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The large intestine epithelium plays an important role in water absorption and participates in fluid, acid-base and electrolyte balance, and the removal of waste products. The large intestine is rich in microorganism-presented enzyme activity. Apart from energy supply, the colon also participates in the synthesis of trophic factors and the modulation of the immune system and the systemic inflammatory response. The current study investigated the effects of dietary HMB administration to pregnant sows on the postnatal development of the colon in their offspring, at weaning. From the 70th to the 90th day of gestation, sows received either a basal diet (n = 12) or the basal diet supplemented with HMB (n = 12) at a dose of 0.2 g/kg of body weight/day. Maternal HMB treatment increased serum IgG and glucose concentrations and decreased serum urea concentration in the piglets. Basal histomorphometric analysis of offspring large intestines showed that prenatal HMB treatment led to a reduction in the thickness of the mucosa, submucosa and both types of myenterons, as well as reduced crypt thickness. The immunoreaction performed to mark T0 lymphocytes and total T lymphocytes in the colon wall showed that prenatal HMB treatment decreased the number of both types of lymphocytes. Greater expression for cadherin was found in the colon of piglets delivered by the HMB-treated sows. The expression of both tight junction proteins (occludin and claudin-3), as well as that of leptin, was stronger in the HMB-treated group. Vasoactive intestinal peptide (VIP) expression was stronger in the submucosal plexuses in the HMB maternal treated piglets, while no changes were observed in the myenteric plexuses. The results obtained indicate that the administration of HMB to pregnant sows significantly influenced the expression of leptin, VIP and some proteins of the intestinal barrier in their offspring, with less influence on large intestine basal morphology.

ObjectiveChildhood trauma exacts a lasting toll on one's own mental health and the health of one's offspring; however, limited research has examined the pathways through which this intergenerational transmission occurs. This study aimed to identify the transactions and mechanisms that link maternal early life trauma, maternal depressive symptoms, and children's internalizing symptoms.MethodA pregnancy cohort of N=1462 mothers (66% Black, 32% White, 2% Other race) reported their childhood trauma exposure and depressive symptoms during pregnancy. Maternal depressive and children's internalizing symptoms were measured repeatedly when offspring were 12, 24, 36, and 48-60months of age. A path model tested the transactional associations between maternal and child symptomatology and mediation of maternal childhood trauma on offspring symptoms via maternal depressive symptoms.ResultsMothers' childhood trauma history was related to greater prenatal and postnatal (12 and 24months) maternal depressive symptoms, which were prospectively associated with offspring internalizing problems at 36 and 48-60months. Child-directed effects on maternal depressive symptoms were not observed. The association of maternal trauma on children's internalizing at 36months was mediated by maternal depressive symptoms at 24months.LimitationsAssessments of the key study variables were provided by mothers. Childhood trauma was evaluated retrospectively.ConclusionWomen's experiences of adversity in childhood have persistent and cumulative effects on their depression during the transition to parenthood, which is associated with risk for children's internalizing. Given the two-generation influence of maternal childhood trauma exposure, attending to its impact may protect both caregivers and their children.

Prenatal dexamethasone has been shown to increase blood pressure in male offspring but the mechanism for the increase in blood pressure is unclear. The present study examined if prenatal programming by maternal injection of dexamethasone on days 15 and 16 of gestation affected the blood pressure comparably in female and male offspring. Our hypothesis was that males would be affected by prenatal dexamethasone to a greater extent than females and that either an increase in renal tubular transporter abundance or an increase in renin or aldosterone system would be associated with hypertension with prenatal programming. Prenatal dexamethasone increased blood pressure at two months and six months of age and resulted in proteinuria and albuminuria at six months in male but not female rat offspring. There was no effect of prenatal dexamethasone on blood pressure and proteinuria at one month in male and in female offspring. While prenatal dexamethasone increased male renal thick ascending limb sodium potassium two chloride cotransporter protein abundance at two months, prenatal dexamethasone on days 15 and 16 of gestation did not affect transporter abundance in males at other ages, nor did it affect proximal tubule sodium/hydrogen exchanger or distal convoluted tubule sodium chloride cotransporter protein abundance at any age. There was no difference in systemic renin or aldosterone in the prenatal dexamethasone group compared to same sex controls. In conclusion, male but not female offspring have an increase in blood pressure and urinary protein excretion with prenatal dexamethasone. The increase in blood pressure with prenatal programming was not associated with a consistent increase in renal tubular transporter protein abundance, nor plasma renin activity and serum aldosterone.

Maternal adversity and prenatal stress confer risk for child behavioral health problems. Few studies have examined this intergenerational process across multiple dimensions of stress; fewer have explored potential protective factors. Using a large, diverse sample of mother-child dyads, we examined associations between maternal childhood trauma, prenatal stressors, and offspring socioemotional-behavioral development, while also examining potential resilience-promoting factors. The Conditions Affecting Neurocognitive Development and Learning and Early Childhood (CANDLE) study prospectively followed 1503 mother-child dyads (65% Black, 32% White) from pregnancy. Exposures included maternal childhood trauma, socioeconomic risk, intimate partner violence, and geocode-linked neighborhood violent crime during pregnancy. Child socioemotional-behavioral functioning was measured via the Brief Infant Toddler Social Emotional Assessment (mean age = 1.1 years). Maternal social support and parenting knowledge during pregnancy were tested as potential moderators. Multiple linear regressions (N = 1127) revealed that maternal childhood trauma, socioeconomic risk, and intimate partner violence were independently, positively associated with child socioemotional-behavioral problems at age one in fully adjusted models. Maternal parenting knowledge moderated associations between both maternal childhood trauma and prenatal socioeconomic risk on child problems: greater knowledge was protective against the effects of socioeconomic risk and was promotive in the context of low maternal history of childhood trauma. Findings indicate that multiple dimensions of maternal stress and adversity are independently associated with child socioemotional-behavioral problems. Further, modifiable environmental factors, including knowledge regarding child development, can mitigate these risks. Both findings support the importance of parental screening and early intervention to promote child socioemotional-behavioral health.

Accumulating evidence suggests that maternal exposure to objectively stressful events and subjective distress during pregnancy may have intergenerational impacts on children's mental health, yet evidence is limited. In a multisite longitudinal cohort (N = 454), we used multi-variable linear regression models to evaluate the predictive value of exposure to stressful events and perceived distress in pregnancy for children's internalizing problems, externalizing problems, and adaptive skills at age 4. We also explored two- and three-way interactions between stressful events, distress, and child sex. Both objective and subjective maternal stress independently predicted children's behavior, with more stressful events and higher distress predicting more internalizing and externalizing problems and worse adaptability; stress types did not significantly interact. There was some evidence that more stressful events predicted higher externalizing behaviors only for girls. Three-way interactions were not significant. The current findings highlight the importance of considering the type of stress measurement being used (e.g., counts of objective event exposure or subjective perceptions), suggest prenatal stress effects may be transdiagnostic, and meet calls for rigor and reproducibility by confirming these independent main effects in a relatively large group of families across multiple U.S. regions. Results point to adversity prevention having a two-generation impact and that pre- and postnatal family-focused intervention targets may help curb the rising rates of children's mental health problems.

