Fetal Environment Research Articles

Technical considerations for placental tissue processing and the subsequent impact on genome-wide DNA methylation analysis

To assess the impact of postnatal processing on placental DNA methylation, array data from flash-frozen placental tissue was compared to perfluorocarbon-immersed and formalin-fixed paraffin-embedded placental tissue. We observed that tissue exposed to perfluorocarbon showed no significant DNA methylation differences when compared to unprocessed tissue, while formalin processing altered the quality and reliability of the data produced on the DNA methylation array platform. Placental DNA methylation allows for the study of gene–environment interactions that influence the fetal environment and development. Our study highlights that placental post-processing techniques must be considered in the evaluation and interpretation of epigenetic studies.

Impact of a Stage-Based Classification on the Incidence of Fetal Growth Restriction, Preterm Birth Rates, and Birthweight in a Rural Community of Central India

Introduction: The objective of this study was to determine the impact of the stage-based classification of fetal growth restriction (FGR) on the magnitude of FGR, preterm births (PTBs), and birthweight (BW) in a rural population of Madhya Pradesh in Central India. Methods: The program covered 168 public sector centers for pregnant women and infants that provided services to nearly 220,000 people. The third-trimester assessments included fetal biometry, growth and environment assessments, and Doppler assessments. Fetal growth was staged using the Barcelona protocol as stages 1–4 FGR, small for gestational age, and no FGR. The data from the last ultrasound assessment before childbirth were considered. Regular training programs covering preconception care, antenatal and postnatal care were organized in the local language for the public sector community health workers of the program district. Childbirth outcomes were collected from the obstetric service of the local public sector hospital. Results: The analysis included 1,229 pregnancies from 2019 to 2023. The overall magnitude of FGR using estimated fetal weight <10th centile was 19.61% and reduced to 13.34% with the stage-based classification. The magnitude of FGR using the stage-based classification reduced from 27.59% in 2019 to 8.95% in 2023. The PTB in the stage-based FGR subgroup declined from 35.0% in 2019 to 3.45% in 2023 and 96.55% of the stage 1 FGR babies in 2023 were delivered at term. The overall mean BW in the program area improved from 2,772.41 (357.11) g in 2019 to 2,819.68 (377.31) g in 2023. The perinatal mortality rate (8.95 per 1,000 pregnancies) in the program area for 2019–2023 was much lower than the 31.9 per 1,000 pregnancies reported for Madhya Pradesh. Conclusion: The change to a stage-based classification of FGR integrated with low-dose aspirin and fetal Doppler studies reduced the incidence of FGR and PTB and perinatal mortality and increased BW in this rural community.

Intergenerational transmission of health inequalities: towards a life course approach to socioeconomic inequalities in health – a review

Adult health inequalities are a persistent public health problem. Explanations are usually sought in behaviours and environments in adulthood, despite evidence on the importance of early life conditions for life...

The Role of Biophysical Factors in Organ Development: Insights from Current Organoid Models.

Biophysical factors play a fundamental role in human embryonic development. Traditional in vitro models of organogenesis focused on the biochemical environment and did not consider the effects of mechanical forces on developing tissue. While most human tissue has a Young's modulus in the low kilopascal range, the standard cell culture substrate, plasma-treated polystyrene, has a Young's modulus of 3 gigapascals, making it 10,000-100,000 times stiffer than native tissues. Modern in vitro approaches attempt to recapitulate the biophysical niche of native organs and have yielded more clinically relevant models of human tissues. Since Clevers' conception of intestinal organoids in 2009, the field has expanded rapidly, generating stem-cell derived structures, which are transcriptionally similar to fetal tissues, for nearly every organ system in the human body. For this reason, we conjecture that organoids will make their first clinical impact in fetal regenerative medicine as the structures generated ex vivo will better match native fetal tissues. Moreover, autologously sourced transplanted tissues would be able to grow with the developing embryo in a dynamic, fetal environment. As organoid technologies evolve, the resultant tissues will approach the structure and function of adult human organs and may help bridge the gap between preclinical drug candidates and clinically approved therapeutics. In this review, we discuss roles of tissue stiffness, viscoelasticity, and shear forces in organ formation and disease development, suggesting that these physical parameters should be further integrated into organoid models to improve their physiological relevance and therapeutic applicability. It also points to the mechanotransductive Hippo-YAP/TAZ signaling pathway as a key player in the interplay between extracellular matrix stiffness, cellular mechanics, and biochemical pathways. We conclude by highlighting how frontiers in physics can be applied to biology, for example, how quantum entanglement may be applied to better predict spontaneous DNA mutations. In the future, contemporary physical theories may be leveraged to better understand seemingly stochastic events during organogenesis.

