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Placenta ischemia, the initiating event in preeclampsia (PE), is associated with fetal growth restriction. Inhibition of the agonistic autoantibody against the angiotensin type 1 receptor AT

In healthy near-term women, blood flow to the uteroplacental circulation is estimated as 841 mL/min, which is greater than in other mammalian species. We argue that as uterine venous Po2 sets the upper limit for O2 diffusion to the fetus, high uterine artery blood flow serves to narrow the maternal arterial-to-uterine venous Po2 gradient and thereby raise uterine vein Po2. In support, we show that the reported levels for uterine artery blood flow agree with what is required to maintain normal fetal growth. Although residence at high altitudes (>2,500 m) depresses fetal growth, not all populations are equally affected; Tibetans and Andeans have higher levels of uterine artery blood flow than newcomers and exhibit normal fetal growth. Estimates of uterine venous Po2 from the umbilical blood-gas data available from healthy Andean pregnancies indicate that their high levels of uterine artery blood flow are consistent with their reported, normal birth weights. Unknown, however, are the effects on placental gas exchange of the lower levels of uterine artery blood flow seen in high-altitude newcomers or hypoxia-associated pregnancy complications. We speculate that, by widening the maternal artery to uterine vein Po2 gradient, lower levels of uterine artery blood flow prompt metabolic changes that slow fetal growth to match O2 supply.

To compare the ability of three fetal growth charts (Fetal Medicine Foundation (FMF), Hadlock and National Institutes of Child Health and Human Development (NICHD) race/ethnicity-specific) to predict large-for-gestational age (LGA) at birth in pregnant individuals with pregestational diabetes, and to determine whether inclusion of hemoglobin A1c (HbA1c) level improves the predictive performance of the growth charts.This was a retrospective analysis of individuals with Type-1 or Type-2 diabetes with a singleton pregnancy that resulted in a non-anomalous live birth. Fetal biometry was performed between 28 + 0 and 36 + 6 weeks of gestation. The primary exposure was suspected LGA, defined as estimated fetal weight ≥ 90Of 358 assessed pregnant individuals with pregestational diabetes (34% with Type 1 and 66% with Type 2), 147 (41%) had a LGA infant at birth. Suspected LGA was identified in 123 (34.4%) by the Hadlock, 152 (42.5%) by the FMF and 152 (42.5%) by the NICHD growth chart. The FMF growth chart had the highest sensitivity (77% vs 69% (NICHD) vs 63% (Hadlock)) and the Hadlock growth chart had the highest specificity (86% vs 76% (NICHD) and 82% (FMF)) for predicting LGA at birth. The FMF growth chart had a significantly higher AUC (0.79 (95% CI, 0.74-0.84)) for LGA at birth compared with the NICHD (AUC, 0.72 (95% CI, 0.68-0.77); P 0.001) and Hadlock (AUC, 0.75 (95% CI, 0.70-0.79); P 0.01) growth charts. Prediction of LGA improved for all three growth charts with the inclusion of HbA1c measurement in comparison to each growth chart alone (P 0.001 for all); the FMF growth chart remained more predictive of LGA at birth (AUC, 0.85 (95% CI, 0.81-0.90)) compared with the NICHD (AUC, 0.79 (95% CI, 0.73-0.84)) and Hadlock (AUC, 0.81 (95% CI, 0.76-0.86)) growth charts.The FMF fetal growth chart had the best predictive performance for LGA at birth in comparison with the Hadlock and NICHD race/ethnicity-specific growth charts in pregnant individuals with pregestational diabetes. Inclusion of HbA1c improved further the prediction of LGA for all three charts. © 2022 The Authors. Ultrasound in ObstetricsGynecology published by John WileySons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.

Previous research suggests that job loss in a household during pregnancy may perturb fetal growth. However, this work often cannot rule out unmeasured confounding due to selection into job loss. Recent work using data on exogenous job loss (due to a plant closure) finds that a father's unexpected job loss during his spouse's pregnancy increases the risk of a low weight birth. Using a unique set of linked registries in Denmark, we build on this work and examine whether associations between a father's unexpected job loss and low birthweight differ by trimester of in utero exposure. We additionally examine trimester-specific associations of job loss with small-for-gestational-age, a proxy for restricted fetal growth, which may cause low birthweight.We apply a sibling control design to over 1.4 million live births in Denmark, 1980 to 2017, to examine whether this plausibly exogenous form of job loss corresponds with increased risk of low weight or small-for-gestational-age births, depending on the timing of displacement in the first, second, or third trimester.Results indicate an elevated risk of low birthweight (OR = 1.80, 95% CI: 1.24, 2.62) and small-for-gestational-age (OR = 1.40, 95% CI: 1.02, 1.93) among gestations exposed to job loss in the second trimester of pregnancy. Sensitivity analyses using continuous outcome measures (e.g., birthweight in grams, birthweight for gestational age percentile) and maternal fixed effects analyses produce substantively similar inference.Findings support the notion that unexpected job loss may affect fetal growth and that the second trimester in particular appears sensitive to this external stressor.

The present systematic review and meta-analysis aim to summarize the effects of maternal undernutrition or overnutrition during pregnancy on the absolute weight and relative weight of the organs (liver, kidneys, heart, spleen, and lung) and glands (adrenal, pancreas, and thyroid) measured during gestation, birth and the postnatal period in lambs. After completing the search, selection, and data extraction steps, the measure of effect was generated by the individual comparison of each variable response compared with the average of the control and treated group (undernutrition or overnutrition) using the DerSimonian and Laird method for random effects. The liver was the organ most affected by maternal undernutrition, as the absolute weight of the liver was reduced during pregnancy, birth, and the postnatal period. The extent of this effect is related to the duration of the intervention. Reductions in the absolute fetal weight of the lungs and spleen have also been observed. No change in organs weight were observed when the results were expressed as relative weight. For overnutrition, the fetal weight of the liver was reduced to both absolute and relative values. In contrast, the relative weight of the kidneys has been increased. For the glands analyzed, no changes in weight were observed in either scenario (absolute or relative weight). Thus, the organs are more likely to suffer weight changes, especially during pregnancy, as a result of maternal nutrition. However, this change in organ weight seems to be closely related to the reduction in body weight of the progeny as a whole.

Obesity in pregnancy is currently the leading cause of gestational complications for the mother and fetus worldwide. Maternal obesity (MO), common in western societies, impedes development of intestinal epithelium in the fetuses, which causes disorders in the nutrient absorption and intestine-related immune responses in offspring. Here, using a mouse model of maternal exercise (ME), we found that exercise during pregnancy protects the impairment of fetal intestinal morphometrical formation and epithelial development due to MO. MO decreased villus length and epithelial proliferation markers in E18.5 fetal small intestine, which was increased due to ME. The expression of the epithelial differentiation markers, Lyz1, Muc2, and Tff3, in fetal small intestine was decreased due to MO, but protected by ME. Consistently, the biomarkers related to mitochondrial biogenesis and oxidative metabolism were downregulated in MO fetal small intestine but recovered by ME. Apelin injection to dams partially mirrored the beneficial effects of ME. ME and apelin injection activated AMPK, the downstream target of apelin receptor signaling, which might mediate the improvement of fetal epithelial development and oxidative metabolism. These findings suggest that ME, a highly accessible intervention, is effective in improving fetal intestinal epithelium of obese dams. Apelin-AMPK-mitochondrial biogenesis axis provides amenable therapeutic targets to facilitate fetal intestinal development of obese mothers.

Fetal growth restriction contributes to the excess perinatal mortality and morbidity associated with twin pregnancies. Regular ultrasound monitoring for fetal growth restriction is an essential component of antenatal care of twin gestations. It is accepted that twins have divergent growth trajectories around 28-30 weeks' gestation and are born smaller compared to singletons. Despite this well-established difference in fetal growth, twin pregnancies have been traditionally managed using growth standards developed for singleton pregnancies. Numerous recent studies have demonstrated a strong case supporting the use of twin-specific growth standards, but clinical implementation has been lacking. In this paper, we will review the evidence on factors affecting fetal growth, the rationale for twin-specific reference charts, clinical evidence for their use, and future direction of research. Applying singleton growth standards to twin pregnancies inflates the abnormal growth rate, and recent clinical evidence from several studies suggests that they are too stringent for classification of twins. The association of adverse perinatal and maternal outcomes such as perinatal death, preterm birth, neonatal care unit admission, hypertensive disorders of pregnancy, and composite neonatal morbidity is stronger when classification is made using twin-specific standards compared to singletons.

