Introduction

Non-communicable diseases (NCDs) including obesity, diabetes and cardiovascular disease are the leading causes of death worldwide, accounting for almost two-thirds of the global mortality rate . This epidemic is observed across all socio-economic strata but is rising fastest among lower-income countries and among marginalized populations in low socio-economic strata. In addition, the World Health Organization has predicted a 17% increase in NCDs over the next decade .

Indigenous populations have a high burden of illness compared to their non-Indigenous counterparts with a life expectancy in many Indigenous populations lower than that of the general population . Indigenous adults have high rates of type 2 diabetes (T2D) and cardiovascular disease . Worldwide, the prevalence of T2D in youth is increasing, disproportionally affecting youth of Indigenous heritage . In adults, diabetes-related complications also appear to disproportionally affect individuals of Indigenous origin . Complication data in youth-onset T2D are now just emerging with much of the limited complication data being derived from studies in predominantly Indigenous populations. Complications appear to occur early and aggressively . Currently, no published reports have examined whether Indigenous youth are more vulnerable to diabetes-associated complications than non-Indigenous youth with T2D.

Evidence to date supports obesity, in utero exposure to maternal malnutrition (under- and over-nutrition), hyperglycaemia, smoking and low socio-economic status as common risk factors for youth-onset T2D and the risk of cardiovascular disease. The effect of stress exposure in utero or in early childhood has not yet clearly been delineated, but it is expected to be an important factor in future health risks to offspring. The rates of overweight and obesity are high in the Indigenous population, both in adults ( http://www.phac-aspac.gc.ca/cd-mc/publictions/diabetes-diabete/facts-figures-faits-chiffres-2011/chaptereng.php ) and in children , and are significantly higher than in the non-Indigenous populations of Canada, New Zealand, Australia and the United States . The smoking rates have significantly decreased over the past several decades in many developed countries including Canada, the United States, New Zealand and Australia. However, in the Indigenous populations of these regions, the same trend has not been seen and rates of smoking remain high . A disparity in the social determinants of health related to colonization, living conditions and low socio-economic status has resulted in a disproportionate burden of chronic mental and physical disease in Indigenous populations . It is well accepted that Indigenous peoples suffer significant psychological and physiological stressors. The reported rates of suicide in Indigenous populations of Australia, Canada and the United States are two to three times higher than the total population rates in these countries with the main risk factors of suicide identified as mental health disorders, stressful life events and substance abuse .

The developmental origins of health and disease (DOHaD) are increasingly acknowledged to be an important predictor of future chronic NCD burden. A substantial body of evidence dating back to the Barker hypothesis suggests that in utero exposures including maternal nutrition, glucose metabolism, smoking, stress and gestational weight gain alter foetal programming and development through epigenetic modifications and other as yet unclear mechanisms. Environmental influences on early-life adaptive processes and subtle effects of foetal programming due to in utero exposures (developmental plasticity) are increasingly acknowledged to play an important role in the future metabolic health of the offspring. This phenomenon is often called ‘metabolic foetal programming’ and is evidence to support the DOHaD theory. The DOHaD theory posits that in utero exposures to metabolic derangement (classically malnutrition) during critical windows of foetal development program cellular energy metabolism, effectively increasing an individual’s susceptibility to cardio-metabolic diseases in adulthood .

Given the heavy burden of NCDs and cardio-metabolic risk described in both Indigenous children and adults, it is imperative to understand the early determinants of health and disease to plan effective interventions. This paper explores the relationship between select maternal health issues and cardio-metabolic outcomes in the offspring with a focus on Indigenous populations.

Maternal diabetes

Worldwide, the prevalence of diabetes in pregnancy is increasing, and, thus, there is a rise in the number of children exposed to diabetes in utero . The majority of this increase is due to increasing rates of gestational diabetes and pregestational T2D with Indigenous women being disproportionally affected. In most studies, the rate of gestational diabetes is higher in Indigenous women than their non-Indigenous counterparts . The published rates of diabetes in pregnancy in Indigenous women around the world vary from approximately 7% to 12% compared to a worldwide prevalence of 2–5% .

