We describe the harmonisation of five UK electronic birth cohorts to the Observational Medical Outcomes Partnership (OMOP) Common Data Model, creating a large scale, standardised resource for maternal and child health research. The Mother and Infant Research Data Analysis (MIREDA) partnership developed and implemented reproducible guidelines for mapping maternal infant relationships and identifying pregnancy episodes within routinely collected healthcare data. Cohorts from England, Scotland, and Wales were transformed despite substantial heterogeneity in data structure, coding systems, and variable definitions. The resulting harmonised resource preserves each cohort as an independent dataset while enabling federated analyses to be conducted across sites without the need to share individual level data. Collectively, the cohorts capture over 17.5 million live births, providing sufficient scale to investigate rare exposures and outcomes, support trial emulation, and evaluate population level policy impacts across the UK. This article details the transformation pipeline and provides reusable methods to support extension to additional cohorts and networks. The harmonised datasets enable interoperable, reproducible research and facilitate cross national comparative studies in maternal and child health. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was funded by the Medical Research Council (MRC) Partnership Grant [MR/X02055X/1]. Born in South London (eLIXIR) is funded by an MRC Longitudinal Population Cohort Grant MR/X009742/1. Additional funding was provided by Health Data Research UK and the National Institute for Health and Care Research (NIHR) Birmingham Biomedical Research Centre. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The datasets are anonymised individual level data. No data were de-anonymised for use in the project. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data for is securely held at each cohort's Trusted Research Environment (TRE) and access is granted via the each TRE's request and governance frameworks.

BACKGROUND:Evidence suggests that the mental health effects of maternal exposure to childhood maltreatment may be transmitted to the next generation, possibly via alterations in maternal stress-sensitive endocrine functioning during gestation, with potential implications for fetal programming. However, empirical evidence supporting this mechanism remains limited. METHODS:We investigated whether maternal exposure to childhood maltreatment, assessed using the Childhood Trauma Questionnaire, was associated with the levels of 15 steroid hormones and the trajectories of 18 steroid hormones and their substrate-to-product ratios, serving as proxies of metabolizing enzyme activity during pregnancy. Maternal morning plasma samples were collected in mid pregnancy (median 20.29, Interquartile Range [IQR] 19.57-21.14) from 563 mothers, and across early (median 13.0, IQR 12.57-13.43), mid (median 19.29, IQR 19.0 - 19.71), and late (median 27.0, IQR 26.57-27.50) pregnancy from 188 mothers. RESULTS:Mothers with moderate-to-severe compared with none-to-low childhood maltreatment had significantly higher mid-pregnancy levels of aldosterone. They also had significantly higher increases in the levels of corticosterone, aldosterone, 11-deoxycortisol, cortisol, cortisone, androstenedione, and testosterone, and in the corticosterone/11-dehydrocorticosterone ratio from early to late pregnancy. These associations were not explained by mother-, child-, and study design-related covariates. CONCLUSIONS:These findings show that maternal exposure to childhood maltreatment may alter maternal steroid hormone functioning during gestation, potentially contributing to its intergenerational programming effects. The results highlight potential targets for prevention to mitigate the intergenerational transmission of these effects.

Prenatal maternal stress is linked to neurodevelopmental outcomes. Maternal hair cortisol concentration in pregnancy is associated with neonatal amygdala microstructure and structural connectivity, suggesting that amygdala is sensitive to antenatal stress. We investigated whether amygdala microstructure and/or connectivity associate with neurodevelopmental outcomes. 174 participants (105 preterm) underwent brain MRI at term-equivalent age and assessment of neurodevelopment, autistic traits, temperament, and executive function at 2 years corrected age. We calculated amygdala microstructure (fractional anisotropy, mean diffusivity, neurite density index, orientation dispersion index) and structural connectivity (mean fractional anisotropy) to 6 regions (insula, putamen, thalamus, inferior temporal gyrus, medial orbitofrontal cortex, rostral anterior cingulate cortex). We used linear regression to model amygdala-outcome associations, adjusting for gestational age at birth and at scan, sex, maternal education and postnatal depression score, and network-based statistics (NBS) for whole-brain analyses. Following correction for multiple comparisons, lower amygdala mean diffusivity (left: β = -0.32, p = 0.026, right: β = -0.38, p = 0.012), higher left amygdala neurite density index (β = 0.35, p = 0.026), and increased left amygdala-putamen connectivity (β = 0.31, p = 0.026) associated with higher autistic traits across the whole sample. NBS additionally revealed amygdala-involving networks associated with cognition and surgency among preterms, and gestation-dependent associations with autistic traits. Findings indicate that neonatal amygdala microstructure may be important in the development of autistic traits.

