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IntroductionPrevious trials of dietary interventions to prevent gestational diabetes mellitus (GDM) have yielded only limited success. Low-carbohydrate diets have shown promise for the treatment of type 2 diabetes, but there is no evidence to support their use in pregnancy. The aim of this study is to explore the feasibility of a moderately reduced-carbohydrate dietary intervention delivered from mid-pregnancy alongside routine antenatal care.Methods and analysisThis is a feasibility randomised controlled trial (RCT) with embedded qualitative study. Sixty women who are pregnant 2 at their antenatal booking appointment, will be randomised 2:1 intervention or control (usual care) and followed up until delivery. The intervention is a moderately reduced-carbohydrate diet (~130–150 g total carbohydrate/day), designed to be delivered alongside routine antenatal appointments. Primary outcomes are measures of adoption of the diet and retention of participants. Secondary outcomes include incidence of GDM, change in markers of glycaemic control, gestational weight gain, total carbohydrate and energy intake. Process outcomes will examine resources and management issues. Exploratory outcomes include further dietary changes, quality of life, maternal and neonatal outcomes, and qualitative measures.Ethics and disseminationThis trial was reviewed and approved by the South-Central Oxford B Research Ethics Committee NHS National Research Ethics Committee and the Health Research Authority (Reference: 20/SC/0442). The study results will inform whether to progress to a full-scale RCT to test the clinical effectiveness of the RECORD programme to prevent GDM in women at high risk. The findings will be published in peer-reviewed journals and presented at conferences.Trial registration numberISRCTN16235884.

Innovations in digital health and machine learning are changing the path of clinical health and care. People from many different geographies and cultures can benefit from the mobility of wearable devices and smartphones to monitor their health in a ubiquitous manner. This paper focuses on reviewing the digital health and machine learning technologies used in gestational diabetes ̶ a subtype of diabetes that occurs during pregnancy. Despite a large number of patients with gestational diabetes, only a handful of digital health applications have been deployed in clinical practice. This paper reviews sensor technologies in blood glucose monitoring devices and machine learning fused digital health innovations for gestational diabetes monitoring and management in both clinical and commercial settings. It is one of the first comprehensive reviews in this area to the best of our knowledge. In conclusion, there is a need to (1) develop digital health technologies and clinically interpretable machine learning methods for patients with gestational diabetes, assisting health professionals with treatment monitoring and planning; (2) adapt and develop clinically proven devices for patient self-management of health and well-being at the hospital and home settings thereby facilitating timely intervention; and (3) ensure innovations are affordable and sustainable for women everywhere Innovations in digital health and machine learning are changing the path of clinical health and care. People from different geographical locations and cultural backgrounds can benefit from the mobility of wearable devices and smartphones to monitor their health ubiquitously. This paper focuses on reviewing the digital health and machine learning technologies used in gestational diabetes ̶ a subtype of diabetes that occurs during pregnancy. This paper reviews sensor technologies used in blood glucose monitoring devices, digital health innovations and machine learning models for gestational diabetes monitoring and management, in clinical and commercial settings, and discusses future directions. Despite one in six mothers having gestational diabetes, digital health applications were underdeveloped, especially the techniques that can be deployed in clinical practice. There is an urgent need to (1) develop clinically interpretable machine learning methods for patients with gestational diabetes, assisting health professionals with treatment, monitoring, and risk stratification before, during and after their pregnancies; (2) adapt and develop clinically-proven devices for patient self-management of health and well-being at home settings (“virtual ward” and virtual consultation), thereby improving clinical outcomes by facilitating timely intervention; and (3) ensure innovations are affordable and sustainable for all women with different socioeconomic backgrounds and clinical resources.

Purpose The purpose of this paper is to analyse the characteristics of the Latin American participation in the United Nations Mission in Colombia (UNMC), looking into the contributions of regional actors to the peace process in the immediate post-conflict. Testimonies from Latin American actors involved in the demobilization, disarmament and reintegration process help identify their perceptions of strengths and shortcomings of the mission. This paper analyses both the enduring relevance of their individual/institutional trajectories and the adaptations needed to implement the Peace Agreement in the Colombian context. Design/methodology/approach This is an exploratory case study. Primary data collection relied on in-depth, semi-structured interviews, allowing the authors to tap into how the trajectories of those involved help explain continuities and innovations of the UNMC regarding previous UN missions. Findings This paper argues that cultural factors are central to understand how Latin Americans participated in the UNMC. The design of the Monitoring and Verification Mechanism and the inclusion of a strong gender agenda make the UNMC a salient case, both for scholars studying Latin American presence in peace processes and for those looking into peace building, more generally. Originality/value The fieldwork, conducted with military/security forces, UN officials and civilians, has made available a diverse spectrum of testimonies that provide crucial insights into “lessons learned”, contributing to tracing the trajectories of these actors and providing insights for the improvement of future political and peacebuilding multilateral missions.

Background Previous epidemiological studies have found positive associations between maternal infections and childhood leukaemia; however, evidence from prospective cohort studies is scarce. We aimed to examine the associations using large-scale prospective data. Methods Data were pooled from six population-based birth cohorts in Australia, Denmark, Israel, Norway, the UK and the USA (recruitment 1950s-2000s). Primary outcomes were any childhood leukaemia and acute lymphoblastic leukaemia (ALL); secondary outcomes were acute myeloid leukaemia (AML) and any childhood cancer. Exposures included maternal self-reported infections [influenza-like illness, common cold, any respiratory tract infection, vaginal thrush, vaginal infections and urinary tract infection (including cystitis)] and infection-associated symptoms (fever and diarrhoea) during pregnancy. Covariate-adjusted hazard ratio (HR) and 95% confidence interval (CI) were estimated using multilevel Cox models. Results Among 312 879 children with a median follow-up of 13.6 years, 167 leukaemias, including 129 ALL and 33 AML, were identified. Maternal urinary tract infection was associated with increased risk of any leukaemia [HR (95% CI) 1.68 (1.10–2.58)] and subtypes ALL [1.49 (0.87–2.56)] and AML [2.70 ([0.93–7.86)], but not with any cancer [1.13 (0.85–1.51)]. Respiratory tract infection was associated with increased risk of any leukaemia [1.57 (1.06–2.34)], ALL [1.43 (0.94–2.19)], AML [2.37 (1.10–5.12)] and any cancer [1.33 (1.09–1.63)]; influenza-like illness showed a similar pattern but with less precise estimates. There was no evidence of a link between other infections and any outcomes. Conclusions Urinary tract and respiratory tract infections during pregnancy may be associated with childhood leukaemia, but the absolute risk is small given the rarity of the outcome.

