet, University of Copenhagen, Copenhagen, 3Department of Obstetrics and Gynecology, Aarhus University Hospital, Aarhus, 4Department of Obstetrics and Gynecology, Aalborg University Hospital, Aalborg, 5The Fertility Clinic, University Hospital, Copenhagen, Denmark Objective: To validate the diagnosis of second trimester miscarriages/deliveries (16+0 weeks to 27+6 weeks of gestation) recorded as miscarriages in the Danish National Patient Registry or spontaneous deliveries in the Danish Medical Birth Registry, and asses the validity of risk factors, pregnancy complications, and cerclage by review of medical records. Materials and methods: In a cohort of 2,358 women with a second trimester miscarriage/delivery in first pregnancy and a subsequent delivery during 1997–2012, we reviewed a representative sample of 682 medical records. We searched for clinically important information and calculated positive predictive values of the registry diagnoses stratified by type of registry, as well as sensitivity, specificity, positive predictive value, and kappa coefficients of risk factors, pregnancy complications, and cerclage. Results: Miscarriage/spontaneous delivery in the second trimester was confirmed in 621/682 patients (91.1%). Pregnancy complications in second trimester miscarriages were underreported, resulting in low sensitivities and poor to moderate agreements between records and registries. There was a good agreement (kappa >0.6) between medical records and the registries regarding risk factors and cerclage. The diagnosis of cervical insufficiency had “moderate” kappa values for both miscarriages and deliveries (0.55 and 0.57). Conclusion: Spontaneous second trimester deliveries and miscarriages recorded in the registers were confirmed by medical records in 91%, but register-based information on pregnancy complications need to be improved. We recommend that all pregnancies ending spontaneously beyond the first trimester are included in the national birth registry and described by appropriate variables. Keywords: second trimester, miscarriage, preterm birth, prematurity, registries, reproducibility of results, cerclage, cervical insufficiency

Sneider K, Langhoff-Roos J, Sundtoft IB, Christiansen OB. Clin Epidemiol. 2015;7:517–527. The authors have advised that a number of errors were made in the data of some of the tables. Page 521, Table 3, there were some errors in the data within the “Multiple pregnancies” and “Major fetal anomaly” rows.The correct Table 3 is as follows: Read the original article

Objective To determine whether infusions with intravenous immunoglobulin (IVIg) during early pregnancy increase live birth rate in women with secondary recurrent miscarriage compared with placebo. Design A single-centre, randomised, double-blind, placebo-controlled trial. Setting A tertiary centre for recurrent miscarriage in Copenhagen, Denmark. Population A group of 82 women with unexplained secondary recurrent miscarriage and at least four miscarriages. Methods Women were randomly assigned to repeated infusions with IVIg or placebo (albumin) from the time of positive pregnancy test to gestational week 15 or pregnancy loss. Main outcome measure Primary outcome was birth with neonatal survival in all randomised women. Results In the intention-to-treat analyses, live birth rates were 23/42 (54.8%) in the IVIg and 20/40 (50.0%) in the placebo group, relative risk 1.11 (95% CI 0.70-1.74). In a per protocol analysis, almost identical results were found. The median gestational length at delivery was higher in the IVIg than the placebo group (282 versus 272 days, P = 0.02) but the mean birthweight was not significantly increased. Conclusions In this trial, which is the largest so far, IVIg did not increase the live birth rate in patients with secondary recurrent miscarriage and the treatment cannot be recommended in clinical practice. [ABSTRACT FROM AUTHOR]

Few, mostly small, studies have investigated the distribution of HLA class II antigens among women with unexplained recurrent miscarriage. Although some studies have reported statistically significant associations between this syndrome and certain HLA-DR antigens--especially the -DR1 and -DR3 antigens--other studies have been unable to demonstrate such associations. For the present meta-analysis, 18 cross-sectional or case-control studies (published or unpublished) reporting on frequencies of HLA-DR1 and -DR3 antigens among Caucasian women with unexplained repeated miscarriage were identified by searching literature databases (MEDLINE and EMBASE), reading the references of identified studies, and by contacting researchers within the field. The studies comprised a total of 1508 patients. The methodological quality of most of the studies was low, especially because of small numbers of patients and because patients with only two miscarriages were included in many studies; this is defined as repeated miscarriage. The odds ratios of repeated miscarriage for the HLA-DR1 and -DR3 antigens were calculated for the individual studies and subsequently the pooled odds ratios for the studies were calculated. The combined odds ratio for HLA-DR1 was 1.29 [95% confidence interval (CI) = 1.05-1.58] (17 studies) which is statistically significant (P <0.05). The combined odds ratio for HLA-DR3 was 1.00 (95% CI 0.80-1.24) (18 studies), which is not significant. The results of the meta-analysis suggest that the HLA-DR antigen DR1 is associated with an increased susceptibility to unexplained repeated miscarriage. [ABSTRACT FROM AUTHOR]

The scientific basis for many traditionally accepted causes of recurrent miscarriage (RM) is weak. A significant proportion of RM cases with relatively few miscarriages can presumably be attributed to the random occurrence of consecutive chromosomally abnormal conceptions. New insights in the immunological interactions taking place at the feto-maternal interface provide us with the opportunity to propose detailed pathophysiological models for immunologically mediated RM. Scientific support for the theory that RM is a consequence of graft rejection-like allo-immune reactions against paternal human leukocyte antigens on the fetus is sparse. Conversely, there is considerable evidence that decidual natural killer cells play a role in the implantation and early invasion of the trophoblast and in the pathogenesis of RM. T helper (Th) cells from women with RM react against trophoblast antigens in vitro with the secretion of mainly interleukin-2 and interferon-γ (a so-called Th1 response), which are known to inhibit trophoblast growth. The predisposition to a Th1 response against a given antigen may be determined by an individual's class II histocompatibility genes. In accordance with this, case-control, prospective and family studies indicate that maternal histocompatibility haplotypes comprising DR1 and DR3 alleles confer susceptibility to RM. The frequent occurrence of autoantibodies in women with RM is compatible with the theory of a Th1 response against trophoblast as a cause of the syndrome, but the autoantibodies themselves probably do not cause RM. [ABSTRACT FROM PUBLISHER]