BACKGROUND:There is an unmet need for biomarkers that can dynamically track maternal vascular health and guide interventions in disordered pregnancies. The retina and choroid provide a window into the systemic vasculature. We aimed to characterize longitudinal trajectories of retinal and choroidal features during healthy pregnancy and explore differences associated with preeclampsia. METHODS:Overall, 251 pregnant women underwent multimodal retinal imaging with color fundus photography, scanning laser ophthalmoscopy, and optical coherence tomography at multiple antenatal (12±3 or 20±3 weeks' gestation and 36±3 weeks' gestation, n=183) or a single third-trimester (36±3 weeks' gestation, n=68) time point. Retinal and choroidal vascular features were extracted using an automated pipeline. We examined gestational trajectories of these features and their associations with blood pressure change and serum angiogenic factors. Trajectories were compared for women with preeclampsia and those without placental dysfunction. RESULTS:Significant reductions in measurements of retinal vessel caliber and density and of choroidal thickness, and increases in retinal thickness measurements, were seen over healthy pregnancy. These changes were not correlated with maternal blood pressure change. Third-trimester retinal arteriolar caliber and density were weakly correlated with placental growth factor (r=0.32, P<0.001 and r=0.31, P<0.001) and soluble fms-like tyrosine kinase 1 (r=-0.21, P=0.006 and r=-0.33, P<0.001) levels. Preeclampsia was associated with significantly greater reductions in retinal arteriolar caliber (P=0.022 for right eye, P=0.019 for left) and density (P<0.001 for each eye) across gestation. CONCLUSIONS:Retinal and choroidal features change throughout pregnancy, and these trajectories are altered in preeclampsia. REGISTRATION:URL: https://doi.org/10.1186/ISRCTN40843826; Unique identifier: ISRCTN40843826.