Effects of Fetal Position on the Loading of the Fetal Brain During the Onset of the Second Stage of Labor.

During vaginal delivery, the delivery requires the fetal head to mold to accommodate the geometric constraints of the birth canal. Excessive molding can produce brain injuries and long-term sequelae. Understanding the loading of the fetal brain during the second stage of labor (fully dilated cervix, active pushing, and expulsion of fetus) could thus help predict the safety of the newborn during vaginal delivery. To this end, this study proposes a finite element model of the fetal head and maternal canal environment that is capable of predicting the stresses experienced by the fetal brain at the onset of the second phase of labor. Both fetal and maternal models were adapted from existing studies to represent the geometry of full-term pregnancy. Two fetal positions were compared: left-occiput-anterior and left-occiput-posterior. The results demonstrate that left-occiput-anterior position reduces the maternal tissue deformation, at the cost of higher stress in the fetal brain. In both cases, stress is concentrated underneath the sutures, though the location varies depending on the presentation. In summary, this study provides a patient-specific simulation platform for the study of vaginal delivery and its effect on both the fetal brain and maternal anatomy. Finally, it is suggested that such an approach has the potential to be used by obstetricians to support their decision-making processes through the simulation of various delivery scenarios.

Progesterone for Neurodevelopment in Fetuses With Congenital Heart Defects

Neurodevelopmental outcomes for children with congenital heart defects (CHD) have improved minimally over the past 20 years. To assess the feasibility and tolerability of maternal progesterone therapy as well as the magnitude of the effect on neurodevelopment for fetuses with CHD. This double-blinded individually randomized parallel-group clinical trial of vaginal natural progesterone therapy vs placebo in participants carrying fetuses with CHD was conducted between July 2014 and November 2021 at a quaternary care children's hospital. Participants included maternal-fetal dyads where the fetus had CHD identified before 28 weeks' gestational age and was likely to need surgery with cardiopulmonary bypass in the neonatal period. Exclusion criteria included a major genetic or extracardiac anomaly other than 22q11 deletion syndrome and known contraindication to progesterone. Statistical analysis was performed June 2022 to April 2024. Participants were 1:1 block-randomized to vaginal progesterone or placebo by diagnosis: hypoplastic left heart syndrome (HLHS), transposition of the great arteries (TGA), and other CHD diagnoses. Treatment was administered twice daily between 28 and up to 39 weeks' gestational age. The primary outcome was the motor score of the Bayley Scales of Infant and Toddler Development-III; secondary outcomes included language and cognitive scales. Exploratory prespecified subgroups included cardiac diagnosis, fetal sex, genetic profile, and maternal fetal environment. The 102 enrolled fetuses primarily had HLHS (n = 52 [50.9%]) and TGA (n = 38 [37.3%]), were more frequently male (n = 67 [65.7%]), and without genetic anomalies (n = 61 [59.8%]). The mean motor score differed by 2.5 units (90% CI, -1.9 to 6.9 units; P = .34) for progesterone compared with placebo, a value not statistically different from 0. Exploratory subgroup analyses suggested treatment heterogeneity for the motor score for cardiac diagnosis (P for interaction = .03) and fetal sex (P for interaction = .04), but not genetic profile (P for interaction = .16) or maternal-fetal environment (P for interaction = .70). In this randomized clinical trial of maternal progesterone therapy, the overall effect was not statistically different from 0. Subgroup analyses suggest heterogeneity of the response to progesterone among CHD diagnosis and fetal sex. ClinicalTrials.gov Identifier: NCT02133573.

