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Fetal growth restriction (FGR) is a leading cause of perinatal morbidity and mortality. Altered placental formation and functional capacity are major contributors to FGR pathogenesis. Relating placental structure to function across the placenta in healthy and FGR pregnancies remains largely unexplored but could improve understanding of placental diseases. We investigated integration of these parameters spatially in the term human placenta using predictive modelling. Systematic sampling was able to overcome heterogeneity in placental morphological and molecular features. Defects in villous development, elevated fibrosis, and reduced expression of growth and functional marker genes (IGF2, VEGA, SLC38A1, SLC2A3) were seen in age-matched term FGR versus healthy control placentas. Characteristic histopathological changes with specific accompanying molecular signatures could be integrated through computational modelling to predict if the placenta came from a healthy or FGR pregnancy. Our findings yield new insights into the spatial relationship between placental structure and function and the aetiology of FGR.

There have been concerted efforts toward cataloging rare and deleterious variants in different world populations using high-throughput genotyping and sequencing-based methods. The Indian population is underrepresented or its information with respect to clinically relevant variants is sparse in public data sets. The aim of this study was to estimate the burden of monogenic disease-causing variants in Indian populations. Toward this, we have assessed the frequency profile of monogenic phenotype-associated ClinVar variants. The study utilized a genotype data set (global screening array, Illumina) from 2795 individuals (multiple in-house genomics cohorts) representing diverse ethnic and geographically distinct Indian populations. Of the analyzed variants from Global Screening Array, ~9% were found to be informative and were either not known earlier or underrepresented in public databases in terms of their frequencies. These variants were linked to disorders, namely inborn errors of metabolism, monogenic diabetes, hereditary cancers, and various other hereditary conditions. We have also shown that our study cohort is genetically a better representative of the Indian population than its representation in the 1000 Genome Project (South Asians). We have created a database, ClinIndb, linked to the Leiden Open Variation Database, to help clinicians and researchers in diagnosis, counseling, and development of appropriate genetic screening tools relevant to the Indian populations and Indians living abroad.

Pathological low birth weight ‘fetal growth restriction’ (FGR) is an important predictor of adverse obstetric outcomes including stillbirth. It is more common amongst native lowlanders when gestating in the hypoxic environment of high altitude, whilst populations who have resided at high altitude for many generations are relatively protected. Genetic study of pregnant populations at high altitude allows for exploration of the hypoxic influence on FGR pathogenesis.Pregnant women were recruited from Sonam Norboo Memorial Hospital, Ladakh between February 2017- January 2019 in this study. Principal component, admixture and genome wide association analysis (GWAS) were applied on umbilical cord blood DNA samples from 316 neonates, to explore ancestry and the genetic influence on low birth weight.Our findings support Tibetan ancestry in the Ladakhi population, with subsequent admixture with neighboring Indo-Aryan populations. Fetal growth protection was evident in Ladakhi neonates. Seven loci from five different genomic regions (ZBTB38, ZFP36L2, HMGA2, CDKAL1, PLCG1) previously associated with birthweight, were likewise similarly associated here. In summary, the Ladakhi population show evidence of enrichment of variants in genes that may help mitigate altitude-associated fetal growth restriction, supporting novel biological pathways and therapeutic targets for FGR, worthy of further investigation.

Fetal growth restriction (FGR) is a complication of pregnancy that reduces birth weight, markedly increases infant mortality and morbidity and is associated with later-life cardiometabolic disease. No specific treatment is available for FGR. Placentas of human FGR infants have low abundance of sodium-coupled neutral amino acid transporter 2 (Slc38a2/SNAT2), which supplies the fetus with amino acids required for growth. We determined the mechanistic role of placental Slc38a2/SNAT2 deficiency in the development of restricted fetal growth, hypothesizing that placenta-specific Slc38a2 knockdown causes FGR in mice. Using lentiviral transduction of blastocysts with a small hairpin RNA (shRNA), we achieved 59% knockdown of placental Slc38a2, without altering fetal Slc38a2 expression. Placenta-specific Slc38a2 knockdown reduced near-term fetal and placental weight, fetal viability, trophoblast plasma membrane (TPM) SNAT2 protein abundance, and both absolute and weight-specific placental uptake of the amino acid transport System A tracer, 14C-methylaminoisobutyric acid (MeAIB). We also measured human placental SLC38A2 gene expression in a well-defined term clinical cohort and found that SLC38A2 expression was decreased in late-onset, but not early-onset FGR, compared with appropriate for gestational age (AGA) control placentas. The results demonstrate that low placental Slc38a2/SNAT2 causes FGR and could be a target for clinical therapies for late-onset FGR.

