In utero exposure to income shocks has a lasting effect on child well-being. In an agricultural economy, fluctuations in rainfall directly affect household income. In this paper, we investigate the short- and long-run impact of pre-pregnancy, prenatal, and early-life exposure to fluctuations in rainfall on height for a sample of 2290 children in rural Pakistan. Given the widespread canal irrigation system prevalent in the country, we also investigate how fluctuations in river water flows affect child health. We find that fluctuations in rainfall during the pre-pregnancy period have the most lasting effects on the stature of children in the short and long run. Exposure of a mother to a 1 standard deviation reduction in rainfall during the pre-pregnancy period led her child to be 0.17 standard deviations (0.53 cm) shorter by age four. This negative impact of a pre-pregnancy rainfall shock on height persisted over time; the child continued to be 0.12 standard deviations (0.83 cm) shorter, on average, by 13 years of age. However, we find that the effect of pre-pregnancy rainfall fluctuations on children’s height is smaller in districts that have access to irrigation facilities.

Early gut microbiome development may impact brain and behavioral development. Using a nonhuman primate model (Macaca mulatta), we investigated the association between social environments and the gut microbiome on infant neurodevelopment and cognitive function. Infant rhesus monkeys (n = 33) were either mother-peer-reared (MPR) or nursery-reared (NR). Neurodevelopmental outcomes, namely emotional responsivity, visual orientation, and motor maturity, were assessed with the Primate Neonatal Neurobehavioral Assessment (PNNA) at 14–30 days. Cognitive development was assessed through tasks evaluating infant reward association, cognitive flexibility, and impulsivity at 6–8 months. The fecal microbiome was quantified from rectal swabs via 16S rRNA sequencing. Factor analysis was used to identify “co-abundance factors” describing patterns of microbial composition. We used multiple linear regressions with AIC Model Selection and differential abundance analysis (MaAsLin2) to evaluate relationships between co-abundance factors, microbiome diversity, and neuro-/cognitive development outcomes. At 30 days of age, a gut microbiome co-abundance factor, or pattern, with high Prevotella and Lactobacillus (β = −0.88, p = 0.04, AIC Weight = 68%) and gut microbiome alpha diversity as measured by Shannon diversity (β = −1.33, p = 0.02, AIC Weight = 80%) were both negatively associated with infant emotional responsivity. At 30 days of age, being NR was also associated with lower emotional responsivity (Factor 1 model: β = −3.13, p < 0.01; Shannon diversity model: β = −3.77, p < 0.01). The infant gut microbiome, along with early-rearing environments, may shape domains of neuro-/cognitive development related to temperament.

The nutritional environment during fetal and early postnatal life has a long-term impact on growth, development, and metabolic health of the offspring, a process termed “nutritional programming.” Rodent models studying programming effects of nutritional interventions use either purified or grain-based rodent diets as background diets. However, the impact of these diets on phenotypic outcomes in these models has not been comprehensively investigated. We used a previously validated (C57BL/6J) mouse model to investigate the effects of infant milk formula (IMF) interventions on nutritional programming. Specifically, we investigated the effects of maternal diet type (i.e., grain-based vs purified) during early lactation and prior to the intervention on offspring growth, metabolic phenotype, and gut microbiota profile. Maternal exposure to purified diet led to an increased post-weaning growth velocity in the offspring and reduced adult diet-induced obesity. Further, maternal exposure to purified diet reduced the offspring gut microbiota diversity and modified its composition post-weaning. These data not only reinforce the notion that maternal nutrition significantly influences the programming of offspring vulnerability to an obesogenic diet in adulthood but emphasizes the importance of careful selection of standard background diet type when designing any preclinical study with (early life) nutritional interventions.

