In Australia, there are two distinct populations, each with vastly disparate health outcomes: Aboriginal and Torres Strait Islander People and non-Aboriginal Australians. Aboriginal Australians have significantly higher rates of health and socioeconomic disadvantage, and Aboriginal babies are also more likely to be born low birth weight or growth restricted. The Developmental Origins of Health and Disease (DOHaD) hypothesis advocates that a sub-optimal intrauterine environment, often manifested as diminished foetal growth, during critical periods of foetal development has the potential to alter the risk of non-communicable disease in the offspring. A better understanding of the role of the intrauterine environment and subsequent developmental programming, in response to both transgenerational and immediate stimuli, in Aboriginal Australians remains a relatively unexplored field and may provide insights into the prevailing health disparities between Aboriginal and non-Aboriginal children. This narrative review explores the role of DOHaD in explaining the ongoing disadvantage experienced by Aboriginal People in today’s society through a detailed discussion of the literature on the association between foetal growth, as a proxy for the quality of the intrauterine environment, and outcomes in the offspring including perinatal health, early life development and childhood education. The literature largely supports this hypothesis and this review therefore has potential implications for policy makers not only in Australia but also in other countries that have minority and Indigenous populations who suffer disproportionate disadvantage such as the United States, Canada and New Zealand.

Footprints in Time: The Longitudinal Study of Indigenous Children (LSIC) is a national study of 1759 Australian Aboriginal and Torres Strait Islander children living across urban, regional and remote areas of Australia. The study is in its 11th wave of annual data collection, having collected extensive data on topics including birth and early life influences, parental health and well-being, identity, cultural engagement, language use, housing, racism, school engagement and academic achievement, and social and emotional well-being. The current paper reviews a selection of major findings from Footprints in Time relating to the developmental origins of health and disease for Australian Aboriginal and Torres Strait Islander peoples. Opportunities for new researchers to conduct further research utilizing the LSIC data set are also presented.

Children of mothers with youth-onset (<18 years) type 2 diabetes (T2D) are at increased risk of youth-onset T2D. In Canada, the highest reported prevalence of youth-onset T2D is in First Nation youth, some of whom harbor a unique genetic predisposition HNF1α polymorphism which has been associated with age of onset and clinical presentation. To describe the characteristics of the Next Generation birth cohort (n=260) at 7–9 years (n=88) and 14–16 years of age (n=27). This is a cross-sectional study of offspring exposed in utero to T2D (Next Generation Birth Cohort). Annual assessments from age 7 include height and weight, and biochemical testing (glucose, insulin, lipids, HbA1c). Descriptive statistics were employed. χ2 tests and repeated-measures ANOVA were used to compare categorical and continuous characteristics, respectively. In total, 11.9% of the total cohort have developed T2D. Of those 14–16.9 years of age, 16.0% have developed T2D. 92% of the offspring ages 7–9 and 70.3% of offspring ages 14–16 are overweight or obese. Children had a significantly higher body mass index z-score than adolescents (2.9 v. 1.5, P=0.001). Comparing the different HNF1α genotypes (G/G wildtype, G/S heterozygote, S/S homozygote); HbA1c (GG: 5.5% v. G/S: 5.7% v. S/S: 8.8%; P=0.0052), insulin (GG: 103 v. G/S: 202; P=0.05) and T2D status (G/G: 5.7% v. G/S: 28.1% v. S/S: 72.7%; P<0.0001) were significantly different between groups. T2D is very common among adolescents of mothers with youth-onset T2D. Early childhood obesity and the HNF1α G319S allele are associated with the incidence of T2D in the Next Gen offspring.