Polycystic ovary syndrome (PCOS): progress towardsabetter understanding and treatment ofthesyndrome.

Polycystic ovary syndrome (PCOS) is the most common endocrine and metabolic disorder in women of reproductive age. It has a strong hereditary component estimated at 60 to 70% in daughters. It has been suggested that environmental factors during the fetal period may be involved in the development of the syndrome in adulthood. However, the underlying mechanisms of its transmission remain unknown, thus limiting the development of effective therapeutic strategies.This article highlights how an altered fetal environment (prenatal exposure to high levels of anti-Müllerian hormone) can contribute to the onset of PCOS in adulthood and lead to the transgenerational transmission of neuroendocrine and metabolic traits through alterations in the DNA methylation process.The originality of the translational findings summarized here involves the identification of potential biomarkers for early diagnosis of the syndrome, in addition to the validation of a promising therapeutic avenue in a preclinical model of PCOS, which can improve the management of patients suffering from the syndrome.

Oxygen and HIF1α-dependent SDF1 expression in primary astrocytes.

In the naturally hypoxic in utero fetal environment of preterm infants, oxygen and oxygen-sensitive signaling pathways play an important role in brain development, with hypoxia-inducible factor-1α (HIF1α) being an important regulator. Early exposure to nonphysiological high oxygen concentrations by birth in room can induce HIF1α degradation and may affect neuronal and glial development. This involves the dysregulation of astroglial maturation and function, which in turn might contribute to oxygen-induced brain injury. In this study, we investigated the effects of early high oxygen exposure on astroglial maturation and, specifically, on astroglial stromal cell-derived factor 1 (SDF1) expression in vivo and in vitro. In our neonatal mouse model of hyperoxia preterm birth brain injury in vivo, high oxygen exposure affected astroglial development and cortical SDF1 expression. These results were further supported by reduced Sdf1 expression, impaired proliferation, decreased total cell number, and altered expression of astroglial markers in astrocytes in primary cultures grown under high oxygen conditions. Moreover, to mimic the naturally hypoxic in utero fetal environment, astroglial Sdf1 expression was increased after low oxygen exposure in vitro, which appears to be regulated by HIF1α activity. Additionally, the knockdown of Hif1α revealed HIF1α-dependent Sdf1 expression in vitro. Our results indicate HIF1α and oxygen-dependent chemokine expression in primary astrocytes and highlight the importance of oxygen conditions for brain development.

Neighborhood eviction trajectories and odds of moderate and serious psychological distress during pregnancy among African American women.

African American mothers are unjustly burdened by both residential evictions and psychological distress. We quantified associations between trajectories of neighborhood evictions over time and the odds of moderate and serious psychological distress (MPD and SPD, respectively) during pregnancy among African American women. We linked publicly available data on neighborhood eviction filing and judgment rates to preconception and during-pregnancy addresses from the Life-course Influences on Fetal Environments (LIFE) Study (2009-2011; n=808). Multinomial logistic regression-estimated odds of MPD and SPD during pregnancy that were associated with eviction filing and judgment rate trajectories incorporating preconception and during-pregnancy addresses (each categorized as low, medium, or high, with two 9-category trajectory measures). Psychological distress was measured with the Kessler Psychological Distress Scale (K6) (K6 scores 5-12=MPD, andK6 scores ≥13=SPD). MPD was reported in 60% of the sample and SPD in 8%. In adjusted models, higher neighborhood eviction filing and judgment rates, as compared with low/low rates, during the preconception and pregnancy periods were associated with 2- to 4-fold higher odds of both MPD and SPD during pregnancy among African American women. In future studies, researchers should identify mechanisms of these findings to inform timely community-based interventions and effective policy solutions to ensure the basic human right to housing for all. This article is part of a Special Collection on Mental Health.

