Waiting for HAPO: Why the results are so anticipated

Multiple guidelines currently give conflicting recommendations about GDM diagnosis, treatment, postpartum care.

Various professional organizations offer guidelines for the diagnosis and treatment of gestational diabetes and for postpartum screening in women diagnosed with gestational diabetes. Although these guidelines draw from the same data, major differences exist between them.

Women diagnosed with gestational diabetes often see multiple health care providers during their pregnancies, and, as a result, these women may receive conflicting information about blood glucose targets, frequency of self-blood glucose monitoring, delivery options and postpartum follow-up, according to researchers who have examined the differences between the guidelines and have spoken with Endocrine Today.

But help may be on the way — with the publishing of highly anticipated Hyperglycemia and Adverse Pregnancy Outcomes (HAPO) study results and also through government initiatives and work done by the CDC.

Endocrinologists and others are anxiously awaiting the more extensive explanation of the HAPO results, as well as the consensus statement that will follow—both of which should offer insight into how best to diagnose and treat gestational diabetes, according to Lois Jovanovic, MD, CEO and chief scientific officer of the Sansum Diabetes Research Institute in Santa Barbara, Calif.

“The truth is, nobody will come to a consensus agreement until we see these results from this huge international study,” said Jovanovic, who is a member of the Endocrine Today Editorial Board.

Endocrine Today interviewed leading researchers and experts for this special report, the people who are grappling with how best to diagnose and treat women with gestational diabetes.

Differences between the guidelines

Lois Jovanovic, MD, is chief scientific officer at Sansum Diabetes Research Institute, Santa Barbara, Calif. Photo by Gary Leonard

Success in a pregnancy complicated by abnormal blood glucose levels requires cooperation between the woman and her health care providers, according to Jennifer Williams, MSN, MPH, APRN-BC, one of the researchers who analyzed the guidelines. With the variety of guidelines available, there is no guarantee that all of a woman’s providers will utilize the same set of guidelines.

“Although differences between guidelines seem small, these differences might foster confusion among women and might cause some frustrations with providers whose patients they see as potentially not complying with the treatment regimen that they suggest,” said Williams, who is a nurse epidemiologist at the Centers for Disease Control and Prevention National Center on Birth Defects and Developmental Disabilities in Atlanta.

Williams and her colleagues published a review of six different guidelines in the Journal of Women’s Health last year. They compared guidelines from the American College of Obstetricians and Gynecologists (ACOG), the ADA, Joslin Diabetes Center, the World Health Organization, the International Diabetes Center and the U.S. Preventive Services Task Force.

Williams and her fellow investigators first noted variations among the guidelines in screening for gestational diabetes. “Most of the guidelines recommended screening patients with risk factors for gestational diabetes, but there were variations among women with low risk factor profiles,” Williams told Endocrine Today.

According to Williams’ study, the ACOG, ADA and Joslin guidelines state that women considered low risk may be excluded from screening for gestational diabetes. The WHO and International Diabetes Center guidelines both suggest screening all women at 24 to 28 weeks of gestation. All guidelines, with the exception of the U.S. Preventive Task Force, recommend screening early in pregnancy for high-risk women. The U.S. Preventive Task Force simply states that not enough evidence exists to recommend screening.

Screening tests and diagnostic tests for GDM vary among guidelines. The ACOG, ADA, International Diabetes Center and Joslin guidelines recommend a two-stage approach, including a 50-g one-hour glucose tolerance test and, if the results are positive, a 100-g three-hour glucose tolerance test. ACOG and ADA leave it up to the physician to determine the threshold values for the 50-g glucose load — either 130 mg/dL or 140 mg/dL. Joslin and the International Diabetes Center set the threshold value at 140 mg/dL. For diagnostic testing, there are two testing methods used, the Carpenter Coustan (plasma or serum) and the National Diabetes Data Group Conversion (plasma only). ACOG gives values for both, ADA and International Diabetes Center for Carpenter Coustan, and Joslin refers to the National Diabetes Data Group Conversion.

WHO guidelines, however, recommend a one-step 75-g glucose tolerance test and WHO considers a diagnosis positive if the fasting value is 126 mg/dL or if the two-hour value is 200 mg/dL.

Williams said that she and her colleagues also “found differences in the target blood glucose levels and when insulin should be initiated and how frequently blood glucose monitoring should be done,” Williams said.