Preterm birth exposes the neonate to hypoxic-ischaemic and excitotoxic insults that impair neurodevelopment and are magnified by the premature loss of placentally supplied, inhibitory neurosteroids. The cerebellum is a neuronally dense brain region, which undergoes critical periods of development during late gestation, when preterm births frequently occur. We propose that neurosteroid replacement therapy using tiagabine and zuranolone will protect the cerebellum against preterm-associated insults. Guinea pig dams received c-section surgery preterm (gestational age (GA) 64) or at term (GA70) with preterm pups administered tiagabine (2.5 mg/kg/day), zuranolone (1 mg/kg/day) or vehicle (15% β-cyclodextrin) until term equivalent age (GA70). Behavioural testing was performed at corrected postnatal day 8 (PND8) and PND41 with tissue collection occurring at PND42. Neurodevelopmental markers (MBP, OLIG2 and NeuN) were assessed within the cerebellum by immunohistochemistry, whilst GABAergic and glutamatergic pathway expression was quantified using high throughput RT-PCR. Zuranolone and, to a lesser extent, tiagabine were able to protect against hyperactive behaviour at PND8 in males, whilst in females, a less marked hyperactive phenotype was present with neither treatment impacting behaviour further. Both treatments improved MBP staining, whilst tiagabine was found to restore oligodendrocyte maturation in females only. GABAergic and glutamatergic pathway expression was found to be restored by both treatments in females. Overall, this study demonstrates the neuroprotective attributes of neurosteroid replacement therapy using tiagabine and zuranolone, thereby demonstrating their potential to mitigate long-term neurodevelopmental impairments. Furthermore, the sexually dimorphic effects observed suggest future investigations may show increased benefit by using sex-specific treatment regimes.

Children born growth-restricted are well recognized to be at an increased risk of poor neurodevelopmental outcomes. This prospective study examined the influence of chest-to-head circumference ratio at birth on neurodevelopment in the first three years among children enrolled in the Japan Environment and Children’s Study. We analyzed information of 84,311 children (43,217 boys, 41,094 girls). Children were divided into low, normal, and high chest-to-head circumference ratio groups. Neurodevelopment was assessed every six months (from 6 months to 3 years) using the Ages and Stages Questionnaire (Japanese translation), with delays defined as scores below 2 standard deviations from the mean. Additionally, we evaluated the contributions of chest and head circumference to the observed association. Linear mixed-effect regression revealed increased risk of delays in communication, gross motor, fine motor, problem-solving, and personal-social skills in the low-ratio group compared to the normal-ratio group. Adjusted risk ratios were in the range of 1.14 – 1.39 in boys and 1.16 – 1.37 in girls, with no such increase observed in the high-ratio group. The heightened risk in the low-ratio group was likely associated with a relatively narrow chest rather than a large head. The area under the ROC curves in predicting any developmental delay at three years for newborn measurements ranged from 0.513 to 0.526 in boys and 0.509 to 0.531 in girls. These findings suggest that a low chest-to-head circumference ratio may indicate children who are at risk for neurodevelopmental deficits. However, the ability to predict poor neurodevelopmental outcomes at three years of age is limited.

Household income and caregiver mental health are important drivers of children’s health and development. The COVID-19 pandemic created huge economic and mental health disruptions. This study examines financial hardship and its relationship with caregiver and child mental health using Australia’s only representative data spanning three years of the pandemic. Analysis of the repeated, cross-sectional National Child Health Poll included 12,408 caregivers and 20,339 children over six waves (June 2020–April 2023). Caregivers reported their income (dichotomised into low versus not) and deprivation (missing one or more of eight essential items, versus not) and mental health for themselves (Kessler-6, poor versus not) and each child (Self-Rated Mental Health, poor/fair versus good/very good/excellent). Binary logistic models were fitted to predict marginal probabilities of mental health measures by low income and deprivation, over time. Results show that while low income decreased from 41% to 34% over the study period, deprivation increased from 30% to 35%. Poor mental health peaked with stay-at-home orders in 2021 before recovering. Caregivers experiencing low income or deprivation had higher rates of poor mental health throughout the study and slower recovery compared to those without financial hardship. Children in families experiencing financial hardship had slightly higher proportions of poor/fair mental health in 2021–2022, but they were mostly equivalent in June 2020 and April 2023 (range 6–8%). Addressing financial hardship may offer an avenue for improving caregiver mental health. This has implications for post-pandemic recovery and addressing contemporary issues of increasing cost of living and limited mental health supports and services.

