OBJECTIVE:To investigate associations between endocrine diseases and pregnancy loss, including associations according to the number of pregnancy losses, temporal patterns, and familial clustering independent of the woman's own endocrine diagnosis. DESIGN:Nationwide population-based cohort study. SUBJECTS:366,539 women born in Denmark between 1977 and 1993 with documented pregnancies in the Danish national registers. EXPOSURE:Presence of endocrine disease diagnosed before or after pregnancy. Subgroup analyses of major endocrine diseases, including hypothyroidism, hyperthyroidism, polycystic ovary syndrome (PCOS), type 1 and 2 diabetes, and gestational diabetes. MAIN OUTCOME MEASURES:Pregnancy loss, defined as the number of pregnancy losses before 22 weeks of gestation (categorized as 0, 1, 2, or ≥3 losses) in association with endocrine disease. Multivariable multinomial logistic regression models calculated odds ratios (ORs) with 95% confidence interval adjusted for maternal age and year of pregnancy. Additional analyses examined associations according to timing of endocrine disease diagnosis relative to the first pregnancy and evaluated familial clustering. RESULTS:Endocrine disease was diagnosed in 56,618 women (15%). In analyses that did not account for temporal order, endocrine disease showed progressively stronger associations with increasing number of pregnancy losses: OR 1.15 (95% CI: 1.12-1.17) for one, OR 1.30 (95% CI: 1.24-1.37) for two, and OR 1.81 (95% CI: 1.70-1.93) for three or more (p<0.001). All major endocrine diseases were significantly associated with pregnancy loss. Women diagnosed with an endocrine disease after their first pregnancy showed a stronger association with pregnancy loss in the first pregnancy (OR 1.24 [95% CI: 1.20-1.29]) than those diagnosed before the first pregnancy (OR 1.11 [95% CI: 1.07-1.15]). Familial endocrine disease in a parent or sister was also positively associated with pregnancy loss (OR 1.07 [95% CI: 1.05-1.09] and OR 1.08 [95% CI: 1.03-1.13], respectively), independent of the woman's own endocrine diagnosis. CONCLUSION:Endocrine diseases and pregnancy loss were strongly associated regardless of temporal order, with progressively stronger associations across increasing numbers of pregnancy losses, with significant familial clustering independent of personal diagnosis, suggesting shared genetic or environmental factors. Our findings support consideration of targeted endocrine evaluation in women with pregnancy loss. Further research should determine optimal screening strategies and timing.

BACKGROUND:Thyroid disease in pregnancy, preconception, and postpartum is a common and clinically relevant problem. Since the publication of the American Thyroid Association (ATA) guidelines in 2017, substantial new clinical and scientific evidence has become available. The aim of these guidelines is to provide clinicians, patients, researchers, and policymakers with evidence-based recommendations on the care of women with thyroid disease before, during, and after pregnancy. METHODS:The clinical questions addressed were informed by prior ATA guidelines, stakeholder feedback, a global needs assessment, and input from the multidisciplinary task force. Systematic literature searches were conducted with the support from a medical librarian and evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation framework. Recommendations were formulated based on the quality of evidence, balance of benefits and harms, patient values, feasibility, and equity. Where data were limited, Good Practice Statements were formulated. The task force included representatives from 10 international societies as well as patient advocacy groups and a methodologist. RESULTS:The updated guidelines include recommendations on thyroid function testing, iodine supplementation, thyroid autoimmunity, hypothyroidism, hypothyroxinemia, hyperthyroidism and Graves' disease, thyroid nodules and cancer, and postpartum thyroid dysfunction for women with infertility, pregnant women, and women during postpartum and/or lactation. Recommendations are presented using recommendation tables, additional practical considerations are highlighted in boxes, and background information is provided in the text, tables, and figures per disease entity and chronological subset. CONCLUSIONS:These 2026 ATA guidelines provide updated, evidence-based recommendations for the diagnosis and management of thyroid disease in women during preconception, pregnancy, and postpartum. While acknowledging that much of the evidence remains of low-to-moderate quality, these guidelines represent current best practices and consensus among international experts from different fields, offering an optimized framework for individualized patient care.