Importance:Preterm birth is a leading cause of atypical brain development and cognitive impairment; however, there are sparse data on its association with statutory educational assessments. Objective:To evaluate school readiness at age 5 years and educational attainment at age 6 to 7 years in children born very preterm and to identify the early-life, neonatal, and socioeconomic factors associated with attainment. Design, Setting, and Participants:This retrospective cohort study included all infants born before gestational age (GA) 32 weeks in England who received care in a neonatal unit and survived to discharge. A linkage between the National Neonatal Research Database and the National Pupil Database was created to integrate neonatal clinical data with educational outcomes. The data analysis was performed between October 1, 2024, and October 31, 2025. Exposure:Gestational age and area-level socioeconomic deprivation. Main Outcomes and Measures:The main outcome was school readiness at age 5 years (as measured by the Early Years Foundation Stage Profile [EYFSP]) and attainment in reading, writing, mathematics, and science at age 6 to 7 years. For each outcome, prevalence of not meeting the expected level of attainment across indices of socioeconomic deprivation and GA stratified by 23 to 26 weeks and 27 to 31 weeks were calculated. Results:Of a total of 15 857 children included (2595 born at GA 23-26 weeks [16.3%] and 13 262 born at GA 27-31 weeks [83.7%]; 8449 boys [53.3%]), 8602 (56.6%) did not meet the school readiness level at age 5 years, and 7789 (51.8%) did not meet expected attainment at age 6 to 7 years for writing, 7216 (48.1%) for math, 6354 (41.9%) for reading, and 5449 (36.0%) for science. Children born at GA 23 to 24 weeks had a higher odds of not meeting expected school readiness levels compared with those born at 31 weeks (adjusted odds ratio [AOR], 2.86 [95% CI, 2.19-3.73]). Children born in areas with the most deprivation had a higher risk of underattainment compared with those in areas with the least deprivation (EYFSP: AOR, 1.27 [95% CI, 1.11-1.45]). In adjusted models, male sex and season of birth were associated with increased risk (EYFSP: AOR, 1.96 [95% CI, 1.82-2.11] and 2.64 [95% CI, 2.41-2.90], respectively) alongside several potentially modifiable risk factors, including smoking during pregnancy (AOR range from 1.19 [95% CI, 1.08-1.31] for math to 1.31 [95% CI, 1.19-1.44] for reading); exposure to postnatal corticosteroids (EYFSP: AOR, 1.37 [95% CI, 1.13-1.65]); severe acquired neonatal brain injuries, particularly periventricular leukomalacia (EYFSP: AOR, 3.05 [95% CI, 2.04-4.58]) and hydrocephalus (EYFSP: AOR, 2.47 [95% CI, 1.48-4.13]); comorbidities of preterm birth, including necrotizing enterocolitis (EYFSP: AOR, 1.60 [95% CI, 1.20-2.14], retinopathy of prematurity (EYFSP: AOR, 1.46 [95% CI, 1.10-1.93], and bronchopulmonary dysplasia (EYFSP: AOR, 1.30 [95% CI, 1.18-1.44]); and nutrition during neonatal care (EYFSP: AOR, 1.19 [95% CI, 1.07-1.33] and 1.51 [95% CI, 1.37-1.66] for mixed feeding and exclusive formula feeding, respectively, vs breastfeeding). Conclusions and Relevance:This cohort study of children born before GA 32 weeks found that preterm birth was associated with a substantial and persistent risk for educational underattainment across early school years, especially when combined with socioeconomic deprivation. Improving outcomes for children born preterm may require reducing social inequalities and minimizing comorbidities of preterm birth. Several modifiable early-life exposures offer practical targets for intervention, including maternal nonsmoking, appropriate corticosteroid use, and breastfeeding. Deferred school entry or targeted academic support may benefit children born very preterm, depending on birth season. These strategies may help parents, clinicians, educators, and policymakers improve long-term educational attainment for children born preterm.

Objectives To quantify the incidence of gestational diabetes mellitus in England, determine inequalities in diagnoses and pregnancy outcomes, and assess the indirect effects of the covid-19 pandemic. Design Contemporary, cross sectional observational study. Setting Primary and secondary care data from NHS England, based on the Hospital Episode Statistics Admitted Patient Care dataset, 1 January 2018 to 31 December 2022. Participants 2 314 365 women, aged 16-50 years, who gave birth to 2 758 170 babies in 184 hospitals. Main outcome measures Rates of gestational diabetes, infants born small for gestational age or large for gestational age, and emergency caesarean births, summarised yearly and monthly, based on socioeconomic deprivation and ethnic group. Results Diagnoses of gestational diabetes increased from about 8% in 2018 to >12% in 2022. The increase was greatest for individuals from non-white ethnic groups (23% for Asian women) or those living in deprivation (14%). Mothers from these backgrounds were also at greater risk of adverse pregnancy outcomes, such as emergency caesarean birth (odds ratio for black mothers 1.36, 95% confidence interval 1.34 to 1.38), preterm birth (odds ratio for deprived mothers 1.29, 1.27 to 1.31), or having an infant small for gestational age (odds ratio for Asian mothers 2.42, 2.39 to 2.45). Also, a diagnosis of gestational diabetes for these women was associated with an increase in the odds of preterm birth. Changes to screening methodology for gestational diabetes during the covid-19 pandemic had no significant effect on the number of diagnoses. Conclusions The study found that one in eight mothers in England had a diagnosis of gestational diabetes, and that profound health inequalities exist in their outcomes. Strategies are urgently needed to provide and improve care for this high risk group, given the implications of gestational diabetes on the short and long term health outcomes for mothers and babies.

