TBD Meeting (4564-19)

WASHINGTON – Pharmacologic treatment of gestational diabetes remains controversial, with the American College of Obstetricians and Gynecologists and the American Diabetes Association firmly recommending insulin as the preferred first-line pharmacologic therapy, and the Society of Maternal-Fetal Medicine more accepting of metformin as a “reasonable and safe first-line” alternative to insulin and stating that there are no strong data supporting metformin over the sulfonylurea glyburide.

If there’s one main take-away, Mark B. Landon, MD, said at the biennial meeting of the Diabetes in Pregnancy Study Group of North America, it was that “the primary concern” about the use of oral agents for treating gestational diabetes mellitus (GDM) is that there is limited long-term follow-up of exposed offspring.

“The claim that long-term safety data are not available for any oral agent is probably the most valid warning [of any of the concerns voiced by professional organizations],” said Dr. Landon, Richard L. Meiling professor and chair of the department of obstetrics and gynecology at The Ohio State University Wexner Medical Center, Columbus.

Otherwise, he said, there are not enough data to firmly prioritize the drugs most commonly used for GDM, and “the superiority of insulin over oral agents simply remains questionable.”

ACOG’s 2017 level A recommendation for insulin as the first-line option when pharmacologic treatment is needed for treating GDM (Obstet Gynecol. 2017;130[1]:e17-37) was followed in 2018 by another updated practice bulletin on GDM (Obstet Gynecol. 2018;131[2]:e49-64) that considered several meta-analyses published in 2017 and reiterated a preference for insulin.

Those recent meta-analyses of pharmacologic treatment of GDM show that the available literature is generally of “poor trial quality,” and that studies are small and not designed to assess equivalence or noninferiority, Mark Turrentine, MD, chair of ACOG’s committee on practice bulletins, said in an interview. “Taking that into account and [considering] that oral antidiabetic medications are not approved by the Food and Drug Administration [for the treatment of GDM], that they cross the placenta, and that we currently lack long-term neonatal safety data ... we felt that insulin is the preferred treatment.”

In its 2017 and 2018 bulletins, ACOG said that metformin is a “reasonable alternative choice” for women who decline insulin therapy or who may be unable to safely administer it (a level B recommendation). The 2018 practice bulletin mentions one additional factor: affordability. “Insurance companies aren’t always covering [insulin],” said Dr. Turrentine, of the department of obstetrics and gynecology, Baylor College of Medicine, Houston. “It’s a challenge – no question.”

ACOG says glyburide should not be recommended as a first-line pharmacologic treatment, “because, in most studies, it does not yield outcomes equivalent to insulin or metformin,” Dr. Turrentine emphasized.
 

Glyburide’s role

Dr. Landon took issue with ACOG’s stance on the sulfonylurea. “Frankly, I think this [conclusion] is debatable,” he said. The trend in the United States – “at least after the 2017 ACOG document came out”– has been toward use of metformin over glyburide when an oral agent is [used], but “I think glyburide has been unfairly trashed. It probably still has a place.”

As Dr. Landon sees it, research published in 2015 put a damper on the use of glyburide, which “had become the number one agent” after an earlier, seminal trial, led by Oded Langer, MD, had shown equivalent glycemic control in about 400 women with GDM who were randomized to receive either insulin or glyburide (N Engl J Med. 2000;343;1134-8). The trial was not powered to evaluate other outcomes, but there were no significant differences in neonatal complications, Dr. Landon said.

One of the 2015 studies – a large, retrospective, population-based study of more than 9,000 women with GDM treated with glyburide or insulin – showed a higher risk of admission to the neonatal intensive care unit (relative risk, 1.41), hypoglycemia in the newborn (RR, 1.40), and large-for-gestational age (RR, 1.43) with glyburide, compared with insulin (JAMA Pediatr. 2015;169[5]:452-8).

A meta-analysis of glyburide, metformin, and insulin showed significant differences between glyburide and insulin in birth weight, macrosomia (RR, 2.62), and neonatal hypoglycemia (RR, 2.04; BMJ. 2015;350;h102). However, “this was basically a conglomeration of studies with about 50 [individuals] in each arm, and in which entry criteria for the diagnosis of GDM were rather heterogeneous,” said Dr. Landon. “There are real problems with this and other meta-analyses.”

The authors of a 2018 multicenter, noninferiority, randomized, controlled trial of about 900 women concluded that their study failed to show that the use of glyburide, compared with insulin, does not result in a greater frequency of perinatal complications. The authors also wrote, however, that the “increase in perinatal complications [with glyburide] may be no more than 10.5%, compared with insulin” (JAMA. 2018;319[17]:1773-80).

That increase, Dr. Landon said, was “not an absolute 10%, but 10% of the complication rate, which probably translates to about 2%.” The only component of a composite outcome (including macrosomia, hypoglycemia, and hyperbilirubinemia) that was significantly different, he noted, was hypoglycemia, which affected 12.2% of neonates in the glyburide group and 7.2% in the insulin group.

Glyburide’s role may well be substantiated in the future, Dr. Landon said during a discussion period at the meeting, through research underway at the University of Pittsburgh aimed at tailoring treatment to the underlying pathophysiology of a patient’s GDM.

The MATCh-GDM study (Metabolic Analysis for Treatment Choice in GDM) is randomizing women to receive usual, unmatched treatment or treatment matched to GDM mechanism – metformin for predominant insulin resistance, glyburide or insulin for predominant insulin secretion defects, and one of the three for combined mechanisms. The study’s principal investigator, Maisa Feghali, MD, of the department of obstetrics, gynecology, and reproductive sciences at the University of Pittsburgh, stressed in a presentation on the study that GDM is a heterogeneous condition and that research is needed to understand the impact of GDM subtypes on treatment response.
 

Metformin outcomes

Concerns about the impact of metformin on short-term perinatal outcomes focus on preterm birth, Dr. Landon said. The only study to date that has shown an increased rate of prematurity, however, is the “seminal” Metformin in Gestational Diabetes (MiG) trial led by Janet A. Rowan, MBChB, that randomized 751 women with GDM in Australia and New Zealand to treatment with metformin or insulin. The researchers found no significant differences between a composite of neonatal complications but did establish that severe hypoglycemia was less common in the metformin group and preterm birth was more common (N Engl J Med. 2008;358:2003-15).

A 2016 systematic review and meta-analysis of short- and long-term outcomes of metformin, compared with insulin, found that metformin did not increase preterm delivery (Diabet Med. 2017;34[1]:27-36). And while the 2015 BMJ meta-analysis found that metformin was associated with higher rates of preterm birth (RR, 1.50), the increased risk “was all driven by the Rowan study,” Dr. Landon said. The 2015 meta-analysis also found that metformin was associated with less maternal weight gain and fewer infants who were large for gestational age.

Metformin is also tainted by high rates of failure in GDM. In the 2008 Rowan study, 46% of patients on metformin failed to achieve glycemic control. “But this is a classic half-full, half-empty [phenomena],” Dr. Landon said. “Some people say this isn’t good, but on the other hand, 54% avoided insulin.”

Indeed, the Society of Maternal-Fetal Medicine (SMFM), in its 2018 statement on the pharmacologic treatment of GDM, said that oral hypoglycemic agents that are used as monotherapy work in “more than half” of GDM pregnancies. The need for adjunctive insulin to achieve glycemic control ranges between 26% and 46% for women using metformin, and 4% and 16% for women using glyburide, it says.

In the society’s view, recent meta-analyses and systemic reviews “support the efficacy and safety of oral agents,” and “although concerns have been raised for more frequent adverse neonatal outcomes with glyburide, including macrosomia and hypoglycemia, the evidence of benefit of one oral agent over the other remains limited.”

The society says that the difference between its statement and the ACOG recommendations is “based on the values placed by different experts and providers on the available evidence,” and it adds that more long-term data are needed.

But as Dr. Landon said, the SMFM is “a little more forgiving” in its interpretation of a limited body of literature. And clinicians, in the meantime, have to navigate the controversy. “The professional organizations don’t make it easy for [us],” he said. At this point, “insulin does not cross the placenta, and the oral agents do cross it. Informed consent is absolutely necessary when choosing oral agents for treating GDM.”
 

Offspring well-being

Of greater concern than neonatal outcomes are the potential long-term issues for offspring, Dr. Landon said. On the one hand, it is theorized that metformin may protect beta-cell function in offspring and thereby reduce the cross-generational effects of obesity and type 2 diabetes. On the other hand, it is theorized that the drug may cause a decrease in cell-cycle proliferation, which could have “unknown fetal programming effects,” and it may inhibit the mTOR signaling pathway, thus restricting the transport of glucose and amino acids across the placenta, he said. (Findings from in vitro research have suggested that glyburide treatment in GDM might be associated with enhanced transport across the placenta, he noted.)

