Stress during pregnancy has been widely studied and associated to different variables, usually with negative results for the health of the mother and the newborn, such as having a higher risk of suffering postpartum depression, premature birth, obstetrics complications or low birthweight, among others. However, there are not many lines of research that study the role that the sex of the baby plays on this specific stress and vice versa. Thus, the main objective was to analyse the relationship between the sex of the offspring and the stress of the mothers in the first trimester of pregnancy. In order to achieve this, 108 women had their biological stress measured (trough hair cortisol levels) and psychological stress evaluated (the Prenatal Distress Questionnaire (PSS), the Perceived Stress Scale (PDQ) and the Stress Vulnerability Inventory (IVE)). The results revealed significant differences in maternal hair cortisol levels in the first trimester based on the sex of the baby they had given birth to (t = −2.04; P < 0.05): the concentration of the hormone was higher if the baby was a girl (164.36:54.45-284.87 pg/mg) than if it was a boy (101.13:37.95-193.56 pg/mg). These findings show that the sex of the future baby could be conditioned, among many other variables, by the mother´s stress levels during conception and first weeks of pregnancy. Further research is needed in this area to support our findings.

We previously demonstrated decreased placental perfusion, reduced amniotic fluid protein content, and increased pregnancy loss in a nonhuman primate model of gestational protein restriction. Here, our objective was to link these detrimental findings with a functional placental assessment. As blood flow is critical to maternal-fetal exchange, we hypothesized that a protein-restricted diet would impair placental taurine uptake. Pregnant rhesus macaques were maintained on either control chow (CON, n = 5), a 33% protein-restricted diet (PR33, n = 5), or a 50% PR diet (PR50, n = 5) prior to and throughout pregnancy. Animals were delivered on gestational day 135 (G135; term is G168). Taurine activity was determined in fresh placental villous explants. Taurine transporter (TauT) protein expression, placental growth factor (PLGF), and insulin-like growth factor (IGF)-1 and IGF-2 protein concentrations were measured, and histological assessment was performed. Fetal body weights and placental weights were comparable between all three groups at G135. Placental taurine uptake was decreased in PR33- and PR50-fed animals compared to CON, yet TauT expression was unchanged across groups. PLGF was significantly increased in PR50 vs. CON, with no change in IGF-1 or IGF-2 expression in placental homogenate from PR-fed animals. Accelerated villous maturation was observed in all PR50 cases, three of five PR33, and was absent in CON. We demonstrate conserved fetal growth, despite a decrease in placental taurine uptake. Increased expression of PLGF and expansion of the syncytiotrophoblast surface area in the severely protein-restricted animals suggest a compensatory mechanism by the placenta to maintain fetal growth.

Observing fetal development in utero is vital to further the understanding of later-life diseases. Magnetic resonance imaging (MRI) offers a tool for obtaining a wealth of information about fetal growth, development, and programming not previously available using other methods. This review provides an overview of MRI techniques used to investigate the metabolic and cardiovascular consequences of the developmental origins of health and disease (DOHaD) hypothesis. These methods add to the understanding of the developing fetus by examining fetal growth and organ development, adipose tissue and body composition, fetal oximetry, placental microstructure, diffusion, perfusion, flow, and metabolism. MRI assessment of fetal growth, organ development, metabolism, and the amount of fetal adipose tissue could give early indicators of abnormal fetal development. Noninvasive fetal oximetry can accurately measure placental and fetal oxygenation, which improves current knowledge on placental function. Additionally, measuring deficiencies in the placenta’s transport of nutrients and oxygen is critical for optimizing treatment. Overall, the detailed structural and functional information provided by MRI is valuable in guiding future investigations of DOHaD.

