Ms Mattei is a fourth-year medical student at Tufts University School of Medicine, Boston, Massachusetts.

Larissa H Mattei, BA

	In the United States, more than 60% of reproductive-age women are overweight and 35% are obese, representing a 70% increase in pre-pregnancy obesity.

 Childhood obesity and early-onset metabolic syndrome have risen in parallel.

 While it is now relatively well-known that maternal obesity, maternal high-fat diet, and high gestational weight gain (GWG) may have harmful effects on fetal and offspring metabolic programming, awareness of the potential harmful programming effects on the fetal brain is less widespread.

	The effect of maternal obesity, high-fat diet, and GWG on fetal neurodevelopment and offspring behavior is the focus of this review.

	Compelling data from large epidemiologic studies have demonstrated an association between maternal obesity and a variety of neurodevelopmental morbidities in offspring. All relationships, odds ratios, relative risks, and IQ decrements reported here achieved statistical significance in the referenced studies, unless otherwise indicated.

Increased odds of cognitive deficits, decreased IQ, and intellectual disability

	Maternal obesity may increase the risk for intellectual disability or cognitive deficits in offspring from 1.3- to 3.6-fold.

 Maternal obesity has been linked to decrements in offspring cognition (eg, 2â5 points lower IQ in offspring of obese women compared to non-obese counterparts),

 with every increase of 1 unit in maternal prepregnancy BMI found to be associated with a significant reduction in offspring IQ and non-verbal IQ, suggesting a dose-response relationship.

 High GWG seems to augment this association.4 Maternal pre-pregnancy obesity pls GWG of > 40 lb was associated with a 3-fold increase in offspring IQ deficit (mean of 6.5 points lower).

 Of note, extremely low maternal pre-pregnancy BMI (<18.5 kg/m2) has also been significantly associated with lower offspring IQ, although the reported decrement is less than in the setting of maternal obesity.

Increased odds of autism spectrum disorders (ASD) 

	The majority of studies that have examined a link between high maternal BMI and childhood diagnosis of ASD have found a significant positive association.

 This risk may be further augmented by intrauterine growth restriction (IUGR),

 gestational or pre-gestational diabetes,

	Two recent studies including matched sibling analyses failed to find a significant relationship between maternal pre-pregnancy BMI and ASD risk,

 suggesting that maternal BMI might be a proxy marker for other familial risk factors conferring an increased risk of ASD in offspring. High GWG was independently associated with offspring ASD risk, even in studies that failed to find an association with maternal pre-pregnancy obesity.

 Of note, paternal obesity has also been demonstrated to be independently associated with increased ASD risk in offspring.

Increased odds of attention deficit hyperactivity disorder (ADHD)

	A dose-dependent increase in ADHD symptoms in children was noted in Swedish, Danish, and Finnish pregnancy cohorts as maternal pre-pregnancy BMI increased from overweight to obese.

 Later studies confirmed this association with up to a 2.8-fold increased risk of offspring ADHD compared to non-obese counterparts.

	A recent study found that the association between maternal obesity and increased risk of ADHD in offspring was true for white but not black women.

Another study failed to find an association between maternal obesity and offspring ADHD after adjusting for confounders such as socioeconomic status.

 Still, the preponderance of epidemiologic evidence suggests that maternal obesity is associated with ADHD risk in offspring.

	A dose-dependent increase in offspring CP risk has been noted as maternal BMI increases from overweight to morbidly obese (from 1.2 to 3.0 times increased odds).

 One study reported that each unit increase in maternal BMI raised the risk of CP by 7%, and each kg of additional weight at 34 weeks increased the risk of CP by 2%.

 While underlying mechanisms have not been fully elucidated, some have postulated that maternal inflammation may be causative, as obesity induces a chronic inflammatory state, and other maternal inflammatory conditions such as chorioamnionitis are known to confer an increased risk for CP.

	Limitations of existing epidemiologic data

	The aforementioned studies defined maternal pre-pregnancy obesity as a reported pre-pregnancy or measured early pregnancy BMI â¥30 kg/m2 or absolute pregnancy weight >90 kg. These definitions do not identify percent of weight due to body fat and/or the distribution of body fat, both of which may have bearing on maternal and fetal health.

	Epidemiological studies are also limited by their inability to demonstrate causation or to elucidate mechanism; the fact that some of these data are from large US or European population-level studies in the 1970sâ1990s, when obesity was less prevalent; and the fact that many of these studies suffer from attrition, sampling biases for control groups, reliance on parental report to evaluate past exposure and offspring diagnosis, lack of statistical power, and inability to adjust for confounders.

	The primary mechanisms that have been proposed to underlie the risk of neurodevelopmental morbidity in offspring of obese women include:

	1) Inflammation-induced malproÂ­gramming

	2) Relative excess and/or deficiencies of circulating nutrients

	3) Metabolic hormone-induced malprogramming, and

	4) Impaired development of serotonergic and dopaminergic signaling

	These mechanisms are not necessarily distinct from one another, and feature several interconnections (Figure). A brief summary of the evidence in these areas follows.