Prenatal alcohol exposure (PAE) is associated with cognitive, behavioural, and developmental impairments throughout the lifespan of affected individuals, but there is limited evidence on how early this impact can be identified through routinely collected childhood data. This paper explores the relationship between PAE and the Early Years Foundation Stage Profile (EYFSP), a statutory teacher-based summative assessment of early development in relation to learning goals. This analysis uses the Born in Bradford dataset, a UK based cohort (n = 13,959; full dataset), which collected self-reported PAE from 11,905 mothers, with 19.8% reporting drinking alcohol at some point during pregnancy. Coarsened exact matching was conducted to examine relationships between patterns of PAE and children achieving a ‘Good Level of Development’ on the EYFSP, a binary variable assessed at 4–5 years of age, controlling for known confounders, including deprivation, mother’s education, exposure to other teratogenic substances, and child’s age at assessment. Additionally, we examined EYFSP sub-scores to identify specific developmental deficits associated with PAE.

The key finding is a statistically significant association between PAE at a level of consuming 5 or more units of alcohol (equivalent to 50 ml or 40 g of pure alcohol) at least once per week from the 4th month of pregnancy onwards and lower EYFSP scores when accounting for established confounding variables. These findings highlight that the detrimental impact of alcohol during pregnancy can be identified using statutory educational assessments. This has implications internationally for prevention work, policy, and commissioning of support services for people impacted by PAE.

While physical activity reduces the risk for chronic disease development, evidence suggests those experiencing early life growth-restriction do not express positive adaptations in response to physical activity. The purpose of this study was to examine the effects of low birthweight (LBW) on markers of chronic disease, adult physical activity, and the response to physical activity engagement in a longitudinal human cohort study. Data from the Framingham Offspring Cohort were organized to include participants with birthweight, physical activity, and chronic disease biomarker/treatment data available at two timepoints (exam 5 and exam 9, 19-year difference). A two-way ANCOVA was performed to determine the association of LBW and sex on physical activity engagement (63.0% female, 10.4% LBW). A multinomial logistic regression was performed to examine the associations of low birthweight and sex on chronic disease development while adjusting for physical activity. LBW was associated with elevated blood glucose and triglycerides (Exam 9). Though not statistically significant (p = 0.08), LBW females potentially spent more time in sedentary activity at exam 5 than LBW males and normal birthweight (NBW) females. LBW males spent significantly more time (p = 0.03) sedentary at exam 9 compared to NBW males and LBW females. There were no differences in the likelihood of chronic disease treatment between groups. Chronic disease biomarkers remained elevated when adjusted for total physical activity. In conclusion, LBW participants in the Framingham Offspring Cohort were not more likely to be treated for chronic diseases when controlling for physical activity engagement, though biomarkers of chronic disease remained elevated.

Previous studies in rodents suggest that mismatch between fetal and postnatal nutrition predisposes individuals to metabolic diseases. We hypothesized that in nonhuman primates (NHP), fetal programming of maternal undernutrition (MUN) persists postnatally with a dietary mismatch altering metabolic molecular systems that precede standard clinical measures. We used unbiased molecular approaches to examine response to a high fat, high-carbohydrate diet plus sugar drink (HFCS) challenge in NHP juvenile offspring of MUN pregnancies compared with controls (CON). Pregnant baboons were fed ad libitum (CON) or 30% calorie reduction from 0.16 gestation through lactation; weaned offspring were fed chow ad libitum. MUN offspring were growth restricted at birth. Liver, omental fat, and skeletal muscle gene expression, and liver glycogen, muscle mitochondria, and fat cell size were quantified. Before challenge, MUN offspring had lower body mass index (BMI) and liver glycogen, and consumed more sugar drink than CON. After HFCS challenge, MUN and CON BMIs were similar. Molecular analyses showed HFCS response differences between CON and MUN for muscle and liver, including hepatic splicing and unfolded protein response. Altered liver signaling pathways and glycogen content between MUN and CON at baseline indicate in utero programming persists in MUN juveniles. MUN catchup growth during consumption of HFCS suggests increased risk of obesity, diabetes, and cardiovascular disease. Greater sugar drink consumption in MUN demonstrates altered appetitive drive due to programming. Differences in blood leptin, liver glycogen, and tissue-specific molecular response to HFCS suggest MUN significantly impacts juvenile offspring ability to manage an energy rich diet.

