Etiologically Based Functional Taxonomy of the Preterm Birth Syndrome.

Preterm birth (PTB) is a complex syndrome traditionally defined by a single parameter, namely, gestational age at birth (ie, ˂37 weeks). This approach has limitations for clinical usefulness and may explain the lack of progress in identifying cause-specific effective interventions. The authors offer a framework for a functional taxonomy of PTB based on (1) conceptual principles established a priori; (2) known etiologic factors; (3) specific, prospectively identified obstetric and neonatal clinical phenotypes; and (4) postnatal follow-up of growth and development up to 2 years of age. This taxonomy includes maternal, placental, and fetal conditions routinely recorded in data collection systems.

Validating the ratio of insulin like growth factor binding protein 4 to sex hormone binding globulin as a prognostic predictor of preterm birth in Viet Nam: a case-cohort study.

OBJECTIVE: To validate a serum biomarker developed in the USA for preterm birth (PTB) risk stratification in Viet Nam. METHODS: Women with singleton pregnancies (n = 5000) were recruited between 19+0-23+6 weeks' gestation at Tu Du Hospital, Ho Chi Minh City. Maternal serum was collected from 19+0-22+6 weeks' gestation and participants followed to neonatal discharge. Relative insulin-like growth factor binding protein 4 (IGFBP4) and sex hormone binding globulin (SHBG) abundances were measured by mass spectrometry and their ratio compared between PTB cases and term controls. Discrimination (area under the receiver operating characteristic curve, AUC) and calibration for PTB <37 and <34 weeks' gestation were tested, with model tuning using clinical factors. Measured outcomes included all PTBs (any birth ≤37 weeks' gestation) and spontaneous PTBs (birth ≤37 weeks' gestation with clinical signs of initiation of parturition). RESULTS: Complete data were available for 4984 (99.7%) individuals. The cohort PTB rate was 6.7% (n = 335). We observed an inverse association between the IGFBP4/SHBG ratio and gestational age at birth (p = 0.017; AUC 0.60 [95% CI, 0.53-0.68]). Including previous PTB (for multiparous women) or prior miscarriage (for primiparous women) improved performance (AUC 0.65 and 0.70, respectively, for PTB <37 and <34 weeks' gestation). Optimal performance (AUC 0.74) was seen within 19-20 weeks' gestation, for BMI >21 kg/m2 and age 20-35 years. CONCLUSION: We have validated a novel serum biomarker for PTB risk stratification in a very different setting to the original study. Further research is required to determine appropriate ratio thresholds based on the prevalence of risk factors and the availability of resources and preventative therapies.

A systematic review to determine use of the Endometriosis Health Profiles to measure quality of life outcomes in women with endometriosis.

