BMC Medicine

IntroductionEndometriosis is a chronic disease and the second most common gynaecological condition in the UK, affecting approximately 1.5 million women. It is characterised by the growth of endometrial tissue outside the uterus, causing varying symptoms and having far reaching socioeconomic impacts. We utilise population level hospital admissions data and Census 2011 to examine the characteristics of women diagnosed with endometriosis in England. MethodsUsing a retrospective cohort design, we used Hospital Episode Statistics (HES) between 2011 and 2021, we linked health data to detailed sociodemographic information from Census 2011, providing individual population-level information on self-reported characteristics. Our outcome of interest was an endometriosis diagnosis in hospital. Our exposures were age on Census Day (five-year age bands), ethnic group, Index of Multiple Deprivation (IMD) decile, household National Statistics Socio-economic Classification (NS-SEC), highest qualification, country of birth, main language, self-reported general health, self-reported disability, rural/urban classification, region, and upper tier local authority (UTLA). We calculated crude and age-standardised rates, and odds of receiving a diagnosis using logistic regression models adjusted sequentially for age and health. ResultsOur results highlight differences in underlying prevalence of endometriosis by sociodemographic characteristic, as well as capturing differences in access to services for women receiving a diagnosis of endometriosis in an NHS hospital. The likelihood of receiving an endometriosis diagnosis was highest in the "White British", "Black Caribbean" and "Mixed White and Black Caribbean" ethnic groups, and lowest in the "Chinese", "Arab" and "Black African" ethnic groups. Women living in the most and least deprived areas were least likely to have an endometriosis diagnosis, possibly reflecting lower access to healthcare services in the most deprived group and more use of private healthcare in the least deprived group. Women self-reporting to be in bad health, or disabled, were more likely to have had an endometriosis diagnosis compared those in very good health or non-disabled women, respectively. ConclusionsOur results demonstrate significant sociodemographic differences between groups of women receiving an endometriosis diagnosis in England. These results should be used to inform healthcare policies to better support groups of women who are most affected by endometriosis and barriers to receiving a diagnosis. Subsequent work should explore presentations in primary care, as well as the broader socioeconomic ramifications of endometriosis. Research in contextO_ST_ABSWhat is already known on this topicC_ST_ABSEndometriosis is a common gynaecological condition which has debilitating impacts across many domains, including physical, psychological, social and economic. It is estimated to affect 1 in 10 reproductive age women in England, however evidence on the differences in endometriosis diagnosis by sociodemographic characteristics is lacking. What this study addsOur study utilises population-level Census and HES data for England to estimate crude and age-standardised rates of endometriosis diagnosis, and odds of receiving an endometriosis diagnosis by a range of sociodemographic characteristics. We estimate the prevalence of an endometriosis diagnosis to be approximately 2% of reproductive age women in our linked population, with an average age at diagnosis of 35 years. Women living in the most and least deprived areas were least likely to have an endometriosis diagnosis; this possibly reflects less access to healthcare services in the most deprived group and more use of private healthcare in the least deprived group. The likelihood of receiving an endometriosis diagnosis was highest in the "White British", "Black Caribbean", and "Mixed White and Black Caribbean" ethnic groups, and lowest in the "Chinese", "Arab", and "Black African" ethnic groups. This study is the most comprehensive analysis of the characteristics of women with an endometriosis diagnosis in England to date. How this study might affect research, practice or policyThis research provides important information to gynaecologists, clinicians and other allied health professionals, as well as policy makers, to illustrate the prevalence of endometriosis and the groups most affected by endometriosis and barriers to receiving a diagnosis. In the Womens Health Strategy for England, menstrual health and gynaecological conditions were identified as one of the priority areas, with a call for evidence and investment in womens health research.

ObjectiveTo examine the impact of in utero exposure to SARS-CoV-2 virus on childrens emergency and planned hospital admissions up to 40 months of age. Design, Setting, and ParticipantsNationwide, birth cohort study using multiple linked administrative datasets in England. Children with conception start dates between 1st February and 31st July 2020 and born alive to mothers residing in England, followed for 40 months. ExposureIn utero SARS-CoV-2 exposure (i.e., maternal infection in pregnancy) during wild-type or Alpha variant dominant periods, characterised via linkage to national testing and hospital data. Main Outcome MeasuresFirst emergency or planned admission before 40 months of age. ResultsOf the 262,086 children included, 14,717 (5.6%) were exposed to SARS-CoV-2 in utero: 6,888 (2.6%) during the wild-type period and 7,829 (3.0%) during the Alpha period. Overall, 89,189 children (34.0%) had at least one emergency admission and 24,635 (9.4%) had at least one planned admission. After adjusting for socio-demographic characteristics and maternal chronic conditions, compared to children unexposed during either period, children exposed in utero during the wild-type period showed no difference in time to the first emergency admission, while Alpha-period exposure was associated with an 8% lower hazard (adjusted HR: 0.92, 99% CI: 0.87 to 0.97). No difference was found in the time to the first planned admission between in utero exposed groups and the unexposed group, nor in the time to either the first emergency or planned admission based on the trimester of in utero exposure. ConclusionsIn this large national birth cohort in England, we did not find an increased hazard of hospital admission by 40 months of age associated with in utero exposure to SARS-CoV-2, in the absence of maternal vaccination. Further follow-up is needed to assess late-onset outcomes and the effect of later circulating SARS-CoV-2 variants. Continued investment in linked maternal-child health data is essential to monitor both immediate and long-term effect of emerging infections during pregnancy. Summary boxO_ST_ABSWhat is already known on this topicC_ST_ABSExisting research has shown a higher risk of preterm births in children who were exposed to SARS-CoV-2 in utero, but health outcomes beyond the neonatal period are not well described. Published evidence on comparing the effects of exposure to different variants in utero on childrens health outcomes remains limited. What this study addsThis study found no evidence of an increased hazard of first emergency or planned hospital admissions up to 40 months of age associated with in utero exposure to SARS-CoV-2 during the wild-type or Alpha periods, in the absence of maternal vaccination.