In the Pima Indians of the south-western United States, the risk of developing T2D was significantly greater in siblings exposed to diabetes in utero compared to siblings born before the mother developed diabetes (odds ratio (OR) 3.7) . By contrast, there were no significant differences in the rate of T2D between siblings born before or after a paternal diagnosis of diabetes . This indicates that exposure to an in utero diabetic environment confers a risk independent of any genetic contribution. In the Pima Indians, maternal diabetes during pregnancy is the strongest single risk factor for youth-onset T2D, accounting for >40% of T2D in that population . Similarly, in Canadian First Nation youth, maternal pregestational diabetes was a significant predictor of youth-onset T2D (OR 14.4) as was maternal gestational diabetes (OR 4.4) . In the multiethnic American SEARCH for Diabetes in Youth study, in utero exposure to maternal diabetes was independently associated with T2D in youth . In addition, the SEARCH study also demonstrated that youth with T2D exposed to maternal diabetes were, on average, 1.68 years younger at diagnosis compared to youth not exposed to maternal diabetes in utero .

The ‘Next Generation Project’ is a prospective longitudinal cohort study following up the offspring of mothers of Canadian First Nation heritage diagnosed with T2D before the age of 18 and prior to pregnancy. Thus, all offspring have been exposed to maternal pregestational T2D . The risk of youth-onset T2D is extraordinarily high in these offspring. Twenty-five percent of those >7 years of age and 43% of those ≥10 years have developed T2D prior to the age of 18 . In this cohort, the mean age of diagnosis of diabetes was 10.4 years, younger than the typical mean age of onset of 13.5 years .

Exposure to maternal diabetes in utero also increases the risk of obesity in the offspring. In the multiethnic EPOCH (Exploring Perinatal Outcomes among Children) study, children exposed to gestational diabetes had increased body mass index (BMI), waist circumference and visceral and subcutaneous fat, with more central fat distribution at age 6–13 years compared to unexposed youth . The Hyperglycemia and Adverse Pregnancy Outcomes Study (HAPO) reported a linear association between maternal glycaemia in pregnancy and neonatal adiposity and birth size, but this relationship did not persist when children were followed up to the age of 2 years . Retrospective studies have demonstrated a positive relationship between maternal glycaemia, even within the ranges of normal, and adiposity of offspring at age 5–7 years . In the Pima Indians, children of mothers with pregestational or gestational diabetes were larger for gestational age and, at age 5, were heavier than children whose mothers had either prediabetes or no diabetes during pregnancy . Sibling studies in the Pima have also demonstrated a significantly higher mean BMI in siblings exposed to maternal pregestational diabetes compared to siblings born prior to the mother’s diagnosis . In the ‘Next Generation Project’, 89% of the cohort of First Nation children exposed to pregestational diabetes were either overweight or obese at ages 2–19 years . In a separate report of Canadian First Nation children, a non-significant association between exposure to maternal obesity during pregnancy and youth-onset T2D in the offspring was observed .

Maternal diabetes

Worldwide, the prevalence of diabetes in pregnancy is increasing, and, thus, there is a rise in the number of children exposed to diabetes in utero . The majority of this increase is due to increasing rates of gestational diabetes and pregestational T2D with Indigenous women being disproportionally affected. In most studies, the rate of gestational diabetes is higher in Indigenous women than their non-Indigenous counterparts . The published rates of diabetes in pregnancy in Indigenous women around the world vary from approximately 7% to 12% compared to a worldwide prevalence of 2–5% .

In the Pima Indians of the south-western United States, the risk of developing T2D was significantly greater in siblings exposed to diabetes in utero compared to siblings born before the mother developed diabetes (odds ratio (OR) 3.7) . By contrast, there were no significant differences in the rate of T2D between siblings born before or after a paternal diagnosis of diabetes . This indicates that exposure to an in utero diabetic environment confers a risk independent of any genetic contribution. In the Pima Indians, maternal diabetes during pregnancy is the strongest single risk factor for youth-onset T2D, accounting for >40% of T2D in that population . Similarly, in Canadian First Nation youth, maternal pregestational diabetes was a significant predictor of youth-onset T2D (OR 14.4) as was maternal gestational diabetes (OR 4.4) . In the multiethnic American SEARCH for Diabetes in Youth study, in utero exposure to maternal diabetes was independently associated with T2D in youth . In addition, the SEARCH study also demonstrated that youth with T2D exposed to maternal diabetes were, on average, 1.68 years younger at diagnosis compared to youth not exposed to maternal diabetes in utero .