OBJECTIVE:Pregnancy outcomes may be improved by optimizing preconception health; however, designing preconception research studies presents distinct challenges. These include estimating feasible recruitment, attrition, and expected pregnancy rates. We systematically reviewed existing preconception studies to quantify recruitment rates, retention, and pregnancies to inform feasibility assessments and sample size calculations for future preconception and pregnancy-related research. DATA SOURCES:NHS Knowledge Hub, TRIP database, Cochrane Library, PubMed, MEDLINE, Embase, CINAHL, Emcare, Web of Science, Scopus, ASSIA, and PsycINFO were searched (database inception-September 2025). STUDY ELIGIBILITY CRITERIA:Eligible studies reported recruitment of nonpregnant women intending to conceive into studies reporting at least one pregnancy outcome. STUDY APPRAISAL AND SYNTHESIS METHODS:Risk of bias and quality assessment were performed using the Newcastle-Ottawa Scale and Cochrane Risk of Bias tool, followed by the Grading of Recommendations Assessment, Development and Evaluation framework. Statistical analysis was performed in R v4.4.1. RESULTS:79 studies (n=117,603 participants; n=53,838 pregnancies) were included. Overall, risk of bias was fair across studies. The heterogeneity across all meta-analyses was high. Recruitment via healthcare settings yielded higher weekly recruitment than other methods (median 9 participants/week; interquartile range, 4-19), compared with studies using only non-healthcare-based recruitment methods (2; interquartile range, 2-4). Weekly recruitment was higher in larger studies and in low- and middle-income countries compared to high-income countries. Attrition prior to conception was lower in observational than in interventional studies and among those with fertility issues compared to those with other medical comorbidities. Among participants who conceived, retention during pregnancy was high across all studies (97.7%; interquartile range, 95.2-99.0), with higher retention in interventional than in observational studies. CONCLUSION:This review provides a quantitative synthesis of recruitment and retention patterns in preconception research, addressing a critical but understudied period to improve maternal and child health. We found that participant characteristics, recruitment strategy, and study design substantially influence recruitment rates, preconception attrition, and pregnancy retention, with important implications for feasibility assessment, anticipated loss to follow-up, and sample size estimation. Our findings highlight the need for recruitment of diverse populations and methodological tools tailored to preconception research. These findings offer empirically grounded parameters to support the design of more efficient, inclusive, and adequately powered preconception and pregnancy-related studies.

AIMS:There is emerging evidence that maternal hyperglycaemia may be associated with adverse offspring neuro-behavioural outcomes, which are foundational to educational success. We hypothesised that higher levels of maternal glucose would be associated with poorer educational attainment in early childhood. METHODS:The sample included 13,627 children from the UK's Born in Bradford cohort. Exposures included maternal fasting glucose, 2-h post-load glucose and a clinical diagnosis of gestational diabetes. The primary outcome was failure to achieve a 'good level of development' on the Early Years Foundation Stage Profile at age five. The association was tested using multivariable Poisson regression, accounting for sibling clusters and using multiple imputation for missing data. RESULTS:Higher maternal fasting glucose (at 26-28 weeks gestation) was associated with an increased risk of failing to achieve a good level of development (adjusted RR 1.04; 95% CI 1.00, 1.08; p = 0.034). This association appeared stronger in children of Pakistani ethnicity compared to White British ethnicity. No association was found for 2-h post-load glucose or gestational diabetes diagnosis. CONCLUSIONS:These findings offer insights into the developmental origins of inequalities in child educational outcomes and highlight potential opportunities to optimise future health and learning through interventions during pregnancy.

