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Pregnancy, metabolism, and the short- and long-term health of women and their children

Pregnancy can be a time of great joy, but also acts as a stress test on a woman’s body. Important physical changes that occur to support pregnancy can also unmask or exacerbate risk of metabolic problems and other conditions in the mother. These, in turn, can have lasting adverse impacts both on a woman’s own health and the health of her offspring. For example, one set of changes affects how women are able to metabolize glucose (sugar), the body’s major source of energy. In some women, these changes can cause their blood glucose levels to rise to such a degree that they are diagnosed with and treated for a condition called gestational diabetes (GDM), a form of diabetes that is diagnosed during pregnancy and is not clearly identified as either preexisting type 1 or type 2 diabetes. GDM is known to confer short- and long-term health risks to mothers and children. Now, through a long-term study involving thousands of women and children, researchers have found that elevated maternal blood glucose levels even below those meeting traditional GDM diagnostic criteria increase the risk of future type 2 diabetes in mothers and impaired glucose metabolism and greater excess fat in children ages 10 to 14 years post-delivery. These and other findings have prompted new NIDDK-supported research efforts with the ultimate goal of promoting healthier outcomes for women and their children both during and post-pregnancy.

Gestational Diabetes

GDM is typically diagnosed just before or during the third trimester of pregnancy; approximately 7 percent of U.S. pregnancies are affected. GDM increases near-term health risks for mothers and babies, including high birth weight babies and delivery complications. Controlling maternal blood glucose levels through lifestyle change (modifications to diet and exercise) and/or with injections of the hormone insulin, if needed, can mitigate some of these risks. Traditional approaches to diagnosing GDM in the United States include a screening test 24 to 28 weeks into pregnancy, during which women are given a sugary drink and then tested for blood glucose levels to see if they are at risk. Women identified as at-risk then go through further testing to see if their blood glucose levels exceed certain threshold values for diabetes. GDM, as diagnosed using these traditional criteria, is not only associated with near-term health risks, but also with longer-term health problems. For the mother, GDM confers a greater risk of developing type 2 diabetes post-pregnancy. For the children of an affected pregnancy, GDM increases the likelihood of developing obesity or type 2 diabetes.

Risks from Elevated Glucose During Pregnancy Even Below Traditionally Defined GDM Levels

In 2008, the landmark NIH-funded Hyperglycemia and Adverse Pregnancy Outcome (HAPO) study reported findings of health problems associated with glucose levels during pregnancy that were above normal (hyperglycemia), but not high enough to be considered diabetes. Studying a racially and ethnically diverse international cohort of over 23,000 pregnant women and their babies, the HAPO researchers found that elevated maternal blood glucose levels below those diagnostic of GDM were associated with increased risk of multiple adverse outcomes for the mother and child. These included high birth weight, low blood glucose in the baby at birth, and need for caesarean delivery. Strikingly, the HAPO researchers observed that even modestly elevated maternal blood glucose levels were associated with risks, which increased with maternal blood glucose levels in a linear fashion for most outcomes. Because HAPO only included women whose glucose levels were not high enough for a diagnosis of GDM at the time, they were not considered to have this disease and thus were not treated for it.

Primarily as a result of HAPO, alternative criteria for diagnosing GDM were proposed and adopted by a number of organizations around the world; these criteria include lower blood glucose level threshold values for a GDM diagnosis. However, these criteria are not widely used in the United States, largely due to findings from an expert panel NIH convened in 2013 regarding GDM diagnosis. The findings pointed out gaps in knowledge about how best to treat women diagnosed with the alternative criteria, and the absence of evidence about long-term outcomes and benefits for these women with or without treatment—as well as the potential for short-term harms, such as the additional stress a woman can experience when diagnosed with GDM. Thus, a critical question regarding maternal blood glucose levels that are elevated but do not meet the traditionally defined criteria for GDM is this: what are the long-term impacts on the health of women and their children?