The ‘Next Generation Project’ is a prospective longitudinal cohort study following up the offspring of mothers of Canadian First Nation heritage diagnosed with T2D before the age of 18 and prior to pregnancy. Thus, all offspring have been exposed to maternal pregestational T2D . The risk of youth-onset T2D is extraordinarily high in these offspring. Twenty-five percent of those >7 years of age and 43% of those ≥10 years have developed T2D prior to the age of 18 . In this cohort, the mean age of diagnosis of diabetes was 10.4 years, younger than the typical mean age of onset of 13.5 years .

Exposure to maternal diabetes in utero also increases the risk of obesity in the offspring. In the multiethnic EPOCH (Exploring Perinatal Outcomes among Children) study, children exposed to gestational diabetes had increased body mass index (BMI), waist circumference and visceral and subcutaneous fat, with more central fat distribution at age 6–13 years compared to unexposed youth . The Hyperglycemia and Adverse Pregnancy Outcomes Study (HAPO) reported a linear association between maternal glycaemia in pregnancy and neonatal adiposity and birth size, but this relationship did not persist when children were followed up to the age of 2 years . Retrospective studies have demonstrated a positive relationship between maternal glycaemia, even within the ranges of normal, and adiposity of offspring at age 5–7 years . In the Pima Indians, children of mothers with pregestational or gestational diabetes were larger for gestational age and, at age 5, were heavier than children whose mothers had either prediabetes or no diabetes during pregnancy . Sibling studies in the Pima have also demonstrated a significantly higher mean BMI in siblings exposed to maternal pregestational diabetes compared to siblings born prior to the mother’s diagnosis . In the ‘Next Generation Project’, 89% of the cohort of First Nation children exposed to pregestational diabetes were either overweight or obese at ages 2–19 years . In a separate report of Canadian First Nation children, a non-significant association between exposure to maternal obesity during pregnancy and youth-onset T2D in the offspring was observed .

Maternal nutrition

Both maternal under-nutrition and over-nutrition have been shown in animal models to affect foetal growth and adiposity . The evidence linking birth weight and adiposity to poorer cardio-metabolic health suggests that maternal nutrition is an important foetal exposure in determining the risk of adult cardiovascular disease . Initially, research into the developmental origins of NCD focused on the mismatch between the in utero environment and the ex utero environment of the offspring. When maternal under-nutrition is paired with foetal and childhood over-nutrition, there is an increased incidence of adiposity, insulin resistance and cardiovascular disease . This observation is supported by experimental evidence from animal models that demonstrate nutritional mismatch between in utero and ex utero life resulting in obesity, insulin resistance and elevated leptin levels, elevated blood pressure, endothelial dysfunction and cardiac disease .

With the relative insulin resistance of pregnancy and the resultant transplacental transfer of glucose, free fatty acids and amino acids to the developing foetus, recent attention is being paid to foetal over-nutrition and future cardio-metabolic risk. Few studies have attempted to dissect the effects of individual macronutrients (fats, protein and carbohydrates) on foetal and neonatal adiposity, with one study focusing on the composition of maternal diet on the adiposity of the offspring . This study suggested differential acquisition of foetal fat depending on the dietary composition consumed by the mother. Diets with low protein and low protein to carbohydrate ratio were positively associated with a higher percentage of abdominal fat in the newborn. Mid-thigh fat was positively associated with a maternal diet composed of high-fat, low-carbohydrate and intermediate-protein content.

Few studies have looked at the influence of maternal vitamin status on offspring adiposity. Studies of maternal vitamin D status have had conflicting results. Crozier et al. reported a positive association between low maternal vitamin D levels and increased fat mass of offspring at ages 4 and 6 years compared to mothers with higher vitamin D levels . A similar association was not found in the Avon Longitudinal Study of Parents and Children (ALSPAC) who concluded there was no strong evidence for maternal vitamin D status to predict metabolic risk in offspring at ages 9 and 15 years .