Physical activity (PA) interventions have a promising role in the management of gestational diabetes mellitus (GDM). Digital technologies can support PA at scale and remotely. The protocol describes a study designed to determine the feasibility and acceptability of a complex intervention; known as +Stay Active. +Stay Active combines motivational interviewing with a bespoke behaviour change informed smartphone application (Stay-Active) to augment PA levels in women with GDM.This is a non-randomised feasibility study using a mixed methods approach. Participants will be recruited from the GDM antenatal clinic at the Women Centre, John Radcliffe Hospital, Oxford. Following baseline assessments (visit 1) including self-reported and device determined PA assessment (wearing a wrist accelerometer), women will be invited to participate in an online motivational interview, then download and use the Stay-Active app (Android or iOS) (visit 2). Women will have access to Stay-Active until 36 weeks gestation, when engagement and PA levels will be reassessed (visit 3). The target sample size is 60 women. Primary outcomes are recruitment and retention rates, compliance and assessment of participant engagement and acceptability with the intervention. Secondary outcomes are assessment of blood glucose control, self-reported and device determined assessment of PA, usage and structured feedback of participant's attitudes to +Stay Active, assessment of health costs and description of maternal and neonatal outcomes. This study will provide key insights into this complex intervention regarding engagement in smartphone technology and the wearing of accelerometers. These data will inform the development of a randomised controlled trial with refinements to intervention implementation.The study has received a favourable opinion from South Central-Hampshire B Research Ethics Committee; REC reference: 20/SC/0342. Written informed consent will be obtained from all participants. Findings will be disseminated through peer-reviewed journals, conferences and seminar presentations.ISRCTN11366562.

Healthcare systems prioritise antenatal and intrapartum care over the postpartum period. This is reflected in clinical resource allocation and in research agendas. But from metabolic disease to mental health, many pregnancy-associated conditions significantly affect patients’ lifelong health. Women from black and ethnic minority backgrounds and lower socioeconomic groups are at greater risk of physical and psychiatric complications of pregnancy compared to white British women. Without sufficiently tailored and accessible education about risk factors, and robust mechanisms for follow-up beyond the traditional 6-week postpartum period, these inequalities are further entrenched. Identifying approaches to address the needs of these patient populations is not only the responsibility of obstetricians and midwives; improvement requires cooperation from healthcare professionals from a wide range of specialties. Healthcare systems must encourage data collection on the long-term effects of metabolic and psychiatric conditions after the postpartum, and s support research that results in evidence-based care for the neglected field of women's postpartum health.

Complex perinatal syndromes (CPS) affecting pregnancy and childhood, such as preterm birth, and intra- and extra-uterine growth restriction, have multiple, diverse contexts of complexity and interaction that determine the short- and long-term growth, health and development of all human beings. Early in life, genetically-guided somatic and cerebral development occurs alongside a psychism “in statu nascendi,” with the neural structures subjected to the effects of the intra- and extra-uterine environments in preparation for optimal postnatal functioning. Different trajectories of fetal cranial and abdominal growth have been identified before 25 weeks’ gestation, tracking differential growth and neurodevelopment at 2 years of age. Similarly, critical time-windows exist in the first 5–8 months of postnatal life because of interactions between the newborn and their environment, mother/care-givers and feeding practices. Understanding these complex relational processes requires abandoning classical, linear and mechanistic interpretations that are placed in rigid, artificial biological silos. Instead, we need to conduct longitudinal, interdisciplinary research and integrate the resulting new knowledge into clinical practice. An ecological-systemic approach is required to understand early human growth and development, based on a dynamic multidimensional process from the molecular or genomic level to the socio-economic-environmental context. For this, we need theoretical and methodological tools that permit a global understanding of CPS, delineating temporal trajectories and their conditioning factors, updated by the incorporation of new scientific discoveries. The potential to optimize human growth and development across chronological age and geographical locations – by implementing interventions or “treatments” during periods of greatest instability or vulnerability – should be recognized. Hence, it is imperative to take a holistic view of reproductive and perinatal issues, acknowledging at all levels the complexity and interactions of CPS and their sensitive periods, laying the foundations for further improvements in growth and development of populations, to maximize global human potential. We discuss here conceptual issues that should be considered for the development and implementation of such a strategy aimed at addressing the perinatal health problems of the new millenium.

Introduction: India is in the process of a major epidemiological transition towards non-communicable diseases. Cardiovascular disease (CVD) is the leading cause of death in women in India. Predisposing independent risk factors include pregnancy-related conditions, e.g., hypertensive disorders of pregnancy (HDP) and gestational diabetes (GDM) - also associated with significant perinatal mortality and morbidity. Early identification, referral and management of pregnant women at increased risk of future CVD may offer opportunities for prevention. In rural India, Community Health Workers (CHWs) provide most antenatal and postnatal care. Innovative solutions are required to address integrated care for rural women during transitions between antenatal, postnatal and general health services. The George Institute's SMARThealth Programme has shown that CHWs in rural India screening non-pregnant adults for cardiovascular risk, using a decision support system, is feasible. Building on this, we developed a targeted training programme for CHWs and a complex system-level intervention that uses mobile clinical decision support for CHWs and primary care doctors to screen high-risk pregnant women. In addition to addressing HDP and GDM, the intervention also screens for anaemia in pregnancy.Methods/Design: A pilot study will be undertaken in two diverse rural districts of India: Jhajjar (Haryana) and Guntur (Andhra Pradesh). Two Primary Health Centre clusters will be randomised to intervention or control groups at each study site. The primary objective of this pilot study is to explore the feasibility and acceptability of the SMARThealth Pregnancy intervention. Secondary objectives are to estimate: (a) prevalence rates of moderate to severe anaemia, HDPs and GDM at the study sites; (b) referral and follow-up rates, and (c) mean haemoglobin and blood pressure values at the routine 6 week postnatal visit. A process evaluation will be conducted to explore the acceptability of the SMARThealth Pregnancy intervention for pregnant women and healthcare workers using qualitative methods.Discussion: It is anticipated that the findings of this pilot study will help determine the feasibility and acceptability of the SMARThealth Pregnancy intervention, and highlight how the intervention might be further developed for evaluation in a larger, cluster randomised controlled trial.Clinical Trial Registration:www.ClinicalTrials.gov, identifier: NCT03968952.