BackgroundAuditing geographical representation in medical publishing could help to mitigate possible national and regional disparities. MethodsUsing the Web of Science indexing database, we collected bibliometric data of original research articles published between 2010-2019 in The New England Journal of Medicine, Nature Medicine, Journal of the American Medical Association, The BMJ, and The Lancet. We studied the corresponding authors geolocation in regard to publication and citation count, their temporal evolution, and the journals and citing organizations nationality. ResultsWe identified 10,558 articles. Based on the nationality of the corresponding authors institutes, only 32 countries published more than 10 publications in 10 years equaling to 98.9% of all publications. English-speaking countries USA (48.2%), UK (15.9%), Canada (5.3%), and Australia (3.2%) were most represented, but with a declining trend in recent years. Normalized to their accumulated citations, 9/32 countries were associated with [≥]10% publication excess, of which USA (n=1,174 publications) and UK (n=410) accounted for 85.7%. Similar findings were replicated at the municipal level where all top 10 most productive cities were located in USA (n=7), UK (n=2), or Canada (n=1), and 21 out of 25 most productive cities published more articles than predicted based on their accumulated citations. Finally, we discovered that both journals published, and researchers cited more commonly research conducted in the same country. DiscussionThe audit revealed Anglocentric dominance, domestic preference occurring in both journals and citation selection, and increased geographical representation in recent years in medical publishing.

BackgroundA full-term pregnancy is associated with a lower cancer risk. The risk of cancer in women with vaginal bleeding in pregnancy is unknown. MethodsWe conducted a registry-based cohort study (1995-2017) in Denmark. We included pregnancies (n=37 082) affected by vaginal bleeding (VB) within 20 gestational weeks among 35 514 women, VB-unaffected pregnancies (n=1 363 614) among 783 314 women, pregnancies ending in a termination (n=324 328) among 239 638 women or miscarriage (n=137 104) among 121 353 women. We computed absolute risk of cancer and hazard ratios (HR) with 95% confidence intervals (CI) adjusted for age, calendar year, morbidity, and socioeconomic factors using Cox proportional hazards regression. ResultsAt the end of the 24-year follow-up, there were 1 320 events among VB-affected cohort, 40 420 events among VB-unaffected cohort, 10 300 events among termination cohort, and 4 790 events among miscarriage cohort. The HR for any cancer was 1.03 (95% CI: 0.97-1.08) when comparing VB-affected vs VB-unaffected pregnancies, 1.03 (95% CI: 0.97-1.09) vs terminations, and 0.90 (95% CI: 0.84-0.95) vs miscarriages. Similar results were obtained for site-specific cancers. ConclusionsWe found no strong evidence for an association between vaginal bleeding in pregnancy and an increased risk of cancer.

BackgroundOsteoarthritis is a major cause of disability worldwide, with its prevalence expected to increase due to ageing populations and rising obesity. Understanding the epidemiological trends in osteoarthritis is critical for public health planning and intervention strategies. MethodsThis study analyzed global, regional, and national data on osteoarthritis incidence, prevalence, and Disability-adjusted life years (DALYs) utilizing the Global Burden of Disease Study 2021. Statistical modelling was used to assess trends over the past 32 years and projections were made for 2050 based on demographic changes and historical data. ResultsIn 2021, 607 (95% UI: 538-671) million people worldwide had osteoarthritis, with 46.6 (95% UI: 41.1-51.6) million new cases and 21.3 (95% UI: 10.2-42.9) million DALYs. Age-standardized incidence, prevalence and DALYs rates increased to 535.00 (95% UI: 472.38-591.97), 6967.29 (95% UI: 6180.70-7686.06), and 244.50 (95% UI: 117.06-493.11) per 100,000 population, with knee osteoarthritis accounting for more than 56%. Age-standardized rates of osteoarthritis were higher in females than in males. East Asia, South Asia, and Western Europe were the regions and China, India, and the United States were the countries with the highest burdens. In addition, high body-mass index (BMI) led to 4.43 (95% UI: -0.42-12.34) million DALYs, with an increase of 205.10%. Bayesian age-period cohort projections showed that the burden of osteoarthritis would continue to rise from 2021 to 2050. ConclusionsThe findings indicated that the burden of osteoarthritis is on a rising trend with an ageing population and increasing global obesity rates, with females and middle-aged and older age groups being the current populations of concern. Comprehensive public health policies and strategies are urgently needed to address its impact. Increased awareness, early detection and effective management are essential to reduce the burden of osteoarthritis in the coming decades, especially among vulnerable groups.

ObjectivesObservational studies have shown the association between knee osteoarthritis (KOA) and neurological disorders with alterations in brain imaging-derived phenotypes (BIDPs). This study aimed at investigating whether alterations in brain structure are correlated with the occurrence of KOA. MethodsBased on the summary data from two large scale genome-wide association studies (GWASs), we performed a bidirectional two-sample Mendelian randomization (MR) analysis using single-nucleotide polymorphisms (SNPs) as instrumental variables (IVs) to determine the potential causal relationships between KOA and BIDPs. ResultsWe identified the genetic correlations of 152 BIDPs with KOA using linkage disequilibrium score regression. MR analysis revealed that increased volume but decreased intensity-contrast of bilateral nucleus accumbens (NAc), as well as increased left paracentral area was positively causally associated with KOA risk. For the IDPs of structural connectivity, we identified causal associations between multiple increased DTI parameter indicators of corticospinal tract (CST) and KOA. Inversely, KOA was positively correlated with the thickness and intensity-contrast of the rostral anterior cingulate, as well as the intensity-contrast of caudal anterior cingulate, insula cortex, and the grey matter volume of pallidum. ConclusionOur study supported bidirectional causal associations between KOA and BIDPs, which may provide new insights into the interaction of KOA with structural alterations in the nervous system.