BACKGROUND: The Endometriosis Health Profiles (EHPs), the EHP-30 and EHP-5, are patient-reported outcome measures that were developed to measure the health-related quality of life (HRQoL) of women living with endometriosis. Prior to their development, a systematic review was undertaken which identified that the HRQoL of women living with endometriosis was poorly understood, with only three medical and one surgical study identified. OBJECTIVE AND RATIONALE: The 20-year anniversary of the EHP-30 provided a timely opportunity to assess how the tools have been used and explore what the findings tell us about the impact of endometriosis and its associated treatments upon women's QoL. Applying robust systematic review methodology, following PRISMA guidelines, we sought to answer: How many studies have used the EHP and for what purpose?; What are the demographic characteristics and international context of the studies?; What is the methodological nature and quality of the studies?; Which interventions have been assessed and what are the reported EHP outcomes?; and Can the EHP outcomes of these interventions be analysed using a meta-analysis and, if so, what do the results show? SEARCH METHODS: The electronic databases MEDLINE, CINAHL, PsycINFO, PubMed, and Google Scholar were searched from the year the EHP was first published, in 2001 to 26 February 2020 using the search terms 'EHP30', 'EHP5', 'EHP-30', 'EHP-5', 'endometriosis health profile 30', and 'endometriosis health profile 5'. We updated the searches on 9 April 2021. All included studies were quality assessed using the Mixed Methods Appraisal Tool (MMAT). OUTCOMES: The review included 139 papers. In clinical intervention studies, the EHPs were deployed most frequently to measure the outcomes of medical (n = 35) and surgical (n = 21) treatment. The EHPs were also used in 13 other intervention studies, 29 non-interventional studies, 32 psychometric/cross cultural validation studies; six diagnostic studies, and in three other studies to measure outcomes in related conditions. They were mainly deployed in studies undertaken in Europe and North America. Overall, regardless of the nature of the intervention, most women reported improvements in HRQoL after treatment. Surgical interventions generally resulted in significant improvements for the longest amount of time. There was also evidence that when participants stopped taking medication their EHP scores worsened, perhaps reinforcing the temporary impact of medical treatment. Younger patients reported more negative impact upon their HRQoL. Further evidence using classical test theory to support the EHPs' robust psychometric properties, including acceptability, dimensionality, reliability, validity (including cross-cultural), and responsiveness, was demonstrated, particularly for the EHP-30. Strikingly, using anchor-based methods, EHP-30 responsiveness studies demonstrate the largest mean changes in the 'control and powerlessness' domain post-intervention, followed by 'pain'. MMAT outcomes indicated the quality of the papers was good, with the exception of five studies. A meta-analysis was not undertaken owing to the heterogeneity of the interventions and papers included in this review. WIDER IMPLICATIONS: Women with endometriosis face a lifetime of surgical and/or medical interventions to keep the condition under control. Less invasive treatments that can lead to improved longer term physical and psycho-social outcomes are needed. The EHPs are reliable, valid, acceptable, and responsive tools, but more assessment of EHP outcomes using modern psychometric methods and in the context of women from ethnically diverse backgrounds and in routine clinical care would be beneficial. Given the brevity of the EHP-5, it may be the most appropriate version to use in routine clinical practice, whereas the longer EHP-30, which provides more granularity, is more appropriate for research.

Normative spatiotemporal fetal brain maturation with satisfactory development at 2 years.

Maturation of the human fetal brain should follow precisely scheduled structural growth and folding of the cerebral cortex for optimal postnatal function1. We present a normative digital atlas of fetal brain maturation based on a prospective international cohort of healthy pregnant women2, selected using World Health Organization recommendations for growth standards3. Their fetuses were accurately dated in the first trimester, with satisfactory growth and neurodevelopment from early pregnancy to 2 years of age4,5. The atlas was produced using 1,059 optimal quality, three-dimensional ultrasound brain volumes from 899 of the fetuses and an automated analysis pipeline6-8. The atlas corresponds structurally to published magnetic resonance images9, but with finer anatomical details in deep grey matter. The between-study site variability represented less than 8.0% of the total variance of all brain measures, supporting pooling data from the eight study sites to produce patterns of normative maturation. We have thereby generated an average representation of each cerebral hemisphere between 14 and 31 weeks' gestation with quantification of intracranial volume variability and growth patterns. Emergent asymmetries were detectable from as early as 14 weeks, with peak asymmetries in regions associated with language development and functional lateralization between 20 and 26 weeks' gestation. These patterns were validated in 1,487 three-dimensional brain volumes from 1,295 different fetuses in the same cohort. We provide a unique spatiotemporal benchmark of fetal brain maturation from a large cohort with normative postnatal growth and neurodevelopment.

Suboptimal gestational weight gain and neonatal outcomes in low and middle income countries: individual participant data meta-analysis.