The embryonic Müllerian ducts give rise to the female reproductive tract (fallopian tubes, uterus and upper vagina in humans, the oviducts in birds). Embryonic Müllerian ducts initially develop in both sexes, but later regress in males under the influence of anti-Müllerian hormone. While the molecular and endocrine control of duct regression in males have been well studied, early development of the ducts in both sexes is less well understood. Here, we describe a novel role for the adhesion G protein-coupled receptor, GPR56, in development of the Müllerian ducts in the chicken embryo. GPR56 is expressed in the ducts of both sexes from early stages. The mRNA is present during the elongation phase of duct formation, and it is restricted to the inner Müllerian duct epithelium. The putative ligand, Collagen III, is abundantly expressed in the Müllerian duct at the same developmental stages. Knockdown of GPR56 expression using in ovo electroporation results in variably truncated ducts, with a loss of expression of both epithelial and mesenchymal markers of duct development. Over-expression of GPR56 in vitro results in enhanced cell proliferation and cell migration. These results show that GPR56 plays an essential role in avian Müllerian duct development through the regulation of duct elongation.

The Lancet Commission on depression by Helen Herrman and colleagues1 highlights the importance of life stages for depression, the first of which is the perinatal period, defined as pregnancy and the first 6 weeks after birth. However, the Commission's recommendations miss the crucial importance of the first postnatal year and the need for specific research and policy actions...

Many populations experience high seasonal temperatures. Pregnant women are considered vulnerable to extreme heat because ambient heat exposure has been linked to pregnancy complications including preterm birth and low birthweight. The physiological mechanisms that underpin these associations are poorly understood. We reviewed the existing research evidence to clarify the mechanisms that lead to adverse pregnancy outcomes in order to inform public health actions. A multi-disciplinary expert group met to review the existing evidence base and formulate a consensus regarding the physiological mechanisms that mediate the effect of high ambient temperature on pregnancy. A literature search was conducted in advance of the meeting to identify existing hypotheses and develop a series of questions and themes for discussion. Numerous hypotheses have been generated based on animal models and limited observational studies. There is growing evidence that pregnant women are able to appropriately thermoregulate; however, when exposed to extreme heat, there are a number of processes that may occur which could harm the mother or fetus including a reduction in placental blood flow, dehydration, and an inflammatory response that may trigger preterm birth. There is a lack of substantial evidence regarding the processes that cause heat exposure to harm pregnant women. Research is urgently needed to identify what causes the adverse outcomes in pregnancy related to high ambient temperatures so that the impact of climate change on pregnant women can be mitigated.

During early embryogenesis in amniotic vertebrates, the gonads differentiate into either ovaries or testes. The first cell lineage to differentiate gives rise to the supporting cells: Sertoli cells in males and pre-granulosa cells in females. These key cell types direct the differentiation of the other cell types in the gonad, including steroidogenic cells. The gonadal surface epithelium and the interstitial cell populations are less well studied, and little is known about their sexual differentiation programs. Here, we show the requirement of the homeobox transcription factor gene TGIF1 for ovarian development in the chicken embryo. TGIF1 is expressed in the two principal ovarian somatic cell populations: the cortex and the pre-granulosa cells of the medulla. TGIF1 expression is associated with an ovarian phenotype in estrogen-mediated sex reversal experiments. Targeted misexpression and gene knockdown indicate that TGIF1 is required, but not sufficient, for proper ovarian cortex formation. In addition, TGIF1 is identified as the first known regulator of juxtacortical medulla development. These findings provide new insights into chicken ovarian differentiation and development, specifically cortical and juxtacortical medulla formation., Summary: The homeobox transcription factor TGIF1 is required for proper ovarian sex differentiation in chicken embryos, regulating development of the cortical and juxtacortical medulla, independently of the supporting cell sex lineage.