The host genetics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have previously been studied based on cases from the earlier waves of the pandemic in 2020 and 2021, identifying 51 genomic loci associated with infection and/or severity. SARS-CoV-2 has shown rapid sequence evolution, increasing transmissibility, particularly for Omicron variants, which raises the question of whether this affected the host genetic factors. We performed a genome-wide association study of SARS-CoV-2 infection with Omicron variants, including more than 150,000 cases from four cohorts. We identified 13 genome-wide significant loci, of which only five were previously described as associated with SARS-CoV-2 infection. The strongest signal was a single nucleotide polymorphism in an intron of ST6GAL1, a gene affecting immune development and function, connected to three other associated loci (harboring MUC1, MUC5AC and MUC16) through O-glycan biosynthesis. Our study provides robust evidence for individual genetic variation related to glycosylation, translating into susceptibility to SARS-CoV-2 infections with Omicron variants. Genome-wide analyses identify 13 loci associated with susceptibility to infection with SARS-CoV-2 Omicron variants, including variation in ST6GAL1, previously associated with influenza susceptibility, and other genes involved in glycosylation processes.

OBJECTIVE:To study whether a machine learning algorithm can effectively predict fetal genetic status, aneuploid or euploid, in cases of pregnancy loss, based solely on readily available clinical data. Accurate early prediction may enable improved clinical decision-making and personalized patient management. DESIGN:Prospective multicenter cohort study within the Copenhagen Pregnancy Loss study, with a development cohort (n = 788) from Copenhagen University Hospital Hvidovre and external validation cohorts from Copenhagen University Hospitals Herlev (n = 229) and North Zealand (n = 199). Enrollment was from November 2020 to May 2022. SUBJECTS:Women ≥18 years with confirmed intrauterine pregnancy loss before 22 weeks at three Danish Copenhagen University Hospitals. EXPOSURE:Ploidy status was determined using cell-free fetal deoxyribonucleic acid analysis from maternal blood. Forty-five clinical predictors, including anthropometric data, medical history, lifestyle factors, and partner information, were analyzed using a gradient boosted model. Feature importance was interpreted through SHapley Additive exPlanations analysis to elucidate key prognostic indicators. MAIN OUTCOME MEASURES:Model discrimination capability assessed by area under the receiver operating characteristic curve and area under the precision-recall curve, sensitivity, specificity, and calibration across cohorts. RESULTS:The machine learning model demonstrated moderate discriminative ability with a cross-validated area under the receiver operating characteristic curve of 0.69 (95% confidence interval 0.65-0.73) in the development cohort, maintaining equivalent performance in external validations. At a 90% specificity threshold, sensitivity was 54.4% in the development cohort (Hvidovre), 47% at Herlev, and 48% at North Zealand. Key predictors included maternal age, gestational age, paternal age, body mass index, vitamin D supplementation, and vitamin E supplementation. CONCLUSION:This study represents the first machine learning approach to distinguish euploid from aneuploid pregnancy losses using clinical data alone, providing a framework for earlier recognition of women with treatable conditions before multiple losses occur. Novel associations between vitamin supplementation and ploidy status invite further mechanistic investigation. However, moderate discriminative performance and population-specific factors highlight the need for additional validation and exploration before clinical integration.