OBJECTIVE: To estimate the associations between gestational weight gain (GWG) during pregnancy and neonatal outcomes in low and middle income countries. DESIGN: Individual participant data meta-analysis. SETTING: Prospective pregnancy studies from 24 low and middle income countries. MAIN OUTCOME MEASURES: Nine neonatal outcomes related to timing (preterm birth) and anthropometry (weight, length, and head circumference) at birth, stillbirths, and neonatal death. ANALYSIS METHODS: A systematic search was conducted in PubMed, Embase, and Web of Science which identified 53 prospective pregnancy studies published after the year 2000 with data on GWG, timing and anthropometry at birth, and neonatal mortality. GWG adequacy was defined as the ratio of the observed maternal weight gain over the recommended weight gain based on the Institute of Medicine body mass index specific guidelines, which are derived from data in high income settings, and the INTERGROWTH-21st GWG standards. Study specific estimates, adjusted for confounders, were generated and then pooled using random effects meta-analysis models. Maternal age and body mass index before pregnancy were examined as potential modifiers of the associations between GWG adequacy and neonatal outcomes. RESULTS: Overall, 55% of participants had severely inadequate (<70%) or moderately inadequate (70% to <90%) GWG, 22% had adequate GWG (90-125%), and 23% had excessive GWG (≥125%). Severely inadequate GWG was associated with a higher risk of low birthweight (adjusted relative risk 1.62, 95% confidence interval 1.51 to 1.72; 48 studies, 93 337 participants; τ2=0.006), small for gestational age (1.44, 1.36 to 1.54; 51 studies, 93 191 participants; τ2=0.016), short for gestational age (1.47, 1.29 to 1.69; 40 studies, 83 827 participants; τ2=0.074), and microcephaly (1.57, 1.31 to 1.88; 31 studies, 80 046 participants; τ2=0.145) compared with adequate GWG. Excessive GWG was associated with a higher risk of preterm birth (1.22, 1.13 to 1.31; 48 studies, 103 762 participants; τ2=0.008), large for gestational age (1.44, 1.33 to 1.57; 47 studies, 90 044 participants; τ2=0.009), and macrosomia (1.52, 1.33 to 1.73; 29 studies, 68 138 participants; τ2=0) compared with adequate GWG. The direction and magnitude of the associations between GWG adequacy and several neonatal outcomes were modified by maternal age and body mass index before pregnancy. CONCLUSIONS: Inadequate and excessive GWG are associated with a higher risk of adverse neonatal outcomes across settings. Interventions to promote optimal GWG during pregnancy are likely to reduce the burden of adverse neonatal outcomes, however further research is needed to assess optimal ranges of GWG based on data from low and middle income countries.

Association between maternal haemoglobin concentrations and maternal and neonatal outcomes: the prospective, observational, multinational, INTERBIO-21st fetal study.

BACKGROUND: Anaemia in pregnancy is a global health problem with associated maternal and neonatal morbidity and mortality. We aimed to investigate the association between maternal haemoglobin concentrations during pregnancy and the risk of adverse maternal and neonatal outcomes. METHODS: In this prospective, observational, multinational, INTERBIO-21st fetal study conducted at maternity units in Brazil, Kenya, Pakistan, South Africa, and the UK, we enrolled pregnant women (aged ≥18 years, BMI <35 kg/m2, natural conception, and singleton pregnancy) who initiated antenatal care before 14 weeks' gestation. At each 5±1 weekly visit until delivery, information was collected about the pregnancy, as well as the results of blood tests taken as part of routine antenatal care, including haemoglobin values. The outcome measures were maternal (gestational diabetes, pregnancy-induced hypertension, and preterm premature rupture of membranes) and neonatal outcomes (small for gestational age, preterm birth, and acute respiratory distress syndrome). FINDINGS: Between Feb 8, 2012, and Nov 30, 2019, 2069 women (mean age 30·7 years [SD 5·0]) had at least one routinely haemoglobin concentration measured at 14-40 weeks' gestation, contributing 4690 haemoglobin measurements for the analysis. Compared with a haemoglobin cutoff of 110 g/L, the risk was increased more than two-fold for pregnancy-induced hypertension at haemoglobin concentrations of 170 g/L (risk ratio [RR] 2·29 [95% CI 1·19-4·39]) and higher, for preterm birth at haemoglobin concentrations of 70 g/L (RR 2·04 [95% CI 1·20-3·48]) and 165 g/L (RR 2·06 [95% CI 1·41-3·02]), and for acute respiratory distress syndrome at haemoglobin concentrations of 165 g/L (RR 2·84 [95% CI 1·51-5·35]). Trimester-specific results are also presented. INTERPRETATION: Our data suggests that the current WHO haemoglobin cutoffs are associated with reduced risk of adverse maternal and neonatal outcomes. The current haemoglobin concentration cutoffs during pregnancy should not only consider thresholds for low haemoglobin concentrations that are associated with adverse outcomes but also define a threshold for high haemoglobin concentrations given the U-shaped relationship between haemoglobin concentration and adverse neonatal and maternal outcomes. FUNDING: Bill & Melinda Gates Foundation.