Autoantibody production is commonly associated with particular HLA class II phenotypes. The aim of the present study was to investigate whether the presence of antiphospholipid (APL) antibodies and other auto antibodies in women with unexplained recurrent miscarriage was associated with particular human leukocyte antigen (HLA)-DR or -DQ alleles or linked epitopes which have previously been reported as being associated with the recurrent miscarriage syndrome or the presence of APL. In a total of 123 Danish and Czech women with recurrent miscarriage, serum was investigated for six different APL antibodies including anticardiolipin (ACL) antibody. Antinuclear antibodies (ANA), anti-zona pellucida antibodies and anti-sperm antibodies were also investigated. The women were HLA-DR and -DQ typed by DNA-based methods. The frequency of HLA-DR phenotypes did not differ significantly between APL antibody positive recurrent miscarriage patients and APL antibody negative recurrent miscarriage patients or healthy controls. Among ACL antibody positive recurrent miscarriage patients, significantly more were positive for the HLA-DR3 phenotype and negative for the HLA-DR2 phenotypes compared with healthy controls (P < 0.05). Among ANA positive recurrent miscarriage women, 55% carried the HLA-DR3 phenotype compared with 28% of ANA negative patients (P < 0.05) and 21% of healthy controls (P < 0.002). In conclusion, among recurrent miscarriage women, the HLA-DR3 phenotypes seem to predispose to formation of ACL antibodies and ANA. The association between APL antibodies and particular HLA alleles and HLA-linked epitopes reported in studies of patients with lupus erythematosus (e.g. HLA-DR7 and -DR4) could not be confirmed in patients with recurrent miscarriage. [ABSTRACT FROM PUBLISHER]

The release of certain cytokines, e.g. tumour necrosis factor (TNF)-α, in the amniotic fluid has been suggested to be a cause of preterm birth. The predisposition to excessive liberation of cytokines from peripheral leukocytes has been shown to depend partly on the individual's HLA-DR genotype. The HLA-DR1 and DR3 alleles have previously been reported as being associated with a TNF-α high responder status and have also been associated with unexplained recurrent spontaneous abortions. In the present study, HLA-DR typing was performed in 10 women who had experienced recurrent very early preterm births resulting in perinatal death, or late spontaneous abortions under a clinical picture resembling that traditionally attributed to cervical incompetence. All patients had had at least one mid-trimester miscarriage in spite of the insertion of a cervical cerclage. Nine out of 10 (90%) patients had the HLA-DR phenotypes DR1 and/or DR3 compared with 37% in the background population (P < 0.005). The results suggest that HLA-DR-associated immunological factors might play a part in recurrent late spontaneous abortions and extremely preterm births under a cervical incompetence-like picture, at least in the subset of cases not treatable by cervical cerclage. [ABSTRACT FROM PUBLISHER]

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 (HbA 1c ) 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 AUC HC/AC  = 0.67, AUC AC  = 0.85, and AUC EFW  = 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 AUC HC/AC  = 0.73, AUC AC  = 0.83, and AUC EFW  = 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 HbA 1c in the analysis., (© 2024 The Author(s). International Journal of Gynecology & Obstetrics published by John Wiley & Sons Ltd on behalf of International Federation of Gynecology and Obstetrics.)

Recurrent pregnancy loss (RPL), defined as two or more pregnancy losses before the 24th week of gestation, affects 1%-3% of women worldwide. Approximately, 40% of RPL cases are secondary RPL (sRPL), where women have given birth before facing pregnancy losses. The underlying causes of RPL remain unclear, but immune-related factors may play a role. Previously, a randomised controlled trial using immunoglobulin (IVIG) in sRPL women with a history of four pregnancy losses performed in our RPL unit did not show significant effects of IVIG treatment overall. Yet, some evidence suggests potential benefits for a subset of sRPL patients. In the cohort used for the randomised controlled trial, we examined the role of maternal HLA class II-presented fetal HLA-derived epitopes in sRPL using the predicted indirectly recognisable HLA epitopes (PIRCHE-II) algorithm. In the placebo group, sRPL mothers with an anti-HLA antibody response had higher PIRCHE-II scores when having a live birth compared with sRPL women who experienced another pregnancy loss. This difference was not observed in the IVIG-treated group. Furthermore, as a proxy for T-cell memory, the number of overlapping peptides between the two paternal haplotypes in couples having live births without treatment displayed a larger number of overlapping peptides. This effect was primarily driven by class II-derived peptides. These results suggest that specific combinations of sRPL mothers and fathers, particularly those with an anti-HLA antibody response, may generate higher PIRCHE-II scores, which could contribute to successful live births. Understanding these immune interactions may provide insights for personalised diagnostic and therapeutic strategies in sRPL., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: Information about outcomes of particular relevance to older prostate cancer survivors is limited. This study aimed to compare health, activities of daily living (ADL), and use of health care services between survivors and matched controls., Methods: A single-centre study on men treated for prostate cancer with curative intent at the age ≥ 70 years 2 to 7 years earlier. Controls matched on age and education were drawn (1:3) from the Trøndelag Health Study (HUNT) in Norway. Self-reported general health, independence in ADL and instrumental activities of daily living (IADL), hospital admissions and emergency room visits were compared by estimating non-adjusted and adjusted (age, education, comorbidity, cohabitant status and pack years of smoking) regression models., Results: The majority of both survivors (N = 233) and controls (N = 699) reported good (58.7% vs. 62.7%) or very good (11.2% vs. 6.8%) health and independence in ADL (95.6% vs. 96.3%) and IADL (82.7% vs. 81.9%). Hospital admission was reported by 17.3% vs. 18.2% and emergency room visit by 23.6% vs. 26.7%. Regression models showed no significant differences between survivors and controls., Conclusions: Older prostate cancer survivors reported similar health, independence in ADL and use of emergency room and hospital admissions as matched controls., Implications for Cancer Survivors: This study shows that survivors after curatively intended treatment of prostate cancer have as good health as matched controls, indicating that many patients tolerate such treatment well despite being of old age and that current practice for selection of patients offered such treatment is appropriate., (© 2024. The Author(s).)