Long-term follow-up studies of offspring are “clearly needed,” Dr. Landon said. At this point, in regard to long-term safety, he and other experts are concerned primarily about the potential for obesity and metabolic dysfunction in offspring who are exposed to metformin in utero. They are watching follow-up from Dr. Rowan’s MiG trial, as well as elsewhere in the literature, on metformin-exposed offspring from mothers with polycystic ovary syndrome.

A follow-up analysis of offspring from the MiG trial found that children of women with GDM who were exposed to metformin had larger measures of subcutaneous fat at age 2 years, compared with children of mothers treated with insulin alone, but that overall body fat was the same, Dr. Landon noted. The investigators postulated that these children may have less visceral fat and a more favorable pattern of fat distribution (Diab Care. 2011;34:2279-84).

A recently published follow-up analysis of two randomized, controlled trials of women with polycystic ovary syndrome is cause for more concern, he said. That analysis showed that offspring exposed to metformin in utero had a higher body mass index and an increased prevalence of obesity or overweight at age 4 years, compared with placebo groups (J Clin Endocrinol Metab. 2018;103[4]:1612-21).

That analysis of metformin-exposed offspring in the context of polycystic ovary syndrome was published after the SMFM statement, as was another follow-up analysis of MiG trial offspring – this one, at ages 7-9 years – that showed an increase in weight, size, and fat mass in one of two subsets analyzed, despite no difference in large-for-gestational age rates between the metformin- and insulin-exposed offspring (BMJ Open Diabetes Res Care. 2018;6[1]: e000456).

In 2018, a group of 17 prominent diabetes and maternal-fetal medicine researchers cited these findings in a response to the SMFM statement and cautioned against the widespread adoption of metformin use during pregnancy, writing that, based on “both pharmacologic and randomized trial evidence that metformin may create an atypical intrauterine environment ... we believe it is premature to embrace metformin as equivalent to insulin or as superior to glyburide, and that patients should be counseled on the limited long-term safety data and potential for adverse childhood metabolic effects” (Am J Obstet Gynecol. 2018;219[4]:367.e1-7).

WASHINGTON – Pharmacologic treatment of gestational diabetes remains controversial, with the American College of Obstetricians and Gynecologists and the American Diabetes Association firmly recommending insulin as the preferred first-line pharmacologic therapy, and the Society of Maternal-Fetal Medicine more accepting of metformin as a “reasonable and safe first-line” alternative to insulin and stating that there are no strong data supporting metformin over the sulfonylurea glyburide.

If there’s one main take-away, Mark B. Landon, MD, said at the biennial meeting of the Diabetes in Pregnancy Study Group of North America, it was that “the primary concern” about the use of oral agents for treating gestational diabetes mellitus (GDM) is that there is limited long-term follow-up of exposed offspring.

“The claim that long-term safety data are not available for any oral agent is probably the most valid warning [of any of the concerns voiced by professional organizations],” said Dr. Landon, Richard L. Meiling professor and chair of the department of obstetrics and gynecology at The Ohio State University Wexner Medical Center, Columbus.

Otherwise, he said, there are not enough data to firmly prioritize the drugs most commonly used for GDM, and “the superiority of insulin over oral agents simply remains questionable.”

ACOG’s 2017 level A recommendation for insulin as the first-line option when pharmacologic treatment is needed for treating GDM (Obstet Gynecol. 2017;130[1]:e17-37) was followed in 2018 by another updated practice bulletin on GDM (Obstet Gynecol. 2018;131[2]:e49-64) that considered several meta-analyses published in 2017 and reiterated a preference for insulin.

Those recent meta-analyses of pharmacologic treatment of GDM show that the available literature is generally of “poor trial quality,” and that studies are small and not designed to assess equivalence or noninferiority, Mark Turrentine, MD, chair of ACOG’s committee on practice bulletins, said in an interview. “Taking that into account and [considering] that oral antidiabetic medications are not approved by the Food and Drug Administration [for the treatment of GDM], that they cross the placenta, and that we currently lack long-term neonatal safety data ... we felt that insulin is the preferred treatment.”

In its 2017 and 2018 bulletins, ACOG said that metformin is a “reasonable alternative choice” for women who decline insulin therapy or who may be unable to safely administer it (a level B recommendation). The 2018 practice bulletin mentions one additional factor: affordability. “Insurance companies aren’t always covering [insulin],” said Dr. Turrentine, of the department of obstetrics and gynecology, Baylor College of Medicine, Houston. “It’s a challenge – no question.”

ACOG says glyburide should not be recommended as a first-line pharmacologic treatment, “because, in most studies, it does not yield outcomes equivalent to insulin or metformin,” Dr. Turrentine emphasized.
 

Glyburide’s role

Dr. Landon took issue with ACOG’s stance on the sulfonylurea. “Frankly, I think this [conclusion] is debatable,” he said. The trend in the United States – “at least after the 2017 ACOG document came out”– has been toward use of metformin over glyburide when an oral agent is [used], but “I think glyburide has been unfairly trashed. It probably still has a place.”

As Dr. Landon sees it, research published in 2015 put a damper on the use of glyburide, which “had become the number one agent” after an earlier, seminal trial, led by Oded Langer, MD, had shown equivalent glycemic control in about 400 women with GDM who were randomized to receive either insulin or glyburide (N Engl J Med. 2000;343;1134-8). The trial was not powered to evaluate other outcomes, but there were no significant differences in neonatal complications, Dr. Landon said.

One of the 2015 studies – a large, retrospective, population-based study of more than 9,000 women with GDM treated with glyburide or insulin – showed a higher risk of admission to the neonatal intensive care unit (relative risk, 1.41), hypoglycemia in the newborn (RR, 1.40), and large-for-gestational age (RR, 1.43) with glyburide, compared with insulin (JAMA Pediatr. 2015;169[5]:452-8).

A meta-analysis of glyburide, metformin, and insulin showed significant differences between glyburide and insulin in birth weight, macrosomia (RR, 2.62), and neonatal hypoglycemia (RR, 2.04; BMJ. 2015;350;h102). However, “this was basically a conglomeration of studies with about 50 [individuals] in each arm, and in which entry criteria for the diagnosis of GDM were rather heterogeneous,” said Dr. Landon. “There are real problems with this and other meta-analyses.”

The authors of a 2018 multicenter, noninferiority, randomized, controlled trial of about 900 women concluded that their study failed to show that the use of glyburide, compared with insulin, does not result in a greater frequency of perinatal complications. The authors also wrote, however, that the “increase in perinatal complications [with glyburide] may be no more than 10.5%, compared with insulin” (JAMA. 2018;319[17]:1773-80).

That increase, Dr. Landon said, was “not an absolute 10%, but 10% of the complication rate, which probably translates to about 2%.” The only component of a composite outcome (including macrosomia, hypoglycemia, and hyperbilirubinemia) that was significantly different, he noted, was hypoglycemia, which affected 12.2% of neonates in the glyburide group and 7.2% in the insulin group.

Glyburide’s role may well be substantiated in the future, Dr. Landon said during a discussion period at the meeting, through research underway at the University of Pittsburgh aimed at tailoring treatment to the underlying pathophysiology of a patient’s GDM.

The MATCh-GDM study (Metabolic Analysis for Treatment Choice in GDM) is randomizing women to receive usual, unmatched treatment or treatment matched to GDM mechanism – metformin for predominant insulin resistance, glyburide or insulin for predominant insulin secretion defects, and one of the three for combined mechanisms. The study’s principal investigator, Maisa Feghali, MD, of the department of obstetrics, gynecology, and reproductive sciences at the University of Pittsburgh, stressed in a presentation on the study that GDM is a heterogeneous condition and that research is needed to understand the impact of GDM subtypes on treatment response.
 

Metformin outcomes

Concerns about the impact of metformin on short-term perinatal outcomes focus on preterm birth, Dr. Landon said. The only study to date that has shown an increased rate of prematurity, however, is the “seminal” Metformin in Gestational Diabetes (MiG) trial led by Janet A. Rowan, MBChB, that randomized 751 women with GDM in Australia and New Zealand to treatment with metformin or insulin. The researchers found no significant differences between a composite of neonatal complications but did establish that severe hypoglycemia was less common in the metformin group and preterm birth was more common (N Engl J Med. 2008;358:2003-15).

A 2016 systematic review and meta-analysis of short- and long-term outcomes of metformin, compared with insulin, found that metformin did not increase preterm delivery (Diabet Med. 2017;34[1]:27-36). And while the 2015 BMJ meta-analysis found that metformin was associated with higher rates of preterm birth (RR, 1.50), the increased risk “was all driven by the Rowan study,” Dr. Landon said. The 2015 meta-analysis also found that metformin was associated with less maternal weight gain and fewer infants who were large for gestational age.