Risk factors for inadequate and excessive gestational weight gain in 25 low- and middle-income countries: An individual-level participant meta-analysis.

BACKGROUND: Many women experience suboptimal gestational weight gain (GWG) in low- and middle-income countries (LMICs), but our understanding of risk factors associated with GWG in these settings is limited. We investigated the relationships between demographic, anthropometric, lifestyle, and clinical factors and GWG in prospectively collected data from LMICs. METHODS AND FINDINGS: We conducted an individual participant-level meta-analysis of risk factors for GWG outcomes among 138,286 pregnant women with singleton pregnancies in 55 studies (27 randomized controlled trials and 28 prospective cohorts from 25 LMICs). Data sources were identified through PubMed, Embase, and Web of Science searches for articles published from January 2000 to March 2019. Titles and abstracts of articles identified in all databases were independently screened by 2 team members according to the following eligibility criteria: following inclusion criteria: (1) GWG data collection took place in an LMIC; (2) the study was a prospective cohort or randomized trial; (3) study participants were pregnant; and (4) the study was not conducted exclusively among human immunodeficiency virus (HIV)-infected women or women with other health conditions that could limit the generalizability of the results. The Institute of Medicine (IOM) body mass index (BMI)-specific guidelines were used to determine the adequacy of GWG, which we calculated as the ratio of the total observed weight gain over the mean recommended weight gain. Study outcomes included severely inadequate GWG (percent adequacy of GWG <70), inadequate GWG (percent adequacy of GWG <90, inclusive of severely inadequate), and excessive GWG (percent adequacy of GWG >125). Multivariable estimates from each study were pooled using fixed-effects meta-analysis. Study-specific regression models for each risk factor included all other demographic risk factors measured in a particular study as potential confounders, as well as BMI, maternal height, pre-pregnancy smoking, and chronic hypertension. Risk factors occurring during pregnancy were further adjusted for receipt of study intervention (if any) and 3-month calendar period. The INTERGROWTH-21st standard was used to define high and low GWG among normal weight women in a sensitivity analysis. The prevalence of inadequate GWG was 54%, while the prevalence of excessive weight gain was 22%. In multivariable models, factors that were associated with a higher risk of inadequate GWG included short maternal stature (<145 cm), tobacco smoking, and HIV infection. A mid-upper arm circumference (MUAC) of ≥28.1 cm was associated with the largest increase in risk for excessive GWG (risk ratio (RR) 3.02, 95% confidence interval (CI) [2.86, 3.19]). The estimated pooled difference in absolute risk between those with MUAC of ≥28.1 cm compared to those with a MUAC of 24 to 28.09 cm was 5.8% (95% CI 3.1% to 8.4%). Higher levels of education and age <20 years were also associated with an increased risk of excessive GWG. Results using the INTERGROWTH-21st standard among normal weight women were similar but attenuated compared to the results using the IOM guidelines among normal weight women. Limitations of the study's methodology include differences in the availability of risk factors and potential confounders measured in each individual dataset; not all risk factors or potential confounders of interest were available across datasets and data on potential confounders collected across studies. CONCLUSIONS: Inadequate GWG is a significant public health concern in LMICs. We identified diverse nutritional, behavioral, and clinical risk factors for inadequate GWG, highlighting the need for integrated approaches to optimizing GWG in LMICs. The prevalence of excessive GWG suggests that attention to the emerging burden of excessive GWG in LMICs is also warranted.

Small vulnerable newborns-big potential for impact.

