Spatial multiomics map of trophoblast development in early pregnancy.

The relationship between the human placenta-the extraembryonic organ made by the fetus, and the decidua-the mucosal layer of the uterus, is essential to nurture and protect the fetus during pregnancy. Extravillous trophoblast cells (EVTs) derived from placental villi infiltrate the decidua, transforming the maternal arteries into high-conductance vessels1. Defects in trophoblast invasion and arterial transformation established during early pregnancy underlie common pregnancy disorders such as pre-eclampsia2. Here we have generated a spatially resolved multiomics single-cell atlas of the entire human maternal-fetal interface including the myometrium, which enables us to resolve the full trajectory of trophoblast differentiation. We have used this cellular map to infer the possible transcription factors mediating EVT invasion and show that they are preserved in in vitro models of EVT differentiation from primary trophoblast organoids3,4 and trophoblast stem cells5. We define the transcriptomes of the final cell states of trophoblast invasion: placental bed giant cells (fused multinucleated EVTs) and endovascular EVTs (which form plugs inside the maternal arteries). We predict the cell-cell communication events contributing to trophoblast invasion and placental bed giant cell formation, and model the dual role of interstitial EVTs and endovascular EVTs in mediating arterial transformation during early pregnancy. Together, our data provide a comprehensive analysis of postimplantation trophoblast differentiation that can be used to inform the design of experimental models of the human placenta in early pregnancy.

Avaliação do crescimento e desenvolvimento infantil e fatores de risco de um município que integra uma universidade brasileira de cunho internacional / Evaluation of childhood growth and development and risk factors of a municipality that is part of an international brazilian university / Evaluación de los factores de crecimiento y desarrollo infantil y de riesgo de un municipio que forma parte de una universidad brasileña internacional

Fatores de risco, incluindo os de cunho materno, interferem no crescimento e desenvolvimento infantil. Nesse sentido, o conhecimento desses fatores e avaliação ade- quada desses processos são necessários para articulação de estratégias preventivas de transtornos futuros. Assim, o estudo visou investigar o crescimento e desenvolvimento de crianças atendidas em consulta de puericultura em unidades básicas de saúde de um mu- nicípio cearense, que integra uma universidade brasileira de cunho internacional, e seus fatores de risco. Trata-se de estudo observacional, analítico, transversal e de abordagem quantitativa, conduzido com crianças e suas mães no Centro de Saúde de Acarape e Posto de Saúde São Benedito (Acarape ­ CE), no período de fevereiro a julho de 2021. Após consentimento, as mães preencheram um questionário, seguido de avaliação do cresci- mento e desenvolvimento das crianças. Os dados obtidos foram analisados. Das 70 crian- ças, 50,00% (n = 17) e 51,43% (n = 18) dos meninos e meninas tinham baixa estatura para idade, respectivamente. Para o desenvolvimento psicossocial, dos 284 testes condu- zidos, 86,27% (n = 245) foram realizados em plenitude pelas crianças. Observou-se as- sociação significativa entre a gestante ter concebido o filho com, no mínimo, 9 meses de período gestacional e esse apresentar relação Peso/Idade adequada e Estatura/Idade ina- dequada. Houve associação significativa entre a criança não ingerir refresco em pó e apre- sentar relação Peso/Idade adequada. Conclui-se que as crianças tinham idade gestacional adequada e apresentavam estado nutricional apropriado, apesar da baixa estatura para idade. Manifestavam desenvolvimento psicossocial, de linguagem e físico normais. Sobre os fatores de risco, esses envolveram os de cunho materno e o consumo de alimentos cariogênicos.

