Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study Associations With Neonatal Anthropometrics

The HAPO Study Cooperative Research Group


Diabetes. 2009;58(2):453-459. 

In This Article


These results support our hypothesis that increasing glucose concentration less severe than diabetes is associated with fetal overgrowth, specifically adiposity. Data presented here show a strong and continuous association between neonatal fat content and maternal glycemia and with fetal insulin levels as measured by cord C-peptide concentrations. These relationships were present for each maternal glucose measurement and cord C-peptide. Relationships persisted even when potential confounding variables such as field center, BMI, height, MAP, gestational age, smoking status, and alcohol use were taken into account. This pattern is similar to that reported for maternal glucose and birth weight > 90th percentile[2] and was also seen for the association with fat free mass, a parameter derived by subtracting fat mass from total body weight. Significant interactions for 1-h plasma glucose and age in relation to sum of skin folds > 90th percentile and triceps skin fold > 90th percentile, which indicated stronger associations with increasing age, may be a chance finding due to the large number of interactions examined.

The findings reported here, however, are not proof of causality. Fetal insulin, stimulated by maternal glucose transport from mother to fetus across the placenta, may act on a variety of nutrients in addition to glucose, resulting in fetal overgrowth and adiposity. DiCianni et al.[12] reported that maternal triglyceride levels were also strongly correlated with fetal growth, a finding that is consistent with the fuel mediated teratogenesis hypothesis of Freinkel.[13]

These findings confirm the link between maternal glycemia and neonatal fat deposition and suggest that the relationship is mediated by fetal insulin production. Furthermore, continuous relationships across the full range of maternal glycemia suggest that the Pedersen hypothesis is not limited to the high end of maternal glycemia but rather describes a basic biological relationship that influences maternal-fetal interactions around fetal growth. Each component of the OGTT and level of cord C-peptide was independently related to skin fold thickness with adjustment for multiple potential confounders. On average, maternal glucose was measured 11 weeks before collection of the cord blood serum C-peptide and measurements of neonatal anthropometrics. Thus, it is not surprising that associations of each glucose measure with anthropometric outcomes were significantly reduced but not eliminated when adjusted for cord C-peptide. Correlations among the glucose measures were modest,[2] and an index of their integrated associations with these anthropometric outcomes is not available. No one glucose measurement was clearly superior to the others, suggesting that fluxes of maternal nutrients whether in the fasting or postprandial state are related to fetal growth.

There is increasing evidence that increased size at birth is associated with an increased likelihood of adiposity in later life and with alterations in glucose metabolism and β-cell function.[14] Increasing hyperglycemia in pregnancy, whether associated with high birth weight or not, is associated with obesity and glucose intolerance later in life.[15] The finding of a continuous relationship between maternal glycemia and neonatal adiposity offers the potential to better understand, and possibly to influence, the development of obesity, a problem that is rapidly becoming epidemic around the world.[16] To date, published studies of relationships between size at birth and risk of obesity in childhood and later life[14] are based primarily on birth weight for gestational age without information on degree of adiposity at birth. Thus, follow-up studies of the HAPO cohort or other populations that have information on both maternal metabolic factors and obesity and neonatal body composition and insulin or C-peptide can be very informative.

Limitations of the data include the fact that a cord C-peptide level was not available for 15% of neonates. Additionally, 14% of neonates who had a cord C-peptide measurement did not have the full set of skin fold measurements. Skin fold thickness is an indirect measure of adiposity. However, the formula for calculation of body fat that is based on baby length, weight, gestational age, and flank skin fold[11] was validated by measurements of TOBEC, and the three skin fold measures are strongly intercorrelated. Maternal body weight was only measured at the time of the OGTT. Prepregnancy body weight was self-reported and incomplete, and weight was not measured at delivery, making maternal weight gain unavailable in a large number of cases. These limitations preclude our ability to evaluate the differential effects of pre-existing obesity and maternal weight gain in contributing to the outcomes measured. However, there was a strong correlation between recalled prepregnancy weight and weight measured at the OGTT.

In summary, our data provide the "missing link" between maternal glycemia, fetal insulin response, and neonatal growth, specifically neonatal adiposity, confirming that the Pederson hypothesis first proposed > 50 years ago[3] is not limited to overt diabetes, but extends across the full range of maternal glycemia. The multicenter nature of the cohort and the consistency of the results across several measures of growth and adiposity make the results particularly robust. The fact that the relationships extend across the entire range of glycemia is also striking. Whether the observed associations of the maternal metabolic environment with fetal growth are indicative of long-term effects on the increasing prevalence of obesity and diabetes in both adolescents and adults remains to be investigated.


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