Metformin is also tainted by high rates of failure in GDM. In the 2008 Rowan study, 46% of patients on metformin failed to achieve glycemic control. “But this is a classic half-full, half-empty [phenomena],” Dr. Landon said. “Some people say this isn’t good, but on the other hand, 54% avoided insulin.”

Indeed, the Society of Maternal-Fetal Medicine (SMFM), in its 2018 statement on the pharmacologic treatment of GDM, said that oral hypoglycemic agents that are used as monotherapy work in “more than half” of GDM pregnancies. The need for adjunctive insulin to achieve glycemic control ranges between 26% and 46% for women using metformin, and 4% and 16% for women using glyburide, it says.

In the society’s view, recent meta-analyses and systemic reviews “support the efficacy and safety of oral agents,” and “although concerns have been raised for more frequent adverse neonatal outcomes with glyburide, including macrosomia and hypoglycemia, the evidence of benefit of one oral agent over the other remains limited.”

The society says that the difference between its statement and the ACOG recommendations is “based on the values placed by different experts and providers on the available evidence,” and it adds that more long-term data are needed.

But as Dr. Landon said, the SMFM is “a little more forgiving” in its interpretation of a limited body of literature. And clinicians, in the meantime, have to navigate the controversy. “The professional organizations don’t make it easy for [us],” he said. At this point, “insulin does not cross the placenta, and the oral agents do cross it. Informed consent is absolutely necessary when choosing oral agents for treating GDM.”
 

Offspring well-being

Of greater concern than neonatal outcomes are the potential long-term issues for offspring, Dr. Landon said. On the one hand, it is theorized that metformin may protect beta-cell function in offspring and thereby reduce the cross-generational effects of obesity and type 2 diabetes. On the other hand, it is theorized that the drug may cause a decrease in cell-cycle proliferation, which could have “unknown fetal programming effects,” and it may inhibit the mTOR signaling pathway, thus restricting the transport of glucose and amino acids across the placenta, he said. (Findings from in vitro research have suggested that glyburide treatment in GDM might be associated with enhanced transport across the placenta, he noted.)

Long-term follow-up studies of offspring are “clearly needed,” Dr. Landon said. At this point, in regard to long-term safety, he and other experts are concerned primarily about the potential for obesity and metabolic dysfunction in offspring who are exposed to metformin in utero. They are watching follow-up from Dr. Rowan’s MiG trial, as well as elsewhere in the literature, on metformin-exposed offspring from mothers with polycystic ovary syndrome.

A follow-up analysis of offspring from the MiG trial found that children of women with GDM who were exposed to metformin had larger measures of subcutaneous fat at age 2 years, compared with children of mothers treated with insulin alone, but that overall body fat was the same, Dr. Landon noted. The investigators postulated that these children may have less visceral fat and a more favorable pattern of fat distribution (Diab Care. 2011;34:2279-84).

A recently published follow-up analysis of two randomized, controlled trials of women with polycystic ovary syndrome is cause for more concern, he said. That analysis showed that offspring exposed to metformin in utero had a higher body mass index and an increased prevalence of obesity or overweight at age 4 years, compared with placebo groups (J Clin Endocrinol Metab. 2018;103[4]:1612-21).

That analysis of metformin-exposed offspring in the context of polycystic ovary syndrome was published after the SMFM statement, as was another follow-up analysis of MiG trial offspring – this one, at ages 7-9 years – that showed an increase in weight, size, and fat mass in one of two subsets analyzed, despite no difference in large-for-gestational age rates between the metformin- and insulin-exposed offspring (BMJ Open Diabetes Res Care. 2018;6[1]: e000456).

In 2018, a group of 17 prominent diabetes and maternal-fetal medicine researchers cited these findings in a response to the SMFM statement and cautioned against the widespread adoption of metformin use during pregnancy, writing that, based on “both pharmacologic and randomized trial evidence that metformin may create an atypical intrauterine environment ... we believe it is premature to embrace metformin as equivalent to insulin or as superior to glyburide, and that patients should be counseled on the limited long-term safety data and potential for adverse childhood metabolic effects” (Am J Obstet Gynecol. 2018;219[4]:367.e1-7).

WASHINGTON – Pharmacologic treatment of gestational diabetes remains controversial, with the American College of Obstetricians and Gynecologists and the American Diabetes Association firmly recommending insulin as the preferred first-line pharmacologic therapy, and the Society of Maternal-Fetal Medicine more accepting of metformin as a “reasonable and safe first-line” alternative to insulin and stating that there are no strong data supporting metformin over the sulfonylurea glyburide.

If there’s one main take-away, Mark B. Landon, MD, said at the biennial meeting of the Diabetes in Pregnancy Study Group of North America, it was that “the primary concern” about the use of oral agents for treating gestational diabetes mellitus (GDM) is that there is limited long-term follow-up of exposed offspring.

“The claim that long-term safety data are not available for any oral agent is probably the most valid warning [of any of the concerns voiced by professional organizations],” said Dr. Landon, Richard L. Meiling professor and chair of the department of obstetrics and gynecology at The Ohio State University Wexner Medical Center, Columbus.

Otherwise, he said, there are not enough data to firmly prioritize the drugs most commonly used for GDM, and “the superiority of insulin over oral agents simply remains questionable.”

ACOG’s 2017 level A recommendation for insulin as the first-line option when pharmacologic treatment is needed for treating GDM (Obstet Gynecol. 2017;130[1]:e17-37) was followed in 2018 by another updated practice bulletin on GDM (Obstet Gynecol. 2018;131[2]:e49-64) that considered several meta-analyses published in 2017 and reiterated a preference for insulin.

Those recent meta-analyses of pharmacologic treatment of GDM show that the available literature is generally of “poor trial quality,” and that studies are small and not designed to assess equivalence or noninferiority, Mark Turrentine, MD, chair of ACOG’s committee on practice bulletins, said in an interview. “Taking that into account and [considering] that oral antidiabetic medications are not approved by the Food and Drug Administration [for the treatment of GDM], that they cross the placenta, and that we currently lack long-term neonatal safety data ... we felt that insulin is the preferred treatment.”

In its 2017 and 2018 bulletins, ACOG said that metformin is a “reasonable alternative choice” for women who decline insulin therapy or who may be unable to safely administer it (a level B recommendation). The 2018 practice bulletin mentions one additional factor: affordability. “Insurance companies aren’t always covering [insulin],” said Dr. Turrentine, of the department of obstetrics and gynecology, Baylor College of Medicine, Houston. “It’s a challenge – no question.”

ACOG says glyburide should not be recommended as a first-line pharmacologic treatment, “because, in most studies, it does not yield outcomes equivalent to insulin or metformin,” Dr. Turrentine emphasized.
 

Glyburide’s role

Dr. Landon took issue with ACOG’s stance on the sulfonylurea. “Frankly, I think this [conclusion] is debatable,” he said. The trend in the United States – “at least after the 2017 ACOG document came out”– has been toward use of metformin over glyburide when an oral agent is [used], but “I think glyburide has been unfairly trashed. It probably still has a place.”

As Dr. Landon sees it, research published in 2015 put a damper on the use of glyburide, which “had become the number one agent” after an earlier, seminal trial, led by Oded Langer, MD, had shown equivalent glycemic control in about 400 women with GDM who were randomized to receive either insulin or glyburide (N Engl J Med. 2000;343;1134-8). The trial was not powered to evaluate other outcomes, but there were no significant differences in neonatal complications, Dr. Landon said.

One of the 2015 studies – a large, retrospective, population-based study of more than 9,000 women with GDM treated with glyburide or insulin – showed a higher risk of admission to the neonatal intensive care unit (relative risk, 1.41), hypoglycemia in the newborn (RR, 1.40), and large-for-gestational age (RR, 1.43) with glyburide, compared with insulin (JAMA Pediatr. 2015;169[5]:452-8).

A meta-analysis of glyburide, metformin, and insulin showed significant differences between glyburide and insulin in birth weight, macrosomia (RR, 2.62), and neonatal hypoglycemia (RR, 2.04; BMJ. 2015;350;h102). However, “this was basically a conglomeration of studies with about 50 [individuals] in each arm, and in which entry criteria for the diagnosis of GDM were rather heterogeneous,” said Dr. Landon. “There are real problems with this and other meta-analyses.”

The authors of a 2018 multicenter, noninferiority, randomized, controlled trial of about 900 women concluded that their study failed to show that the use of glyburide, compared with insulin, does not result in a greater frequency of perinatal complications. The authors also wrote, however, that the “increase in perinatal complications [with glyburide] may be no more than 10.5%, compared with insulin” (JAMA. 2018;319[17]:1773-80).

That increase, Dr. Landon said, was “not an absolute 10%, but 10% of the complication rate, which probably translates to about 2%.” The only component of a composite outcome (including macrosomia, hypoglycemia, and hyperbilirubinemia) that was significantly different, he noted, was hypoglycemia, which affected 12.2% of neonates in the glyburide group and 7.2% in the insulin group.

