Consequences of fetal programming for cardiovascular disease in adulthood

This Spotlight Issue of Microcirculation contains six current perspectives on the role of the intrauterine environment, especially maternal nutritional status and maternal diabetes, in influencing fetal growth and cardiovascular health in the offspring in later life. The reviews address issues such as the existence of a commonality of mechanism following both under-nutritional and over-nutritional states in utero; alterations in the placental fetal microcirculation in response to maternal and fetal changes; transmission of metabolic or nutritional perturbations affecting fetal endogenous antioxidant defense pathways; the presence of a disadvantageous microvascular phenotype resulting from perinatal priming; interactions between developmental programming and genetic variation in noncommunicable adult diseases such as hypertension and hypercholesterolemia; and unresolved questions on the independency and causal mechanisms for low birth weight/intrauterine growth restriction and the risk of developing the metabolic syndrome. These timely reviews highlight the accumulating evidence that changes in the intrauterine environment have pronounced effects on vascular function in the offspring whether due to maternal diabetes or altered maternal nutritional status or fetal and perinatal overnutrition.     

Maternal/Fetal Determinants of Insulin Resistance in Women During Pregnancy and in Offspring Over Life

Insulin resistance is a component of the pathophysiology of both type 2 diabetes and gestational diabetes mellitus (GDM), but is also characteristic of normal glycemic physiology during pregnancy. In recent years, many studies have tried to understand determinants of insulin resistance in normal pregnancy and GDM, revealing that the placenta is capable of secreting many cytokines and hormones, classically considered as adipokines. More specifically, it appears that leptin and TNFα could be implicated in gestational insulin resistance and GDM pathophysiology. In addition, the maternal metabolic milieu was also identified as a key determinant of later insulin resistance in offspring, a phenomenon often described as ‘fetal programming’. This article reviews the established risk factors and the more novel suspected biomarkers involved in maternal insulin resistance during pregnancy as well as the maternal and early life determinants of insulin resistance in offspring later in their life. We are also highlighting recent reports of the potential mechanisms involved in ‘programming’ of insulin resistance such as epigenetic modulation.     

Do pregnancy complications and CVD share common antecedents?

Considerable data link low birth weight, due to intrauterine growth restriction, to increased offspring risk of vascular disease in later adult life. This is considered to be the result, in part, of programming through fetal nutrition. These data support the hypothesis that pregnancy outcome in terms of birth weight is linked to the infant's subsequent health. In contrast, much less attention has been focused on the relationship between adverse pregnancy outcomes, such as pre-eclampsia, gestational diabetes, pre-term delivery and intrauterine growth restriction, and the mother's subsequent health. Interesting data have accumulated linking the maternal vascular, metabolic and inflammatory complications of pregnancy to an increased risk of vascular disease in later life (Table 1). This paper reviews the emerging evidence to support this fascinating concept, addresses potential mechanisms and discusses potential clinical implications.     

Metabolic Programming,Epigenetics, and Gestational Diabetes Mellitus

The link between an adverse intrauterine environment and the development of disease later in life has been observed in offspring of pregnancies complicated by obesity and diabetes, but the molecular mechanisms underlying this phenomenon are unknown. In this review, we highlight recent publications exploring the role of gestational diabetes mellitus in the programming of disease in the offspring. We also review recent publications aiming to identify mechanisms responsible for the “programming effect” that results from exposure to diabetes in utero. Finally, we highlight research on the role of epigenetic regulation of gene expression in an animal model of uteroplacental insufficiency where the offspring develop diabetes as a model by which an exposure to the mother can alter epigenetic modifications that affect expression of key genes and ultimately lead to the development of diabetes in the offspring.     

Associations of maternal type 1 diabetes with childhood adiposity and metabolic health in the offspring: a prospective cohort study

Aims/hypothesis

Exposure to an intrauterine hyperglycaemic environment has been suggested to increase the offspring’s later risk for being overweight or having metabolic abnormalities, but conclusive evidence for pregnancies affected by maternal type 1 diabetes is still lacking. This study aims to analyse the relationship between maternal type 1 diabetes and the offspring’s metabolic health and investigate whether birthweight and/or changes in the offspring’s metabolome are in the potential pathway.