This study examined associations between pregnancy and infant birth outcomes with child telomere length at age 17 years; and investigated if there are sex differences between pregnancy complications and telomere length. We utilised the population-based prospective Raine cohort study in Western Australia, Australia. 2900 pregnant women were recruited at 16–20 weeks’ gestation (Gen 1), and their children (Gen 2) were followed up over several years. Generalised linear models were used to examine relationships between pregnancy or birth outcomes (gestational diabetes, pre-eclampsia, preterm birth, low birth weight, macrosomia), and as a composite, with telomere length, measured via a DNA sample from blood at 17 years of age. Analyses were adjusted for a range of confounders. Among the 1202 included children, there were no differences in child telomere length for any of the individual maternal or birth weight pregnancy outcomes nor were there any significant interactions between each of the complications (individual or composite) and the sex of the child. However, females born from any of the 5 adverse outcomes had shorter telomeres (estimated mean (SE) = -0.159 (0.061), p = 0.010) than females born in the absence of these complications. Specifically, females born from a pre-eclamptic pregnancy had shorter telomeres than females not born from a pre-eclamptic pregnancy (estimated mean (SE) = -0.166 (0.072), p = 0.022). No relationships were observed in males. Further longitudinal studies are needed to understand mediating factors that are important in predicting offspring telomere length and the necessity to investigate females and males independently.

Paternal exposures (and other non-maternal factors) around pregnancy could have important effects on offspring health. One challenge is that data on partners are usually from a subgroup of mothers with data, potentially introducing selection bias, limiting generalisability of findings. We aimed to investigate the potential for selection bias in studies using partner data.

We characterise availability of data on father/partner and mother health behaviours (smoking, alcohol, caffeine and physical activity) around pregnancy from three UK cohort studies: the Avon Longitudinal Study of Parents and Children (ALSPAC), Born in Bradford and the Millennium Cohort Study. We assess the extent of sample selection by comparing characteristics of families where fathers/partners do and do not participate. Using the association of parental smoking during pregnancy and child birthweight as an example, we perform simulations to investigate the extent to which missing father/partner data may induce bias in analyses conducted only in families with participating fathers/partners.

In all cohorts, father/partner data were less detailed and collected at fewer timepoints than mothers. Partners with a lower socio-economic position were less likely to participate. In simulations based on ALSPAC data, there was little evidence of selection bias in associations of maternal smoking with birthweight, and bias for father/partner smoking was relatively small. Missing partner data can induce selection bias. In our example analyses of the effect of parental smoking on offspring birthweight, the bias had a relatively small impact. In practice, the impact of selection bias will depend on both the analysis model and the selection mechanism.

Reducing inequalities in preconception health and care is critical to improving the health and life chances of current and future generations. A hybrid workshop was held at the 2023 UK Preconception Early and Mid-Career Researchers (EMCR) Network conference to co-develop recommendations on ways to address inequalities in preconception health and care. The workshop engaged multi-disciplinary professionals across diverse career stages and people with lived experience (total n = 69). Interactive discussions explored barriers to achieving optimal preconception health, driving influences of inequalities and recommendations. The Socio-Ecological Model framed the identified themes, with recommendations structured at interpersonal (e.g. community engagement), institutional (e.g. integration of preconception care within existing services) and environmental/societal levels (e.g. education in schools). The co-developed recommendations provide a framework for addressing inequalities in preconception health, emphasising the importance of a whole-systems approach. Further research and evidence-based interventions are now needed to advance the advocacy and implementation of our recommendations.

Exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), an environmental endocrine disruptor and model AhR agonist, is linked to skeletal abnormalities, cardiac edema, stunted growth rate, altered metabolism, and neurobehavioral deficits. We have previously reported transgenerational reproductive outcomes of developmental TCDD exposure in adult zebrafish (Danio rerio), an NIH-validated model for developmental and generational toxicology. Using the same paradigm of sublethal TCDD exposure (50 pg/ml) at both 3 and 7 weeks post fertilization (wpf), we investigated several novel endpoints, including longitudinal morphometrics and anxiety-linked behavior, in fish exposed as juveniles. We also assessed developmental abnormalities and neurobehavior in their F1 larval offspring. TCDD exposure induced timepoint-dependent decreases in several craniofacial and trunk morphometrics across juvenile development. In early adulthood, however, only exposed males underwent a transient period of compensatory growth, ending between 7 and 12 months post fertilization (mpf). At 12 mpf, exposed adult fish of both sexes displayed increased exploratory behaviors in a novel tank test. The F1 offspring of parents exposed at both 3 and 7 wpf were hyperactive, but neurobehavioral outcomes diverged depending on parental exposure window. F1 exposure-lineage larvae had increased rates of edema and skeletal abnormalities, but fewer unhatched larvae compared to controls. Parent- and timepoint-specific effects of exposure on abnormality rate were also evaluated; these outcomes were considerably less severe. Our novel behavioral findings expand current knowledge of the long-term and intergenerational consequences of early-life TCDD exposure in a zebrafish model, in addition to delineating minor longitudinal morphometric changes in exposed fish and abnormalities in larval offspring.

In mammals, DNA methylation (DNAme) erasure and reinstatement during embryo development and germline establishment are sensitive to the intrauterine environment. Maternal intake of a high-fat diet (HFD), associated with excessive gestational weight gain, has transgenerational effects on offspring health, which may be mediated by changes in DNAme in the germline. Here, we tested the impact of a maternal HFD on embryonic germline DNAme erasure using a rat strain that expresses green fluorescent protein specifically in germ cells. DNAme was analysed by methyl-seq capture in germ cells collected from male and female F1 gonads at gestational day 16. Our data show that although HFD induced global hypomethylation in both sexes, DNAme erasure in female germ cells was more advanced compared to male germ cells. The delay in DNAme erasure in males and the greater impact of HFD suggest that male germ cells are more vulnerable to alterations by exogenous factors.

Early nutritional and growth experiences can impact development, metabolic function, and reproductive outcomes in adulthood, influencing health trajectories in the next generation. The insulin-like growth factor (IGF) axis regulates growth, metabolism, and energetic investment, but whether it plays a role in the pathway linking maternal experience with offspring prenatal development is unclear. To test this, we investigated patterns of maternal developmental weight gain (a proxy of early nutrition), young adult energy stores, age, and parity as predictors of biomarkers of the pregnancy IGF axis (n = 36) using data from the Cebu Longitudinal Health and Nutrition Survey in Metro Cebu, Philippines. We analyzed maternal conditional weight measures at 2, 8, and 22 years of age and leptin at age 22 (a marker of body fat/energy stores) in relation to free IGF-1 and IGFBP-3 in mid/late pregnancy (mean age = 27). Maternal IGF axis measures were also assessed as predictors of offspring fetal growth. Maternal age, parity, and age 22 leptin were associated with pregnancy free IGF-1, offspring birth weight, and offspring skinfold thickness. We find that free IGF-1 levels in pregnancy are more closely related to nutritional status in early adulthood than to preadult developmental nutrition and demonstrate significant effects of young adult leptin on offspring fetal fat mass deposition. We suggest that the previously documented finding that maternal developmental nutrition predicts offspring birth size likely operates through pathways other than the maternal IGF axis, which reflects more recent energy status.

Early life stress (ELS) and a Western diet (WD) promote mood and cardiovascular disorders, however, how these risks interact in disease pathogenesis is unclear. We assessed effects of ELS with or without a subsequent WD on behaviour, cardiometabolic risk factors, and cardiac function/ischaemic tolerance in male mice. Fifty-six new-born male C57BL/6J mice were randomly allocated to a control group (CON) undisturbed before weaning, or to maternal separation (3h/day) and early (postnatal day 17) weaning (MSEW). Mice consumed standard rodent chow (CON, n = 14; MSEW, n = 15) or WD chow (WD, n = 19; MSEW + WD, n = 19) from week 8 to 24. Fasted blood was sampled and open field test and elevated plus maze (EPM) tests undertaken at 7, 15, and 23 weeks of age, with hearts excised at 24 weeks for Langendorff perfusion (evaluating pre- and post-ischaemic function). MSEW alone transiently increased open field activity at 7 weeks; body weight and serum triglycerides at 4 and 7 weeks, respectively; and final blood glucose levels and insulin resistance at 23 weeks. WD increased insulin resistance and body weight gain, the latter potentiated by MSEW. MSEW + WD was anxiogenic, reducing EPM open arm activity vs. WD alone. Although MSEW had modest metabolic effects and did not influence cardiac function or ischaemic tolerance in lean mice, it exacerbated weight gain and anxiogenesis, and improved ischaemic tolerance in WD fed animals. MSEW-induced increases in body weight (obesity) in WD fed animals in the absence of changes in insulin resistance may have protected the hearts of these mice.