Glyburide’s role may well be substantiated in the future, Dr. Landon said during a discussion period at the meeting, through research underway at the University of Pittsburgh aimed at tailoring treatment to the underlying pathophysiology of a patient’s GDM.

The MATCh-GDM study (Metabolic Analysis for Treatment Choice in GDM) is randomizing women to receive usual, unmatched treatment or treatment matched to GDM mechanism – metformin for predominant insulin resistance, glyburide or insulin for predominant insulin secretion defects, and one of the three for combined mechanisms. The study’s principal investigator, Maisa Feghali, MD, of the department of obstetrics, gynecology, and reproductive sciences at the University of Pittsburgh, stressed in a presentation on the study that GDM is a heterogeneous condition and that research is needed to understand the impact of GDM subtypes on treatment response.
 

Metformin outcomes

Concerns about the impact of metformin on short-term perinatal outcomes focus on preterm birth, Dr. Landon said. The only study to date that has shown an increased rate of prematurity, however, is the “seminal” Metformin in Gestational Diabetes (MiG) trial led by Janet A. Rowan, MBChB, that randomized 751 women with GDM in Australia and New Zealand to treatment with metformin or insulin. The researchers found no significant differences between a composite of neonatal complications but did establish that severe hypoglycemia was less common in the metformin group and preterm birth was more common (N Engl J Med. 2008;358:2003-15).

A 2016 systematic review and meta-analysis of short- and long-term outcomes of metformin, compared with insulin, found that metformin did not increase preterm delivery (Diabet Med. 2017;34[1]:27-36). And while the 2015 BMJ meta-analysis found that metformin was associated with higher rates of preterm birth (RR, 1.50), the increased risk “was all driven by the Rowan study,” Dr. Landon said. The 2015 meta-analysis also found that metformin was associated with less maternal weight gain and fewer infants who were large for gestational age.

Metformin is also tainted by high rates of failure in GDM. In the 2008 Rowan study, 46% of patients on metformin failed to achieve glycemic control. “But this is a classic half-full, half-empty [phenomena],” Dr. Landon said. “Some people say this isn’t good, but on the other hand, 54% avoided insulin.”

Indeed, the Society of Maternal-Fetal Medicine (SMFM), in its 2018 statement on the pharmacologic treatment of GDM, said that oral hypoglycemic agents that are used as monotherapy work in “more than half” of GDM pregnancies. The need for adjunctive insulin to achieve glycemic control ranges between 26% and 46% for women using metformin, and 4% and 16% for women using glyburide, it says.

In the society’s view, recent meta-analyses and systemic reviews “support the efficacy and safety of oral agents,” and “although concerns have been raised for more frequent adverse neonatal outcomes with glyburide, including macrosomia and hypoglycemia, the evidence of benefit of one oral agent over the other remains limited.”

The society says that the difference between its statement and the ACOG recommendations is “based on the values placed by different experts and providers on the available evidence,” and it adds that more long-term data are needed.

But as Dr. Landon said, the SMFM is “a little more forgiving” in its interpretation of a limited body of literature. And clinicians, in the meantime, have to navigate the controversy. “The professional organizations don’t make it easy for [us],” he said. At this point, “insulin does not cross the placenta, and the oral agents do cross it. Informed consent is absolutely necessary when choosing oral agents for treating GDM.”
 

Offspring well-being

Of greater concern than neonatal outcomes are the potential long-term issues for offspring, Dr. Landon said. On the one hand, it is theorized that metformin may protect beta-cell function in offspring and thereby reduce the cross-generational effects of obesity and type 2 diabetes. On the other hand, it is theorized that the drug may cause a decrease in cell-cycle proliferation, which could have “unknown fetal programming effects,” and it may inhibit the mTOR signaling pathway, thus restricting the transport of glucose and amino acids across the placenta, he said. (Findings from in vitro research have suggested that glyburide treatment in GDM might be associated with enhanced transport across the placenta, he noted.)

Long-term follow-up studies of offspring are “clearly needed,” Dr. Landon said. At this point, in regard to long-term safety, he and other experts are concerned primarily about the potential for obesity and metabolic dysfunction in offspring who are exposed to metformin in utero. They are watching follow-up from Dr. Rowan’s MiG trial, as well as elsewhere in the literature, on metformin-exposed offspring from mothers with polycystic ovary syndrome.

A follow-up analysis of offspring from the MiG trial found that children of women with GDM who were exposed to metformin had larger measures of subcutaneous fat at age 2 years, compared with children of mothers treated with insulin alone, but that overall body fat was the same, Dr. Landon noted. The investigators postulated that these children may have less visceral fat and a more favorable pattern of fat distribution (Diab Care. 2011;34:2279-84).

A recently published follow-up analysis of two randomized, controlled trials of women with polycystic ovary syndrome is cause for more concern, he said. That analysis showed that offspring exposed to metformin in utero had a higher body mass index and an increased prevalence of obesity or overweight at age 4 years, compared with placebo groups (J Clin Endocrinol Metab. 2018;103[4]:1612-21).

That analysis of metformin-exposed offspring in the context of polycystic ovary syndrome was published after the SMFM statement, as was another follow-up analysis of MiG trial offspring – this one, at ages 7-9 years – that showed an increase in weight, size, and fat mass in one of two subsets analyzed, despite no difference in large-for-gestational age rates between the metformin- and insulin-exposed offspring (BMJ Open Diabetes Res Care. 2018;6[1]: e000456).

In 2018, a group of 17 prominent diabetes and maternal-fetal medicine researchers cited these findings in a response to the SMFM statement and cautioned against the widespread adoption of metformin use during pregnancy, writing that, based on “both pharmacologic and randomized trial evidence that metformin may create an atypical intrauterine environment ... we believe it is premature to embrace metformin as equivalent to insulin or as superior to glyburide, and that patients should be counseled on the limited long-term safety data and potential for adverse childhood metabolic effects” (Am J Obstet Gynecol. 2018;219[4]:367.e1-7).

WASHINGTON – Research on pravastatin for the prevention of preeclampsia is moving along after “reassuring” data from pilot studies, with a large National Institutes of Health–funded trial currently recruiting women with a prior history of the disorder with preterm delivery at less than 34 weeks, Maged Costantine, MD, said at the biennial Diabetes in Pregnancy Study Group of North America meeting.

Creatas Images

More should be learned about low-dose aspirin, in the meantime, once the outcomes of a global study involving first-trimester initiation are published, said another speaker, Cynthia Gyamfi-Bannerman, MD, MS. Low-dose aspirin currently is recommended for preeclampsia prevention starting between 12 and 28 weeks, optimally before 16 weeks.

The biological plausibility of using pravastatin for preeclampsia prevention stems from the overlapping pathophysiology of preeclampsia with atherosclerotic cardiovascular disease – endothelial dysfunction and inflammation are common key mechanisms – as well as common risk factors, including diabetes and obesity, said Dr. Costantine, director of the division of maternal-fetal medicine at Ohio State University, Columbus, who is chairing the study.

In animal models of preeclampsia, pravastatin has been shown to upregulate placental growth factor, reduce antiangiogenic factors such as soluble fms-like tyrosine kinase 1 (sFlt1), and upregulate endothelial nitric oxide synthase. Mice have shown improved vascular reactivity, decreased proteinuria, decreased oxidative stress, and other positive effects, without any detrimental outcomes.

A pilot randomized controlled trial conducted with the Obstetric-Fetal Pharmacology Research Units Network and published in the American Journal of Obstetrics and Gynecology in 2016 assigned 10 women to 10 mg daily pravastatin and 10 women to placebo. The drug reduced maternal cholesterol concentrations but there were no differences in birth weight or umbilical cord cholesterol concentrations between the two groups.

Women in the pravastatin group were less likely to develop preeclampsia (none, compared with four in the placebo group), less likely to have an indicated preterm delivery (one, compared with five in the placebo group), and less likely to have their neonates admitted to the neonatal ICU.

There were no differences in side effects, congenital anomalies, or other adverse events. Dr. Costantine, principal investigator of the pilot study, and his colleagues wrote in the paper that the “favorable risk-benefit analysis justifies continued research with a dose escalation” (Am J Obstet Gynecol. 2016 Jun;214[6]:720.e1-17).

The new multicenter randomized controlled trial is randomizing 1,550 women to either 20 mg pravastatin or placebo starting between 12 weeks 0 days and 16 weeks 6 days. The primary outcome is a composite of preeclampsia, maternal death, or fetal loss. Secondary outcomes include a composite of severe maternal morbidity and various measures representing preeclampsia severity and complications, as well as preterm delivery less than 37 weeks and less than 34 weeks and various fetal/neonatal outcomes.

“In addition, we’ll look at development,” Dr. Costantine said, with offspring assessed at 2 and 5 years of age. The trial is sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Heart, Lung, and Blood Institute.