Sex and fetal genome influence gene expression in pig endometrium at the end of gestation

BackgroundA fine balance of feto-maternal resource allocation is required to support pregnancy, which depends on interactions between maternal and fetal genetic potential, maternal nutrition and environment, endometrial and placental functions. In particular, some imprinted genes have a role in regulating maternal-fetal nutrient exchange, but few have been documented in the endometrium. The aim of this study is to describe the expression of 42 genes, with parental expression, in the endometrium comparing two extreme breeds: Large White (LW); Meishan (MS) with contrasting neonatal mortality and maturity at two days of gestation (D90-D110). We investigated their potential contribution to fetal maturation exploring genes-fetal phenotypes relationships. Last, we hypothesized that the fetal genome and sex influence their endometrial expression. For this purpose, pure and reciprocally crossbred fetuses were produced using LW and MS breeds. Thus, in the same uterus, endometrial samples were associated with its purebred or crossbred fetuses.ResultsAmong the 22 differentially expressed genes (DEGs), 14 DEGs were differentially regulated between the two days of gestation. More gestational changes were described in LW (11 DEGs) than in MS (2 DEGs). Nine DEGs were differentially regulated between the two extreme breeds, highlighting differences in the regulation of endometrial angiogenesis, nutrient transport and energy metabolism. We identified DEGs that showed high correlations with indicators of fetal maturation, such as ponderal index at D90 and fetal blood fructose level and placental weight at D110.We pointed out for the first time the influence of fetal sex and genome on endometrial expression at D90, highlighting AMPD3, CITED1 and H19 genes. We demonstrated that fetal sex affects the expression of five imprinted genes in LW endometrium. Fetal genome influenced the expression of four genes in LW endometrium but not in MS endometrium. Interestingly, both fetal sex and fetal genome interact to influence endometrial gene expression.ConclusionsThese data provide evidence for some sexual dimorphism in the pregnant endometrium and for the contribution of the fetal genome to feto-maternal interactions at the end of gestation. They suggest that the paternal genome may contribute significantly to piglet survival, especially in crossbreeding production systems.

Nrf2 pre-recruitment at Enhancer 2 is a hallmark of H2 O2 -induced epigenetic transcriptional memory in the HMOX1 gene in human umbilical artery endothelial cells.

Maternal obesity (MO) is a significant cause of increased cardiometabolic risk in offspring, who present endothelial dysfunction at birth. Alterations in physiologic and cellular redox status are strongly associated with altered gene regulation in arterial endothelium. However, specific mechanisms by which the pro-oxidant fetal environment in MO could modulate the vascular gene expression and function during the offspring's postnatal life are elusive. We tested if oxidative stress could reprogram the antioxidant-coding gene's response to a pro-oxidant challenge through an epigenetic transcriptional memory (ETM) mechanism. A pro-oxidant double-hit protocol was applied to human umbilical artery endothelial cells (HUAECs) and EA.hy 926 endothelial cell lines. The ETM acquisition in the HMOX1 gene was analyzed by RT-qPCR. HMOX1 mRNA decay was evaluated by Actinomycin-D treatment and RT-qPCR. To assess the chromatin accessibility and the enrichment of NRF2, RNAP2, and phosphorylation at serin-5 of RNAP2, at HMOX1 gene regulatory regions, were used DNase HS-qPCR and ChIP-qPCR assays, respectively. The CpG methylation pattern at the HMOX1 core promoter was analyzed by DNA bisulfite conversion and Sanger sequencing. Data were analyzed using two-way ANOVA, and p < 0.05 was statistically significant. Using a pro-oxidant double-hit protocol, we found that the Heme Oxygenase gene (HMOX1) presents an ETM response associated with changes in the chromatin structure at the promoter and gene regulatory regions. The ETM response was characterized by a paused-RNA Polymerase 2 and NRF2 enrichment at the transcription start site and Enhancer 2 of the HMOX1 gene, respectively. Changes in DNA methylation pattern at the HMOX1 promoter were not a hallmark of this oxidative stress-induced ETM. These data suggest that a pro-oxidant milieu could trigger an ETM at the vascular level, indicating a potential epigenetic mechanism involved in the increased cardiovascular risk in the offspring of women with obesity.