To describe the natural history of fibroids in pregnancy in a racially diverse cohort and explore whether fibroid changes were associated with participant characteristics.Prospective cohort study.Twelve clinical sites.Pregnant women (n = 2774; 27% non-Hispanic White, 28% non-Hispanic Black, 29% Hispanic, 17% Asian/Pacific Islander) who had up to 6 obstetric ultrasounds in gestational weeks 10-41.Sonographers recorded fibroid number and volume of the 3 largest fibroids at each visit. Generalized linear mixed models estimated the trajectories of fibroid number and total volume (overall and stratified by total volume at first visualization: equivalent to a fibroid of1 cm [small], 1 to3 cm [medium], or ≥3 cm [large] in diameter). We tested the interactions between the trajectories and race/ethnicity, age (26, 26-30, 31-34, and ≥35 years), body mass index (25, 25-29.9, and ≥30 kg/mAverage change in total fibroid volume during pregnancy.Overall, 9.6% (266/2,774) of women had a visualized fibroid at any time during pregnancy, including 9% (67/745) of non-Hispanic White women, 14% (106/770) of non-Hispanic Black women, 6% (47/794) of Hispanic women, and 10% (46/465) of Asian or Pacific Islander women. The mean total fibroid volume decreased by 1.0% (95% confidence interval [CI], -1.9%, -0.2%) per week, with a variation in starting total volume. On average, the total volume increased by 2.0% (95% CI, -0.3%, 4.5%) per week among women with small volume; decreased by 0.5% (95% CI, -2.0%, 1.0%) per week among women with medium volume; and decreased by 2.2% (95% CI, -3.4%, -1.0%) per week among women with large volume at first visualization. The volume change also varied by race or ethnicity, parity, age, and miscarriage history. For example, non-Hispanic Black women's total fibroid volume decreased more than those of non-Hispanic White, Hispanic and Asian/Pacific Islander women (-2.6%, 0.1%, 0.5%, and 0.9% average change per week, respectively). The visualized fibroid number declined on an average by 1.2% per week (95% CI, -1.9%, -0.5%) without significant variation by demographic characteristics.The total fibroid volume declined on average throughout pregnancy. However, summarizing across all fibroids disguises substantial heterogeneity by starting total fibroid volume and maternal characteristics. The findings may be a useful reference for clinicians to anticipate how fibroids may change in obstetric patients.NCT00912132.

This was an observational study of low-risk singleton pregnancies in an ethnic Chinese population. Foetal biometric variables which included biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC) and femur length (FL) were measured repeatedly. The standard views for measurement were obtained according to INTERGROWTH-21st criteria. A linear mixed model with fractional polynomial regression was used to describe the longitudinal design. The study included 1289 foetuses and a total of 5125 ultrasound scans, of which each foetus was scanned at least three times, the intervals between scans being at least two weeks. The parameters of the linear mixed models were estimated by Stata v.16 (College Station, TX). Using these parameters, the equations of the mean and variance for BPD, HC, AC and FL were constructed. The conditional percentiles or

The placenta is a temporary organ that plays critical roles at the maternal-fetal interface. Normal development and function of the placenta is dependent on hormonal signaling pathways that make the placenta a target of endocrine disrupting chemical (EDC) action. Studies showing association between prenatal exposure, hormone disruption, and reproductive damage indicate that EDCs are developmentally toxic and can impact future generations. In this context, new placental models (trophoblast-derived cell lines, organotypic or 3D cell models, and physiologically based kinetic models) have been developed in order to create new approach methodology (NAM) to assess and even prevent such disastrous toxic harm in future generations. With the widespread discouragement of conducting animal studies, it has become irrefutable to develop in vitro models that can serve as a substitute for in vivo models. The goal of this review is to discuss the newest in vitro models to understand the maternal-fetal interface and predict placental development, physiology, and dysfunction generated by failures in molecular hormone control mechanisms, which, consequently, may change epigenetic programming to increase susceptibility to metabolic and other disorders in the offspring. We summarize the latest placental models for developmental toxicology studies, focusing mainly on three-dimensional (3D) culture models.

Choline, folic acid, and Vitamin D are essential for fetal brain development that may be the first steps in the pathogenesis of the psychotic spectrum. Micronutrient deficiencies have been associated with changes in fetal brain development, manifest as early problems in childhood behavior, and cognition, and later as increased incidence of psychotic and autism spectrum disorders. Micronutrient supplements may not only prevent deficiency, but they may also positively affect brain development in the context of other maternal risk factors, including maternal infection, stress, inflammation, and substance abuse. Many genes associated with later psychotic illness are highly expressed in the fetal brain, where they are responsible for various neurodevelopmental mechanisms. Interaction of micronutrient vitamins with these genetically programmed mechanisms to prevent pathological brain development associated with later psychosis is under active investigation. In addition to their effects on brain development, micronutrient vitamins have effects on other aspects of gestation and fetal development, including the prevention of premature delivery and other developmental abnormalities. Supplemental micronutrient vitamins should be part of good prenatal care, as has already happened for folic acid and Vitamin D and is now advocated by the American Medical Association for choline. The benefits of these micronutrient supplements include protection of brain development and the possibility of decreased risk for future psychotic disorders in those children who are either genetically or environmentally vulnerable. The purpose of this review is to present the current evidence supporting the safety and effectiveness of micronutrients in gestation and to suggest areas for future research.

The study of fetal development allows for evaluating the different strategies adopted by mammal species to maximize neonatal survival. Autonomous locomotion is fundamental for newborns to perform foraging activities and increases newborn survival from predation. In this study, we assess the gestational bone development of 53 collared (CP, Pecari tajacu) and 61 white-lipped (WLP, Tayassu pecari) peccaries, collected through the collaboration of subsistence hunters in the Amazon. The bone mineralization and biometry of the axial and appendicular skeleton were assessed by ultrasound examinations, and the timing of the main bone developmental events was calculated in relation to the total dorsal length (TDL) and the percentage of the total gestational period (GP). The first US signs of mineralization of the axial skeleton in CP and WLP were observed in fetuses with 3.4 cm (42 gestation days, 30% GP

One of the hallmarks of twin pregnancies is the slower rate of fetal growth when compared with singleton pregnancies during the third trimester. The mechanisms underlying this phenomenon and whether it represents pathology or benign physiological adaptation are currently unclear. One important implication of these questions relates to the type growth charts that should be used by care providers to monitor growth of twin fetuses. If the slower growth represents pathology (ie, intrauterine growth restriction caused uteroplacental insufficiency), it would be preferable to use a singleton growth chart to identify a small twin fetus that is at risk for perinatal mortality and morbidity. If, however, the relative smallness of twins is the result of benign adaptive mechanisms, it is likely preferable to use a twin-based charts to avoid overdiagnosis of intrauterine growth restriction in twin pregnancies. In the current review, we addressed this question by describing the differences in fetal growth between twin and singleton pregnancies, reviewing the current knowledge regarding the mechanisms responsible for slower fetal growth in twins, summarizing available empirical evidence on the diagnostic accuracy of the 2 types of charts for intrauterine growth restriction in twin pregnancies, and addressing the question of whether uncomplicated dichorionic twins are at an increased risk for fetal death when compared with singleton fetuses. We identified a growing body of evidence that shows that the use of twin charts can reduce the proportion of twin fetuses identified with suspected intrauterine growth restriction by up to 8-fold and can lead to a diagnosis of intrauterine growth restriction that is more strongly associated with adverse perinatal outcomes and hypertensive disorders than a diagnosis of intrauterine growth restriction based on a singleton-based chart without compromising the detection of twin fetuses at risk for adverse outcomes caused by uteroplacental insufficiency. We further found that small for gestational age twins are less likely to experience adverse perinatal outcomes or to have evidence of uteroplacental insufficiency than small for gestational age singletons and that recent data question the longstanding view that uncomplicated dichorionic twins are at an increased risk for fetal death caused by placental insufficiency. Overall, it seems that, based on existing evidence, the of use twin charts is reasonable and may be preferred over the use of singleton charts when monitoring the growth of twin fetuses. Still, it is important to note that the available data have considerable limitations and are primarily derived from observational studies. Therefore, adequately-powered trials are likely needed to confirm the benefit of twin charts before their use is adopted by professional societies.