Methods

We analysed data from 610 and 2169 offspring having a first-degree relative with type 1 diabetes from the TEENDIAB and BABYDIAB/BABYDIET cohorts, respectively. Anthropometric and metabolic outcomes, assessed longitudinally at 0.3–18 years of age, were compared between offspring of mothers with type 1 diabetes and offspring of non-diabetic mothers but with fathers or siblings with type 1 diabetes using mixed regression models. Non-targeted metabolomic measurements were carried out in 500 individuals from TEENDIAB and analysed with maternal type 1 diabetes and offspring overweight status.

Results

The offspring of mothers with type 1 diabetes had a higher BMI SD score (SDS) and an increased risk for being overweight than the offspring of non-diabetic mothers (e.g. OR for overweight status in TEENDIAB 2.40 [95% CI 1.41, 4.06]). Further, waist circumference SDS, fasting levels of glucose, insulin and C-peptide, and insulin resistance and abdominal obesity were significantly increased in the offspring of mothers with type 1 diabetes, even when adjusted for potential confounders and birthweight. Metabolite patterns related to androgenic steroids and branched-chain amino acids were found to be associated with offspring’s overweight status, but no significant associations were observed between maternal type 1 diabetes and metabolite concentrations in the offspring.

Conclusions/interpretation

Maternal type 1 diabetes is associated with offspring’s overweight status and metabolic health in later life, but this is unlikely to be caused by alterations in the offspring’s metabolome.

     

胚胎发育不良与成年后代谢性疾病的关系

胚胎发育不良与成年后许多代谢性疾病的发生密切相关,大量的流行病学资料支持这一观点,并在多种动物模型上得到了证实。胚胎发育过程主要受母体孕时状况以及胚胎生长环境的影响。母体营养不良、感染、吸烟、缺氧、妊娠糖尿病等不良状况都将对胎儿的多个系统功能产生影响,这种影响不但可持续一生,并导致个体成年后易发生2型糖尿病、高血压、肥胖等代谢性疾病。目前的研究认为,胚胎发育的宫内程序化改变及氧化应激可能是其共同的致病机制。     

The prenatal environment and type 1 diabetes

There is ample evidence that environmental factors are involved in the aetiology of type 1 diabetes, but the nature and timing of the interactions are poorly understood. The intrauterine environment is known to play a role in the later development of type 2 diabetes, and this review considers a possible role in type 1 diabetes. Autoimmune type 1 diabetes is rare in those diagnosed before 6 months of age, but endogenous autoantibodies predictive of future type 1 diabetes may be detectable by 6–12 months of age, suggesting that environmental factors may operate before this age in some cases. Indirect evidence of a protective effect for the intrauterine environment comes from the observation that mothers with type 1 diabetes are less likely than affected fathers to transmit diabetes to their offspring, although the precise role (if any) is unclear. The risk of childhood-onset type 1 diabetes increases with maternal age at delivery, and with high birthweight, but these associations are weak and heterogeneous, and these factors are unlikely to be directly causally related to type 1 diabetes. No firm conclusion can be drawn from studies of maternal enteroviral infection or from various nutritional exposures. The birth process itself may play a role, as suggested by the slightly increased risk in children born by Caesarean section; lack of contact with maternal bacteria is one suggested mechanism. In sum, there is circumstantial evidence, but no proof of principle, that maternal or intrauterine conditions may modulate genetic risk of type 1 diabetes. The disease process culminating in type 1 diabetes typically begins in early life, but it is not clear whether the trail begins before or after birth.     

