Gestational diabetes and some of its treatments pose long-term risks to mothers, children
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Gestational diabetes is a leading common complication of pregnancy in the United States, affecting up to one in 20 women.
Results of a study published in 2021 in JAMA showed the incidence of gestational diabetes in the U.S. increased from 47.6 per 1,000 live births to 63.5 per 1,000 live births between 2011 and 2019. The increase appeared highest among Asian Indian individuals at a rate of 129.1 per 1,000 live births in 2019.
For women, gestational diabetes is associated with an increased risk for developing type 2 diabetes and its comorbidities. For children, maternal gestational diabetes increases risks for adverse neonatal outcomes and cardiometabolic risks later in life.
However, certain treatments for gestational diabetes, particularly metformin, present their own risks. Guidelines vary in their recommendations for first-line treatment with some calling for insulin and others suggesting metformin as a reasonable option.
“Gestational diabetes has increasingly become a significant issue in terms of prevalence, much of which can be traced to the increased obesity epidemic,” Linda A. Barbour, MD, MSPH, FACP, professor in endocrinology, metabolism and diabetes and maternal-fetal medicine at University of Colorado, told Endocrine Today. “Nearly two-thirds of pregnant women are coming into pregnancy either overweight or obese, and that is a significant risk factor for developing gestational diabetes. The treatment of gestational diabetes is almost equally controversial as the best way to diagnose it.”
Guideline variations
Hyperglycemia during pregnancy can be asymptomatic, and screening with various glucose tolerance test protocols is advised. Risk factors for gestational diabetes include older age, obesity, multiple parity and metabolic syndrome. Prepregnancy weight loss and lifestyle modification can mitigate risks.
Guidance from medical societies unanimously advises lifestyle modifications first to treat gestational diabetes, followed by medical therapy. However, recommendations on the best first-line treatment vary.
Both the ADA and American College of Obstetricians and Gynecologists (ACOG) recommend insulin, whereas the Society for Maternal-Fetal Medicine (SMFM) supports metformin as an alternative first-line therapy.
“The ADA and the ACOG recommend that when treatment with lifestyle and nutrition are not enough to maintain good glycemic control, then insulin should be used as first-line treatment. ACOG states that metformin is a reasonable alternative if women decline insulin or their caregivers don’t think they can safely administer it, but SMFM suggests that for women who are not adequately controlled with lifestyle modifications, metformin is a reasonable and safe first-line pharmacological alternative to insulin,” Denice S. Feig, MD, MSc, professor of medicine obstetrics and gynecology, and health policy, management and evaluation at the University of Toronto, and head of the Diabetes in Pregnancy Program at Mount Sinai Hospital, told Endocrine Today.
Moreover, although glyburide has been associated with macrosomia and neonatal hypoglycemia, SMFM is not completely opposed to glyburide either.
“Glyburide was the most commonly used agent for women with gestational diabetes until about 2016 when it fell out of favor for a number of reasons,” Barbour said. “For one, glyburide also crosses the placenta, as does metformin, and it also appears to not offer as good control as insulin, which does not cross the placenta. However, glyburide was not always dosed correctly in many of the previous trials, which could have played a role in its efficacy and ability to appropriately titrate the dose. Many women in those trials ended up with hypoglycemia, possibly because it was not consistently given 1 hour before eating given that it has a peak effect in about 3 hours after a dose. It is still used today, but not as much as it once was and is less favored by the ADA, ACOG and SMFM.”
Although used globally and often to treat gestational diabetes, metformin is where the professional societies’ guidelines differ. SMFM suggests metformin is equivalent to insulin in the first-line setting, but ADA and ACOG disagree, stating that insulin is the preferred therapy.
“The best data to date indicate insulin is the best first-line treatment option; however, confounding this is access to care,” Suchitra Chandrasekaran, MD, assistant professor in the department of maternal and fetal medicine at Emory Healthcare, told Endocrine Today. “The access and comfort of initiating insulin is challenging, and patient compliance is another issue. If a patient doesn’t like to take insulin, then there is the risk for uncontrolled glucose. This might be where the oral medication metformin is a reasonable option to consider.”
Barbour said insulin can be expensive and is more difficult to use for some women, in which case metformin may be safer to use than nothing at all.
“In the metformin in gestational [MiG] diabetes trial, a large percentage of women failed on metformin and had to go on insulin — up to 44% of the cohort. So sometimes, metformin just doesn’t work,” she said. “In addition, metformin readily crosses the placenta, and it has been shown to be concentrated in both the placenta and the fetus, with higher levels found in the fetus than in the mother. What concerns me most is that metformin is concentrated in mitochondria, which is not the case the in first trimester; but by the second trimester when the embryo becomes a fetus, there are a lot of cation transporters that allow metformin to cross the placenta.”