Pregnancy complications adversely impact both mother and/or fetus throughout the lifespan. Fetal growth restriction (FGR) occurs when a fetus fails to reach their intrauterine potential for growth, it is the second highest leading cause of infant mortality, and leads to increased risk of developing non-communicable diseases in later life due 'fetal programming'. Abnormal placental development, growth and/or function underlies approximately 75% of FGR cases and there is currently no treatment save delivery, often prematurely. We previously demonstrated in a murine model of FGR that nanoparticle mediated, intra-placental human IGF-1 gene therapy maintains normal fetal growth. Multiple models of FGR currently exist reflecting the etiologies of human FGR and have been used by us and others to investigate the development of in utero therapeutics as discussed here. In addition to the in vivo models discussed herein, utilizing human models including in vitro (Choriocarcinoma cell lines and primary trophoblasts) and ex vivo (term villous fragments and placenta cotyledon perfusion) we have demonstrated robust nanoparticle uptake, transgene expression, nutrient transporter regulation without transfer to the fetus. For translational gene therapy application in the human placenta, there are multiple avenues that require investigation including syncytial uptake from the maternal circulation, transgene expression, functionality and longevity of treatment, impact of treatment on the mother and developing fetus. The potential impact of treating the placenta during gestation is high, wide-ranging across pregnancy complications, and may offer reduced risk of developing associated cardio-metabolic diseases in later life impacting at both an individual and societal level.

Epidemiologic studies have shown an association between an adverse intrauterine environment (eg, exposure to malnutrition) and an increased risk of developing cardiometabolic disease in adulthood. These studies laid the foundation for the developmental origins of health and disease hypothesis, which states that limited nutrient supply to the fetus results in physiologic and metabolic adaptations that favor survival but result in unfavorable consequences in the offspring if there is excess nutrition after birth. This discrepancy in the pre- and postnatal milieus, perceived as stress by the offspring, may confer an increased risk of developing cardiometabolic disease later in life. Thus, early life exposures result in programming or changes in cellular memory that have effects on health throughout the life course. One of the mechanisms by which programming occurs is via epigenetic modifications of genes, processes that result in functionally relevant changes in genes (ie, gene expression) without an alteration in the genotype. In this review, we will describe how fetal exposures, including under- and overnutrition, affect neonatal and childhood growth and the future risk for cardiometabolic disease.

Peer reviewed: True, Adverse maternal environments such as small size, malnutrition, and metabolic conditions are known to influence fetal growth outcomes. Similarly, fetal growth and metabolic alterations may alter the intrauterine environment and affect all fetuses in multiple gestation/litter-bearing species. The placenta is the site of convergence between signals derived from the mother and the developing fetus/es. Its functions are fuelled by energy generated by mitochondrial oxidative phosphorylation (OXPHOS). The aim of this study was to delineate the role of an altered maternal and/or fetal/intrauterine environment in feto-placental growth and placental mitochondrial energetic capacity. To address this, in mice, we used disruptions of the gene encoding phosphoinositol 3-kinase (PI3K) p110α, a growth and metabolic regulator to perturb the maternal and/or fetal/intrauterine environment and study the impact on wildtype conceptuses. We found that feto-placental growth was modified by a perturbed maternal and intrauterine environment, and effects were most evident for wildtype males compared to females. However, placental mitochondrial complex I+II OXPHOS and total electron transport system (ETS) capacity were similarly reduced for both fetal sexes, yet reserve capacity was additionally decreased in males in response to the maternal and intrauterine perturbations. These were also sex-dependent differences in the placental abundance of mitochondrial-related proteins (e.g., citrate synthase and ETS complexes), and activity of growth/metabolic signalling pathways (AKT and MAPK) with maternal and intrauterine alterations. Our findings thus identify that the mother and the intrauterine environment provided by littermates modulate feto-placental growth, placental bioenergetics, and metabolic signalling in a manner dependent on fetal sex. This may have relevance for understanding the pathways leading to reduced fetal growth, particularly in the context of suboptimal maternal environments and multiple gestation/litter-bearing species.

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.

Fetal development is characterized by great plasticity and the ability to respond to environmental factors, where DNA methylation is essential for proper embryonic development. One-carbon metabolism provides methyl groups for methylation and fetal DNA development and is highly dependent on maternal nutritional status. During pregnancy, the supply of methyl donors is critical and the demand for nutrients that support this process, such as folate and vitamin B12, is increased. Insufficiency or imbalance of these 2 micronutrients can alter epigenetic patterns, DNA synthesis and repair, and affect fetal growth and development, having negative long-term consequences on the offspring's health. Folate and vitamin B12 status have been associated with wide DNA methylation, as well as with specific genes related to neurological functions, embryonic development, energy metabolism, growth, and leptin. Furthermore, inadequate concentrations of both vitamins have been associated with an increased risk of perinatal outcomes such as neural tube defects, prematurity, low birth weight, pre-eclampsia, as well as maternal and infant obesity and insulin resistance, and decreased infant neurocognitive development. Supplementation, combined with a healthy diet, could be an essential strategy to prevent these results and improve maternal and fetal health.El desarrollo fetal se caracteriza por una gran plasticidad y capacidad para responder a factores ambientales, donde la metilación del ADN es indispensable para el desarrollo embrionario adecuado. El metabolismo de un carbono proporciona grupos metilo para la metilación y el desarrollo del ADN fetal, y depende en gran medida del estado nutricio materno. El embarazo es una etapa donde el suministro de donantes de metilo es crítico y la demanda de nutrimentos que apoyen este proceso, como lo son el folato y la vitamina B12, está aumentada. La insuficiencia o desequilibrio de estos dos micronutrimentos puede alterar los patrones epigenéticos, la síntesis y reparación del ADN, y afectar procesos del crecimiento y desarrollo fetal, teniendo consecuencias negativas en la salud de la descendencia a largo plazo. El estado del folato y la vitamina B12 se han asociado con la metilación global del ADN, así como con genes específicos relacionados con funciones neurológicas, con el desarrollo embrionario, el metabolismo energético, el crecimiento, y con la leptina. Además, estados alterados de ambas vitaminas se han asociado con mayor riesgo de resultados perinatales como defectos del tubo neural, prematurez, bajo peso al nacer, preeclampsia, así como obesidad y resistencia a la insulina materna e infantil, y disminución del desarrollo neurocognitivo infantil. La suplementación, aunada a una dieta adecuada, podría ser una estrategia necesaria para prevenir dichos resultados y mejorar la salud maternofetal.

NEW FINDINGS: What is the topic of this review? How the placenta, which transports nutrients and oxygen to the fetus, may alter its support of fetal growth developmentally and with adverse gestational conditions. What advances does it highlight? Placental formation and function alter with the needs of the fetus for substrates for growth during normal gestation and when there is enhanced competition for substrates in species with multiple gestations or adverse gestational environments, and this is mediated by imprinted genes, signalling pathways, mitochondria and fetal sexomes. ABSTRACT: The placenta is vital for mammalian development and a key determinant of life-long health. It is the interface between the mother and fetus and is responsible for transporting the nutrients and oxygen a fetus needs to develop and grow. Alterations in placental formation and function, therefore, have consequences for fetal growth and birthweight, which in turn determine perinatal survival and risk of non-communicable diseases for the offspring in later postnatal life. However, the placenta is not a static organ. As this review summarizes, research from multiple species has demonstrated that placental formation and function alter developmentally to the needs of the fetus for substrates for growth during normal gestation, as well as when there is greater competition for substrates in polytocous species and monotocous species with multiple gestations. The placenta also adapts in response to the gestational environment, integrating information about the ability of the mother to provide nutrients and oxygen with the needs of the fetus in that prevailing environment. In particular, placental structure (e.g. vascularity, surface area, blood flow, diffusion distance) and transport capacity (e.g. nutrient transporter levels and activity) respond to suboptimal gestational environments, namely malnutrition, obesity, hypoxia and maternal ageing. Mechanisms mediating developmentally and environmentally induced homeostatic responses of the placenta that help support normal fetal growth include imprinted genes, signalling pathways, subcellular constituents and fetal sexomes. Identification of these placental strategies may inform the development of therapies for complicated human pregnancies and advance understanding of the pathways underlying poor fetal outcomes and their consequences for health and disease risk.

Objectives Fetal growth and size are associated with stillbirth risk. We wanted to investigate the week by week predictive value of fetal size at term on the prospective risk of stillbirth. Methods Anonymised database from the UK GAP program, with 2,094,702 term (≥37 weeks) deliveries including 4,670 stillbirths. Prospective stillbirth risk was defined as fetal death in the current week divided by total undelivered pregnancies. The data were analysed in five centile bands for stillbirth risk and risk ratios (RR) for 38, 39, 40 and 41+ weeks, using appropriate for gestational age (AGA) at 37 weeks as reference. Results Baseline stillbirth risk at 37 weeks was 0.29 per 1,000 and rose to 1.39 at 41+ weeks, with RR increasing to 4.8. In the 390 centile band, risk increased from 0.40 to 1.50 (RR 1.4 to 5.2) and for >97 centiles, it rose from 0.80 to 2.13 (RR 2.8–7.3). Conclusions Prospective risk of fetal death at term is related to fetal size. The information provided, together with other considerations and results of investigations where available, will help clinicians to determine the advice to give to mothers about the best timing for delivery, balancing the baby’s risk of compromise with iatrogenic sequelae of early delivery.