ObjectiveMaternal health and wellness during pregnancy are associated with long-term health outcomes in children. The current study examined whether infants of women who participated in a mindfulness-based intervention during pregnancy that reduced levels of stress and depression, increased physical activity, and improved glucose tolerance differed on biobehavioral markers of psychopathological and physical health risk compared with infants of women who did not.MethodsParticipants were 135 mother-infant dyads drawn from a racially and ethnically diverse, low-income sample experiencing high stress. The women participated in an intervention trial during pregnancy that involved assignment to either mindfulness-based intervention or treatment-as-usual (TAU). Infants of women from both groups were assessed at 6 months of age on sympathetic (preejection period), parasympathetic (respiratory sinus arrhythmia), and observed behavioral (negativity and object engagement) reactivity and regulation during the still face paradigm. Linear mixed-effects and generalized linear mixed-effects models were used to examine treatment group differences in infant outcomes.ResultsRelative to those in the intervention group, infants in the TAU group showed a delay in sympathetic activation and subsequent recovery across the still face paradigm. In addition, infants in the intervention group engaged in higher proportions of self-regulatory behavior during the paradigm, compared with the TAU group. No significant effect of intervention was found for parasympathetic response or for behavioral negativity during the still face paradigm.ConclusionsFindings provide evidence that maternal participation in a short-term, group mindfulness-based intervention during pregnancy is associated with the early development of salutary profiles of biobehavioral reactivity and regulation in their infants. Because these systems are relevant for psychopathology and physical health, prenatal behavioral interventions may benefit two generations.

Modern developmental science is informed by several shared principles and adopts a lifespan approach that goes from infancy to senescence. Increasingly, disciplines outside psychology are adopting research frameworks (e.g., fetal origins, developmental origins of health and disease, first 1000 days) that prioritize prenatal experience as a driver of children's long-term health and developmental outcomes. Despite originating in medical literatures, these new frameworks share many of the core tenets of modern developmental theories. However, they also raise new questions and provoke a broader consideration of developmental influences, outcomes, and contexts. In this article, we describe these frameworks and consider how they align with, differ from, and inform modern developmental science.

The pregnancy period represents a unique window of opportunity to identify risks to both the fetus and mother and to deter the intergenerational transmission of adversity and mental health problems. Although the maternal–fetal dyad is especially vulnerable to the effects of stress during pregnancy, less is known about how the dyad is also receptive to salutary, resilience-promoting influences. The present review adopts life span and intergenerational perspectives to review four key areas of research. The first part describes how pregnancy is a sensitive period for both the mother and fetus. In the second part, the focus is on antecedents of maternal prenatal risks pertaining to prenatal stress response systems and mental health. The third part then turns to elucidating how these alterations in prenatal stress physiology and mental health problems may affect infant and child outcomes. The fourth part underscores how pregnancy is also a time of heightened fetal receptivity to maternal and environmental signals, with profound implications for adaptation. This section also reviews empirical evidence of promotive and protective factors that buffer the mother and fetus from developmental and adaptational problems and covers a sample of rigorous evidence-based prenatal interventions that prevent maladaptation in the maternal–fetal dyad before babies are born. Finally, recommendations elaborate on how to further strengthen understanding of pregnancy as a period of multilevel risk and resilience, enhance comprehensive prenatal screening, and expand on prenatal interventions to promote maternal–fetal adaptation before birth.

Becoming a mother is a fundamental life-transforming event characterized by high psychosocial distress. Most prenatal programming leaves women feeling unprepared for the realities of early parenthood. The purpose of this study was to design, implement, and evaluate a brief enhancement to existing prenatal programming, Welcome to Parenthood® (W2P). Using a single-group, longitudinal design, we implemented W2P with a community sample of 454 primiparous women via 11 Parent Link Centres in Alberta, Canada. The women completed questionnaires during late pregnancy, and 2 and 6 months postpartum to capture adverse childhood experiences (ACE), depressive symptoms (Edinburgh Postpartum Depression Scale; EPDS), and infant development (Ages and Stages Questionnaires; ASQs). Outcomes were compared with the naturalistic values from All Our Families community cohort from the same province and to the ASQ reference samples. By the end of W2P, depressive symptoms decreased significantly (p

Acrylamide (AA) is a chemical substance with a potentially carcinogenic effect. Its presence in food or animal food arises from its thermal processing. The experiment was conducted to evaluate the effect of AA exposure (3.0 mg/kg. b.w./day) of pregnant dams during the second half of the pregnancy on bone development in offspring. As an model animal, guinea pig was used. While term body weight of newborns was not influenced by maternal AA treatment, shorter bones with reduced bone diaphysis cross-sectional area were observed in experimental group. Numerous negative, offspring sex-dependent effects of maternal AA exposure were observed in femoral epiphysis and metaphysis as well as the articular and growth plate cartilages. These effects resulted from the AA-induced alterations in bone metabolism, as indicated by the changes in the expression of numerous proteins involved in bone development: receptor activator of nuclear factor kappa-Β ligand (RANKL), tissue inhibitor of metalloproteinases 2 (TIMP-2), bone morphogenetic protein 2 (BMP-2), vascular endothelial growth factor (VEGF), and cartilage oligomeric matrix protein (COMP), all of whose expression was measured as well as distribution of immature collagen fibres was determined. Based on the results, it can be concluded that the exposure of pregnant dams to AA negatively affected the structure of compact bone in bone diaphysis, microarchitecture of trabecular bone in metaphysis and epiphysis as well as the structure of the articular and growth plate cartilages in their offspring. The AA-induced bone impairment increased osteoclast differentiation, as observed through the change in the RANKL/OPG ratio, which in turn inhibited osteoblast function by decreasing the expression of other proteins. The data of the present study suggests that maternal AA exposure can result in insufficient bone gain and even bone loss after the birth.

Significant racial health disparities in infant mortality, preterm birth, and infant neurodevelopment exist in the United States. These disparities highlight a critical public health problem: Children of color are at a developmental disadvantage before birth. In this article, we describe how pregnant women from marginalized communities are disproportionately more likely to experience chronic stress in the form of discrimination, historical trauma, and acculturation. We integrate these understudied forms of chronic stress into allostatic load and prenatal programming models to describe how they can affect the health of two generations: the pregnant woman and her child. We describe psychophysiological ramifications of this early-life stress in infants of color. The prenatal programming field has largely ignored the experiences of women of color, and we highlight the need for researchers to include, or focus exclusively on, diverse samples in their research to reduce disparities that are evident at birth.

Maternal mental health problems during pregnancy, especially mood and anxiety disorders and symptoms, are common. They not only hinder maternal well-being and health during pregnancy but also are associated with physical and mental health adversities in the offspring. We provide here a review of the studies published between 2017 and 2019, which reported on the associations between maternal mental health problems during pregnancy and child neurocognitive outcomes. We identified eight studies, which reported a mixed pattern of findings. While the balance of evidence favors lack of associations, small sample sizes and heterogeneity in study designs, exposures, outcomes, and covariate adjustments between the studies preclude firm conclusions. The reviewed studies encourage further research filling in the knowledge gaps we identified.