In the meantime, he said, the use of pravastatin to ameliorate early-onset preeclampsia is being tested in a small European proof-of-concept trial that has randomized women with early-onset preeclampsia (between 24 and 31 6/7 weeks) to 40 mg pravastatin or placebo. The primary outcome is reduction of antiangiogenic markers. Results are expected in another year or 2, he said.

The aspirin trial referred to by Dr. Gyamfi-Bannerman has been looking at the 81-mg dose of aspirin initiated between 6 0/7 and 13 6/7 weeks in nulliparous women who had no more than two previous pregnancy losses. The key question of the Aspirin Supplementation for Pregnancy Indicated Risk Reduction in Nulliparas (ASPIRIN) trial – conducted in the NICHD Global Network for Women’s and Children’s Health – is whether low-dose aspirin can reduce the rate of preterm birth. Preeclampsia is a secondary outcome (https://clinicaltrials.gov/ct2/show/NCT02409680).

“It may eventually be that the use of baby aspirin is further expanded to reduce the risk of preterm birth,” she said.

Overall, “we need more data on first-trimester use [of low-dose aspirin] and long-term outcomes,” Dr. Gyamfi-Bannerman said. And with respect to preeclampsia prevention specifically, more research is needed looking at risk reduction levels within specific groups of patients.

Since 2014, the U.S. Preventive Services Task Force (USPSTF) has called for low-dose aspirin at 81 mg/day in women who have one or more high-risk factors for preeclampsia (including type 1 or type 2 diabetes mellitus), and consideration of such treatment in patients with several moderate-risk factors. The American College of Obstetricians and Gynecologists’ recommendation varies slightly in that it advises treatment in patients with more than one (versus several) moderate-level risk factors (Obstet Gynecol. 2018;132[1]:e44-52).

Moderate-level risk factors include nulliparity, obesity, family history of preeclampsia, a baseline demographic risk (African-American or low socioeconomic status), and prior poor history (intrauterine growth restriction/small-for-gestational-age, previous poor outcome). “This is just about everyone I see,” Dr. Gyamfi-Bannerman said.

Dr. Gyamfi-Bannerman said she’d “love to see more data on higher doses” of low-dose aspirin – data that compares 81 mg/day with 150 mg/day, for instance.

A study published in 2017 in the New England Journal of Medicine randomized 1,776 women at high risk for preeclampsia to 150 mg/day or placebo and found a significant reduction in preterm preeclampsia (4.3% vs. 1.6%) in the aspirin group. Women in this European trial were deemed to be at high risk, however, based on a first-trimester screening algorithm that incorporated serum markers (maternal serum pregnancy-associated plasma protein A and placental growth factor) and uterine artery Doppler measures (N Engl J Med. 2017 Aug 17;377[7]:613-22).

“So it was a very interesting study, very provocative, but it’s hard to know how it would translate to the U.S. population [given that such screening practices] are not the way most of us are practicing here,” said Dr. Gyamfi-Bannerman, codirector of the Preterm Birth Prevention Center at Columbia University, New York, and professor of obstetrics and gynecology at the university.

The USPSTF based its recommendations on a systematic review that pooled data from 15 high-quality randomized controlled trials, including 13 that reported preeclampsia incidence among women at highest risk of disease. They found a 24% reduction in preeclampsia, but the actual risk reduction depends on the baseline population risk and may be closer to 10%, she said.

In a presentation on gaps in knowledge, Leslie Myatt, PhD, of the department of obstetrics and gynecology at Oregon Health and Science University, Portland, emphasized that preeclampsia is a syndrome with a heterogeneity of presentation and pathophysiology. “We don’t completely understand the pathophysiology,” he said.

Research needs to be “directed at the existence of multiple pathways [and subtypes],” he said, such that future therapies can be targeted and personalized.

Dr. Costantine did not report any disclosures. Dr. Gyamfi-Bannerman reported a Society of Maternal Fetal Medicine/AMAG Pharmaceuticals unrestricted grant and Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Heart, Lung and Blood Institute funding. Dr. Myatt reported that he has no financial or other ties that pose a conflict of interest.

WASHINGTON – Research on pravastatin for the prevention of preeclampsia is moving along after “reassuring” data from pilot studies, with a large National Institutes of Health–funded trial currently recruiting women with a prior history of the disorder with preterm delivery at less than 34 weeks, Maged Costantine, MD, said at the biennial Diabetes in Pregnancy Study Group of North America meeting.

Creatas Images

More should be learned about low-dose aspirin, in the meantime, once the outcomes of a global study involving first-trimester initiation are published, said another speaker, Cynthia Gyamfi-Bannerman, MD, MS. Low-dose aspirin currently is recommended for preeclampsia prevention starting between 12 and 28 weeks, optimally before 16 weeks.

The biological plausibility of using pravastatin for preeclampsia prevention stems from the overlapping pathophysiology of preeclampsia with atherosclerotic cardiovascular disease – endothelial dysfunction and inflammation are common key mechanisms – as well as common risk factors, including diabetes and obesity, said Dr. Costantine, director of the division of maternal-fetal medicine at Ohio State University, Columbus, who is chairing the study.

In animal models of preeclampsia, pravastatin has been shown to upregulate placental growth factor, reduce antiangiogenic factors such as soluble fms-like tyrosine kinase 1 (sFlt1), and upregulate endothelial nitric oxide synthase. Mice have shown improved vascular reactivity, decreased proteinuria, decreased oxidative stress, and other positive effects, without any detrimental outcomes.

A pilot randomized controlled trial conducted with the Obstetric-Fetal Pharmacology Research Units Network and published in the American Journal of Obstetrics and Gynecology in 2016 assigned 10 women to 10 mg daily pravastatin and 10 women to placebo. The drug reduced maternal cholesterol concentrations but there were no differences in birth weight or umbilical cord cholesterol concentrations between the two groups.

Women in the pravastatin group were less likely to develop preeclampsia (none, compared with four in the placebo group), less likely to have an indicated preterm delivery (one, compared with five in the placebo group), and less likely to have their neonates admitted to the neonatal ICU.

There were no differences in side effects, congenital anomalies, or other adverse events. Dr. Costantine, principal investigator of the pilot study, and his colleagues wrote in the paper that the “favorable risk-benefit analysis justifies continued research with a dose escalation” (Am J Obstet Gynecol. 2016 Jun;214[6]:720.e1-17).

The new multicenter randomized controlled trial is randomizing 1,550 women to either 20 mg pravastatin or placebo starting between 12 weeks 0 days and 16 weeks 6 days. The primary outcome is a composite of preeclampsia, maternal death, or fetal loss. Secondary outcomes include a composite of severe maternal morbidity and various measures representing preeclampsia severity and complications, as well as preterm delivery less than 37 weeks and less than 34 weeks and various fetal/neonatal outcomes.

“In addition, we’ll look at development,” Dr. Costantine said, with offspring assessed at 2 and 5 years of age. The trial is sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Heart, Lung, and Blood Institute.

In the meantime, he said, the use of pravastatin to ameliorate early-onset preeclampsia is being tested in a small European proof-of-concept trial that has randomized women with early-onset preeclampsia (between 24 and 31 6/7 weeks) to 40 mg pravastatin or placebo. The primary outcome is reduction of antiangiogenic markers. Results are expected in another year or 2, he said.

The aspirin trial referred to by Dr. Gyamfi-Bannerman has been looking at the 81-mg dose of aspirin initiated between 6 0/7 and 13 6/7 weeks in nulliparous women who had no more than two previous pregnancy losses. The key question of the Aspirin Supplementation for Pregnancy Indicated Risk Reduction in Nulliparas (ASPIRIN) trial – conducted in the NICHD Global Network for Women’s and Children’s Health – is whether low-dose aspirin can reduce the rate of preterm birth. Preeclampsia is a secondary outcome (https://clinicaltrials.gov/ct2/show/NCT02409680).

“It may eventually be that the use of baby aspirin is further expanded to reduce the risk of preterm birth,” she said.

Overall, “we need more data on first-trimester use [of low-dose aspirin] and long-term outcomes,” Dr. Gyamfi-Bannerman said. And with respect to preeclampsia prevention specifically, more research is needed looking at risk reduction levels within specific groups of patients.

Since 2014, the U.S. Preventive Services Task Force (USPSTF) has called for low-dose aspirin at 81 mg/day in women who have one or more high-risk factors for preeclampsia (including type 1 or type 2 diabetes mellitus), and consideration of such treatment in patients with several moderate-risk factors. The American College of Obstetricians and Gynecologists’ recommendation varies slightly in that it advises treatment in patients with more than one (versus several) moderate-level risk factors (Obstet Gynecol. 2018;132[1]:e44-52).

Moderate-level risk factors include nulliparity, obesity, family history of preeclampsia, a baseline demographic risk (African-American or low socioeconomic status), and prior poor history (intrauterine growth restriction/small-for-gestational-age, previous poor outcome). “This is just about everyone I see,” Dr. Gyamfi-Bannerman said.