The identification of early-life determinants of overweight is crucial to start early prevention. As weight gain accelerates between 2 and 6 years, we studied the association between diet quality in children aged 3 years and the change in BMI and overweight incidence in the following 7 years. From the Dutch GECKO Drenthe birth cohort, 1001 children born in 2006 or 2007 with complete data on diet (food frequency questionnaire at the age of 3 years) and growth at the age of 3 and 10 years were included. Diet quality was estimated with the evidence-based Lifelines Diet Score (LLDS). Measured height and weight at the age of 3 and 10 years were used to calculate BMI z-scores standardized for age and sex. The associations of the LLDS (in quintiles) with BMI-z change and overweight incidence were studied with linear and logistic regression analyses. Overweight prevalence in the total study population increased from 8.3% at the age of 3 years to 16.7% at the age of 10 years. The increase in overweight prevalence ranged from 14.7% in Q1 to 3.5% in Q5. Children with a better diet quality (higher quintiles of LLDS) increased significantly less in BMI-z (confounder adjusted βLLDS = −0.064 (−0.101; −0.026)). Children with a poor diet quality at the age of 3 years had a considerably higher risk for overweight at the age of 10 years (confounder adjusted OR for Q1 vs. Q5 was 2.86 (95% CI 1.34–6.13). These results show the importance of diet in healthy development in the early life following the first 1000 days when new habits for a mature diet composed of food groups with lifelong importance are developed, providing a relevant window for overweight prevention early in life.

Nutrition during the first 1000 days of life represents a window of opportunity to reduce the risk of metabolic dysfunctions later in life. Exclusive breastfeeding (EBF) and adequate introduction of solid foods are essential to promote metabolic and nutritional benefits. We evaluated the association of infant feeding practices from birth to 6 months (M) with adiposity indicators at 12 M. We performed a secondary analysis of 106 healthy term infants born from a cohort of healthy pregnant women. Type of breastfeeding (exclusive or nonexclusive), the start of complementary feeding (CF) (before (<4 M) or after (≥4 M)), and adiposity (body mass index – BMI, body mass index-for-age – BMI/A, waist circumference – WC, and waist circumference–length ratio – WLR) were evaluated at 12 M using descriptive statistics, mean differences, X2, and linear regression models. During the first 6 M, 28.3% (n = 30) of the infants received EBF. Early CF (<4 M) was present in 26.4% (n = 28) of the infants. Children who started CF < 4 M were less breastfed, received added sugars as the most frequently introduced food category, and showed higher BMI, BMI/A, WC, and WLR; those who consumed added sugars early (<4 M) had a higher WC. Starting CF < 4 M was the main factor associated with a higher WC at 12 M. Unhealthy infant feeding practices, such as lack of EBF, early CF, and early introduction of sugars, may be associated with higher adiposity at 12 M.

The 1918 Influenza pandemic had long-term impacts on the cohort exposed in utero which experienced earlier adult mortality, and more diabetes, ischemic heart disease, and depression after age 50. It is possible that the Coronavirus Disease 2019 (COVID-19) pandemic will also have long-term impacts on the cohort that was in utero during the pandemic, from exposure to maternal infection and/or the stress of the pandemic environment. We discuss how COVID-19 disease during pregnancy may affect fetal and postnatal development with adverse impacts on health and aging. Severe maternal infections are associated with an exaggerated inflammatory response, thromboembolic events, and placental vascular malperfusion. We also discuss how in utero exposure to the stress of the pandemic, without maternal infection, may impact health and aging. Several recently initiated birth cohort studies are tracking neonatal health following in utero severe acute respiratory syndrome virus 2 (SARS-CoV-2) exposure. We suggest these cohort studies develop plans for longer-term observations of physical, behavioral, and cognitive functions that are markers for accelerated aging, as well as methods to disentangle the effects of maternal infection from stresses of the pandemic environment. In utero exposure to COVID-19 disease could cause developmental difficulties and accelerated aging in the century ahead. This brief review summarizes elements of the developmental origins of health, disease, and ageing and discusses how the COVID-19 pandemic might exacerbate such effects. We conclude with a call for research on the long-term consequences of in utero exposure to maternal infection with COVID-19 and stresses of the pandemic environment.