1.Study questionDo singletons conceived by medically assisted reproduction (MAR) experience an elevated incidence of childhood cancers and are they at a greater risk of such cancers compared to naturally-conceived singletons? Summary answerWe found no strong evidence the adjusted risk of childhood cancers is increased for MAR-conceived singletons. What is known alreadyThere is longstanding concern children conceived via MAR may be at increased risk of childhood cancer. Current epidemiological evidence does not support such a relationship. Study design, size, durationWe conducted a retrospective population-based cohort study of 5,104,121 singletons born in Australia between 1991 and 2019. Median follow-up time varied from 4 to 10 years depending on mode of conception. Participants/materials, setting, methodsWe linked birth records to public medical insurance data of the mother to ascertain MAR conception. We classified treatment as ovulation induction/intrauterine insemination (OI/IUI) or assisted reproductive technology (ART; IVF/ICSI), with ART coded as either fresh embryo transfer or frozen embryo transfer. The cohort included 4,924,354 naturally-conceived singletons and 179,767 singletons conceived via MAR. We calculated standardised incidence ratios (SIRs) to ascertain differences in population incidence of childhood cancer, and generated hazard ratios (HRs) using flexible parametric survival models controlling for key confounders. We report absolute incidence and risk differences for both statistical approaches. Main results and the role of chanceThere was no increase in the incidence or risk of all childhood cancers combined for singletons conceived via MAR, either any MAR or specific MAR types. There was some evidence the incidence of leukemias, myeloproliferative diseases, and myelodysplastic diseases was increased after ART compared to the general population (SIR: 1.32, 95% CI 1.02-1.68; equating to 2.09, 95% CI 0.13-4.44 extra cancers per 100,000 person-years), but no increased risk after adjusting for available confounders (HR: 1.04, 95% CI 0.73-1.46). These cancers showed increased incidence and risk for those conceived via IVF (SIR: 1.54, 95% CI 1.01-2.26; HR: 1.77, 95% CI 1.06-2.95), but not ICSI (SIR: 1.27, 95% CI 0.83-1.85; HR: 0.76, 95% CI 0.48-1.22). Incidence of renal tumours was elevated after IVF (SIR: 2.37, 95% CI 1.02-4.67; equating to 1.83, 95% CI 0.03-3.99 extra cancers per 100,000 person-years) and frozen transfer ART (SIR: 2.52, 95% CI 1.09-4.97; equating to 2.12, 95%CI 0.12-5.53 extra cancers per 100,000 person-years), however risk was not elevated after adjusting for available confounders (HR: 1.06, 95% CI 0.47-2.38; and HR: 1.63, 95% CI 0.73-3.61 respectively). Limitations, reasons for cautionWe did not have information on parental cause of infertility, which could be a confounder for childhood cancer, although we did adjust for parental history of cancer. For many specific cancer types, fewer than 50 cases were observed in total. Given the number of comparisons reported and closeness of the lower-bound confidence interval to 1, we cannot exclude that a significant association between conception via IVF and leukemias, myeloproliferative diseases, and myelodysplastic diseases reflects a type I error. Wider implications of the findingsOur findings align generally with published meta-analyses on the risk of childhood cancers following MAR conception and reinforce the need for very large studies to increase confidence. Parents who have conceived via MAR and their offspring can be reassured there is not strong evidence the treatments increase the overall incidence or risk of childhood cancer. Study funding/competing interest(s)This work was funded by the National Health and Medical Research Council (NHMRC: APP1164852). Dr ARW declares that their involvement in this work was supported by employment at UNSW Sydney. Prof CMV declares payment to their institution from the National Health and Medical Research Council (APP1164852). Prof NH declares payment to their institution from the National Health and Medical Research Council (APP1164852); royalties and licenses for Berek and Hackets Gynecologic Oncology (Walters Kluwer); royalties and licenses for Hacker and Moores Essentials of Obstetrics and Gynecology (Elsevier); consulting fees from Darwin Hospital and Gold Coast University Hospital; support for attending the British Gynaecological Cancer Society meeting in Aberdeen, UK, Jun 2023; support for attending the Symposium on Gynaecological Cancer in Budapest, Hungary, Nov 2023; support for attending the International conference of the Rajiv Gandhi Cancer Centre in Delhi, India, Mar 2025; and membership of the Medical Advisory Committee for TruScreen (Australia and New Zealand). A/Prof SO declares that they received payment to their institution from the National Health and Medical Research Council (APP1164852); they received a grant from the European Society for Human Reproduction and Embryology (Open call 2022) including payment to their institution; and that they are a member of the Advisory Board of the Cervical Screening Program in Norway through The Norwegian Institute of Public Health (NIPH), for which they were reimbursed travel expenses to their institution. Prof MC declares support for Theramex European Society for Human Reproduction and Embryology registration and Fertility Society of Australia and New Zealand registration and accommodation. A/Prof USD declares that her involvement in this work was supported via an Early Career Fellowship from the Cancer Institute NSW (ID: 2020/ECF1163) and employment at UNSW Sydney. A/Prof USD also declares payment to their institution from the National Health and Medical Research Council (APP2035240) and the Medical Research Future Fund (APP2032214; APP2038377), and the Australian Research Council (DP240100072) as well as current grants from NSW Health, Prince of Wales Hospital Foundation, and unpaid involvement as an Associate Editor for the "Journal of Psycho-Oncology Research and Practice". Prof LJ declares payment to their institution from the National Health and Medical Research Council (APP1164852). Prof RJN declares they are the Chair of the Clinical Advisory Committee, Westmead Fertility; External mentor at VinMec hospital; Editorial Editor at the journal "Fertility and Sterility"; and has received funding from the National Health and Medical Research Council (NHMRC) for the NHMRC Centre for Research Excellence in Womens Health in Reproductive Life (CRE WHiRL). A/Prof CS declares stock or stock options associated with CSL Ltd, Sigma Healthcare Ltd, Resmed Inc, Medical Developments International Ltd, Vitrafy Life Sciences Ltd, Intuitive Surgical, and Steris PLC. Prof GMC declares payment to their institution from the National Health and Medical Research Council (APP1164852). Prof CV declares payment to their institution from the National Health and Medical Research Council (APP1164852); research grants receive from Merck KGaA and Ferring; payments for honoraria from Merk Ltd, Merk Sharpe & Dohme, Ferring, Organon, Gedeon-Richter for being an invited lecturer in scientific meetings/conferences on multiple occasions as well as member of advisory boards for these companies who have a commercial portfolio in the field of assisted reproduction technology (ART); and speaking fees from IBSA, Vianex, Sonapharm; travel support for their participation in scientific meetings/conferences both nationally and internationally, usually as an invited speaker for the following companies - Merck Ltd, Merck Sharpe & Dohme, Ferring, Organon, Gedeon-Richter; unpaid involvement as a Board member of the Hellenic Society of Fertility and Sterility, Member of the Editorial Board of the journal "Human Reproduction", Senior Deputy of the Coordination Committee of the Special Interest Group "Reproductive Endocrinology" of the European Society for Human Reproduction and Embryology, Member of the Editorial Board of the journal "F&S Reviews", Member of the Editorial Board of the journal "RBM Online", Member of the Editorial Board of the journal "Reproductive Biology & Endocrinology", Member of the Editorial Board of the journal "Frontiers in Endocrinology", and Member of the Editorial Board of the journal "Reproductive Sciences". SubjectReproductive epidemiology