Animal models of gestational diabetes: characteristics and consequences to the brain and behavior of the offspring

Gestational diabetes (GD) is the glucose intolerance that occurs during pregnancy. Mothers who develop diabetes during gestation are at increased risk of developing type 2 diabetes mellitus (T2DM) later in life, and the risk of adverse fetal and neonatal outcomes are also increased as a function of maternal hyperglycemia. Infants who are exposed to fetal hyperglycemia show an increased risk of becoming obese and developing T2DM later in life. Due to the need of new research on this field, and the difficulty of performing studies in human brain, studies using experimental models are necessary to suggest possible ways to avoid or inhibit offspring brain damage or harmful metabolic alterations. Here, it was made a review about the characteristics of the main animal models of GD, and what are the consequences to the brain and behavior of the offspring. In many experimental models, either by pharmacological induction, diet manipulation, or in the use of transgenic animals, glycemic conditions are severe. S961, a selective insulin receptor antagonist, revealed an increased fasting blood glucose level and glucose intolerance during mid-gestation, which returned to basal levels postpartum in mice. GD contributes to offspring neuroinflammation, influences neuronal distribution in central nervous system (CNS), and apoptosis during embryogenesis, which in turn may contribute to changes in behavior and memory in adult life and aging. The usage of animal models to study GD allows to examine extensively the characteristics of this condition, the molecular mechanisms involved and the consequences to the brain and behavior of the offspring.

     

Obesity and Diabetes in Mothers and Their Children: Can We Stop the Intergenerational Cycle?

Obesity prevalence in the United States has reached an alarming level. Consequently, more young women are entering pregnancy with body mass indices of at least 30 kg/m². While higher maternal weight entering pregnancy is related to several adverse pregnancy outcomes, some of the strongest and most compelling data to date have linked prepregnancy obesity to gestational diabetes mellitus (GDM). The mechanisms by which excess maternal weight influences metabolic dysfunction in pregnancy are similar to those in obese nonpregnant women; adipocytes are metabolically active and release a number of hormones implicated in insulin resistance. Heavier mothers are also more likely to have higher glucose levels that do not exceed the cutoff for GDM, but nevertheless predict poor perinatal outcomes. Longer-term complications of GDM include increased risk of maternal type 2 diabetes and offspring obesity. Promising intervention studies to decrease the intergenerational cycle of obesity and diabetes are currently underway.     

Prenatal imprinting of postnatal specific appetites and feeding behavior

Epigenetic influences on the fetus's genotype have been shown to occur during intrauterine life. Experimentally imposed extracellular dehydration in pregnant rats (a model for human hyponatremia caused by gravidic vomiting) brings about a dramatic enhancement of salt appetite not only in the dam, but also in offspring when they reach adulthood. This phenomenon has been verified in human newborn infants and adults whose mothers experienced nausea and/or vomiting during pregnancy. Alcohol consumption during pregnancy enhances its palatability for the offspring. Ingestion of olfactory test substances like anise or carrot by the mother during pregnancy gives rise to a preference for the same testants in the offspring. Under- or overnutrition in the pregnant mother appears to play a role in reprogramming the postnatal regulation of both feeding and fat reserves in offspring. Both maternal under- and overnutrition during pregnancy predispose the offspring to later development of obesity and type 2 diabetes mellitus. A careful examination of the systems concerned with the regulation of food intake, and the neurosubstances involved in such regulation, reveals some of the mechanisms by which maternal nutritional status can affect the offspring and their food-related behaviors.     

Perinatal exposure to high-fat diet programs energy balance, metabolism and behavior in adulthood

The perinatal environment plays an important role in programming many aspects of physiology and behavior including metabolism, body weight set point, energy balance regulation and predisposition to mental health-related disorders such as anxiety, depression and attention deficit hyperactivity disorder. Maternal health and nutritional status heavily influence the early environment and have a long-term impact on critical central pathways, including the melanocortinergic, serotonergic system and dopaminergic systems. Evidence from a variety of animal models including rodents and nonhuman primates indicates that exposure to maternal high-fat diet (HFD) consumption programs offspring for increased risk of adult obesity. Hyperphagia and increased preference for fatty and sugary foods are implicated as mechanisms for the increased obesity risk. The effects of maternal HFD consumption on energy expenditure are unclear, and future studies need to address the impact of perinatal HFD exposure on this important component of energy balance regulation. Recent evidence from animal models also indicates that maternal HFD consumption increases the risk of offspring developing mental health-related disorders such as anxiety. Potential mechanisms for perinatal HFD programming of neural pathways include circulating factors, such as hormones (leptin, insulin), nutrients (fatty acids, triglycerides and glucose) and inflammatory cytokines. As maternal HFD consumption and obesity are common and rapidly increasing, we speculate that future generations will be at increased risk for both metabolic and mental health disorders. Thus, it is critical that future studies identify therapeutic strategies that are effective at preventing maternal HFD-induced malprogramming.     