This study aimed to investigate the association between maternal insulin resistance (IR) in the late second trimester and pregnancy outcomes, as well as to identify risk factors of IR among women with gestational diabetes mellitus (GDM).A retrospective study was conducted among 2647 women diagnosed with GDM. IR was evaluated using the homeostasis model assessment method for IR (HOMA-IR) in the late second trimester (between 24 and 28 weeks), and the lipid profiles were measured at the same time. Patients were divided into groups based on quartiles of HOMA-IR. The information on pregnancy outcomes and risk factors was extracted from the medical records of all participants and entered electronically. Logistic regression models were used to analyze the associations between HOMA-IR and pregnancy outcomes, as well as the associations between risk factors and HOMA-IR.Greater IR was associated with cesarean delivery, preterm delivery, macrosomia, and large for gestational age newborns, but only significantly associated with preterm delivery after adjustment for potential confounders (P .001). Prepregnancy body mass index (BMI), weight gain before diagnosis of GDM, and triglycerides were significantly related with IR in the late second trimester (P .001). Besides, the total area under the curve of the diagnostic 75-g oral glucose tolerance test and glycosylated hemoglobin A1c increased from the lowest to the highest HOMA-IR groups.Increasing IR in the late second trimester predicts adverse pregnancy outcomes especially for preterm delivery in women with GDM. Additionally, prepregnancy BMI and weight gain before diagnosis of GDM are independent risk factors for the development of IR.背景: 本研究旨在探讨妊娠期糖尿病(gestational diabetes mellitus, GDM)患者中孕期后期的胰岛素抵抗水平(insulin resistance, IR)与其妊娠结局的关系, 及GDM患者IR相关的危险因素。 方法: 本研究为回顾性研究, 共纳入2647名GDM患者。回顾临床资料, 采用妊娠24至28周指标计算稳态模型评估IR水平(homeostasis model assessment insulin resistance, HOMA-IR)以评价患者中孕期后期IR水平, 并于同期检测患者血脂水平。根据HOMA-IR的四分位值将患者分为四组。患者的妊娠结局及相关危险因素由患者病历提取并电子录入。Logistics回归模型被用于分析HOMA-IR与妊娠结局的关系, 及各危险因素与HOMA-IR的关系。 结果: 更高水平的IR与剖宫产分娩、早产、巨大儿及大于胎龄儿相关, 但经混杂因素校正后仅与早产结局显著相关(P.001)。孕前体重指数(body mass index, BMI)、GDM诊断前孕期体重增长及甘油三酯水平与中孕期后期的IR水平显著相关(P.001)。此外, 75克口服糖耐量诊断试验曲线下面积与糖化血红蛋白A1c水平在HOMA-IR四分组中逐渐升高。 结论: 中孕期后期IR水平增加可预测GDM患者不良妊娠结局特别是早产的发生。另外, 孕前BMI及GDM诊断前孕期体重增长是中孕期后期高IR水平的独立危险因素。.

Background Gestational diabetes (GDM) is a global problem affecting millions of pregnant women, including in mainland China. These women are at high risk of Type II diabetes (T2DM). Cost-effective and clinically effective interventions are needed. We aimed to explore Chinese women’s perspectives, concerns and motivations towards participation in early postpartum interventions and/or research to prevent the development of T2DM after a GDM-affected pregnancy. Methods We conducted a qualitative study in two hospitals in Chengdu, Southwest China. Face-to-face semi-structured interviews were conducted with 20 women with recent experience of GDM: 16 postpartum women and 4 pregnant women. Women were asked about their attitudes towards postpartum screening for type 2 diabetes, lifestyle interventions, mHealth delivered interventions and pharmacologic interventions (specifically metformin). An inductive approach to analysis was used. Interviews were recorded, transcribed, and coded using NVivo 12 Pro. Results Most women held positive attitudes towards participating in T2DM screening, and were willing to participate in postpartum interventions to prevent T2DM through lifestyle change or mHealth interventions. Women were less likely to agree to pharmacological intervention, unless they had family members with diabetes or needed medication themselves during pregnancy. We identified seven domains influencing women’s attitudes towards future interventions: (1) experiences with the health system during pregnancy; (2) living in an enabling environment; (3) the experience of T2DM in family members; (4) knowledge of diabetes and perception of risk; (5) concerns about personal and baby health; (6) feelings and emotions, and (7) lifestyle constraints. Those with more severe GDM, an enabling environment and health knowledge, and with experience of T2DM in family members expressed more favourable views of postpartum interventions and research participation to prevent T2DM after GDM. Those who perceived themselves as having mild GDM and those with time/lifestyle constraints were less likely to participate. Conclusions Women with experiences of GDM in Chengdu are generally willing to participate in early postpartum interventions and/or research to reduce their risk of T2DM, with a preference for non-drug, mHealth based interventions, integrating lifestyle change strategies, blood glucose monitoring, postpartum recovery and mental health. Supplementary Information The online version contains supplementary material available at 10.1186/s12978-021-01180-1., Plain language summary Gestational diabetes mellitus (GDM) is a common pregnancy complication affecting up to 1 in 6 pregnant women worldwide. Whilst the condition usually resolves soon after delivery, women are at high risk of developing type 2 diabetes mellitus (T2DM). In this study, we asked women living in Chengdu, a city in western China, about what they knew about their risk of diabetes and how they felt about participating in interventions after birth to prevent T2DM. After listening to the views of 20 women, we concluded that in this setting most women are happy to attend T2DM screening programs after birth, and would be willing to consider participating in interventions and research after birth to prevent T2DM. The interventions most preferred were those that aimed at lifestyle changes, and many women said would like to receive this information through their smartphone, for example through an app or social media channel. Women were reluctant to take medications to prevent T2DM. The main factors that influenced how women felt towards interventions to prevent T2DM were: (1) their experiences with the health system during pregnancy; (2) whether the home environment was supportive to make changes to diet and lifestyle; (3) any experiences of T2DM in family members; (4) their knowledge of diabetes and perception of risk; (5) concerns about personal and baby health; (6) feelings and emotions in the postnatal period, and (7) lifestyle constraints making it difficult to make dietary changes. Supplementary Information The online version contains supplementary material available at 10.1186/s12978-021-01180-1.

Funder: Nuffield Department of Population Health, University of Oxford, AIMS: To undertake a Priority Setting Partnership (PSP) to establish priorities for future research in diabetes and pregnancy, according to women with experience of pregnancy, and planning pregnancy, with any type of diabetes, their support networks and healthcare professionals. METHODS: The PSP used established James Lind Alliance (JLA) methodology working with women and their support networks and healthcare professionals UK-wide. Unanswered questions about the time before, during or after pregnancy with any type of diabetes were identified using an online survey and broad-level literature search. A second survey identified a shortlist of questions for final prioritisation at an online consensus development workshop. RESULTS: There were 466 responses (32% healthcare professionals) to the initial survey, with 1161 questions, which were aggregated into 60 unanswered questions. There were 614 responses (20% healthcare professionals) to the second survey and 18 questions shortlisted for ranking at the workshop. The top 10 questions were: diabetes technology, the best test for diabetes during pregnancy, diet and lifestyle interventions for diabetes management during pregnancy, emotional and well-being needs of women with diabetes pre- to post-pregnancy, safe full-term birth, post-natal care and support needs of women, diagnosis and management late in pregnancy, prevention of other types of diabetes in women with gestational diabetes, women's labour and birth experiences and choices and improving planning pregnancy. CONCLUSIONS: These research priorities provide guidance for research funders and researchers to target research in diabetes and pregnancy that will achieve greatest value and impact.