Prenatal smoke exposure (PSE) is associated with reduced birth weight, impaired fetal development, and increased risk for diseases later in life. Changes in DNA methylation may be involved, as multiple large-scale epigenome-wide association studies showed that PSE is robustly associated with DNA methylation changes in blood among offspring in early life. Insulin-like growth factor-1 (IGF1) is important in growth, differentiation, and repair processes after injury. However, no studies investigated the organ-specific persistence of PSE-induced methylation change of Igf1 into adulthood. Based on our previous studies on the PSE effect on Igf1 promoter methylation in fetal and neonatal mouse offspring, we now have extended our studies to adulthood. Our data show that basal Igf1 promoter methylation generally increased in the lung but decreased in the liver (except for 2 persistent CpG sites in both organs) across three different developmental stages. PSE changed Igf1 promoter methylation in all three developmental stages, which was organ and sex specific. The PSE effect was less pronounced in adult offspring compared with the fetal and neonatal stages. In addition, the PSE effect in the adult stage was more pronounced in the lung compared with the liver. For most CpG sites, an inverse correlation was found for promoter methylation and mRNA expression when the data of all three stages were combined. This was more prominent in the liver. Our findings provide additional evidence for sex- and organ-dependent prenatal programming, which supports the developmental origins of health and disease (DOHaD) hypothesis.

It is increasingly being postulated that among-individual variation in mitochondrial function underlies variation in individual performance (e.g. growth rate) and state of health. It has been suggested (but not adequately tested) that environmental conditions experienced before birth have been suggested to programme postnatal mitochondrial function, with persistent effects potentially lasting into adulthood. We tested this hypothesis in an avian model by experimentally manipulating prenatal conditions (incubation temperature and stability), then measuring mitochondrial aerobic metabolism in blood cells from the same individuals during the middle of the growth period and at adulthood. Mitochondrial aerobic metabolism changed markedly across life stages, and part of these age-related changes were influenced by the prenatal temperature conditions. A high incubation temperature induced a consistent and long-lasting increase in mitochondrial aerobic metabolism. Postnatal mitochondrial aerobic metabolism was positively associated with oxidative damage on DNA but not telomere length. While we detected significant within-individual consistency in mitochondrial aerobic metabolism across life-stages, the prenatal temperature regime only accounted for a relatively small proportion (

This study is part of a coordinated-multicentre Project, funded by the Ministerio deEconomia y Competitividad (PI08/0208; PI11/00325; PI14/00612), Instituto de Salud Car-los III–Fondo Europeo de Desarrollo Regional, Union Europea, Una manera de hacer Eu-ropa, Centro de Investigacion Biomedica en Red de salud Mental, CIBERSAM, by theCERCA Programme/Generalitat de Catalunya and Secretaria d’Universitats i Recerca delDepartament d’Economia I Coneixement (2017SGR1355), Departament de Salut de laGeneralitat de Catalunya, en la convocatoria corresponent a l’any 2017 de concessio desubvencions del Pla Estrategic de Recerca i Innovacio en Salut (PERIS) 2016-2020,modalitat Projectes de recerca orientats a l’atencio primaria, amb el codi d’expedientSLT006/17/00345

BACKGROUND Many pregnant women are consuming diets of poor overall quality. Although many studies have linked poor prenatal diet quality to an increased risk of specific diseases in offspring, it is not known if exposure to poor prenatal diet affects core neurophysiological regulatory systems in offspring known to lie upstream of multiple diseases. OBJECTIVE We aimed to examine the association between prenatal diet quality and autonomic nervous system (ANS) function in infants at 6 mo of age. METHODS Data from 400 women (aged >18 y, with uncomplicated pregnancies) and their infants participating in the Maternal-Infant Research on Environmental Chemicals-Infant Development cohort were used to investigate links between prenatal diet quality and infant ANS function at 6 mo of age. Prenatal diet quality was assessed using the Healthy Eating Index (2010), calculated from a validated FFQ completed by women during the first trimester. Infant ANS function was measured using 2 assessments of heart rate variability (HRV) including root mean square of successive differences (RMSSD) and SD of N-N intervals (SDNN). Associations were analyzed before and after adjustment for socioeconomic status, maternal depression symptoms, maternal cardiometabolic dysfunction, breastfeeding, and prenatal smoking. RESULTS Poorer prenatal diet quality was associated with lower infant HRV assessed using RMSSD (B: 0.07; 95% CI: 0.01, 0.13; R2 = 0.013) and SDNN (B: 0.18; 95% CI: 0.02, 0.35; R2 = 0.011). These associations remained significant after adjustment for confounding variables [RMSSD: B: 0.09; 95% CI: 0.003, 0.18; squared semipartial correlation (sp2) = 0.14 and SDNN B: 0.24; 95% CI: 0.0, 0.49; sp2 = 0.13]. CONCLUSIONS In a large cohort study, poorer prenatal diet quality was associated with lower offspring HRV, a marker of decreased capacity of the ANS to respond adaptively to challenge. Therefore, poor prenatal diet may play a significant role in the programming of multiple organ systems and could increase general susceptibility to disease in offspring.

Although shyness is a ubiquitous phenomenon with early developmental origins, little research has examined the influence of prenatal exposures on the developmental trajectory of shyness. Here, we examined trajectories of shyness from childhood to adulthood in three groups (N= 254), with varying degrees of prenatal adversity as indicated by the number of stressful exposures: extremely low birth weight (ELBW; n= 56); ELBW survivors not prenatally exposed to exogenous corticosteroids (ELBW+NS,n= 56); and normal birth weight (NBW,n= 142) controls. Multilevel modeling revealed that the ELBW+S individuals exhibited the highest levels of childhood shyness, which remained stable into adulthood. The ELBW+NS and NBW controls had comparably low levels of childhood shyness; however, the ELBW+NS individuals experienced patterns of increasing shyness, while NBW controls displayed decreases in shyness into adulthood. We speculate that individuals exposed to multiple prenatal stressors (i.e., ELBW+S) may be developmentally programmed to be more sensitive to detecting social threat, with one manifestation being early developing, stable shyness, while increasing shyness among ELBW+NS individuals may reflect a later developing shyness influenced by postnatal context. We discuss the implications of these findings for understanding the developmental origins and developmental course of human shyness from childhood through adulthood.

The experiment was undertaken to assess whether the continuation or change of the parents’ diet affects the previously programmed bone metabolism of the male offspring during its growth and development. A total of 16 male and 32 female Wistar rats were divided into groups and fed a standard (diet S) or high-energy (diet F). After the induction of obesity, the rats from groups S and F, as the parent generation, were used to obtain male offspring, which were kept with their mothers until the weaning day (21 days of age). In our earlier study, we documented the programming effects of the diet used in parents on the skeletal system of offspring measured on the weaning day. Weaned male offspring constitute one control group—parents and offspring fed the S diet. There were three experimental groups, where: parents received diet S and offspring were fed with the F diet; parents were treated with the diet F, while offspring received the S diet; and parents and offspring were fed with the diet F. The analyses were performed at 49 and 90 days of life. After sacrifice, cleaned-off soft tissue femora were assessed using peripheral quantitative computed tomography (pQCT), dual X-ray absorptiometry (DXA), and a three-point bending test. We observed that changing and continuation of nutrition, applied previously in parents, significantly influenced the metabolism of the bone tissue in male offspring, and the osteotropic effects differed, depending on the character of the nutrition modification and age. Additionally, an important conclusion of our study, regarding the previous, is that nutrition modification, affecting the metabolism of bone tissue, also depends on the sex.