(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.

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., (© 2023 The Authors. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd.)

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., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

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.)., (© The Author(s) 2023. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Immune system aberrations are suggested to be an important factor in the pathophysiology of unexplained secondary recurrent pregnancy loss (sRPL). The objective was to investigate if the sex ratio of the firstborn child in sRPL patients differs from the background population and whether the sex of the firstborn child has a negative impact on the pregnancy prognosis alone and/or in combination with carriage of male-specific minor histocompatibility (H-Y) restricting HLA class II alleles. From January 2016 to October 2022, 582 patients with unexplained RPL were admitted to the RPL Center of Western Denmark and continuously followed-up. HLA-DRB1 and -DQB1 typing was performed as part of the routine diagnostic work-up. In sRPL patients, a history of a firstborn boy was significantly more frequent than in the Danish background population and was associated with significantly lower odds of a successful reproductive outcome in the first pregnancy after admission compared to a firstborn girl (OR=0.41, 95% CI: 0.20-0.83, p = 0.014). The odds of a successful reproductive outcome were enhanced in patients carrying ≥ 1 H-Y-restricting HLA class II alleles with a first-born girl compared to a firstborn boy (OR=3.33, 95% CI: 1.40-7.88, p = 0.005), while no difference in successful reproductive outcome was seen in sRPL patients not carrying these alleles (OR=1.20, 95% CI: 0.33-4.43, p = 0.781). The sex ratio of children born after RPL was similar to the Danish background population. These findings confirm previous findings and suggests that a harmful immune response triggered by H-Y-antigen exposure during a previous pregnancy in preconditioned women may cause sRPL., Competing Interests: Declaration of interest None, (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

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, β2 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., 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 © 2023 Nørgaard-Pedersen, Steffensen, Kesmodel and Christiansen.)

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., Competing Interests: Competing interests: USK received consulting fees from Merck for Update of patient information leaflet and from IBSA Nordic for Clinical instruction and support for attending meeting/congress from Merck., (© 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.)

Study Question: Are low or high plasma mannose-binding lectin (p-MBL) levels associated with recurrent pregnancy loss (RPL) and the reproductive and perinatal outcomes before and after RPL?, Summary Answer: The prevalence of low p-MBL levels was significantly higher in RPL patients, while high levels were significantly less prevalent. No association was found between p-MBL level and reproductive and perinatal outcomes before and after RPL., What Is Known Already: Mannose-binding lectin (MBL) is an important component in the innate immune system. Low p-MBL levels have been associated with RPL, while the correlation with high levels has been poorly studied. Adverse perinatal outcomes are generally more frequent among RPL patients, but reports concerning the association between maternal p-MBL levels and perinatal outcomes, including birth weight (BW) and gestational age (GA), are conflicting., Study Design Size Duration: This study was a combined cross-sectional and cohort study of 267 RPL patients admitted to the RPL Center of Western Denmark between January 2016 and March 2020. RPL patients were followed until birth of a liveborn child or until end of follow-up, March 2021. A sample of 185 healthy female blood donors of reproductive age was used as a MBL reference group., Participants/materials Setting Methods: All RPL patients had ≥3 consecutive pregnancy losses, a regular menstrual cycle and no known significant chromosomal or uterine malformations. At the first consultation, routine blood samples including p-MBL measurement and detailed obstetrical and perinatal information were collected. p-MBL levels in RPL patients were compared to the MBL reference group. A logistic regression analysis adjusted for relevant confounders assessed the association between low p-MBL levels and an unsuccessful reproductive outcome in RPL patients in first pregnancy after admission. Perinatal outcomes before and after RPL were compared between RPL subgroups according to low (≤500 µg/l), intermediate (501-3000 µg/l) and high (>3000 µg/l) p-MBL levels., Main Results and the Role of Chance: Significantly more RPL patients had low p-MBL levels (prevalence proportion ratio (PPR): 1.79, 95% CI: 1.34-2.38) and fewer had high p-MBL levels (PPR: 0.56, 95% CI: 0.40-0.79) compared to the reference group, while the prevalence of intermediate p-MBL level was not different between the groups (PPR: 0.86, 95% CI: 0.69-1.08). In the prospective study, low p-MBL level was not a significant risk factor for a pregnancy loss in the first pregnancy after admission after adjustment for age, BMI and smoking. Neither before nor after the RPL diagnosis were maternal p-MBL levels significantly associated with BW or GA., Limitations Reasons for Caution: Only 161 (60.3%) patients had given birth after RPL during the follow-up period, which limited the possibility to detect clear associations between p-MBL levels and perinatal outcomes after RPL., Wider Implications of the Findings: In agreement with several previous studies, low p-MBL levels are strongly associated with RPL, while this study for the first time documents that high levels may play a protective role, which suggests a causal relationship. We suggest that larger prospective studies evaluate the association between p-MBL levels and RPL prognosis., Study Funding/competing Interests: No external funding was received. We acknowledge the Department of Obstetrics and Gynaecology at Aalborg University Hospital for financial support. U.S.K. has reported personal fees from Merck, consulting fees from IBSA Nordic, and a grant from Gedeon Richter, Merck and IBSA Nordic outside of the submitted work., Trial Registration Number: ID from clinicaltrials.gov is NCT04017754., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Human Reproduction and Embryology.)