Adverse pregnancy outcomes including prematurity and low birth weight (LBW) have been associated with life-long chronic disease risk for the infant. Stress during pregnancy increases the risk of adverse pregnancy outcomes. Many studies have reported the incidence of adverse pregnancy outcomes in Indigenous populations and a smaller number of studies have measured rates of stress and depression in these populations. This study sought to examine the potential association between stress during pregnancy and the rate of adverse pregnancy outcomes in Australian Indigenous women residing in rural and remote communities in New South Wales. This study found a higher rate of post-traumatic stress disorder, depression and anxiety symptoms during pregnancy than the general population. There was also a higher incidence of prematurity and LBW deliveries. Unfortunately, missing post-traumatic stress disorder and depressive symptomatology data impeded the examination of associations of interest. This was largely due to the highly sensitive nature of the issues under investigation, and the need to ensure adequate levels of trust between Indigenous women and research staff before disclosure and recording of sensitive research data. We were unable to demonstrate a significant association between the level of stress and the incidence of adverse pregnancy outcomes at this stage. We recommend this longitudinal study continue until complete data sets are available. Future research in this area should ensure prioritization of building trust in participants and overestimating sample size to ensure no undue pressure is placed upon an already stressed participant.

Childhood obesity rates are higher among Indigenous compared with non-Indigenous Australian children. It has been hypothesized that early-life influences beginning with the intrauterine environment predict the development of obesity in the offspring. The aim of this paper was to assess, in 227 mother–child dyads from the Gomeroi gaaynggal cohort, associations between prematurity, Gestation Related-Optimal Weight (GROW) centiles, maternal adiposity (percentage body fat, visceral fat area), maternal non-fasting plasma glucose levels (measured at mean gestational age of 23.1 weeks) and offspring BMI and adiposity (abdominal circumference, subscapular skinfold thickness) in early childhood (mean age 23.4 months). Maternal non-fasting plasma glucose concentrations were positively associated with infant birth weight (P=0.005) and GROW customized birth weight centiles (P=0.008). There was a significant association between maternal percentage body fat (P=0.02) and visceral fat area (P=0.00) with infant body weight in early childhood. Body mass index (BMI) in early childhood was significantly higher in offspring born preterm compared with those born at term (P=0.03). GROW customized birth weight centiles was significantly associated with body weight (P=0.01), BMI (P=0.007) and abdominal circumference (P=0.039) at early childhood. Our findings suggest that being born preterm, large for gestational age or exposed to an obesogenic intrauterine environment and higher maternal non-fasting plasma glucose concentrations are associated with increased obesity risk in early childhood. Future strategies should aim to reduce the prevalence of overweight/obesity in women of child-bearing age and emphasize the importance of optimal glycemia during pregnancy, particularly in Indigenous women.

Although low birth weight (LBW) increases the risk for type 2 diabetes (T2DM), the relationship between high birth weight (HBW) and T2DM is less definitive and largely confined to North American Indigenous populations. We re-examined the relationship between LBW (<2500 g) and HBW (>4000 g) and both T2DM and gestational diabetes (GDM) among First Nations and non-First Nations women in Saskatchewan. We analyzed new data for female subjects from a 2001 case-control study that led to our hefty fetal phenotype hypothesis. Using survival analysis techniques and a validated algorithm for identifying diabetes in health care administrative data, we followed a 1950–1984 birth cohort of 2003 women until March 31, 2013. Cox regression analysis determined the time to occurrence of first episode of GDM and diagnosis of T2DM by birth weight and ethnicity. First Nations women with HBW demonstrated a greater risk for developing both T2DM [hazard ratios (HR) 1.568; 95% confidence interval (CI) 1.188, 2.069] and GDM (HR 1.468; 95% CI 1.016, 2.121) than those with normal birth weight (NBW). Non-First Nations women with LBW had a greater risk of developing GDM than those with NBW (HR 1.585; 95% CI 1.001, 2.512). HBW is a risk factor for GDM and T2DM among First Nations women. This is likely due to exposure of these women to their own mothers’ diabetic pregnancies or gestational impaired glucose tolerance. This inter-generational amplification of T2DM risk mediated through prenatal exposures appears to play a substantial role in the epidemic of T2DM among First Nations peoples.

