NIH – Maternal Nutrition and Pre-pregnancy Obesity: Effects on Mothers, Infants and Children (R01 Clinical Trial Optional)

May 21, 2018 by School of Medicine Webmaster

This Funding Opportunity Announcement (FOA) encourages R01 applications to improve health outcomes for women, infants and children, by stimulating interdisciplinary research focused on maternal nutrition and pre-pregnancy obesity. Maternal health significantly impacts not only the mother but also the intrauterine environment, and subsequently fetal development and the health of the newborn. More than 50% of pregnant women are overweight or obese and 8% of reproductive-age women are extremely obese. Maternal pre-pregnancy obesity is a contributing factor in the etiology of poor maternal outcomes such as gestational diabetes, pregnancy-induced hypertension, risk of pre-term birth, pre-eclampsia and eclampsia, venous thromboembolism, and fetal macrosomia. Obese women have a higher rate of instrumental delivery and caesarean section, and longer postpartum hospital stays than non-obese women.  Obstetric management of morbidly obese pregnant women (BMI >40 kg/m2) is challenging due to the increased likelihood of complications during pregnancy. Maternal obesity contributes to development of a number of negative maternal health outcomes, more complicated and potential pre-term deliveries, and greater use of health care services and resources.

Maternal health has a significant impact on the uterine environment and therefore fetal development and newborn health. A growing body of evidence illustrates that infants born to obese women are more likely to be born prematurely, experience birth defects have low birth weight, higher mortality rates, and long-term risks for obesity later in life. Risk of adverse infant outcomes, among overweight and obese women, varies by pre-pregnancy weight and is further impacted by gestational weight gain. Obese pregnant women have a higher incidence of having an infant with congenital abnormalities; obesity during pregnancy can obviate detection of these abnormalities via ultrasound. Children born to obese women are twice as likely to be obese and develop Type 2 diabetes later in life. Thus, prevention and management of overweight and obesity in pregnancy is of major concern to nurses, obstetricians and gynecologists.

Factors in the uterine environment, other than pre-pregnancy obesity, such as maternal nutrition, can also impact infant outcomes, predisposing the developing fetus to obesity in childhood, adolescence or adult life. Environmental factors and maternal stress during in utero development or in early post-natal life can have an intergenerational impact on gene expression, epigenetics, and phenotype. Maternal diet and nutrient supply are principal environmental factors that can alter structure, function and metabolism of the developing embryo. Alterations of the maternal diet have been shown to produce modifications in the fetal epigenome. In macaques, a chronic high- fat, calorie-dense maternal diet leads to epigenetic alterations of fetal genes such that accumulation of fetal liver triglycerides occurs. Maternal nutrition may also play a role in regulating accumulation of white adipose tissue mass after birth. In rats, high-fat diets and maternal obesity during gestation and lactation promote not only obesity but also insulin resistance. Maternal undernutrition also promotes hyperphagia, cardiometabolic dysfunction and obesity in the offspring, through increased NPY expression and corticosterone secretion. In rodents, protein malnutrition during gestation leads to elevated hepatic glucose production and elevated levels of cholesterol in the liver, with trans-generational effects, resulting in obese and insulin-resistant progeny even in the second generation. Human dietary restriction in early gestation results in greater risk of adult CHD and obesity. Modification of the maternal diet should aim at optimizing the perinatal environment to ensure the appropriate metabolic response of the offspring in later life.

Research suggests that appetite and energy homeostatic mechanisms are programmed during critical periods in the intrauterine and early postnatal environment, when placental function and the plasticity of the nervous system allow perinatal factors to influence fetal fuel supply, metabolic pathways, organ growth and organ function, inducing changes that carry into adulthood and across generations. Maternal undernutrition coinciding with the period of maximal placental growth is thought to lead to increased abundance of mRNA for IGF-I and IGF-II receptors in fetal adipose tissue and increased sensitivity to or production of cortisol by fetal adipocytes, thus promoting adiposity. Increased maternal nutrition in late gestation, however, appears to result in decreased fetal adiposity. It is probable that energy homeostasis is centrally mediated and genetically determined. However, the plasticity of central neural pathways during the perinatal period lends itself to modification by extrinsic factors. For instance, development of adipose tissue mitochondria may be reprogrammed in late gestation. Hence, nutritional interventions delivered during these critical periods of development could potentially be developed in order to modify genetic susceptibility to obesity of the offspring. Through metabolic imprinting, the set-point for body weight achieved during adulthood could be established.

The risk of adverse infant outcomes varies with maternal pre-pregnant weight, the maternal diet, and the timing of nutrient restriction or excess, but is further impacted by other factors such as gestational diabetes, gestational weight gain, parity, environmental factors, maternal exposure to smoking, maternal psychosocial stress, maternal sleep health, the maternal microbiome, and other facets of the maternal lifestyle.

