The current study represents, to the best of our knowledge, the first report demonstrating that the association of maternal pre-pregnancy BMI with subsequent severity of child ADHD symptoms is mediated by alterations in child executive function. Moreover, this effect persists and is substantially unaltered after adjusting for a number of potential confounders, including key pregnancy and birth outcomes and maternal and child characteristics that are established risk factors for ADHD. When examined across clinical categories for BMI, the effect is particularly salient among the children of obese compared to those of overweight or normal pre-pregnancy weight women. The magnitude of the observed effect on child ADHD symptoms and underlying executive function is striking (0.54 and 0.62 standard deviation units, respectively, 
). In terms of potential clinical significance, these observed differences in ADHD symptoms extrapolate to an approximately 2.8-fold increase in ADHD risk in offspring of obese (21.4% with CBCL score >1) compared to non-obese mothers (7.5% with CBCL score >1).
Our finding that child executive function mediates the association between maternal pre-pregnancy BMI and child ADHD symptoms is important for two reasons. First, it serves to improve our understanding of the underlying etiological mechanism(s). Second, it has clinical implications, in that it suggests a specific, targeted intervention strategy that can be developed and tested in at-risk children of obese mothers. Executive function may be a malleable trait, particularly during critical postnatal developmental periods when key brain networks that sustain attention processing are developing and are maximally plastic 
. We note that the pattern of performance among the at-risk children in our study of the executive function task (i.e., higher number of omission errors but no difference in reaction time and number of false alarms) is reflective of inattentive rather than impulsive behavior 
. Specific interventions are now available to train executive function (and particularly attention) in children 
, and it is possible that the application of such interventions may prevent or attenuate subsequent behavioral deficits in this population.
The biological pathways underlying the observed effects in the current study likely relate to inflammation. The state of obesity before and during pregnancy is a major reason for increased systemic inflammation in not only the maternal but also the fetal compartment 
. Fetal exposure to a pro-inflammatory milieu during critical periods of brain development is believed to represent a key mechanism underlying the development of suboptimal alterations in brain structure and subsequent neurocognitive function. Several experimental studies in animals have shown that exposure to infection or administration of pro-inflammatory cytokines adversely impacts key neurotrophic factors 
, neurogenesis 
, apopotosis 
, neurotransmitter levels 
and myelination 
. In fact, a very recent study demonstrated that cell fate itself is altered when neural progenitor cells are exposed to high levels of the pro-inflammatory cytokine interleukin-1β (IL-1β), with gliogenesis being promoted at the expense of neurogenesis 
. Thus, exposure to infection and high levels of pro-inflammatory cytokines can disrupt the normal developmental trajectory of the fetal brain and produce long-term or permanent consequences for gray matter volume and white matter integrity 
. It is believed that such alterations in fetal neurodevelopment underlie the association observed in epidemiological studies between exposure to prenatal infection (another condition that is associated with a pro-inflammatory milieu during pregnancy) and increased risk for neuropsychiatric disorders 
. Biological markers of inflammation were unfortunately unavailable in this study cohort, however, our on-going studies are currently addressing this important issue with a comprehensive characterization of maternal, placental and fetal biology across gestation and birth and serial follow-up assessments in newborns, infants and children using neuroimaging studies of brain structure, white matter maturation and functional connectivity. We also note that fetal exposure to a pro-inflammatory milieu during gestation is a non-specific marker of subsequent ADHD risk, in that it also is associated with a host of other suboptimal mental and physical health outcomes, including child obesity, metabolic dysfunction, and increased risk of other cognitive and affective problems. Thus, it is likely that for any given individual the risk of specifically developing ADHD in the context of inflammation may be influenced (moderated) by additional factors such as genetic vulnerability 
and other environmental exposures 
Consistent with previous reports 
, maternal pre-pregnancy BMI but not gestational weight gain was associated with child ADHD symptoms. This finding mirrors observations related to other outcomes such as child adiposity and insulin sensitivity, wherein maternal pre-pregnancy BMI also is a stronger predictor than maternal weight gain during pregnancy 
. Furthermore, we recently have reported that pre-pregnancy BMI, not weight or fat gain during pregnancy, is significantly associated with increased C-reactive protein (CRP) levels during pregnancy 
(one of the best systemic biomarkers of an inflammatory state), suggesting that maternal adiposity before conception may be a stronger determinant of systemic inflammation and its sequelae than gestational weight or fat gain per se
. This, in turn, raises the intriguing possibility that the state of maternal health prior to pregnancy may have a more important bearing on gestational, birth and subsequent child outcomes than events in the index pregnancy. We note a growing body of evidence is beginning to shed light on the mechanisms by which maternal life-course factors may influence birth and child outcomes 
. Adopting this life-course perspective to the current findings, it seems reasonable, plausible and even probable that an individual’s susceptibility to developing ADHD may be traced back not only to conditions in intrauterine life but even further back to her or his mother’s state prior to conception. Indeed, pre-pregnancy BMI is a good integrative summary measure of maternal state that captures a host of maternal conditions and exposures over the life course (e.g. nutritional, endocrine and immune/inflammatory state) that have been patterned by her own early programming and pathway mechanisms.
A recent study in two independent cohorts was not able to replicate the association between maternal pre-pregnancy BMI and child attention problems which led the authors to the conclusion that such previously observed associations were due to residual confounding 
. However, there are notable differences between those studies and the current study. Child behavior was assessed already at 36 and 38 months, respectively, which may be too early to reliably detect attention problems. Furthermore, children of overweight and obese mothers were collapsed in one group and tested against normal weight mothers, which may have diluted the effects of maternal obesity. Thus, while it is possible that the effects of pre-pregnancy BMI may be confounded, exacerbated or attenuated by other pregnancy-related factors and/or postnatal conditions and experiences, important strengths of our study include the prospective, longitudinal design and the ability to address the potential confounding effects of many of these factors by study design (e.g., maternal smoking and drug use). In addition, we assessed and statistically accounted for the possible effects of several other key potential confounding factors (e.g., obstetric risk conditions, maternal depression at the time the CBCL was assessed).
Another strength of the present study is our use of a population-based, as opposed to a clinical, sample of mother-child dyads, in which the distribution of maternal BMI and other maternal and child characteristics closely resembles that of the general population. Therefore, the results of the current study likely are more generalizable than those from studies encompassing or enriched by individuals with a clinical diagnosis of ADHD (which are susceptible to a referral bias).
Obesity during pregnancy is increasing worldwide 
. Based on recent estimates, about one-third of women in childbearing age in the United States enter their pregnancy obese 
. Since ADHD confers a major burden on the child, family, society and health care costs, identification of possible modifiable targets for primary intervention is of great interest, importance and relevance. Many questions remain, such as of the precise mechanisms underlying prenatal programming of childhood ADHD by maternal adiposity. To address these questions, a multi-level approach is required that includes molecular and cellular studies, the use of appropriate animal models, and well-designed prospective, longitudinal human studies that incorporate the assessments of immune and metabolic measures during pregnancy 
. Nonetheless, the results of this study add further evidence to the growing awareness that neurodevelopmental disorders including ADHD may have their foundations in very early life