DDIT4L regulates mitochondrial and innate immune activities in early life.

Pattern recognition receptor responses are profoundly attenuated before the third trimester of gestation in the relatively low-oxygen human fetal environment. However, the mechanisms regulating these responses are uncharacterized. Herein, genome-wide transcription and functional metabolic experiments in primary neonatal monocytes linked the negative mTOR regulator DDIT4L to metabolic stress, cellular bioenergetics, and innate immune activity. Using genetically engineered monocytic U937 cells, we confirmed that DDIT4L overexpression altered mitochondrial dynamics, suppressing their activity, and blunted LPS-induced cytokine responses. We also showed that monocyte mitochondrial function is more restrictive in earlier gestation, resembling the phenotype of DDIT4L-overexpressing U937 cells. Gene expression analyses in neonatal granulocytes and lung macrophages in preterm infants confirmed upregulation of the DDIT4L gene in the early postnatal period and also suggested a potential protective role against inflammation-associated chronic neonatal lung disease. Taken together, these data show that DDIT4L regulates mitochondrial activity and provide what we believe to be the first direct evidence for its potential role supressing innate immune activity in myeloid cells during development.

Cardio-Metabolic Health of Offspring Exposed in Utero to Human Immuno-Deficiency Virus and Anti-Retroviral Treatment: A Systematic Review.

Antiretroviral treatment (ART) use during pregnancy continues to rise as it is known to decrease the likelihood of HIV transmission from mother to child. However, it is still unknown whether foetal exposure to (ART) may affect the foetal environment, predisposing the offspring to cardiometabolic risk. Therefore, the aim of this study was to systematically review the cardio-metabolic effects of in utero exposure to HIV/ART on offspring. We carried out a systematic review and obtained literature from the Google scholar, PubMed, ProQuest, Web of Science, and Scopus databases. Two independent reviewers evaluated the titles, abstracts, and full-length English contents. Data from the eligible studies were included. The search yielded 7596 records. After assessing all of these records, 35 of the full-length articles were included in this systematic review. Several studies showed that low birth weight, small head circumference, and altered mitochondrial content were more common among HIV-exposed uninfected (HEU) children compared to HIV-unexposed uninfected children (HUU). A few studies demonstrated elevated triglyceride levels, lower levels of insulin, and increased blood pressure, oxidative stress, vascular dysfunction, cardiac damage, and myocardial dysfunction among HEU children compared with HUU children. Most findings showed that there were cardio-metabolic health risk factors among HEU children, indicating that maternal exposure to HIV and ART may negatively affect foetal health, which may lead to cardio-metabolic morbidity later in life.

GATA1 Target Gene CSF2RB Is Functionally Coupled to MPL and Marks a TPO-Dependent Preleukemic TAM Cell Population Sustained By the Fetal Liver but Not Bone Marrow