Background In many couples experiencing reproductive failure, the underlying causes remain unknown. Microbiome research has primarily focused on the vaginal niche, with scarce attention to the gut microbiome and the male reproductive tract. We aimed to determine whether dysbiosis in the vagina, gut, or semen is associated with reproductive outcomes in couples with infertility (microbiome in in-vitro fertilisation cohort [Mi-IVF]) and couples with recurrent pregnancy loss (microbiome in recurrent pregnancy loss cohort [Mi-RPL]). Methods We conducted deep shotgun metagenomic sequencing of samples collected from female participants (aged 18–41 years) and their male partners (aged ≥18 years) from two independent, multicentre, prospective cohorts: Mi-IVF, which comprised couples with infertility and female participants participating without their partner enrolled in the ReproUnion Biobank and Infertility Cohort (RUBIC); and Mi-RPL, which comprised couples with three or more consecutive pregnancy losses (including biochemical losses) or two unexplained second-trimester losses. Participants were recruited between March 22, 2018, and Oct 17, 2023, at publicly funded fertility and RPL clinics at Copenhagen University Hospitals in Denmark. Vaginal and gut microbiomes in female participants and seminal microbiomes in male participants were profiled and assessed for associations with reproductive outcomes (ie, time to livebirth, defined as delivery of a live infant at 22 weeks of gestation or later [primary outcome], and pregnancy establishment [pregnancy rate per transfer in Mi-IVF or pregnancy within 1 year in Mi-RPL], pregnancy loss versus livebirth among established pregnancies, and time to first pregnancy [secondary outcomes]) using Cox proportional hazards models, generalised estimating equations, and logistic regression. Findings Cohorts comprised 249 female participants and 95 male participants or couples in Mi-IVF and 104 female participants and 96 male participants or couples in Mi-RPL. Seminal V-dysbiosis, defined by seminal samples having similarity to vaginal dysbiosis-associated community state types, was associated with longer time to livebirth in Mi-IVF, where livebirth occurred in 13 (57%) of 23 couples with seminal V-dysbiosis and 62 (85%) of 73 couples without seminal V-dysbiosis (hazard ratio [HR] 0·37 [95% CI 0·19–0·71], p=0·0031 ). Seminal V-dysbiosis was associated with higher pregnancy loss risk in Mi-IVF (average marginal effects [AME] 26·48 percentage points [95% CI 3·65–49·30], p=0·023) and Mi-RPL (18·59 percentage points [1·67–35·51], p=0·031) cohorts. Increasing female gut dysbiosis score was consistently associated with longer time to livebirth in the Mi-IVF (HR 0·84 [95% CI 0·72–0·98], p=0·027) and Mi-RPL (0·72 [0·54–0·95], p=0·019) cohorts. Median standardised Enterotype Dysbiosis Score among female participants with versus without livebirth was –0·06 (IQR –1·01 to 0·83) and 0·20 (–0·43 to 1·06), respectively, in Mi-IVF rectal samples, and –0·52 (–0·84 to 0·27) and 0·72 (–0·08 to 1·34), respectively, in Mi-RPL faecal samples. Higher gut dysbiosis score was also associated with lower pregnancy establishment in Mi-IVF (AME –6·57 percentage points per 1-SD increase per embryo transfer [95% CI –11·13 to –2·01], p=0·0047) and Mi-RPL (AME –6·37 percentage points per 1-SD increase in pregnancy within 1 year [95% CI –12·40 to –0·34], p=0·038) but was not associated with pregnancy loss. Vaginal dysbiosis showed no consistent associations with reproductive outcomes. Interpretation Seminal V-dysbiosis and increasing gut dysbiosis were associated with adverse reproductive outcomes. These findings of previously unrecognised, potentially modifiable microbial risk factors support the value of couples-level microbiome assessment and provide rationale for future interventional trials. Funding EU Interreg ÖKS, the Capital Region of Denmark, Region of Skaane, Ferring Pharmaceuticals, A P Moller Foundation, Independent Research Fund Denmark, Rigshospitalet Research Fund, and The Research Funds of the Capital Region of Copenhagen.

• Does adenomyosis increase risk of euploid pregnancy loss (PL)? • Is there a correlation of euploid PL and direct and/or indirect features of adenomyosis? No increased risk of euploid PL was observed in women with ultrasonographic signs of adenomyosis according to the revised MUSA (Morphological Uterus Sonographic Assessment) criteria. Adenomyosis is defined by benign invasion of the endometrium into the myometrium and disruption of the uterine anatomy. Diagnosis by histology is the gold standard, usually after hysterectomy. Recently, focus on non-invasive diagnostics has increased with the revised MUSA criteria for using transvaginal ultrasound for the diagnosis of adenomyosis. The impact of adenomyosis on fertility is conflicting as current literature range from showing no effect to lower live birth rates after in vitro fertilization and increased risk of PL in women with adenomyosis. The included patients are from an ongoing prospective cohort study in Denmark focused on PL from year 2020-2025, n = 2800. In a random sample of 375 women, two trained sonographers conducted a retrospective analysis of 3D ultrasound uterine volumes without Doppler. A questionnaire on physical health symptoms was answered 14 days after the pregnancy loss including questions on menstrual pain Women were included at the time of PL diagnosis. The ploidy status of the fetus, aneuploid or euploid, was determined using cell free fetal DNA analysis or direct sequencing of fetal tissue. 3D ultrasound uterine volumes without Doppler were performed four to eight weeks post-pregnancy loss. The revised MUSA-criteria were applied to describe adenomyosis by 3D ultrasonography by two sonographers. Women in the cohort were aged 20-45 years, with a mean BMI of 23.7 and with a mean gestational age of 9.3 weeks at time of the PL. In the evaluated 375 3D ultrasonographic scans, we did not observe any significant difference in the amount of direct and indirect MUSA features between women with euploid and aneuploid PL. Women with two or more PLs had a higher prevalence of irregular (OR = 1.57, p = 0.04) and disrupted junction zones (OR = 1.63, p = 0.03), compared to women with only one PL. Globular uterus tended to be more frequent in women with more than one PL (OR 1.7, p = 0.09), however insignificantly. Higher cumulative number of MUSA features was associated with higher age of the women, r-value 0.16 (p = 0.001). Women with severe menstrual pain more often experienced euploid PL, OR 1.44 (p = 0.03). The 3D-volumes were without Doppler, resulting in unassessed translesional vascularity, risking underestimating the effect of adenomyosis. Junctional-zone changes are more frequent in women with more than two PLs, indicating that changes in the junctional zone could be involved in the pathogenesis of some PL increasing the recurrence risk. The amount of direct and indirect MUSA features were comparable in women with euploid vs. aneuploid PL. No