Abstract BACKGROUND Adrenal insufficiency is primarily treated with replacement of cortisol, which is the predominant circulating glucocorticoid. Human adrenals also secrete corticosterone and emerging evidence suggests this may be a safer glucocorticoid replacement therapy. However, little is known about corticosterone in humans, particularly related to its metabolism. METHODS To investigate the secretion and metabolism of corticosterone in comparison with cortisol, we: 1) investigated the diurnal rhythm of circulating cortisol/ corticosterone in 7 healthy volunteers; 2) quantified A-ring reduction of both hormones in human hepatic cytosol and 3) measured glucocorticoid metabolites in vivo in 24 healthy men; 4) determined the pharmacokinetics of corticosterone via intravenous infusion of 2,2,4,6,6,17α,21,21-[ 2 H] 8 -corticosterone; 5) assessed the response of corticosterone and cortisol to 1mcg ACTH in 279 healthy volunteers. RESULTS The natural diurnal rhythm of corticosterone closely mirrored that of cortisol, and accounted for ∼3% of total circulating glucocorticoid concentrations. Daily corticosterone production, as measured through urinary steroid profiling, was approximately 10-fold lower than cortisol, and corticosterone demonstrated substantially greater metabolism by both 5α- and 5β-reductase than cortisol. In keeping with greater metabolism, the half-life of corticosterone was 28.5 ± 3.3 minutes. Finally, corticosterone demonstrated a greater relative rise in response to ACTH than cortisol, particularly in men, revealing sex-specific differences. CONCLUSIONS Corticosterone is a dynamic glucocorticoid with faster metabolism and greater response to stimulation than cortisol in humans. These data raise the possibility of distinct roles for these two glucocorticoids and highlight important pharmacokinetic differences with implications for the therapeutic potential of corticosterone replacement in humans.

Preterm birth is closely associated with immune dysregulation in early life and subsequent learning and psychiatric disorders, but methods for stratifying infants at risk remain elusive. Protein epigenetic Scores (EpiScores) are DNA methylation (DNAm)-based proxies of circulating proteins and can capture health-related exposures such as chronic inflammation. EpiScore of C-reactive protein (DNAm CRP) is associated with inflammatory burden in early life, atypical brain development following preterm birth and adult cognitive ability. To evaluate the utility of neonatal protein EpiScores for predicting childhood cognition, we examined associations of DNAm CRP and 42 other saliva-based EpiScores enriched for inflammatory proteins correlated with low gestational age, with cognition in a cohort of 231 children, including 154 preterm children assessed at 2 years and 127 preterm and term-born children assessed at 5 years. DNAm CRP was negatively associated with 5-year Mullen Scales of Early Learning Composite (ELC) (β = -0.273, p = 0.002). Association magnitudes were larger for children born earlier (DNAm CRP x gestational age, βinteraction = 0.181). DNAm CD209 was positively associated with 5-year ELC (β = 0.267, adjusted p < 0.005). Fourteen other EpiScores were nominally associated with either 2-year Bayley-III Cognitive composite or 5-year ELC (absolute β range 0.180 to 0.245, p < 0.05). For preterm children, associations of DNAm CCL18 with 2-year cognition (β = 0.182, p = 0.039) and of DNAm CRP (β = -0.318, p = 0.021) and DNAm CRTAM (β = -0.307, p = 0.008) with 5-year cognition remained significant after adjustment for inflammatory exposures. We demonstrate associations between a range of neonatal salivary EpiScores and childhood cognition, suggesting the clinical value of EpiScores as early life markers of cognitive ability in children at risk of impairment warrants further investigation.

Global economic development has been associated with an increased prevalence of obesity and related health problems. Increased caloric intake and reduced energy expenditure are both cited as development-related contributors to the obesity crisis, but their relative importance remains unresolved. Here, we examine energy expenditure and two measures of obesity (body fat percentage and body mass index, BMI) for 4,213 adults from 34 populations across six continents and a wide range of lifestyles and economies, including hunter-gatherer, pastoralist, farming, and industrialized populations. Economic development was positively associated with greater body mass, BMI, and body fat, but also with greater total, basal, and activity energy expenditure. Body size-adjusted total and basal energy expenditures both decreased approximately 6 to 11% with increasing economic development, but were highly variable among populations and did not correspond closely with lifestyle. Body size-adjusted total energy expenditure was negatively, but weakly, associated with measures of obesity, accounting for roughly one-tenth of the elevated body fat percentage and BMI associated with economic development. In contrast, estimated energy intake was greater in economically developed populations, and in populations with available data (n = 25), the percentage of ultraprocessed food in the diet was associated with body fat percentage, suggesting that dietary intake plays a far greater role than reduced energy expenditure in obesity related to economic development.