AimsTo estimate the impact of Englands proposed smokefree generation (SFG) policy on smoking at time of delivery (SATOD), adverse maternal and offspring outcomes, and the cost-effectiveness of the policy compared with no intervention. DesignDecision analytic modelling using the Economics of Smoking in Pregnancy (ESIP) model, taking a health service and personal social services perspective. Three scenarios (central, pessimistic, optimistic) were simulated deterministically and through probabilistic sensitivity analyses (10,000 iterations). SettingEngland, United Kingdom. ParticipantsA synthetic birth cohort of 19,843 women projected to give birth in 2042 at a mean maternal age of 28, representing the women affected by the first 15 years of the proposed 2027 SFG policy. Intervention and comparatorThe intervention is Englands proposed SFG policy to ban tobacco sales to those born on or after 1 January 2009. The comparator is no change in policy. MeasurementsThe primary outcome is incremental cost-effectiveness ratio (ICER) per quality-adjusted life year (QALY) gained for combined maternal lifetime and offspring outcomes to age 15. Secondary outcomes are maternal and offspring outcomes (analysed separately), reductions in adverse pregnancy and offspring outcomes, life years gained, and benefit-cost ratio. FindingsAcross all scenarios, SFG dominated the comparator, with projections of both cost savings to health and personal social services and QALY gains. In the central scenario, SFG was projected to save 338 GBP and gain 0.152 QALYs per mother and child combined. The policy was estimated to avert 18 stillbirths, 58 premature births and 260 low-birthweight infants in 2042, and reduce child asthma prevalence by 0.8 percentage points and child mortality by 0.7 percentage points at age 15. When controlling for uncertainty, this dominance persisted in probabilistic sensitivity analyses, with all three scenarios having a 100% chance of being cost-effective. Additional analyses assuming 15-fold increased costs for each of the three scenarios still found SFG to be dominant. ConclusionsIn England, introducing a smokefree generation policy is projected to reduce smoking in pregnancy, prevent adverse birth outcomes, and deliver substantial health gains for mothers and children while reducing healthcare costs.

BackgroundOsteomyelitis (OM) poses a significant clinical challenge, especially among individuals with diabetes mellitus (DM). While both type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) have been linked to an elevated risk of OM, the precise causal relationships remain uncertain. MethodsWe conducted Mendelian randomization (MR) analyses using summary statistics from genome-wide association studies (GWAS) to explore the causal effects of T1DM, T2DM, their complications, and glycemic traits on OM risk. The study utilized the inverse variance weighted (IVW) method, along with weighted median and MR-Egger for causal estimation, and performed various sensitivity analyses to ensure robustness. Multivariable MR (MVMR) analysis assessed direct effects, while two-step mediation MR analyses investigated the mediating role of DM between rheumatoid arthritis (RA) and OM. ResultsThe MR analysis unveiled distinct causal effects of T1DM and T2DM on OM risk. Genetically determined T2DM, rather than its complications, significantly increased OM risk (primary dataset: IVW: OR = 1.13, 95% CI 1.056-1.209, p = 4E-04; validation dataset: IVW: OR = 1.317, 95% CI 1.14-1.522, p =2E-04; Meta-analysis: OR=1.206; 95% CI 1.037-1.402; p=0.014), with no observable heterogeneity or horizontal pleiotropy. MVMR analysis confirmed the robustness of the causal association between T2DM and OM, even after adjusting for potential confounders such as body mass index. Conversely, T1DM and its complications showed no significant causal link with OM in either the primary dataset (IVW: p = 0.071), the validation dataset (IVW: p = 0.276), or the meta-analysis (IVW: p = 0.242). Additionally, there was no robust evidence supporting the causal risk of glycemic traits on OM. Mediation MR analysis underscored T2DM as a pivotal contributor to the differential effects of RA on OM. ConclusionsMendelian randomization analysis provides compelling evidence of a significant causal relationship between genetically determined T2DM and increased OM risk, while T1DM exhibits distinct causal effects. Additionally, our findings highlight the role of T2DM in mediating the association between RA and OM. Further research is warranted to elucidate the underlying mechanisms and guide targeted interventions for OM prevention and management in diabetic populations.

