Background: While the human fetal immune system defaults to a program of tolerance, there is 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 pro-inflammatory 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 to 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 pro-inflammatory cytokines. Engagement of the C-type lectin CD161 on these cells inhibited TCR-dependent production of IFNγ in a fetal-specific manner. IFNγ-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.

Anaemia in pregnancy is a persistent health problem in Nepal and could be reduced through nutrition counselling and strengthened iron folic acid supplementation programmes. We analysed 24-hour diet recall data from 846 pregnant women in rural plains Nepal, using linear programming to identify the potential for optimised food-based strategies to increase iron adequacy. We then conducted qualitative research to analyse how anaemia was defined and recognised, how families used food-based strategies to address anaemia, and the acceptability of optimised food-based strategies. We did 16 interviews of recently pregnant mothers, three focus group discussions with fathers, three focus group discussions with mothers-in-law and four interviews with key informants. Dietary analyses showed optimised diets did not achieve 100 % of recommended iron intakes, but iron intakes could be doubled by increasing intakes of green leaves, egg and meat. Families sought to address anaemia through food-based strategies but were often unable to because of the perceived expense of providing an ‘energy-giving’ diet. Some foods were avoided because of religious or cultural taboos, or because they were low status and could evoke social consequences if eaten. There is a need for counselling to offer affordable ways for families to optimise iron adequacy. The participation of communities in tailoring advice to ensure cultural relevance and alignment with local norms is necessary to enable its effectiveness.

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.

Objective: Investigate cost‐effectiveness of first trimester pre‐eclampsia screening using the Fetal Medicine Foundation (FMF) algorithm and targeted aspirin prophylaxis in comparison with standard care.Design: Retrospective observational study.Setting: London tertiary hospital.Population: 5957 pregnancies screened for pre‐eclampsia using the National Institute for Health and Care Excellence (NICE) method.Methods: Differences in pregnancy outcomes between those who developed pre‐eclampsia, term pre‐eclampsia and preterm pre‐eclampsia were compared by the Kruskal–Wallis and Chi‐square tests. The FMF algorithm was applied retrospectively to the cohort. A decision analytic model was used to estimate costs and outcomes for pregnancies screened using NICE and those screened using the FMF algorithm. The decision point probabilities were calculated using the included cohort.Main outcome measures: Incremental healthcare costs and QALY gained per pregnancy screened.Results: Of 5957 pregnancies, 12.8% and 15.9% were screen‐positive for development of pre‐eclampsia using the NICE and FMF methods, respectively. Of those who were screen‐positive by NICE recommendations, aspirin was not prescribed in 25%. Across the three groups, namely, pregnancies without pre‐eclampsia, term pre‐eclampsia and preterm pre‐eclampsia there was a statistically significant trend in rates of emergency caesarean (respectively 21%, 43% and 71.4%; P < 0.001), admission to neonatal intensive care unit (NICU) (5.9%, 9.4%, 41%; P < 0.001) and length of stay in NICU. The FMF algorithm was associated with seven fewer cases of preterm pre‐eclampsia, cost saving of £9.06 and QALY gain of 0.00006/pregnancy screened.Conclusions: Using a conservative approach, application of the FMF algorithm achieved clinical benefit and an economic cost saving.

Objective: Women who have delivered a small‐for‐gestational‐age (SGA) infant are at an increased risk of developing cardiovascular disease (CVD) in later life. Endothelial dysfunction is a subclinical sign of early CVD. It is unknown whether women who have recently had a pregnancy complicated by SGA, in the absence of other maternal and fetal diseases, have subclinical endothelial dysfunction. Our aim was to assess maternal endothelial function 6 months after a pregnancy complicated by SGA.Methods: This was a case–control study conducted in a tertiary referral hospital in London, UK, over a 15‐month period. Flow‐mediated dilatation (FMD) of the brachial artery was measured in women 6.9 ± 2.5 months after childbirth. Forty‐four women were included in the study, of whom 15 had a SGA neonate (mean ± SD customized birth centile of 1.9 ± 2.3) and 29 delivered an appropriately grown baby (mean ± SD customized birth centile of 47.5 ± 26.3). The primary continuous variable, FMD, was assessed in each group and compared using unpaired t‐test.Results: Women who had a SGA neonate had lower postpartum FMD (6.79 ± 0.95%) than did those who had an appropriately grown offspring (10.26 ± 2.44% (95% CI for difference between groups, −5.37 to −1.57); P = 0.0007). There were no differences in postnatal maternal blood pressure, abdominal circumference, weight and glucose, insulin and lipid profiles between the two groups.Conclusions: Women who had a pregnancy affected by SGA, probably due to placental failure in the absence of pre‐eclampsia, have evidence of subclinical endothelial dysfunction within 6 months of childbirth. These women may benefit from lifestyle measures focused on the primary prevention of CVD. Further research in larger populations is needed to ascertain if such postpartum maternal endothelial dysfunction is a pregnancy‐induced phenomenon or if it is related to the pre‐existing maternal phenotype, and whether it persists long term. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

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, and 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 etiology of FGR.