Background: The antenatal identification of placental dysfunction in small-for-gestational-age fetuses with normal fetal Doppler flows remains an obstetrical challenge. In a significant fraction of such pregnancies, placental dysfunction is revealed by clinical manifestations such as preeclampsia, preterm delivery, or severe small-for-gestational-age at birth or by abnormal findings in the postnatal placental histologic examination. Therefore, new methods to identify placental function directly in pregnancy at the time of small-for-gestational-age diagnosis is highly needed. T2*-weighted placental magnetic resonance imaging is sensitive to changes in placental morphology and oxygenation and is thereby related to placental function. Previous studies have demonstrated that pregnancies complicated by low birthweight and preeclampsia are characterized by low placental T2* values. However, the specific performance of placental T2* in the prediction of placenta-related outcomes in small-for-gestational-age pregnancies with normal fetal Doppler flows remains to be explored., Objective: In small-for-gestational-age pregnancies with normal fetal Doppler flows, we aimed to evaluate T2*-weighted placental magnetic resonance imaging as an antenatal biomarker of placental dysfunction. In addition, we aimed to investigate the correlation between placental T2* and Doppler flow measurements of fetal and uterine arteries at the time of magnetic resonance imaging., Study Design: In this prospective cohort study, the inclusion criterion was suspected small-for-gestational-age (ultrasound estimated fetal weight Z-score ≤-2.0 [2.3rd centile]) with normal fetal Doppler flows (middle cerebral artery pulsatility index Z-score > -2.0 and umbilical artery pulsatility index Z-score <2.0). The T2*-weighted placental magnetic resonance imaging scan was performed at inclusion in a 1.5 T system. The outcomes was placental dysfunction at birth defined by low birthweight (Z-score ≤-2.0), preeclampsia, preterm delivery (gestational age<37 weeks), or abnormal placental histologic examination such as placental vascular malperfusion according to the Amsterdam Consensus Statement., Results: We included 92 pregnancies at 26+5 to 39+6 weeks gestation. The median time interval between the magnetic resonance imaging scan and birth was 4.6 weeks (interquartile range, 2.7-7.8 weeks). At birth, 55% (51/92) of pregnancies revealed at least 1 sign of placental dysfunction; 49% (40/81) had abnormal placental histologic examination, 29% (27/92) were born with low birthweight, 13% (12/92) were delivered preterm, and 7% (6/92) had preeclampsia. When adjusted for gestational age at magnetic resonance imaging, the placental T2* Z-score was a significant predictor of abnormal placental histologic examination (area under the curve, 0.73; P=.001), small-for-gestational-age at birth (area under the curve, 0.63; P=.030), preeclampsia (area under the curve, 0.88; P=.005), and preterm delivery (area under the curve, 0.81; P=.001). The placental T2* was reduced in pregnancies with a combination of clinical manifestations and abnormal placental histologic examination (T2* Z-score=-1.52±1.35 [mean±standard deviation]; P=.0001) and in clinically uneventful pregnancies with abnormal placental histologic examination (T2* Z-score=-0.79±0.97; P=.045). At the time of magnetic resonance imaging, the placental T2* Z-score showed a significant linear correlation with the uterine artery pulsatility index Z-scores (r=-0.24; P=.016) and the middle cerebral artery pulsatility index Z-scores (r=0.29; P=.017) but not with the umbilical artery pulsatility index Z-scores (r=0.18; P=.17) and the cerebroplacental ratio (r=0.03; P=.77)., Conclusion: This study indicates that placental dysfunction is frequent in small-for-gestational-age fetuses with normal fetal Doppler flows. In this cohort, T2*-weighted placental magnetic resonance imaging is a sensitive biomarker of placental dysfunction regardless of the clinical manifestations. This finding supports a paradigm shift in the conception of placental dysfunction that may cover a wide spectrum of clinical and subclinical manifestations., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Women positive for thyroid peroxidase antibodies (TPO-Ab) have a higher risk of recurrent pregnancy loss. Evidence on whether levothyroxine treatment improves pregnancy outcomes in women who are TPO-Ab positive women with recurrent pregnancy loss is scarce. The aim of this study was to determine if levothyroxine increases live birth rates in women who were TPO-Ab positive with recurrent pregnancy loss and normal thyroid function., Methods: The T4LIFE trial was an international, double-blind, placebo-controlled, phase 3 study done in 13 secondary and tertiary hospitals in the Netherlands, one tertiary hospital in Belgium, and one tertiary hospital in Denmark. Women (18-42 years) who were TPO-Ab positive, had two or more pregnancy losses, and had a thyroid stimulating hormone (TSH) concentration within the institutional reference range were eligible for inclusion. Women were excluded if they had antiphospholipid syndrome (lupus anticoagulant, anticardiolipin IgG or IgM antibodies, or β2-glycoprotein-I IgG or IgM antibodies), other autoimmune diseases, thyroid disease, previous enrolment in this trial, or contraindications for levothyroxine use. Before conception, women were randomly assigned (1:1) to receive either levothyroxine or placebo orally once daily. The daily dose of levothyroxine was based on preconception TSH concentration and ranged from 0·5-1·0 μg/kg bodyweight. Levothyroxine or placebo was continued until the end of pregnancy. The primary outcome was live birth, defined as the birth of a living child beyond 24 weeks of gestation measured in the intention-to-treat population. The trial was registered within the Netherlands Trial Register, NTR3364 and with EudraCT, 2011-001820-39., Results: Between Jan 1, 2013, and Sept 19, 2019, 187 women were included in the study: 94 (50%) were assigned to the levothyroxine group and 93 (50%) were assigned to the placebo group. The trial was prematurely stopped when 187 (78%) of the 240 predefined patients had been included because of slow recruitment. 47 (50%) women in the levothyroxine group and 45 (48%) women in the placebo group had live births (risk ratio 1·03 [95% CI 0·77 to 1·38]; absolute risk difference 1·6% [95% CI -12·7 to 15·9]). Seven (7%) women in the levothyroxine group and seven (8%) in the placebo group reported adverse events, none of them were directly related to the study procedure., Interpretation: Compared with placebo, levothyroxine treatment did not result in higher live birth rates in euthyroid women with recurrent pregnancy loss who were positive for TPO-Ab. On the basis of our findings, we do not advise routine use of levothyroxine in women who are TPO-Ab positive with recurrent pregnancy loss and normal thyroid function., Funding: Dutch Organization for Health Research and Development, Fonds NutsOhra, Dutch Patient Organization of Thyroid Disorders, the Jan Dekkerstichting and Dr Ludgardine Bouwmanstichting, and a personal donation through the Dutch Patient Organization of Thyroid Disorders., Competing Interests: Declaration of interests MG received research and educational grants from Guerbet, Merck, and Ferring, not related to the presented work, paid to their institution. AH reports an unrestricted educational grant from Ferring, not related to the presented work, paid to their institution. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