Every generation, the human genome is shuffled during meiosis and a single fertilized egg gives rise to all of the cells of the body1. Meiotic errors leading to chromosomal abnormalities are known causes of pregnancy loss2,3, but genetic aetiologies of euploid pregnancy loss remain largely unexplained4. Here we characterize sequence diversity in early pregnancy loss through whole-genome sequencing of 1,007 fetal samples and 934 parental samples from 467 trios affected by pregnancy loss (fetus, mother and father). Sequenced parental genomes enabled us to determine both the parental and meiotic origins of chromosomal abnormalities, detected in half of our set. It further enabled us to assess de novo mutations on both homologous chromosomes from parents transmitting extra chromosomes, and date them, revealing that 6.6% of maternal mutations occurred before sister chromatid formation in fetal oocytes. We find a similar number of de novo mutations in the trios affected by pregnancy loss as in 9,651 adult trios, but three times the number of pathogenic small (<50 bp) sequence variant genotypes in the loss cases compared with adults. Overall, our findings indicate that around 1 in 136 pregnancies is lost due to a pathogenic small sequence variant genotype in the fetus. Our results highlight the vast sequence diversity that is lost in early pregnancy.

Infertility affects approximately 15% of couples worldwide. In the affected women, thyroid dysfunction is a possible explanation. Thyroid hormones are essential to reproduction and thyroid disease is common in women of reproductive age. Thus, all women seeking fertility treatment should be screened for thyroid dysfunction and any aberrations corrected before starting fertility treatment. This will resolve some cases of infertility and secure adequate thyroid hormones for fetal development. Fertility treatment often involves high levels of estrogen administration or production, which affect thyroid binding hormone levels. Knowledge of these alterations is necessary to properly diagnose and treat women undergoing fertility treatment.

What is the prevalence of stress, depression and anxiety among couples experiencing pregnancy loss and is this affected by reproductive history? Depression, stress, and anxiety are common after pregnancy loss, especially among women. Couples with prior losses and failed primary treatment are especially vulnerable. Studies of mental health consequences of pregnancy loss present a complex and inconsistent picture and reported rates of depression, stress, and anxiety varies significantly in prior research. Several factors likely contribute to this variability: many studies are relatively old and may not reflect current experiences and cultural norms and samples sizes are generally small which may impact reliability and generalizability of the results. Furthermore, research often focuses solely on the mother, overlooking potential mental health impacts on partners. Prospective cohort study with 2,085 women and 1,212 partners included between November 2020 and December 2024. Women with miscarriage before 22 weeks’ gestation and their partners. Two to eight weeks after the loss, participants completed psychometric scales including Major Depression Index (MDI), Perceived Stress Scale (PSS) and Generalized Anxiety Disorder-7 (GAD-7). Univariate comparison of the psychometric scales to eight covariates were performed on women and partners separately and adjusted for age where relevant. Odds-ratios were found using a proportional-odds model, and confidence intervals and p-values were estimated using a Wald’s test. For women, median (IQR) on the MDI was 15 (9; 25), 253 (12.2%) had moderate/severe depression. Median on the PSS was 18 (13; 24), 1030 women (49.4%) were stressed (PSS>18). Median on the GAD-7 was 6 (2; 9), 499 women (24.1%) had moderate/severe anxiety. Having children was correlated with lower scores, OR (95% CI): MDI: 0.67 (0.57; 0.78), p < 0.001; PSS: 0.75 (0.64; 0.87), p < 0.001; GAD-7: 0.78 (0.67; 0.91), p = 0.004. Prior losses correlated with higher scores: MDI 1.17 (1.10;1.23), p < 0.001; PSS 1.15 (1.09; 1.22), p < 0.001; GAD-7: 1.15 (1.09; 1.22), p < 0.001, as did repeated treatment due to retained tissue: MDI: 1.41 (1.13; 1.76), p = 0.005 and PSS: 1.31 (1.05; 1.63), p = 0.03. Among partners, median score (IQR) on the MDI was 8 (4, 15), 46 (3.8%) had moderate/severe depression. PSS median: 14 (9, 18), 286 (23.6%) were stressed; GAD-7: 3 (0, 6) and 99 (8.3%) had moderate/severe anxiety. Prior losses correlated with higher scores on the MDI: 1.14 (1.06; 1.23), p = 0.007, PSS: 1.12 (1.05; 1.20), P = 0.01, and GAD7: 1.10 (1.03; 1.19), p = 0.03. Studies based on self-reported symptoms have inherent limitations in that participants may over- or under-report symptoms due to recall bias and differences in interpretations of symptom severity. However, the rating scales used are validated and widely used internationally. The results of this study imply that pregnancy loss care could be improved by including mental health assessments for both women and their partners. Couples with prior losses and women where primary treatment is insufficient are especially at risk and tailored care should be provided. No