BACKGROUND:Children born preterm face elevated risks of neurodevelopmental impairments across domains. Prior studies have relied on expert-imposed typologies within single domains. This study applies statistical learning to a national database to identify transdomain clusters and their maternal and neonatal predictors. METHODS:Latent class analysis (LCA) was used to derive transdomain clusters from parent-reported visual, auditory, neuromotor, and communication impairments in preterm-born children at two years corrected age using the UK National Neonatal Research Database data (N = 27,261). Replication was conducted in an independent sample from Wales (N = 975). Clusters were clinically validated using cerebral palsy diagnosis, Bayley Scales of Infant and Toddler Development (3rd edition), and global neurodevelopmental delay. Random forest identified cluster-specific and shared predictors. FINDINGS:Four homogeneous clusters were derived (silhouette score = 0.71) and replicated in Wales with high balanced accuracy (93%): (1) typically developing (84.8%), (2) communication impairments (8.4%), (3) neuro-motor impairments (4.1%), and (4) multiple neuro-morbidity (2.7%). Clusters had high clinical validity and were distinguishable by shared and cluster-specific predictors. Neonatal brain injuries were most predictive of neuro-motor and multiple neuro-morbidity clusters. Birthweight, gestational age, socio-economic deprivation, and sex were stronger predictors of the communication cluster than preterm co-morbidities. INTERPRETATION:This study provides first evidence of the transdomain nature of neurodevelopmental impairments after preterm birth using LCA. The finding that socio-demographic and perinatal factors rather than co-morbidities increase the risk of communication impairment highlights the importance of environmental modification alongside clinical interventions. Applying data-driven approaches to routinely collected data may offer a cost-effective way to stratify at-risk children and inform targeted support strategies. FUNDING:UKRI Medical Research Council.

People with severe mental illness have high rates of obesity, type 2 diabetes, and cardiovascular disease. Emerging evidence suggests that metabolic dysfunction may be causally linked to the risk of severe mental illness. However, more research is needed to identify reliable metabolic markers which may have an impact on mental health outcomes, and to determine the mechanisms behind their impact. In the METPSY research study, we will investigate the relationship between metabolic markers and clinical outcomes of severe mental illness in young adults. We will recruit 120 young adults aged 16–25 years living in Scotland with major depressive disorder, bipolar disorder, schizophrenia, or no severe mental illness (controls) for a prospective observational study. We will assess clinical symptoms at three in-person visits (baseline, 6 months, and 12 months) using the Structured Clinical Interview for DSM-5, and collect blood samples at each of these visits for agnostic profiling of metabolic biomarkers through an untargeted metabolomic screen, using the rapid hydrophilic interaction liquid chromatography ion mobility mass spectrometry method (RHIMMS). Participants will also complete remote assessments at 3 and 9 months after the baseline visit: Ecological Momentary Assessments to measure mental health, wrist actigraphy to measure rhythms of rest and activity, and continuous glucose monitoring to measure metabolic changes. Throughout the 12-month enrolment period, we will also measure objective markers of sleep using a radar sleep monitor (Somnofy). Using advanced statistical techniques and machine learning analysis, we will seek to better understand the mechanisms linking metabolic health with mental health in young adults with schizophrenia, bipolar disorder, and severe depression. Clinical trial number: Not applicable

Placental ageing refers to the physiological accumulation of a senescent phenotype over a healthy pregnancy. In pregnancies affected by complications such as pre-eclampsia and fetal growth restriction, placental ageing is notably accelerated and observed at an earlier gestational age. Metformin is used during pregnancy for an increasing variety of indications, including treatment of gestational diabetes, and may have a role in slowing cellular ageing. It is therefore essential to understand the potential impact of metformin on placental ageing. Placental samples (n = 105) were obtained from women with body mass index ≥30 kg/m2 and who were randomized to treatment with metformin or placebo during pregnancy. Ageing was assessed by measuring telomere length, histological examination, and using array-based technologies to investigate gene expression and methylation. Results were validated using isolated human trophoblasts treated in vitro with metformin, and in a complementary mouse model. There were no differences between metformin-exposed and control placentas in terms of telomere length, fibrosis or calcification. There were no differences in placental gene expression or methylation patterns by metformin status. In our mouse model, no genes classically associated with cellular ageing were differentially expressed and no senescence pathway showed evidence of enrichment with metformin treatment. There was no evidence that metformin either slows or accelerates placental ageing pathways in the complementary models that we investigated. Our findings are reassuring with regard to the safety of metformin used to treat gestational diabetes, but do not support a role for metformin in the prevention of adverse pregnancy outcomes in non-diabetic women. KEY POINTS: Accelerated placental ageing, where the senescent phenotype that normally accumulates over a healthy pregnancy is observed at a premature gestational age, is associated with adverse pregnancy outcomes. Metformin has been proposed as an anti-ageing drug elsewhere. Therefore, metformin could alter the trajectory of placental ageing and prevent associated pregnancy complications. The present study incorporated human data from a randomized clinical trial and complementary models. Metformin did not impact methylation-predicted gestational age, telomere length, gene expression or histological ageing in human placentas treated in vivo, isolated trophoblasts treated in vitro or mouse models. Metformin neither decelerated nor accelerated placental ageing, thereby supporting its continued use in the obstetric setting, for instance in the treatment of gestational diabetes. Metformin cannot be recommended to prevent adverse pregnancy outcomes because we found no evidence suggesting it decelerates placental ageing. Further research is warranted to find drug therapies for this purpose.

