Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study : Associations with Neonatal Anthropometrics
The HAPO Study Cooperative Research Group

Abstract
Objective
To examine associations of neonatal adiposity with maternal glucose levels and cord serum C-peptide in a multicenter multinational study, the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study, thereby assessing the Pederson hypothesis linking maternal glycemia and fetal hyperinsulinemia to neonatal adiposity.

Research Design and MethodsEligible pregnant women underwent a standard 75-g oral glucose tolerance test between 24 and 32 weeks gestation (as close to 28 weeks as possible). Neonatal anthropometrics and cord serum C-peptide were measured. Associations of maternal glucose and cord serum C-peptide with neonatal adiposity (sum of skin folds >90th percentile or percent body fat > 90th percentile) were assessed using multiple logistic regression analyses, with adjustment for potential confounders, including maternal age, parity, BMI, mean arterial pressure, height, gestational age at delivery, and the baby's sex.

ResultsAmong 23,316 HAPO Study participants with glucose levels blinded to caregivers, cord serum C-peptide results were available for 19,885 babies and skin fold measurements for 19,389. For measures of neonatal adiposity, there were strong statistically significant gradients across increasing levels of maternal glucose and cord serum C-peptide, which persisted after adjustment for potential confounders. In fully adjusted continuous variable models, odds ratios ranged from 1.35 to 1.44 for the two measures of adiposity for fasting, 1-h, and 2-h plasma glucose higher by 1 SD.

ConclusionsThese findings confirm the link between maternal glucose and neonatal adiposity and suggest that the relationship is mediated by fetal insulin production and that the Pedersen hypothesis describes a basic biological relationship influencing fetal growth.

Introduction
The objective of the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study was to clarify the risk of adverse outcome associated with degrees of glucose intolerance during pregnancy that are less severe than overt diabetes. Glucose tolerance was measured by a 75-g 2-h oral glucose tolerance test (OGTT) in a large, heterogeneous, multinational, ethnically diverse cohort of women at 2432 (mean 28) weeks gestation with medical caregivers blinded to status of glucose tolerance (except when predefined thresholds were met).[1] Associations between maternal glycemia and increased size at birth, delivery by cesarean section, development of neonatal hypoglycemia, and the presence of fetal hyperinsulinemia were the predefined primary outcomes of the study. Results of the study showing continuous relationships of maternal glucose levels below those diagnostic of diabetes with each of the primary outcomes have been reported.[2] Associations of maternal glucose and birth weight >90th percentile and fetal hyperinsulinemia [cord C-peptide concentration greater than the HAPO Study 90th percentile (1.7
ìg/l)] were strong. Weaker associations were found with cesarean delivery and clinical neonatal hypoglycemia.[2]

In 1952, Pedersen[3] postulated that maternal hyperglycemia was transmitted to the fetus, which, in turn, produced and released large amounts of insulin, with the resultant fetal hyperinsulinemia being the cause of various aspects of diabetic fetopathy, including deposition of large amounts of body fat, which gave the infant its characteristic appearance. Pedersen documented increased body weight in infants of diabetic mothers compared with control subjects. Fetal hyperinsulinemia, in the absence of maternal diabetes, has been demonstrated to cause "diabetes-like" fetopathy in rhesus monkey offspring.[4] At least some of the increased fetal weight has been shown to be attributable to increased fat accretion.[5]

In 1977, Whitelaw[6] reported an association between diabetic control and skin fold thickness in infants of diabetic mothers. Sparks reported that body fat more specifically represents effects of the in utero environment, whereas lean body mass represents more of the genetic component of growth.[7] For example, male neonates have greater birth weight than females primarily because of increases in lean body mass.[8] Therefore, we elected to estimate body composition, in particular fat mass and percent body fat, as specific outcomes in the HAPO Study cohort.

These reports and many others validate the basic tenets of the Pedersen hypothesis. However, efforts to define the strength of associations with hyperglycemia are confounded by treatment. Furthermore, the direct link between maternal glycemia, fetal insulin response, and neonatal body composition has not yet been demonstrated in the subdiabetic glucose range. Goals of this report are 1) to examine associations of maternal glycemia with newborn anthropometrics (skin folds, percent body fat); and 2) to present data linking fetal hyperinsulinemia (assessed by cord serum C-peptide) to the development of larger and more obese babies.

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