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    Maternal obesity and the fetal brain

     

    Inflammation-induced malprogramming

    Both maternal obesity and pregnancy itself are associated with chronic systemic inflammation.32 Obese women have been demonstrated to have exaggerated physiologic responses to pregnancy, with increased circulating levels of pro-inflammatory cytokines compared to their normal weight counterparts.33-35 Maternal BMI has been shown to be directly correlated with maternal blood concentrations of cytokines and with activation of pro-inflammatory pathways in the placenta.33,36

    Placental and intrauterine inflammation are associated with altered fetal cytokine expression, fetal neuronal damage, and changes in neonatal brain gene expression.35,37 Elevated levels of maternal pro-inflammatory cytokines during gestation have been linked to an increased risk for ASD and neurodevelopmental delay in children.38 Children with ASD have also been shown to have elevated plasma markers of inflammation.39,40

    It is postulated that underlying maternal and placental inflammation in the setting of maternal obesity plays a key role in fetal brain inflammation and subsequent abnormal offspring neurodevelopment.27,35 This concept has been corroborated by animal studies. Rat offspring exposed to maternal obesity and a high-fat diet in utero demonstrated increased neuronal and systemic inflammation, poor memory retention, and changes in anxiety levels and spatial reasoning.27,41,42

    Rodent and non-human primate models of maternal obesity and high-fat diet in pregnancy have demonstrated increased brain inflammation, decreased sociability, increased hyperactivity, and impaired hippocampal learning in offspring.42-44 A murine model of maternal inflammation demonstrated deficits in offspring social behavior, and highlighted a critical role for the cytokine interleukin-6 in mediating these behavioral changes.45

    Relative excess or deficiency of circulating nutrients

    Maternal obesity is associated with increased circulating free fatty acids and glucose, due to diet, increased insulin resistance, and increased adipose tissue lipolysis.27,31,46 The fetus is exposed to an excess of certain circulating nutrients. Obesity has also been shown to coexist with states of subclinical malnutrition characterized by excess energy intake with a relative deficiency in circulating micronutrients.27 Excess free fatty acids and glucose in maternal circulation and deficiencies of vitamin D, B12, folate, and iron have been implicated in abnormal neurodevelopment of the fetus.27

    Obese pregnant women were also found to have lower levels of nutritional antioxidants, suggesting that fetuses of obese women may be exposed to more oxidative stress and inflammation than those of lean women.47

    Metabolic hormone-induced malprogramming

    Fetuses of obese women may be chronically exposed to insulin resistance and a glucose-rich environment, even in the absence of diagnosed gestational or pre-gestational diabetes.48 The fetal pancreas compensates by producing increased insulin, and the pro-inflammatory environment compounds fetal insulin resistance via inflammatory changes in fetal adipose tissue.49 Insulin acts on the fetal brain as a growth factor, and excess insulin exposure can cause disruptions in neural circuitry, brain development, and behavior.48 Maternal hyperinsulinemia in the setting of Type 2 diabetes and gestational diabetes have been shown to be associated with increased risk of ASD and neurodevelopmental delay.50

    Leptin levels are also elevated in obese mothers.50,51 Leptin functions as a critical neurotrophic factor, and leptin signaling abnormalities during fetal development have been associated with decreased neuronal stem cell differentiation and growth.52 Leptin receptors are widely distributed in brain regions involved in behavioral regulation,53 so derangement in leptin signaling during key developmental periods is another potential mechanism underlying abnormal neurodevelopment in fetuses of obese women.13

     

    Andrea G Edlow, MD, MSc
    Dr Edlow is an attending physician in the Division of Maternal-Fetal Medicine, Department of Ob-Gyn, Tufts Medical Center, Boston, ...
    Larissa H Mattei, BA
    Ms Mattei is a fourth-year medical student at Tufts University School of Medicine, Boston, Massachusetts.

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