ImportanceMaternal diabetes (MD) and maternal obesity (MO) have been robustly established to confer health risks in offspring. Additionally, mounting evidence suggests that these fetal programming effects vary by sex, but whether these factors independently or interactively influence infant brain development remains unclear. ObjectivesTo characterize interactions between MD, MO, and sex on offspring subcortical brain volumes. Design, setting and participantsThis was a cross-sectional study of 1,966 infants from six international cohorts. ExposuresMD and MO Main outcomes and measuresMRI-based subcortical brain volumes (thalamus, amygdala, hippocampus, pallidum, putamen, caudate) were segmented and mixed effects models were used to examine associations, controlling for age at scan, prematurity, birthweight, maternal education, and intracranial volume. Backward elimination regression was used to identify the best fitting model (3-way interaction, 2-way interaction, no interaction) for each region and false discovery rate (FDR) corrections were applied. ResultsOf 1,966 infants, 46% were female (N=909), 9% were exposed to MD (N=172), and 21% were exposed to MO (N=386). MRI scans were performed at (mean{+/-}SD) 25.9{+/-}18.8 days of age. There was a significant interaction between MD, MO and sex in the thalamus (standardized {beta}=-0.32, 95%CI -0.54 to -0.11, FDR corrected P=0.014). In female infants, MD (standardized {beta}=-0.10, 95%CI -0.02 to -0.003, P=0.04) and MO (standardized {beta} =-0.09, 95%CI -0.14 to -0.03, P=0.003) were independently and negatively associated with thalamic volume. In males, a significant interaction between MD and MO was observed (standardized {beta} =-0.20, 95%CI -0.34 to -0.06, P=0.005), with post hoc analysis showing that males with combined exposure to MD and MO had lower thalamic volume compared to those with one or neither exposure (all Ps<0.05). In the hippocampus, an interaction between MO and infant sex was identified (standardized {beta} =0.15, 95%CI 0.05 to 0.26, FDR corrected P=0.015), whereby MO (independent of MD) was associated with lower offspring hippocampal volume in females only (standardized {beta} =-0.12, 95%CI -0.2 to -0.05, P=0.002). Conclusion and relevanceOur results suggest independent, interactive associations of intrauterine exposure to MD and MO with infant subcortical brain volumes, varying by sex. This has implications for future metabolic disorders, among other health risks. SummaryThis study aims to investigate how sex modulates the influence of intrauterine exposure to maternal diabetes (MD) and maternal obesity (MO) on infant subcortical brain volumes. We observed sex-specific associations of gestational exposure to MD or MO with infant brain volumes in regions critical for motivation, emotion, and signal integration. In female offspring, MD and MO were negatively and independently associated with thalamic volume, while MO was negatively associated with hippocampal volume. In males, combined exposure to MD and MO was associated with lower thalamic volume. Sex modulates the influence of prenatal exposure to MD and/or MO on early brain development. This has implications for future metabolic disorders, among other health risks.

Background and AimsExcessive use of alcohol is one of the leading risks for mortality and disability globally. In Australia, alcohol was the fifth-highest risk factor contributing to disease burden in 2019. Estimates of the avoidable (future) alcohol related burden can help make the case for investment in preventive measures. This analysis aims to estimate the avoidable burden related to alcohol consumption in Australia. Design, setting, participants and interventionThe Alcohol Policy model (TAP), a proportional multi-state lifetable model was developed and used to estimate the avoidable alcohol-related disease, injury and healthcare cost burden by comparing a scenario where the Australian adult population (aged [&ge;] 15 years) continues to drink alcohol at current rates to an identical population that consumes no alcohol. Taking 2020 as the base year, an open cohort was modelled over a 60-year time horizon. MeasurementsChanges in population alcohol consumption are modelled to lead to changes in 1) incident cases and mortality from alcohol-related diseases and injuries, 2) long-term health outcomes summarised as health adjusted life years (HALYs) and 3) healthcare costs. Results are reported in single years, over 25 years and 60 years (for HALYs and healthcare costs). No discounting was applied. FindingsOver the first 25 years, elimination of alcohol consumption at the population level could prevent over 25.9 million incident cases of alcohol-related diseases and injuries (89% acute causes, 1% cancers and 10% other modelled chronic diseases). This translates to 5.1 (95% uncertainty interval [UI] 4.0 to 6.2) million HALYs gained and AUD 55 (95% UI 36 to 75) billion saved in healthcare costs. Over a 60-year period, the potential health benefits increase to 17 (95%UI 14 to 21) million HALYs and is associated with AUD 68 (95%UI 9.6 to 130) billion in healthcare cost-savings. ConclusionOur findings show that the avoidable alcohol-related disease, injury and healthcare cost burden in Australia is substantial. These findings reinforce the need for investment in effective and cost-effective polices that reduce alcohol consumption.