Risk factors, including maternal ones, interfere with child growth and de- velopment. In this sense, knowledge of these factors and adequate evaluation of these processes are necessary to articulate preventive strategies for future disorders. Thus, the study aimed to investigate the growth and development of children seen in childcare con- sultations in primary health units in Ceará, part of a Brazilian university of international character, and their risk factors. This is an observational, analytical, cross-sectional study with a quantitative approach, conducted with children and their mothers at the Acarape Health Center and São Benedito Health Center (Acarape ­ CE), from February to July 2021. After consent, the mothers completed a questionnaire, followed by an assessment of the children's growth and development. The data obtained were analyzed. Of the 70 children, 50.00% (n = 17) and 51.43% (n = 18) of the boys and girls were short for their age, respectively. Of the 284 tests conducted for psychosocial development, 86.27% (n = 245) were entirely performed by the children. A significant association was observed between the pregnant woman having conceived her child at least nine months of gestation and having an adequate Weight/Age and Height/Age ratio. There was a significant asso- ciation between the child not ingesting powdered soft drinks and having an appropriate Weight/Age ratio. It was concluded that the children had an adequate gestational age and had an appropriate nutritional status, despite their low height for their age. They showed normal psychosocial, language, and physical development. The risk factors involved those of mother nature and the consumption of cariogenic foods.

Los factores de riesgo, incluidos los maternos, interfieren en el crecimiento y desarrollo infantil. En este sentido, el conocimiento de estos factores y la evaluación adecuada de estos procesos son necesarios para articular estrategias preventivas de futu- ros trastornos. Así, el estudio tuvo como objetivo investigar el crecimiento y desarrollo de niños atendidos en consultas de puericultura en unidades básicas de salud de un muni- cipio de Ceará, que forma parte de una universidad brasileña de carácter internacional, y sus factores de riesgo. Se trata de un estudio observacional, analítico, transversal, con enfoque cuantitativo, realizado con niños y sus madres en el Centro de Salud de Acarape y el Centro de Salud São Benedito (Acarape ­ CE), de febrero a julio de 2021. Después del consentimiento, las madres completaron un cuestionario, seguido de una evaluación del crecimiento y desarrollo de los niños. Los datos obtenidos fueron analizados. De los 70 niños, el 50,00% (n = 17) y el 51,43% (n = 18) de los niños y niñas eran bajos para su edad, respectivamente. Para el desarrollo psicosocial, de las 284 pruebas realizadas, el 86,27% (n = 245) fueron realizadas íntegramente por los niños. Se observó una asociación significativa entre la gestante haber concebido a su hijo con al menos 9 meses de gesta- ción y tener una adecuada relación Peso/Edad y Talla/Edad. Hubo asociación significativa entre el niño que no ingiere gaseosas en polvo y presentar una adecuada relación Peso/Edad. Se concluyó que los niños tenían una edad gestacional adecuada y un estado nutricional adecuado, a pesar de su baja talla para su edad. Presentaron un desarrollo psi- cosocial, lingüístico y físico normal. En cuanto a los factores de riesgo, estos involucraron los de naturaleza materna y el consumo de alimentos cariogénicos.

The composition of human vaginal microbiota transferred at birth affects offspring health in a mouse model.

Newborns are colonized by maternal microbiota that is essential for offspring health and development. The composition of these pioneer communities exhibits individual differences, but the importance of this early-life heterogeneity to health outcomes is not understood. Here we validate a human microbiota-associated model in which fetal mice are cesarean delivered and gavaged with defined human vaginal microbial communities. This model replicates the inoculation that occurs during vaginal birth and reveals lasting effects on offspring metabolism, immunity, and the brain in a community-specific manner. This microbial effect is amplified by prior gestation in a maternal obesogenic or vaginal dysbiotic environment where placental and fetal ileum development are altered, and an augmented immune response increases rates of offspring mortality. Collectively, we describe a translationally relevant model to examine the defined role of specific human microbial communities on offspring health outcomes, and demonstrate that the prenatal environment dramatically shapes the postnatal response to inoculation.

Intermembrane distances at the feto-maternal interface in epitheliochorial placentation.