More than two-thirds of women during childbearing years (20–39 years old) are overweight or obese in the United States, with protein intake among 20–49-year-old women being 1.6 times higher than recommended (75.4 g/day versus 46 g/day) that can be considered as a relatively high-protein diet (HPD). Both gestational obesity and HPDs during gestation adversely affect offspring health. This study investigates the impact of HPDs fed during gestation and lactation on obese mothers and their offspring in Wistar rats. Dams randomized to either a normal-protein diet (NPD) or HPD (n = 12/group). Pups from each maternal group were weaned to either NPD or HPD for 17 weeks (n = 12/group). No effect of maternal or weaning diet on food intake, body weight, or body fat/weight ratio was observed. However, NPD dams exhibited higher glucose area under the curve compared with HPD dams (p < 0.03). At weaning, offspring born to NPD dams showed higher fasting plasma glucose (P < 0.03) and insulin/glucose ratio (P = 0.05) than those born to HPD dams. The Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) index was higher in offspring born to NPD dams (P < 0.04) and weaned to NPD (P < 0.05) at week 17. These findings underscore the role of high-protein maternal and weaning diets in pregnancy outcomes for obese mothers, particularly in glucose homeostasis, although gestational obesity may overshadow other parameters. Further research is needed to fully understand the impact on both maternal and offspring health and their underlying mechanisms in this context.

Early-life family meal participation has been associated with several aspects of nutritional health, but longitudinal associations with linear growth have not yet been investigated. The aim of this study was to investigate whether family meal participation at 12 months of age associates with anthropometric measures 3 years later. We used follow-up data from children born to mothers in the Norwegian Fit for Delivery trial (NFFD) and included 368 first-borns with dietary and anthropometric data at 12 months and 4 years of age. We treated the sample as a cohort and conducted subgroup analyses by randomization status. A family meal participation score was used as exposure, and weight, height, and body mass index (BMI) as outcomes in crude and multivariable linear regression models adjusted for maternal education, randomization status, and child sex.

Higher family meal participation score at 12 months was positively associated with length at 12 months (B = 0.198, 95% CI 0.028, 0.367, p = 0.022) and 4 years (B = 0.283, 95% CI 0.011, 0.555, p = 0.042) in multivariable models. After additional adjustment for maternal height the associations attenuated and were no longer significant. An inverse association with BMI at 4 years of age was observed in children born to mothers that had been exposed to the NFFD intervention (B = −0.144, 95% CI −0.275, −0.014, p = 0.030), but attenuated after adjustment for maternal BMI.

The longitudinal association observed between early family meal participation and child height was largely explained by maternal height. The relationship with BMI differed according to maternal participation in a lifestyle intervention trial during pregnancy.

This study aimed to investigate the association between maternal birth weight (MBW) with preterm delivery (PTD) in the Japanese population. To this end, a total of 78,972 Japanese pregnant women were included in a prospective birth cohort study. Multiple logistic regression and multinominal logistic regression models were applied to investigate the associations of MBW with PTD (delivery from 22 to < 37 weeks of gestation), early PTD (delivery from 22 to < 34 weeks), and late PTD (delivery from 34 to < 37 weeks). The results showed that MBW was inversely associated with PTD, early PTD, and late PTD (p-for-trend < 0.0001, 0.0014, and < 0.0001, respectively). The adjusted odds ratios per each 500 g of MBW decrease were 1.167 (95% confidence interval [CI]: 1.118–1.218) for PTD, 1.174 (95% CI: 1.070–1.287) for early PTD and 1.151 (95% CI: 1.098–1.206) for late PTD. The effect size of the association of MBW with early PTD was similar to that with late PTD. This study demonstrated for the first time an association of a low MBW with PTD, early PTD, and late PTD in a Japanese nationwide cohort.