Background Preeclampsia is a disease specific to pregnancy that can cause severe maternal and foetal morbidity and mortality. Early identification of women at higher risk for preeclampsia could potentially aid early prevention and treatment. Although a plethora of preeclampsia prediction models have been developed in recent years, individualised prediction of preeclampsia is rarely used in clinical practice. Objectives The objective of this systematic review was to provide an overview of studies on preeclampsia prediction. Study design Relevant research papers were identified through a MEDLINE search up to 1 January 2017. Prognostic studies on the prediction of preeclampsia or preeclampsia-related disorders were included. Quality screening was performed with the Quality in Prognostic Studies (QUIPS) tool. Results Sixty-eight prediction models from 70 studies with 425,125 participants were selected for further review. The number of participants varied and the gestational age at prediction varied widely across studies. The most frequently used predictors were medical history, body mass index, blood pressure, parity, uterine artery pulsatility index, and maternal age. The type of predictor (maternal characteristics, ultrasound markers and/or biomarkers) was not clearly associated with model discrimination. Few prediction studies were internally (4%) or externally (6%) validated. Conclusions To date, multiple and widely varying models for preeclampsia prediction have been developed, some yielding promising results. The high degree of between-study heterogeneity impedes selection of the best model, or an aggregated analysis of prognostic models. Before multivariable preeclampsia prediction can be clinically implemented universally, further validation and calibration of well-performing prediction models is needed.

ObjectiveTo determine the socioeconomic gradient of birthweights in England with reference to the prescriptive INTERGROWTH-21st Birthweight Standard.DesignNational cross-sectional study using data from Hospital Episode Statistics.SettingNational Health Service in England.ParticipantsAll singleton babies, live born between 34 weeks’ gestation and 42 weeks’ gestation, between 1 April 2011 and 31 March 2012.Main outcome measuresBirthweight distribution of babies with a birthweight of 90th centile, that is, small for gestational age (SGA) or large for gestational age (LGA) using Index of Multiple Deprivation quintiles as a proxy for socioeconomic status.ResultsOf 508 230 babies born alive between 1 April 2011 and 31 March 2012, 38 838 (7.6%) were SGA and 81 026 (15.9%) were LGA. Median birthweight was 3405 g, median z-score was 0.25 (SD 1.06). Birthweight z-score demonstrated a social gradient, from 0.26 (SD 1.1) in the most deprived areas to 0.53 (1.0) in the least deprived. Women in the most deprived areas were twice as likely to have SGA babies using the INTERGROWTH-21st chart (OR 1.94; 95% CI 1.87 to 2.01) compared with those in the least deprived areas. If all women had the same rate of SGA equivalent to those living in the least deprived areas, approximately 12 410 (30%) fewer babies would be born SGA in England each year.ConclusionsThis study gives a measure of the social gradient in singleton SGA and LGA babies across England using an international standard of newborn size at birth.

The "delayed infection hypothesis" states that a paucity of infections in early childhood may lead to higher risks of childhood leukemia (CL), especially acute lymphoblastic leukemia (ALL). Using prospectively collected data from six population-based birth cohorts we studied the association between birth order (a proxy for pathogen exposure) and CL. We explored whether other birth or parental characteristics modify this association. With 2.2 × 106 person-years of follow-up, 185 CL and 136 ALL cases were ascertained. In Cox proportional hazards models, increasing birth order (continuous) was inversely associated with CL and ALL; hazard ratios (HR) = 0.88, 95% confidence interval (CI): (0.77-0.99) and 0.85: (0.73-0.99), respectively. Being later-born was associated with similarly reduced hazards of CL and ALL compared to being first-born; HRs = 0.78: 95% CI: 0.58-1.05 and 0.73: 0.52-1.03, respectively. Successive birth orders were associated with decreased CL and ALL risks (P for trend 0.047 and 0.055, respectively). Multivariable adjustment somewhat attenuated the associations. We found statistically significant and borderline interactions between birth weight (p = 0.024) and paternal age (p = 0.067), respectively, in associations between being later-born and CL, with the lowest risk observed for children born at

Background Sepsis is a leading cause of maternal death. Antimicrobials save lives, but inappropriate overuse increases risk of antimicrobial resistance(AMR). Objective A scoping review comparing peripartum prophylactic antimicrobial use in low and middle-income countries(LMICs) with World Health Organization(WHO) recommendations for prevention and treatment of maternal peripartum infection. Search strategy Medline, Embase, Global Health, LILACS and the WHO Library databases were searched. Selection criteria Publications from LMICs since 2015 describing maternal prophlyactic antibiotics for Group B Streptococcus(GBS), preterm-prelabour rupture of membranes(PPROM), caesarean section(CS), manual placental removal(MROP) and 3rd /4th degree perineal tears[1]. Data collection and analysis Publications were screened, and duplicates removed. A scoping review was conducted using PRISMA guidelines[9]. Owing to study heterogeneity, a narrative synthesis was performed. Main results Of 1886 studies, 27 met eligibility criteria from 13 countries involving 43,774 women. Polymerase Chain Reaction (PCR) screening for GBS is feasible, though limited financially. In PPROM, up to 42% of GBS isolates demonstrated erythromycin resistance[2]. Evidence around CS antimicrobial prophylaxis largely supports WHO recommendations, however prolonged or multidrug regimes were reported. Conclusion There is limited evidence to challenge current WHO recommendations to prevent peripartum infection in LMICs. However, implementation challenges exist. Given the emergence of AMR, research is needed to ensure peripartum prophylactic antimicrobial choices remain effective.

