HAPO

In Review

Metzger BE, et al. "Hyperglycemia and adverse pregnancy outcomes". The New England Journal of Medicine. 2008. 358(19):1991-2002.
PubMed • Full text • PDF

Clinical Question

In pregnant women, does non-diabetic maternal hyperglycemia increase the risk of adverse pregnancy outcomes?

Bottom Line

In pregnant women, non-diabetic maternal hyperglycemia is associated with multiple adverse pregnancy outcomes especially increased birth weight and increased cord-blood serum C-peptide.

Major Points

Gestational diabetes mellitus (GDM) and diabetes mellitus during pregnancy are associated with adverse perinatal outcomes. However, the risk associated with maternal hyperglycemia less severe than that in diabetes mellitus is less clear.

The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) is a cohort study which studied the association between non-diabetic maternal hyperglycemia and adverse perinatal outcomes. In the final analysis, 23,316 pregnant women were included. The study showed that non-diabetic maternal hyperglycemia is associated with increased birth weight and increased cord-blood serum C-peptide. In addition, there's a significant but weaker association with neonatal hypoglycemia, primary cesarean delivery, preterm delivery, intensive neonatal care, hyperbilirubinemia, preeclampsia, and shoulder dystocia or birth injury.

Results of the study were reviewed to establish the 2010 International Association of Diabetes and Pregnancy Study Groups Recommendations on the Diagnosis and Classification of Hyperglycemia in Pregnancy. The threshold diagnostic values for GDM are based on the HAPO study where the risk of adverse outcomes exceed the estimated risk by 1.75 times.

Guidelines

ADA Standards of Medical Care in Diabetes (2015, adapted)

• Test for undiagnosed type 2 diabetes at the first prenatal visit in those with risk factors, using standard diagnostic criteria. (Level of evidence: B)
• Test for GDM at 24–28 weeks of gestation in pregnant women not previously known to have diabetes. (Level of evidence: A)
• Screen women with GDM for persistent diabetes at 6-12 weeks postpartum, using the OGTT and clinically appropriate nonpregnancy diagnostic criteria. (Level of evidence: E)
• Women with a history of GDM should have lifelong screening for the development of diabetes or prediabetes at least every 3 years. (Level of evidence: B)
• Women with a history of GDM found to have prediabetes should receive lifestyle interventions or metformin to prevent diabetes. (Level of evidence: A)

IADPSG Recommendations on the Diagnosis and Classification of Hyperglycemia in Pregnancy (2010, adapted)

• The threshold fasting, 1-hour post OGTT, and 2-hour post OGTT plasma glucose values for diagnosing GDM are 5.1 mmol/l (92 mg/dl), 10.0 mmol/l (180 mg/dl), and 8.5 mmol/l (153 mg/dl) respectively
• These values are defined based on the HAPO study where the risk for adverse outcomes reached 1.75 times the estimated risk of these outcomes

Design

• Multicenter cohort study
• N=23,316 patients
• Setting: 15 centers in 9 countries
• Enrollment: 2000-2006
• Primary outcome: birth weight >90th percentile for gestational age, primary cesarean delivery, neonatal hypoglycemia, and cord-blood serum C-peptide level>90th percentile

Population

Inclusion Criteria

• pregnant women

Exclusion Criteria

• age <18 years
• plan to undergo delivery at another hospital
• date of last menstrual period is uncertain and no ultrasonographic estimation between 6-24 weeks of gestational age
• inability to complete OGTT within 32 weeks of gestation
• multiple pregnancy
• conception by gonadotropin ovulation induction or in-vitro fertilization
• glucose testing before recruitment or diagnosis of diabetes during the current pregnancy
• diagnosis of diabetes before current pregnancy and requiring anti-hyperglycemic treatment
• participation in another study that could interfere with the HAPO study
• infection with HIV, hepatitis B or C
• previous participation in the HAPO study
• inability to converse in the languages used on center forms without the aid of an interpreter