Maternal lipid metabolism

There are limited human studies isolating the role of lipid metabolism and maternal fat intake with health outcomes in the offspring. In pregnancies complicated by gestational diabetes with well-controlled glycaemia, maternal serum free fatty acids predicted foetal size and abdominal circumference and newborn serum free fatty acids and fat mass . In addition, higher maternal n-6 polyunsaturated fatty acid (PUFA) levels at 34 weeks have been shown to predict higher fat mass in offspring at 4 years of age . Animal models have shown that rats fed high-fat diets during pregnancy have pups with higher levels of insulin and leptin as well as a higher whole-body adiposity . In addition, a recent review of studies in rodents have revealed that a maternal diet high in fat or low in protein results in offspring with hepatic steatosis and/or cardiac steatosis suggesting foetal programming for future ectopic lipid accumulation. Ectopic lipid accumulation is an independent risk factor for the development of the metabolic syndrome .

Maternal adiposity

Previous epidemiologic and experimental evidence for the DOHaD theory focused on maternal under-nutrition and macro- and micronutrient deficiencies. The current epidemic of maternal overweight and obesity has resulted in increasing interest in the role of maternal adiposity on the cardio-metabolic health of the offspring. In the United States and Canada, it is estimated that up to one-third of women of childbearing age are obese . Obesity in pregnancy is known to be associated with an increased risk of maternal glucose intolerance and gestational diabetes, itself a risk factor for future cardio-metabolic disease in offspring (see the section on maternal diabetes).

Prepregnancy maternal obesity has also been shown to be an independent risk factor for obesity and development of the metabolic syndrome in the offspring. In the American SEARCH for Diabetes in Youth study, 19.7% of youth-onset T2D was independently attributed to exposure to maternal obesity during gestation . In addition, excessive gestational weight gain is associated with increased adiposity in offspring . In a study focused on Indigenous offspring, children born to a mother who was obese during the pregnancy had 4.8 times the odds of obesity themselves at age 1–5 years compared to offspring of mothers who were not obese in pregnancy. Other epidemiological evidence has revealed an independent positive relationship between maternal BMI and BMI, insulin resistance and other measures of adiposity in the offspring . Recently, it has been reported that children born to women with prepregnancy obesity prior to gastric bypass surgery have an increased risk of obesity and cardio-metabolic disease compared to their siblings born post surgery after their mother had normalized her weight . Adult outcomes of offspring born to mothers who were overweight or obese in pregnancy have been reported by investigators in Scotland using national birth, hospital admission and death records . Results from 37,709 individuals revealed that maternal BMI was associated with higher rates of all-cause mortality and admission to hospital for cardiovascular events independent of maternal age at gestation, sex, current age of offspring, birth weight, gestational age and gestation at measurement of BMI.

Maternal smoking

There is a growing body of evidence demonstrating a relationship between maternal smoking during pregnancy and subsequent cardio-metabolic risk in the offspring. Data specific to Indigenous populations are sparse. However, smoking rates in Indigenous women of childbearing age are high , as are rates of maternal smoking during pregnancy . The association between maternal smoking and low birth weight is well established and is not reviewed in this article.

Foetal exposure to maternal smoking and subsequent overweight and obesity in the offspring during childhood have been shown in many studies . In a study of American Indian children, children exposed to maternal smoking in pregnancy had a 2× odds of being overweight at age 3 compared to children not exposed . Early data in non-Indigenous populations suggest that maternal smoking negatively affects the lipid profile and is specifically associated with lower high-density lipoprotein cholesterol (HDL-c) in childhood . Maternal smoking in pregnancy was not related to levels of lipoprotein (a) in a cohort of aboriginal children at a mean age of 11.34 years .