Dr. Gyamfi-Bannerman said she’d “love to see more data on higher doses” of low-dose aspirin – data that compares 81 mg/day with 150 mg/day, for instance.

A study published in 2017 in the New England Journal of Medicine randomized 1,776 women at high risk for preeclampsia to 150 mg/day or placebo and found a significant reduction in preterm preeclampsia (4.3% vs. 1.6%) in the aspirin group. Women in this European trial were deemed to be at high risk, however, based on a first-trimester screening algorithm that incorporated serum markers (maternal serum pregnancy-associated plasma protein A and placental growth factor) and uterine artery Doppler measures (N Engl J Med. 2017 Aug 17;377[7]:613-22).

“So it was a very interesting study, very provocative, but it’s hard to know how it would translate to the U.S. population [given that such screening practices] are not the way most of us are practicing here,” said Dr. Gyamfi-Bannerman, codirector of the Preterm Birth Prevention Center at Columbia University, New York, and professor of obstetrics and gynecology at the university.

The USPSTF based its recommendations on a systematic review that pooled data from 15 high-quality randomized controlled trials, including 13 that reported preeclampsia incidence among women at highest risk of disease. They found a 24% reduction in preeclampsia, but the actual risk reduction depends on the baseline population risk and may be closer to 10%, she said.

In a presentation on gaps in knowledge, Leslie Myatt, PhD, of the department of obstetrics and gynecology at Oregon Health and Science University, Portland, emphasized that preeclampsia is a syndrome with a heterogeneity of presentation and pathophysiology. “We don’t completely understand the pathophysiology,” he said.

Research needs to be “directed at the existence of multiple pathways [and subtypes],” he said, such that future therapies can be targeted and personalized.

Dr. Costantine did not report any disclosures. Dr. Gyamfi-Bannerman reported a Society of Maternal Fetal Medicine/AMAG Pharmaceuticals unrestricted grant and Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Heart, Lung and Blood Institute funding. Dr. Myatt reported that he has no financial or other ties that pose a conflict of interest.

WASHINGTON – Research on pravastatin for the prevention of preeclampsia is moving along after “reassuring” data from pilot studies, with a large National Institutes of Health–funded trial currently recruiting women with a prior history of the disorder with preterm delivery at less than 34 weeks, Maged Costantine, MD, said at the biennial Diabetes in Pregnancy Study Group of North America meeting.

Creatas Images

More should be learned about low-dose aspirin, in the meantime, once the outcomes of a global study involving first-trimester initiation are published, said another speaker, Cynthia Gyamfi-Bannerman, MD, MS. Low-dose aspirin currently is recommended for preeclampsia prevention starting between 12 and 28 weeks, optimally before 16 weeks.

The biological plausibility of using pravastatin for preeclampsia prevention stems from the overlapping pathophysiology of preeclampsia with atherosclerotic cardiovascular disease – endothelial dysfunction and inflammation are common key mechanisms – as well as common risk factors, including diabetes and obesity, said Dr. Costantine, director of the division of maternal-fetal medicine at Ohio State University, Columbus, who is chairing the study.

In animal models of preeclampsia, pravastatin has been shown to upregulate placental growth factor, reduce antiangiogenic factors such as soluble fms-like tyrosine kinase 1 (sFlt1), and upregulate endothelial nitric oxide synthase. Mice have shown improved vascular reactivity, decreased proteinuria, decreased oxidative stress, and other positive effects, without any detrimental outcomes.

A pilot randomized controlled trial conducted with the Obstetric-Fetal Pharmacology Research Units Network and published in the American Journal of Obstetrics and Gynecology in 2016 assigned 10 women to 10 mg daily pravastatin and 10 women to placebo. The drug reduced maternal cholesterol concentrations but there were no differences in birth weight or umbilical cord cholesterol concentrations between the two groups.

Women in the pravastatin group were less likely to develop preeclampsia (none, compared with four in the placebo group), less likely to have an indicated preterm delivery (one, compared with five in the placebo group), and less likely to have their neonates admitted to the neonatal ICU.

There were no differences in side effects, congenital anomalies, or other adverse events. Dr. Costantine, principal investigator of the pilot study, and his colleagues wrote in the paper that the “favorable risk-benefit analysis justifies continued research with a dose escalation” (Am J Obstet Gynecol. 2016 Jun;214[6]:720.e1-17).

The new multicenter randomized controlled trial is randomizing 1,550 women to either 20 mg pravastatin or placebo starting between 12 weeks 0 days and 16 weeks 6 days. The primary outcome is a composite of preeclampsia, maternal death, or fetal loss. Secondary outcomes include a composite of severe maternal morbidity and various measures representing preeclampsia severity and complications, as well as preterm delivery less than 37 weeks and less than 34 weeks and various fetal/neonatal outcomes.

“In addition, we’ll look at development,” Dr. Costantine said, with offspring assessed at 2 and 5 years of age. The trial is sponsored by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Heart, Lung, and Blood Institute.

In the meantime, he said, the use of pravastatin to ameliorate early-onset preeclampsia is being tested in a small European proof-of-concept trial that has randomized women with early-onset preeclampsia (between 24 and 31 6/7 weeks) to 40 mg pravastatin or placebo. The primary outcome is reduction of antiangiogenic markers. Results are expected in another year or 2, he said.

The aspirin trial referred to by Dr. Gyamfi-Bannerman has been looking at the 81-mg dose of aspirin initiated between 6 0/7 and 13 6/7 weeks in nulliparous women who had no more than two previous pregnancy losses. The key question of the Aspirin Supplementation for Pregnancy Indicated Risk Reduction in Nulliparas (ASPIRIN) trial – conducted in the NICHD Global Network for Women’s and Children’s Health – is whether low-dose aspirin can reduce the rate of preterm birth. Preeclampsia is a secondary outcome (https://clinicaltrials.gov/ct2/show/NCT02409680).

“It may eventually be that the use of baby aspirin is further expanded to reduce the risk of preterm birth,” she said.

Overall, “we need more data on first-trimester use [of low-dose aspirin] and long-term outcomes,” Dr. Gyamfi-Bannerman said. And with respect to preeclampsia prevention specifically, more research is needed looking at risk reduction levels within specific groups of patients.

Since 2014, the U.S. Preventive Services Task Force (USPSTF) has called for low-dose aspirin at 81 mg/day in women who have one or more high-risk factors for preeclampsia (including type 1 or type 2 diabetes mellitus), and consideration of such treatment in patients with several moderate-risk factors. The American College of Obstetricians and Gynecologists’ recommendation varies slightly in that it advises treatment in patients with more than one (versus several) moderate-level risk factors (Obstet Gynecol. 2018;132[1]:e44-52).

Moderate-level risk factors include nulliparity, obesity, family history of preeclampsia, a baseline demographic risk (African-American or low socioeconomic status), and prior poor history (intrauterine growth restriction/small-for-gestational-age, previous poor outcome). “This is just about everyone I see,” Dr. Gyamfi-Bannerman said.

Dr. Gyamfi-Bannerman said she’d “love to see more data on higher doses” of low-dose aspirin – data that compares 81 mg/day with 150 mg/day, for instance.

A study published in 2017 in the New England Journal of Medicine randomized 1,776 women at high risk for preeclampsia to 150 mg/day or placebo and found a significant reduction in preterm preeclampsia (4.3% vs. 1.6%) in the aspirin group. Women in this European trial were deemed to be at high risk, however, based on a first-trimester screening algorithm that incorporated serum markers (maternal serum pregnancy-associated plasma protein A and placental growth factor) and uterine artery Doppler measures (N Engl J Med. 2017 Aug 17;377[7]:613-22).

“So it was a very interesting study, very provocative, but it’s hard to know how it would translate to the U.S. population [given that such screening practices] are not the way most of us are practicing here,” said Dr. Gyamfi-Bannerman, codirector of the Preterm Birth Prevention Center at Columbia University, New York, and professor of obstetrics and gynecology at the university.

The USPSTF based its recommendations on a systematic review that pooled data from 15 high-quality randomized controlled trials, including 13 that reported preeclampsia incidence among women at highest risk of disease. They found a 24% reduction in preeclampsia, but the actual risk reduction depends on the baseline population risk and may be closer to 10%, she said.

In a presentation on gaps in knowledge, Leslie Myatt, PhD, of the department of obstetrics and gynecology at Oregon Health and Science University, Portland, emphasized that preeclampsia is a syndrome with a heterogeneity of presentation and pathophysiology. “We don’t completely understand the pathophysiology,” he said.

Research needs to be “directed at the existence of multiple pathways [and subtypes],” he said, such that future therapies can be targeted and personalized.