Background Altered hypothalamic-pituitary-adrenal axis (HPA) functioning is one of the potential mechanisms bridging exposure to maternal prenatal psychological distress (PPD) and later risk for offspring psychiatric illness. Research on infant cortisol stress reactivity, on scarcely studied recovery and their associations with maternal PPD is needed to clarify these mechanisms. Knowledge on sex differences in prospective settings is largely lacking. We aimed at filling these gaps by building upon our previous report showing that exposure to maternal prenatal depressive and anxiety symptoms associates with slower cortisol recovery among 10-week-old female infants. Methods In all, 363, 205 and 263 infants at 10 weeks, six and 14 months of age from the FinnBrain Birth Cohort Study participated in a stress test comprising of venipuncture and nasopharynx sampling. Five saliva cortisol samples were collected during each visit to measure cortisol reactivity and recovery. PPD was assessed from maternal self-reports for depressive, anxiety and pregnancy-related anxiety symptoms at gestational weeks 14, 24 and 34. Results An 11% enhanced recovery among 14-month-old females was associated with higher depressive and anxiety symptoms (95% CI=1-23%) and pregnancy-related anxiety symptoms (2-21%). No alterations in the female cortisol reactivity or male cortisol stress responses were observed. Conclusions The opposite directions in the associations between the PPD exposure and infant cortisol recovery among 10-week-old and 14-month-old females suggest sex- and age-dependent associations between HPA axis functioning and PPD exposure among healthy infants. Follow-up is needed to characterize the impact of this altered negative feedback mechanism on later health.

To improve care for the estimated 17.1 million children with psychiatric disorders in the United States (1), it is critical to explore all possible connections to better understand these disorders' origins. The onset of neurodevelopmental/psychiatric disorders varies person-to-person. However, even for disorders diagnosed after infancy, there is a growing appreciation that the origins of these disorders are at the earliest stages of brain development—prenatally. Furthermore, not only is it crucial to understand what is unusual during development, but also why this occurs. A significant contributor to abnormal prenatal brain development is physiological stress during pregnancy (2–6). Physiological stress induces a significant shift from homeostasis, and may arise from chemical exposures, psychological stress, infections, and illnesses such as preeclampsia or gestational diabetes. Epidemiological studies link maternal stress with offspring neurodevelopmental impairments (2), and animal studies have demonstrated causality of this relationship. For example, preeclampsia—a disorder with disrupted maternal vascular and immune biology—increases risk of neuropsychiatric problems among children (3). Evidence has come from human and non-human preeclampsia studies implicating what in the offspring brain has changed: its morphology, white matter, and vasculature. When we ask the further question of why these changes occur with preeclampsia or any maternal stress, it is critical to consider the biology of not only mother and offspring but also their link—the placenta. Changes in placenta may be a critical factor for offspring neurodevelopment (Figure 1). Open in a separate window Figure 1 Examples of placental mechanisms as the link between maternal physiological stressors and offspring brain outcomes.

Decades of research indicate that individuals exposed to childhood adversity are at risk for poor physical and mental health across their life span. More recently, intergenerational transmission of trauma and prenatal programming frameworks suggest an even longer reach for adverse childhood experiences (ACEs), with consequences that extend to subsequent generations. Beyond the individual-level consequences typically observed by empirical studies of ACEs, mothers' experiences of early adversity may also compromise the maternal-child dyadic relationship. We propose a conceptual model whereby mothers' ACEs impact maternal-infant dyadic functioning and later biobehavioral health outcomes through heightened perinatal psychosocial risk. We provide support for the proposed paths and mechanistic processes in our model with data drawn from Las Madres Nuevas, a longitudinal study of low-income Mexican-origin families who participated in a series of home and laboratory visits from the prenatal period through early childhood. Higher ACEs exposure among Las Madres Nuevas participants was associated with numerous perinatal psychosocial risk factors, which predicted poorer mother-infant dyadic functioning. Compromised dyadic functioning during infancy was associated with later maternal mental health and child behavior problems. We conclude with discussion of prevention and treatment strategies that can buffer against proposed risk pathways, including perinatal assessment of maternal ACEs and psychosocial risk, perinatal treatment of maternal distress, and mother-infant therapy in the postpartum period. It is our hope that the proposed conceptual model will serve as a guide for future research to examine the lasting consequences of childhood adversities within and across generations among high-risk populations. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Natural disasters have detrimental effects not only on local infrastructure in an affected population but may also have an impact on the human biological condition, particularly during critical periods of life. This study aimed to assess the nutritional and weight status of women and their children who had experienced cyclone Aila prenatally and postnatally in comparison with a non‐affected neighbouring group. The study sample involved N = 597 dyads consisting of mothers and their prepubertal children prenatally or postnatally (during infancy) exposed to a natural disaster and a control group from a neighbouring region (West Bengal, India). The analysed anthropometric indices involved body mass index (BMI) and mid‐upper arm circumference (MUAC). Moreover, several socioeconomic characteristics were collected (mother's and father's education, family size and family income). Analyses revealed that the group factor (Aila‐exposed or non‐exposed groups) had the highest impact on both children's and their mothers' BMI and MUAC (p

Prenatal maternal stress is highly prevalent and predicts many child psychopathologies. Here, we apply the fetal programming hypothesis as an organizational framework to address the possibility that exposure to maternal stress during pregnancy affects fetal neurodevelopmental pathways that enhance risk for subsequent psychopathology. This chapter evaluates the empirical literature assessing the ontogenetic influences of prenatal maternal stress on child brain maturation. We conducted a systematic review investigating prenatal stress broadly defined and any direct measure of brain development including electroencephalography (EEG) and event-related potential (ERP), structural and functional magnetic resonance imaging (MRI), and diffusion tensor imaging (DTI). Lastly, we propose the following areas as promising avenues of future research to further elucidate the underlying etiology of such findings: investigation of sex/gender specific mechanisms, genetic interactions, pre- and postnatal effects, and opportunities for intervention.

ObjectivesTo examine the association between prenatal stress and infant physical health in the first year of life within an understudied, racially and ethnically diverse, highly stressed community sample. We expected that greater stress exposure would predict higher rates of infant illness.Study designLow-income, racially/ethnically diverse, overweight women with low medical risk pregnancies were recruited (2011-2014) during pregnancy. Pregnancy Stressful Life Events were assessed retrospectively (mean, 11.88months postpartum). Perceived stress was assessed twice during pregnancy (at a mean of 17.4weeks and again at a mean of 25.6weeks) and at 6months postpartum. Women with live births (n=202) were invited; 162 consented to the offspring study. Medical records from pediatric clinics and emergency departments for 148 infants were abstracted for counts of total infectious illnesses, total noninfectious illness, and diversity of illnesses over the first year of life.ResultsThe final analytic sample included 109 women (mean age, 28.08years) and their infants. In covariate-adjusted negative binomial models, maternal perceptions of stress across pregnancy were positively associated with infant illness. Each 1-point increase in average stress was associated with a 38% increase in incidence of infant infections (Incidence rate ratio, 1.38; 95% CI, 1.01-1.88; P&nbsp

Individual differences in risk for neuropsychiatric disorders are shaped before the individual is born. In this chapter, we summarize existing evidence from animal and human studies describing prenatal programming in the fetus and placenta in response to prenatal maternal stress, and associated outcomes seen in offspring neurobehavioral development and risk for psychopathology. First, we review fetal neurobehavioral development and assessment, including fetal physiological monitoring and fetal neuroimaging. We then highlight extant research on associations between fetal neurobehavior and later outcomes. Emerging research also points to the involvement of the placenta, which regulates the prenatal environment. We continue by describing how maternal stress can disrupt the placenta’s fundamental functions, highlighting the role of nutrient transfer, placental barrier permeability, serotonin signaling, and epigenetic changes to placental genes. We close by discussing the importance of sex differences in fetal and placental programming as well as developmental timing of exposures, and future directions for research.