Despite major achievements in child survival, the burden of neonatal mortality has remained high and even increased in some countries since 1990. Currently, most neonatal deaths are attributable to being born preterm, small for gestational age (SGA), or with low birthweight (LBW). Besides neonatal mortality, these conditions are associated with stillbirth and multiple morbidities, with short-term and long-term adverse consequences for the newborn, their families, and society, resulting in a major loss of human capital. Prevention of preterm birth, SGA, and LBW is thus critical for global child health and broader societal development. Progress has, however, been slow, largely because of the global community's failure to agree on the definition and magnitude of newborn vulnerability and best ways to address it, to frame the problem attractively, and to build a broad coalition of actors and a suitable governance structure to implement a change. We propose a new definition and a conceptual framework, bringing preterm birth, SGA, and LBW together under a broader umbrella term of the small vulnerable newborn (SVN). Adoption of the framework and the unified definition can facilitate improved problem definition and improved programming for SVN prevention. Interventions aiming at SVN prevention would result in a healthier start for live-born infants, while also reducing the number of stillbirths, improving maternal health, and contributing to a positive economic and social development in the society.

Machine learning for accurate estimation of fetal gestational age based on ultrasound images.

Accurate estimation of gestational age is an essential component of good obstetric care and informs clinical decision-making throughout pregnancy. As the date of the last menstrual period is often unknown or uncertain, ultrasound measurement of fetal size is currently the best method for estimating gestational age. The calculation assumes an average fetal size at each gestational age. The method is accurate in the first trimester, but less so in the second and third trimesters as growth deviates from the average and variation in fetal size increases. Consequently, fetal ultrasound late in pregnancy has a wide margin of error of at least ±2 weeks' gestation. Here, we utilise state-of-the-art machine learning methods to estimate gestational age using only image analysis of standard ultrasound planes, without any measurement information. The machine learning model is based on ultrasound images from two independent datasets: one for training and internal validation, and another for external validation. During validation, the model was blinded to the ground truth of gestational age (based on a reliable last menstrual period date and confirmatory first-trimester fetal crown rump length). We show that this approach compensates for increases in size variation and is even accurate in cases of intrauterine growth restriction. Our best machine-learning based model estimates gestational age with a mean absolute error of 3.0 (95% CI, 2.9-3.2) and 4.3 (95% CI, 4.1-4.5) days in the second and third trimesters, respectively, which outperforms current ultrasound-based clinical biometry at these gestational ages. Our method for dating the pregnancy in the second and third trimesters is, therefore, more accurate than published methods.

Does antenatal cholecalciferol supplementation affect the mode or timing of delivery? Post hoc analyses of the MAVIDOS randomized controlled trial.

BACKGROUND: Observational studies relating maternal 25-hydroxyvitamin D status to timing and mode of delivery have reported inconsistent results. We assessed the effect of antenatal cholecalciferol supplementation on the incidence of preterm birth, delivery mode and post-partum haemorrhage (PPH). METHODS: MAVIDOS was a randomized, double-blind, placebo-controlled trial of 1000 IU/day cholecalciferol from 14 weeks' gestation until delivery. Gestational age, mode of delivery [categorized as spontaneous vaginal delivery (SVD), instrumental (including forceps and vacuum extraction) or Caesarean section] and PPH (>500 ml estimated blood loss) were determined from medical records. RESULTS: A total of 965 women participated in the study until delivery. Gestation at birth and incidence of preterm birth (cholecalciferol 5.7%, placebo 4.5%, P = 0.43) were similar between the two treatment groups. SVD (versus instrumental or Caesarean delivery) was more likely in women randomized to cholecalciferol [Relative Risk (RR) 1.13, 95% confidence interval (CI) 1.02,1.25] due to lower instrumental (RR 0.68, 95%CI 0.51,0.91) but similar risk of Caesarean delivery (RR 0.94, 95%CI 0.74,1.19). PPH was less common in women randomized to cholecalciferol [32.1% compared with placebo (38.1%, P = 0.054) overall], but similar when stratified by delivery mode. CONCLUSIONS: Antenatal cholecalciferol supplementation did not alter timing of birth or prevalence of preterm birth but demonstrated a possible effect on the likelihood of SVD.

Hormonal regulation of mammary gland development and lactation.

