The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study was performed in response to the need for internationally agreed upon diagnostic criteria for gestational diabetes, based upon their predictive value for adverse pregnancy outcome. Increases in each of the 3 values on the 75-g, 2-hour oral glucose tolerance test are associated with graded increases in the likelihood of pregnancy outcomes such as large for gestational age, cesarean section, fetal insulin levels, and neonatal fat content. Based upon an iterative process of decision making, a task force of the International Association of Diabetes and Pregnancy Study Groups recommends that the diagnosis of gestational diabetes be made when any of the following 3 75-g, 2-hour oral glucose tolerance test thresholds are met or exceeded: fasting 92 mg/dL, 1-hour 180 mg/dL, or 2 hours 153 mg/dL. Various authoritative bodies around the world are expected to deliberate the adoption of these criteria.
At present, there is a lack of international consistency with regard to the diagnosis of gestational diabetes mellitus (GDM). While a glucose tolerance test (GTT) is commonly employed, glucose challenge dosages vary and diagnostic thresholds are myriad. The 75-g glucose challenge is widely used throughout the world for diagnostic testing in the nonpregnant state. At the Third International Workshop-Conference on GDM in 1990 a series of recommendations were made that included universal employment of the 75-g glucose challenge during pregnancy. Some sets of diagnostic criteria, such as those proposed by the World Health Organization (WHO), were simply based on criteria used in nonpregnant individuals, and did not take into account changes in carbohydrate metabolism brought about by the pregnant state. Others, such as the O’Sullivan criteria in use in North America, were based on data from pregnant women, but were derived mathematically as being 2 SD above the mean, and were validated for their predictive value for future diabetes in the mother, rather than on pregnancy outcomes. The organizers advocated for international agreement on all aspects of diagnostic testing, and for the development of criteria based on pregnancy outcomes.
Subsequently a group of investigators from the disciplines of obstetrics and gynecology, diabetology, and neonatology, based in North America, Europe, Asia, and the Middle East, met to plan a study to examine the relationship between maternal glucose and adverse neonatal outcomes. A 1992 workshop sponsored by the National Institute of Child Health and Human Development (NICHD) and the National Institute of Diabetes and Digestive and Kidney Diseases supported the rationale behind this effort, concluding that carefully designed studies were critical to answer outstanding questions about the sensitivity, specificity, and cost-effectiveness of efforts to diagnose and treat GDM to prevent adverse perinatal effects.
The Fourth International Workshop-Conference on GDM in 1997 noted that the prevalence of GDM was increasing around the world, and that “…although…some progress has been made toward building consensus there remains a compelling need to develop diagnostic criteria for GDM that are based on the specific relationships between hyperglycemia and risk of adverse outcome.”
Another area of controversy surrounded the potential benefit, or lack of benefit, of screening a population for GDM and treating when the diagnosis was made. As recently as 2008 the US Preventive Services Task Force (USPSTF) Guide To Clinical Preventive Service recommended as follows: “The USPSTF concludes that the current evidence is insufficient to assess the benefits and harms of screening for GDM either before or after 24 weeks gestation.” The opposing view to this assertion is based upon studies showing increased perinatal morbidity even when only 1 GTT value is elevated.
The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study was designed to answer some of the questions posed above. While there was little or no argument that type 1 and type 2 diabetes increase the risk of any number of adverse pregnancy outcomes, the HAPO study sought to determine the level of glucose intolerance during pregnancy, short of overt diabetes, that is associated with adverse outcomes. The study design has been described in detail elsewhere. More than 25,000 nondiabetic gravidas were enrolled in 15 field centers located in 9 different countries. Each subject underwent a 75-g, 2-hour oral GTT (OGTT) at between 24-32 weeks’ gestation (mean gestational age, 27.8 weeks); subjects and caregivers were blinded to the GTT results unless the fasting plasma glucose was >105 mg/dL or the 2-hour value was >200 mg/dL, in which case the caregiver was informed of the results and the subject was excluded from participation so that she could be treated as determined by the caregiver. As a safety precaution, a sample for random plasma glucose was collected at 34-37 weeks and unblinded if the value was ≥160 mg/dL. Participants were also unblinded for any glucose value <45 mg/dL.
At the time of delivery, cord blood samples were obtained and analyzed at the central laboratory for glucose and for C-peptide. C-peptide was chosen as a marker for fetal insulin levels because, in the presence of hemolysis, it is much more stable than insulin in stored specimens. Neonatal anthropometric measurements were collected within 72 hours of delivery. These consisted of weight, length, head circumference, and skinfold thickness measured at the flank, subscapular, and triceps areas. Additional data were abstracted from maternal and neonatal medical records.