For all lives regardless of sex, the longitudinal increase in blood pressure (BP) with age is attributed to lifestyle, internal environments like systemic brain-derived neurotrophic factor (BDNF) signaling, and external environments, allowing the individuals to better adapt to the developmental and environmental changes. Basic levels of renin-angiotensin-aldosterone system (RAAS) components in males and females define the fundamental sex difference in BP, which may be set by prenatal programming and the profound influence of BP after birth. The innate sex difference in BP is magnified during puberty growth and later on, affected and modified by menopause in women. At the age of 70 and older, blood pressure has been found to be similar for men and women. Understanding the prenatal setup and development of sexual dimorphism in BP may provide preventative therapeutic strategies, including timing and choice of drugs, for individuals with abnormal BP.

The development of attachment has its roots in prenatal experiences. The primal period of life (from conception to the end of the first year) is characterized by eight critical stages, each stage having its own developmental crisis. Preconception, conception, implantation, the discovery stage, and umbilical affect are the prenatal stages described here. Birth and imprinting moment are perinatal stages; psychological birth is the postnatal stage, ending the primal period. The development of the internal working model of attachment is driven by three fundamental processes: embryonic imprinting, fetal programming, and postnatal interactions. Attachment-oriented psychotherapy should include not only the postnatally developed attachment patterns but also the prenatally developed survival patterns and embryonic imprints. The neurosequential development of the brain and its functions should be respected. Secure attachment is linked with a safe prenatal life. Insecure-ambivalent attachment is linked to sympathetic fight/flight pattern programmed by traumatic prenatal experiences. Insecure-avoidant attachment is based on life-threatening prenatal shock, leading to parasympathetic reactions.

Studies of low birth weight offspring have a long history in pig science. These pigs have reduced growth potential and poor carcass quality compared to their higher birth weight littermates. In contemporary commercial sows with between 10 and 15 total pigs born/litter, between-litter differences in average birth weight appear to make the largest contribution to variation in postnatal growth performance, independent of numbers born. Low birth weight is a characteristic of a subpopulation of these sows, likely as a consequence of an imbalance between ovulation rate and uterine capacity due to ongoing selection for litter size. Based on experimental studies, we hypothesize that increased crowding at day 30 of gestation primarily affects placental development and persistent negative impacts on placental growth then affect fetal development. However, embryonic myogenic gene expression is already affected at day 30. Latent effects of metabolic state on oocyte quality and early embryonic development have also been reported. In contrast to effects of uterine crowding, the embryo is primarily affected by previous catabolism. The large body of literature on gene imprinting, and the interactions between metabolism, nutrition, and methylation state, suggest that classic imprinting mechanisms may be involved. However, the potential use of genomics, epigenomics, nutrigenomics, and proteomics to investigate these mechanisms brings new demands on experimental design and data management that present a considerable challenge to the effectiveness of future research on prenatal programming in the pig.

Polygenic risk scores for major depressive disorder (PRS-MDD) have been identified in large genome-wide association studies, and recent findings suggest that PRS-MDD might interact with environmental risk factors to shape human limbic brain development as early as in the prenatal period. Striatal structures are crucially involved in depression; however, the association of PRS-MDD with infant striatal volumes is yet unknown. In this study, 105 Finnish mother-infant dyads (44 female, 11-54 days old) were investigated to reveal how infant PRS-MDD is associated with infant dorsal striatal volumes (caudate, putamen) and whether PRS-MDD interacts with prenatal maternal depressive symptoms (Edinburgh Postnatal Depression Scale, gestational weeks 14, 24, 34) on infant striatal volumes. A robust sex-specific main effect of PRS-MDD on bilateral infant caudate volumes was observed. PRS-MDD were more positively associated with caudate volumes in boys compared to girls. No significant interaction effects of genotype PRS-MDD with the environmental risk factor "prenatal maternal depressive symptoms" (genotype-by-environment interaction) nor significant interaction effects of genotype with prenatal maternal depressive symptoms and sex (genotype-by-environment-by-sex interaction) were found for infant dorsal striatal volumes. Our study showed that a higher PRS-MDD irrespective of prenatal exposure to maternal depressive symptoms is associated with smaller bilateral caudate volumes, an indicator of greater susceptibility to major depressive disorder, in female compared to male infants. This sex-specific polygenic effect might lay the ground for the higher prevalence of depression in women compared to men.

During pregnancy, programming of the fetal central nervous system (CNS) establishes vulnerabilities for emergence of neuropsychiatric phenotypes later in life. Psychosocial influences during pregnancy, such as stressful life events or chronic stress, correlate with offspring neuropsychiatric disorders and with inflammation, respectively. Stress promotes inflammation, but the role of inflammation as a mediator between maternal psychosocial stress and offspring neuropsychiatric outcomes has not been extensively studied in humans. This review summarizes clinical evidence linking specific types of stress to maternal inflammatory load during pregnancy. We propose that inflammation is a mediator in the relationship between psychosocial stress and offspring neuropsychiatric outcomes, potentially influenced by poor maternal glucocorticoid-immune coordination. We present relevant experimental animal research supporting this hypothesis. We conclude that clinical and preclinical research support the premise that stress-induced maternal immune activation (MIA) contributes in part to prenatal programming of risk. Programming of risk is likely due to a combination of vulnerabilities, including multiple or repeated inflammatory events, timing of such events, poor maternal regulation of inflammation, genetic vulnerability, and lifestyle contributors.

Maternal nutrition is critically important for fetal development. Recent human studies demonstrate a strong connection between diet during pregnancy and offspring risk for neuropsychiatric disorders including depression, anxiety, and attention-deficit/hyperactivity disorder. Animal models have emerged as a crucial tool for understanding maternal nutrition's contribution to prenatal programming and the later development of neuropsychiatric disorders. This review highlights preclinical studies examining how maternal consumption of the three macronutrients (protein, fats, and carbohydrates) influence offspring negative-valence behaviors relevant to neuropsychiatric disorders. We highlight the translational aspects of animal models and so examine exposure periods that mirror the neurodevelopmental stages of human gestation. Because of our emphasis on programmed changes in neurobehavioral development, studies that continue diet exposure until assessment in adulthood are not discussed. The presented research provides a strong foundation of preclinical evidence of nutritional programming of neurobehavioral impairments. Alterations in risk assessment and response were observed alongside neurodevelopmental impairments related to neurogenesis, synaptogenesis, and synaptic plasticity. To date, the large majority of studies utilized rodent models, and the field could benefit from additional study of large-animal models. Additional future directions are discussed, including the need for further studies examining how sex as a biological variable affects the contribution of maternal nutrition to prenatal programming.