Baseline Characteristics

• Age: 29.2±5.8 years
• Caucasian: 48.3%
• BMI: 27.7±5.1 kg/m²
• Caucasian: 48.3%
• Mean arterial pressure (mm Hg): 80.9±8.3
• Fasting plasma glucose (mg/dl): 80.9±6.9
• 1-hour plasma glucose post-OGTT (mg/dl): 134.1±30.9
• 2-hour plasma glucose post-OGTT (mg/dl): 111.0±23.5
• Family history of diabetes: 22.7%

Interventions

• OGTT (75-g dose of glucose) between 24-32 weeks of gestation (target time of testing, 28 weeks)
• Gestational age and expected date of delivery were determined from the date of the last menstrual period or ultrasound if required

Outcomes

outcomes were reported as adjusted odds ratio (95% CI) associated with an increase by 1 SD in fasting plasma glucose, 1-hour plasma glucose, and 2-hour plasma glucose

Primary Outcomes

birth weight above 90th percentile for gestational age

fasting plasma glucose: 1.38 (1.32-1.44)

1-hour plasma glucose: 1.46 (1.39-1.53)

2-hour plasma glucose: 1.38 (1.32-1.44)

primary cesarean delivery

fasting plasma glucose: 1.11 (1.06-1.15)

1-hour plasma glucose: 1.10 (1.06-1.15)

2-hour plasma glucose: 1.08 (1.03-1.12)

neonatal hypoglycemia

fasting plasma glucose: 1.08 (0.98-1.19)

1-hour plasma glucose: 1.13 (1.03-1.26)

2-hour plasma glucose: 1.10 (1.00-1.12)

cord-blood serum C-peptide level above the 90th percentile

fasting plasma glucose: 1.55 (1.47-1.64)

1-hour plasma glucose: 1.46 (1.38-1.54)

2-hour plasma glucose: 1.37 (1.30-1.44)

Secondary Outcomes

delivery before 37 weeks of gestation

fasting plasma glucose: 1.05 (0.99–1.11)

1-hour plasma glucose: 1.18 (1.12–1.25)

2-hour plasma glucose: 1.16 (1.10–1.23)

shoulder dystocia or birth injury

fasting plasma glucose: 1.18 (1.04–1.33)

1-hour plasma glucose: 1.23 (1.09–1.38)

2-hour plasma glucose: 1.22 (1.09–1.37)

intensive neonatal care

fasting plasma glucose: 0.99 (0.94–1.05)

1-hour plasma glucose: 1.07 (1.02–1.13)

2-hour plasma glucose: 1.09 (1.03–1.14)

hyperbilirubinemia

fasting plasma glucose: 1.00 (0.95–1.05)

1-hour plasma glucose: 1.11 (1.05–1.17)

2-hour plasma glucose: 1.08 (1.02–1.13)

preeclampsia

fasting plasma glucose: 1.21 (1.13–1.29)

1-hour plasma glucose: 1.28 (1.20–1.37)

2-hour plasma glucose: 1.28 (1.20–1.37)

perinatal death

fasting plasma glucose: 0.91 (0.76–1.08)

1-hour plasma glucose: 0.93 (0.78–1.11)

2-hour plasma glucose: 0.99 (0.83–1.18)

the study did not have adequate statistical power to analyze perinatal death as an outcome

Criticisms

• Data on nutritional status and weight gain during pregnancy were not collected. These factors could affect perinatal outcomes
• Previous gestational diabetes, maternal BMI, or previous macrosomia, are possible confounders which may have influenced the route of delivery
• This is an observational study, therefore, it cannot be concluded that maternal hyperglycemia is causally related to the observed adverse outcomes

Funding

The Eunice Kennedy Shriver National Institute of Child Health and Human Development; the National Institute of Diabetes and Digestive and Kidney Diseases; the National Center for Research Resources; the American Diabetes Association; and grants from Diabetes UK, Kaiser Permanente Medical Center, KK Women's and Children's Hospital, Mater Mother's Hospital, Novo Nordisk, the Myre Sim Fund of the Royal College of Physicians of Edinburgh, and the Howard and Carol Bernick Family Foundation