Associations between maternal smoking during pregnancy and other cardio-metabolic risk factors have been described. Several studies have demonstrated higher blood pressure in children exposed to maternal smoking during pregnancy compared to children not exposed. However, this finding was not uniform and the effect size appears to be relatively small after adjustment for potential confounders . In a large birth cohort study, exposure to maternal smoking in the third trimester was associated with the development of insulin resistance at age 10 years . This was not explained by the lower birth weight. Data from the British National Child Development Study suggest that maternal smoking during pregnancy is a risk factor for the development of diabetes in the offspring in adulthood independent of BMI . The underlying mechanisms to explain these findings remain unclear but the proposed mechanisms are discussed below.

Maternal stress

The relationship between stress and disease, including cardio-metabolic disorders in adults, is well established though the understanding of the pathophysiologic mechanisms remains imperfect. One study examining the role of marginalization of the Sami people of northern Norway and the risk of cardiovascular disease revealed that Sami people living in a predominantly Norwegian area had more than two times the risk of cardiovascular disease than Sami living in Sami majority areas . Much less evidence exists for the potentially important role of maternal stress during pregnancy on cardio-metabolic disease risk in offspring. For Indigenous women who face a significant burden of stress, the implication of in utero exposure to maternal stress is being recognized as a significant void in our understanding of the developmental origins of health and disease.

To date, much of the work on in utero exposure to maternal stress has focused on childhood neurocognitive and behavioural outcomes. To this end, stress in pregnancy has been associated with impaired neurocognitive development in the offspring and attention-deficit hyperactivity disorder (ADHD) . Recent evidence supports the effect of stress in pregnancy with low birth weight of offspring suggesting that maternal stress may be an important component influencing the cardio-metabolic risk in offspring who are born small for gestational age. Additionally, women of low socio-economic status have been reported to have poor diet quality in the first trimester of pregnancy with diet quality being negatively correlated with depression and stress suggesting the potential of stress to act through diet in conferring cardio-metabolic risk . Animal models of stress in pregnancy have shown impacts on offspring cardiovascular response to stress and glucose tolerance . To date, there are no published studies on perinatal stress and long-term cardio-metabolic risk in offspring into adulthood. Epidemiological evidence may come from the Amsterdam Born Children and their Development (ABCD) study, a longitudinal cohort study that collected data on maternal stress in pregnancy and adiposity, lipid profiles, insulin sensitivity and blood pressure in the offspring . Indeed, they have recently reported higher systolic and mean blood pressures in 5–7-year-old offspring of mothers reporting multiple psychosocial stressors during pregnancy compared to the offspring of mothers with no reported stressors .

Mechanism of risk

While the observational data reviewed in this manuscript are compelling, the mechanisms by which in utero exposures increase the risk of the development of obesity, T2D and cardiovascular disease in children remain poorly understood. The mechanisms are likely to be complex and, in part, involve alterations in the structure and/or function of main metabolic regulatory organs, the adipoinsular axis and/or epigenetic modifications.

Alterations in the adipoinsular axis

The adipoinsular axis describes the interaction between adipocytokines, leptin and insulin produced by the adipocyte (adipocytokines and leptin) and pancreas (insulin), respectively. The adipoinsular axis connects the endocrine pancreas, adipose tissue and the areas of the brain that regulate hunger and the storage of fat. Abnormalities of this axis may result in abnormal appetite regulation and/or abnormal energy regulation resulting in hyperphagia and excess fat storage leading to obesity and insulin resistance . The intimate relationship between glycaemia and adiposity is, in part, a direct result of the adipoinsular axis which connects the pancreatic insulin response to the fed and fasted state to adipose hormone signalling through leptin to mediate hunger, satiety and differential fuel storage and metabolism.

In utero exposures that alter the adipoinsular axis affect energy metabolism and appetite regulation predisposing the exposed offspring to increased adiposity (storage of fuel) and abnormal appetite signalling. Animal and human evidence for dysregulation of the adipoinsular axis has been gleaned from studies of leptin levels in cord blood and in infants born to mothers with varying degrees of exposure to over-nutrition in pregnancy. In the offspring of mothers with gestational diabetes, leptin and insulin concentrations were elevated relative to infants born to normoglycaemic mothers . Alterations in leptin and insulin signalling in the foetal and newborn period may disrupt the regulatory mechanisms and sensitivity to these signals in later life resulting in the increased risk of overweight, obesity and glucose dysregulation.