BACKGROUND: While the human fetal immune system defaults to a program of tolerance, there is a concurrent need for protective immunity to meet the antigenic challenges encountered after birth. Activation of T cells in utero is associated with the fetal inflammatory response, with broad implications for the health of the fetus and of the pregnancy. However, the characteristics of the fetal effector T cells that contribute to this process are largely unknown. METHODS: We analyzed primary human fetal lymphoid and mucosal tissues and performed phenotypic, functional, and transcriptional analysis to identify T cells with proinflammatory potential. The frequency and function of fetal-specific effector T cells was assessed in the cord blood of infants with localized and systemic inflammatory pathologies and compared with that of healthy term controls. RESULTS: We identified a transcriptionally distinct population of CD4(+) T cells characterized by expression of the transcription factor promyelocytic leukemia zinc finger (PLZF). PLZF(+)CD4(+) T cells were specifically enriched in the fetal intestine, possessed an effector memory phenotype, and rapidly produced proinflammatory cytokines. Engagement of the C-type lectin CD161 on these cells inhibited TCR-dependent production of IFN-γ in a fetal-specific manner. IFN-γ–producing PLZF(+)CD4(+) T cells were enriched in the cord blood of infants with gastroschisis, a natural model of chronic inflammation originating from the intestine, as well as in preterm birth, suggesting these cells contribute to fetal systemic immune activation. CONCLUSION: Our work reveals a fetal-specific program of protective immunity whose dysregulation is associated with fetal and neonatal inflammatory pathologies. FUNDING: This work was supported by the UCSF Clinical and Translational Science Institute (CTSI) Pilot Award for Basic and Translational Investigators (2014908), UCSF (K12HD072222), the NIAID (K08 AI128007 and 1F31AI136336-01), a National Science Foundation (NSF) Graduate Research Fellowship (1650113 ), and an Academy for Medical Sciences Clinical Lecturer grant (535274).

Maternal anaemia prevalence in low‐income countries is unacceptably high. Our research explored the individual‐, family‐ and community‐level factors affecting antenatal care uptake, iron folic acid (IFA) intake and consumption of micronutrient‐rich diets among pregnant women in the plains of Nepal. We discuss how these findings informed the development of a home visit and community mobilisation intervention to reduce anaemia in pregnancy. We used a qualitative methodology informed by the socio‐ecological framework, conducting semi‐structured interviews with recently pregnant women and key informants, and focus group discussions with mothers‐in‐law and fathers. We found that harmful gender norms restricted women's access to nutrient‐rich food, restricted their mobility and access to antenatal care. These norms also restricted fathers' role to that of the provider, as opposed to the caregiver. Pregnant women, mothers‐in‐law and fathers lacked awareness about iron‐rich foods and how to manage the side effects of IFA. Fathers lacked trust in government health facilities affecting access to care and trust in the efficacy of IFA. Our research informed interventions by (1) informing the development of intervention tools and training; (2) informing the intervention focus to engaging mothers‐in‐law and men to enable behaviour change; and (3) demonstrating the need to work in synergy across individual, family and community levels to address power and positionality, gender norms, trust in health services and harmful norms. Participatory groups and home visits will enable the development and implementation of feasible and acceptable strategies to address family and contextual issues generating knowledge and an enabling environment for behaviour change.

Background States which reduce foetal oxygen delivery are associated with impaired intrauterine growth. Hypoxia results when barometric pressure falls with ascent to altitude, and with it the partial pressure of inspired oxygen (‘hypobaric hypoxia’). birthweight is reduced when native lowlanders gestate at such high altitude (HA)—an effect mitigated in native (millennia) HA populations. Studying HA populations offer a route to explore the mechanisms by which hypoxia impacts foetal growth. Methods Between February 2017 and January 2019, we prospectively studied 316 pregnant women, in Leh, Ladakh (altitude 3524 m, where oxygen partial pressure is reduced by 1/3) and 101 pregnant women living in Delhi (low altitude, 216 m above sea level). Results Of Ladakhi HA newborns, 14% were small for gestational age (10th weight centile. Conclusions This study showed that Ladakhi offspring birthweight is relatively spared from the expected adverse HA effects. Furthermore, maternal body composition and greater UtA size may be physiological HA adaptations and warrant further study, as they offer potential mechanisms to overcome hypoxia-related growth issues. Impact Reduced foetal oxygen delivery seen in native lowlanders who gestate at HA causes foetal growth restriction—an effect thought to be mitigated in native HA populations. We found that greater maternal body mass and UtA diameter were associated with increased offspring birthweight in a (Ladakh) HA population. This supports a role for them as physiological mediators of adaptation and provides insights into potential mechanisms that may treat hypoxia-related growth issues.