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.

Objective: Metabolomic profiling of seminal plasma has been suggested as a possible approach for a fast and non-invasive male infertility evaluation diagnosis. However, metabolomics profiles in normozoospermic men have not been thoroughly investigated, and the influence of ejaculation-abstinence has not been described. To provide interim reference values and find associations between the metabolomics profiles of human seminal plasma and length of ejaculation-abstinence period in normozoospermic men., Study Design: Semen samples collected after long (4-7 days) and short abstinence (2 h) from 31 normozoospermic males were assessed for routine quality parameters before the seminal plasma was separated by centrifugation. Metabolomics profiles of the seminal plasma were then determined using untargeted Nuclear Magnetic Resonance Spectroscopy., Results: In total, 30 metabolites were identified. Pyruvate showed a higher concentration, while fructose, acetate, choline, methanol, N-acetylglucosamine, O-acetylcarnitine, uridine, and sn-glycero-3-phosphocoline showed lower concentrations in samples collected after short abstinence (vs. long). All metabolites showed lower absolute amounts (volume × concentration) following shorter abstinence. However, the lower sperm concentration in samples collected after short abstinence resulted in higher absolute amounts of pyruvate and taurine per spermatozoa: pyruvate 1.92 (1.12-3.87) vs. 1.29 (0.83-2.62) (P < 0.001) and taurine 0.58 (0.36-0.92) vs. 0.43 (0.28-0.95) (P < 0.05) ng/10 6 spermatozoa. Simultaneously, there was a higher percentage of progressively motile spermatozoa in samples collected after the short abstinence., Conclusion: The generally lower concentrations of seminal metabolites after short abstinence periods may be related to the shorter time available for secretion and collection of these metabolites by the accessory glands and the epididymides. The concomitant lower number of spermatozoa in the second ejaculate resulted in increased absolute amounts of pyruvate and taurine per spermatozoa, accompanied by increased spermatozoa motility in these samples. The simultaneous increase in percentages of motile spermatozoa and absolute amounts of pyruvate and taurine per spermatozoa after shorter abstinence might indicate that these two metabolites play a more critical role in sperm motility, which should be further investigated in future studies., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Known etiologic factors can only be found in about 50% of patients with recurrent pregnancy loss (RPL). We hypothesized that male microchimerism is a risk factor for RPL and aimed to explore whether information on family tree and reproductive history, obtained from 383 patients with unexplained RPL, was supportive of this hypothesis. The male:female sex ratio of older siblings was 1.49 (97:65) in all RPL patients and 1.79 (52:29) in secondary RPL (sRPL) patients, which differed significantly from the expected 1.04 ratio ( p = 0.027 and p = 0.019, respectively). In contrast, the sex ratio of younger siblings was close to the expected ratio. Sex ratio of the firstborn child before sRPL was 1.51 ( p = 0.026). When combined, 79.1% of sRPL patients had at least one older brother, a firstborn boy, or both. This differed significantly from what we expected based on the distribution of younger siblings and a general 1.04 sex ratio of newborns ( p = 0.040). We speculate whether (s)RPL patients possibly acquired male microchimerism from older brother(s) and/or previous birth of boy(s) by transplacental cell trafficking. This could potentially have a detrimental impact on their immune system, causing a harmful response against the fetus or trophoblast, resulting in RPL.