Prenatal diethylstilbestrol (DES) exposure is associated with increased risk of hormonally mediated cancers and other medical conditions. We evaluated the association between DES and risk of pancreatic cancer and pancreatic disorders, type 2 diabetes, and gallbladder disease, which may be involved with this malignancy. Our analyses used follow-up data from the US National Cancer Institute DES Combined Cohort Study. Cox proportional hazards models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for age, sex, cohort, body mass index, smoking, and alcohol for the association between prenatal DES exposure and type 2 diabetes, gallbladder disease (mainly cholelithiasis), pancreatic disorders (mainly pancreatitis), and pancreatic cancer among 5667 exposed and 3315 unexposed individuals followed from 1990 to 2017. Standardized incidence rate (SIR) ratios for pancreatic cancer were based on age-, race-, and calendar year-specific general population cancer incidence rates. In women and men combined, the hazards for total pancreatic disorders and pancreatitis were greater in the prenatally DES exposed than the unexposed (HR = 11, 95% CI 2.6–51 and HR = 7.0, 95% CI 1.5–33, respectively). DES was not associated overall with gallbladder disease (HR = 1.2, 95% CI 0.88–1.5) or diabetes (HR = 1.1, 95% CI 0.9–1.2). In women, but not in men, DES exposure was associated with increased risk of pancreatic cancer compared with the unexposed (HR: 4.1, 95% CI 0.84–20) or general population (SIR: 1.9, 95% CI 1.0–3.2). Prenatal DES exposure may increase the risk of pancreatic disorders, including pancreatitis in women and men. The data suggested elevated pancreatic cancer risk in DES-exposed women, but not in exposed men.

Estimation of pre-pregnancy weight is difficult because measurements taken before pregnancy are rarely available. No studies have compared various ‘proxy’ measures using recalled weight or based on early pregnancy weight with actual measurements of pre-pregnancy weight. The Southampton Women’s Survey recruited women during 1998–2002 who were not pregnant. Data on 198 women with an estimated date of conception within 3 months of recruitment were analysed. Three proxy measures were considered: (1) recalled pre-pregnancy weight obtained during early pregnancy, (2) measured weight in early pregnancy and (3) estimated pre-pregnancy weight using a published model. Mean (standard deviation) recalled weight was 1.65 (3.03) kg lighter than measured pre-pregnancy weight, while early pregnancy weight and weights from the published model were 0.88 (2.34) and 0.88 (2.33) kg heavier, respectively. The Bland–Altman limits of agreement for recalled weight were −7.59 to 4.29 kg, wider than those for the early pregnancy weight: −3.71 to 5.47 kg and the published model: −3.68 to 5.45 kg. For estimating pre-pregnancy weight, we recommend subtraction of 0.88 kg from early pregnancy weight or the published model, or addition of 1.65 kg to recalled weight. Estimates of pre-pregnancy body mass index and gestational weight gain categories were very similar when using early pregnancy and published model weights, but they differed from those using recalled weight. Our findings indicate that calculations of first trimester weight gain using recalled weight must be treated cautiously, and a measured weight in early pregnancy provides a more precise assessment of pre-pregnancy weight than recalled weight.

Maternal body mass index (BMI) and gestational weight gain (GWG) impacts both the mother’s and the child’s health, and epigenetic modifications have been suggested to mediate some of these effects in offspring. This systematic review aimed to summarize the current literature on associations between maternal BMI and GWG and epigenetic marks. We performed systematic searches in PubMed and EMBASE and manual searches of reference lists. We included 49 studies exploring the association between maternal BMI and/or GWG and DNA methylation or miRNA; 7 performed in maternal tissues, 13 in placental tissue and 38 in different offspring tissues. The most consistent findings were reported for the relationship between maternal BMI, in particular pre-pregnant BMI, and expression of miRNA Let-7d in both maternal blood and placental tissue, methylation of the gene HIF3A in umbilical cord blood and umbilical tissue, and with expression in the miR-210 target gene, BDNF in placental tissue and cord blood. Correspondingly, methylation of BDNF was also found in placental tissue and cord blood. The current evidence suggests that maternal BMI is associated with some epigenetic signatures in the mother, the placenta and her offspring, which could indicate that some of the effects proposed by the Developmental Origins of Health and Disease-hypothesis may be mediated by epigenetic marks. In conclusion, there is a need for large, well-designed studies and meta-analyses that can clarify the relationship between BMI, GWG and epigenetic changes.