INTRODUCTION: In an epitheliochorial placenta, the apical membranes of trophoblast cells and of uterine epithelial cells are in contact to each other (feto-maternal contact). In addition, there are also folds in which the trophoblast membrane is in contact with itself (feto-fetal contact) and areas where apical uterine epithelial membrane is in contact with itself (materno-maternal contact). METHODS: We use transmission electron microscopy of placental samples from pigs. (n = 3), cows (n = 2), sheep (n = 2), goat (n = 2) and roe deer (n = 1) to study the intermembrane distance in these three contact types. RESULTS: The measured intermembrane distances vary between 8 and 25 nm. One common feature is that the distance at feto-fetal contact sites is about 6-10 nm wider than at materno-maternal sites and feto-maternal sites show intermediate values. DISCUSSION: This finding suggests that the membrane distance at feto-maternal contact sites is determined by heterophilic binding of larger fetal to smaller maternal binding molecules. Homophilic binding of smaller maternal or larger fetal molecules lead to the smaller or wider intermembrane distances at materno-maternal or feto-fetal contact sites respectively. The observation that this similar pattern of membrane distances is present in pigs and in ruminants suggest that an evolutionary mechanism is involved in determining the intermembrane distance in epitheliochorial placentas.

Rhythm of Fetoplacental 11ß-Hydroxysteroid Dehydrogenase Type 2 - Fetal Protection From Morning Maternal Glucocorticoids.

CONTEXT: Excess glucocorticoids impact fetal health. Maternal glucocorticoids peak in early morning. Fetoplacental 11ß-hydroxysteroid dehydrogenase type 2 (11ß-HSD2) inactivates cortisol to cortisone, protecting the fetus from high glucocorticoids. However, time-specific alterations of human fetoplacental 11ß-HSD2 have not been studied. OBJECTIVE: We hypothesized that fetoplacental 11ß-HSD2 activity shows time-specific alteration and acute affective or anxiety disorders impact fetoplacental 11ß-HSD2 activity. METHODS: In this observational study we investigated 78 pregnant European women undergoing amniocentesis (15.9 ± 0.9 weeks of gestation). Amniotic fluid was collected (8:00 to 16:30 hours) for analysis of fetoplacental 11ß-HSD2 activity, using cortisol (F):cortisone (E) ratio in amniotic fluid, E/(E + F). Fetoplacental 11ß-HSD2 rhythm and association with "acute affective or anxiety disorder" (patients with at least one of: a major depressive episode, specific phobia, panic disorder, generalized anxiety disorder, mixed anxiety and depressive disorder) and "acute anxiety disorder" (one of: panic disorder, generalized anxiety disorder, mixed anxiety, depressive disorder), assessed using Mini International Neuropsychiatric Interview, were investigated. RESULTS: Activity of 11ß-HSD2 correlated with time of amniocentesis, peaking in the morning (r = -0.398; P < 0.001) and increased with acute affective or anxiety disorder (mean [M] = 0.70 vs M = 0.74; P = 0.037) and acute anxiety disorder (M = 0.70 vs M = 0.75; P = 0.016). These associations remained significant when controlling for confounders. 11ß-HSD2 activity correlated negatively with pre-pregnancy body mass index (r = -0.225; P = 0.047). CONCLUSION: Our study indicates a time-specific alteration of fetoplacental 11ß-HSD2 activity with peaking levels in the morning, demonstrating a mechanism of fetal protection from the morning maternal glucocorticoid surge.

Bovine peripheral blood MSCs chemotax towards inflammation and embryo implantation stimuli.

Mesenchymal stem cells (MSCs) have a great potential in regenerative medicine because of their multipotential and immunoregulatory capacities, while in early pregnancy they could participate in the immunotolerance of the mother towards the embryo. Peripheral blood constitutes an accessible source of MSCs. We successfully isolated peripheral blood MSC (pbMSCs) lines, with or without previous bone marrow mobilization. All pbMSCs lines obtained in both conditions presented classical MSC markers and properties, alkaline phosphatase activity and multipotent capacity to differentiate among adipogenic, osteogenic or chondrogenic lineages, and suppressed the proliferation of T cells. pbMSCs showed migratory capacity without cytokine stimulation while increasing their migration rate in the presence of inflammatory or embryo implantation stimuli. Interestingly, in contrast to MSCs derived from endometrial tissue, three pbMSCs lines also showed increased migration towards the IFN-τ implantation cytokine. Moreover, the secretome produced by an early implantation stage embryonic trophectoderm cell line showed a chemoattractant effect in pbMSCs. Our results suggest that circulating MSCs are present in the peripheral blood under healthy conditions. The fact that both the inflammation and implantation signals induced pbMSCs chemotaxis highlights MSC heterogeneity and suggests that their migratory capacity may differ according to their tissue of origin and would suggest the possible active recruitment of MSCs from bone marrow during pregnancy to repress the immune response to prevent the embryo rejection by the maternal organism.