Still, for certain situations that may require a therapy other than insulin, metformin remains an option.
In the metformin in women with type 2 diabetes in pregnancy (MiTY) trial, Feig and colleagues found that mothers using metformin in addition to insulin had better glucose levels, required lower insulin doses, gained less weight and had fewer caesarean deliveries than those assigned placebo. Infants exposed to metformin in utero had a reduced risk of being extremely large with weight more than 4 kg and had lower adiposity measures, but they also had an increased risk for being born small for gestational age (13% vs. 6%, RR = 1.96; 1.1-3.64; P = .026).
“We don’t yet know if metformin exposure in children of mothers with type 2 diabetes will benefit them in the long-term, from being less large at birth, or will harm those who were born small,” she said.
Short- and long-term consequences
Gestational diabetes is associated with both short- and long-term complications for both the mother and child, according to experts.
“The motivation for why we try to control blood glucose so tightly during pregnancy and why we treat even mildly elevated blood glucose levels is because of the perinatal outcomes — babies exposed to hyperglycemia in utero are at risk for producing too much insulin which can lead to fetal overgrowth,” Camille Powe, MD, endocrinologist and co-director of the diabetes in pregnancy program at Massachusetts General Hospital, told Endocrine Today.
As a result of the increased fat accumulation and larger size at birth, babies exposed to gestational diabetes are at increased risk for birth trauma and other injuries during delivery.
“Because babies are used to high blood glucose in utero, they make their own insulin, and that can continue for a bit postpartum. During the neonatal period, babies who are exposed to high glucose in utero can have neonatal hypoglycemia, which can necessitate treatment and sometimes result in neonatal intensive care unit admission,” Powe said. “Other common complications associated with gestational diabetes include an increased risk for hyperbilirubinemia and respiratory distress syndrome.”
For the mother, short-term risks include cesarean delivery and the development of hypertensive disorders during pregnancy, such as preeclampsia. In the long term, mothers are at significantly increased risk for progression to type 2 diabetes, and children have an increased risk for childhood obesity.
“There are also a number of randomized trials of women with gestational diabetes or PCOS in which participants were randomized to metformin vs. insulin for gestational diabetes or to metformin vs. no treatment to prevent miscarriage in PCOS,” Barbour said. “There is some indication — in the 9-year-olds in the Auckland cohort of the MiG trial and in the 5- to 10-year-olds in the PCOS trials — that there was an increased risk for childhood overweight.”
Chandrasekaran said more focus is being placed on the postpartum period to discuss appropriate weight loss between pregnancies as well as lifestyle and diet modifications to reduce these risks.
“More data are coming down the pipeline indicating potential changes in epigenetics. There may be some changes in brain signals with insulin resistance, glucose dysregulation and obesity even into childhood,” Chandrasekaran said. “It is a very rich arena for research in terms of looking mechanistically at what is happening to the neonates, and ultimately, the risk for metabolic disease once neonates become reproductive-age adolescents entering into potential pregnancies themselves. It is a cyclical process.”
Feig agreed.
“It is becoming clearer that having gestational diabetes is a window not only into the mother’s life, but also into the baby’s future and it is really important that we get it all right,” Feig said.
Inequities
There are also racial and ethnic disparities that accompany gestational diabetes.
“We see the highest rates of gestational diabetes in Asian and Latina women, and the reason for the disparities are multifactorial,” Powe said. “There are disparities because the health care system is not delivering the best care equitably to individuals of different racial, ethnic and socioeconomic backgrounds. Outcomes are not equal in terms of adverse consequences of high blood glucose and pregnancy.”
Barbour said she is concerned about the known inequities in access to care, early diagnosis, appropriate treatment and postpartum prevention of type 2 diabetes.
“Unfortunately, there are so many inequities because a lot of women don’t receive medical care prior to their pregnancy,” Barbour said. “It is important that all women have better access to care prior to pregnancy. Many women cannot easily access good care or cannot afford insulin or don’t have health insurance, so they cannot be optimally treated. In my experience, women who do the poorest are usually those who have not been diagnosed early on and have not received good care prior to pregnancy.”
This is the most profound and compelling reason for preconception counseling, Barbour added.
“Many women do not know that they have type 2 diabetes and have no idea how important it is to get their glucose under control before they get pregnant,” she said. “If a woman does have undiagnosed type 2 diabetes and gets diagnosed for the first time during pregnancy, then they and the baby are at significant increased risk for various complications, including major malformations. Appropriately treating their diabetes prior to pregnancy reduces this risk to that of women without diabetes.”