BackgroundPregnancy requires a delicate balance between the maternal immune system and inflammatory responses. Elevated maternal body mass index (BMI) significantly compromises the immune system and increases systemic inflammation. High maternal BMI is associated with adverse pregnancy outcomes, including an increased risk of both pre-eclampsia and preterm birth, which may be mediated through immune-related blood cell changes. MethodsThis study used Mendelian randomisation (MR) to investigate the causal relationship between maternal BMI and pregnancy outcomes, including birth weight, placental weight, gestational duration, and pre-eclampsia. We applied two-step MR to assess whether immune-related blood counts, such as neutrophils, lymphocytes, and platelets, mediate these relationships. Single nucleotide polymorphism (SNP) effect estimates for maternal BMI and pregnancy outcomes were sourced from publicly available genome-wide association studies (GWAS), with pregnancy outcomes partitioned into maternal genetic effects to proxy genetic effects on the intrauterine environment. ResultsWe found that elevated maternal BMI causally increased placental weight ({beta}IVW = 0.164sd, P = 2.92 x 10-7) and risk of pre-eclampsia (ORiVW 1.75, P = 6.3 x 10-30). The effect of maternal BMI on placental weight was larger than its effect on birth weight. Mediation analysis found no evidence of the involvement of immune-related blood counts in these relationships. ConclusionsMaternal BMI has a significant impact on pregnancy outcomes, particularly by increasing placental weight and the risk of pre-eclampsia. These findings highlight BMI-driven placental adaptations as key contributors to pregnancy complications.

ObjectivesTo investigate the risk of miscarriage associated with first trimester antidepressant use. DesignPopulation-based cohort study. SettingUK Clinical Practice Research Datalink (CPRD) GOLD. Participants661 825 individuals who had 1 021 384 pregnancies in CPRD GOLD between 1996 and 2018. Main outcome measuresMiscarriage defined as a pregnancy loss prior to 24 weeks gestation. ResultsAmong the eligible pregnancies, 73 540 were prescribed antidepressants in trimester one (7.2%); 14.7% antidepressant prescribed pregnancies ended in miscarriage, as opposed to 12.4% of those not prescribed antidepressants. Antidepressant use during trimester one was associated with miscarriage in the unadjusted models (hazard ratio (HR) 1.21, 95% confidence interval (CI) 1.19 to 1.23), which attenuated following adjustment for covariates (aHR 1.04, 95% CI 1.02 to 1.06). These findings translated to an absolute risk adjusted for confounders of 13.1% (95% CI 13.0 to 13.2) in the unexposed compared to 13.6% (95% CI 13.3 to 13.8) in the first trimester antidepressant exposed. The propensity score matched model showed similar results (aHR 1.09, 95% CI 1.02 to 1.17, respectively). In those with depression or anxiety in the 12 months before pregnancy, our estimate didnt change (aHR 1.04, 95% CI 1.01 to 1.08). ConclusionFirst trimester antidepressant use was associated with a small yet clinically insignificant increase in risk of miscarriage, with no evidence suggesting taking antidepressants before pregnancy and into first trimester increases the risk of miscarriage. The conclusions are less clear for incident antidepressant use in trimester one, however issues including gestational dating in early pregnancy and probable residual confounding prohibit us from interpreting this observation as causal.

ObjectivesTo explore the association between antidepressant use during pregnancy and birth outcomes. DesignCohort study. SettingElectronic health record data. Participants2 528 916 singleton births from the UKs Clinical Practice Research Datalink (1996-2018), Norways Medical Birth Registry (2009-2020), and Swedens Medical Birth Register (2006-2020). Main outcome measuresStillbirth, neonatal death, pre- and post-term delivery, small and large for gestational age, and low Apgar score five minutes post-delivery. ResultsA total of 120 209 (4.8%) deliveries were exposed to maternal antidepressant use during pregnancy. Maternal antidepressant use during pregnancy was associated with increased odds of stillbirth (adjusted pooled OR (aOR) 1.16, 95% CI 1.05 to 1.28), preterm delivery (aOR 1.26, 95% CI 1.23 to 1.30), and Apgar score < 7 at 5 minutes (aOR 1.83, 95% CI 1.75 to 1.91). These findings persisted in the discordant sibling analysis, but with higher uncertainty. The adjusted predicted absolute risk for stillbirth was 0.34% (95% CI 0.33 to 0.35) among the unexposed and 0.40% (95% CI 0.36 to 0.44) in the antidepressant exposed. Restricting to women with depression or anxiety, the association between antidepressant exposure and stillbirth attenuated (aOR 1.07, 95% CI 0.94 to 1.21). Paternal antidepressant use was modestly associated with preterm delivery and low Apgar score. Most antidepressants were associated with preterm delivery (except paroxetine) and Apgar score (except mirtazapine and amitriptyline). ConclusionsMaternal antidepressant use during pregnancy may increase the risk of stillbirth, preterm delivery, and low Apgar score, although the absolute risks remained low. Confounding by severity of indication cannot be ruled out, as the severity of symptoms was not available. The modest association between paternal antidepressant use and both preterm delivery and low Apgar score suggests that residual confounding by familial environment cannot be ruled out.

