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Review: Mechanisms of Maternal Obesity with Neuromorbidity in Offspring

Key findings

  • Prenatal and lactational exposure to maternal obesity are associated with neurodevelopmental and psychiatric disorders in offspring
  • Researchers at Massachusetts General Hospital recently reviewed the putative mechanisms by which prenatal exposure to maternal obesity results in malprogramming of the fetal brain
  • Animal studies have suggested mechanisms including fetal brain inflammation, in utero priming of brain microglia, alterations in synaptic pruning and synaptic plasticity, and impaired central serotonergic and dopaminergic signaling
  • Both human and animal studies suggest a critical role for the placenta in mediating the deleterious impact of maternal obesity on fetal brain development

Nearly half of children born in the U.S. in 2020 will be exposed to maternal overweight or obesity during fetal life—a consequence of the worldwide epidemic of maternal obesity. In addition to having cardiometabolic effects, prenatal and lactational exposures to maternal obesity are associated with neurodevelopmental and psychiatric disorders in offspring.

In Prenatal Diagnosis, Sezen Kislal, PhD, former research fellow, Lydia L. Shook, MD, maternal-fetal medicine fellow, and Andrea G. Edlow, MD, MSc, an investigator in the Vincent Center for Reproductive Biology at Massachusetts General Hospital, summarize these links and review putative mechanisms.

Epidemiologic Studies

Large mother–offspring cohort studies have demonstrated an association between maternal obesity and attention deficit hyperactivity disorder, anxiety and depression, intellectual disability and impaired cognition, autism spectrum disorder and disordered eating in offspring.

However, epidemiologic studies cannot establish direct causal relationships. The positive associations may reflect confounding by genetic, socioeconomic or postnatal environmental factors such as lactation and the early childhood nutritional environment.

Animal Studies

To investigate the relative contributions of the obese intrauterine versus the postnatal environment, researchers have turned to animal models. Through such means as strictly controlling maternal diet, animal research makes it easier to evaluate how maternal obesity or high-fat diet during gestation and lactation affects offspring neurodevelopment.

Recapitulating many of the results of human studies, animal models have demonstrated that offspring exposed to obese dams are at increased risk of adverse outcomes such as cognitive deficits, increased anxiety-like and depressive behaviors, decreased sociability, hyperactivity, increased reward-based eating and other addictive behaviors. Data conflict about whether there are sex differences in the vulnerability to these outcomes.


Animal studies have also shed light on the mechanisms underlying adverse outcomes in offspring, for example:

  • Fetal brain inflammation
  • In utero priming of brain microglia
  • Alterations in synaptic pruning and synaptic plasticity
  • Impaired central serotonergic and dopaminergic signaling

The Placenta–Fetal Brain Connection

The placenta is known to play a critical role in programming the fetal brain in response to maternal challenges such as malnutrition, stress and infection. Animal studies are providing evidence that, similarly, the placenta is key to malprogramming the fetal brain in response to maternal obesity.

The mechanisms aren't well understood, but obesity-induced placental alterations appear to include increases in the inflammatory response, immune cell activation and lipid depositions that lead to inflammation, fetal immune activation, lipotoxicity, increased oxidative stress and reduced antioxidant capacity in the fetus.

Laying the Groundwork for Therapies

The hope is that an improved understanding of the mechanisms underlying adverse neurodevelopmental outcomes in offspring will lead to targeted perinatal therapies. These could be administered to the pregnant or lactating woman during key developmental windows to ameliorate harmful obesity-associated consequences.

Learn more about the Vincent Center for Reproductive Biology

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Related topics


Perinatal exposure to maternal obesity has lasting adverse cardiometabolic effects on children, including increased risk of cardiovascular mortality in adulthood.


In a large cohort of U.K. women, genetic predisposition to high blood pressure and higher body mass index was significantly associated with hypertensive disorders of pregnancy.