First-degree male relatives of polycystic ovary syndrome (PCOS) sufferers can develop metabolic abnormalities evidenced by elevated circulating cholesterol and triglycerides, suggestive of a male PCOS equivalent. Similarly, male sheep overexposed to excess androgens in fetal life develop dyslipidaemia in adolescence. Dyslipidaemia, altered lipid metabolism, and dysfunctional hepatic mitochondria are associated with the development of non-alcoholic liver disease (NAFLD). We therefore dissected hepatic mitochondrial function and lipid metabolism in adolescent prenatally androgenized (PA) males from an ovine model of PCOS. Testosterone was directly administered to male ovine fetuses to create prenatal androgenic overexposure. Liver RNA sequencing and proteomics occurred at 6 months of age. Hepatic lipids, glycogen, ATP, reactive oxygen species (ROS), DNA damage, and collagen were assessed. Adolescent PA males had an increased accumulation of hepatic cholesterol and glycogen, together with perturbed glucose and fatty acid metabolism, mitochondrial dysfunction, with altered mitochondrial transport, decreased oxidative phosphorylation and ATP synthesis, and impaired mitophagy. Mitochondrial dysfunction in PA males was associated with increased hepatic ROS level and signs of early liver fibrosis, with clinical relevance to NAFLD progression. We conclude that excess in utero androgen exposure in male fetuses leads to a PCOS-like metabolic phenotype with dysregulated mitochondrial function and likely lifelong health sequelae.

During pregnancy, the regulation of several neuroendocrine systems is altered to support the pregnancy and facilitate the transition to motherhood. These adaptations are organised by the mother's brain and include those that serve to optimise foetal growth, protect the foetus(es) from adverse prenatal programming by maternal stress, facilitate timely parturition and ensure the offspring are nourished and cared for after birth. Although pregnancy hormones are important in inducing and maintaining many of these adaptations, their effects are often mediated via interactions with neuropeptide systems in the brain. In particular, endogenous opioids in the maternal brain play key roles in altered regulation of the stress axis, the oxytocin system, the prolactin system and the neural circuits controlling maternal behaviour. Together, these adaptations maximise the likelihood of a successful pregnancy outcome.

At the Prenatal Programming and Toxicity (PPTox) Conference I in 2008, I presented an overview of the developmental origins of health and disease field focusing on environmental chemical exposures and disease outcomes. At that time, I noted that the field was getting off the ground with a focus on developmental exposure to a small number of endocrine disrupting chemicals (EDCs) and disease outcomes across the lifespan in animal models. In this update, I note that the DOHaD field has changed significantly over the last decade. There are new windows of susceptibility including preconception, prepuberty, a focus on the mother and not just the offspring, and a significant focus on the new field of epigenetic transgenerational inheritance. New disease focus areas have sprung up including obesity, type 2 diabetes and fatty liver disease, all with a connection to developmental exposures to EDCs. There is also a focus on the study of new EDCs, molecular mechanisms, the development of new biomarkers of exposure and disease outcomes and studies focusing on intervention and prevention studies.

The ability to regulate stress is a critical developmental milestone of early childhood that involves a set of interconnected behavioral and physiological processes and is influenced by genetic and environmental stimuli. Prenatal exposure to traumatic stress and trauma, including intimate partner violence (IPV), increases risk for offspring biobehavioral regulation problems during childhood and adolescence. Although individual differences in susceptibility to prenatal stress have been largely unexplored, a handful of studies suggest children with specific genetic characteristics are most vulnerable to prenatal stress. We evaluated the brain-derived neurotrophic factor Val66Met gene (BDNF) as a moderator of the effect of prenatal IPV exposure on infant temperamental and cortisol regulation in response to a psychosocial challenge. Ninety-nine mother–infant dyads recruited from the community were assessed when infants (51% female) were 11 to 14 months. Maternal reports of IPV during pregnancy and infant temperament were obtained, and infant saliva was collected for genotyping and to assess cortisol reactivity (before and after the Strange Situation Task). Significant genetic moderation effects were found. Among infants with the BDNF Met allele, prenatal IPV predicted worse temperamental regulation and mobilization of the cortisol response, while controlling for infant postnatal exposure to IPV, other maternal traumatic experiences, and infant sex. However, prenatal IPV exposure was not associated with temperamental or cortisol outcomes among infant carriers of the Val/Val genotype. Findings are discussed in relation to prenatal programming and biological susceptibility to stress.

Contains fulltext : 194061.pdf (Publisher’s version ) (Closed access) Maternal psychological stress, depression, and anxiety during pregnancy (prenatal stress; PNS) are thought to impact fetal development with long-term effects on offspring outcome. These effects would include physical and mental health, including psychopathology. Maternal sleep, diet, and exercise during pregnancy are lifestyle behaviors that are understudied and often solely included in PNS studies as confounders. However, there are indications that these lifestyle behaviors may actually constitute essential mediators between PNS and fetal programming processes. The goal of this theoretical review was to investigate this idea by looking at the evidence for associations between PNS and sleep, diet, and exercise, and by piecing together the information on potential underlying mechanisms and causal pathways through which these factors may affect the offspring. The analysis of the literature led to the conclusion that sleep, diet, and exercise during pregnancy, may have fundamental roles as mediators between PNS and maternal pregnancy physiology. By integrating these lifestyle behaviors into models of prenatal programming of development, a qualitatively higher and more comprehensive understanding of the prenatal origins of psychopathology can be obtained. The review finalizes by discussing some of the present challenges facing the field of PNS and offspring programming, and offering solutions for future research. 16 p.

Two sets of evidence reviewed herein, one indicating that prenatal stress is associated with elevated behavioral and physiological dysregulation and the other that such phenotypic functioning is itself associated with heightened susceptibility to positive and negative environmental influences postnatally, raises the intriguing hypothesis first advanced by Pluess and Belsky (2011) that prenatal stress fosters, promotes, or “programs” postnatal developmental plasticity. Here we review further evidence consistent with this proposition, including new experimental research systematically manipulating both prenatal stress and postnatal rearing. Collectively this work would seem to explain why prenatal stress has so consistently been linked to problematic development: stresses encountered prenatally are likely to continue postnatally, thereby adversely affecting the development of children programmed (by prenatal stress) to be especially susceptible to environmental effects. Less investigated are the potential benefits prenatal stress may promote, due to increased plasticity, when the postnatal environment proves to be favorable. Future directions of research pertaining to potential mechanisms instantiating postnatal plasticity and moderators of such prenatal-programming effects are outlined.

Prenatal programming models have rarely been applied to research on children with prenatal substance exposure, despite evidence suggesting that prenatal drug exposure is a form of stress that impacts neurodevelopmental outcomes and risk for psychopathology. Utilizing data from two longitudinal multisite studies comprising children prenatally exposed to substances as well as a nonexposed comparison group (Maternal Lifestyle Study, n = 1,388; Infant Development, Environment, and Lifestyle study, n = 412), we tested whether early phenotypic indicators of hypothesized programming effects, indexed by growth parameters at birth and infant temperament, served as a link between prenatal substance exposure and internalizing and externalizing behavior at age 5. Latent profile analysis indicated that individual differences in reactivity and regulation for infants prenatally exposed to substances was best characterized by four temperament profiles. These profiles were virtually identical across two independent samples, and demonstrated unique associations with adjustment difficulties nearly 5 years later. Results of path analysis using structural equation modeling also showed that increased prenatal substance exposure was linked to poorer growth parameters at birth, profiles of temperamental reactivity in infancy, and internalizing and externalizing behavior at age 5. This pathway was partially replicated across samples. This study was among the first to link known individual-level correlates of prenatal substance exposure into a specific pathway to childhood problem behavior. Implications for the developmental origins of a child's susceptibility to psychopathology as a result of intrauterine substance exposure are discussed.

