For gestational diabetes, one step or two?

Amy Carpenter Aquino

December 2019—The controversy surrounding the approved methods for screening gestational diabetes mellitus took the form of a debate at this year’s AACC annual meeting, with two speakers defending the one-step or two-step method.

Florence M. Brown, MD, assistant professor of medicine at Harvard Medical School and co-director of the diabetes in pregnancy program at the Joslin Diabetes Center and Beth Israel Deaconess Medical Center, Boston, favors the use of the one-step International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria to detect GDM.

“My position today is we should use the one-step IADPSG criteria to detect gestational diabetes,” Dr. Brown said. Her institution began using the criteria shortly after they were published in 2011 but returned to the two-step criteria after the American College of Obstetricians and Gynecologists reaffirmed its position to use the two-step method in a 2013 practice bulletin “That continues to be the case.”

Dr. Brown presented the case of a 33-year-old pregnant woman with a prior history of gestational diabetes. The patient was referred to Dr. Brown because of an elevated amniotic fluid level, a fetal abdominal circumference greater than the 90th percentile, and a one-hour glucose loading test (GLT) of 151 mg/dL at 31 weeks of gestation. She had passed two other GLT tests earlier in pregnancy.

“She had pronounced fasting hyperglycemia, which the glucose load tolerance screen did not pick up,” Dr. Brown said. The patient’s fasting blood sugar level was greater than 110 mg/dL and she had additional risk factors for GDM: a strong family history of type two diabetes and obesity with a BMI of 39. “She was counseled on lifestyle management and management with ongoing titration of insulin for the remainder of her pregnancy.”

“Even though the obstetrician had done the ACOG-recommended screening for this patient, why do a screening test on somebody who already has a 50 percent chance of developing gestational diabetes just on the basis of having had gestational diabetes in her previous pregnancy?” she asked.

GDM diagnosis is controversial because of the differences between the two screening methods, Dr. Brown said. The two-step method involves a nonfasting one-hour 50-g GLT. If the result is positive, the GLT is followed by a diagnostic fasting three-hour 100-g oral glucose tolerance test, with values checked at fasting and one, two, and three hours. GDM is diagnosed if there are two or more abnormal values. “The thresholds that are currently in use are the NDDG [National Diabetes Data Group] or the Carpenter and Coustan criteria,” Dr. Brown said. ACOG, the National Institutes of Health consensus conference, and the American Diabetes Association endorse the two-step method.

The ADA also endorses the one-step IADPSG screening criteria, which is a single diagnostic fasting 75-g two-hour OGTT, with blood sugars checked at fasting, one hour, and two hours, she said. GDM is diagnosed if one or more values is positive. The Endocrine Society, World Health Organization, and International Federation of Gynecology and Obstetrics endorse the one-step method.

That the ADA endorses the two-step method with two different sets of thresholds and the one-step method with one set of thresholds “is very confusing and we need consensus,” Dr. Brown said.

The two-step method got its start in a 1964 study of 752 pregnant women who received a 100-g three-hour OGTT with whole blood samples checked at fasting and one, two, and three hours (O’Sullivan JB, et al. Diabetes. 1964;​13:278–285).

“The glucose thresholds they chose were two standard deviations above the mean of 97.7th percentile, and they required two abnormal values,” she said. “They had been following a group of women who had been getting a glucose tolerance test routinely, and they applied these thresholds to these women.” Eight years after they were diagnosed with GDM, 29 percent of the women had developed type two diabetes. At 16 years it was 60 percent. “The gestational diabetes prevalence, based on the thresholds they chose, was 2.5 percent, at a time when the diabetes prevalence in the United States was just 1.24 percent.”

In 1973, the authors recommended a nonfasting 50-g glucose loading test to identify high-risk women in a very low prevalence population. The threshold was a one-hour whole blood glucose of 130 mg/dL, and with that they had 80 percent sensitivity. “Later, a one-hour plasma threshold of 140 mg/dL was found to have approximately the same sensitivity,” Dr. Brown said.

“At a time when the prevalence of gestational diabetes was 2.5 percent, a false-negative rate of 20 percent was acceptable at an absolute of 0.5 percent.”

The diagnostic 100-g OGTT thresholds now are the NDDG and the Carpenter and Coustan criteria for measuring plasma, and two abnormal values are needed for a GDM diagnosis.