Impact of exosome-mediated feto-maternal interactions on pregnancy maintenance and development of obstetric complications.

Pregnancy is an immunological paradox, a phenomenon in which the foetus and the placenta, containing foreign antigens to the mother, develop without inducing rejection by the maternal immune system. Cell-to-cell communication between the foetus and the mother is mediated by secreted factors such as cytokines, hormones and extracellular vesicles (EVs) for a successful pregnancy and to avoid rejection. Exosomes, the smallest of EVs, are released extracellularly, where they are taken up by proximal or distant recipient cells. Here, we discuss the role of EVs, especially exosomes in feto-maternal communication during pregnancy. This review will provide an overview of the functional roles exosomes may play during embryo implantation, modulating immune responses during pregnancy and the onset of labour. Moreover, we will discuss exosomal function in obstetric pathology, and the development of pregnancy-associated complications such as preeclampsia and preterm birth as well as the biomarker potential of exosomes for detecting such conditions.

NK and T Cell Differentiation at the Maternal-Fetal Interface in Sows During Late Gestation.

The phenotype and function of immune cells that reside at the maternal-fetal interface in humans and mice have been, and still are, extensively studied with the aim to fully comprehend the complex immunology of pregnancy. In pigs, information regarding immune cell phenotypes is limited and mainly focused on early gestation whereas late gestation has not yet been investigated. We designed a unique methodology tailored to the porcine epitheliochorial placenta, which allowed us to address immune phenotypes separately in the maternal endometrium (ME) and fetal placenta (FP) by flow cytometry. In-depth phenotyping of NK cells, non-conventional and conventional T cells within maternal blood (mBld), ME, FP, and fetal spleen (fSpln) revealed major differences between these anatomic sites. In both maternal compartments, all NK cells were perforin+ and had NKp46-defined phenotypes indicative of late-stage differentiation. Likewise, T cells with a highly differentiated phenotype including CD2+CD8α+CD27dim/-perforin+ γδ T cells, CD27-perforin+ cytolytic T cells (CTLs), and T-bet+ CD4+CD8α+CD27- effector memory T (Tem) cells prevailed within these compartments. The presence of highly differentiated T cells was also reflected in the number of cells that had the capacity to produce IFN-γ. In the FP, we found NK cells and T cell populations with a naive phenotype including CD2+CD8α-CD27+perforin- γδ T cells, T-bet-CD4+CD8α-CD27+ T cells, and CD27+perforin- CTLs. However, also non-naive T cell phenotypes including CD2+CD8α+CD27+perforin- γδ T cells, T-bet+CD4+CD8α+CD27- Tem cells, and a substantial proportion of CD27-perforin+ CTLs resided within this anatomic site. Currently, the origin or the cues that steer the differentiation of these putative effector cells are unclear. In the fSpln, NKp46high NK cells and T cells with a naive phenotype prevailed. This study demonstrated that antigen-experienced immune cell phenotypes reside at the maternal-fetal interface, including the FP. Our methodology and our findings open avenues to study NK and T cell function over the course of gestation. In addition, this study lays a foundation to explore the interplay between immune cells and pathogens affecting swine reproduction.

Embryo-Maternal Interactions Underlying Reproduction in Mammals.

This Special Issue, "Embryo-Maternal Interactions Underlying Reproduction in Mammals", gathers a collection of 23 articles, 16 original research articles and 7 up-to-date reviews, providing new findings or summarizing current knowledge on embryo-maternal interactions in seven different mammalian species including humans. Considering the different players involved in these embryo-maternal interactions, articles are mainly focused on one of these different players: the oviduct, the uterus, the embryo or the emergent extracellular vesicles. Additionally, a few articles bring up the impact of reproductive, but also non-reproductive, diseases, as well as stress factors, on the establishment of pregnancy. We hope the readers enjoy this collection of articles and that the knowledge assembled here will support and inspire current and future research investigations. We would like to thank all authors for their contributions to this Special Issue.