Little is known about the development of the human entorhinal cortex (EC), a major hub in a widespread network for learning and memory, spatial navigation, high-order processing of object information, multimodal integration, attention and awareness, emotion, motivation, and perception of time. We analyzed a series of 20 fetal and two adult human brains using Nissl stain, acetylcholinesterase (AChE) histochemistry, and immunocytochemistry for myelin basic protein (MBP), neuronal nuclei antigen (NeuN), a pan-axonal neurofilament marker, and synaptophysin, as well as postmortem 3T MRI. In comparison with other parts of the cerebral cortex, the cytoarchitectural differentiation of the EC begins remarkably early, in the 10th week of gestation (w.g.). The differentiation occurs in a superficial magnocellular layer in the deep part of the marginal zone, accompanied by cortical plate (CP) condensation and multilayering of the deep part of CP. These processes last until the 13-14th w.g. At 14 w.g., the superficial lamina dissecans (LD) is visible, which divides the CP into the lamina principalis externa (LPE) and interna (LPI). Simultaneously, the rostral LPE separates into vertical cell-dense islands, whereas in the LPI, the deep LD emerges as a clear acellular layer. In the 16th w.g., the LPE remodels into vertical cell-dense and cell-sparse zones with a caudorostral gradient. At 20 w.g., NeuN immunoreactivity is most pronounced in the islands of layer II cells, whereas migration and differentiation inside-out gradients are seen simultaneously in both the upper (LPE) and the lower (LPI) pyramidal layers. At this stage, the EC adopts for the first time an adult-like cytoarchitectural organization, the superficial LD becomes discernible by 3T MRI, MBP- expressing oligodendrocytes first appear in the fimbria and the perforant path (PP) penetrates the subiculum to reach its molecular layer and travels along through the Cornu Ammonis fields to reach the suprapyramidal blade of the dentate gyrus, whereas the entorhinal-dentate branch perforates the hippocampal sulcus about 2-3 weeks later. The first AChE reactivity appears as longitudinal stripes at 23 w.g. in layers I and II of the rostrolateral EC and then also as AChE-positive in-growing fibers in islands of superficial layer III and layer II neurons. At 40 w.g., myelination of the PP starts as patchy MBP-immunoreactive oligodendrocytes and their processes. Our results refute the possibility of an inside-out pattern of the EC development and support the key role of layer II prospective stellate cells in the EC lamination. As the early cytoarchitectural differentiation of the EC is paralleled by the neurochemical development, these developmental milestones in EC structure and connectivity have implications for understanding its normal function, including its puzzling modular organization and potential contribution to consciousness content (awareness), as well as for its insufficiently explored deficits in developmental, psychiatric, and degenerative brain disorders.

To derive a prescriptive sex-specific fetal growth standard and assess clinical management and outcomes according to sex-specific growth status. This was a secondary analysis of the Nulliparous Pregnancy Outcomes Study: Monitoring Mothers-to-Be (nuMoM2b), a prospective observational study of 10,038 nulliparas from eight U.S. centers who underwent ultrasounds at 14–20 and 22–29 weeks with outcomes ascertained after delivery. From these, we selected a nested cohort of lower risk participants (excluded those with chronic hypertension, pre-gestational diabetes, suspected aneuploidy, and preterm delivery) to derive a sex-specific equation for expected fetal growth using fetal weights by ultrasound and at birth. We compared the male-female discrepancy in the rate of weight 90th (large for gestational age [LGA]) percentiles between the sex-specific and sex-neutral (Hadlock) standards. Using the full unselected cohort, we then assessed outcomes and clinical management according to sex-specific SGA and LGA status. Overall, 7280 infants in the lower risk nested cohort were used to derive a sex-specific equation with fetal sex included as an equation intercept. The sex-neutral standard diagnosed SGA more often in female newborns (21% vs. 13%, p < .001) and LGA more often in male newborns (5% vs. 3%, p < .001). The sex-specific standard resolved these disparities (SGA: 9% vs. 10%, p = .23; LGA: 13% vs. 13%, p = .58). To approximate an unselected population, 1059 participants initially excluded for risk factors for abnormal growth were then included for our secondary objective (N = 8339). In this unselected cohort, 39% (95% CI 37.0–42.0%) of the 1498 newborns classified as SGA by the sex-neutral standard were reclassified as appropriate for gestational age (AGA) by the sex-specific standard. These reclassified newborns were more likely to be delivered for growth restriction despite having lower risk of morbidity (females) or comparable risk of morbidity (males) compared to newborns considered AGA by both methods. Of the 6485 newborns considered AGA by the sex-neutral standard, 737 (11.4%, 95% CI 10.6–12.2%) were reclassified as LGA by the sex-specific standard. These reclassified newborns had higher rates of cesarean for arrest of descent, cesarean for arrest of dilation, and shoulder dystocia than newborns considered AGA by both methods. None were reclassified from LGA to AGA by the sex-specific standard. The Hadlock sex-neutral standard generates sex disparities in SGA and LGA at birth. Our sex-specific standard resolves these disparities and has the potential to improve accuracy of growth pathology risk stratification.

OBJECTIVE: To explore the pattern of fetal cortical development in pregnancies complicated by pre-eclampsia (PE), with and without a small-for-gestational-age (SGA) fetus, compared to uncomplicated pregnancies. METHODS: This was a prospective observational study including singleton pregnancies complicated by normotensive SGA (birth weight < 10(th) centile) (n = 77), PE with an appropriate-for-gestational-age (AGA) fetus (n = 76) or PE with a SGA fetus (n = 67), and 128 uncomplicated pregnancies (normotensive AGA) matched by gestational age at ultrasound. All pregnancies underwent detailed neurosonography, using a transabdominal and transvaginal approach, at 31-35 weeks' gestation to assess the depth of the insula, Sylvian fissure, parieto-occipital sulcus, cingulate sulcus and calcarine sulcus. All measurements were adjusted for biparietal diameter (BPD). In addition, a grading score of cortical development was assigned to each brain structure, ranging from Grade 0 (no development) to Grade 5 (maximum development). Univariate and multiple regression analyses were conducted. RESULTS: Similar to findings in previous studies, normotensive pregnancies with a SGA fetus showed significant differences in cortical development compared with controls, with reduced Sylvian fissure depth adjusted for BPD (14.5 ± 2.4 vs 16.6 ± 2.3; P < 0.001) and increased insula depth adjusted for BPD (33.2 ± 2.0 vs 31.8 ± 2.0; P < 0.001). Interestingly, a similar cortical development pattern was observed in PE pregnancies with a SGA fetus and in PE pregnancies with an AGA fetus, manifested by reduced Sylvian fissure depth adjusted for BPD (14.2 ± 2.3 and 14.3 ± 2.3 vs 16.6 ± 2.3; P < 0.001 for both) and greater insula depth adjusted for BPD (33.2 ± 2.1 and 32.8 ± 1.7 vs 31.8 ± 2.0; P < 0.001 for both) compared with controls. No significant differences were observed in parieto-occipital, cingulate sulcus or calcarine sulcus depth across the study groups. The Sylvian fissure was scored as Grade 4 in significantly more (93.2% vs 59.5%) and as Grade 5 in significantly fewer (2.7% vs 37.3%) PE pregnancies with an AGA fetus compared with controls (P < 0.05 for both). These differences remained significant even after statistical adjustment for potential confounders, including ethnicity, low socioeconomic status, nulliparity, chronic hypertension, pregestational diabetes, assisted reproductive technologies, smoking and fetal gender, with the application of Benjamini-Hochberg procedure for multiple comparisons. CONCLUSIONS: PE with or without SGA is associated with a differential fetal cortical development pattern which is similar to that described previously in small fetuses. Future research is warranted to elucidate better the mechanism(s) underlying these changes. © 2022 International Society of Ultrasound in Obstetrics and Gynecology.

Fetal alcohol exposure can lead to a range of developmental disorders, including impaired fetal growth and development of multiple organ systems. These disorders are grouped under the term fetal alcohol spectrum disorders (FASDs). Adequate nutrition and a conducive intrauterine environment are essential for healthy fetal development. Nutrient deficiencies resulting from inadequate maternal nutrient ingestion may be compounded by alcohol-induced altered nutrient metabolism, placental clearance, and malabsorption. Alcohol-induced alteration of the intrauterine environment is the main source of developmental deficits and nutritional insufficiencies can worsen the effects on fetal development. In this review, we discuss studies examining the collective and interactive effects of nutrition (specifically iron, selenium, vitamin A, thiamine, zinc, folate, vitamin B12, choline, and amino acids) relative to gestational alcohol consumption and its effects on fetal growth and development. We also summarize scientific reports that tested potential benefits of micronutrient supplementation in animal models of fetal alcohol spectrum disorders and in humans. In summary, the deleterious effects of alcohol exposure in relation to nutrient homeostasis further validate that avoidance of alcohol consumption during pregnancy is the most effective way to mitigate the teratogenic effects of alcohol.