The analysis of published and original data demonstrates that prenatal stress induced by viral and bacterial infection, or changes in the physiological concentrations of neurohormones in early ontogeny can cause unfavorable impacts on the development of neuroendocrine and immune systems. In early pregnancy bacterial infection simulated by lipopolysaccharide in an experiment activates the maternal immune system, which enhances the synthesis of pro- and anti-inflammatory cytokines in both maternal and fetal organisms. Consequently, cytokines promote the secretion of a hormonal cascade in the hypothalamic-pituitary-adrenal system, thus eliciting the hormonal response to stress. Various stress factors during critical periods of neuroendocrine and immune system development modulate the epigenetic mechanisms controlling specific genes, which can affect the structure and function of these systems and increase the risk of various pathologies in the offspring.

AIM We aimed to determine whether maternal hemoglobin levels or anemia during pregnancy are associated with the development of asthma among offspring. METHODS Data were retrieved from the birth register database of Kuopio University Hospital between 1989 and 2007 (n = 38 381). Hemoglobin levels were measured during three trimesters of pregnancy and anemia was defined according to the World Health Organization criteria. The prevalence of asthma was determined from the register of reimbursement for medication for asthma at the Finnish Social Security Institution. Cox proportional hazard regression analysis was performed to evaluate the possible associations between prenatal factors and development of asthma ever. RESULTS A total of 8198 (21.4%) women had anemia at some stage of pregnancy. Mild maternal anemia during the first trimester was associated with an increased risk of asthma among male offspring (adjusted hazard ratio, 1.46; 95% confidence interval, 1.11-1.94) compared with those with normal maternal hemoglobin levels. This finding remained significant also after applying the Bonferroni correction. CONCLUSION Male offspring with maternal anemia during the first trimester of pregnancy had significantly more asthma ever than the offspring of women with normal hemoglobin levels during pregnancy. These findings were not strong but suggest possible sex-specific effects of maternal health on prenatal programming and future risk of asthma.

Anticipated increases in the world population to 9 billion people will lead to increased demand for food. Dairy products represent one of the most sustainable animal sources of food protein because ruminants can utilize byproduct and forage feeds unsuitable for human consumption. Continued improvements in productivity will depend on deeper understanding of the biology of lactation, including developmental programming of tissues critical to that process. Although prenatal programming of postnatal phenotype is well documented for growth, behavior, and disease, there may also be instances of "programming" that last for a specific physiological stage (e.g., lactation). We distinguish between these 2 terms by the use of developmental programming to describe a permanent effect, whereas the more general term is used to describe nonpermanent impacts on the mammary gland. Despite this complexity, here we review the evidence that exposure to elevated temperature and humidity during late gestation can program reduced yields in the subsequent lactation, largely through effects at the mammary gland. Furthermore, we provide emerging evidence that adult capacity for milk synthesis can be programmed in the calf that dam is carrying by events during fetal life occurring 2 yr before. Specifically, calves born to dams that are heat stressed for the final 6 wk of gestation produce 19% less milk in lactation relative to calves from dams provided with evaporative cooling. Importantly, the increased milk yield in animals derived from dams under evaporative cooling occurred without a greater decline in BW that accompanies negative energy balance during early lactation. Therefore, the increase in milk production suggests an increase in the efficiency of conversion of feed to milk. These data indicate that a brief period of heat stress late in development reduces the physiological efficiency of the cow in a coordinated manner to result in a substantial decline in productivity. It is likely that this programming effect would be observed across genetic lines and result in poor sustainability of milk production. Milk will continue to be an important source of high-quality, human-edible food and technologies that improve the efficiency of production will be critical to enhance sustainability. These data provide compelling support for the concept that programming impacts on the dam and the developing fetus will play a role in optimizing the efficiency of production.

Maternal programming of offspring energy balance has been viewed as an adaptation in which the gestational environment prepares the offspring to thrive and reproduce in that same postnatal environment. Programming might have the opposite effect, however, when gestational and postnatal environments are mismatched. Gestational programming would represent a trade-off if the mother can maximize fitness in one possible energetic future but cannot maximize fitness in another. The vast majority of research concerns rats, mice, or sheep, and dams are typically food restricted by 30-70% of ad libitum intake resulting in low birth weight and adult obesity in offspring. Few previous studies have used a lower level of food restriction, and no experiments, to the best of our knowledge, were designed to determine whether the effects of gestational restriction have postgestational effects independent of the effects that occurred during gestation. In the present experiment, Syrian hamsters were either restricted to 90% of their ad libitum food intake or fed ad libitum during pregnancy. All litters were cross-fostered at birth and all were fed ad libitum during lactation. Half of the litters from ad libitum-fed pregnant dams were fostered to dams that had been food restricted during pregnancy and half of the litters from food-restricted pregnant dams were fostered to ad libitum-fed dams. The latter group allowed us to test the hypothesis that the effects of having a gestationally food-restricted mother affects offspring characteristics independent of the prenatal programming. First, we found significant increases in the postnatal body weight of the offspring of ad libitum-fed mothers fostered to food-restricted dams, supporting the hypothesis that the effects of gestational restriction carry over to postnatal maternal ability (e.g., milk yield, milk content, or parental behavior). Second, the carry-over effects of gestational food restriction on offspring postnatal body weight were significant in male but not female offspring. This occurred even though this group had significantly lower food intake than offspring of ad libitum-fed mothers with ad libitum-fed foster mothers. In addition, and contrary to expectation, gestational food restriction had no significant effect on adult baseline food hoarding or food hoarding in response to food restriction. These results suggest that even mild energetic challenges during gestation can have postgestational effects on maternal ability, and the effects on offspring are sex-specific.

The formation of pro-/eukaryotic systems is the general biological mechanism of formation and variability of the phenotype of plants, animals, human beings under the influence of external Wednesday, i.e. formation of adaptive potency conditions to external Wednesday that increases the «biological status» prokaryotic structures in sustaining body health. Prominent role in the formation of the phenotype of micro media, immunological tolerance (immunological programming), as a basis for the formation of individual pro-/eukaryotic interactions in perinatal age, the dominant role of maternal influence in this process on the one hand, micro-variability due to external stress impact on the other, makes it possible to consider pro-/eukaryotic interaction as a possible mechanism of perinatal programming and epigenetics inheritance and therefore, as one possible approach for correction of chronic and congenital pathology. This points to the need to improve monitoring ofthe formation microbiocenosis of children, improve the methods of assessment and correction.

