In this follow-up study of children whose mothers participated in a randomized controlled trial, we did not find that treatment of mild GDM during pregnancy reduced BMI in 4- to 5-year-olds even though macrosomia at birth was substantially lower in the intervention group than the control group. Statistical power was adequate. The multivariable-adjusted effect estimate for BMI Z score was 0.08 with a lower 95% confidence limit of −0.29. Thus we effectively ruled out any reduction in BMI greater than one-fourth to one-third of SD, which equates to only 0.3–0.4 kg/m2 (also about 0.3–0.4 kg) for the average 4- to 5-year-old boy or girl whose BMI is in the range of 16–17 kg/m2.
Given that animal experiments and many observational studies suggest that GDM may cause offspring obesity, it is natural to wonder why the results of this study were null. Observational studies may overestimate treatment effects because of confounding; minimizing confounding is the principal reason for doing randomized trials. Because all mothers in ACHOIS had mild GDM, we could not assess the effect of treatment of more severe GDM, which might be necessary to program offspring obesity. Another possibility is that postnatal factors that determine a child's height and weight, such as diet and physical activity, overwhelm any effects of treating GDM during pregnancy. We did not have data on child behaviors to assess this possibility.
Alternatively, the long-term effect of GDM on childhood obesity and its reduction through treatment may not appear until later in childhood. In studies based in a specialty clinic, Metzger and colleagues (5
) observed that children of diabetic mothers were heavier than population control subjects at birth, but not at ages 1, 2, or 3 years. Only in school age did the excess weight reappear. Likewise, in a study of Pima Indian sib-pairs, associations of GDM with higher offspring BMI were apparent from age 9 years through early adulthood, but not at 6–9 years of age (4
). Consistent with these observations, in the pre-birth cohort study Project Viva, we recently reported that children of mothers with GDM had less rapid weight gain in the first 6 months of life than children of nondiabetic mothers (14
). The explanation for the age-associated disappearance and re-emergence of the association of GDM with higher child weight status is unknown. One possibility is that GDM has differential effects on lean and fat mass in the early years of life. In the Hyperglycemia and Adverse Pregnancy Outcomes Study, higher maternal glucose levels were associated with the sum of skinfold thicknesses at birth (a direct measure of adiposity) (15
). Among 3-year-old children in Project Viva, GDM was associated with increased systolic blood pressure and the sum of skinfold thicknesses (a direct measure of adiposity) but not with BMI, which comprises both lean and fat mass (16
). Unfortunately, we could not directly evaluate whether mild GDM caused higher BMI in later childhood in the present analysis because the CYWHS surveillance of the height and weight of the children does not extend past 5 years of age.
A less likely explanation for null results is selection bias. We obtained outcome data on fewer than half of South Australian ACHOIS subjects. However, differences according to treatment group at baseline and in the newborn period were similar among participants and nonparticipants, and adjustment for a range of covariates did not materially change effect estimates. These observations suggest that loss to follow-up did not substantially bias the results.
Inaccurate outcome measurement is also unlikely to explain the null results. Child and family health nurses measured height and weight with standard protocols. Moreover, while nondifferential error in exposure measurement can bias estimates toward the null value, noise in measurement of the outcome merely makes estimates less precise but does not introduce bias.
It is also unlikely that the observed effects of the ACHOIS intervention on infant outcomes were the result of chance, and that further child follow-up revealed the fallacy. The intervention reduced the risk of several newborn morbidities in addition to macrosomia, including the primary outcomes of fetal and neonatal death and birth injuries (10
). Also, recent data from a U.S.-based randomized trial of the treatment of mild GDM showed reductions in macrosomia (6 vs. 14%), newborn fat mass, caesarean section, and shoulder dystocia, although a composite neonatal end point was not demonstrably different in the intervention versus control group (17
). Consistency across these two studies suggests a real effect of GDM treatment on important infant health outcomes.
To conduct this study, we recognized that routine surveillance offered a low-cost way to obtain outcome data for research studies. This type of collaboration has the potential to increase knowledge and improve health by combining research studies, public health programs, and surveillance activities.
Measuring health outcomes among children whose mothers participated in randomized trials during pregnancy is not only the most direct way of confirming animal experiments of prenatal programming, but also may reveal how to improve child and adult health outcomes by intervening at early stages of human development. In this study, however, we did not substantiate our hypothesis that treatment of mild GDM during pregnancy reduces BMI in preschool-age children. Studies are needed that involve longer follow-up of children whose mothers participated in completed randomized trials of GDM treatment. Moreover, any newly designed trials of treatment or prevention of GDM would benefit from funding to follow the children long term with measures of body composition.