Background: There is increasing pressure to get women and babies home rapidly after birth. Babies born to mothers with gestational diabetes mellitus (GDM) currently get 24-hour inpatient monitoring. We investigated whether a low-risk group of babies born to mothers with GDM could be defined for shorter inpatient hypoglycaemia monitoring. Methods: Observational study conducted in a tertiary maternity hospital in 2018. Singleton, term infants born to women with GDM and no other risk factors for hypoglycaemia, were included. Capillary blood glucose (BG) testing and clinical observations for signs of hypoglycaemia during the first 24-hours after birth. BG was checked in all babies before the second feed. Subsequent testing occurred if the first result was Results: Fifteen of 106 babies developed hypoglycaemia within the first 24-hours. Maternal and newborn characteristics were not predictive. All babies with hypoglycaemia had an initial capillary BG ≤2.6mmol/L (Area under the ROC curve (AUC) 0.96, 95% Confidence Interval (CI) 0.91-1.0). This result was validated on a further 65 babies, of whom 10 developed hypoglycaemia, in the first 24-hours of life.Conclusions for practice: Using the 2.6mmol/L threshold, extended monitoring as an inpatient could have been avoided for 60% of newborns in this study. Whilst prospective validation is needed, this approach could help tailor postnatal care plans for babies born to mothers with GDM.

Background There is increasing pressure to get women and babies home rapidly after birth. Babies born to mothers with gestational diabetes mellitus (GDM) currently get 24-h inpatient monitoring. We investigated whether a low-risk group of babies born to mothers with GDM could be defined for shorter inpatient hypoglycaemia monitoring. Methods Observational, retrospective cohort study conducted in a tertiary maternity hospital in 2018. Singleton, term babies born to women with GDM and no other risk factors for hypoglycaemia, were included. Capillary blood glucose (BG) testing and clinical observations for signs of hypoglycaemia during the first 24-h after birth. BG was checked in all babies before the second feed. Subsequent testing occurred if the first result was Results Fifteen of 106 babies developed hypoglycaemia within the first 24-h. Maternal and neonatal characteristics were not predictive. All babies with hypoglycaemia had an initial capillary BG ≤ 2.6 mmol/L (Area under the ROC curve (AUC) 0.96, 95% Confidence Interval (CI) 0.91–1.0). This result was validated on a further 65 babies, of whom 10 developed hypoglycaemia, in the first 24-h of life. Conclusion Using the 2.6 mmol/L threshold, extended monitoring as an inpatient could have been avoided for 60% of babies in this study. Whilst prospective validation is needed, this approach could help tailor postnatal care plans for babies born to mothers with GDM.

Background: Anthropogenic climate change has led to increasingly extreme temperatures worldwide. Sub-Saharan Africa (SSA), including West Africa, is considered especially vulnerable to the impacts of climate extremes. In SSA women make up 50% of agricultural workforce and often work throughout pregnancy, while maternal exposure to high temperatures increases the risk of adverse birth outcomes. Understanding the physiological mechanisms responsible is central to designing targeted interventions to reduce the risks of heat exposure. Method: This observational cohort study utilised the high heat stress in West Africa to gain understanding of the physiological impact of heat on maternal and fetal physiology. Pregnant subsistence farmers who performed manual tasks throughout pregnancy were observed during field visits where environmental measurements, maternal physiology (e.g. heat strain) and fetal stress (fetal heart rate > 160 or < 115, or increase in umbilical artery resistance index) were measured. Results: A total of 92 participants were included (122 field visits). Extreme heat stress was observed in 31% of field visits. Maternal temperature, heat strain and fetal heart rate were all significantly increased from baseline to working. Fetal stress occurred in 41/122 (33%) field visits. Multilevel modelling revealed that fetal stress was significantly associated with both Universal Thermal Climate Index (OR 1·17, CI 1·05;1·29, p=0.01) and gestational age (OR 1·12, CI 1·02;1·22, p=0.02). Interpretation: Decreasing maternal exposure to heat stress in later pregnancy may reduce fetal stress, a potential pathophysiological mechanism leading to adverse birth outcomes. There is an urgent need to explore this further. Funding Information: This project was funded by the Wellcome Trust through the Wellcome Trust Global Health PhD Fellowship awarded to AB (216336/Z/19/Z). Declaration of Interests: None declared. Ethics Approval Statement: The study was approved by the Gambia government/MRC Joint ethics committee and the London School of Hygiene and Tropical Medicine Ethics Advisory Board (ref: 16405) in accordance with the Declaration of Helsinki (2013).

Sepsis is life-threatening organ dysfunction caused by a dysregulated host response to infection.1 The incidence of sepsis, as estimated by the Global Burden of Disease study, was 48.9 million cases with 11 million deaths in 2017.2 In sub-Saharan Africa (SSA), the burden is highest, with an estimated 16.7 million cases and sepsis accounting for up to 45% of all deaths, in many SSA countries.2 Maternal sepsis is a sepsis that occurs during pregnancy, childbirth, postabortion or in the postpartum period and neonatal sepsis is a sepsis that occurs within the first 28 days of life. Reliable estimates of the incidence and mortality of maternal and neonatal sepsis in SSA are incomplete. Notwithstanding this limitation, the most recent estimate suggests that sepsis is responsible for 130 000 maternal deaths3 and 300 000 neonatal deaths annually, though this may be an underestimate,4 in view of the recent Global Burden of Disease study report.2 Sepsis-related deaths in SSA reflect underlying political, poverty, health inequity and health system challenges across Africa.5 These challenges affect preventative and public health efforts to prevent sepsis and limit prompt and effective recognition and treatment of sepsis to prevent mortality. The challenges include access to clean water and sanitation, vaccination and provision of primary care in addition to access to antimicrobial agents and strategies for their stewardship.6–9 In 2017, the World Health Assembly (WHA) passed a resolution to improve the prevention, diagnosis and management of sepsis (WHA 70.7).10 This resolution recommended key action areas for member states and future priorities.11 Based on these recommendations, we outline nine key areas to accelerate progress in reducing death due to maternal and neonatal sepsis in SSA. ### 1. Increase sepsis awareness in the community Despite sepsis being a major cause of health loss globally, public awareness remains low,11 with the delayed time from …