Molecular regulation of vascular smooth muscle cell phenotype switching by trophoblast cells at the maternal-fetal interface.

INTRODUCTION: Establishment of hemochorial placenta is associated with development and remodelling of uterine vasculature at the maternal fetal interface. This results in calibration of high resistance uterine arteries to flaccid low resistance vessels resulting in increased blood flow to the placenta and fetus in humans and rodents. Mechanisms underlying these remodelling events are poorly understood. In this report, we examine regulation of vascular remodelling using vascular smooth muscle cell (VSMC) phenotype switching as a primary parameter. METHODS: Cellular dynamics was assessed by Immunofluorescence, qRT-PCR, western blotting in timed pregnant rat tissue. In vitro co-culture of trophoblast cells with vascular smooth muscle cells was used to understand regulation mechanism. RESULTS: Analysis of cellular dynamics on days 13.5, 16.5 and 19.5 of gestation in the rat metrial gland, the entry point of uterine arteries, revealed that invasion of trophoblast cells preceded disappearance of VSMC α-SMA, a contractile state marker. Co-culture of VSMCs with trophoblast cells in vitro recapitulated trophoblast-induced de-differentiation of VSMCs in vivo. Interestingly, co-culturing with trophoblast cells activated PDGFRß signalling in VSMCs, an effect mediated by secreted PDGF-BB from trophoblast cells. Trophoblast cells failed to elicit its effect on VSMC de-differentiation upon inhibition of PDGFRß signalling using a selective inhibitor. Moreover, co-culturing with trophoblast cells also led to substantial increase in Akt activation and a modest increase in Erk phosphorylation in VSMCs and this effect was abolished by PDGFRß inhibition. DISCUSSION: Our results highlight that trophoblast cells direct VSMC phenotype switching and trophoblast derived PDGF-BB is one of the modulator.

Relationship Between Pregnancy and Acute Disseminated Encephalomyelitis: A Single-Case Study.

The relationship between pregnancy and autoimmune diseases is unclear. This study investigated the possible role of local immune changes and the activation state of the HMGB1/TLR4/Nf-κB/IL-6 pathway at the maternal-fetal interface during pregnancy in the pathogenesis of acute disseminated encephalomyelitis (ADEM). Clinical data and blood samples of a patient with ADEM were collected to observe the dynamic changes in lymphocyte populations after an abortion. The expression of HMGB1, TLR4, Nf-κB, AQP4, IL-2, IL-4, IL-6, and TNF-α in the fetal membrane and placenta was compared between the patient with pregnancy-related ADEM and a woman with a normal pregnancy using Real-time qPCR and western blotting (WB). The patient was diagnosed with ADEM in the early stage of pregnancy after showing limb weakness symptoms. In the third month of gestation, the symptoms worsened, with a disturbance of consciousness and breathing. After the abortion, the patient relapsed with vertigo and visual rotation. Analysis of lymphocyte subsets by flow cytometry showed that B lymphocytes increased, while natural killer T lymphocytes decreased. WB and Real-time qPCR showed that the expression levels of HMGB1, TLR4, Nf-κB, AQP4, and IL-6 in the fetal membrane and placenta were higher in the patient with pregnancy-related ADEM than in the woman with a normal pregnancy, while those of IL-2 were lower in the patient than in the woman with a normal pregnancy. The local immune changes and the activation of the HMGB1/TLR4/Nf-κB/IL-6 pathway at the maternal-fetal interface may be related to the pathogenesis of ADEM.

Measuring the Outcomes of Maternal COVID-19-related Prenatal Exposure (MOM-COPE): study protocol for a multicentric longitudinal project.