Paediatric cancers differ from adult cancers on the basis of their genetics and biology. Understanding these differences can identify factors important in oncogenesis during development. One exemplar are the genetically linked myeloid pre-leukemic and leukemic disorders in newborns and children with Trisomy 21 (T21) or Down syndrome (DS). DS children have a 400-fold increased risk of developing myeloid leukemia (ML-DS) in early life. ML-DS is preceded by a fetal/neonatal pre-leukemic phase known as transient abnormal myelopoiesis (TAM), when T21 hemopoietic cells acquire mutations in the GATA1 gene. These mutations produce an N-terminal truncated GATA1 protein (GATA1s). Remarkably, the proliferative effect exerted by T21 and GATA1s is developmentally restricted. As hemopoiesis shifts from fetal liver to new-born bone marrow, TAM usually spontaneously regresses. The biological basis for the requirement of a fetal liver environment for TAM cells and their failure to thrive in the bone marrow is unknown. However, a clue is that TAM cells can proliferate in bone marrow if they acquire oncogenic mutations, typically in genes of the JAK-STAT signalling pathway. These mutations transform the TAM clone to an ML-DS clone. To address the question of why TAM cells survive only in a fetal liver environment, we performed scRNA sequencing, coupled with genotyping from 3 primary TAM samples. 4 T21 and 3 disomic cord blood samples were used as controls (Fig1A). We identified a marked expansion of mutant TAM GATA1s cells, compared to controls, at the earliest GATA1-expressing progenitor stages (Fig1A). TAM GATA1s cells displayed transcriptional upregulation of the PI3K/AKT/mTOR, TNFA/NFκB and JAK/STAT pathways and enhanced STAT3 regulon activity when compared to controls (Fig1A). We hypothesized that aberrant cytokine receptor activation leading to increased STAT3 activity is essential for GATA1s cell proliferation. Differential gene expression between TAM GATA1s cells and disomic cells, pointed to CSF2RB, a cytokine receptor that directly activates the JAK-STAT signalling pathway (Fig1A). Next, we demonstrated that CSF2RB is overexpressed at the protein level in TAM and marks 80% of CD34 + cells compared to 5% CD34+ control cells. Using CUT&amp;TAG we confirmed binding of GATA1s and GATA2 at two GATA sites in the CSF2RB locus in CMK cells (Fig 1A). CRISPR-Cas9 disruption of either GATA2, or the -12kb GATA motif led to downregulation of CSF2RB protein (Fig1A). We are testing if GATA1 represses CSF2RB and whether GATA1s fails to repress CSF2RB, allowing sustained abnormal CSF2RB expression in TAM. CSF2RB gene knockout in GATA1s cells leads to cell death. Taken together, CSF2RB is a direct GATA target gene and abnormal sustained, CSF2RB expression in TAM cells is required for GATA1s cell survival. Classically, CSF2RB partners with the α-chain of either IL3, IL5 or GMCSF receptors. Interestingly, none of the α-chains are expressed at the protein or RNA level in TAM CSF2RB+ cells, suggesting that CSF2RB might partner with another cytokine receptor. We nominated MPL, the thrombopoietin (TPO) receptor as a new candidate binding partner of CSF2RB for the following reasons: (i) we documented co-expression of MPL with CSF2RB at the RNA and protein level in TAM cells. (ii) we confirmed functional coupling between CSF2RB and MPL in Ba/F3 and TF-1 cells, where at equivalent MPL levels, TPO signalling via the JAK-STAT pathway is enhanced by CSF2RB. This effect is stronger at high TPO levels. (iii) A mutation in CSFR2RB (A455D) that we described in ML-DSrequires interaction with human MPL to induce autonomous growth of cytokine-dependent hematopoietic cells. Notably, direct interaction between MPL and CSF2RB A455D is detected by BRET assays. We hypothesize that high levels of fetal liver derived TPO sustain TAM proliferation because of the functional coupling between MPL and CSF2RB (Fig1B). This proliferation signal is lost as cells migrate to the low TPO bone marrow environment. Further work will assess TPO concentration in DS fetal liver and whether TAM cells display increased proliferation in response to varying TPO doses. In summary, we propose a model whereby reduced TPO levels experienced by TAM cells as they migrate from fetal liver to bone marrow creates selective pressure for acquisition of secondary mutations that permit TAM cells to proliferate independently of the high TPO environment of the fetal liver (Fig1B).

