The HAPO trial: hyperglycemia and adverse pregnancy outcomes [Classics Series]

1. Impaired glucose tolerance on the 2-hour glucose tolerance test was associated with increased odds of primary cesarean delivery, large for gestational age (LGA) infantts, cord-blood serum C-peptide >90^th %ile and neonatal hypoglycemia.

2. Impaired glucose tolerance was also associated with increased risk of preterm delivery, shoulder dystocia and preeclampsia.

Original date of publication: May 2008

Study Rundown: The Pedersen hypothesis, postulated by Jorgen Pedersen in 1952, states that maternal hyperglycemia leads to fetal hyperglycemia, invoking an exaggerated production of insulin in the neonate. This increased insulin production acts as a fetal growth factor and contributes to metabolic derangements after delivery. Considering the numerous and meaningful risks of adverse pregnancy outcomes associated with maternal diabetes mellitus pre-existent to pregnancy, researchers questioned whether women with a lesser degree of impaired glucose tolerance or those with gestational diabetes, were also at increased risk for adverse pregnancy outcomes. However, assessment of whether gestational diabetes is associated with adverse outcomes is complex. Diagnostic criteria for gestational diabetes were originally designed to identify women at risk for developing diabetes later in life, not to predict degree of maternal hyperglycemia in pregnancy. Historically, there has been a lack of consensus guidelines on the diagnosis of gestational diabetes such that the 1-hour, 2-hour and 3-hour oral glucose tolerance tests (OGTT) have all been used to make the diagnosis. Confounders like obesity and co-existent medical morbidities that track closely with glucose intolerance and adverse neonatal outcomes complicate assessment. In the present work, researchers prospectively assessed a large, international cohort of women to compare incidences of adverse outcomes including fetal macrosomia, primary cesarean delivery and elevated cord-blood serum C-peptide levels between women with normal and those with impaired glucose tolerance testing.

This landmark study demonstrated that impaired carbohydrate tolerance in pregnancy , even less severe than overt diabetes, is associated with an increased risk of adverse pregnancy outcomes. Findings of an elevated umbilical cord blood serum C-peptide level is consistent with the Pedersen hypothesis of neonatal insulin production. This large prospective cohort included a diverse study population of women from all over the world including Ireland, Australia, Israel and the U.S.A. Findings were limited by the current nearly universal use of the 1-hour 50-gram oral glucose tolerance test as well as the lack of information on potential confounders including maternal BMI, gestational weight gain and personal history of prior delivery of a macrosomic infant. Additionally, the rate of follow-up in the blinded group (women with normal glucose testing results) was only 54%, introducing the possibility of selection bias. Results from this cohort study do not inform causality. Future investigations might assess therapeutic thresholds and the impact of treatment.

Click to read the study in NEJM

Relevant reading: Relation of glucose tolerance to complications of pregnancy in nondiabetic women

Dr. Alan Peaceman, MD, Northwestern University School of Medicine; Chief, Division of Obstetrics and Gynecology-Maternal Fetal Medicine, talks to 2 Minute Medicine:

“This large, international prospective study identifies a clear association between impaired maternal glucose tolerance and adverse maternal and neonatal outcomes. Findings support the hypothesis of maternal hyperglycemia leading to fetal hyperinsulinemia and underscore the need for uniform diagnostic and therapeutic thresholds.”

In-Depth [randomized controlled trial]: Across 15 centers in nine countries, a total of 25 505 women with ongoing pregnancies underwent 75-gram oral glucose tolerance testing from 24 to 32 weeks gestation. Results remained blinded if fasting blood glucose was 105mg/dL or less and 2-hour blood glucose was 200mg/dL or less. Women with increased fasting, 1-hour or 2-hour blood glucose levels of 1-standard deviation were assessed. Primary outcomes were delivery via primary cesarean section, large for gestational age (LGA) infant, neonatal hypoglycemia and cord-blood serum C-peptide >90^th %ile. Additional outcomes assessed included delivery before 37 weeks gestation, shoulder dystocia and preeclampsia.

Impaired glucose tolerance in the fasting, 1-hour and 2-hour glucose levels was associated with an increased odds of an LGA infant (ORs: 1.38, 1.46, 1.38, respectively), cord-blood serum C-peptide level >90^th %ile (ORs: 1.55, 1.46, 1.37), neonatal hypoglycemia (ORs: 1.08, 1.08, 1.13) and primary cesarean delivery (OR: 1.11, 1.10, 1.08) as well as increased odds of preterm delivery (1.05, 1.18, 1.16), shoulder dystocia (1.18, 1.23, 1.22) and preeclampsia (1.21, 1.28, 1.28).

Image: PD

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