Barker et al. proposed that low birth weight predisposes to higher death rates in adult life. We previously confirmed this fact in a cohort of young adults who were born in a remote Australian Aboriginal community between 1956 and 1985. We now present data in these same people with four more years of follow-up and a greater number of deaths. The fates of participants were documented from age 15 years until death, start of dialysis, or until the end of 2010 and causes of death were derived from clinic narratives and dialysis records. Rates of natural deaths were compared by birth cohorts and birth weight, and hazard ratios were calculated using Cox proportional hazards methods, by birth weight and adjusted for birth cohort and sex. Over follow-up of 19,661 person-years, 61 people died of natural causes between age 15 and the censor date. Low birth weights (<2.5 kg) were associated with higher rates of natural death, with HR (95% CI) 1.76 (1.1–2.9, P=0.03), after adjustment for year of birth and sex. The effect was particularly prominent for deaths at <41 years of age, and with deaths from respiratory conditions/sepsis and unusual causes. A predisposing effect of low birth weight on adult deaths was confirmed. This phenomenon, occurring in the context of dramatically improved survivals of lower birth weight infants and children since the early 1960s, helps explain the current epidemic of chronic disease in Aboriginal people. Birth weights continue to improve, so excess deaths from this source should progressively be minimized.

Maternal adversity and fetal glucocorticoid exposure has long-term effects on cardiovascular, metabolic and behavioral systems in offspring that can persist throughout the lifespan. These data, along with other environmental exposure data, implicate epigenetic modifications as potential mechanisms for long-term effects of maternal exposures on adverse health outcomes in offspring. Advances in microarray, sequencing and bioinformatic approaches have enabled recent studies to examine the genome-wide epigenetic response to maternal adversity. Studies of maternal exposures to xenobiotics such as arsenic and smoking have been performed at birth to examine fetal epigenomic signatures in cord blood relating to adult health outcomes. However, there have been no epigenomic studies examining these effects in animal models. On the other hand, to date, only a few studies of the effects of maternal psychosocial stress have been performed in human infants, and the majority of animal studies have examined epigenomic outcomes in adulthood. In terms of maternal exposure to excess glucocorticoids by synthetic glucocorticoid treatment, there has been no epigenetic study performed in humans and only a few studies undertaken in animal models. This review emphasizes the importance of examining biomarkers of exposure to adversity throughout development to identify individuals at risk and to target interventions. Thus, research performed at birth will be reviewed. In addition, potential subject characteristics associated with epigenetic modifications, technical considerations, the selection of target tissues and combining human studies with animal models will be discussed in relation to the design of experiments in this field of study.

The hypothalamic–pituitary–adrenal axis (HPAA) plays a critical role in the functioning of all other biological systems. Thus, studying how the environment may influence its ontogeny is paramount to understanding developmental origins of health and disease. The early post-conceptional (EPC) period could be particularly important for the HPAA as the effects of exposures on organisms’ first cells can be transmitted through all cell lineages. We evaluate putative relationships between EPC maternal cortisol levels, a marker of physiologic stress, and their children’s pre-pubertal HPAA activity (n=22 dyads). Maternal first-morning urinary (FMU) cortisol, collected every-other-day during the first 8 weeks post-conception, was associated with children’s FMU cortisol collected daily around the start of the school year, a non-experimental challenge, as well as salivary cortisol responses to an experimental challenge (all Ps<0.05), with some sex-related differences. We investigated whether epigenetic mechanisms statistically mediated these links and, therefore, could provide cues as to possible biological pathways involved. EPC cortisol was associated with >5% change in children’s buccal epithelial cells’ DNA methylation for 867 sites, while children’s HPAA activity was associated with five CpG sites. Yet, no CpG sites were related to both, EPC cortisol and children’s HPAA activity. Thus, these epigenetic modifications did not statistically mediate the observed physiological links. Larger, prospective peri-conceptional cohort studies including frequent bio-specimen collection from mothers and children will be required to replicate our analyses and, if our results are confirmed, identify biological mechanisms mediating the statistical links observed between maternal EPC cortisol and children’s HPAA activity.