The diabetic pregnancy and offspring BMI in childhood: a systematic review and meta-analysis

Aims/hypothesis  

Offspring of mothers with diabetes are at increased risk of metabolic disorders in later life. Increased offspring BMI is a plausible mediator. We performed a systematic review and meta-analysis of studies examining offspring BMI z score in childhood in relation to maternal diabetes.     

Breast feeding and the risk of obesity and related metabolic diseases in the child

Breast feeding is the best way to nurture healthy newborns of healthy mothers. A number of studies have shown that breast feeding may protect against the later development of obesity and related metabolic diseases. Using data from our own meta-analysis as well as studies by other groups, in this review we systematically examine the current state of evidence regarding this topic. Breast feeding, in general, is shown to be associated later in a child's life with decreased risk of overweight, decreased blood cholesterol and blood pressure, and a reduced risk of developing type 2 diabetes. Additionally, we review data of our Kaulsdorf Cohort Study (KCS) showing, however, that these effects might be reversed when the mother is affected by a non-communicable disease such as diabetes mellitus, which alters the composition of breast milk. In particular, exposure to breast milk from diabetic mothers during the first days of life (first week; early neonatal period) seems to increase rather than decrease risk of overweight and, consecutively, impaired glucose tolerance in childhood. Taken together, current findings show clearly that breast feeding is effective in lowering the risk of developing key features of the metabolic syndrome in later life, and should therefore be promoted. With increasing prevalence of overweight and diabetes in women, however, more research is urgently needed to clarify whether breast feeding might even have negative consequences for risk of overweight and diabetogenic disturbances when the mother suffers from a metabolic disorder. From a more general perspective, breast feeding and its long-term consequences are an important paradigm for "perinatal programming" of health and disease.     

Links Between Maternal Cardiovascular Disease and the Health of Offspring

Maternal cardiovascular disease (CVD) during pregnancy is on the rise worldwide, as both more women with congenital heart disease are reaching childbearing age, and conditions such as diabetes, hypertension, and obesity are becoming more prevalent. However, the extent to which maternal CVD influences offspring health, as a neonate and later in childhood and adolescence, remains to be fully understood. The thrifty phenotype hypothesis, by which a fetus adapts to maternal and placental changes to survive a nutrient-starved environment, may provide an answer to the mechanism of maternal CVD and its impact on the offspring. In this narrative review, we aim to provide a review of the literature pertaining to the impact of maternal cardiovascular and hypertensive disease on the health of neonates, children, and adolescents. This review demonstrates that maternal CVD leads to higher rates of complications among neonates. Ultimately, our review supports the hypothesis that maternal CVD leads to intrauterine growth restriction (IUGR), which, through the thrifty phenotype hypothesis and vascular remodelling, can have health repercussions, including an impact on CVD risk, both in the immediate newborn period as well as later throughout the life of the offspring. Further research remains crucial in elucidating the mechanism of maternal CVD long-term effects on offspring, as further understanding could lead to preventive measures to optimise offspring health, including modifiable lifestyle changes. Potential treatments for this at-risk offspring group could mitigate risk, but further studies to provide evidence are needed.     

Consequences of fetal exposure to maternal diabetes in offspring

CONTEXT: Type 2 diabetes is the result of both genetic and environmental factors. Fetal exposure to maternal diabetes is associated with a higher risk of abnormal glucose homeostasis in offspring beyond that attributable to genetic factors, and therefore, may participate in the excess of maternal transmission of type 2 diabetes. Evidence acquisition: A MEDLINE search covered the period from 1960-2005. EVIDENCE SYNTHESIS: Human studies performed in children and adolescents suggest that offspring who had been exposed to maternal diabetes during fetal life exhibit higher prevalence of impaired glucose tolerance and markers of insulin resistance. Recent studies that directly measured insulin sensitivity and insulin secretion have shown an insulin secretory defect even in the absence of impaired glucose tolerance in adult offspring. In animal models, exposure to a hyperglycemic intrauterine environment also led to the impairment of glucose tolerance in the adult offspring. These metabolic abnormalities were transmitted to the next generations, suggesting that in utero exposure to maternal diabetes has an epigenetic impact. At the cellular level, some findings suggest an impaired pancreatic beta-cell mass and function. Several mechanisms such as defects in pancreatic angiogenesis and innervation, or modification of parental imprinting, may be implicated, acting either independently or in combination. CONCLUSION: Thus, fetal exposure to maternal diabetes may contribute to the worldwide diabetes epidemic. Public health interventions targeting high-risk populations should focus on long-term follow-up of subjects who have been exposed in utero to a diabetic environment and on a better glycemic control during pregnancy.     