Diabetic pregnancies are cleary associated with maternal type 2 diabetes and metabolic syndrome as well as atherosclerotic diseases in the offspring. The global prevalence of hyperglycemia in pregnancy was estimated as 15.8% of live births to women in 2019, with an upward trend. Numerous parental risk factors as well as trans-generational mechanisms targeting the utero-placental system, leading to diabetes, dysmetabolic and atherosclerotic conditions in the next generation, seem to be involved within this pathophysiological context. To focus on the predictable impact of trans-generational diabetic programming, we studied age- and gender-matched offspring of diabetic and nondiabetic mothers. The offspring generation consists of three groups: C57BL/6-J-Ins2Akita (positive control group), wild-type C57BL/6-J-Ins2Akita (experimental group), and C57BL/6-J mice (negative control group). We undertook intraperitoneal glucose tolerance tests at 3 and 11 weeks of age. Moreover, this in vivo model was complemented by a corresponding in silico model. Although at 3 weeks of age, no significant effects could be observed, we could demonstrate at 11 weeks of age characteristic and significant differences in relation to maternal diabetic imprinting based on the in silico model-based predictors. These predictors allow the generation of a concise classification tree assigning maternal diabetic imprinting correctly in 91% of study cases. Our data show that hyperglycemic in utero milieu contributes to trans-generational diabetic programming leading to impaired glucose tolerance in the offspring of diabetic mothers early on. These observations can be clearly and early distinguished from genetically determined diabetes, for example, type 1 diabetes, in which basal glucose values are significantly raised.

Prenatal glucocorticoid overexposure has been shown to programme adult cardiovascular function in a range of species, but much less is known about the long-term effects of neonatal glucocorticoid overexposure. In horses, prenatal maturation of the hypothalamus–pituitary–adrenal axis and the normal prepartum surge in fetal cortisol occur late in gestation compared to other precocious species. Cortisol levels continue to rise in the hours after birth of full-term foals and increase further in the subsequent days in premature, dysmature and maladapted foals. Thus, this study examined the adult cardiovascular consequences of neonatal cortisol overexposure induced by adrenocorticotropic hormone administration to full-term male and female pony foals. After catheterisation at 2–3 years of age, basal arterial blood pressures (BP) and heart rate were measured together with the responses to phenylephrine (PE) and sodium nitroprusside (SNP). These data were used to assess cardiac baroreflex sensitivity. Neonatal cortisol overexposure reduced both the pressor and bradycardic responses to PE in the young adult males, but not females. It also enhanced the initial hypotensive response to SNP, slowed recovery of BP after infusion and reduced the gain of the cardiac baroreflex in the females, but not males. Basal diastolic pressure and cardiac baroreflex sensitivity also differed with sex, irrespective of neonatal treatment. The results show that there is a window of susceptibility for glucocorticoid programming during the immediate neonatal period that alters cardiovascular function in young adult horses in a sex-linked manner.

Epigenetic age acceleration (AA) has been associated with adverse environmental exposures and many chronic conditions. We estimated, in the NINFEA birth cohort, infant saliva epigenetic age, and investigated whether parental socio-economic position (SEP) and pregnancy outcomes are associated with infant epigenetic AA. A total of 139 saliva samples collected at on average 10.8 (range 7–17) months were used to estimate Horvath’s DNA methylation age. Epigenetic AA was defined as the residual from a linear regression of epigenetic age on chronological age. Linear regression models were used to test the associations of parental SEP and pregnancy outcomes with saliva epigenetic AA. A moderate positive association was found between DNA methylation age and chronological age, with the median absolute difference of 6.8 months (standard deviation [SD] 3.9). The evidence of the association between the indicators of low SEP and epigenetic AA was weak; infants born to unemployed mothers or with low education had on average 1 month higher epigenetic age than infants of mothers with high education and employment (coefficient 0.78 months, 95% confidence intervals [CIs]: −0.79 to 2.34 for low/medium education; 0.96, 95% CI: −1.81 to 3.73 for unemployment). There was no evidence for association of gestational age, birthweight or caesarean section with infant epigenetic AA. Using the Horvath’s method, DNA methylation age can be fairly accurately predicted from saliva samples already in the first months of life. This study did not reveal clear associations between either pregnancy outcomes or parental socio-economic characteristics and infant saliva epigenetic AA.

