We conducted an analysis using data from the NCPP to better understand the effect of GDM on childhood growth. Our results expand the knowledge in this area as we found that maternal GDM status is associated with childhood growth independent of birthweight. We observed that offspring of mothers with GDM were heavier as determined by three anthropometric measures examined at age 7, compared to offspring of mothers without GDM, even after adjustment for birthweight. Also, offspring of mothers with GDM show a 61–81% higher odds of overweight status ages 7 and 4, respectively, compared to offspring of mothers without GDM.
Previous studies examined several different anthropometric measures during childhood at different points during childhood among offspring of mothers with GDM. Several studies evaluated overweight or obesity defined using either the 85th, 90th or 95th percentile of BMI or weight [20
], BMI z-score [18
], BMI [21
] and skinfold thickness [25
]. Only one study evaluated offspring fat mass and waist circumference [26
]. In addition, with the exception of birthweight, few of the studies assessed childhood anthropometry before the age of 5 [21
]. In one study, Gillman and colleagues [24
] included birthweight in the multivariable model and unlike the results of our study, they did not find a statistically significant association between offspring exposure to GDM and overweight status in childhood among 9–14 year old participants [OR = 1.3; 95% CI 0.9, 1.9] and after the addition of mother’s BMI at the time of the child’s anthropometry assessment, the association attenuated [OR = 1.2; 95% CI 0.8, 1.7]. Whitaker and colleagues did not find an association between intrauterine exposure to GDM and overweight status in childhood defined by BMI z-score for offspring ages 8–10 years of age in a sample of medically insured, non-Hispanic white diet-treated GDM mothers even without adjustment for birthweight [18
]. Our study results may differ from the null findings in previous studies due to several factors. First, the difference in results may be explained by the secular improvements in the detection and treatment of GDM. Second, our study was conducted using data from a historical cohort unexposed to the nutritional affluence of more contemporary cohorts used in other studies. Given strong influence of environmental factors and increased access and availability of calories in a contemporary cohort, these factors may be more overwhelming than the effect of the intrauterine exposure to maternal hyperglycemia. Third, overweight in these studies were assessed at older ages which allows for increased influence of the environmental factors with increasing age.
However, similar to Wright et al., we observed no significant difference in childhood growth in offspring of mothers with GDM compared to offspring of mothers without GDM at ages 3 and 4. Several factors may have contributed to the lack of association between GDM and childhood growth at ages 3 and 4. First, weight and BMI do not fully capture growth. Body composition measures, including fat free mass and lean mass which were unavailable for analysis, may be better measures of growth in childhood. Second, data from previous studies suggest that it is not until after ~5 years of age that there is a significant difference in weight of offspring of mothers with GDM compared to those whose mothers did not have GDM. These studies suggest that GDM may have a delayed influence that increases with time [17
There are several mechanisms that may explain our findings. First, our findings support the idea that intrauterine exposures and programming may have long term effects on childhood growth. While the short term effect may be manifested in infant birthweight, there may be an alternative pathway linking GDM to overweight status in childhood since the observed association persisted even after adjustment for birthweight. This idea of an alternative pathway is supported by Pettit’s finding in the Pima Indians that offspring of mothers with GDM with normal birthweight had an increased risk of childhood obesity [31
]. Second, there may be a combination of metabolic alterations or genetic factors that play a role. In a recent study, Catalano et al. found that newborns of mothers with mild glucose intolerance had a 20% higher body fat mass than infants born to mothers with normal glucose tolerance, suggestive of an early alteration in fat metabolism due to antenatal exposure to maternal hyperglycemia [32
]. Another possible explanation for the persistent relationship between GDM and overweight status in childhood may be that offspring of mothers with GDM adopt some unhealthy dietary and physical activity patterns of their mothers and may share obesity-related genes. This explanation however, is challenged by the results of Dabelea et al. [33
] which show that among Pima Indians, offspring exposed to diabetes in utero had higher BMI than their unexposed siblings. These results suggest that there may be some programming effect of GDM on the fetus, making exposed offspring more susceptible to being heavier in childhood.
The relative importance of tight glycemic control and lifestyle behavior change among mothers with GDM in the prevention of overweight status among offspring is unclear. Hillier et al. [20
] found an almost twofold increased risk of elevated weight at 5–7 years among offspring of mothers with untreated GDM, whereas the association with treated GDM was weaker and similar to milder impaired glucose tolerance. However, results from a randomized controlled trial, showed that treatment of mild GDM with dietary advice, blood glucose monitoring and insulin therapy as needed, resulted in reduced incidence of macrosomia in the intervention group, but there was no effect on BMI in 4–5 year olds [34
]. These results suggest that there is more to the relationship between GDM and overweight status in childhood beyond shared obesity-related genes between the mother and offspring, which is a commonly offered explanation. Further investigation of gene environment interactions in utero and postnatally are necessary to better discern these potential relationships.
Our study has several strengths. First, the study has a large diverse population-based sample though the analytic sample was reduced compared to the initial cohort. Second, we were able to examine the association of offspring exposure to GDM and weight and overweight over a 7 year time frame. Third, our study allows us to examine the association between GDM and childhood growth in a period of time with low prevalence of diabetes and obesity unlike most other observational studies using more contemporary populations or high risk populations with high prevalence of obesity and diabetes.
Nonetheless, several limitations deserve comment. First, there may be some selection bias due to missing data and differential loss to follow up such that mothers included in the analysis were more likely to be white and have completed high school. Second, there is some error in the assessment of gestational age as would be expected since this study was conducted before the implementation of routine ultrasound to determine gestational age. Gestational age in this study was determined by using self-reported date of the last menstrual period (LMP). We were conservative in our approach and limited the analytic sample births to mothers with a gestational age between 36 and 42 weeks gestation. Third, we were not able to adjust for unmeasured confounders such as family environment, diet and exercise which could be independent risk factors for both GDM and overweight status in childhood. Fourth, there may be some misclassification of GDM. However, the incidence of metabolic alterations in offspring of mothers with diabetes is not dependent on the type of diabetes. The risk of overweight and obesity during childhood and adulthood seem to follow similar profiles in offspring of mothers with Type 1 and Type 2 Diabetes [17
]. The OGTT thresholds used to diagnose GDM in the NCPP are higher (125 mg/dl vs. 95 mg/dl) compared to those currently recommended by the NDG or Carpenter-Coustan criteria. Thus, we may have underestimated the number of women with GDM and underestimated the magnitude of association between GDM and early childhood growth. Finally, generalizability is limited, since participants in the NCPP were enrolled over 40 years ago and were comprised largely of low income women.
We conclude that the GDM is predictor of early childhood growth independent of birthweight. Therefore clinicians might focus on peri-conceptional interventions that prevent insulin sensitivity and the development of GDM. Current evidence indicates that physical activity prior and during pregnancy results in an almost 50% reduction in the development of GDM [36
]. In addition, interventions to improve glucose control and increase healthy behaviors during pregnancy may impact the development of overweight and obesity in the offspring. Alternatively, since implementation of a lifestyle intervention may be challenging during pregnancy, mothers with GDM might be directed to a lifestyle intervention as part of their post partum follow-up care. Such intervention might reduce the risk of recurrent GDM with a subsequent pregnancy as well as improve lifestyle behaviors of the mother and child.