Adverse childhood experiences (ACEs) of parents are associated with a variety of negative health outcomes in offspring. Little is known about the mechanisms by which ACEs are transmitted to the next generation. Given that maternal depression and anxiety are related to ACEs and negatively affect children’s behaviour, these exposures may be pathways between maternal ACEs and child psychopathology. Child sex may modify these associations. Our objectives were to determine: (1) the association between ACEs and children’s behaviour, (2) whether maternal symptoms of prenatal and postnatal depression and anxiety mediate the relationship between maternal ACEs and children’s behaviour, and (3) whether these relationships are moderated by child sex. Pearson correlations and latent path analyses were undertaken using data from 907 children and their mothers enrolled the Alberta Pregnancy Outcomes and Nutrition study. Overall, maternal ACEs were associated with symptoms of anxiety and depression during the perinatal period, and externalizing problems in children. Furthermore, we observed indirect associations between maternal ACEs and children’s internalizing and externalizing problems via maternal anxiety and depression. Sex differences were observed, with boys demonstrating greater vulnerability to the indirect effects of maternal ACEs via both anxiety and depression. Findings suggest that maternal mental health may be a mechanism by which maternal early life adversity is transmitted to children, especially boys. Further research is needed to determine if targeted interventions with women who have both high ACEs and mental health problems can prevent or ameliorate the effects of ACEs on children’s behavioural psychopathology.

Children of parents with major mood and psychotic disorders are at increased risk of psychopathology, including psychotic symptoms. It has been suggested that the risk of psychosis may be more often transmitted from parent to opposite-sex offspring (e.g., from father to daughter) than to same-sex offspring (e.g., from father to son). To test whether sex-specific transmission extends to early manifestations of psychosis, we examined sex-specific contributions to psychotic symptoms among offspring of mothers and fathers with depression, bipolar disorder and schizophrenia. We assessed psychotic symptoms in 309 offspring (160 daughters and 149 sons) aged 8–24 years (mean=13.1, s.d.=4.3), of whom 113 had a mother with schizophrenia, bipolar disorder or major depression and 43 had a father with schizophrenia, bipolar disorder or major depression. In semi-structured interviews, 130 (42%) offspring had definite psychotic symptoms established and confirmed by psychiatrists on one or more assessments. We tested the effects of mental illness in parents on same-sex and opposite-sex offspring psychotic symptoms in mixed-effect logistic regression models. Psychotic symptoms were more prevalent among daughters of affected fathers and sons of affected mothers than among offspring of the same sex as their affected parent. Mental illness in the opposite-sex parent increased the odds of psychotic symptoms (odds ratio (OR)=2.65, 95% confidence interval (CI) 1.43–4.91, P=0.002), but mental illness in the same-sex parent did not have a significant effect on psychotic symptoms in offspring (OR=1.13, 95% CI 0.61–2.07, P=0.697). The opposite-sex-specific parent-of-origin effects may suggest X chromosome-linked genetic transmission or inherited chromosomal modifications in the etiology of psychotic symptoms.

The preconception, pregnancy and immediate postpartum and newborn periods are times for mothers and their offspring when they are especially vulnerable to major stressors – those that are sudden and unexpected and those that are chronic. Their adverse effects can transcend generations. Stressors can include natural disasters or political stressors such as conflict and/or migration. Considerable evidence has accumulated demonstrating the adverse effects of natural disasters on pregnancy outcomes and developmental trajectories. However, beyond tracking outcomes, the time has arrived for gathering more information related to identifying mechanisms, predicting risk and developing stress-reducing and resilience-building interventions to improve outcomes. Further, we need to learn how to encapsulate both the quantitative and qualitative information available and share it with communities and authorities to mitigate the adverse developmental effects of future disasters, conflicts and migrations. This article briefly reviews prenatal maternal stress and identifies three contemporary situations (wildfire in Fort McMurray, Alberta, Canada; hurricane Harvey in Houston, USA and transgenerational and migrant stress in Pforzheim, Germany) where current studies are being established by Canadian investigators to test an intervention. The experiences from these efforts are related along with attempts to involve communities in the studies and share the new knowledge to plan for future disasters or tragedies.