ImportanceGlucocorticoid steroids are increasingly prescribed during the periconceptual period with the hypothesis that they reduce intrauterine inflammation and improve pregnancy rates. There is no robust evidence to support this practice, and the potential harm has not been well characterised. ObjectiveTo examine the risk of adverse perinatal outcomes associated with non-medically indicated glucocorticoid steroid use during the periconceptual period. DesignPopulation-wide linked retrospective cohort study. SettingVictoria, Australia. ParticipantsAfter excluding women with medical indications for steroid use (autoimmune disease, chronic asthma and previous organ transplant), our total cohort included 805,353 births between 2009 and 2021. ExposurePrescriptions of glucocorticoid steroids dispensed during the periconceptual period (12 weeks prior to conception - end of first trimester). Main Outcome(s) and Measure(s)Four primary outcomes were examined - spontaneous preterm birth before 37 completed weeks gestation, small for gestational age (<10th birthweight centile), major congenital abnormality and perinatal mortality. A doubly robust inverse probability weighted regression adjustment model was used to estimate the association between glucocorticoid steroid exposure and outcomes and presented as adjusted relative risks (aRR) with corresponding 95% confidence intervals (95% CI). ResultsThere were 12,301 (1.5%) pregnancies exposed to glucocorticoid steroids during the periconceptual period and 793,052 unexposed. Among the steroid-exposed cohort, major congenital abnormalities occurred in 4.5% of pregnancies, compared with 3.5% among those unexposed to steroids. This resulted in a 23% increased risk of major congenital abnormality (aRR 1.23, 95%CI 1.13-1.34). There were no significant associations between steroid exposure and spontaneous preterm birth (2.4 vs 2.5%; aRR 1.05, 95%CI 0.93-1.19), small for gestational age neonates (9.4 vs 9.3%; aRR 1.02, 95%CI 0.97-1.07) or perinatal mortality (0.5 vs 0.7%; aRR 1.05, 95%CI 0.87-1.26). Conclusions and RelevanceIn our cohort, periconceptual steroid exposure was associated with an increased risk of major congenital abnormality. In the absence of clear clinical indications, avoiding the prescription of periconceptual steroids is critically important. KEY POINTSO_ST_ABSQuestionC_ST_ABSWhat are the risks of adverse perinatal outcomes among patients prescribed glucocorticoid steroids during the periconceptual period? FindingsPericonceptual steroid use is associated with an increased risk of major congenital abnormality. MeaningIn the absence of an indication, periconceptual steroid use does not have clear evidence of benefit, there is now also evidence of significant harm and this practice should not be recommended.

IntroductionCurrent advice to improve fertility includes reducing alcohol and caffeine consumption, achieving healthy weight-range, and stopping smoking. Advice is informed by observational evidence, which is often biased by confounding. MethodsThis study uses data from the Norwegian Mother, Father and Child Cohort Study (MoBa) and the Medical Birth Registry of Norway. First, we analysed associations between health behaviours prior to pregnancy (alcohol and caffeine consumption, body-mass index (BMI) and smoking) and multiple indicators of fertility (including number of children, time to conception, and miscarriage) (n=83,128 women, 67,555 men), adjusting for birthyear, education and attention deficit and hyperactive-impulsive (ADHD) traits. Second, we used individual-level Mendelian randomisation (MR) to explore possible causal effects of health behaviours on fertility outcomes (n=27,216 women, 26,131 men). Finally, we performed summary-level MR for available outcomes (n=91,462-1,232,091) and conducted multi-variable MR to control for education and ADHD liability. ResultsIn observational analysis, higher BMI and smoking (and to a lesser extent caffeine) were predominantly associated with reduced fertility outcomes. Unexpectedly, higher alcohol consumption was associated with predominantly improved fertility outcomes. There was little evidence from individual-level MR analyses, except smoking and higher BMI were associated with younger age at first birth in women (mean difference in years, per SD increase in genetic score; smoking: -2.65 (95%CI: -3.57, -1.73); BMI: -0.11 (95%CI: -0.16, -0.08)) and men (smoking: -2.82 (95%CI: -4.07, -1.58); BMI: -0.17 (95%CI: -0.23, -0.11)). These results were replicated in the summary-level MR analysis, however effects attenuated after adjusting for education and ADHD liability. ConclusionsMost observational evidence for associations between health behaviours and fertility was not supported by MR analyses, suggesting possible residual confounding. Evidence from MR analyses supported an effect of smoking and higher BMI on younger age of first birth, but multivariable MR suggested this might be explained by underlying liability to ADHD and low educational attainment.

BackgroundWomen with only pregnancy terminations or only miscarriages have an increased mortality risk. We investigated the association between vaginal bleeding (VB) in pregnancy ending in childbirth and womens mortality. MethodsWe conducted a cohort study in Denmark, which included 1,354,181 women and their 3,162,317 pregnancies (1979-2017) followed through 2018. We ascertained 70,835 VB-affected pregnancies and comparators: 2,236,359 VB-unaffected pregnancies ending in childbirth; 589,697 terminations; and 265,940 miscarriages. We computed all-cause and cause-specific mortality rates per 10,000 person-years (PY) and hazard ratios (HRs) with 95% confidence intervals (CIs) using Cox proportional hazards regression adjusted for age, calendar year, preexisting conditions, and socioeconomic factors. ResultsThere were 2,320 deaths from any cause among women following VB-affected pregnancy (mortality rate: 15.2, 95% CI: 14.6-15.9 per 10,000 PY); 55,030 deaths following VB-unaffected pregnancy (12.7, 12.6-1.28); 27,500 deaths following a termination (21.9, 21.6-22.1), and 10,865 deaths following a miscarriage (19.2, 18.8-19.6). For comparison of VB-affected vs VB-unaffected pregnancies, associations with all-cause (HR: 1.14, 95% CI: 1.09-1.19), natural-causes (HR: 1.15, 95% CI: 1.09-1.22) and non-natural causes (HR: 1.27, 95% CI: 1.08-1.48) mortality attenuated in a sensitivity analysis of pregnancies recorded in 1994-2017 (HR: 1.00, 95% CI: 0.90-1.12, HR: 0.98, 95% CI: 0.85-1.14, and HR: 1.04, 95% CI: 0.71-1.51, respectively). Contrasts with remaining comparators did not suggest increased risks of all-cause, natural, or non-natural mortality causes. ConclusionsWe found no evidence of an increased risk of mortality in women following VB-affected vs VB-unaffected pregnancy, termination, or miscarriage. Key MessagesO_LIPrevious studies mostly focused on short-term outcomes of the newborns and mothers following the vaginal bleeding-affected pregnancy. This study investigated the association between vaginal bleeding in pregnancy ending in childbirth and womens mortality. C_LIO_LIThis registry-based cohort study found no evidence of an increased risk of all-cause or cause-specific mortality from natural or non-natural causes in women following vaginal bleeding-affected pregnancy compared with vaginal bleeding-unaffected pregnancy, termination, or miscarriage C_LI