The 4 primary outcomes for which the study was powered included macrosomia (birthweight >90th centile for gestational age, gender, parity, ethnicity, and field center), primary cesarean delivery, clinical neonatal hypoglycemia (as noted in the medical record), and hyperinsulinemia (cord serum C-peptide >90th centile for the study group as a whole). A number of secondary outcomes were also considered. These included preterm birth (defined as <37 weeks’ gestation), shoulder dystocia and/or birth injury, sum of skinfold thicknesses >90th centile for gestational age, gender, ethnicity, parity and field center, percent body fat >90th centile for gestational age (calculated from birthweight, length, and flank skinfold ), admission for neonatal intensive care, hyperbilirubinemia, and preeclampsia.
Participants were enrolled between July 2000 and April 2006. Data were analyzed, blinded to test results, for 23,316 mother-newborn pairs. The mean fasting plasma glucose value across all participants was 80.9 mg/dL. At 1 and 2 hours after the 75-g oral glucose challenge the means were 134.1 and 111 mg/dL, respectively. The average gestational age at delivery was 39.4 weeks; 6.9% of deliveries were preterm. Participants were ethnically diverse, with 48% white non-Hispanic, 12% black non-Hispanic, 29% Asian/Oriental, 8% Hispanic, and 3% other or unknown.
For categorical analyses, fasting plasma glucose values were divided a priori into 7 categories in 5-mg/dL increments, with the lowest category being <75 mg/dL and the highest being ≥100 mg/dL. The 1- and 2-hour value categories were chosen to yield proportions of the population that were similar to those of the fasting plasma glucose categories. The lowest 2 categories contained approximately 50% of subjects. The highest 2 categories contained only 1% and 3% of subjects, to determine whether there was a threshold for any effects present. As shown in the Figure , the 4 primary outcomes were all related to each of the 3 glucose determinations in a continuous and graded manner. Clinical neonatal hypoglycemia, which occurred in only 2.1% of the total population in the study, showed the least robust association with fasting and other OGTT values, whereas the other 3 outcomes were more strongly related. For example, the prevalence of cord C-peptide >90th centile increased from 3.7% when fasting plasma glucose was <75 mg/dL to 32.4% when it was ≥100 mg/dL. When logistic models were constructed to account for potential confounders of location (ie, field center), age, body mass index, and a number of other variables, the relationships described above held although they were somewhat attenuated.
The relationship between OGTT values and each of the 4 primary outcomes was also evaluated using glucose as a continuous variable, and correcting for the potential confounders described above. As shown in Table 1 these relationships were expressed as the odds ratio (OR) for a given outcome for each SD increase in glucose. The association between each of the OGTT values and each of the primary outcomes remained significant with the exception of that between both fasting plasma glucose and 2-hour plasma glucose with clinical neonatal hypoglycemia. A number of secondary outcomes were also evaluated. Both preeclampsia and shoulder dystocia/birth injury were significantly associated with each of the glucose values. Preterm delivery was associated with the 1- and 2-hour glucose values, but not with fasting plasma glucose.
| Outcome | FPG | 1-h PG | 2-h PG | |||
|---|---|---|---|---|---|---|
| OR b | 95% CI | OR | 95% CI | OR | 95% CI | |
| Birthweight >90th centile | 1.38 | (1.32–1.44) | 1.46 | (1.39–1.53) | 1.38 | (1.32–1.44) |
| Primary cesarean delivery c | 1.11 | (1.06–1.15) | 1.10 | (1.06–1.15) | 1.08 | (1.03–1.12) |
| Clinical neonatal hypoglycemia | 1.08 | (0.98–1.19) | 1.13 | (1.03–1.26) | 1.10 | (1.00–1.12) |
| Cord C-peptide >90th centile | 1.55 | (1.47–1.64) | 1.46 | (1.38–1.54) | 1.37 | (1.30–1.44) |
| Preterm delivery, <37 wk | 1.05 | (0.99–1.11) | 1.18 | (1.12–1.25) | 1.16 | (1.10–1.23) |
| Shoulder dystocia and/or birth injury | 1.18 | (1.04–1.33) | 1.23 | (1.09–1.38) | 1.22 | (1.09–1.37) |
| Sum of skinfolds >90th centile | 1.39 | (1.33–1.47) | 1.42 | (1.35–1.49) | 1.36 | (1.30–1.43) |
| Intensive neonatal care | 0.99 | (0.94–1.05) | 1.07 | (1.02–1.13) | 1.09 | (1.03–1.14) |
| Hyperbilirubinemia | 1.00 | (0.95–1.05) | 1.11 | (1.05–1.17) | 1.08 | (1.02–1.13) |
| Preeclampsia | 1.21 | (1.13–1.29) | 1.28 | (1.20–1.37) | 1.28 | (1.20–1.37) |
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