Obesity and gestational diabetes during pregnancy have multiple short- and long-term consequences for both mother and child. One common feature of pregnancies complicated by maternal obesity and gestational diabetes is maternal hyperinsulinaemia, which has effects on the mother and her adaptation to pregnancy. Even though insulin does not cross the placenta insulin can act on the placenta as well affecting placental growth, angiogenesis and lipid metabolism. Obese and gestational diabetic pregnancies are often characterised by maternal hyperglycaemia resulting in exposure of the fetus to high levels of glucose, which freely crosses the placenta. This leads to stimulation of fetal ß-cells and insulin secretion in the fetus. Fetal hyperglycaemia/hyperinsulinaemia has been shown to cause multiple complications in fetal development, such as altered growth trajectories, impaired neuronal and cardiac development and early exhaustion of the pancreas. These changes could increase the susceptibility of the offspring to develop cardiometabolic diseases later in life. In this review, we aim to summarize and review the mechanisms by which maternal and fetal hyperinsulinaemia impact on (i) maternal health during pregnancy; (ii) placental and fetal development; (iii) offspring energy homeostasis and long-term cardiometabolic health; (iv) how interventions can alleviate these effects.

Animal and human data demonstrate independent relationships between fetal growth, hypothalamic-pituitary-adrenal axis function (HPA-A) and adult cardiometabolic outcomes. While the association between fetal growth and adult cardiometabolic outcomes is well-established, the role of the HPA-A in these relationships is unclear. This study aims to determine whether HPA-A function mediates or moderates this relationship. Approximately 2900 pregnant women were recruited between 1989-1991 in the Raine Study. Detailed anthropometric data was collected at birth (per cent optimal birthweight [POBW]). The Trier Social Stress Test was administered to the offspring (Generation 2; Gen2) at 18 years; HPA-A responses were determined (reactive responders [RR], anticipatory responders [AR] and non-responders [NR]). Cardiometabolic parameters (BMI, systolic BP [sBP] and LDL cholesterol) were measured at 20 years. Regression modelling demonstrated linear associations between POBW and BMI and sBP; quadratic associations were observed for LDL cholesterol. For every 10% increase in POBW, there was a 0.54 unit increase in BMI (standard error [SE] 0.15) and a 0.65 unit decrease in sBP (SE 0.34). The interaction between participant’s fetal growth and HPA-A phenotype was strongest for sBP in young adulthood. Interactions for BMI and LDL-C were non-significant. Decomposition of the total effect revealed no causal evidence of mediation or moderation.

BackgroundThe age at onset of the association between poverty and poor health is not understood. Our hypothesis was that individuals from highest household income (HI), compared to those with lowest HI, will have increased fetal size in the second and third trimester and birth.Methods.Second and third trimester fetal ultrasound measurements and birth measurements were obtained from eight cohorts. Results were analysed in cross-sectional two-stage individual patient data (IPD) analyses and also a longitudinal one-stage IPD analysis.ResultsThe eight cohorts included 21 714 individuals. In the two-stage (cross-sectional) IPD analysis, individuals from the highest HI category compared with those from the lowest HI category had larger head size at birth (mean difference 0.22 z score (0.07, 0.36)), in the third trimester (0.25 (0.16, 0.33)) and second trimester (0.11 (0.02, 0.19)). Weight was higher at birth in the highest HI category. In the one-stage (longitudinal) IPD analysis which included data from six cohorts (n=11 062), head size was larger (mean difference 0.13 (0.03, 0.23)) for individuals in the highest HI compared with lowest category, and this difference became greater between the second trimester and birth. Similarly, in the one-stage IPD, weight was heavier in second highest HI category compared with the lowest (mean difference 0.10 (0 .00, 0.20)) and the difference widened as pregnancy progressed. Length was not linked to HI category in the longitudinal model.ConclusionsThe association between HI, an index of poverty, and fetal size is already present in the second trimester.

The cost of reproduction greatly affects a species’ life history strategy. Baleen whales exhibit some of the fastest offspring growth rates in the animal kingdom. We quantified the energetic cost of gestation for southern right whales (Eubalaena australis) by combining whaling catch records of pregnant females with photogrammetry data on southern right whale mothers and calves from two breeding grounds in Argentina and Australia. The relationship between calf birth size and maternal length was determined from repeated measurements of individual females before and after giving birth. Fetal growth was determined from generalized linear models fitted to fetal length data from whaling operations between 1961 and 1967. Fetal length was converted to volume and mass, using the volume-to-length relationship of newborn southern right whales calves, and published tissue composition and energy content estimates. Fetal maintenance costs (heat of gestation) and the energy content of the placenta were predicted from published relationships and added to the fetal growth cost to calculate the total cost of gestation. Our findings showed that fetal growth rates and birth size increased linearly with maternal length, with calves being born at ∼35% maternal length. Fetal length increased curvilinearly through gestation, which resulted in an exponential increase in fetal volume and mass. Consequently, the cost of gestation was very low during the first (0.1% of total cost) and second trimester (4.9%), but increased rapidly during the last trimester (95.0%). The heat of gestation incurred the highest cost for pregnant females (73.8%), followed by fetal growth (21.2%) and the placental energy content (5.0%). Key points: Baleen whales exhibit some of the fastest fetal growth rates in the animal kingdom. Despite this, the energetic cost of gestation is largely unknown, as well as the influence of maternal body size on fetal growth rates and calf birth sizes. We combined historical whaling records and drone photogrammetry data to determine fetal growth rates and birth sizes in southern right whales (Eubalaena australis), from which we estimated the cost of gestation. Calf birth size, and consequent fetal growth rates, increased positively with maternal body size. The cost of gestation was negligible for southern right whale females during the first two trimesters, but increased rapidly during the last trimester. These results show that late gestation incurs a significant cost for baleen whale females, and needs to be accounted for in bioenergetic models.

This study aimed to investigate the correlation between prenatal dexamethasone exposure (PDE) and susceptibility to pulmonary fibrosis in offspring. Healthy female Wistar rats were given dexamethasone (0.2 mg/kg.d) or an equal volume of normal saline subcutaneously from 9 to 20 days after conception. Some of their female offspring underwent ovariectomy (OV) at 22 weeks after birth. All animals were euthanized at 28 weeks after birth. The morphological changes related to pulmonary fibrosis and extracellular matrix-related gene expression were detected, and Two-way ANOVA analyzed the interaction between PDE and OV. The results showed that adult offspring rats in FD group (female rats with PDE treatment) had early pulmonary fibrosis changes, such as pulmonary interstitial thickening, and increased expression of type IV collagen (COL4), α -smooth muscle actin (α-SMA) and fibronectin (FN) in lung tissues compared with those in FC group (female rats with saline treatment). In addition, adult offspring rats in FDO group (female rats with PDE and OV treatment) showed signs of pulmonary fibrosis, including apparent extracellular matrix deposition, increased lung injury scores (P＜0.01, P＜0.05), and extracellular matrix related gene expression (P＜0.01, P＜0.05), compared with rats in FDS (female rats with PDE treatment alone) or rats in FCO group (female rats with OV treatment alone). Moreover, PDE and OV had an interactive effect on the development of pulmonary fibrosis in female adult offspring. This study first reported the correlation between PDE and susceptibility to pulmonary fibrosis in female offspring rats, as well as the synergistic effect of PDE and OV in this pathological event, which provided a basis for further understanding of the pathogenesis of fetal originated pulmonary fibrosis.