Background Women who have had small for gestational age offspring have an increased risk of cardiovascular disease in later life. Endothelial dysfunction is a subclinical sign of early cardiovascular disease. It is unknown whether women who have recently had a pregnancy complicated by fetal growth restriction, in the absence of other maternal and fetal disease, have subclinical endothelial dysfunction. Objective To assess maternal endothelial function six months after a pregnancy complicated by fetal growth restriction. Methods This was a case–control study, conducted in a tertiary referral hospital in London over a 15-month period. Flow-mediated dilatation (FMD) of the brachial artery was measured in women, six months (+/− 2.5 months) after the birth of their child. Forty-four women were studied; 15 had a growth restricted offspring (customised birth centile 1.9 ± 2.3; mean ± SD) and 29 women had delivered an appropriately grown baby (customized birth centile 47.5 ± 26.3). Results were analysed using an unpaired t-test and the means of the primary continuous variable (FMD % change). Results Women who had a growth restricted offspring had lower postpartum FMD (6.79% ± 0.95%) compared with mothers who had an appropriately grown offspring, FMD 10.26% ± 2.44%; 95% CI −5.37 to −1.57 (p = 0.0007;). There were no differences in postnatal measures of maternal blood pressure, abdominal circumference, weight, glucose, insulin and lipid profiles between the two groups. Conclusions Within six months of childbirth, women who have had a pregnancy affected by fetal growth restriction due to likely placental failure, but in the absence of pre-eclampsia, have evidence of subclinical endothelial dysfunction. These women may benefit from lifestyle measures focused on the primary prevention of cardiovascular disease. Further research, with larger populations, is needed to discover whether this postpartum maternal endothelial dysfunction is a pregnancy-induced phenomenon, or related to pre-existing maternal phenotype and indeed whether it persists long term.

OBJECTIVE Fathers of low–birth weight offspring are more likely to have type 2 diabetes and cardiovascular disease in later life. We investigated whether paternal insulin resistance and cardiovascular risk factors were evident at the time that fetal growth–restricted offspring were born. RESEARCH DESIGN AND METHODS We carried out a case-control study of men who fathered pregnancies affected by fetal growth restriction, in the absence of recognized fetal disease (n = 42), compared with men who fathered normal–birth weight offspring (n = 77). All mothers were healthy, nonsmoking, and similar in age, BMI, ethnicity, and parity. Within 4 weeks of offspring birth, all fathers had measures of insulin resistance (HOMA index), blood pressure, waist circumference, endothelial function (flow-mediated dilatation), lipid profile, weight, and smoking habit. Comparison was made using multivariable logistical regression analysis. RESULTS Fathers of fetal growth–restricted offspring [mean (SD) 1.8th (2.2) customized birth centile] were more likely to have insulin resistance, hypertension, central adiposity, and endothelial dysfunction and to smoke cigarettes compared with fathers of normal grown offspring. After multivariable analysis, paternal insulin resistance and smoking remained different between the groups. Compared with fathers of normal grown offspring, men who fathered pregnancies affected by fetal growth restriction had an OR 7.68 (95% CI 2.63–22.40; P < 0.0001) of having a 1-unit higher log HOMA-IR value and 3.39 (1.26–9.16; P = 0.016) of being a smoker. CONCLUSIONS Men who recently fathered growth-restricted offspring have preclinical evidence of the insulin resistance syndrome and are more likely to smoke than fathers of normal grown offspring. Paternal lifestyle may influence heritable factors important for fetal growth.

Background The fetal insulin hypothesis suggests that poor fetal growth and diabetes are two phenotypes of genetically determined insulin resistance (IR). Evidence for the hypothesis arises through the study of mutations in maturity-onset diabetes of the young (MODY). Genetic inheritance of a mutation in glucokinase (a MODY gene) results in lower offspring birthweight if inherited through the father. We have previously shown that men, at the time of fathering a growth restricted pregnancy, are more insulin resistant. These findings support the hypothesis that inheritance of a genetic variant passed from father to offspring will result in fetal growth restriction (FGR) and paternal diabetes risk. Methods In this study we used whole exome sequencing (WES) of DNA from 10 growth restricted offspring, in order to identify novel and rare variants in recognised MODY genes that might be influencing fetal growth. Results were validated with Sanger sequencing or Taqman genotyping. Results In 2 of the 10 offspring sampled, single point heterozygous mutations were identified in MODY recognised genes ( HNF1β and NOTCH2 ). These variants were rare and predicted to be pathogenic. In a 3 rd case, 2 rare heterozygous mutations in synergistically acting MODY genes ( HNF1α and HNF4α ) were identified. In a 4 th case a very rare homozygous MODY mutation in KCNJ11 was identified. Conclusions Through WES, rare genetic variants in genes associated with MODY were discovered in 4/10 separate offspring affected by FGR. Whilst proof of cause is required they are implicated in growth restriction through their predicted pathogenicity, rareness and known biological mechanisms.

Background Low birth weight is associated with an increased risk of developing type-2 diabetes in later life. The fathers of low birth weight offspring are themselves more likely to have type-2 diabetes in later life. As part of a larger study to determine whether offspring with fetal growth restriction (FGR) inherit insulin resistance (IR) from their fathers, we designed a case-control study to compare IR and endothelial function in men who father FGR offspring (cases) with men who father normal birth weight offspring (controls). Methods We recruited 30 fathers of ongoing FGR pregnancies, defined as fetal growth Results Fathers of FGR pregnancies had greater IR, (p=0.0015), impaired FMD (p=0.029), higher systolic (p=0.007) and diastolic (p=0.0001) blood pressures, greater waist circumferences (p Conclusions Fathers of FGR pregnancies have a metabolic and vascular phenotype that predisposes to type 2 diabetes and cardiovascular disease at the time of an affected pregnancy. We are investigating whether this observation can be explained by altered insulin control genes inherited by the growth-restricted fetus from the father.