Lactation is critical to infant short-term and long-term health and protects mothers from breast cancer, ovarian cancer and type 2 diabetes mellitus. The mammary gland is a dynamic organ, regulated by the coordinated actions of reproductive and metabolic hormones. These hormones promote gland development from puberty onwards and induce the formation of a branched, epithelial, milk-secreting organ by the end of pregnancy. Progesterone withdrawal following placental delivery initiates lactation, which is maintained by increased pituitary secretion of prolactin and oxytocin, and stimulated by infant suckling. After weaning, local cytokine production and decreased prolactin secretion trigger large-scale mammary cell loss, leading to gland involution. Here, we review advances in the molecular endocrinology of mammary gland development and milk synthesis. We discuss the hormonal functions of the mammary gland, including parathyroid hormone-related peptide secretion that stimulates maternal calcium mobilization for milk synthesis. We also consider the hormonal composition of human milk and its associated effects on infant health and development. Finally, we highlight endocrine and metabolic diseases that cause lactation insufficiency, for example, monogenic disorders of prolactin and prolactin receptor mutations, maternal obesity and diabetes mellitus, interventions during labour and delivery, and exposure to endocrine-disrupting chemicals such as polyfluoroalkyl substances in consumer products and other oestrogenic compounds.

Preeclampsia prediction with blood pressure measurements: A global external validation of the ALSPAC models.

OBJECTIVE: The prediction of preeclampsia in pregnancy has resulted in a plethora of prognostic models. Yet, very few make it past the development stage and most fail to influence clinical practice. The timely identification of high-risk pregnant women could deliver a tailored antenatal care regimen, particularly in low-resource settings. This study externally validated and calibrated previously published models that predicted the risk of preeclampsia, based on blood pressure (BP) at multiple time points in pregnancy, in a geographically diverse population. METHODS: The prospective INTERBIO-21st Fetal Study included 3,391 singleton pregnancies from Brazil, Kenya, Pakistan, South Africa, Thailand and the UK, 2012-2018. Preeclampsia prediction was based on baseline characteristics, BP and deviation from the expected BP trajectory at multiple time points in pregnancy. The prediction rules from the Avon Longitudinal Study of Parents and Children (ALSPAC) were implemented in the INTERBIO-21st cohort. RESULTS: Model discrimination was similar to the development cohort. Performance was best with baseline characteristics and a BP measurement at 34 weeks' gestation (AUC 0.85, 95 % CI 0.80-0.90). The ALSPAC models largely overestimated the true risk of preeclampsia incidence in the INTERBIO-21st cohort. CONCLUSIONS: After recalibration, these prediction models could potentially serve as a risk stratifying tool to help identify women who might benefit from increased surveillance during pregnancy.

Protocol for an observational study investigating hormones triggering the onset of sustained lactation: the INSIGHT study.

INTRODUCTION: Lactation is a hormonally controlled process that promotes infant growth and neurodevelopment and reduces the long-term maternal risk of diabetes, cardiovascular disease and breast cancer. Hormones, such as prolactin and progesterone, mediate mammary development during pregnancy and are critical for initiating copious milk secretion within 24-72 hours post partum. However, the hormone concentrations mediating lactation onset are ill defined. METHODS AND ANALYSIS: The primary objective of the investigating hormones triggering the onset of sustained lactation study is to establish reference intervals for the circulating hormone concentrations initiating postpartum milk secretion. The study will also assess how maternal factors such as parity, pregnancy comorbidities and complications during labour and delivery, which are known to delay lactation, may affect hormone concentrations. This single-centre observational study will recruit up to 1068 pregnant women over a 3-year period. A baseline blood sample will be obtained at 36 weeks' gestation. Participants will be monitored during postpartum days 1-4. Lactation onset will be reported using a validated breast fullness scale. Blood samples will be collected before and after a breastfeed on up to two occasions per day during postpartum days 1-4. Colostrum, milk and spot urine samples will be obtained on a single occasion. Serum hormone reference intervals will be calculated as mean±1.96 SD, with 90% CIs determined for the upper and lower reference limits. Differences in hormone values between healthy breastfeeding women and those at risk of delayed onset of lactation will be assessed by repeated measures two-way analysis of variance or a mixed linear model. Correlations between serum hormone concentrations and milk composition and volume will provide insights into the endocrine regulation of milk synthesis. ETHICS AND DISSEMINATION: Approval for this study had been granted by the East of England-Cambridgeshire and Hertfordshire Research Ethics Committee (REC No. 20/EE/0172), by the Health Research Authority (HRA), and by the Oxford University Hospitals National Health Service Foundation Trust. The findings will be published in high-ranking journals and presented at national and international conferences. TRIAL REGISTRATION NUMBER: ISRCTN12667795.