Dr. Costantine did not report any disclosures. Dr. Gyamfi-Bannerman reported a Society of Maternal Fetal Medicine/AMAG Pharmaceuticals unrestricted grant and Eunice Kennedy Shriver National Institute of Child Health and Human Development/National Heart, Lung and Blood Institute funding. Dr. Myatt reported that he has no financial or other ties that pose a conflict of interest.

WASHINGTON – Insulin is the preferred agent for type 2 diabetes in pregnant women, yet about a third of pregnancies still have an adverse outcome, according Kim Boggess, MD, who spoke at the biennial meeting of the Diabetes in Pregnancy Study Group of North America.

“We are not where we need to be,” said Dr. Boggess, who is leading a trial that brings metformin, the first-line agent for type 2 diabetes outside of pregnancy, back into the picture for pregnant women – as an add-on to insulin.

It is an interesting twist, because pregnant women taking metformin for preexisting type 2 or gestational diabetes have been shown in some studies to require supplemental insulin, more than occasionally, to achieve target glycemic control.

This was the case in a small, randomized, controlled trial at Dr. Boggess’ institution, the University of North Carolina at Chapel Hill, in which 43% of pregnant women with type 2 diabetes who were assigned to metformin required supplemental insulin (Am J Perinatol. 2013;30[6]:483-90). The study also found, however, that women treated with metformin had significantly fewer episodes of hypoglycemia, compared with women using insulin (0% vs. 36%, respectively) and fewer reports of glucose values less than 60 mg/dL (7.1% vs. 50%).

“I don’t consider this [need for supplemental insulin] ‘metformin failure,’ because studies that use metformin as monotherapy and that [show some patients] ultimately requiring insulin support ... also show that these women need less insulin,” she said. “What’s the risk of insulin alone? Hypoglycemia. So using less insulin could be a good thing.”

Other research suggests there may be less maternal weight gain, less neonatal hypoglycemia, fewer neonatal complications, and improved maternal glycemic control in patients treated with metformin, alone or with add-on insulin, than with insulin alone. “We’re starting to get a sense in the literature that, at least in the [pregnant] population with type 2 diabetes, there may be a role for metformin,” said Dr. Boggess, professor and program director for maternal-fetal medicine at the university.

* This article was updated 1/2/2020.

WASHINGTON – Insulin is the preferred agent for type 2 diabetes in pregnant women, yet about a third of pregnancies still have an adverse outcome, according Kim Boggess, MD, who spoke at the biennial meeting of the Diabetes in Pregnancy Study Group of North America.

“We are not where we need to be,” said Dr. Boggess, who is leading a trial that brings metformin, the first-line agent for type 2 diabetes outside of pregnancy, back into the picture for pregnant women – as an add-on to insulin.

It is an interesting twist, because pregnant women taking metformin for preexisting type 2 or gestational diabetes have been shown in some studies to require supplemental insulin, more than occasionally, to achieve target glycemic control.

This was the case in a small, randomized, controlled trial at Dr. Boggess’ institution, the University of North Carolina at Chapel Hill, in which 43% of pregnant women with type 2 diabetes who were assigned to metformin required supplemental insulin (Am J Perinatol. 2013;30[6]:483-90). The study also found, however, that women treated with metformin had significantly fewer episodes of hypoglycemia, compared with women using insulin (0% vs. 36%, respectively) and fewer reports of glucose values less than 60 mg/dL (7.1% vs. 50%).

“I don’t consider this [need for supplemental insulin] ‘metformin failure,’ because studies that use metformin as monotherapy and that [show some patients] ultimately requiring insulin support ... also show that these women need less insulin,” she said. “What’s the risk of insulin alone? Hypoglycemia. So using less insulin could be a good thing.”

Other research suggests there may be less maternal weight gain, less neonatal hypoglycemia, fewer neonatal complications, and improved maternal glycemic control in patients treated with metformin, alone or with add-on insulin, than with insulin alone. “We’re starting to get a sense in the literature that, at least in the [pregnant] population with type 2 diabetes, there may be a role for metformin,” said Dr. Boggess, professor and program director for maternal-fetal medicine at the university.

* This article was updated 1/2/2020.

WASHINGTON – Insulin is the preferred agent for type 2 diabetes in pregnant women, yet about a third of pregnancies still have an adverse outcome, according Kim Boggess, MD, who spoke at the biennial meeting of the Diabetes in Pregnancy Study Group of North America.

“We are not where we need to be,” said Dr. Boggess, who is leading a trial that brings metformin, the first-line agent for type 2 diabetes outside of pregnancy, back into the picture for pregnant women – as an add-on to insulin.

It is an interesting twist, because pregnant women taking metformin for preexisting type 2 or gestational diabetes have been shown in some studies to require supplemental insulin, more than occasionally, to achieve target glycemic control.

This was the case in a small, randomized, controlled trial at Dr. Boggess’ institution, the University of North Carolina at Chapel Hill, in which 43% of pregnant women with type 2 diabetes who were assigned to metformin required supplemental insulin (Am J Perinatol. 2013;30[6]:483-90). The study also found, however, that women treated with metformin had significantly fewer episodes of hypoglycemia, compared with women using insulin (0% vs. 36%, respectively) and fewer reports of glucose values less than 60 mg/dL (7.1% vs. 50%).

“I don’t consider this [need for supplemental insulin] ‘metformin failure,’ because studies that use metformin as monotherapy and that [show some patients] ultimately requiring insulin support ... also show that these women need less insulin,” she said. “What’s the risk of insulin alone? Hypoglycemia. So using less insulin could be a good thing.”

Other research suggests there may be less maternal weight gain, less neonatal hypoglycemia, fewer neonatal complications, and improved maternal glycemic control in patients treated with metformin, alone or with add-on insulin, than with insulin alone. “We’re starting to get a sense in the literature that, at least in the [pregnant] population with type 2 diabetes, there may be a role for metformin,” said Dr. Boggess, professor and program director for maternal-fetal medicine at the university.

* This article was updated 1/2/2020.

WASHINGTON – Metformin’s role in preventing or delaying the onset of type 2 diabetes in women with a history of gestational diabetes mellitus has been firmly established by the Diabetes Prevention Program (DPP) trial – most recently, by 15-year follow-up data reported this year – and the drug should be front and center for clinicians who hope to stave off the “remarkable” incidence of type 2 diabetes after GDM, Robert E. Ratner, MD, maintained at the biennial meeting of the Diabetes in Pregnancy Study Group of North America.

The DPP included “the single largest population of women with a history of GDM that’s been looked at in a randomized controlled trial,” and considering its multiethnic population, the trial offers a reliable representative sample to ponder today when evaluating long-term use of metformin after GDM, said Dr. Ratner, a principal investigator of the National Institutes of Health–sponsored DPP and the DPP Outcomes Study and a former chief scientific & medical officer for the American Diabetes Association.

The drug stacked up equally to lifestyle interventions among DPP participants who had a history of GDM, but it’s important to appreciate that these interventions were intensive and that metformin is inexpensive, well tolerated, and “has a long safety record,” he said.
 

Results of follow-up out to 15 years

Of the more than 3,000 men and women enrolled in the landmark DPP, conducted during 1996-2001, 350 were women with a documented history of GDM and over 1,400 were women who had deliveries but no history of GDM. All participants had impaired glucose tolerance – defined for the trial as having both a fasting plasma glucose value of 95-125 mg/dL and a 2-hour value of 140-199 mg/dL after a 75-g glucose load – and were randomized to placebo, metformin, or intensive lifestyle intervention.

Metformin therapy reduced the incidence of diabetes by approximately 50% in women with a history of GDM, compared with the placebo group – as did lifestyle – over 3 years. The number needed to treat to prevent one case of diabetes was five. Women without a history of GDM, on the other hand, saw only a 14% reduction with metformin when compared with placebo (and a 49% reduction with lifestyle).

“In women with a history of GDM ... one pill twice a day for $4 a month worked as well as intensive lifestyle [change],” Dr. Ratner said, referring to the initial GDM-specific analysis of DPP data published in 2008 (J Clin Endocrinol Metab. 2008;93[12]:4774-9).

In a 10-year postrandomization follow-up, published in 2015, both metformin and lifestyle continued to be equally effective for the GDM group, reducing the progression to diabetes by 40% and 35%, respectively (J Clin Endocrinol Metab. 2015;100:1646-53). The number needed to treat to prevent one case of diabetes was seven. (Among women without a history of GDM, metformin did not reduce progression to diabetes.)

A recent DPP Outcomes Study analysis of metformin’s impact on diabetes prevention at 15 years, moreover, showed a 41% risk reduction among women with a history of GDM (Diabetes Care. 2019;42[4]:601-8).
 

Advice on prescribing metformin prophylactically

Asked after his presentation whether women with a history of GDM and either an elevated fasting plasma glucose value or an elevated 2-hour oral glucose tolerance test (GTT) value – or neither of the two – would benefit from taking metformin, Dr. Ratner said that “we’re stuck with inclusion criteria of the DPP, in which they had to meet both criteria ... What I’d say, though, is that not everyone with a history of GDM needs to be on metformin prophylactically. But [for women who have] prediabetes as defined by the ADA, the cost-benefit analysis points toward metformin.”