Parental high-fat programming of offspring development,health and β-cells

Recent studies extend the concept of developmental and adaptive plasticity to include a paternal role in the programming of metabolic disease, including diabetes. Parents greatly influence the development and health of their offspring. Although genetic imprinting plays a major role in determining offspring health outcomes, non-genetic transmission is also a critical determinant. Programming by parental high-fat feeding has demonstrated adverse effects on β-cell development and function in offspring. However, maternal and paternal programming effects vary in their potency, with mothers holding the greater influence due to their direct involvement in offspring development and health. Maintenance of parental health pre-conception and during the early phases of offspring life is critical to improve health outcomes of offspring, with the benefit of positive effects on parental health. Preservation and protection of β-cells throughout offspring life, even before conception, is a strategy to enhance β-cell survival in offspring.     

Care of the Infant of the Diabetic Mother

Gestational diabetes mellitus (GDM) from all causes of diabetes is the most common medical complication of pregnancy and is increasing in incidence, particularly as type 2 diabetes continues to increase worldwide. Despite advances in perinatal care, infants of diabetic mothers (IDMs) remain at risk for a multitude of physiologic, metabolic, and congenital complications such as preterm birth, macrosomia, asphyxia, respiratory distress, hypoglycemia, hypocalcemia, hyperbilirubinemia, polycythemia and hyperviscosity, hypertrophic cardiomyopathy, and congenital anomalies, particularly of the central nervous system. Overt type 1 diabetes around conception produces marked risk of embryopathy (neural tube defects, cardiac defects, caudal regression syndrome), whereas later in gestation, severe and unstable type 1 maternal diabetes carries a higher risk of intrauterine growth restriction, asphyxia, and fetal death. IDMs born to mothers with type 2 diabetes are more commonly obese (macrosomic) with milder conditions of the common problems found in IDMs. IDMs from all causes of GDM also are predisposed to later-life risk of obesity, diabetes, and cardiovascular disease. Care of the IDM neonate needs to focus on ensuring adequate cardiorespiratory adaptation at birth, possible birth injuries, maintenance of normal glucose metabolism, and close observation for polycythemia, hyperbilirubinemia, and feeding intolerance.     

The influence of maternal body mass index,maternal diabetes mellitus,and maternal smoking during pregnancy on the risk of childhood‐onset type 1 diabetes mellitus in the offspring: Systematic review and meta‐analysis of observational studies