Association between fetal abdominal growth trajectories, maternal metabolite signatures early in pregnancy, and childhood growth and adiposity: prospective observational multinational INTERBIO-21st fetal study.

BACKGROUND: Obesity predominantly affects populations in high-income countries and those countries facing epidemiological transition. The risk of childhood obesity is increased among infants who had overweight or obesity at birth, but in low-resource settings one in five infants are born small for gestational age. We aimed to study the relationships between: (1) maternal metabolite signatures; (2) fetal abdominal growth; and (3) postnatal growth, adiposity, and neurodevelopment. METHODS: In the prospective, multinational, observational INTERBIO-21st fetal study, conducted in maternity units in Pelotas (Brazil), Nairobi (Kenya), Karachi (Pakistan), Soweto (South Africa), Mae Sot (Thailand), and Oxford (UK), we enrolled women (≥18 years, with a BMI of less than 35 kg/m2, natural conception, and a singleton pregnancy) who initiated antenatal care before 14 weeks' gestation. Ultrasound scans were performed every 5±1 weeks until delivery to measure fetal growth and feto-placental blood flow, and we used finite mixture models to derive growth trajectories of abdominal circumference. The infants' health, growth, and development were monitored from birth to age 2 years. Early pregnancy maternal blood and umbilical cord venous blood samples were collected for untargeted metabolomic analysis. FINDINGS: From Feb 8, 2012, to Nov 30, 2019, we enrolled 3598 pregnant women and followed up their infants to 2 years of age. We identified four ultrasound-derived trajectories of fetal abdominal circumference growth that accelerated or decelerated within a crucial 20-25 week gestational age window: faltering growth, early accelerating growth, late accelerating growth, and median growth tracking. These distinct phenotypes had matching feto-placental blood flow patterns throughout pregnancy, and different growth, adiposity, vision, and neurodevelopment outcomes in early childhood. There were 709 maternal metabolites with positive effect for the faltering growth phenotype and 54 for the early accelerating growth phenotype; 31 maternal metabolites had a negative effect for the faltering growth phenotype and 76 for the early accelerating growth phenotype. Metabolites associated with the faltering growth phenotype had statistically significant odds ratios close to 1·5 (ie, suggesting upregulation of metabolic pathways of impaired fetal growth). The metabolites had a reciprocal relationship with the early accelerating growth phenotype, with statistically significant odds ratios close to 0.6 (ie, suggesting downregulation of fetal growth acceleration). The maternal metabolite signatures included 5-hydroxy-eicosatetraenoic acid, and 11 phosphatidylcholines linked to oxylipin or saturated fatty acid sidechains. The fungicide, chlorothalonil, was highly abundant in the early accelerating growth phenotype group. INTERPRETATION: Early pregnancy lipid biology associated with fetal abdominal growth trajectories is an indicator of patterns of growth, adiposity, vision, and neurodevelopment up to the age of 2 years. Our findings could contribute to the earlier identification of infants at risk of obesity. FUNDING: Bill & Melinda Gates Foundation.

Pregnancy Vitamin D Supplementation and Childhood Bone Mass at Age 4 Years: Findings From the Maternal Vitamin D Osteoporosis Study (MAVIDOS) Randomized Controlled Trial.