Maternal microbiota communicates with the fetus through microbiota-derived extracellular vesicles

BackgroundReports regarding the presence of bacteria in the fetal environment remain limited and controversial. Recently, extracellular vesicles secreted by the human gut microbiota have emerged as a novel mechanism for host-microbiota interaction. We aimed to investigate the presence of bacterial extracellular vesicles in the fetal environment during healthy pregnancies and determine whether extracellular vesicles derived from the gut microbiota can cross biological barriers to reach the fetus.ResultsBacterial extracellular vesicles were detectable in the amniotic fluid of healthy pregnant women, exhibiting similarities to extracellular vesicles found in the maternal gut microbiota. In pregnant mice, extracellular vesicles derived from human maternal gut microbiota were found to reach the intra-amniotic space.ConclusionsOur findings reveal maternal microbiota-derived extracellular vesicles as an interaction mechanism between the maternal microbiota and fetus, potentially playing a pivotal role in priming the prenatal immune system for gut colonization after birth.Au1faBx7d8xEuZZWHtt5CfVideo

Deteriorating Semen Quality: The Role of the Environment.

Since the end of the last century, several reports have suggested that semen quality is declining, especially in Western countries. Furthermore, cross-sectional studies using similar protocols have suggested regional differences in semen quality of young and fertile men. Reasons for these regional differences and local adverse trends in semen quality are unknown, but environmental factors are suspected to have a role. Besides adulthood environmental exposures, those occurring during testicular development may also affect semen quality. Longitudinal follow-up studies and mixture risk analyses are needed to study the effect of fetal, childhood, and adult life environment on semen quality.

The dogma of the sterile uterus revisited: does microbial seeding occur during fetal life in humans and animals?

Opposing conclusions have been drawn regarding the presence of viable bacteria in the healthy pregnant uterus. Current evidence in humans and animals suggests that fetomaternal tissues present only traces of bacteria whose viability is still to be proven. The debate about the pioneer colonization of the fetus is still open, being the 'in utero colonization' hypothesis versus the 'sterile womb paradigm' the two opposing sides. The seed in this field of research sprouted in human medicine in the last decade and became a central topic in other mammals as well. We aimed to review the literature on bacterial colonization of the healthy placenta, amniotic fluid, and meconium as representatives of the fetal environment. What emerges is that confirming the colonization of fetomaternal tissues by viable bacteria is challenging in humans as well as in animals. Contamination represents the major risk in this type of research as it can be related to different parts of the study design. Sampling at natural parturition or postpartum introduces risk for colonization by the vaginal microbiome of the mother or from the environment. Culture does not reveal the presence of unculturable microorganisms, and sequencing does not allow confirming bacterial viability, while also introducing the variability associated with the data analysis. Therefore, on the basis of the present review, we provide some guidelines on the best practices when performing this type of studies. What emerges from the current literature in humans and animals is that fetomaternal tissues are characterized by a very low biomass, that the viability of bacteria eventually present is still to be confirmed, while massive colonization happens at birth, priming the individual, regardless of the species.

Association between placental oxygen transport and fetal brain cortical development: a study in monochorionic diamniotic twins.

Normal cortical growth and the resulting folding patterns are crucial for normal brain function. Although cortical development is largely influenced by genetic factors, environmental factors in fetal life can modify the gene expression associated with brain development. As the placenta plays a vital role in shaping the fetal environment, affecting fetal growth through the exchange of oxygen and nutrients, placental oxygen transport might be one of the environmental factors that also affect early human cortical growth. In this study, we aimed to assess the placental oxygen transport during maternal hyperoxia and its impact on fetal brain development using MRI in identical twins to control for genetic and maternal factors. We enrolled 9 pregnant subjects with monochorionic diamniotic twins (30.03 ± 2.39 gestational weeks [mean ± SD]). We observed that the fetuses with slower placental oxygen delivery had reduced volumetric and surface growth of the cerebral cortex. Moreover, when the difference between placenta oxygen delivery increased between the twin pairs, sulcal folding patterns were more divergent. Thus, there is a significant relationship between placental oxygen transport and fetal brain cortical growth and folding in monochorionic twins.