Recurrent pregnancy loss (RPL) has an estimated incidence of 1-3% of all couples. The etiology is considered to be multifactorial. Extracellular vesicles (EVs) take part in numerous different physiological processes and their contents show the originating cell and pathophysiological states in different diseases. In pregnancy disorders, changes can be seen in the composition, bioactivity and concentration of placental and non-placental EVs. RPL patients have an increased risk of pregnancy complications. The aim of this prospective study was to examine whether measuring different specific EV markers in plasma before and during pregnancy could be used as predictors of pregnancy loss (PL) in women with RPL. Thirty-one RPL patients were included in this study; 25 had a live birth (LB group) and six had a new PL (PL group). Five blood samples were obtained, one before achieved pregnancy and the others in gestational week 6, 8, 10 and 16. Moreover, some of the patients received intravenous immunoglobulin (IVIG) infusions as part of treatment, and it was also examined whether this treatment influenced the EV levels. Seventeen EV markers specific for the immune system, coagulation, placenta and hypoxia were analyzed in the samples with EV Array, a method able to capture small EVs by using an antibody panel targeting membrane proteins. Comparing the LB and PL groups, one EV marker, CD9, showed a significant increase from before pregnancy to gestational week 6 in the PL group. The changes in the other 16 markers were nonsignificant. One case of late-onset PL showed steeply increasing levels, with sudden decrease after gestational week 10 in nine of 17 markers. Moreover, there was an overall increase of all 17 markers after IVIG treatment in the LB group, which was significant in 15 of the markers. Whether increases in EVs positive for CD9 characterize RPL patients who subsequently miscarry should be investigated in future larger studies.

Many cases of recurrent pregnancy loss (RPL) defined as ≥3 consecutive pregnancy losses are suggested to be caused by an aberrant maternal immune response against the fetus or trophoblast. Human leukocyte antigen (HLA)-DRB1 and -DQB1 polymorphisms are associated with most autoimmune disorders and studies of HLA-DBB1 polymorphism in RPL patients are thus relevant. In previous studies, the HLA-DRB1*03 allele was found with increased prevalence in RPL patients. We wanted to clarify whether HLA-DRB1 alleles indeed were associated with RPL among women of Caucasian descent. A total of 1078 women with unexplained RPL and 2066 bone marrow donors were HLA-DRB1-typed and subsets were also HLA-DQB1 typed. All patients were initially HLA-DRB1-typed by DNA-based low-resolution techniques and subsets of patients and all controls were typed by high-resolution techniques. Among patients, the HLA-DRB1*07 allele frequency was significantly increased compared with controls; OR 1.29 (95 % CI 1.09-1.52), p < 0.0025; after correction for multiple comparisons pc = 0.031. The HLA-DRB1*07/*07 genotype was highly increased in patients with RPL compared with controls: OR 2.27 (1.31-3.93), p = 0.0027. The frequency of the HLA-DRB1*07 phenotype in RPL patients had increased significantly (p = 0.002) in three studies from our group published 1994-2021. The allele frequency of HLA-DRB1*03 was not increased in RPL patients compared with controls; OR 0.96 (0.83-1.12). In conclusion, the previous association between HLA-DRB1*03 and RPL could not be confirmed in our study whereas an association to HLA-DRB1*07 was detected for the first time. Since the latter association is a new finding, it should be confirmed in future studies., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

The physical and psychological effect of miscarriage is commonly underappreciated. The journey from diagnosis of miscarriage, through clinical management, to supportive aftercare can be challenging for women, their partners, and caregivers. Diagnostic challenges can lead to delayed or ineffective care and increased anxiety. Inaccurate diagnosis of a miscarriage can result in the unintended termination of a wanted pregnancy. Uncertainty about the therapeutic effects of interventions can lead to suboptimal care, with variations across facilities and countries. For this Series paper, we have developed recommendations for practice from a literature review, appraisal of guidelines, and expert group discussions. The recommendations are grouped into three categories: (1) diagnosis of miscarriage, (2) prevention of miscarriage in women with early pregnancy bleeding, and (3) management of miscarriage. We recommend that every country reports annual aggregate miscarriage data, similarly to the reporting of stillbirth. Early pregnancy services need to focus on providing an effective ultrasound service, as it is central to the diagnosis of miscarriage, and be able to provide expectant management of miscarriage, medical management with mifepristone and misoprostol, and surgical management with manual vacuum aspiration. Women with the dual risk factors of early pregnancy bleeding and a history of previous miscarriage can be recommended vaginal micronised progesterone to improve the prospects of livebirth. We urge health-care funders and providers to invest in early pregnancy care, with specific focus on training for clinical nurse specialists and doctors to provide comprehensive miscarriage care within the setting of dedicated early pregnancy units., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

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.)

Women who have had repeated miscarriages often have uncertainties about the cause, the likelihood of recurrence, the investigations they need, and the treatments that might help. Health-care policy makers and providers have uncertainties about the optimal ways to organise and provide care. For this Series paper, we have developed recommendations for practice from literature reviews, appraisal of guidelines, and a UK-wide consensus conference that was held in December, 2019. Caregivers should individualise care according to the clinical needs and preferences of women and their partners. We define a minimum set of investigations and treatments to be offered to couples who have had recurrent miscarriages, and urge health-care policy makers and providers to make them universally available. The essential investigations include measurements of lupus anticoagulant, anticardiolipin antibodies, thyroid function, and a transvaginal pelvic ultrasound scan. The key treatments to consider are first trimester progesterone administration, levothyroxine in women with subclinical hypothyroidism, and the combination of aspirin and heparin in women with antiphospholipid antibodies. Appropriate screening and care for mental health issues and future obstetric risks, particularly preterm birth, fetal growth restriction, and stillbirth, will need to be incorporated into the care pathway for couples with a history of recurrent miscarriage. We suggest health-care services structure care using a graded model in which women are offered online health-care advice and support, care in a nurse or midwifery-led clinic, and care in a medical consultant-led clinic, according to clinical needs., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background and Aim: Venous thromboembolism (VTE) is associated with excess mortality and morbidity in cancer, and is influenced by patient-, tumor-, and treatment-related factors. We aimed to investigate the impact of such factors in a national cohort of patients with epithelial ovarian cancer (EOC)., Methods: Patients in the Danish Gynecologic Cancer Database (DGCD) with EOC from 2005 to 2014 were followed from time of diagnosis to VTE, or censoring. Surgery, chemotherapy, and vascular epithelial growth factor (VEGF)-inhibitors were included as time-varying exposures in Cox proportional hazard regression models., Results: A total of 551 VTE events were registered in 4991 EOC patients. Median follow-up time was 2.9 years. The 2-year cumulative incidence of VTE was 7.2%. Patients were at highest risk during the first year after EOC diagnosis. Previous VTE was associated with a hazard ratio (HR) of 3.26 (95% confidence interval [CI] 2.42-4.39). Exposure to major pelvic surgery was associated with a HR of 3.21 (95% CI 2.29-4.50). Exposure to chemotherapy or (VEGF)-inhibitors were associated with HRs of 1.91 (95% CI 1.56-2.33) and 1.05 (95% CI 0.57-1.93), respectively. Hazard ratios for patients with clear cell histopathology was 1.46 (95% CI 0.97-2.20) and 2.42 for International Federation of Gynaecology and Obstetrics stage III--IV (95% CI 1.93-3.03)., Conclusions: EOC is associated with a high risk of VTE, particularly within the first year after diagnosis. Major pelvic surgery and chemotherapy were strongly associated with VTE. Person-related risk factors were increasing age and previous VTE. Advanced stage was an independent tumor-related risk factor. These findings support the indication for thrombosis prophylaxis during chemotherapy., (© 2021 International Society on Thrombosis and Haemostasis.)