The guidelines also vary in postpartum instructions. While some guidelines recommend a schedule of postpartum testing for type 2 diabetes, other guidelines do not address postpartum follow-up.

Jennifer Williams

Williams said, “One of the most important things that we found is that counseling about prevention of conversion to type 2 diabetes is absent in most of the guidelines.” Many women with GDM will convert to type 2 diabetes, often while still in their reproductive years. They then have an elevated risk for having a child with a birth defect and other adverse pregnancy outcomes. It is important not to miss opportunities for prevention of type 2 diabetes in these women, Williams said.

In fact, the ACOG guidelines state that the benefits of screening for diabetes after delivery are not proven, according to Catherine Kim, MD, MPH, assistant professor in the departments of medicine and obstetrics and gynecology at the University of Michigan in Ann Arbor.

“It’s not exactly a ringing endorsement for diabetes screening, whereas the ADA and other groups do recommend screening and they do endorse specific tests,” Kim told Endocrine Today.

Consensus awaited

New comprehensive data in this area could lead to some consensus on diagnosis and treatment among the specialties and societies. Boyd E. Metzger, MD, professor at Northwestern University Medical School in Chicago, presented the results from the HAPO study—a seven-year trial that evaluated blood glucose levels and their association with adverse outcomes for women and their babies—at the ADA meeting last year.

Boyd E. Metzger

The complexity and expense of the HAPO study stalled its completion, Metzger said. In the meantime, health care providers were left to sort through the various guidelines in order to treat their patients. “People have been doing the best they could with less than complete information to support diagnosing and treating [gestational diabetes],” Metzger said.

For the last 25 years, endocrinologists have primarily followed the ADA guidelines and have used the International Workshop-Conferences in Gestational Diabetes Mellitus as a source for the general approach to diagnosis and treatment. “But diagnosis has had no new data like the kind that’s been collected in the HAPO study,” Metzger said.

He expects the results will be published within the year. A consensus meeting will be held in June to discuss the HAPO findings and the expert advice of about 400 people. “Ultimately, in the next year or two, [the consensus meeting] should result in making changes in the way gestational diabetes is diagnosed,” Metzger said.

The road to HAPO

When gestational diabetes was first identified as a separate entity, health care providers wanted to identify mothers who were at high risk for diabetes after pregnancy. “The focus wasn’t on the outcome of the pregnancy, because it wasn’t realized then — 40, 50 years ago — that the babies born to mothers with gestational diabetes shared some of the same risks that babies of mothers with known or overt diabetes have,” Metzger said.

Since then, research has shown that between 35% and 50% of women with gestational diabetes will go on to develop type 2 diabetes within five years after delivery, Metzger said. Studies have also shown a significant elevation in cardiovascular disease for those women with a history of gestational diabetes, according to Kim.

Children born to mothers with gestational and type 2 diabetes face risks of their own — most of which are well known, but new data are emerging. In a September 2007 study, Teresa A. Hillier, MD, MS, senior investigator and The Center for Health Research, Portland, Ore., and her colleagues found a direct correlation between a mother’s increased hyperglycemia during pregnancy and the child’s increased risk of childhood obesity.

For these reasons, researchers identified a need to undertake the HAPO study — the kind of study that would analyze where along the line of high glucose is the risk high enough for a woman to benefit from treatment.

HAPO also offered a means to silence the naysayers who claimed that the elevation of blood sugar was not causing the problems, but, rather, that the high risks that lead to gestational diabetes—such as high blood pressure and obesity—actually cause the problems during pregnancy.

“The HAPO study provided enough information to make adjustments for taking into account the weight, age, and different ethnic groups of patients and to come up with information that applied across all these conditions. [It showed] that the mother’s glucose level is an important determinant of the outcome of the pregnancy,” Metzger said.

Consensus statement may lead to change

Will the HAPO consensus statement change the diagnosis of gestational diabetes? Metzger said the study has revealed that the blood sugar levels used to diagnose gestational diabetes should likely be lower than those used in the past.

“The findings show that the mother’s glucose level is associated with the risk of these different outcomes, and, therefore, the fact that these associations are present can allow the results to be used for changing the diagnostic criteria,” Metzger said.

“But how they should be changed is [what] needs broad consensus … What you should call normal and abnormal is not something one person can decide.”

“The HAPO results clearly show that normal [glucose level] means normal outcome,” Jovanovic told Endocrine Today. HAPO demonstrated that the risk of infants being born with macrosomia increased four to six times the spread from the lowest fasting blood glucose level (75 mg/dL) to the highest (105 mg/dL).