(Abstracted from Nature 2025;642(8068):672–681) Mutations in germ cells are passed from parent to child and occur before fertilization; variations can be evaluated using somatic tissue samples, and germline mutations that appear de novo in offspring (DNMs) have been studied extensively. Many DNMs are paternal, but some have nearly equal maternal and paternal contribution.

Do women experiencing pregnancy loss have undetected high thyroid stimulating hormone (TSH) levels? Is thyroid (dys)function associated with the risk of a euploid pregnancy loss? Few women with pregnancy loss and high TSH were detected with current guidelines. High total triiodothyronine (TT3) and thyroxine (TT4) increased euploid pregnancy loss risk. Thyroid dysfunction has been associated with adverse reproductive events including pregnancy loss which affects >20 million women worldwide each year. Approximately 55% of pregnancy losses are due to lethal chromosome abnormalities (aneuploid losses), whereas fetuses with a normal number of chromosomes (euploid) are potentially viable. Pregnancy loss of a euploid fetus is suspected to be due to maternal comorbidity e.g. thyroid dysfunction. However, no guidelines address TSH screening in women experiencing pregnancy loss until they have had recurrent pregnancy losses, and studies of thyroid function and pregnancy loss have not previously distinguished between euploid and aneuploid losses. Prospective cohort study aiming at including 3,000 women experiencing missed abortions or ongoing spontaneous abortions of confirmed intrauterine pregnancies. The study started in November 2020 and continues inclusions until May 2025. Based on patient records and questionnaires, we included women without known thyroid disease who participated in the study from November 2020 until May 2024. Regional laboratory data from hospitals and general practitioners provided information on thyroid function tests performed before the inclusion. Women presenting with pregnancy loss at three Danish university hospitals had blood drawn at the time of pregnancy loss upon informed consent. We measured TSH, free T4 and TT4, TT3, human chorionic gonadotropin (hCG), thyroid peroxidase and thyroglobulin antibodies (TPOAb, TgAb). Antibody positivity: >60 kIU/L. Fetal chromosome status was determined by cell-free fetal DNA or fetal tissue sequencing to detect aneuploidy. Logistic regression covariates: age, body mass index, gestational week at inclusion. Among 2,010 included women, 60 (3.0%) had a TSH>4 mIU/L (American Thyroid Association (ATA) pregnancy guidelines cut-off) and 15 (0.7%) a TSH>6 mIU/L (proposed treatment indication in 2025 ATA guidelines). Of these, TSH had been measured as part of current practice in 8 of 60 (13.3%) and 3 of 15 (20.0%) during pregnancy. Two women had a TSH>100 mIU/L. We then assessed if thyroid function was associated with euploid pregnancy loss (constituting 51% of the losses). There was a significant positive association between the risk of euploid pregnancy loss and TT3 (adjusted odds ratio (aOR) 2.0, 95% confidence interval (CI) 1.5;2.6) and TT4 (aOR 1.09 (1.05;1.13)). This remained significant when adjusting for TSH, TPOAb, TgAb, and hCG (TT3 aOR 2.7 (1.44;5.33), TT4 aOR 1.16 (1.06;1.27)). There was no association between euploid pregnancy loss and TSH (aOR 0.9 (0.8;1.1)), FT4 (aOR 1.0 (1.0;1.0)), TPOAb positivity (aOR 0.99 (0.68;1.43)), nor TgAb positivity (aOR 0.96 (0.66;1.41)). Euploid loss rate was higher in women with TT3 >2.6 nmol/L (laboratory cut-off) vs TT3≤2.6 nmol/L (n = 61/85, 71.8% vs. n = 470/1,521 48.6%, p < 0.001) and TT4 >140 nmol/L (laboratory cut-off) vs ≤ 140 nmol/L (n = 248/425 58.4% vs. n = 552/1,180 46.8%, p < 0.001). The findings are observational and cannot inform of causality. However, levothyroxine treatment is recommended to women with a high TSH during pregnancy, or planning pregnancy, if this is detected. The findings that high TT3 and TT4 are associated with ploidy status need further investigation before treatment options can be considered. Women with pregnancy loss constitutes a black box in current screening programs. Few women with high TSH had been tested before or during pregnancy. TSH screening of women experiencing a pregnancy loss should be considered. Future studies should explore if gestational thyrotoxicosis is a risk to potentially viable fetuses. No