Indigenous women and children experience some of the most profound health disparities globally. These disparities are grounded in historical and contemporary trauma secondary to colonial atrocities perpetuated by settler society. The health disparities that exist for chronic diseases may have their origins in early-life exposures that Indigenous women and children face. Mechanistically, there is evidence that these adverse exposures epigenetically modify genes associated with cardiometabolic disease risk. Interventions designed to support a resilient pregnancy and first 1000 days of life should abrogate disparities in early-life socioeconomic status. Breastfeeding, prenatal care and early child education are key targets for governments and health care providers to start addressing current health disparities in cardiometabolic diseases among Indigenous youth. Programmes grounded in cultural safety and co-developed with communities have successfully reduced health disparities. More works of this kind are needed to reduce inequities in cardiometabolic diseases among Indigenous women and children worldwide.

The Indian residential school (IRS) system in Canada ran for over a century until the last school closed in 1996. Conditions in the IRSs resulted in generations of Indigenous children being exposed to chronic childhood adversity. The current investigation used data from the 2008–2010 First Nations Regional Health Survey to explore whether parental IRS attendance was associated with suicidal thoughts and attempts in childhood, adolescence and in adulthood among a representative sample of First Nations peoples living on-reserve across Canada. Analyses of the adult sample in Study 1 (unweighted n=7716; weighted n=186,830) revealed that having a parent who attended IRS was linked with increased risk for suicidal thoughts and attempts in adolescence and adulthood. Although females were negatively affected by having a parent who attended IRS, the link with suicidal ideation in adulthood was greater for males. Analyses of the youth sample in Study 2 (unweighted n=2883; weighted n=30,190) confirmed that parental IRS attendance was associated with an increased risk for suicidal ideation and attempts. In contrast to the adult sample, parental IRS attendance had a significantly greater relation with suicidal ideation among female youth. A significant interaction also emerged between parental IRS attendance and age in the youth sample, with the influence of parental attendance being particularly strong among youth ages 12–14, compared with those 15–17 years. These results underscore the need for culturally relevant early interventions for the large proportions of Indigenous children and youth intergenerationally affected by IRSs and other collective traumas.

The epidemic of prescription and non-prescription opioid misuse is of particular importance in pregnancy. The Society of Obstetricians and Gynaecologists of Canada currently recommends opioid replacement therapy with methadone or buprenorphine for opioid-dependent women during pregnancy. This vulnerable segment of the population has been shown to be at increased risk of blood-borne infectious diseases, nutritional insecurity and stress. The objective of this study was to describe an urban cohort of pregnant women on opioid replacement therapy and to evaluate potential effects on the fetus. A retrospective chart review of all women on opioid replacement therapy and their infants who delivered at The Ottawa Hospital General and Civic campuses between January 1, 2013 and March 24, 2017 was conducted. Data were collected on maternal characteristics, pregnancy outcomes, neonatal outcomes and corresponding placental pathology. Maternal comorbidities identified included high rates of infection, tobacco use and illicit substance use, as well as increased rates of placental abruption compared with national averages. Compared with national baseline averages, the mean neonatal birth weight was low, and the incidence of small for gestational age infants and congenital anomalies was high. The incidence of NAS was comparable with estimates from other studies of similar cohorts. Findings support existing literature that calls for a comprehensive interdisciplinary risk reduction approach including dietary, social, domestic, psychological and other supports to care for opioid-dependent women in pregnancy.