ImportanceHigher maternal pre-pregnancy body mass index (BMI) is associated with adverse pregnancy and perinatal outcomes. However, which of these associations are causal remains unclear. ObjectiveTo explore the relation of maternal pre-pregnancy BMI with pregnancy and perinatal outcomes by integrating evidence from three different methods (i.e. multivariable regression, Mendelian randomization, and paternal negative control analyses). DesignTriangulation of multivariable regression, Mendelian randomization and paternal negative control results from up to 14 studies in the MR-PREG collaboration. SettingEurope and North America. ParticipantsUp to 497,932 women of European ancestry. ExposureMaternal pre- or early-pregnancy BMI based on self-reported or measured weight and height. Main outcomes and MeasuresMiscarriage, stillbirth, hypertensive disorders of pregnancy, gestational hypertension, preeclampsia, gestational diabetes, maternal anaemia, perinatal depression, pre-labour rupture of membranes, induction of labour, caesarean section, preterm birth, small- and large-for-gestational age, low and high birthweight, low Apgar score at 1 and 5 minutes, neonatal intensive care unit admission, and no initiation of breastfeeding. ResultsMultivariable regression, Mendelian randomization and paternal negative control analyses supported an association of higher maternal BMI with lower risk of small-for-gestational age and higher risk of hypertensive disorders of pregnancy, gestational hypertension, preeclampsia, gestational diabetes, pre-labour membrane rupture, induction of labour, large-for-gestational age, and high birthweight. As an example, higher maternal BMI was associated with higher risk of gestational hypertension in multivariable regression (OR: 1.67; 95% CI: 1.64, 1.71 per standard unit in BMI) and Mendelian randomization (OR: 1.58; 95% CI: 1.29, 1.93), which was not seen for paternal BMI (OR: 1.02; 95% CI: 0.99, 1.05). Findings did not support a relation between maternal BMI and perinatal depression. For other outcomes, evidence was inconclusive due to inconsistencies across the applied approaches or substantial imprecision in effect estimates from Mendelian randomization. Conclusions and RelevanceOur findings support a causal role for maternal pre-/early-pregnancy BMI on a range of adverse pregnancy and perinatal outcomes. Pre-conception interventions to support women maintaining a healthy BMI may reduce the burden of obstetric and neonatal complications. KEY POINTSO_ST_ABSQuestionC_ST_ABSWhat is the effect of higher maternal pre-/early-pregnancy body mass index (BMI) on adverse pregnancy and perinatal outcomes? FindingsWe found consistent evidence that higher maternal BMI was related to higher risk of gestational hypertension, preeclampsia, gestational diabetes, pre-labour membrane rupture, induction of labour, and having a large-for-gestational-age baby, lower risk of having a small-for-gestational-age baby, and not related to perinatal depression. MeaningThese findings highlight the importance of supporting women to achieve/maintain a healthy pre-conception BMI to reduce the burden of obstetric and neonatal complications.

SummaryThis 12-month study in 286 early postmenopausal women evaluated the efficacy and safety of SBD111, a synbiotic medical food, in reducing bone loss. SBD111 did not significantly reduce bone loss for the full cohort, but did produce evidence of reduced bone loss in women with osteopenia and BMI [&ge;] 30. PurposeTo determine the efficacy of SBD111, a synbiotic medical food comprising probiotics and prebiotics, in reducing bone loss in women post-menopause, including prespecified subpopulations of women with osteopenia or elevated BMI. MethodsIn this prospective, multicenter, double-blind, randomized, placebo-controlled clinical food trial (NCT05009875), 286 healthy, non-osteoporotic women between 1-6 years post-menopause were enrolled and consumed SBD111 (4.75x1010 colony forming units) or placebo (maltodextrin) capsules twice daily for 12-months. The primary endpoint was change in areal BMD at the lumbar spine (LS). Secondary endpoints included change in areal BMD at the femoral neck (FN) and total hip (TH), trabecular volumetric BMD at the LS, markers of bone turnover and inflammation, and safety. Changes in gut microbiome composition were exploratory. The hypotheses being tested were formulated before data collection. Results286 Women [age 55 {+/-} 3 years (mean {+/-} standard deviation)] were enrolled, with 221 (77%) completing the study. For the primary outcome, SBD111 administration was not associated with significantly less bone loss in the LS after 12-months [0.15% (-0.52%, 0.82%), mean effect size (95% CI) by linear mixed effects regression]. However, SBD111 was associated with reduced BMD loss in the TH for women with BMI [&ge;] 30 [0.97% (0.015%, 1.925%)] and modestly reduced BMD loss in the FN for women with osteopenia [0.89% (-0.277%, 2.051%)]. ConclusionsThese findings indicate SBD111 did not significantly reduce BMD loss for the full cohort. However, the trial produced evidence that SBD111 reduced bone loss in women with osteopenia and BMI [&ge;] 30.

This study aims to elucidate the association of circadian rhythm disruption with male testosterone levels and reproductive health using integrated epidemiological and experimental evidence. In the UK Biobank (n = 38,562), rest-activity rhythm amplitude was associated with lower serum testosterone levels (-0.21 nmol/L comparing the lowest vs. highest quartiles) and increased risks of orchitis and hydrocele (hazard ratios: 1.23 and 1.14, respectively). These findings were replicated in an occupational study of shift workers in China (n = 118), where shift work was independently associated with decreased testosterone levels ({beta} = -0.301, P = 0.015). In mouse models, circadian disruption induced testicular and epididymal atrophy, spermatogenic disorders, and suppressed circulating testosterone levels, accompanied by downregulation of key steroidogenic proteins. Together, these findings provide converging evidence that circadian rhythm disruption impairs testosterone synthesis, potentially through dysregulation of steroidogenesis, highlighting circadian rhythm as a modifiable environmental determinant of male reproductive health.