BACKGROUND:Thyroid peroxidase antibody (TPOAb) positivity is the most important risk factor for hypothyroidism and determines thyroid function follow-up during pregnancy. TPOAb positivity is usually defined by manufacturer cut-offs which typically derived from non-pregnant populations. However, as a state of immune tolerance, pregnancy can affect TPOAb concentrations. To improve the understanding of clinical relevance of TPOAb concentrations during pregnancy, we investigated the association of TPOAbs with maternal thyroid function. METHODS:We performed an individual participant data meta-analysis embedded in the Consortium on Thyroid and Pregnancy. Participants with multiple gestations, pre-existing thyroid disease, thyroid (interfering) medication usage, or conception by in vitro fertilization were excluded. We used mixed effects regression models to assess the association of TPOAb percentiles calculated in each cohort with maternal thyroid function. RESULTS:The study population comprised 62,634 pregnant women from 24 cohorts. As compared to TPOAb percentiles ≤80, there were progressively higher mean thyroid stimulating hormone (TSH) concentrations across TPOAb percentiles ≥89, with corresponding mean differences ranging from +0.11 SD (95 % confidence interval [CI] +0.04 SD, +0.19 SD) at the 89th percentile to +1.04 SD (95 % CI + 0.96 SD, 1.11 SD) at the 100th percentile. Higher TPOAb percentiles were associated with progressively lower mean free thyroxine (FT4) concentrations across TPOAb percentiles ≥91, with corresponding mean differences ranging from -0.08 SD (95 % CI -0.16 SD, -0.01 SD) at the 91st percentile to -0.48 SD (95 % CI -0.56 SD, -0.4 SD) at the 100th percentile. From the 89th TPOAb percentile upwards, there were progressively higher risks of TSH >4.0 mU/L, with absolute risks of 2.4 %, 4.0 %, and 28.1 % in cases of ≤80th, 89th, and 100th TPOAb percentiles, respectively. Higher TPOAb percentiles were also associated with lower thyroidal response to human chorionic gonadotropin stimulation and higher risks of overt and subclinical hypothyroidism. In 19 of the included cohorts, there were 0.4-6.3 % of pregnant women with TPOAb concentrations lower than the positivity cut-offs but larger than or equal to the 89th-percentile concentrations. The associations of TPOAbs with TSH and with FT4 were most apparent during early pregnancy (P for interaction <0.001 for both TSH and FT4). CONCLUSIONS:During pregnancy, TPOAbs were dose-dependently associated with TSH, FT4, and the risk of abnormal thyroid function. With concentrations below currently used positivity cut-offs, TPOAbs could be associated with lower maternal thyroid function, which indicates clinically relevant thyroid autoimmunity. These findings implicates that high normal TPOAb concentrations upon first assessment in pregnancy may warrant active follow-up.

