In a multi-ethnic population from Colorado, we found that exposure to diabetes in utero was associated with an altered growth trajectory in children (27 months through 13 years of age, p=0.008), in particular a higher BMI growth velocity starting at ages 10 to 13 years (p=0.005). The effect of exposure on the BMI growth trajectory in childhood was independent of potential confounders such as demographic (sex, race/ethnicity) and developmental characteristics (gestational age), or markers of other in utero exposures (maternal age, income and education, pre-pregnant BMI). Importantly, no significant differences in growth trajectories were noted in infancy and early childhood. This study used longitudinal analysis to examine the impact of in utero diabetes exposure on BMI growth trajectories from birth to adolescence.
Our findings are consistent with the long-term patterns of accelerated BMI growth associated with in utero
diabetes exposure reported in other studies. Silverman et al (21
) observed a period of catch-down growth among a population of NHW and AA offspring of diabetic pregnancies compared to offspring of non-diabetic pregnancies in Chicago. The initial period of poor growth or catch-down weight in the first year of life was followed by a higher BMI in adolescence among offspring of diabetic mothers relative to non-exposed peers. Among Pima Indian youth, Touger et al (18
) reported a change in weight z score between birth and 1.5 years of age of −0.56 vs. 0.12, (p<0.01) for exposed verses unexposed offspring suggesting early catch-down growth, but a higher weight z score at age 7.7 years of 1.26 in exposed vs. 0.00 in unexposed children (p<0.01). In an earlier study, Dabelea et al (17
) reported no differences in mean BMI among Pima Indian sib-pairs exposed and unexposed to diabetes in utero
at ages 5–8 years, but significantly higher BMI levels in exposed siblings at ages 9–12 years, which persisted throughout adolescence into young adulthood. Our study did not identify specific periods of catch-down growth in exposed versus unexposed infants; the overall growth trajectory up to 26 months of age was not significantly different between the two groups. Interestingly, in a recent follow up study of a randomized clinical trial in Australia, treatment of mild GDM did not result in BMI differences in offspring at 4–5 years of age (22
). All the data summarized above suggested that the long-term effects of GDM exposure on childhood obesity become apparent later during childhood (e.g., during puberty). Our findings are consistent with previous reports and provide novel and direct evidence that exposure to diabetes in utero
results in accelerated BMI growth starting in late childhood.
The mechanisms underlying the accelerated BMI growth trajectory in childhood among offspring of diabetic pregnancies are the object of extensive research. Several mechanisms that are not mutually exclusive may explain this association. They include genetic predisposition and shared familial factors, as well as specific intrauterine effects (i.e., fuel-mediated teratogenesis, also known as fetal overnutition). For example, exposure to maternal diabetes in utero
may modulate delivery of lipid substrates to the fetus, resulting in adipocyte dysregulation and fatty acid accumulation (23
). More research is needed in this area because distinguishing between specific intrauterine mechanisms and general familial (genetic and nongenetic) factors is important for the development of randomized trials aimed at testing effective interventions.
In our study, differences in pubertal development between exposed and unexposed offspring did not explain differences in growth trajectories (data not shown), and exposed offspring were in fact less likely to have begun puberty by the time of the EPOCH visit. However, the role of pubertal development as a potential mediator or modifier of the long-term consequences of exposure to diabetes in utero on childhood adiposity patterns requires additional study and prospective follow up of this cohort.
We believe that our data have important public health implications. Efforts to intervene or treat obese adults have generally been unsuccessful, and thus, identifying mechanisms and critical periods that influence obesity risk in future generations represent an important opportunity to develop targeted prevention efforts to break the vicious cycle of obesity. Importantly, the Bogalusa Heart Study demonstrated that cardiovascular risk factors, including obesity, track from childhood into adulthood (24
). Our data suggest that exposure to diabetes in utero
results in accelerated BMI growth during late childhood years. Further follow up of this cohort is necessary to determine if the accelerated growth trajectory continues into teenage and early adult period. Because no differences in growth trajectories were observed early in life, the perinatal and early childhood periods may represent windows of opportunity for targeted efforts aimed at preventing the increased risk of obesity associated with in utero
exposure, manifesting in late childhood/early pubertal years. Such preventive strategies among high risk children include promotion of breastfeeding, which has been associated with reduced risk of obesity in late adolescence and adulthood (25
), encouragement of physical activity, and promotion of healthy foods, such as fruits, vegetables, whole-grain breads and cereals, low fat diary products and no sweetened drinks.
Our study has several limitations. We did not have sufficient data points on each subject to construct individual growth curves or accurately estimate whether exposure to diabetes in utero
influences the age at adiposity rebound, another marker of increased risk for later-life obesity (26
). Our study, like others (27
) used maternal pre-pregnancy BMI as a proxy for genetic predisposition. This is problematic because maternal obesity is a risk factor for the exposure considered in this study (27
) and may represent over adjustment. However, in our population, adjustment for maternal pre-pregnant BMI did not eliminate the observed relationship between exposure to diabetes in utero
and increased growth trajectory during late childhood, suggesting that the observed association is not completely accounted for by genetic predisposition to obesity. We were unable to assess the impact of maternal hyperglycemia less severe than the cutoff for diagnosis of GDM. Offspring exposed to less extreme levels of hyperglycemia in utero
were captured in our unexposed group, thus possibly biasing our results towards the null. The relatively young age of our cohort prevented assessment of accelerated growth after puberty, when differences are likely to be more pronounced (29
): only 30% of exposed youth and 50% of unexposed youth reported a Tanner stage greater than 2, indicating they had begun puberty. Prospective follow up of this population is necessary to understand the impact of exposure to diabetes in utero
on BMI trajectories during teen and early adult years.
Our study also has important strengths. First, the longitudinal analysis utilizing mixed linear effects models made efficient use of the data, allowing us to explore more than just linear changes in BMI between two time periods. Our methods represent a novel approach to assess the influence of in utero diabetes exposure on childhood growth. Additional strengths include the ethnically diverse cohort including NHW, Hispanic and AA youth and our validated exposure, assessed without concern for recall bias.
In summary, this study provides novel evidence of an altered childhood growth patterns for youth exposed to diabetes in utero. Among a diverse population of young children, exposure to diabetes in utero was associated with an overall higher growth trajectory in late childhood and accelerated BMI growth velocity starting at ages 10 to 13 years, relative to unexposed children. These results provide further support for the hypothesis that fetal exposure to a diabetic intrauterine environment influences childhood growth and obesity risk.