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Review: Cardiometabolic Effects of Exposure to Maternal Obesity

Key findings

  • Human and animal studies have linked maternal obesity to increased risk of obesity and adiposity, hypertension and vascular endothelial dysfunction, hyperglycemia and insulin resistance, hyperlipidemia and nonalcoholic fatty liver disease
  • These outcomes may be mediated by hyperphagia and reward-based eating, changes in hypothalamic satiety setpoints and malprogramming of offspring skeletal muscle, adipose tissue, liver and pancreas
  • Research is needed to establish whether lifestyle interventions for obese/overweight pregnant women could mitigate cardiometabolic morbidity in offspring

The prevalence of maternal obesity has risen to epidemic levels in recent decades, paralleled by rising childhood and adolescent obesity and metabolic dysfunction. Maternal obesity is now known to affect not only maternal health and pregnancy outcomes but also the child's risk of cardiometabolic dysfunction.

Sezen Kislal, PhD, formal research fellow in the Vincent Center for Reproductive Biology at Massachusetts General Hospital, Lydia L. Shook, MD, maternal-fetal medicine fellow, and Andrea G. Edlow, MD, MSc, an investigator in the Vincent Center for Reproductive Biology, review in Prenatal Diagnosis the human and animal data supporting this conclusion and possible mechanisms by which exposure to maternal obesity puts offspring at risk.

Human Data

Multiple large population cohort studies have demonstrated associations between maternal obesity and cardiometabolic disorders in offspring. Findings include:

  • Overweight and obesity in children and adolescents, even after adjusting for potential confounders such as shared genetics or postnatal environment
  • Increased adiposity, particularly central adiposity, in newborns and children
  • Metabolic syndrome (central adiposity, insulin resistance, dyslipidemia and hypertension) in children and adolescents, with females more vulnerable to increased adiposity and insulin resistance in particular
  • Nonalcoholic fatty liver disease in adolescent girls
  • Adult cardiovascular disease and associated mortality—this link is now considered indisputable

Animal Data

Animal models have advantages over human studies, including their ability to strictly control maternal diet before, during and after pregnancy. Such research has demonstrated associations between maternal obesity and excess body weight, adiposity, glucose intolerance and insulin resistance, vascular pathology and hypertension, hyperlipidemia, hyperleptinemia and liver dysfunction in offspring.

Animal models also facilitate the study of possible mechanisms of offspring cardiometabolic morbidity. Findings include:

  • Hyperphagia and reward-based eating behavior—Offspring exposed to a high-fat diet in utero and during lactation demonstrated preferences for sugary and fatty foods and ate more than offspring fed a balanced diet. In other research, maternal overnutrition altered the development of the mesolimbic dopamine reward circuitry
  • Changes in hypothalamic satiety setpoints—Maternal obesity and feeding of a high-fat diet significantly change leptin-mediated satiety signaling in the hypothalamus of offspring (leptin, an adipose tissue hormone, also increases energy expenditure)
  • Malprogramming of offspring skeletal muscle, adipose tissue, liver and pancreas—May promote a more pro-inflammatory, insulin-resistant phenotype

Most animal research utilizes high-fat diets, but high-carbohydrate maternal diets have also been demonstrated to result in harmful metabolic programming in offspring. Animal data differ with respect to which offspring sex is more vulnerable to cardiometabolic risk, depending on the outcome in question.

Human Intervention Studies

A recent Cochrane Review compared usual care with lifestyle interventions in obese pregnant women, but only two studies of sufficient quality reported on offspring. These showed no significant impact of lifestyle interventions on birthweight or childhood adiposity.

Trials of dietary supplements and medication to improve maternal and offspring outcomes in obese women are similarly sparse. Three studies that investigated the efficacy of metformin in obese pregnant women are the subject of another Cochrane Review, but there was no effect on birth weight and no data were reported on childhood obesity or cardiometabolic outcomes.

Long-term follow-up of offspring from the MiG TOFU study—in which women with gestational diabetes were randomized to receive either metformin or insulin therapy—suggest maternal metformin may in fact have adverse programming consequences, as children exposed to metformin were larger by measures of weight, arm and waist circumferences at 9 years of age.

Additional research is needed to understand how maternal interventions during key developmental windows might reduce risks in offspring.

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