Prenatal exposure to mercury in utero causes abnormal foetal growth and adverse outcomes. DNA methylation is currently considered a possible mechanism through which this occurs. However, few studies have investigated the association between prenatal exposure to mercury and DNA methylation in detail. This study aimed to clarify the relationship between prenatal exposure to total mercury (Hg) and DNA methylation and its associations with sex-specific characteristics in male and female offspring. In a birth cohort study known as the Chiba study of Mother and Child Health, the DNA methylation status in cord tissue and Hg concentrations in cord serum were examined. A total of 67 participants (27 males and 40 females) were analysed based on Spearmanʼs correlations, adjusted by a false discovery rate of the sex of each offspring. Only one methylated locus was positively correlated with Hg concentrations in cord serum in male offspring, but not in female offspring, and was annotated to the haloacid dehalogenase-like hydrolase domain-containing protein 1 (HDHD1) gene on chromosome X. This locus was located in the intron of the HDHD1 gene body and is a binding site for the zinc finger protein CCCTC-binding factor. One of the other loci, located in HDHD1, was highly methylated in the group with higher mercury concentrations, and this locus was in the gene body of HDHD1. Our results suggest that prenatal exposure to Hg might affect the epigenetic status of male foetuses.

Polycyclic aromatic hydrocarbons (PAHs) may contribute to obesity. Childhood obesity is a strong predictor of adult obesity and morbidity; however, the relationship between PAHs and obesity in young children (e.g., aged 3–5) has not been studied. We examined the association between urinary PAH metabolites and measures of obesity in children. We analyzed data from 3667 children aged 3–18 years who participated in the Canadian Health Measures Survey (CHMS, 2009–2015). We ran separate multivariable linear models to estimate the association between quartiles of PAH metabolites and each of body mass index (BMI) percentile, waist circumference (WC), and waist-to-height ratio (WHtR) in the total population, as well as in the age subgroups 3–5, 6–11, and 12–18, adjusting for age, sex, ethnicity, education, income quintile, diet, creatinine, and exposure to environmental tobacco smoke. A multinomial logistic regression model estimated adjusted odds ratios for risk of central obesity. BMI, WC, and WHtR were positively associated with total PAH and naphthalene metabolites in the total population aged 3–18 and in age groups 6–11 and 12–18. In 3–5 year olds, WHtR, but not BMI, was significantly associated with total PAH, naphthalene, and phenanthrene metabolites. Overall, those in the highest quartile for naphthalene or total PAH metabolites had three times greater odds of having central obesity compared with those in the lowest quartile. Urinary PAH metabolites are associated with WHtR, an indicator of central obesity and predictor of health risks associated with obesity, in children as young as 3–5.

Maternal supraphysiological estradiol (E2) environment during pregnancy leads to adverse perinatal outcomes. However, the influence of oocyte exposure to high E2 levels on perinatal outcomes remains unknown. Thus, a retrospective cohort study was conducted to explore the effect of high E2 level induced by controlled ovarian stimulation (COH) on further outcomes after frozen embryo transfer (FET). The study included all FET cycles (n = 10,581) between 2014 and 2017. All cycles were categorized into three groups according to the E2 level on the day of the human Chorionic Gonadotropin trigger. Odds ratios (ORs) and their confidence intervals (CIs) were calculated to evaluate the association between E2 level during COH and pregnancy outcomes and subsequent neonatal outcomes. From our findings, higher E2 level was associated with lower percentage of chemical pregnancy, clinical pregnancy, ongoing pregnancy, and live birth as well as increased frequency of early miscarriage. Preterm births were more common among singletons in women with higher E2 level during COH (aOR1 = 1.93, 95% CI: 1.22–3.06; aOR2 = 2.05, 95% CI: 1.33–3.06). Incidence of small for gestational age (SGA) was more common in both singletons (aOR1 = 2.01, 95% CI: 1.30–3.11; aOR2 = 2.51, 95% CI: 1.69–3.74) and multiples (aOR1 = 1.58, 95% CI: 1.03–2.45; aOR2 = 1.99, 95% CI: 1.05–3.84) among women with relatively higher E2 level. No association was found between high E2 level during COH and the percentage of macrosomia or large for gestational age. In summary, oocyte exposure to high E2 level during COH should be brought to our attention, since the pregnancy rate decreasing and the risk of preterm birth and SGA increasing following FET.