Background: International guidelines recommend that the indication to perform thyroid function testing during pregnancy is based on the presence of risk factors for thyroid function test abnormalities. However, the discriminative ability of currently recommended risk factors is questionable. To inform on an update of the American Thyroid Association Guidelines for the Diagnosis and Management of Thyroid Disease in Preconception, Pregnancy, and the Postpartum, we aimed to systematically review the literature to evaluate evidence for current risk factors and potential novel ones for thyroid function test abnormalities in pregnancy. Methods: A systematic literature search was performed on Embase, Medline Ovid, and the Cochrane Library from inception to October 17, 2024, to identify articles on the associations of any candidate variables with thyroid function test abnormalities, thyroid antibody positivity, or results of continuous thyroid function tests in pregnancy. Additional records were identified through citation searching. Study quality was assessed using the Newcastle-Ottawa Scale. We summarized the results using a narrative synthesis. Results: A total of 81 articles were included, describing 36 candidate variables. Thyroid antibody positivity was associated with a higher risk of overt or subclinical hypothyroidism compared with antibody negativity (absolute risks: 2.4-7.0% vs. 0.1-0.2% for overt hypothyroidism and 1.9-29.0% vs. 2.0-5.7% for subclinical hypothyroidism). In cases of iodine deficiency, sufficiency, and intake above pregnancy requirements or excess, the absolute risks for subclinical hypothyroidism were 2.2-42.6%, 1.42-16.0%, and 3.8-24.3%, respectively. A limited number of studies were available for history of autoimmune diseases, family history of thyroid disease, symptoms of hypothyroidism, and history of pregnancy loss, preterm delivery, or infertility. There was little or no association of current risk factors with isolated hypothyroxinemia or (subclinical) hyperthyroidism. We did not identify novel risk factors for thyroid function test abnormalities. Conclusions: Evidence for most currently recommended risk factors remains limited and heterogeneous, and no novel risk factor was identified. While risk factors can help guide thyroid function testing in pregnancy, a clinical risk assessment cannot be replaced. Future studies are needed to detect novel risk factors that can improve the accuracy and efficiency of identifying pregnant women at high risk of thyroid function test abnormalities, in particular, overt hypothyroidism.

Does adenomyosis progress over time in women with two or more pregnancy losses? Among women with two or more pregnancy losses, adenomyosis tends to gradually progress over time with notable changes observed in the junctional zone. Adenomyosis is characterized by the presence of ectopic endometrial tissue (both glands and stroma) within the myometrium. While definitive diagnosis requires histopathological examination of the uterus, uterine imaging such as magnetic resonance imaging (MRI) and transvaginal ultrasound (TVUS) is suggested to detect adenomyosis. The Morphological Uterus Sonographic Assessment (MUSA) consensus group has defined direct and indirect ultrasound signs of adenomyosis. Several factors may contribute to the development of adenomyosis after pregnancy loss, such as trophoblast invasion and disruption of the junctional zone. Longitudinal prospective cohort study of women with pregnancy loss, recruited from four Danish public hospitals between November 2020-January 2025. A retrospective analysis of 3D ultrasound uterine volumes, acquired four to eight weeks post-pregnancy loss from 245 women with two or more pregnancy losses, was conducted by two independent sonographers to identify direct and indirect adenomyosis criteria. We compared the prevalence and distribution of MUSA signs between the first to the later scan (following another pregnancy loss) and explored the impact of surgical treatment for the pregnancy loss on adenomyosis development using Chi-squared and Z-tests. The detection of no MUSA direct features was more frequent at first inclusion (5%), compared to later assessments (2%), while the presence of a single direct feature was observed in 54% of cases at initial inclusions, compared to 35% in later inclusions (p-value=0.004). The detection of two direct features became more prevalent at later inclusions (24% vs 46%; p-value=0.004). No significant difference was found in the frequency of indirect MUSA features between the first and later inclusions, despite an overall increase in the number of indirect criteria over time (p-value=0.07). A sub analysis demonstrated a progressive increase in the detection of echogenic buds and lines at the junctional zone over time (26% vs 42%; p-value=0.01) and simultaneously also an enhancement of irregular junctional zone (44% vs 72%; p-value=0.001). Additionally, surgical treatment of the pregnancy loss was significantly correlated with an increased prevalence of echogenic buds and lines at the junctional zone compared to women without surgical treatment (51% vs 31%; p-value=0.026). We cannot rule out that the different time intervals between the pregnancy loss and the follow-up visit, where the 3D-volume analysis was undertaken, could impact our results. We are also limited by the absence of dynamical ultrasound evaluation and histopathological confirmation of adenomyosis. These results demonstrate a progressive increase in adenomyosis detection over time and after pregnancy losses in patients with marked differences in the junctional zone assessment and a clinically relevant impact of surgical treatment. These findings highlight the need for further investigation into the link between pregnancy loss and adenomyosis development. No

