While diabetes during pregnancy is associated with a significant risk of adverse perinatal outcomes, there is no consensus on the risks of adverse outcomes resulting from abnormal glucose levels below the established threshold for gestational diabetes. In response to this controversy, the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study was established to clarify unanswered questions concerning the association of glucose with risks of adverse pregnancy outcomes.

The prospective, observational HAPO Study enrolled 23,316 pregnant women who had no prior diagnosis of diabetes during or antedating pregnancy. Participants underwent a standard 75 g 2-hour oral glucose tolerance test (OGTT) between 24 and 32 weeks’ gestation. Neonatal anthropometrics were obtained following delivery, and follow-up data, including hospital readmissions, were collected at 4-6 weeks post-delivery. The primary outcome measures assessed in relation to maternal glycemia included primary cesarean delivery, increased birthweight (defined as > 90th percentile for gestational age), neonatal hypoglycemia, and fetal hyperinsulinism. The study found that increased maternal glycemia was associated with both birthweight and cord serum C-peptide > 90th percentile. Greater maternal glucose levels were also associated with increased risk of primary cesarean delivery and clinical neonatal hypoglycemia.

Subsequent to the conclusion of the HAPO Study, a follow-up study (HAPO-FUS) was initiated to determine whether elevated blood sugar during pregnancy, below the threshold for gestational diabetes, influences either development of type 2 diabetes mellitus in mothers or adiposity and disorders of glucose metabolism in offspring at 8-12 years of age. The HAPO Follow-Up Study enrolled 4800 mother-child pairs who originally participated in the HAPO Study. Mothers and children were required to undergo a single study visit for measurement of height, weight, blood pressure, body fat, insulin, and blood sugar and lipid levels. The primary outcome measures assessed in relation to maternal glycemia during pregnancy included development of diabetes in mothers, and obesity and altered glucose metabolism in children, as well as other metabolic abnormalities in both mothers and offspring.

The primary objective of the HAPO Study was to investigate the association of elevated glucose levels below the diagnostic threshold for GDM with risks of adverse pregnancy outcomes. Subsequent to the completion of the HAPO Study, a follow-up study (HAPO-FUS) was initiated to determine whether these elevated blood sugar levels during pregnancy below the diagnostic threshold for GDM influence either development of type 2 diabetes mellitus in mothers or adiposity and disorders of glucose metabolism in offspring 8-12 years after the birth of the child.

The primary outcome measures assessed in relation to maternal glycemia during pregnancy include development of diabetes in mothers and obesity and altered glucose metabolism in children.

All pregnant women at the HAPO clinical centers were eligible for the study unless they met any of the following exclusion criteria:

• Less than 18 years of age • Planned delivery at a non-field center hospital • Date of last menstrual period not certain and no ultrasound (US) estimation from 6 to 24 weeks of gestational age available • Unable to complete the oral glucose tolerance test (OGTT) within 32 weeks gestation • Multiple pregnancy • Conception using gonadotropin ovulation induction or by in vitro fertilization • Glucose testing prior to recruitment or a diagnosis of diabetes during this pregnancy • Diagnosis of diabetes antedating pregnancy requiring treatment • with medication • HIV, hepatitis B, or hepatitis C positive

Mother-child pairs who participated in the original HAPO study were eligible for the HAPO Follow-Up Study.

The HAPO Study found that increased maternal glycemia was associated with both birthweight and cord serum C-peptide > 90th percentile. Greater maternal glucose levels were also associated with increased risk of primary cesarean delivery and clinical neonatal hypoglycemia.

The HAPO Follow-up Study found that higher levels glucose during pregnancy, even below the traditional diagnostic threshold for gestational diabetes, were significantly associated with a higher maternal risk for diabetes and prediabetes during long-term follow-up after pregnancy. In addition, exposure to higher levels of glucose in utero was associated with childhood insulin resistance.