Objectives: Based on the current state of knowledge, elevated levels of oxidative stress markers may be considered as risk factors for pregnancy complications. The aim of the research was to assess the correlation between selected oxidative stress biomarkers with the occurrence of foetal chromosomal aberration and congenital malformations. Material and methods : This retrospective research lasted for two years. The purpose was to determine serum levels of selected oxidative stress markers, including total protein (TP), glutathione (GSH), S-nitrosothiols (RSNO), nitric oxide (NO), trolox equivalent antioxidant capacity (TEAC) and glutathione S-transferase (GST) at 11–13 + 6 gestational weeks in 38 women with confirmed foetal developmental abnormalities and in 34 healthy pregnancies in order to assess their utility as predictors of abnormal foetal development. Results: Serum concentrations of TP (56.90 ± 5.30 vs 69.1 ± 15.30 mg/mL), TEAC (4.93 ± 0.82 vs 5.64 ± 0.74 μM/mL) and GST (15.94 ± 4.52 vs 21.72 ± 6.81 nM/min/mg) were statistically significantly (p < 0.05) lower in the group of patients with developmental abnormalities in the fetus, whereas GSH levels (6.43 ± 1.24 vs 4.98 ± 1.88 nM/mg) were significantly higher, compared to the group of healthy fetuses. There were no differences in the concentration of these markers between chromosomal aberrations and fetal dysmorphia in subjects. A significant difference in odds ratio obtained for GSH (OR = 0.57, 95% CL: 0.40–0.80) indicates that its higher concentration can relate to reduced risk of developmental abnormalities, whereas odds ratio for TP (OR=1.11, 95% CL: 1.04–1.17), TEAC (OR = 3.54, 95% CL: 1.56–8.05) and GST (OR = 1.18, 95% CL: 1.03–1.17) indicate that their elevation may increase the risk of developmental abnormalities Conclusions: Elevated levels of TP, GST, TEAC and low GSH level may be relevant to predict congenital defects.

Epigenetics is the branch of genetics that studies the different mechanisms that influence gene expression without direct modification of the DNA sequence. An ever-increasing amount of evidence suggests that such regulatory processes may play a pivotal role both in the initiation of pregnancy and in the later processes of embryonic and fetal development, thus determining long-term effects even in adult life. In this narrative review, we summarize the current knowledge on the role of epigenetics in pregnancy, from its most studied and well-known mechanisms to the new frontiers of epigenetic regulation, such as the role of ncRNAs and the effects of the gestational environment on fetal brain development. Epigenetic mechanisms in pregnancy are a dynamic phenomenon that responds both to maternal–fetal and environmental factors, which can influence and modify the embryo-fetal development during the various gestational phases. Therefore, we also recapitulate the effects of the most notable environmental factors that can affect pregnancy and prenatal development, such as maternal nutrition, stress hormones, microbiome, and teratogens, focusing on their ability to cause epigenetic modifications in the gestational environment and ultimately in the fetus. Despite the promising advancements in the knowledge of epigenetics in pregnancy, more experience and data on this topic are still needed. A better understanding of epigenetic regulation in pregnancy could in fact prove valuable towards a better management of both physiological pregnancies and assisted reproduction treatments, other than allowing to better comprehend the origin of multifactorial pathological conditions such as neurodevelopmental disorders.

Vanadium(V) and vanadium(IV) are the predominant redox forms present in the environment, and epidemiological studies have reported that prenatal vanadium exposure is associated with restricted fetal growth and adverse birth outcomes. However, data about the toxic effects of vanadium(IV) oxide (V

Equine placental development is a long process with unique features. Implantation occurs around 40 days of gestation (dpo) with the presence of a transient invasive placenta from 25–35 to 100–120 dpo. The definitive, non-invasive placenta remains until term (330 days). This definitive placenta is diffuse and epitheliochorial, exchanging nutrients, gas and waste with the endometrium through microvilli, called microcotyledons. These are lined by an external layer of haemotrophic trophoblast. Moreover, histotrophic exchange remains active through the histotrophic trophoblast located along the areolae. Placental development is dependent on the maternal environment that can be affected by several factors (e.g. nutrition, metabolism, age, embryo technologies, pathologies) that may affect fetal development as well as long-term offspring health. The first section of the review focuses on normal placental development as well as definitive placental structure. Differences between the various regions of the placenta are also highlighted. The latter sections provide an overview of the effects of the maternal environment and reproductive pathologies, respectively, on trophoblast/placental gene expression and structure. So far, only pre-implantation and late gestation/term data are available, which demonstrate important placental plasticity in response to environmental variation, with genes involved in oxidative stress and tissue differentiation mostly involved in the pre-implantation period, whereas genes involved in feto-placental growth and nutrient transfers are mostly perturbed at term.

To learn whether and how lipid levels are associated with gestational hypertension and fetal growth in normal pregnancy.In a case-control study course, 464 patients with gestational hypertension were pooled into a case group; a total of 1077 women with full-term pregnancies and no pregnancy complications were selected as controls. In a cross-sectional study, whether maternal lipid levels were associated with fetal growth were evaluated in 1077 healthy controls.Maternal lipids and glucose levels and fetal measurements.Maternal levels of triglyceride (TG) were significantly higher in the case group than in controls at gestational weeks 12-16. Levels of TG, total cholesterol (TC) and low-densitylipoprotein (LDL-C) in control mothers increased gradually and significantly with increasing gestational week, however, these lipid concentrations lost these steady elevating trends with gestational week increases in the cases. Binary logistic regression showed that TG is a risk factor associated with hypertension at gestational weeks 12-16 and independent to maternal blood levels of LDL-C and glucose. Of the healthy mothers at gestational weeks 12-16, quantile regression showed that TG levels were not associated with real-time fetal growth measurements or final birthweight. The reference standards for maternal TG levels were estimated via the 10th, 25th, 50th, 75th, and 90th percentiles by gestational week.Maternal TG levels are associated with gestational hypertension, and a wide range of TG levels is sufficient for fetal growth within a given gestational week.

Objective In this brief review, the authors focus on the effects of gestational exposures to urban air pollution on fetal development and neonatal outcomes. Source of data In this review the authors used PubMed, Web of Science and SciELO research platforms, analyzing papers from the last 30 years. Summary of the findings Epidemiological and experimental evidence agree that gestational exposure to air pollution in urban increases the risks for low birth weight, preterm birth, congenital malformation, intrauterine growth restriction, and neonatal mortality. Furthermore, exposures are associated with increased risks for preeclampsia, hypertension, gestational diabetes. Conclusions Therefore, it is time for greater involvement and engagement of the health sector in the discussion of public policies that may affect the quality of the environment, and that directly or indirectly impact the health of those who were not yet born.

Customized intrauterine growth charts are widely used for growth monitoring and research. They are based on three assumptions: (1) estimated fetal weight (EFW) has a normal distribution with a constant coefficient of variation at all gestational ages; (2) Hadlock's growth curve accurately describes the relation between EFW and gestational ages; (3) associations between EFW and the fetal and maternal characteristics included in the customization model (fetal sex, pre-pregnancy weight, height, parity) are proportional throughout pregnancy. The aim of this study was to test whether these underlying assumptions are verified.Data came from (1) the French Longitudinal Study of Children (ELFE) cohort, which recruited births after 32 weeks' gestation in 349 maternity hospitals in France in 2011, and (2) the National Perinatal Survey, which included births from all French maternity hospitals in 2016. The study population included, respectively, 6 920 and 8 969 singleton non-malformed term live births with data on customization characteristics and EFW. We computed the coefficient of variation by gestational age and then modeled the association of gestational age, maternal and fetal characteristics with EFW at the second and third trimester ultrasound and with birthweight using linear regression. To assess the proportionality of the impact of maternal and fetal characteristics, we computed the percent change in weight associated with these characteristics at these three time points.The coefficient of variation was close to 12% at each gestational age, but EFW was not normally distributed, leading to small but systematic underestimation of fetuses under the 10th percentile. Weights representing the 50th and 10th percentiles based on Hadlock's growth trajectory were lower than observed or predicted weights. Most characteristics more strongly impacted weight at birth than during pregnancy. In the French Longitudinal study of Children (ELFE) cohort, boys were 1.8% (95% confidence interval [CI] 1.3-2.4) heavier than girls in the third trimester, whereas this percentage was 4.6% (95% CI 4.0-5.2) at birth. In the National Perinatal Survey, these percentages were 2.3% (95% CI 1.8-2.8) and 4.3% (95% CI 3.8-4.8).These results from two independent sources revealed discrepancies between routine clinical EFW data used for growth monitoring and the customized growth model's assumptions.

Maternal exposure to polychlorinated biphenyls (PCBs) results in adverse effects on fetal development. However, the underlying mechanism has not been sufficiently explored in respect to particular PCBs. Placental angiogenesis plays a crucial role in feto-maternal substances transportation and fetal development. The present study was conducted to investigate the effects of prenatal PCB118 exposure on placental angiogenesis and fetal growth. The pregnant dam received PCB118 at environmentally relevant doses (0, 20, or 100 μg/kg/day) intragastrically from gestational day (GD) 7.5-18.5 to establish an in vivo model. Compared with the control group, the fetal body and placental weights of the PCB118 (100 μg/kg/day) group were significantly decreased and the intrauterine growth retardation (IUGR) rates were increased both in the female and male fetus. Furthermore, we found that placental histology was significantly impaired and the number of blood vessels was decreased in the PCB118 group. Additionally, gestational exposure to PCB118 caused anomalous mRNA expression of the genes in the placenta regarding angiogenesis. These findings indicate that PCB118 may contribute to the occurrence of IUGR by provoking placental angiogenesis dysfunction. This study clarified the adverse effects and potential mechanism of prenatal PCBs exposure on fetal growth, providing a new theoretical and experimental basis for future treatment and prevention.