BACKGROUND:Pregnancy is a state of increased metabolic demand that necessitates major changes in endocrine physiology. Gestational thyroid dysfunction and gestational diabetes are common endocrine conditions of pregnancy that frequently coincide. Although the effects of thyroid hormones on glucose metabolism are well documented, important knowledge gaps remain in terms of the extent and clinical relevance of these effects during pregnancy. The aim of this meta-analysis is to assess the association of thyroid function test results with gestational diabetes and markers of glucose metabolism. METHODS:In this systematic review and individual participant data meta-analysis, we searched Ovid MEDLINE, EMBASE, and Web of Science from database inception to Dec 12, 2024, for prospective population-based cohort studies with individual patient data on thyroid function, gestational diabetes, and measures of glucose homoeostasis during pregnancy. Furthermore, open invitations to join the Consortium on Thyroid and Pregnancy were issued to identify unpublished datasets. We excluded participants with multiple pregnancies; pre-existing thyroid disease or diabetes; current use of medications that could affect thyroid or glucose levels; or a history of infertility treatment, miscarriage, or stillbirth. Exposures were maternal gestational concentrations of thyroid-stimulating hormone (TSH), free T4 (FT4), free T3 (FT3), and total T3; thyroperoxidase antibody positivity; thyroglobulin antibody positivity; and thyroid disease entities (ie, subclinical hypothyroidism, overt and subclinical hyperthyroidism, and isolated hypothyroxinaemia), which were defined according to current guidelines. The primary outcome was presence of gestational diabetes as defined in individual cohorts. Individual participant data were analysed using generalised linear mixed-effects regression models adjusting for maternal age, BMI, smoking status, parity, ethnicity, fetal sex, and gestational age at blood sampling. We preregistered our study protocol with PROSPERO (CRD42022371927). FINDINGS:We identified 638 published studies with our systematic search, of which 21 studies based on 17 cohorts met inclusion criteria; 11 of these prospective cohort studies provided individual participant data, and data from an additional 14 cohorts were added via personal contacts and open invitations, resulting in a study population of 63 548 participants from 25 cohorts after exclusions. Of the 52 632 participants in 17 cohorts with TPOAb measurements available to define thyroid disease entities, 1687 (3·2%) of these participants had subclinical hypothyroidism, 1153 (2·2%) had isolated hypothyroxinaemia, and 2958 (4·7%) had gestational diabetes. Compared with euthyroidism, isolated hypothyroxinaemia was associated with a higher risk of gestational diabetes (absolute risk 6·5% [72 of 1113] for isolated hypothyroxinaemia vs 3·5% [1555 of 44 787] for euthyroidism; adjusted odds ratio [aOR] 1·52 [95% CI 1·17-1·98], p=0·0017; 45 900 participants). A lower FT4 concentration was associated with a higher risk of gestational diabetes (non-linear, p<0·0001). A higher risk of gestational diabetes was found both with a higher FT3 concentration (aOR 1·18 [95%CI 1·10-1·28], p<0·0001) and with a higher FT3-to-FT4 ratio (non-linear; p<0·0001). No evidence was found of associations of TSH, thyroid antibodies, or other thyroid function test abnormalities with gestational diabetes. I2 statistics for the primary analyses ranged from 0-43%, indicating low to moderate heterogeneity. The funnel plot for overt hyperthyroidism indicated a possibility for publication bias (p=0·049), but funnel plots for all other variables did not. INTERPRETATION:A lower FT4 concentration and isolated hypothyroxinaemia during pregnancy are associated with a higher risk of gestational diabetes. Our results challenge the long-standing notion that subclinical hypothyroidism or thyroid autoimmunity are risk factors for gestational diabetes and support both the risk profile for gestational thyroid dysfunction and ongoing efforts on optimisation of treatment targets for pregnant people taking levothyroxine. Follow-up studies are required to establish to what extent levothyroxine initiation or dose adjustments can affect insulin resistance and antihyperglycaemic therapies during pregnancy. FUNDING:The Netherlands Organization for Scientific Research, ZonMw, and the EU Horizon 2020 Program.

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