“The continuum between 75 mg/dL and 105 mg/dL is linear. It is this gray zone that you don’t hear a lot of debate over,” Jovanovic said. “So most of [the consensus meeting] will be argument over what numbers are we going to pick.

“My opinion is that we should go for normal and anything above normal increases the risk, and, therefore, fasting should be less than 70 mg/dL and the one-hour should be less than 130 mg/dL,” Jovanovic said.

Based on emerging studies and results from studies such as the Diabetes Prevention Program, investigators are finding that treatment is effective in women with gestational diabetes. “What’s likely to be the end result two or three years down the line is that we’ll have an approach to making a diagnosis that’s based on the results of the HAPO study,” Metzger said.

“And at the same time we’ll have stronger evidence that, in fact, treatment is beneficial. The results of these two kinds of approaches reinforce each other,” he said.

Advocating for routine screening

While HAPO may lead to a consensus on diagnosis, Kim and other experts in the field are advocating for a consensus on routine post-partum screening of all women with a history of gestational diabetes. According to one of Kim’s studies, the Fourth International Workshop-Conference for Gestational Diabetes recommended that physicians use an oral glucose tolerance test to screen for diabetes at least six weeks after delivery. If glucose levels are normal, physicians should screen these women at a minimum of three-year intervals.

Kim and her colleagues found that the oral glucose tolerance test is the most cost-effective test to use at each of these intervals. “It’s important to make sure that women with a previous history [of gestational diabetes] get tested, and, moreover, that they have good family planning and know that getting tested and subsequent good glucose control before another pregnancy can really help a second baby.”

In April 2007, the CDC Division of Reproductive Health convened a panel of experts that included Kim, representatives from ACOG and the ADA. A main objective in the CDC Division of Reproductive Health is to seek ways to help increase postpartum screening for type 2 diabetes, according to Lucinda England, MD, MSPH, a medical epidemiologist in the CDC Division of Reproductive Health.

“Right now, we don’t know how many women get tested postpartum, but in the small studies that have been done, it appears to be less than half. We would very much like for that to improve,” England told Endocrine Today. “Beyond that, we are interested in identifying ways for women to get plugged into programs where they can receive assistance with diet and increasing their physical activity.

“We’re mainly consulting with organizations … and experts in the field to get a better understanding of where the science is right now and what the research and programmatic gaps are. That information will help to form a longer-term strategic plan,” England said.

Gestational Diabetes Act

According to Metzger, the incidence of gestational diabetes has increased, even with the current criteria. “Between 1990 to 2000 the prevalence of gestational diabetes increased about 40% to 50%,” he said.

As a result, politicians have also recognized a need for change. In March 2007, Senators Hillary Rodham Clinton and Susan M. Collins reintroduced the Gestational Diabetes Act of 2007. The bill was referred to the Senate Committee on Health, Education, Labor and Pensions in March 2007, but no vote has been scheduled to date.

If passed, the bill would create a CDC Research Advisory Committee to monitor gestational diabetes and obesity during pregnancy, fund projects to assist health care providers in teaching women about the effects of their health during pregnancy, and expand current research by the NIH and CDC to help lower the incidence of gestational diabetes.

“With the large and increasing amount of obesity and the relatively sedentary lifestyle that most people lead, the risk of going on to have diabetes is high and it’s soon,” Metzger said. – by Tina DiMarcantonio

Is pharmacologic intervention needed to prevent type 2 after gestational diabetes?

For more information:

• Hillier TA, Pedula KL, Schmidt MM, et al. Childhood obesity and metabolic imprinting: The ongoing effects of maternal hyperglycemia. Diabetes Care. 2007;30:2287-2292.
• Kim C, Herman WH, Vijan S. Efficacy and cost of postpartum screening strategies for diabetes among women with histories of gestational diabetes mellitus. Diabetes Care. 2007;30:1102-1106.
• Metzger BE. Hyperglycemia and adverse pregnancy outcome (HAPO) highlights. Presented at the American Diabetes Association 67th Annual Sessions; June 22-26, 2007; Chicago.
• Mulholland C, Njoroge T, Mersereau P, Williams J. Comparison of guidelines available in the United States for diagnosis and management of diabetes before, during and after pregnancy. J Womens Health. 2007;16:790-801.