Maternal Hyperglycemia Induces Autonomic Dysfunction and Heart Failure in Older Adult Offspring.

Offspring exposed to an adverse fetal environment, such as gestational diabetes, may manifest increased susceptibility to several chronic diseases later in life. In the present study, the cardiovascular function of three different ages of offspring from diabetic rats was evaluated. Diabetes mellitus was induced in pregnant rats by a single dose of streptozotocin (50 mg/kg). The offspring from diabetic (OD) and control rats (OC) were evaluated at three different ages: 6, 12 or 18 months. In the corresponding OC groups, fasting glycemia, baseline mean arterial pressure, and sympathetic tonus increased in the OD rats at 12 (OD12) and 18 (OD18) months of age, while cardiac hypertrophy was observed in all OD groups. Cardiac function evaluation in vivo showed low left ventricular systolic pressure and+dP/dt in the OD18 rats, suggesting a systolic dysfunction. OD12 and OD18 groups showed high left ventricle end-diastolic pressure, suggesting a diastolic dysfunction. OD groups showed an age-related impairment of both baroreflex-mediated tachycardia and baroreflex-mediated bradycardia in OD12 and OD18 rats. In isolated hearts from OD18 rats, both inotropic and tachycardiac responses to increasing isoproterenol were significantly reduced compared to the corresponding OC group. These results suggest that gestational diabetes triggers the onset of hyperglycemia hypertension with impaired baroreflex sensitivity and heart failure in older age of offspring, representing important risk factors for death. Therefore, ensuring optimal glycemic control in diabetic pregnancy is important and serves as a key to preventing cardiovascular disease in the offspring in their older age.

In Utero Exposure to Metals and Birth Outcomes in an Artisanal and Small-Scale Gold Mining Birth Cohort in Madre de Dios, Peru.

Few birth cohorts in South America evaluate the joint effect of minerals and toxic metals on neonatal health. In Madre de Dios, Peru, mercury exposure is prevalent owing to artisanal gold mining, yet its effect on neonatal health is unknown. We aimed to determine whether toxic metals are associated with lower birth weight and shorter gestational age independently of antenatal care and other maternal well-being factors. Data are from the COhorte de NAcimiento de MAdre de Dios (CONAMAD) birth cohort, which enrolled pregnant women in Madre de Dios prior to their third trimester and obtained maternal and cord blood samples at birth. We use structural equation models (SEMs) to construct latent variables for the maternal metals environment (ME) and the fetal environment (FE) using concentrations of calcium, iron, selenium, zinc, magnesium, mercury, lead, and arsenic measured in maternal and cord blood, respectively. We then assessed the relationship between the latent variables ME and FE, toxic metals, prenatal visits, hypertension, and their effect on gestational age and birth weight. Among 198 mothers successfully enrolled and followed at birth, 29% had blood mercury levels that exceeded the U.S. Centers for Disease Control and Prevention threshold of and 2 mothers surpassed the former threshold for blood lead. The current threshold value is . Minerals and toxic metals loaded onto ME and FE latent variables. ME was associated with FE (0.24; 95% CI: 0.05, 0.45). FE was associated with longer gestational age (2.31; 95% CI: , 4.51) and heavier birth weight. Mercury exposure was not directly associated with health outcomes. A 1% increase in maternal blood lead shortened gestational age by 0.05 d (; 95% CI: , ), which at the threshold resulted in a loss of 3.6 gestational days and in birth weight for newborns. Prenatal care visits were associated with improved birth outcomes, with a doubling of visits from 6 to 12 associated with 5.5 more gestational days (95% CI: 1.6, 9.4) and of birth weight (95% CI: 287.6, 350.7). Maternal lead, even at low exposures, was associated with shorter gestation and lower birth weight. Studies that focus only on harmful exposures or nutrition may mischaracterize the dynamic maternal ME and FE. SEMs provide a framework to evaluate these complex relationships during pregnancy and reduce overcontrolling that can occur with linear regression. https://doi.org/10.1289/EHP10557.