Cardiometabolic disorders (CMDs), including ischemic heart disease, stroke and type 2 diabetes are the leading causes of mortality and morbidity in women worldwide. The burden of CMDs falls disproportionately on low and middle-income countries (LMICs), placing substantial demands on already pressured health systems. Cardiometabolic disorders may present up to a decade earlier in some LMIC settings, and are associated with high-case fatality rates. Early identification and ongoing postpartum follow-up of women with pregnancy complications such as hypertensive disorders of pregnancy (HDPs), and gestational diabetes mellitus (GDM) may offer opportunities for prevention, or help delay onset of CMDs. This mini-review paper presents an overview of the key challenges faced in the early identification, referral and management of pregnant women at increased risk of CMDs, in low-resource settings worldwide. Evidence-based strategies, including novel diagnostics, technology and innovations for early detection, screening and management for pregnant women at high-risk of CMDs are presented. The review highlights the key research priorities for addressing cardiometabolic risk in pregnancy in low-resource settings.

Introduction: Climate change predictions indicate that global temperatures are likely to exceed those seen in the last 200,000 years, rising by around 4°C above pre-industrial levels by 2100 (without effective mitigation of current emission rates). In regions of the world set to experience extreme temperatures, women often work outside in agriculture even during pregnancy. The implications of heat strain in pregnancy on maternal health and pregnancy outcome are not well understood. This protocol describes a study to assess the physiological response of pregnant women to environmental heat stress and the immediate effect this has on fetal wellbeing. Methods and analysis: The study will be performed in West Kiang district, The Gambia; a semi-arid zone in West Africa with daily maximum temperatures ranging from approximately 32 to 40°C. We will recruit 125 pregnant women of all ages who perform agricultural work during their pregnancy. Participants will be followed every two months until delivery. At each study visit fetal growth will be measured by ultrasound scan. During the course of their working day we will take the following measurements: continuous maternal physiological measurements (heart rate, respiratory rate, chest skin temperature and tri-axis accelerometer data); intermittent maternal tympanic core temperature, four point skin temperature, blood pressure; intermittent fetal heart rate and, if eligible, umbilical artery doppler; intermittent environmental measurements of air temperature, humidity, solar radiation and wind speed. Venous blood and urine will be collected at beginning and end of day for biomarkers of heat strain or fetal distress and hydration status.

Fetal growth is a complex and highly orchestrated process. Monitoring fetal growth is one of the cornerstones of the evaluation of fetal well-being. This chapter explores the global epidemiology of poor fetal growth, the controversies around the definition of the condition, and the scientific validity of the multitude of growth charts and approaches to fetal growth currently in use around the world. In 2014, the accepted approaches to fetal growth were challenged by the findings of the international INTERGROWTH-21st Project. This major international project demonstrated that the growth of babies in utero and the size of babies around the world are remarkably similar if maternal environmental, social, and medical conditions are relatively optimal. From this study, the first standards for fetal and newborn growth have been produced. The management of babies detected to be large for gestational age (LGA) also remains controversial and a clinical challenge. With increasing rates of maternal obesity and gestational diabetes, a growing proportion of babies are born LGA or detected to be LGA in utero. Other than the treatment for gestational diabetes, the evidence for effective interventions to prevent the development of LGA during pregnancy is limited. Key issues regarding the management of LGA include the most appropriate timing and mode of delivery to prevent shoulder dystocia and birth trauma.

Background: Selenium (Se), an essential trace mineral, has been implicated in preterm birth (PTB). We aimed to determine the association of maternal Se concentrations during pregnancy with PTB risk and gestational duration in a large number of samples collected from diverse populations. Methods: Gestational duration data and maternal plasma or serum samples of 9946 singleton live births were obtained from 17 geographically diverse study cohorts. Maternal Se concentrations were determined by Inductively coupled plasma mass spectrometry (ICP-MS) analysis. The associations between maternal Se with PTB and gestational duration were analyzed using linear and logistic regressions. The results were then combined using fixed and random effect meta-analysis. Findings: In all study samples, the Se concentrations followed a normal distribution with a mean of 93.8 ng/ml (range: 26.1 to 228.7 ng/ml) but varied substantially across different sites. The fixed-effect meta-analysis across the 17 cohorts showed that Se was significantly associated with PTB (p = 0.04) and gestational duration (p = 2.9e-6) with effect size estimates of an OR= 1.04 (95% CI: 1.0 to 1.07) for PTB per 10 ng/ml decrease in Se concentration and 0.44 days (95% CI: 0.26 – 0.62) longer gestation per 10 ng/ml increase in Se concentration. However, there was a substantial heterogeneity among study cohorts. The largest effect sizes were observed in UK (Liverpool) cohort, while the most statistically significant associations were observed in samples from Malawi. After excluding these two cohorts, the fixed effect meta-analysis was no longer significant, and the random-effect meta-analysis of all data sets also did not achieve statistical significance. Interpretation: While our study observed statistically significant associations between maternal Se concentration and PTB at some sites, this did not generalize across the entire cohort. Whether population-specific factors explain the heterogeneity of our findings warrants further investigation. Targeted Se supplementation could play a role in reducing PTB in some settings, however further evidence is needed to understand the biologic pathways, clinical efficacy and safety, before changes to antenatal nutritional recommendations are considered. Funding Statement: Payment for access to data and article-processing charges for this publication was covered by The Bill & Melinda Gates Foundation (Grant no: OPP1175128, OPP1152451). The NEST study acknowledges the support from National Institute of Environmental Health Sciences, the US Environmental Protection Agency, the National Institute of Diabetes and Digestive and Kidney Diseases, and the Duke Cancer Institute. Th CPPOP study acknowledge support from the UCSF California Preterm Birth Initiative. The iLiNS-DYAD-M trial acknowledge the support by a grant to the University of California, Davis from The Bill & Melinda Gates Foundation [OPP49817] and a grant to the University of California, Davis from the Office of Health, Infectious Diseases, and Nutrition, Bureau for Global Health, U.S. Agency for International Development (USAID) through the Food and Nutrition Technical Assistance III Project (FANTA). MDIG, AMANHI, GAPPS and INTERBIO cohorts acknowledge the support by The Bill & Melinda Gates Foundation. Declaration of Interests: The authors declare no conflicts of interest regarding the content of this paper. Ethics Approval Statement: Our study protocol was approved by the Institute Review Board (IRB) of the CCHMC and by the corresponding Ethics Committees of each participating institution.

