While a number of early-life risk factors for high childhood BMI have already been identified, the pathways that connect these risk factors are not well understood. We found that gender, diabetes exposure in utero, size for gestational age, weight gain in the first year of life, and total breastfeeding duration (inverse) showed significant association with higher childhood BMI (table ). Mediation analysis suggested that the protective effect of breastfeeding duration on childhood BMI may be largely mediated by slower infant weight gain, and the increased risk of higher childhood BMI conveyed by exposure to diabetes in utero may be partially explained by greater birth size.
Two hypotheses regarding the observed protective effects of breastfeeding against childhood obesity [18
] have been proposed. The first proposes that the difference in nutritional content between breast milk (high fat, low protein) and formula (low fat, high protein) contributes to early adiposity rebound and greater subsequent childhood obesity in formula-fed infants [33
]. The second suggests that the protective effect is due to lower plasma concentrations of insulin, a hormone that promotes fat storage, in breastfed infants compared to formula-fed infants [34
Rapid weight gain in infancy has also been associated with childhood obesity [13
]. An association between breastfeeding duration and rapid infant weight gain has been seen previously [35
]. We also showed that rapid infant weight gain is a significant mediator of the association between shorter breastfeeding duration and higher childhood BMI (p < 0.0001; fig. ). It is possible that infant feeding patterns may be influenced by rapid infant weight gain. For example, babies that are ‘falling off’ their growth curve may be weaned due to their mother's or physician's perception of insufficient growth. We hypothesize that the association between rapid postnatal infant growth and increased childhood BMI is due to a diet-induced altered metabolic state in infancy, the effects of which persist throughout childhood.
Potential pathways to higher childhood BMI as defined by mediation analyses. Note that unmeasured confounding factors may bias the direct effects and the mediated effects.
Exposure to gestational diabetes has been associated with greater fat mass at birth [38
], and childhood obesity has been associated with exposure to diabetes in utero [10
]. We found that exposure to diabetes in uterowas associated with higher childhood BMI, and that greater birth size acted as a partial mediator in this association. It has been hypothesized that exposure to diabetes in utero may lead to childhood obesity via fetal hyperglycemia and hyperinsulinemia. Fetal hyperinsulinemia can act as a growth hormone, leading to larger birth size, and may induce insulin resistance, leading to overgrowth of fat cells and obesity in postnatal life. Other research suggests that exposure to diabetes in utero may lead to childhood obesity in the absence of higher birthweight due to in utero programming effects [41
]. This may explain why the mediating effect of higher birthweight does not explain all of the association between exposure to diabetes in utero and higher childhood BMI.
Furthermore, mediator analysis of the subgroup that excluded the 47 subjects exposed to gestational diabetes in utero (no analysis subjects were exposed to type 2 diabetes in utero) estimated that birth size mediated 59% of the effect of exposure to type 1 diabetes in utero on increased childhood BMI (τ for type 1 diabetes exposure in utero: 0.235, τ′ for type 1 diabetes exposure in utero: 0.096, Z = 4.52, p < 0.0001; fig. ). The mediating role of birth size in the pathway between type 1 diabetes exposure in utero and higher childhood BMI has not yet been demonstrated.
Both low birthweight [15
] and high birthweight [13
] have been associated with childhood obesity. We found larger size for gestational age, a marker of in utero growth permissiveness, was associated with higher childhood BMI (table ). Adjustment for infant weight gain strengthened
the effect of higher birthweight on higher childhood BMI, suggesting that, although high birthweight infants gain less weight in the 1st year of life, they still remain at higher risk for higher childhood BMI. Similarly, a study in the Pima Indians found that children exposed to diabetesin uterohad higher birthweights, slower weight gain (‘catch-down growth’) in infancy, and subsequent greater childhood obesity [42
The main strengths of this analysis are the large sample size, the prospective, longitudinal nature of the data, and the long follow-up time. We were able to explore associations and interrelations between known early-life exposures and higher childhood BMI. Study weaknesses include lack of other measures of fat mass and physical activity data. More accurate measures of childhood fat mass may help to more specifically identify the early life risk factors that are most important for preventing chronic disease processes in children. Physical activity may explain (low levels of physical activity may result in higher BMI), or counteract (via high muscle mass) the potentially ill effects of higher childhood BMI. We were also unable to analyze some known risk factors for higher childhood BMI, such as maternal diet and weight gain during pregnancy. Parental height and weight were not included in this analysis due to concerns that the very low response rate and the self-reported nature of these data would produce an unstable and biased result. While the mediation analysis assumes causality, the observational study design prevents determination of causality. In addition, there may be unmeasured confounders in our mediation analyses (e.g. physical activity, genetics, etc.).
It is possible that a number of the analysis subjects had already started to undergo body changes related to puberty. However, a sensitivity analysis revealed that reducing the upper age limit of subjects in the analysis from 11.5 years (boys) and 11 years (girls) down to 9.5 years and 9 years, respectively, did not change the results. Finally, the DAISY population may not be representative of the general population, as enrollment is based on HLA genotype or family history of type 1 diabetes. However, these sampling variables were not associated with this analysis outcome, and we did not include any records that may have been affected by the autoimmune disease process. Therefore, the cohort selection is unlikely to affect the results.
In conclusion, we defined two separate pathways between early life risk factors and higher childhood BMI in a cohort of healthy U.S. children. Our results suggest that infants that are breastfed for a shorter period of time tend to gain weight faster during the 1st year of life, and are subsequently more likely to have higher childhood BMI. Likewise, larger birth size may partially mediate the association between diabetes exposurein utero and higher childhood BMI. Future research should be directed towards better understanding how genetics (such as parental BMI) and fetal exposures (such as weight gain during pregnancy) interact with early life (composition of infant diet, infant weight gain) and childhood diet and physical activity patterns in determining childhood risk of higher BMI. Such research may lead to targeted mother and infant nutritional recommendations that would reduce risk of higher BMI throughout childhood, and thus potentially reduce the risk of obesity-related diseases throughout life.