INTRODUCTION: COVID-19 is a highly infectious respiratory disease that rapidly emerged as an unprecedented epidemic in Europe, with a primary hotspot in Northern Italy during the first months of 2020. Its high infection rate and rapid spread contribute to set the risk for relevant psychological stress in citizens. In this context, mother-infant health is at risk not only because of potential direct exposure to the virus but also due to high levels of stress experienced by mothers from conception to delivery. Prenatal stress exposure associates with less-than-optimal child developmental outcomes, and specific epigenetic mechanisms (eg, DNA methylation) may play a critical role in mediating this programming association. METHODS AND ANALYSIS: We present the methodological protocol for a longitudinal, multicentric study on the behavioural and epigenetic effects of COVID-19-related prenatal stress in a cohort of mother-infant dyads in Northern Italy. The dyads will be enrolled at 10 facilities in Northern Italy. Saliva samples will be collected at birth to assess the methylation status of specific genes linked with stress regulation in mothers and newborns. Mothers will provide retrospective data on COVID-19-related stress during pregnancy. At 3, 6 and 12 months, mothers will provide data on child behavioural and socioemotional outcomes, their own psychological status (stress, depressive and anxious symptoms) and coping strategies. At 12 months, infants and mothers will be videotaped during semistructured interaction to assess maternal sensitivity and infant's relational functioning. ETHICS AND DISSEMINATION: This study was approved by the Ethics Committee (Pavia). Results will be published in peer-reviewed journals and presented at national and international scientific conferences. TRIAL REGISTRATION NUMBER: NCT04540029; Pre-results.

Factores maternos y fetales asociados a la inducción del trabajo de parto, Hospital Vicente Corral Moscoso, Cuenca 2019 / Maternal and fetal factors associated with induction of labor, Hospital Vicente Corral Moscoso, Cuenca 2019

Antecedentes: La inducción del parto es una práctica frecuente en obstetricia, observándose un aumento de sus cifras en las últimas décadas a nivel mundial. Objetivo: Determinar los factores maternos y fetales asociados a la inducción del parto en pacientes hospitalizadas en el departamento de Ginecología y Obstetricia del hospital Vicente Corral Moscoso, Cuenca, 2019. Métodos: Estudio analítico realizado a 208 gestantes ingresadas en el área de Ginecología y Obstetricia. La información se procesó en el programa SPSS versión 15. Para el análisis utilizamos estadística descriptiva en base a frecuencias y porcentajes, se midió la asociación estadística con la prueba Chi 2 y Razón de Prevalencia (RP), intervalo de confianza 95%, considerando estadísticamente significativo p < 0,05. Resultados: La edad media fue 24,7 (DS± 5,93), predominó la instrucción secundaria, estado civil estable. Hubo asociación y significancia estadística de factores materno fetales a inducción como: ruptura prematura de membranas RP 2,97 (IC95%: 2,09­4,24 valor p 0,000); preeclampsia RP 2,13 (IC95%: 1,46­3,10 valor p 0,000); embarazo término tardío RP 2,91 (IC95%: 2,12­3,99 valor p 0,000); restricción del crecimiento RP 3,22 (IC95%: 2,62-3,95 valor p 0,000). No así para corioamnionitis RP 3,08 (IC95%: 2,53­3,76 valor p 0,33) y muerte fetal RP 1,55 (IC95%: 0,68­3,54 valor p 0,31). Conclusiones: Se encontró asociación y significancia estadística con factores materno fetales e inducción como: ruptura prematura de membranas, preeclampsia, embarazo término tardío, restricción del crecimiento. No para corioamnionitis y muerte fetal.

Background: Induction of labor is a frequent practice in obstetrics, with an increase in its numbers being observed in recent decades worldwide. Objective: To determine the maternal and fetal factors associated with labor induction in hospitalized patients in the Gynecology and Obstetrics department of the Vicente Corral Moscoso hospital, Cuenca, 2019. Methods: Analytical study carried out on 208 pregnant women admitted to the Gynecology and Obstetrics area who met the inclusion criteria. The information was processed in the SPSS version 15 program. For the analysis we used descriptive statistics based on frequencies and percentages, the statistical association was measured with the Chi 2 test and Prevalence Ratio (RP), 95% confidence interval, considering statistically significant p <0.05. Results: The mean age was 24.7 (SD ± 5.93), secondary education, stable marital status predominated. There was association and statistical significance of maternal-fetal factors to induction of labor such as: premature rupture of membranes RP 2.97 (95% CI: 2.09­4.24 p-value 0.000); preeclampsia RP 2.13 (95% CI: 1.46­3.10 p-value 0.000); late term pregnancy RP 2.91 (95% CI: 2.12­3.99 p-value 0.000); intrauterine growth restriction RP 3.22 (95% CI: 2.62-3.95 p-value 0.000). Not so for chorioamnionitis RP 3.08 (95% CI: 2.53­3.76 p value 0.33) and fetal death RP 1.55 (95% CI: 0.68­3.54 p value 0.31). Conclusions: There was an association and statistical significance with maternal-fetal factors associated with induction such as: premature rupture of membranes, pre-eclampsia, late-term pregnancy, intrauterine growth restriction. Not so for chorioamnionitis and fetal death.