Dr. Brown posed two questions to help determine whether there is a benefit to treating GDM: Does treatment of mild gestational diabetes reduce adverse outcomes, and are adverse outcomes in pregnancy independently related to maternal hyperglycemia, or are other factors—such as maternal BMI or age—the main drivers?

The Australian Carbohydrate Intolerance Study in Pregnant Women (24 to 34 weeks’ gestation) trial addressed whether treatment of mild GDM makes a difference in fetal and maternal health (Crowther CA, et al. N Engl J Med. 2005;352[24]:​2477–2486). The two-step inclusion criteria were an abnormal 50-g glucose loading test (≥140 mg/dL) or risk factors, and a 75-g OGTT with a two-hour value ≥140 mg/dL. Women with fasting glucose levels ≥140 mg/dL, or a two-hour value on the 75-g OGTT ≥198 mg/dL, were excluded because they were considered to have diabetes.

Treating women for GDM was found to lead to fewer composite serious perinatal outcomes and diminished depression at 12 months postpartum. Reductions were seen in birth weight and in rates of infants who were large for gestational age and had macrosomia. The rate of induction of labor increased.

The Maternal-Fetal Medicine Units Network study of nearly 960 women addressed the same question (Landon MB, et al. N Engl J Med. 2009;361[14]:​1339–1348). Inclusion criteria began with a one-hour GLT with a value of 135–199 mg/dL. Women who met that threshold then had a three-hour 100-g OGTT in which a fasting glucose result of <95 mg/dL and two or three abnormal values above the thresholds of a one-hour 180 mg/dL, a two-hour 155 mg/dL, or a three-hour 140 mg/dL would be considered mild gestational diabetes. “These would be the Carpenter and Coustan thresholds,” Dr. Brown said.

The MFMU Network study found reductions in birth weight, macrosomia, and fat mass in women treated for GDM, in addition to a lower prevalence of cesarean delivery, lower frequency of shoulder dystocia, and reductions in preeclampsia and gestational hypertension.

So the answer to the question of whether treatment of mild GDM reduces adverse outcomes is yes, Dr. Brown said.

Are adverse outcomes in pregnancy independently related to maternal hyperglycemia or are other factors, such as BMI or age, the main drivers? Here Dr. Brown referenced the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study (N Engl J Med. 2008;358[19]:1991–2002). More than 23,000 women underwent a 75-g OGTT between 24 and 32 weeks of gestation (fasting and one and two hours). The primary outcomes evaluated across different increasing glucose categories were birth weight greater than the 90th percentile, primary cesarean section, clinical neonatal hypoglycemia, and cord-blood serum C-peptide level greater than the 90th percentile. “For all these adverse outcomes,” she said, “there is a linear relationship between the adverse outcomes and the glucose levels.”

There was a similar linear relationship between fasting, one-hour, and two-hour glucose levels and the secondary adverse outcomes: premature delivery, shoulder dystocia, hyperbilirubinemia, preeclampsia, and a need for intensive neonatal care.

“And these associations of the primary and secondary outcomes with glucose were independent of BMI,” Dr. Brown said, so, yes, “adverse outcomes in pregnancy are independently related to maternal hyperglycemia.”

The IADPSG convened an international consensus conference in 2008 with the goal of using the HAPO study outcomes data to determine thresholds for a glucose tolerance test (Diabetes Care. 2010;33[3]:676–682).

“They chose neonatal outcomes: greater than 90th percentile for birth weight, body fat, and cord-blood C-peptide,” Dr. Brown said. Conference members found linear relationships with these outcomes for maternal fasting, one-hour, and two-hour glucose across increasing levels of hyperglycemia. “So where do we draw the thresholds when this is a linear relationship? There’s no inflection point to help us know where to make these thresholds.”

“They had to draw the line somewhere,” Dr. Brown continued, “so they recommended one-step testing for all pregnant women between 24 and 28 weeks of gestation,” and that they be screened and diagnosed using a one-step fasting two-hour 75-g OGTT. The glucose thresholds were determined by choosing the glucose values when the odds ratio for the neonatal outcomes of HAPO were 1.75, compared with mean glucose values. Based on this odds ratio, the fasting level was 92 mg/dL (5.1 mmol/L), the one-hour level was 180 mg/dL (10 mmol/L), and the two-hour level was 153 mg/dL (8.5 mmol/L). One abnormal glucose level result was required for diagnosis.