The aim of this study was to determine in utero fetal-placental growth patterns using in vivo three-dimensional (3D) quantitative magnetic resonance imaging (qMRI).Healthy women with singleton pregnancies underwent fetal MRI to measure fetal body, placenta, and amniotic space volumes. The fetal-placental ratio (FPR) was derived using 3D fetal body and placental volumes (PV). Descriptive statistics were used to describe the association of each measurement with increasing gestational age (GA) at MRI.Fifty-eight (58) women underwent fetal MRI between 16 and 38 completed weeks gestation (mean = 28.12 ± 6.33). PV and FPR varied linearly with GA at MRI (rWe describe in-utero growth trajectories of fetal-placental volumes in healthy pregnancies using qMRI. Understanding healthy in utero development can establish normative benchmarks where departures from normal may identify early in utero placental failure prior to the onset of fetal harm.

Background: We previously identified associations between trimester-specific NO2 exposures and reduced fetal growth in the Spanish INfancia y Medio Ambiente (INMA) project. Here, we use temporally refined exposure estimates to explore the impact of narrow (weekly) windows of exposure on fetal growth. Methods: We included 1,685 women from INMA with serial ultrasounds at 12, 20, and 34 gestational weeks. We measured biparietal diameter (BPD), femur length, and abdominal circumference (AC) and from them calculated estimated fetal weight (EFW). We calculated z-scores describing trajectories of each parameter during early (0-12 weeks), mid (12-20 weeks), and late (20-34 weeks) pregnancy, based on longitudinal growth curves from mixed-effects models. We estimated weekly NO2 exposures at each woman's residence using land-use regression models. We applied distributed lag nonlinear models to identify sensitive windows of exposure. We present effect estimates as the percentage change in fetal growth per 10 μg/m3 increase in NO2 exposure, and we calculated cumulative effect estimates by aggregating estimates across adjacent lags. Results: We identified weeks 5-12 as a sensitive window for NO2 exposure on late EFW (cumulative β = -3.0%; 95% CI = -4.1%, -1.9%). We identified weeks 6-19 as a sensitive window for late growth in BPD (cumulative β = -2.0%; 95% CI = -2.7%, -1.4%) and weeks 8-13 for AC (cumulative β = -0.68%; 95% CI = -0.97%, -0.40%). We found suggestive evidence that third trimester NO2 exposure is associated with increased AC, BPD, and EFW growth in late pregnancy. Conclusions: Our findings are consistent with the hypothesis that NO2 exposure is associated with alterations in growth of EFW, BPD, and AC dependent on the specific timing of exposure during gestation. This work was supported by grant R01ES028842 from NIH/NIEHS; grants Red INMA G03/176, CB06/02/004; FIS-FEDER: PI03/1615, PI04/1509, PI04/1112, PI04/1931, PI05/1079, PI05/1052, PI06/0867, PI06/1213, PI07/0314, PI09/02647, PI11/01007, PI11/02591, PI11/02038, PI13/1944, PI13/2032, PI14/00891, PI14/01687, PI16/1288, PI17/00663, FIS-PI18/01142 incl. FEDER funds; Miguel Servet-FEDER CP11/00178, CP15/00025, CPII16/00051, CPII18/00018, and CP16/00128 from Instituto de Salud Carlos III, grant 1999SGR 00241from Generalitat de Catalunya-CIRIT, grant FP7-ENV-2011 cod 282957 and HEALTH.2010.2.4.5-1 from the EU Commission, grant UGP-15-230, UGP-15-244, and UGP-15-249 from Generalitat Valenciana: FISABIO, grant 2005111093 from Alicia Koplowitz Foundation 2017, Department of Health of the Basque Government, grant DFG06/002 from the Provincial Government of Gipuzkoa, and annual agreements with the municipalities of the study area (Zumarraga, Urretxu, Legazpi, Azkoitia y Azpeitia y Beasain). We also acknowledge support from the Spanish Ministry of Science and Innovation and the State Research Agency through the “Centro de Excelencia Severo Ochoa 2019-2023” Program (CEX2018-000806-S), and support from the Generalitat de Catalunya through the CERCA Program.

Weight percentiles are generally reported without any indication of error. This variation can lead a fetus being mistakenly classified erroneously as having intrauterine growth restriction (IUGR) or macrosomia. The goal of this study was to compare estimated weight percentiles with the actual observed weight percentile for each gestational age in a large cohort of fetuses being scanned in our institution.After IRB approval the radiology information system data base was retrospectively searched for all obstetrical US reports obtained during the late second and third trimesters from July 1, 2014, until July 1, 2020. Demographic information, fetal weight, and weight percentile information were obtained from these reports. Quantile-quantile plots were created for all gestational ages and all ethnicities.Our study included 6259 ultrasounds in 4060 patients. Mean maternal age of the total group was 31.68 years (ranging 15-53 years). When all subjects were considered, the median values in our QQ plots approximated the line of identity. However, there was considerable variation for a given estimate, implying that estimated fetal weight percentiles are only very rough predictors of the actual percentile.Estimated fetal weight percentiles are only very rough predictors of the actual percentile. We therefore suggest that estimates of the weight percentile should be reported along with an estimate of the expected variation. Recognition of variations in weight percentile should be considered in the greater clinical context, and could potentially prevent misdiagnosis of growth restriction and macrosomia as well as the subsequent overutilization of resources, unnecessary interventions, and maternal stress.

Adequate dietary fiber intake during gestation is critical for maternal-fetal health. This experiment aims to uncover the impacts of maternal long-term intake of inulin on fetal development and its underlying mechanism. Eighty female Sprague-Dawley rats were randomly assigned to two groups receiving either a fiber-free diet or an inulin diet (inulin) for three parities. On the 19

The mammalian blastocyst consists of three distinct cell types: epiblast, trophoblast (TB), and primitive endoderm (PrE). Although embryonic stem cells (ESCs) and trophoblast stem cells (TSCs) retain the functional properties of epiblast and TB, respectively, stem cells that fully recapitulate the developmental potential of PrE have not been established. Here, we report derivation of primitive endoderm stem cells (PrESCs) in mice. PrESCs recapitulate properties of embryonic day 4.5 founder PrE, are efficiently incorporated into PrE upon blastocyst injection, generate functionally competent PrE-derived tissues, and support fetal development of PrE-depleted blastocysts in chimeras. Furthermore, PrESCs can establish interactions with ESCs and TSCs and generate descendants with yolk sac–like structures in utero. Establishment of PrESCs will enable the elucidation of the mechanisms for PrE specification and subsequent pre- and postimplantation development.

Objective To investigate the association of the maternal serum albumin (MAlb) level with fetal growth and fetal growth restriction (FGR) risk in term-born singletons. Design Prospective cohort study. Setting Four hospital maternity units of the Tongji Maternal and Child Health Cohort study initiated from September 2013 to April 2016 at Wuhan City, in central China. Patient(s) A total of 3,065 mother–offspring pairs. Intervention(s) None. Main Outcome Measure(s) Fetal growth was evaluated by birth weight (BW) and birth length. Fetal growth restriction was defined as BW below the 10th percentile. Result(s) All MAlb levels were within the upper limit of normal. After adjustment for liver function parameters, inflammatory indicators, and others, a reverse U-shaped relationship between MAlb and fetal growth was observed. Specifically, BW increased significantly with an increasing MAlb level when the MAlb level was 36.1 g/L (per g/L: β = −15.1; 95% CI, −21.2, −8.9). There was a similar association between MAlb and birth length. Furthermore, the adjusted odd ratios of FGR across increasing tertiles of the MAlb levels were 1.0 (reference), 1.1 (0.7, 1.8), and 1.7 (1.0, 2.6). Conclusion(s) There was a reverse U-shaped association between MAlb and fetal growth. A higher MAlb level was associated with an increased risk of FGR. Clinical Trial Registration Number NCT03099837.

Maternal infection during pregnancy is known to alter the development and function of offspring’s immune system, leading to inappropriate immune responses to common childhood infections and immunizations. Although this is an expanding field, maternal parasitic infections remain understudied. Millions of women of reproductive age are currently at risk for parasitic infection, whereas many pregnant, chronically infected women are excluded from mass drug administration due partially to a lack of resources, as well as fear of unknown adverse fetal developmental outcomes. In areas endemic for multiple parasitic infections, such as sub-Saharan Africa, there are increased rates of morbidity and mortality for various infections during early childhood in comparison with nonendemic areas. Despite evidence supporting similar immunomodulatory effects between various parasite species, there is no clear mechanistic understanding of how maternal infection reprograms offspring immunity. This brief review will compare the effects of selected maternal parasitic infections on offspring immunity.