Seasonality of antenatal care attendance, maternal dietary intake, and fetal growth in the VHEMBE birth cohort, South Africa.

BACKGROUND: Seasonality of food availability, physical activity, and infections commonly occurs within rural communities in low and middle-income countries with distinct rainy seasons. To better understand the implications of these regularly occurring environmental stressors for maternal and child health, this study examined seasonal variation in nutrition and health care access of pregnant women and infants in rural South Africa. METHODS: We analyzed data from the Venda Health Examination of Mothers, Babies and their Environment (VHEMBE) birth cohort study of 752 mother-infant pairs recruited at delivery from August 2012 to December 2013 in the Vhembe District of Limpopo Province, the northernmost region of South Africa. We used truncated Fourier series regression to assess seasonality of antenatal care (ANC) attendance, dietary intake, and birth size. We additionally regressed ANC attendance on daily rainfall values. Models included adjustment for sociodemographic characteristics. RESULTS: Maternal ANC attendance, dietary composition, and infant birth size exhibited significant seasonal variation in both unadjusted and adjusted analyses. Adequate frequency of ANC attendance during pregnancy (≥ 4 visits) was highest among women delivering during the gardening season and lowest during the lean (rainy) season. High rainfall during the third trimester was also negatively associated with adequate ANC attendance (adjusted OR = 0.59, 95% CI: 0.40, 0.86). Carbohydrate intake declined during the harvest season and increased during the vegetable gardening and lean seasons, while fat intake followed the opposite trend. Infant birth weight, length, and head circumference z-scores peaked following the gardening season and were lowest after the harvest season. Maternal protein intake and ANC ≤ 12 weeks did not significantly vary by season or rainfall. CONCLUSIONS: Seasonal patterns were apparent in ANC utilization, dietary intake, and fetal growth in rural South Africa. Interventions to promote maternal and child health in similar settings should consider seasonal factors.

Prepregnancy Obesity, Maternal Dietary Intake, and Oxidative Stress Biomarkers in the Fetomaternal Unit.

BACKGROUND: Obesity and pregnancy increase levels of maternal oxidative stress (OS). However, little is known about the maternal, placental, and neonatal OS status. OBJECTIVE: To analyze the relation between prepregnancy obesity and the expression of OS markers and antioxidant capacity in the fetomaternal unit and their association with dietary intake. METHODS: This cross-sectional study included 33 women with singleton, noncomplicated pregnancies. Two groups were formed: women with prepregnancy body mass index (pBMI) within normal range (18.5-24.9 kg/m2, n = 18) and women with pBMI ≥ 30 kg/m2, suggestive of obesity (n = 15). Dietary and clinical information was obtained by questionnaire and from clinical records. Total antioxidant capacity (TAC) and malondialdehyde (MDA) concentration were measured on maternal and cord serum by colorimetric techniques, and placental expression of glutathione peroxidase 4 (GPx4) was measured by immunohistochemistry. RESULTS: Placental GPx4 expression was lower in the group with pBMI suggestive of obesity than in the normal weight group (ß = -0.08, p = 0.03, adjusted for gestational age and magnesium intake). Concentrations of TAC and MDA in maternal and cord blood were not statistically different between groups (p>0.05). Cord MDA concentration was related to maternal MDA concentration (ß = 0.40, p < 0.01), vitamin A intake (tertile 2: ß = -0.04, p = 0.40, tertile 3: ß = 0.13, p = 0.03, vs tertile 1), and placental GPx4 expression (ß = -0.09, p = 0.02). CONCLUSION: Prepregnancy obesity is associated with a decrease in GPx4 expression in the placenta, which is related to OS in the newborn. The influence of micronutrient intake on OS biomarkers highlights the importance of nutritional assessment during pregnancy and adequate prenatal care.