Low socioeconomic status (SES) has been associated with an increased risk of depression and psychiatric disorders in general. In this systematic review and meta-analysis, we provide an estimate of the risk of clinical depression associated with low SES across cultures, age groups, and study designs. Finally, we tested whether associations between SES and depression differed by the income of the country in which the study was conducted. A literature search across 5 databases returned 7943 studies. Title, abstract, and full-text screening resulted in 162 included studies of which 122 were meta-analyzed, 22 were included in a cross-sectional narrative review, and 19 studies were included in a longitudinal narrative review. Meta-analyses were divided into risk estimates for composite SES, income, education, and employment. Sensitivity analyses based on differences in economic situation in the country of study origin were performed to investigate a possible source of between-study heterogeneity. Low SES was associated with an increased risk of depression across all measures of SES. Low income was associated with the highest odds ratio for depression (1.96; 95% CI, 1.53-2.52). Sensitivity analyses revealed no significant differences in between-study heterogeneity or risk of depression between high- and low-income economy groups. Comparable risks of depression across economy groups suggest that income relative to your peers, rather than absolute income, is a risk factor for depression. Preventive measures and possible policy interventions are discussed.

BACKGROUND:Clinical guidelines in the UK and elsewhere do not specifically address hybrid closed loop (HCL) use in the postpartum period when the demands of caring for a newborn are paramount. Our aim was to evaluate the safety and efficacy of HCL use during the first 6 months postpartum compared with standard care. METHODS:In this prespecified extension to a multicentre, randomised controlled trial, pregnant women with type 1 diabetes at nine UK sites were followed up for 6 months postpartum. Eligible participants (AiDAPT participants recruited after the implementation of the postpartum protocol amendment approval, those still pregnant or within six months of delivery at the time of amendment implementation and still using HCL or continuous glucose monitoring [CGM] therapy) continued their randomly assigned treatment, either standard insulin therapy with CGM or HCL therapy (CamAPS FX system version 0.3.1, CamDiab, Cambridge, UK). Participants were randomised in a 1:1 ratio with stratification by clinical site using randomly permuted block sizes of 2 or 4. The primary outcome was the between-group difference in percentage time in range ([TIR] 3·9-10·0 mmol/L [70-180mg/dL]), measured during the periods of month 0 up to 3, months 3 to 6, and over 6 months postpartum. The study is registered at ClinicalTrials.gov (ISRCTN56898625) and is complete. FINDINGS:Of the 124 AiDAPT trial participants, 66 (53%) were ineligible for inclusion in the postpartum extension, and 57 participants consented to continue their treatment per original random allocation. The mean age was 31 years (SD 4), and all participants had early pregnancy HbA1c 59·4 mmol/mol (SD 10·5 [7·6% SD 1·0%]). In the 6 months postpartum, mean time with glucose levels within the target range was higher in the HCL group compared with the standard care group (72% [SD 12%] vs 54% [17%]), with an adjusted treatment difference of 15% (95% CI 7 to 22). Results for hyperglycaemia (>10·0 mmol/L) and mean CGM glucose also favoured HCL (-14% [95% CI -23% to -6%] and -1·3 mmol/L [-2·3 to -0·3], respectively). Hypoglycaemia rates were low, with no between-group differences (2·4% vs 2·6%). There were no treatment effect changes depending on postpartum period (0 up to 3 months vs 3 to 6 months) and no unanticipated safety problems. INTERPRETATION:Participants in the HCL group maintained 70% TIR during the first 6 months postpartum, supporting continued use of HCL rather than standard insulin therapy for people with diabetes once they have given birth. FUNDING:National Institute for Health Research, Juvenile Diabetes Research Foundation, and Diabetes Research & Wellness Foundation. CGM devices were provided by Dexcom at a discounted price.