Introduction: Newborns exposed to sildenafil citrate (SC) in utero have increased rates of persistent pulmonary hypertension. The mechanism behind this has not yet been fully elucidated. We aimed to utilize a combination of clinically relevant MRI techniques to comprehensively characterize the haemodynamics of the fetal sheep whilst under the influence of SC. We hypothesized that these MRI techniques would detect SC-induced increases in pulmonary blood flow and oxygen delivery prior to birth. Methods: At 116–117 days gestational age (term, 150 days), pregnant Merino ewes (n = 9) underwent fetal catheterization surgery. MRI scans were performed during a basal state and then repeated during a constant umbilical vein infusion of SC to measure blood flow and oxygenation within the major vessels of the fetal circulation using phase-contrast-MRI and T2 oximetry. Results: Right and left ventricular cardiac outputs were not different between states. Pulmonary blood flow increased during the SC state resulting in elevated pulmonary oxygen delivery. Right to left heart shunting through the foramen ovale was reduced without reducing cerebral oxygen delivery. Conclusion: SC induces alterations to pulmonary haemodynamics in utero; a characteristic that if maintained may underlie or act as a precursor towards the elevated rates of poor pulmonary outcomes after birth. These MRI techniques are the first to comprehensively characterize sildenafil’s direct impact on the pulmonary vasculature and its indirect detriment to the flow of oxygen-rich blood through the foramen ovale.

Human prenatal development is divided into an embryonic period and a fetal period. Intense organogenetic activity occurs in the embryonic period of prenatal life, while the fetal period is marked by less intense changes. Knowledge of the embryology of the orbit not only allows insights into how normal variations in the orbital structure arise but also provides an understanding of how congenital deformities occur when normal orbital development goes awry. In order to explore our understanding of the developmental anatomy of the orbit during the fetal period of prenatal life, the authors have summarized the major milestones in orbital morphogenesis, a temporally precise and morphogenetically intricate process. This process can be considered as an anatomic series of complex, well-orchestrated changes in morphology as well as a series of complex biochemical and molecular events that coordinate and control the anatomic development. Identifying and linking signaling pathways and regulatory genes linked with normal orbital morphogenesis is a crucial step to offer patients with chronic or incurable orbital diseases effective treatment options in the future.Die pränatale Entwicklung des Menschen wird in eine Embryonalperiode und eine Fetalperiode unterteilt. Das Wissen über die fetale Entwicklung der Orbita ermöglicht nicht nur Einblicke in die Entstehung normaler Variationen in der Orbitastruktur, sondern liefert auch ein Verständnis dafür, wie angeborene Missbildungen und Anomalien auftreten, wenn die normale Orbitalentwicklung fehlschlägt. Die Autoren haben die Meilensteine in der Orbitalmorphogenese, einem zeitlich genauen und morphogenetisch komplizierten Prozess, zusammengefasst. Dieser Prozess kann als anatomische Reihe komplexer, gut koordinierter Veränderungen der Morphologie sowie als eine Reihe komplexer biochemischer und molekularer Ereignisse betrachtet werden, die die anatomische Entwicklung koordinieren und kontrollieren. Die Identifizierung und Verknüpfung von Signalwegen und regulatorischen Genen, die mit einer normalen orbitalen Morphogenese verbunden sind, ist ein entscheidender Schritt, um Patienten mit chronischen oder unheilbaren Erkrankungen der Orbita in Zukunft wirksame Behandlungsoptionen anbieten zu können.

The aim of this study was to assess the effect of continued smoking before and during pregnancy on mid-trimester fetal head development. A total of 250 pregnant women enrolled in the study. All participants were confirmed to be smokers or non-smokers by verifying breath carbon monoxide readings. Biparietal diameter (BPD), head circumference (HC), lateral ventricle (LV), and cisterna magna (CM) were evaluated by ultrasound between 20-22 weeks of pregnancy. Gender and gestational age-adjusted BPD z- scores were not statistically different between smokers and non-smokers (-0.75 ± 1.6 vs -0.51 ± 1, p = .3). HC measurements and z- scores were significantly lower in the smoking group than in the non-smoking groups (183.38 ± 14.56 vs. 189.28 ± 12.53, p = .003, 0.18 ± 1.39 multiple of median (MoM) vs. 0.56 ± 0.92, respectively, p = .023). At linear regression analysis, maternal smoking was the only independent factor associated with fetal HC z score (p = .041). In conclusion, continued smoking during pregnancy reduces fetal HC and has no effect on BPD, LV, or CM measurements at mid-gestation.IMPACT STATEMENTWhat is already known on this subject? Smoking during pregnancy is one of the most common environmental factors affecting fetal and neonatal growth and well-being. Despite the well-known effects of smoking on somatic growth, current studies have shown that it selectively affects some parts of the fetal brain, even in appropriately growing fetuses.What do the results of this study add? Continued smoking during pregnancy reduces fetal HC and has no effect on BPD, LV or CM measurements at mid-gestation. Since smoking is well known for its early and late childhood behavioral and neurological consequences, smaller mid-trimester fetal HC measurements should bring maternal smoking to mind as one of the potentially reversible causes.What are the implications of these findings for clinical practice and/or further research? The harmful effects of smoking start before the third trimester and antenatal counseling should be started early in the gestation. Every effort should be made to quit smoking before or early in pregnancy.

BACKGROUND: Amino acids are key to protein synthesis, energy metabolism, cell signaling and gene expression; however, the contribution of specific maternal amino acids to fetal growth is unclear. METHODS: We explored the effect of maternal circulating amino acids on fetal growth, proxied by birthweight, using two-sample Mendelian randomisation (MR) and summary data from a genome-wide association study (GWAS) of serum amino acids levels (sample 1, n = 86,507) and a maternal GWAS of offspring birthweight in UK Biobank and Early Growth Genetics Consortium, adjusting for fetal genotype effects (sample 2, n = 406,063 with maternal and/or fetal genotype effect estimates). A total of 106 independent single nucleotide polymorphisms robustly associated with 19 amino acids (p < 4.9 × 10-10) were used as genetic instrumental variables (IV). Wald ratio and inverse variance weighted methods were used in MR main analysis. A series of sensitivity analyses were performed to explore IV assumption violations. FINDINGS: Our results provide evidence that maternal circulating glutamine (59 g offspring birthweight increase per standard deviation increase in maternal amino acid level, 95% CI: 7, 110) and serine (27 g, 95% CI: 9, 46) raise, while leucine (-59 g, 95% CI: -106, -11) and phenylalanine (-25 g, 95% CI: -47, -4) lower offspring birthweight. These findings are supported by sensitivity analyses. INTERPRETATION: Our findings strengthen evidence for key roles of maternal circulating amino acids during pregnancy in healthy fetal growth. FUNDING: A full list of funding bodies that contributed to this study can be found under Acknowledgments.

Aims: We aimed to investigate the associations between perceived maternal stress or salivary cortisol levels during pregnancy and birthweight. Methods: In 2010-2012, we recruited 92 women living in Stockholm, Sweden, and followed them from before conception and through pregnancy and childbirth. Their Perceived Stress Scale (PSS) scores and salivary cortisol levels were collected at 26-28 gestational weeks. Birthweight was collected from medical records. Linear regression analyses and Pearson correlations were performed between the PSS scores or cortisol levels and birthweight, respectively, adjusted for gestational age. Results: No significant associations were found between PSS scores or cortisol levels and birthweight. There was a trend towards higher salivary cortisol levels among infants with lower birthweights, and this effect was attenuated after adjusting for gestational age. Morning cortisol levels (r = -0.31, p = 0.01), the decline in cortisol levels (r = -0.26, p = 0.03) and evening cortisol levels (r = -0.21, p = 0.09) were negatively correlated with PSS scores. Conclusion: Maternal stress during pregnancy was not associated with birthweight. The inverse correlation between PSS scores and cortisol levels may indicate other mechanisms for maternal stress on child outcomes than the previous explanation of hypothalamic-pituitary-adrenal axis activity.

Per- and polyfluoroalkyl substances (PFASs) such as perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) are persistent in the environment and bioaccumulate in wildlife and humans, potentially causing adverse health effects at all stages of life. Studies from human pregnancy have shown that exposure to these contaminants are associated with placental dysfunction and fetal growth restriction; however, studies in humans are confounded by genetic and environmental factors. Here, we synthesize the available results from mouse models of pregnancy to show the causal effects of prenatal exposure to PFOA and PFOS on placental and fetal development and on neurocognitive function and metabolic disorders in offspring. We also propose gaps in the present knowledge and provide suggestions for future research studies.