There is emerging evidence that events occurring before and shortly after birth may be important in determining the risk of childhood‐onset type 1 diabetes mellitus (T1DM). We aimed to summarize and synthesize the associations between maternal body mass index (BMI), maternal diabetes mellitus (DM), and maternal smoking during pregnancy and the risk of childhood‐onset T1DM in the offspring by performing a systematic review and meta‐analysis of observational studies. A random effects model was used to generate the summary risk estimates. The PubMed and Web of Science databases were searched to identify relevant observational studies. Twenty one observational studies were included in the present meta‐analysis. Compared with offspring of mothers with normal weight, offspring of women with overweight or obesity were at an increased risk of developing childhood‐onset T1DM (overweight: relative risk [RR] 1.09, 95% confidence interval [CI], 1.03‐1.15; obesity: RR 1.25, 95% CI, 1.16‐1.34; per 5 kg m^?2 increase in BMI: RR 1.10, 95% CI, 1.06‐1.13). No association was found for maternal underweight (RR 0.92, 95% CI, 0.75‐1.13). Maternal DM was associated with an increased risk of childhood‐onset T1DM (RR 3.26, 95% CI, 2.84‐3.74). Regarding the type of maternal DM, the greatest risk of T1DM in the offspring appeared to be conferred by maternal T1DM (RR 4.46, 95% CI, 2.89‐6.89), followed by maternal gestational diabetes mellitus (RR 1.66, 95% CI, 1.16‐2.36), and lastly by maternal type 2 diabetes mellitus (RR 1.11, 95% CI, 0.69‐1.80). Additional analysis of studies comparing maternal versus paternal T1DM within the same population revealed that offspring of fathers with T1DM had a 1.5 times higher risk of developing childhood‐onset T1DM than offspring of mothers with T1DM (RR 9.58, 95% CI, 6.33‐14.48 vs. RR 6.24, 95% CI, 5.52‐7.07). Furthermore, a reduced risk of childhood‐onset T1DM was observed in infants born to mothers who smoked during pregnancy compared with infants born to mothers who did not smoke during pregnancy (RR 0.79, 95% CI, 0.71‐0.87). In summary, our findings add further evidence that early‐life events or environmental factors may play a role in modulating infants' risk of developing T1DM later in life.     

Maternal diabetes compromises the organization of hypothalamic feeding circuits and impairs leptin sensitivity in offspring

Maternal diabetes is a common complication of pregnancy, and the offspring of diabetic mothers have a higher risk of developing obesity and type 2 diabetes later in life. Despite these observations, the precise biological processes mediating this metabolic programming are not well understood. Here, we explored the consequences of maternal diabetes on the organization of hypothalamic neural circuits involved in the regulation of energy balance. To accomplish this aim, we used a mouse model of maternal insulin deficiency induced by streptozotocin injections. Maternal diabetes was found to be associated with changes in offspring growth as revealed by a significantly higher pre- and postweaning body weight in the offspring of insulin-deficient dams relative to those of control mice. Mice born to diabetic dams also showed increased fasting glucose levels, increased insulin levels, and increased food intake during their adult lives. These impairments in metabolic regulation were associated with leptin resistance during adulthood. Importantly, the ability of leptin to activate intracellular signaling in arcuate neurons was also significantly reduced in neonates born to diabetic dams. Furthermore, neural projections from the arcuate nucleus to the paraventricular nucleus were markedly reduced in the offspring of insulin-deficient dams. Together, these data show that insulin deficiency during gestation has long-term consequences for metabolic regulation. They also indicate that animals born to diabetic dams display abnormally organized hypothalamic feeding pathways that could result from the attenuated responsiveness of hypothalamic neurons to the neurotrophic actions of leptin during neonatal development.     

Intrauterine growth restriction and developmental programming of the metabolic syndrome: a critical appraisal

According to the "small baby syndrome hypothesis," low birthweight and intrauterine growth restriction (IUGR) occurring in westernized countries mainly through altered placental flow, have been linked to increased metabolic syndrome risk in later life. Independency and causal mechanisms of this phenomenological association are a matter of controversy. By means of epidemiological as well as experimental methods, using meta-analyses and different rodent models of pre- and/or neonatal malnutrition and altered placental flow (uterine artery ligation; Lig), we systematically addressed the phenomenon. Our data and systematic literature analysis revealed that neither epidemiological nor experimental evidence seems to exist linking prenatal underfeeding, low birthweight, IUGR, or decreased placental flow in rats (Lig-model) as independent risk factors to increased metabolic syndrome risk in later life. Rather, pre- and/or neonatal overfeeding, elevated birthweight, rapid neonatal weight gain, and especially increased adiposity during critical periods of perinatal life may increase long-term risks. Perinatally acquired microstructural and epigenomic alterations in regulatory systems of metabolism and body weight seem to be critical, leading to a cardiometabolic risk disposition throughout life. While experimental data in Lig-offspring seem to be considerably biased, prenatal stress and postnatal overfeeding/rapid neonatal weight gain might be causally linked to a long-term deleterious outcome in growth restricted newborns. From a clinical point of view, prevention of causes of IUGR, as well as avoidance of perinatal overnourishment, might be prophylactic approaches to avoid perinatal programming of cardiometabolic risks.