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., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

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.

Purpose: To reveal the phenotypic differences between human ocular surface stromal cells (hOSSCs) cultured from the corneal, limbal, and scleral compartments., Methods: A comparative analysis of cultured hOSSCs derived from four unrelated donors was conducted by multichromatic flow cytometry for six distinct CD antigens, including the CD73, CD90, CD105, CD166, CD146, and CD34., Results: The hOSSCs, as well as the reference cells, displayed phenotypical profiles that were similar in high expression of the hallmark mesenchymal stem cell markers CD73, CD90, and CD105, and also the cancer stem cell marker CD166. Notably, there was considerable variation regarding the expression of CD34, where the highest levels were found in the corneal and scleral compartments. The multi-differentiation potential marker CD146 was also expressed highly variably, ranging from 9% to 89%, but the limbal stromal and endometrial mesenchymal stem cells significantly surpassed their counterparts within the ocular and reference groups, respectively. The use of six markers enabled investigation of 64 possible variants, however, just four variants accounted for almost 90% of all hOSSCs, with the co-expression of CD73, CD90, CD105, and CD166 and a combination of CD146 and CD34. The limbal compartment appeared unique in that it displayed greatest immunophenotype diversity and harbored the highest proportion of the CD146+CD34- pericyte-like forms, but, interestingly, the pericyte-like cells were also found in the avascular cornea., Conclusion: Our findings confirm that the hOSSCs exhibit an immunophenotype consistent with that of MSCs, further highlight the phenotypical heterogeneity in stroma from distinct ocular surface compartments, and finally underscore the uniqueness of the limbal region., Competing Interests: There are no conflicts of interest., (Copyright © 2020 Liu et al.)

Background: Offspring of mothers with gestational diabetes mellitus (GDM) have increased risk of developing metabolic disorders as they grow up. Microbial colonization of the newborn gut and environmental exposures affecting the configuration of the gut microbiota during infancy have been linked to increased risk of developing disease during childhood and adulthood. In a convenience sample, we examined whether the intestinal tract of children born to mothers with GDM is differentially colonized in early life compared to offspring of mothers with normal gestational glucose regulation. Secondly, we examined whether any such difference persists during infancy, thus potentially conferring increased risk of developing metabolic disease later in life. Methods: Fecal samples were collected from children of mothers with ( n = 43) and without GDM ( n = 82) during the first week of life and again at an average age of 9 months. The gut microbiota was characterized by 16S rRNA gene amplicon sequencing (V1-V2). Differences in diversity and composition according to maternal GDM status were assessed, addressing potential confounding by mode of delivery, perinatal antibiotics treatment, feeding and infant sex. Results: Children of mothers with GDM were featured by a differential composition of the gut microbiota, both during the first week of life and at 9 months, at higher taxonomic and OTU levels. Sixteen and 15 OTUs were differentially abundant after correction for multiple testing during the first week of life and at 9 months, respectively. Two OTUs remained differentially abundant after adjustment for potential confounders both during the first week of life and at 9 months. Richness (OTU) was decreased in neonates born to mothers with GDM; however, at 9 months no difference in richness was observed. There was no difference in Shannon's diversity or Pielou's evenness at any timepoint. Longitudinally, we detected differential changes in the gut microbiota composition from birth to infancy according to GDM status. Conclusion: Differences in glycaemic regulation in late pregnancy is linked with relatively modest variation in the gut microbiota composition of the offspring during the first week of life and 9 months after birth., (Copyright © 2020 Crusell, Hansen, Nielsen, Allin, Rühlemann, Damm, Vestergaard, Rørbye, Jørgensen, Christiansen, Heinsen, Franke, Hansen, Lauenborg and Pedersen.)