In the 2021 study by Shah and colleagues, researchers found that gestational diabetes rates increased among all race and ethnicity subgroups for all age groups. After Asian Indian women, Hispanic women had the highest rates, with Puerto Rican women at highest risk (2019 gestational diabetes rate, 75.8; 95% CI, 71.8-79.9; RR = 1.31; 95% CI, 1.24-1.39).
“The observed heterogeneity in rates of gestational diabetes within subgroups of non-Hispanic Asian and Hispanic individuals at first live birth highlight the importance of ascertaining and reporting rates specific to these disaggregated non-Hispanic Asian and Hispanic subgroups,” Shah and colleagues wrote. “The reported trends herein may also guide strategies to equitably address increasing gestational diabetes rates by investigating the determinants of gestational diabetes and interventions to address them in populations with high burden. Addressing modifiable prenatal risk factors and implementing strategies to prevent gestational diabetes and postnatal diabetes in all individuals, with particular focus on groups with disproportionately high gestational diabetes rates, may help to reduce disparities in long-term cardiovascular and metabolic disease outcomes.”
Much to be learned
Looking ahead, experts agreed that there is still much to be learned about gestational diabetes.
“We currently treat gestational diabetes as if it is all the same — we have a standard protocol. But we know there’s a lot of heterogeneity in outcomes for women with gestational diabetes,” Powe said. “For example, some babies experience consequences at very small elevations in glucose, and other babies may not experience those consequences at even higher glucose levels. There is a lot we need to uncover about variation and outcomes.”
Additionally, diagnosis and treatment should be easier, Powe added.
“We rely on oral glucose tolerance tests for diagnosis that the mother has to show up fasting for, and it’s a several hours-long procedure that not every mother completes because not every mother wants to go through that or maybe we are not able to accommodate everyone to do it,” Powe said. “This is how we sometimes end up with variations in care in terms of diagnosis. Finger-prick tests that we use for monitoring once we make the diagnosis are also extremely burdensome and disruptive, and so we need ways to diagnose and treat this disease that doesn’t put as much burden on our patients. We can address these issues by having better personalized treatment and a better understanding of where to target our interventions.”
Feig agreed and said prevention of gestational diabetes is ideal.
“There is ongoing research looking at preconception counseling to prevent gestational diabetes, and that is exactly where we need to start. There is a lot of controversy on how to screen for and diagnose the disease, how to do it early on in pregnancy and whether it is worthwhile to treat gestational diabetes early in pregnancy. We also don’t know the ideal treatment or diet for these women,” Feig said. “Gestational diabetes represents a window of opportunity where we have identified young women that we know are at increased risk for type 2 diabetes, and so it would be nice to have interventions to prevent the progression to type 2 diabetes. There’s been some lifestyle interventions, but these women have many challenges, and we need interventions that can be performed at home. Women need individual coaching support and community support.”
Barbour said there is a great need for a better approach to preconception counseling.
“Preconception counseling should be administered to all women of childbearing age to help women get to a better weight and know exactly what they can do before they get pregnant because it makes so much difference if they are at risk for diabetes. And if they do not want pregnancy, then adequate contraception should be provided. This is where the U.S. really fails,” Barbour said. “It is also imperative that we gain a better understanding of the best treatment for gestational diabetes and learn more about the long-term effects of the disease on the baby. Additionally, we need to find out what the optimal weight is to gain or maybe not to gain in pregnancy, and there are ongoing trials looking into this now.”
More needs to be learned about the biology of gestational diabetes, Chandrasekaran said.
“We are very good at diagnosing it, we’re very good at treating it, but we’re still not very good at preventing it,” she said. “We still have a lot to learn there and maybe even more importantly, learn that not all gestational diabetes is the same. Perhaps there are different phenotypes of the disease process. Once we understand that, it could optimize how we can not only prevent the disease, but also more effectively provide the best treatment and care for our pregnant patients.”
- References:
- Barbour LA, Feig, DS. Diabetes Care. 2019;doi:10.2337/dci18-0055.
- Feig DS, et al. Lancet Diabetes Endocrinol. 2020;doi:10.1016/S2213-8587(20)30310-7.
- Rowan JA, et al. BMJ Open Diabetes Res Care. 2018;doi:10.1136/bmjdrc-2017-000456.
- Shah NS, et al. JAMA. 2021;doi:10.1001/jama.2021.7217.
- For more information:
- Linda A. Barbour, MD, can be reached at lynn.barbour@cuanschutz.edu.
- Suchitra Chandrasekaran, MD, can be reached at suchitra.chandrasekaran@emory.edu.
- Denice S. Feig, MD, MSc, can be reached at d.feig@utoronto.ca; Twitter: @DeniceFeig.
- Camille E. Powe, MD, can be reached at camille.powe@mgh.harvard.edu; Twitter: @CEPoweMD.
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