Findings from the HAPO Follow-up Study

Researchers with the HAPO Follow-up Study (HAPO FUS) sought to address this question. Recognizing the enormously valuable information that could be gained from further study of HAPO participants, HAPO FUS researchers, with funding from NIDDK and additional support from the Eunice Kennedy Shriver National Institute of Child Health and Human Development, recruited a subset of the original HAPO mother-child pairs and performed comprehensive metabolic tests 10 to 14 years post-delivery to help answer questions about the long-term impacts of these maternal glucose levels. Participating mothers were tested for type 2 diabetes and prediabetes and were also asked to fill out health-related questionnaires. The researchers measured the children’s height, weight, waist circumference, and body fat (adiposity), and also tested them for blood glucose levels and other measures related to diabetes. A total of 4,967 women and 4,832 children participated in HAPO FUS.

The HAPO FUS researchers recently published several major study results. They first studied participating mothers whose pregnancies during HAPO met, in retrospect, the alternate criteria for GDM, although they did not meet the traditional criteria for GDM. This group included about 14 percent of the women. Over half of these women developed type 2 diabetes or prediabetes in the 10 to 14 years post-delivery, versus only 20.1 percent of the women who had lower glucose levels. Moreover, even after adjusting for many known risk factors for type 2 diabetes, women who retrospectively met the alternative criteria for GDM were over five times more likely to develop diabetes than women who had lower glucose levels.

When the researchers examined participating children, they found that the likelihood of having any excess weight, at the level of either overweight or obesity, did not differ significantly between the children of mothers whose glucose levels met the alternate GDM criteria and the other children. However, narrowing their focus to just higher levels of excess weight in the children, they found that the likelihood of having obesity was significantly greater among children of affected pregnancies. (For these analyses, the researchers also took into account each mother’s body mass index, BMI—a measure of weight relative to height—during pregnancy, as that, too, can influence the risk of excess weight in her offspring.) Furthermore, the researchers found evidence that children from pregnancies meeting the alternate GDM criteria were more likely than the other children to have developed insulin resistance, another risk factor for type 2 diabetes. No difference was seen between girls and boys in this regard.

Having examined the impact of maternal glucose levels meeting the alternative GDM criteria on risk for metabolic problems in the children, the HAPO FUS researchers then asked whether there was a direct correlation between maternal blood glucose levels—including those below levels meeting the alternative GDM criteria—and measures of childhood adiposity years later. After taking into account maternal BMI during pregnancy, they observed increasing risk of childhood adiposity with increasing maternal glucose levels during pregnancy. The overall outcome was largely similar for boys and girls.

Future Directions

The HAPO FUS findings are important as they demonstrate that elevated maternal blood glucose levels below those traditionally used to diagnose GDM are associated with long-term health risks for mothers and children. However, large gaps in knowledge remain—for example, how maternal blood glucose levels change across the entire course of pregnancy is unknown. It is also unclear whether screening for GDM earlier in pregnancy than the late second to third trimester, treating GDM at an earlier stage of pregnancy, or providing treatment for lower (but still elevated) maternal blood glucose levels would result in health benefits for mothers and children. As other NIDDK-supported studies have demonstrated the devastating impact of type 2 diabetes in youth, closing these knowledge gaps could have critical ramifications for the health of future generations.

To begin to address these questions that are so important to both diabetes care and prevention, the NIDDK is cultivating new research in this area, starting with a newly funded pregnancy research consortium. This clinical consortium will employ cutting-edge technology to ascertain the “profile” of blood glucose levels in women across the span of pregnancy, beginning in the first trimester. Such information could help lay the foundation for future clinical studies and trials evaluating new approaches to GDM screening, diagnosis, and intervention, with the ultimate goal of improving the health of women and their children.

Lowe WL Jr, Lowe LP, Kuang A,…Metzger BE; HAPO Follow-up Study Cooperative Research Group. Maternal glucose levels during pregnancy and childhood adiposity in the Hyperglycemia and Adverse Pregnancy Outcome Follow-up Study. Diabetologia 62: 598-610, 2019.

Lowe WL Jr, Scholtens DM, Kuang A,…Metzger BE; HAPO Follow-up Study Cooperative Research Group. Hyperglycemia and Adverse Pregnancy Outcome Follow-up Study (HAPO FUS): Maternal gestational diabetes mellitus and childhood glucose metabolism. Diabetes Care 42: 372-380, 2019.

Lowe WL Jr, Scholtens DM, Lowe LP,…Metzger BE; HAPO Follow-up Study Cooperative Research Group. Association of gestational diabetes with maternal disorders of glucose metabolism and childhood adiposity. JAMA 320: 1005-1016, 2018.

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