Objective To assess potential risk factors in identifying women at risk for gestational diabetes mellitus (GDM). Methods The present study included data collected as part of a prospective cohort study, and included women with singleton pregnancies who underwent initial prenatal examination at a tertiary women and children's hospital in Guangzhou, China between February 1, 2012, and December 31, 2015. Maternal characteristics and medical history were investigated to evaluate associations with GDM. A risk factor scoring system for the prediction of GDM was generated using logistic regression. Results Overall, 1129 (13.5%) of 8381 women were diagnosed with GDM. Women older than 35 years had a 3.95‐fold increased risk of GDM (95% confidence interval 2.80–5.58) compared with women aged 16–25 years; obese women had a 6.54‐fold higher risk (95% confidence interval 3.50–12.23) compared with underweight women. A risk scoring system was established based on age, body mass index, family history of diabetes, weight gain, and history of GDM. Screening for women with a score of 12 or more would have reduced the number undergoing oral glucose tolerance testing by 2131 (25.4%) patients with a sensitivity of 87% for GDM detection. Conclusion The assessment of risk factors for GDM could provide a foundation for improving risk‐based screening strategies in this and similar populations.

The exact genetic mechanism regulating avian gonadal sex differentiation has not been completely resolved. The most likely scenario involves a dosage mechanism, whereby the Z-linked DMRT1 gene triggers testis development. However, the possibility still exists that the female-specific W chromosome may harbor an ovarian determining factor. In this study, we provide evidence that the universal gene regulating gonadal sex differentiation in birds is Z-linked DMRT1 and not a W-linked (ovarian) factor. Three candidate W-linked ovarian determinants are HINTW, female-expressed transcript 1 (FET1), and female-associated factor (FAF). To test the association of these genes with ovarian differentiation in the chicken, we examined their expression following experimentally induced female-to-male sex reversal using the aromatase inhibitor fadrozole (FAD). Administration of FAD on day 3 of embryogenesis induced a significant loss of aromatase enzyme activity in female gonads and masculinization. However, expression levels of HINTW, FAF, and FET1 were unaltered after experimental masculinization. Furthermore, comparative analysis showed that FAF and FET1 expression could not be detected in zebra finch gonads. Additionally, an antibody raised against the predicted HINTW protein failed to detect it endogenously. These data do not support a universal role for these genes or for the W sex chromosome in ovarian development in birds. We found that DMRT1 (but not the recently identified Z-linked HEMGN gene) is male upregulated in embryonic zebra finch and emu gonads, as in the chicken. As chicken, zebra finch, and emu exemplify the major evolutionary clades of birds, we propose that Z-linked DMRT1, and not the W sex chromosome, regulates gonadal sex differentiation in birds.

The ability to generate hematopoietic stem cells from human pluripotent cells would enable many biomedical applications. We find that hematopoietic CD34+ cells in spin embryoid bodies derived from human embryonic stem cells (hESCs) lack HOXA expression compared with repopulation-competent human cord blood CD34+ cells, indicating incorrect mesoderm patterning. Using reporter hESC lines to track the endothelial (SOX17) to hematopoietic (RUNX1C) transition that occurs in development, we show that simultaneous modulation of WNT and ACTIVIN signaling yields CD34+ hematopoietic cells with HOXA expression that more closely resembles that of cord blood. The cultures generate a network of aorta-like SOX17+ vessels from which RUNX1C+ blood cells emerge, similar to hematopoiesis in the aorta-gonad-mesonephros (AGM). Nascent CD34+ hematopoietic cells and corresponding cells sorted from human AGM show similar expression of cell surface receptors, signaling molecules and transcription factors. Our findings provide an approach to mimic in vitro a key early stage in human hematopoiesis for the generation of AGM-derived hematopoietic lineages from hESCs.

Objectives A diagnosis of hypertensive disorders during pregnancy (HDPs) or gestational diabetes mellitus (GDM) is highly predictive of women at increased risk of developing chronic hypertension, Type 2 diabetes, and cardiovascular disease. This study investigates perceptions of women and healthcare providers in rural India regarding these long‐term risks. Design Qualitative study using modified grounded theory. Setting Two states in rural India: Haryana and Andhra Pradesh. Population Pregnant and postpartum women, community health workers (CHWs), primary care physicians, obstetricians, laboratory technicians, and healthcare officials. Methods In‐depth interviews and focus group discussions explored: (1) priorities for high‐risk pregnant women; (2) detection and management of HDPs and GDM; (3) postpartum management, and (4) knowledge of long‐term sequelae of high‐risk conditions. A thematic analysis was undertaken. Results Seven focus group discussions and 11 in‐depth interviews (n = 71 participants) were performed. The key priority area for high‐risk pregnant women was anaemia. Blood pressure measurement was routinely embedded in antenatal care; however, postpartum follow up and knowledge of the long‐term complications were limited. GDM was not considered a common problem, although significant variations and challenges to GDM screening were identified. Knowledge of the long‐term sequelae of GDM with regard to an increased risk of Type 2 diabetes and cardiovascular disease among doctors was minimal. Conclusions There is a need for improved education, standardisation of testing and postpartum follow up of HDPs and GDM in rural Indian settings. Funding SN is supported by an MRC Clinical Research Training Fellowship (MR/R017182/1). The George Institute for Global Health Global Women's Health programme provided financial support for the research assistant and fieldwork costs in India. Tweetable abstract Improved education and postpartum care of women with hypertension and diabetes in pregnancy in rural India are needed to prevent long‐term risks., Tweetable abstract Improved education and postpartum care of women with hypertension and diabetes in pregnancy in rural India are needed to prevent long‐term risks.