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.1,2 Childhood obesity and early-onset metabolic syndrome have risen in parallel.1-3 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.
Evidence from epidemiologic studies
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.4-7 Maternal obesity has been linked to decrements in offspring cognition (eg, 2â5 points lower IQ in offspring of obese women compared to non-obese counterparts),4,8,9 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.8 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).4 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.4,6
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.10-13 This risk may be further augmented by intrauterine growth restriction (IUGR),14 preterm birth,12 high GWG,13 gestational or pre-gestational diabetes,10,11 and preeclampsia.15
Two recent studies including matched sibling analyses failed to find a significant relationship between maternal pre-pregnancy BMI and ASD risk,16,17 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.16,17 Of note, paternal obesity has also been demonstrated to be independently associated with increased ASD risk in offspring.18
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.19 Later studies confirmed this association with up to a 2.8-fold increased risk of offspring ADHD compared to non-obese counterparts.20-22
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.23 Another study failed to find an association between maternal obesity and offspring ADHD after adjusting for confounders such as socioeconomic status.24 Still, the preponderance of epidemiologic evidence suggests that maternal obesity is associated with ADHD risk in offspring.
Increased odds of cerebral palsy (CP)
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).25-28 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%.25 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.26,29