	Both maternal obesity and pregnancy itself are associated with chronic systemic inflammation.

 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.

 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.

	Placental and intrauterine inflammation are associated with altered fetal cytokine expression, fetal neuronal damage, and changes in neonatal brain gene expression.

 Elevated levels of maternal pro-inflammatory cytokines during gestation have been linked to an increased risk for ASD and neurodevelopmental delay in children.

 Children with ASD have also been shown to have elevated plasma markers of inflammation.

	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.

 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.

	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.

 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.

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.

 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.

 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.

	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.

	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.

 The fetal pancreas compensates by producing increased insulin, and the pro-inflammatory environment compounds fetal insulin resistance via inflammatory changes in fetal adipose tissue.

 Insulin acts on the fetal brain as a growth factor, and excess insulin exposure can cause disruptions in neural circuitry, brain development, and behavior.

 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.

	Leptin levels are also elevated in obese mothers.

 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.

 Leptin receptors are widely distributed in brain regions involved in behavioral regulation,

 so derangement in leptin signaling during key developmental periods is another potential mechanism underlying abnormal neurodevelopment in fetuses of obese women.

Impaired development of serotonergic and dopaminergic signaling

	Maternal obesity may also increase the risk of neurodevelopmental and psychiatric disorders through abnormal development of the serotonergic (5-hydroxytryptamine or 5-HT) and dopaminergic (DA) systems. 5-HT signaling plays a significant role in neuronal migration, cortical neurogenesis, and synaptogenesis during fetal brain development.

 In murine and non-human primate models, offspring exposed to maternal high-fat diet had decreased 5-HT synthesis, and increased anxiety behavior, hyperactivity, and hypothalamic inflammation.

	Subclinical inflammation in maternal obesity may also decrease 5-HT production in offspring through increased breakdown of the 5-HT precursor tryptophan.

 In rodent models, pro-inflammatory cytokines have been demonstrated to reduce 5-HT neuron axonal density and embryonic neuronal survival in brain regions critical for behavioral regulation.

 Suppressed 5-HT synthesis has been observed in humans with ADHD, ASD, anxiety, and depression.

 Thus, altered 5-HT production may be one mechanism by which maternal obesity increases risk for neurodevelopmental disorders in offspring.

	The dopaminergic system mediates reward neural circuitry and is similarly affected by maternal obesity. Rat offspring exposed to high-fat diets in utero had impaired mesolimbic dopaminergic signaling, resulting in impaired stress response and reward response to food.

 In mice, a maternal high-fat diet caused epigenetic changes in offspring DNA leading to dopamine dysregulation and changes in food preferences.

	Offspring changes in dopaminergic signaling may again be mediated through maternal inflammation; in a rat model of maternal inflammation, dopamine circuitry in offspring was dysregulated.

 Impaired dopaminergic signaling has been implicated in the development of ASD, ADHD, disordered eating, and other psychiatric disorders in humans.

	Maternal lifestyle and dietary changes, metformin treatment, and nutrient supplementation have all been explored as interventions to improve offspring neurodevelopment in maternal obesity.

 In animal studies, prepregnancy and lactational change from a high-fat diet to a control diet reduced offspring adiposity, circulating leptin, and anxiety behaviors.

 In a rat model of diet-induced obesity, maternal metformin treatment reduced fetal and placental inflammation.

 Observational data have pointed to polyunsaturated fatty acids, including omega-3 and omega-6 fatty acids, as possible candidate therapeutics in maternal obesity. Omega-3 fatty acids protect against brain inflammation and enhance serotonin signaling.

 Maternal omega-3 fatty acid deficiency has been associated with increased risk of offspring ASD and ADHD.

	A retrospective analysis of data from the Nursesâ Health Study II suggested that maternal intake of high levels of omega-6 fatty acids was associated with a 34% reduction in offspring ASD risk.

 Human pilot studies of obese maternal supplementation with omega-3 fatty acids have demonstrated reduction in maternal and placental inflammation.

 An ongoing clinical trial in obese pregnant women employs BMI-based prenatal micronutrient supplementation, with the goal of decreasing maternal and fetal oxidative stress and inflammation.

	â¢ Preconception counseling of obese and overweight women may be appropriate to discuss risks and to encourage weight loss and adoption of a healthy diet prior to pregnancy.

	â¢ Maternal preconception lifestyle change and weight loss may also reduce the risk for preeclampsia and gestational/pregestational diabetes, which have also been associated with iatrogenic prematurity and an increased risk for ASD and other neurodevelopmental morbidity in offspring.

	â¢ Evidence is insufficient to recommend routine omega-3 or omega-6 fatty acid supplementation in obese pregnant women to reduce the risk of offspring neurodevelopmental morbidity.

	â¢ Evidence is insufficient to recommend routine use of metformin in obese pregnant women to reduce the risk of offspring neurodevelopmental morbidity.

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Articles

The problems go beyond fetal metabolic programming. Obesity has effects on fetal neurodevelopment.

Larissa H Mattei, BA

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Maternal obesity and the fetal brain