In the Maternal Vitamin D Osteoporosis Study (MAVIDOS) randomized trial, vitamin D supplementation in pregnancy did not lead to greater neonatal bone mass across the trial as a whole, but, in a prespecified secondary analysis by season of birth, led to greater neonatal bone mass among winter-born babies. Demonstrating persistence of this effect into childhood would increase confidence in a long-term benefit of this intervention. We investigated whether antenatal vitamin D supplementation increases offspring bone mineralization in early childhood in a prespecified, single-center follow-up of a double-blinded, multicenter, randomized controlled clinical trial based in the UK (MAVIDOS). A total of 1123 women in early pregnancy with a baseline 25-hydroxyvitamin D level 25-100 nmol/L from three research centers (2008-2014) were randomized to 1000 IU/d cholecalciferol or matched placebo from 14 weeks of gestation to delivery. Offspring born at the Southampton, UK research center were assessed at age 4 years (2013-2018). Anthropometry and dual-energy X-ray absorptiometry (DXA) were performed (yielding whole body less head [WBLH] bone mineral content [BMC], areal bone mineral density [aBMD], bone area [BA], and body composition). Of 723 children, 564 (78.0%) children attended the 4-year visit, 452 of whom had a useable DXA. Maternal vitamin D supplementation led to greater WBLH aBMD in the children compared with placebo (mean [95% confidence interval {CI}]: supplemented group: 0.477 (95% CI, 0.472-0.481) g/cm2; placebo group: 0.470 (95% CI, 0.466-0.475) g/cm2, p = 0.048). Associations were consistent for BMC and lean mass, and in age- and sex-adjusted models. Effects were observed across the whole cohort irrespective of season of birth. Maternal-child interactions were observed, with a greater effect size among children with low milk intake and low levels of physical activity. Child weight, height, and body mass index (BMI) were similar by maternal randomization group. These findings suggest a sustained beneficial effect of maternal vitamin D supplementation in pregnancy on offspring aBMD at age 4 years, but will require replication in other trials. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Fatal COVID-19 outcomes are associated with an antibody response targeting epitopes shared with endemic coronaviruses.

The role of immune responses to previously seen endemic coronavirus epitopes in severe acute respiratory coronavirus 2 (SARS-CoV-2) infection and disease progression has not yet been determined. Here, we show that a key characteristic of fatal outcomes with coronavirus disease 2019 (COVID-19) is that the immune response to the SARS-CoV-2 spike protein is enriched for antibodies directed against epitopes shared with endemic beta-coronaviruses and has a lower proportion of antibodies targeting the more protective variable regions of the spike. The magnitude of antibody responses to the SARS-CoV-2 full-length spike protein, its domains and subunits, and the SARS-CoV-2 nucleocapsid also correlated strongly with responses to the endemic beta-coronavirus spike proteins in individuals admitted to an intensive care unit (ICU) with fatal COVID-19 outcomes, but not in individuals with nonfatal outcomes. This correlation was found to be due to the antibody response directed at the S2 subunit of the SARS-CoV-2 spike protein, which has the highest degree of conservation between the beta-coronavirus spike proteins. Intriguingly, antibody responses to the less cross-reactive SARS-CoV-2 nucleocapsid were not significantly different in individuals who were admitted to an ICU with fatal and nonfatal outcomes, suggesting an antibody profile in individuals with fatal outcomes consistent with an "original antigenic sin" type response.

Complex Perinatal Syndromes Affecting Early Human Growth and Development: Issues to Consider to Understand Their Aetiology and Postnatal Effects.

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.

SMARThealth Pregnancy: Feasibility and Acceptability of a Complex Intervention for High-Risk Pregnant Women in Rural India: Protocol for a Pilot Cluster Randomised Controlled Trial.

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.

Association of maternal prenatal selenium concentration and preterm birth: a multicountry meta-analysis.

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 analysis. The associations between maternal Se with PTB and gestational duration were analysed using logistic and linear regressions. The results were then combined using fixed-effect 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 (SD: 28.5 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 and gestational duration with effect size estimates of an OR=0.95 (95% CI: 0.9 to 1.00) for PTB and 0.66 days (95% CI: 0.38 to 0.94) longer gestation per 15 ng/mL increase in Se concentration. However, there was a substantial heterogeneity among study cohorts and the random-effect meta-analysis did not achieve statistical significance. The largest effect sizes were observed in UK (Liverpool) cohort, and most significant associations were observed in samples from Malawi. INTERPRETATION: While our study observed statistically significant associations between maternal Se concentration and PTB at some sites, this did not generalise across the entire cohort. Whether population-specific factors explain the heterogeneity of our findings warrants further investigation. Further evidence is needed to understand the biologic pathways, clinical efficacy and safety, before changes to antenatal nutritional recommendations for Se supplementation are considered.