There is an established link between birth parameters and risk of adult-onset cancers. The Developmental Origins of Health and Disease concept provides potential underlying mechanisms for such associations, including intrauterine exposure to endogenous hormones (androgens and estrogens), insulin-like growth factors, etc. However, there is conflicting evidence on the association between birth parameters and the cancer mortality risk. Therefore, we aimed to review and analyse the available data on the association linking birth weight and birth length with cancer mortality. Eleven studies were identified, published until April 2019. A significant association between birth weight and the prognosis of cancer (overall) was found (relative risk, RR 1.06, 95% confidence interval, CI: 1.01, 1.11), with low heterogeneity (I2 = 27.7%). In addition, higher birth weight was associated with poorer prognosis of prostate cancer (RR 1.21, 95% CI: 1.02, 1.44). However, the association of birth weight with breast cancer mortality risk in women was not significant (RR 1.16, 95% CI: 0.93, 1.44), which might be due to high statistical heterogeneity (I2 = 67.9%). Birth length was not associated with cancer mortality risk (RR 1.0, 95% CI: 0.90–1.11). It might be inferred that birth parameters are not associated with cancer mortality as strongly as with the risk of developing cancer. Also, the association between birth parameters and cancer mortality risk is not uniform and varies according to its subtypes, and study characteristics/design. This highlights the need for further prospective studies.

Early-life environmental and nutritional exposures are considered to contribute to the differences in cardiovascular disease (CVD) burden. Among sub-Saharan African populations, the association between markers of early-life exposures such as leg length and sitting height and CVD risk is yet to be investigated. This study assessed the association between leg length, sitting height, and estimated 10-year atherosclerotic cardiovascular disease (ASCVD) risk among Ghanaian-born populations in Europe and Ghana. We constructed sex-specific quintiles for sitting height and leg length for 3250 participants aged 40–70 years (mean age 52 years; men 39.6%; women 60.4%) in the cross-sectional multicenter Research on Diabetes and Obesity among African Migrants study. Ten-year risk of ASCVD was estimated using the Pooled Cohort Equations; risk ≥7.5% was defined as “elevated” CVD risk. Prevalence ratios (PR) were estimated to determine the associations between sitting height, leg length, and estimated 10-year ASCVD risk. For both men and women, mean sitting height and leg length were highest in Europe and lowest in rural Ghana. Sitting height was inversely associated with 10-year ASCVD risk among all women (PR for 1 standard deviation increase of sitting height: 0.75; 95% confidence interval: 0.67, 0.85). Among men, an inverse association between sitting height and 10-year ASCVD risk was significant on adjustment for study site, adult, and parental education but attenuated when further adjusted for height. No association was found between leg length and estimated 10-year ASCVD risk. Early-life and childhood exposures that influence sitting height could be the important determinants of ASCVD risk in this adult population.

Prenatal exposure to persistent organic pollutants (POPs) has been associated with the development of metabolic syndrome-related diseases in offspring. According to epidemiological studies, father’s transmission of environmental effects in addition to mother’s can influence offspring health. Moreover, maternal prenatal dietary folic acid (FA) may beneficially impact offspring health. The objective is to investigate whether prenatal FA supplementation can overcome the deleterious effects of prenatal exposure to POPs on lipid homeostasis and inflammation in three generations of male rat descendants through the paternal lineage. Female Sprague-Dawley rats (F0) were exposed to a POPs mixture (or corn oil) +/− FA supplementation for 9 weeks before and during gestation. F1 and F2 males were mated with untreated females. Plasma and hepatic lipids were measured in F1, F2, and F3 males after 12-h fast. Gene expression of inflammatory cytokines was determined by qPCR in epididymal adipose tissue. In F1 males, prenatal POPs exposure increased plasma lipids at 14 weeks old and hepatic lipids at 28 weeks old and prenatal FA supplementation decreased plasma total cholesterol at 14 weeks old. Prenatal POPs exposure decreased plasma triglycerides at 14 weeks old in F2 males. No change was observed in inflammatory markers. Our results show an impact of the paternal lineage on lipid homeostasis in rats up to the F2 male generation. FA supplementation of the F0 diet, regardless of POPs exposure, lowered plasma cholesterol in F1 males but failed to attenuate the deleterious effects of prenatal POPs exposure on plasma and hepatic lipids in F1 males.