The maternal-to-zygotic transition revisited.

The development of animal embryos is initially directed by maternal gene products. Then, during the maternal-to-zygotic transition (MZT), developmental control is handed to the zygotic genome. Extensive research in both vertebrate and invertebrate model organisms has revealed that the MZT can be subdivided into two phases, during which very different modes of gene regulation are implemented: initially, regulation is exclusively post-transcriptional and post-translational, following which gradual activation of the zygotic genome leads to predominance of transcriptional regulation. These changes in the gene expression program of embryos are precisely controlled and highly interconnected. Here, we review current understanding of the mechanisms that underlie handover of developmental control during the MZT.

Immune Checkpoint Molecules in Reproductive Immunology.

Immune checkpoint molecules, like CTLA-4, TIM-3, PD-1, are negative regulators of immune responses to avoid immune injury. Checkpoint regulators are thought to actively participate in the immune defense of infections, prevention of autoimmunity, transplantation, and tumor immune evasion. Maternal-fetal immunotolerance represents a real immunological challenge for the immune system of the mother: beside acceptance of the semiallogeneic fetus, the maternal immune system has to be prepared for immune defense mostly against infections. In this particular situation, the role of immune checkpoint molecules could be of special interest. In this review, we describe current knowledge on the role of immune checkpoint molecules in reproductive immunology.

Genetics of human female infertility†.

About 10% of women of reproductive age are unable to conceive or carry a pregnancy to term. Female factors alone account for at least 35% of all infertility cases and comprise a wide range of causes affecting ovarian development, maturation of oocytes, and fertilization competence, as well as the potential of a fertilized egg for preimplantation development, implantation, and fetal growth. Genetic abnormalities leading to infertility in females comprise large chromosome abnormalities, submicroscopic chromosome deletion and duplications, and DNA sequence variations in the genes that control numerous biological processes implicated in oogenesis, maintenance of ovarian reserve, hormonal signaling, and anatomical and functional development of female reproductive organs. Despite the great number of genes implicated in reproductive physiology by the study of animal models, only a subset of these genes is associated with human infertility. In this review, we mainly focus on genetic alterations identified in humans and summarize recent knowledge on the molecular pathways of oocyte development and maturation, the crucial role of maternal-effect factors during embryogenesis, and genetic conditions associated with ovarian dysgenesis, primary ovarian insufficiency, early embryonic lethality, and infertility.

Predictions of children's emotionality from evolutionary and epigenetic hypotheses.

Sex-dependent effects of mismatched prenatal-postnatal maternal conditions are predicted by combining two evolutionary hypotheses: that foetal conditions provide a forecast of likely postnatal environments (Predictive Adaptive Response), and that the female foetus is better adapted than the male to maternal adversity (Trivers-Willard hypothesis). Animal studies have implicated glucocorticoid mechanisms modifiable by effects of postnatal tactile stimulation on glucocorticoid receptor gene expression. In this study we examined behavioural predictions in humans based on these evolutionary and epigenetic models. Mothers in a general population cohort provided self-reported anxiety scores at 20 weeks pregnancy, and at 9 weeks, 14 months and 3.5 years postpartum, and frequency of infant stroking at 9 weeks. Mothers and teachers reported child symptoms at 7 years. SEM models with maximum-likelihood estimates made use of data from 887 participants. There was a three-way interaction between prenatal and postnatal anxiety and maternal stroking in the prediction of irritability, seen only in girls. This arose because lower maternal stroking was associated with higher irritability, only in the mismatched, low-high and high-low maternal anxiety groups. We provide evidence that mechanisms likely to have evolved well before the emergence of humans, contribute to the development of children's emotionality and risk for depression.