Gestational diabetes mellitus (GDM) is one of the most common pregnancy complications, with both short- and long-term consequences. We conducted a user needs assessment of GDM care and management through semi-structured interviews with healthcare professionals and women with GDM. Examining current GDM care, we found that time management, number and attendance of appointments, information, resources and education, and cultural social and language differences were affecting factors. Furthermore, participants suggested a digital tool to include notification and prompts, risk stratification, and information and resources. The results of this study form the foundation of a user-centred digital tool that has the potential to transform GDM care and management.

Importance:International guidelines recommend the use of antenatal corticosteroids (ACS) in pregnancies at risk of imminent preterm birth before 34 weeks' gestation. However, whether ACS leads to long-term risk of infection from childhood to adulthood is unknown. Objective:To determine whether preterm (<37 weeks' gestation) and full-term (37-41 weeks' gestation) children exposed to ACS are more susceptible to respiratory and nonrespiratory infections compared with ACS-unexposed children throughout childhood and adolescence. Design, Setting, and Participants:This population-based cohort study used data from the multicenter Consortium for the Study of Pregnancy Treatments (Co-OPT) study, including data from nationwide registries for mothers and their children in Finland and Scotland. Singleton children born from 1997 to 2018 and 2006 to 2018 in Scotland and Finland, respectively, were followed up until 2018, death, or first infection. Data were analyzed between June 2022 and October 2023. Exposures:Maternal ACS treatment. Main Outcomes and Measures:Primary and secondary outcomes were the first diagnosis of respiratory or nonrespiratory infection after birth-related hospital discharge. Outcomes were stratified by gestational age at birth. Results:Among 1 548 538 included mother-child pairs (mean [SD] maternal age, 29.4 [5.7] years; mean [SD] gestational age at birth, 39.2 [1.7] weeks; 759 082 [49.0%] female neonates), 49 263 children (3.2%) were ACS-exposed, of whom 34 806 (70.7%) were preterm and 14 457 (29.3%) were full term at birth. ACS-exposed children had more respiratory and nonrespiratory infections than nonexposed children (incidence rate, 65.2 vs 39.8 and 30.0 vs 17.9 per 1000 person-years, respectively). Compared with nonexposed children, higher risks for respiratory and nonrespiratory infections were found among ACS-exposed children born at 34 weeks 0 days to 36 weeks 6 days' gestation (adjusted hazard ratios [HRs], 1.10 [95% CI, 1.06-1.14] and 1.19 [95% CI, 1.15-1.24]), 37 0/7 to 38 6/7 weeks' gestation (adjusted HRs, 1.27 [95% CI, 1.21-1.32] and 1.17 [95% CI, 1.11-1.23]), and 39 weeks 0 days to 41 weeks 6 days' gestation (adjusted HRs, 1.23 [95% CI, 1.16-1.30] and 1.31 [95% CI, 1.22-1.40]). However, ACS-exposed children born at 28 weeks 0 days to 31 weeks 6 days' gestation and 32 weeks 0 days to 33 weeks 6 days' gestation showed no association between ACS exposure and respiratory and nonrespiratory infections. Conclusion and Relevance:In this cohort study, exposure to ACS was associated with increased risks of infections in full-term children until age 21 years. In preterm children born before 34 weeks' gestation, no association between ACS and infections was found. To minimize the adverse effects of ACS treatment, more stringent criteria for ACS administration and better prediction tools for preterm birth are required.