Offspring born to women with gestational diabetes, having been exposed to both hyperglycemia and hyperinsulinemia from exogenous insulin, demonstrate either increased fetal weight, or small birth weights if insulin -resistance develops. Leptin from placenta of diabetic mothers may also cross to the fetus, impacting neural pathways through its neurotropic effects and plausibly regulating energy homeostasis. Gestational weight gain is also found to be directly associated not only with the birth weight of the offspring, but also their risk for obesity in childhood and adolescence.

Maternal parity may play a role in subsequent adiposity, as offspring of primiparous mothers although smaller appear to deposit more adipose tissue than those born to multiparous mothers. Suggestions have been made that this may be due to accelerated loss of brown adipose tissue-specific UCP1 and decreased metabolism, or a resetting of the leptin and glucocorticoid axis within the adipocyte. From animal studies it appears that increased maternal age may also contribute to increased fat deposition in the offspring. In animals, post-natal factors can overcome genetic predisposition to obesity. Post-natal nutrition and the nutrients and hormones in breast milk are modifiable factors that may impact future obesity risk. Maternal diet is a primary determinant of milk composition. Feeding dams a high fat diet in association with maternal obesity have an additive effect on increasing weight and promoting hypertension and hyperglycemia in the offspring as they reach adulthood. The amount of milk consumed and the composition of the milk affect development of obesity in later life. Studies are needed to understand if similar consequences occur in humans.

The gut microbiome plays an important role in regulating fat storage and predisposition to obesity. Alterations of the gut microbiome are associated with obesity and responsive to weight loss. Studies have shown that gut microbes play an important role in metabolism and fat storage. There is evidence that diet modification, such as reduction of fat intake, may affect the gut microbiota in multiple pathways increasing metabolism and reducing obesity. Restoration of the gut microbiota to a healthy state may improve conditions associated with obesity and help maintain a healthy weight.

Maternal care is known to have direct effects on gene expression and stress pathways. Maternal pre- and post-natal stressors, both psychosocial and physical, may impact neuro-endocrine pathways that cause changes, related both to metabolism and the stress response, that carry on to adulthood.

Reports indicate that there is a dose-dependent association between maternal smoking during pregnancy and childhood obesity. Many aspects of the maternal lifestyle also appear to be related to childhood obesity, such as sleep duration. Prevalence of childhood obesity is reported to be lower among mothers who slept more than 8 hours during early pregnancy. Women who slept less than 6 hours a night had longer labors and were more likely to have cesarean deliveries.

Other post-natal factors such as neonatal feeding practices, breastfeeding initiation and duration, ambient temperature at rearing, vitamin supplementation can be modified to optimize the perinatal environment. Healthy practices during this period may help to ensure appropriate metabolic responses of the both offspring and mother, thus preventing obesity and promoting health in both.

Identifying modifiable factors during pregnancy and the immediate post-partum period, and implementing health promotive strategies that achieve primal, primary and secondary prevention of obesity, reduction of risks for adverse events and improvement of health outcomes for mother, infants and children are the focus of this FOA.

Examples of projects considered to be appropriate to this announcement include but are not limited to those that:

  • Identify components of the maternal diet, caloric levels of nutrient supply, timing of nutritional restriction/ excess during gestation and lactation, or combinations thereof, which predispose towards development of obesity in the mother postpartum and the offspring during development.
  • Explore the effects of supplementation with dietary micronutrients, such as vitamins related to methionine and DNA methylation (e.g. folic acid, vit B6) on food intake and/or energy expenditure of the mother and the child, maternal and newborn outcomes, and post-partum weight gain.
  • Assess interventions that target modifiable factors in the maternal pre- and post-natal environment which may modulate genetic susceptibility to obesity. These factors may include psychosocial stressors, maternal behaviors such as smoking, alcohol or substance abuse, exposure to infectious and pharmacological agents, management of co-morbidities, sleep habits, timing and patterns of infant feeding, and child rearing practices.
  • Describe preventive health practices that may override obesity-predisposing non- modifiable factors such as birth order, ethnicity, age and parity.
  • Examine the effects of pre-pregnancy obesity on maternal outcomes (e.g., gestational diabetes, pre-eclampsia, complications of labor and delivery), type of delivery (e.g., vaginal and cesarean section), the delivery experience (hospital and home deliveries), and newborn infant outcomes (e.g., prematurity, low birth weight, large for gestational age, birth defects).
  • Define effective and safe prenatal weight- reduction goals for pre-pregnant obese and non-obese women to prevent excessive gestational weight gain
  • Describe the impact of weight reduction techniques known to be effective in non-pregnant women, such as nutritional interventions and physical activity, on maternal outcomes.
  • Develop and test strategies to promote the delivery of healthy infants born to obese women

These suggested areas of research are not listed in any priority and are not to be viewed as an exhaustive or exclusive list. This FOA is not intended to support epidemiological studies on the incidence or prevalence of obesity. Studies using animal models would not be considered appropriate to this announcement.

Deadlines:  standard dates and standard AIDS dates apply


Filed Under: Funding Opportunities