Perinatal asphyxia (PA) is a burdening pathology with high short-term mortality and severe long-term consequences. Its incidence, reaching as high as 10 cases per 1000 live births in the less developed countries, prompts the need for better awareness and prevention of cases at risk, together with management by easily applicable protocols. PA acts first and foremost on the nervous tissue, but also on the heart, by hypoxia and subsequent ischemia-reperfusion injury. Myocardial development at birth is still incomplete and cannot adequately respond to this aggression. Cardiac dysfunction, including low ventricular output, bradycardia, and pulmonary hypertension, complicates the already compromised circulatory status of the newborn with PA. Multiorgan and especially cardiovascular failure seem to play a crucial role in the secondary phase of hypoxic-ischemic encephalopathy (HIE) and its high mortality rate. Hypothermia is an acceptable solution for HIE, but there is a fragile equilibrium between therapeutic gain and cardiovascular instability. A profound understanding of the underlying mechanisms of the nervous and cardiovascular systems and a close collaboration between the bench and bedside specialists in these domains is compulsory. More resources need to be directed toward the prevention of PA and the consecutive decrease of cardiovascular dysfunction. Not much can be done in case of an unexpected acute event that produces PA, where recognition and prompt delivery are the key factors for a positive clinical result. However, the situation is different for high-risk pregnancies or circumstances that make the fetus more vulnerable to asphyxia. Improving the outcome in these cases is possible through careful monitoring, identifying the high-risk pregnancies, and the implementation of novel prenatal strategies. Also, apart from adequately supporting the heart through the acute episode, there is a need for protocols for long-term cardiovascular follow-up. This will increase our recognition of any lasting myocardial damage and will enhance our perspective on the real impact of PA. The goal of this article is to review data on the cardiovascular consequences of PA, in the context of an immature cardiovascular system, discuss the potential contribution of cardiovascular impairment on short and long-term outcomes, and propose further directions of research in this field.

The present review aims to offer a non-comprehensive outline of the current state-of-the-art and future perspectives on management and therapeutic tools for intrauterine growth restriction (IUGR) and associated prenatal programming in both human and animal species. Animals are used as models for the study of phenomena related to IUGR, but also for research on prenatal therapies with the main objective of designing and developing preventive and therapeutic strategies. The research is currently paying attention on maternal-focused pharmacological treatments and nutritional strategies but also on fetal-focused treatments. Fetal-focused treatments, administered either directly at the fetus or by using infusion of umbilical cord, amniotic sac or placenta, which avoids the administration of substances at high doses to the mother for allowing their availability at the fetoplacental level. The results obtained in this area of research using large animals (rabbits, pigs and ruminants) have a dual interest, for translational biomedicine and for veterinary medicine and animal production.

The fetal origin of adult disease hypothesis postulates that a stressful in utero environment can have deleterious consequences on fetal programming, potentially leading to chronic disease in later life. Factors known to impact fetal programming include the timing, intensity, duration and nature of the external stressor during pregnancy. As such, dynamic modulation of fetal programming is heavily involved in shaping health throughout the life course, possibly by influencing metabolic parameters including insulin action, hypothalamic-pituitary-adrenal activity and immune function. The ability of prenatal insults to program adult disease is likely to occur as a result of reduced functional capacity in key organs-a "thrifty" phenotype-where more resources are re-allocated to preserve critical organs such as the brain. Notably, it has been postulated that the manifestation of neuropsychiatric disorders in individuals priorly exposed to prenatal stress may arise from the interaction between hereditary factors and the intrauterine environment, which together precipitate disease onset by disrupting the trajectory of normal brain development. In this review we discuss the evidence linking prenatal programming to neuropsychiatric disorders, mainly schizophrenia, via a "Thrifty psychiatric phenotype" concept. We start by outlining the conception of the thrifty psychiatric phenotype. Next, we discuss the convergence of potential mechanistic pathways through which prenatal insults may trigger epigenetic changes that contribute to the increased morbidity and early mortality observed in neuropsychiatric disorders. Finally, we touch on the public health importance of fetal programming for these disorders. We conclude by providing a brief outlook on the future of this evolving field of research.

We have previously demonstrated that dexamethasone administered to pregnant rats during specific times during gestation results in a reduction in glomerular number and hypertension in offspring at 2 and 6 months of age. In this study, we examined the effect of prenatal dexamethasone administered daily on days 15 and 16 of gestation in male and female offspring after 1 year of age on glomerular filtration rate. The prenatal dexamethasone male group had a higher systolic blood pressure than the vehicle male group. Females had lower systolic blood pressures than the males and prenatal dexamethasone did not affect blood pressure in female offspring. Prenatal dexamethasone resulted in a reduction in glomerular filtration rate in male but not in female rats. When corrected for body weight, the control male rats had a lower glomerular filtration rate than the control female rats. Males had greater protein excretion than females and prenatal dexamethasone increased the protein excretion only in male rats. Glomerulosclerosis was also greater in male rats than females but was not affected by prenatal dexamethasone. In summary, male rats appear to have evidence of a decline in glomerular filtration rate after 1 year of age and prenatal dexamethasone programs an accelerated decline in glomerular filtration rate in male but not in female offspring.

Suboptimal conditions during prenatal ontogeny can impair development of several physiological systems and result in cardiometabolic diseases in adulthood. The kidney has been identified as one of the most sensitive organs for developmental programming, but underlying mechanisms are not fully understood. Therefore, in our study we explored the consequences of prenatally increased angiotensin II (Ang II) on the structural development of the kidney and its damage by infiltrated immune cells under normal diet and after an increased salt intake, as a second insult representing a lifestyle factor in humans. Female rats were implanted with osmotic mini-pumps continuously releasing Ang II of dose 2 µg/kg/h during last two weeks of pregnancy, whereas control females were sham operated. Immunohistological and ultrastructural evaluations of the kidneys and their infiltration with immune cells were performed in mature male progeny kept either on a standard or increased salt (2% NaCl) diet. Glomerular volume decreased and the cortical tubulointerstitial injury increased in the offspring prenatally exposed to Ang II with no additional effect of increased salt. Ultrastructural examination demonstrated degenerative changes in proximal tubules, mainly fewer and shorter microvilli in the brush border, enlarged mitochondria, and an increased number of lysosomes in the epithelial cells in the progeny prenatally exposed to Ang II. Moreover, the treatment resulted in increased infiltration of T-cells and macrophages in the renal cortex compared to controls. These changes paralleled with reduced numbers of cytotoxic T-cells in circulation and higher oxidative burst of neutrophils in the progeny of Ang II-treated mothers compared to controls. Altogether, results suggest that prenatally increased Ang II promoted infiltration of immune cells in the kidney and subsequent oxidative stress, which induced a damage of renal glomerular and tubular system entailing negative consequences on the cardiovascular system.Impact statementSuboptimal prenatal conditions can contribute to development of cardiovascular diseases and an altered renin-angiotensin-aldosterone system (RAAS) can be involved in the process. In our study, increased angiotensin II in pregnant female rats resulted in renal cortical interstitial damage, and renal ultrastructural changes in the glomeruli, the brush border of proximal tubules and mitochondria in mature male offspring. The treatment promoted infiltration of T cells and macrophages in the kidneys and primed an oxidative burst of circulating neutrophils, indicating a pro-inflammatory state in the progeny of angiotensin II-treated mothers. Deregulated RAAS of mothers is involved in developmental programming of hypertension in adult male offspring via damaging kidney morphology and function. These findings suggest that preventing the activation of RAAS and oxidative stress during perinatal development might protect against hypertension development in adult male progeny.