Progesterone is essential for the maintenance of pregnancy. Several small trials have suggested that progesterone supplementation may reduce the risk of miscarriage in women with recurrent or threatened miscarriage. Cochrane Reviews summarized the evidence and found that the trials were small with substantial methodologic weaknesses. Since then, the effects of first-trimester use of vaginal micronized progesterone have been evaluated in 2 large, high-quality, multicenter placebo-controlled trials, one targeting women with unexplained recurrent miscarriages (the PROMISE [PROgesterone in recurrent MIScarriagE] trial) and the other targeting women with early pregnancy bleeding (the PRISM [PRogesterone In Spontaneous Miscarriage] trial). The PROMISE trial studied 836 women from 45 hospitals in the United Kingdom and the Netherlands and found a 3% greater live birth rate with progesterone but with substantial statistical uncertainty. The PRISM trial studied 4153 women from 48 hospitals in the United Kingdom and found a 3% greater live birth rate with progesterone, but with a P value of .08. A key finding, first observed in the PROMISE trial, and then replicated in the PRISM trial, was that treatment with vaginal micronized progesterone 400 mg twice daily was associated with increasing live birth rates according to the number of previous miscarriages. Prespecified PRISM trial subgroup analysis in women with the dual risk factors of previous miscarriage(s) and current pregnancy bleeding fulfilled all 11 conditions for credible subgroup analysis. For the subgroup of women with a history of 1 or more miscarriage(s) and current pregnancy bleeding, the live birth rate was 75% (689/914) with progesterone vs 70% (619/886) with placebo (rate difference 5%; risk ratio, 1.09, 95% confidence interval, 1.03-1.15; P=.003). The benefit was greater for the subgroup of women with 3 or more previous miscarriages and current pregnancy bleeding; live birth rate was 72% (98/137) with progesterone vs 57% (85/148) with placebo (rate difference 15%; risk ratio, 1.28, 95% confidence interval, 1.08-1.51; P=.004). No short-term safety concerns were identified from the PROMISE and PRISM trials. Therefore, women with a history of miscarriage who present with bleeding in early pregnancy may benefit from the use of vaginal micronized progesterone 400 mg twice daily. Women and their care providers should use the findings for shared decision-making., (Copyright © 2019 The Author(s). Published by Elsevier Inc. All rights reserved.)

Extracellular vesicles (EVs), which are small cell-derived compartments, take part in numerous different physiological processes. The contents of EVs reveal the cell of origin and indicates pathophysiological states in different diseases. In pregnancy disorders, changes have been reported in the composition, bioactivity and concentration of placental and non-placental EVs. The purpose of this study was to monitor the effects on EVs in patients receiving intravenous immunoglobulin (IVIG) or placebo (albumin) treatment due to recurrent pregnancy loss (RPL). In a placebo-controlled trial study of IVIG treatment, plasma collected from 39 women with RPL were investigated using the Extracellular Vesicle Array (EV Array). Plasma was sampled consecutively (from gestational week (GW) 5) and the protein phenotypes of the smaller EVs (sEVs) were analyzed for the presence of 34 markers. The levels of sEVs or changes in their levels in early pregnancy were correlated with treatment. There was statistically significant increased levels of sEVs in patients who received IVIG versus placebo. In conclusion, the treatment with high-doses of IVIG clearly boosted the production and release of sEVs to the circulation; however, the biological role of this boost remains to be clarified in further studies., Competing Interests: Declaration of Competing Interest The authors hereby declare no conflict of interest., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Purpose: Recurrent pregnancy loss (RPL) is defined as three or more consecutive pregnancy losses and affects 1-3% of couples trying to conceive. Pregnancy loss is more common among RPL patients' siblings than in the general population. Our objective was to investigate whether first-degree relatives with pregnancy losses influenced the chance of live birth in the first pregnancy after referral among women with RPL. Materials and methods: This is a cohort study of 2138 women with RPL seen at the Danish RPL Unit at Copenhagen University Hospital, Rigshospitalet between January 1st 2000 and December 31st 2017 with follow-up until December 2018. Pregnancies among first-degree relatives were reported by patients at their first consultation. Chance of live birth after referral was compared by logistic regression analysis. Results: Overall, 76% of the referred women achieved a pregnancy after referral and of these, 58% delivered a live born child. Women whose mother had experienced pregnancy loss were referred at a younger age than women with no pregnancy losses among first-degree relatives (mean age 33.6 (SD 4.6) versus 34.3 (SD 4.5), p  = 0.002). Pregnancy losses among first-degree relatives did not influence chance of live birth. Conclusions: Our results indicate that pregnancy losses among first-degree family members is not an important risk factor for outcome of the first pregnancy after referral among women with RPL.

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., (Copyright © 2019 Elsevier Inc. All rights reserved.)

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.

Objective: To determine the incidence of symptomatic and incidental venous thromboembolism (VTE) at time of diagnosis and throughout the first year, in patients with suspected epithelial ovarian cancer (EOC)., Methods: Patients were recruited consecutively in the gynecological outpatient clinic at Aalborg University Hospital, Denmark from December 2014 to May 2017. All patients underwent a whole leg compression ultrasound scan (CUS), Computed Tomography (CT) of the thorax in arterial phase at time of inclusion, to be able to diagnose deep vein thrombosis (DVT) and pulmonary embolism (PE), respectively. Patients were followed and systematically screened for VTE throughout 12 months., Results: Ninety-seven patients with suspected EOC were enrolled in the study and followed up. Within the group of EOC patients (N = 53) eleven were diagnosed with VTE during the first year from EOC diagnosis, the incidence of VTE at time of diagnosis was low (2/53-3.8%). No patients with borderline or benign ovarian neoplasms were diagnosed with VTE. One EOC patient had a VTE during the postoperative period and further eight EOC patients were diagnosed with VTE within the first year, during periods undergoing non-surgical cancer treatment. Median time to VTE was 87 days., Conclusions: The one year cumulative incidence of VTE in EOC patients was 20.8% with a low incidence at time of diagnosis. A substantial number of VTE cases (73%) appeared during periods of non-surgical oncologic treatment. Future research should focus on risk factors and timing of VTE in EOC patients, as this could have important implications for future prophylaxis guidelines., (Copyright © 2019 Elsevier Ltd. All rights reserved.)