And with respect to early initiation and long-term use of the drug, “I would have absolutely no qualms about medicating a 25-year-old who had developed GDM and who in the postpartum period has prediabetes,” Dr. Ratner said during an open discussion. “She’s actually at the highest risk for developing type 2 very early.”

Kim Boggess, MD, who also presented on long-term use of metformin after GDM, said in the discussion period that she is often quick to recommend metformin therapy to her patients who have an elevated fasting plasma glucose value in the postpartum period, even when a 75-g oral GTT has not yet been performed. (The ADA and the American College of Obstetricians and Gynecologists recommend completion of an oral GTT at 4-12 weeks postpartum after GDM.)

“I start them [on metformin] especially if they’ve had a cesarean section. Even 2, 3, 4 weeks of profound hyperglycemia could have potentially deleterious effects,” said Dr. Boggess, professor and maternal-fetal medicine program director at the University of North Carolina, Chapel Hill. “If someone comes in [shortly after] and looks like they have pristine control, then it might be worth stopping the metformin for 3-5 days (and retesting).”

Dr. Ratner said that, in this clinical scenario, he would first ensure that the fasting glucose value “is a true fasting glucose” and “if it’s substantially elevated – I’m talking 100, 105, 110 mg/dL – I’d start metformin, and I’m not even sure I’d do the GTT.” But, he advised, “if you’re going to do the GTT, I’d stop the metformin the day before.”

In her presentation, Dr. Boggess pointed out that metformin wasn’t shown to be superior to lifestyle interventions in the DPP for preventing progression to type 2 DM, and that some women are more motivated for intensive lifestyle change than others. The ADA recommends, in fact, that either metformin or lifestyle interventions be prescribed to women with a history of GDM who are found to have prediabetes.

What is needed, Dr. Boggess said, are more data on the effects of metformin on cardiovascular disease risk, as well as larger studies of metformin in the postpartum period “to help us determine the best dose.” Some research on metformin use in the postpartum period has reported gastrointestinal side effects and dissatisfaction, she noted.

Dr. Ratner said that metformin’s main drawback is the need for occasional testing of B₁₂ levels. Regarding weight loss and what was observed in the DPP, he said, women with a history of GDM who were randomized to intensive lifestyle interventions did not lose as much weight as women without a history of GDM.

Women who entered the DPP with a GDM history, he noted in his presentation, were essentially a “cohort of survivors.” They had an average age of 43 (compared with 52 years in the parous women without GDM) and a mean interval from the index GDM pregnancy of 11 years, which means that women with the highest risk of diabetes conversion were excluded, Dr. Ratner said.

Age was the only significantly different baseline characteristic between parous women with and without GDM, he noted. Women with a history of GDM who were randomized to placebo had a 71% higher incidence of diabetes than women without such a history – a striking natural history, Dr. Ratner said.

He and Dr. Boggess each reported that they have no financial or other interests that pose a conflict of interest.

WASHINGTON – Metformin’s role in preventing or delaying the onset of type 2 diabetes in women with a history of gestational diabetes mellitus has been firmly established by the Diabetes Prevention Program (DPP) trial – most recently, by 15-year follow-up data reported this year – and the drug should be front and center for clinicians who hope to stave off the “remarkable” incidence of type 2 diabetes after GDM, Robert E. Ratner, MD, maintained at the biennial meeting of the Diabetes in Pregnancy Study Group of North America.

The DPP included “the single largest population of women with a history of GDM that’s been looked at in a randomized controlled trial,” and considering its multiethnic population, the trial offers a reliable representative sample to ponder today when evaluating long-term use of metformin after GDM, said Dr. Ratner, a principal investigator of the National Institutes of Health–sponsored DPP and the DPP Outcomes Study and a former chief scientific & medical officer for the American Diabetes Association.

The drug stacked up equally to lifestyle interventions among DPP participants who had a history of GDM, but it’s important to appreciate that these interventions were intensive and that metformin is inexpensive, well tolerated, and “has a long safety record,” he said.
 

Results of follow-up out to 15 years

Of the more than 3,000 men and women enrolled in the landmark DPP, conducted during 1996-2001, 350 were women with a documented history of GDM and over 1,400 were women who had deliveries but no history of GDM. All participants had impaired glucose tolerance – defined for the trial as having both a fasting plasma glucose value of 95-125 mg/dL and a 2-hour value of 140-199 mg/dL after a 75-g glucose load – and were randomized to placebo, metformin, or intensive lifestyle intervention.

Metformin therapy reduced the incidence of diabetes by approximately 50% in women with a history of GDM, compared with the placebo group – as did lifestyle – over 3 years. The number needed to treat to prevent one case of diabetes was five. Women without a history of GDM, on the other hand, saw only a 14% reduction with metformin when compared with placebo (and a 49% reduction with lifestyle).

“In women with a history of GDM ... one pill twice a day for $4 a month worked as well as intensive lifestyle [change],” Dr. Ratner said, referring to the initial GDM-specific analysis of DPP data published in 2008 (J Clin Endocrinol Metab. 2008;93[12]:4774-9).

In a 10-year postrandomization follow-up, published in 2015, both metformin and lifestyle continued to be equally effective for the GDM group, reducing the progression to diabetes by 40% and 35%, respectively (J Clin Endocrinol Metab. 2015;100:1646-53). The number needed to treat to prevent one case of diabetes was seven. (Among women without a history of GDM, metformin did not reduce progression to diabetes.)

A recent DPP Outcomes Study analysis of metformin’s impact on diabetes prevention at 15 years, moreover, showed a 41% risk reduction among women with a history of GDM (Diabetes Care. 2019;42[4]:601-8).
 

Advice on prescribing metformin prophylactically

Asked after his presentation whether women with a history of GDM and either an elevated fasting plasma glucose value or an elevated 2-hour oral glucose tolerance test (GTT) value – or neither of the two – would benefit from taking metformin, Dr. Ratner said that “we’re stuck with inclusion criteria of the DPP, in which they had to meet both criteria ... What I’d say, though, is that not everyone with a history of GDM needs to be on metformin prophylactically. But [for women who have] prediabetes as defined by the ADA, the cost-benefit analysis points toward metformin.”

And with respect to early initiation and long-term use of the drug, “I would have absolutely no qualms about medicating a 25-year-old who had developed GDM and who in the postpartum period has prediabetes,” Dr. Ratner said during an open discussion. “She’s actually at the highest risk for developing type 2 very early.”

Kim Boggess, MD, who also presented on long-term use of metformin after GDM, said in the discussion period that she is often quick to recommend metformin therapy to her patients who have an elevated fasting plasma glucose value in the postpartum period, even when a 75-g oral GTT has not yet been performed. (The ADA and the American College of Obstetricians and Gynecologists recommend completion of an oral GTT at 4-12 weeks postpartum after GDM.)

“I start them [on metformin] especially if they’ve had a cesarean section. Even 2, 3, 4 weeks of profound hyperglycemia could have potentially deleterious effects,” said Dr. Boggess, professor and maternal-fetal medicine program director at the University of North Carolina, Chapel Hill. “If someone comes in [shortly after] and looks like they have pristine control, then it might be worth stopping the metformin for 3-5 days (and retesting).”

Dr. Ratner said that, in this clinical scenario, he would first ensure that the fasting glucose value “is a true fasting glucose” and “if it’s substantially elevated – I’m talking 100, 105, 110 mg/dL – I’d start metformin, and I’m not even sure I’d do the GTT.” But, he advised, “if you’re going to do the GTT, I’d stop the metformin the day before.”

In her presentation, Dr. Boggess pointed out that metformin wasn’t shown to be superior to lifestyle interventions in the DPP for preventing progression to type 2 DM, and that some women are more motivated for intensive lifestyle change than others. The ADA recommends, in fact, that either metformin or lifestyle interventions be prescribed to women with a history of GDM who are found to have prediabetes.

What is needed, Dr. Boggess said, are more data on the effects of metformin on cardiovascular disease risk, as well as larger studies of metformin in the postpartum period “to help us determine the best dose.” Some research on metformin use in the postpartum period has reported gastrointestinal side effects and dissatisfaction, she noted.

Dr. Ratner said that metformin’s main drawback is the need for occasional testing of B₁₂ levels. Regarding weight loss and what was observed in the DPP, he said, women with a history of GDM who were randomized to intensive lifestyle interventions did not lose as much weight as women without a history of GDM.

Women who entered the DPP with a GDM history, he noted in his presentation, were essentially a “cohort of survivors.” They had an average age of 43 (compared with 52 years in the parous women without GDM) and a mean interval from the index GDM pregnancy of 11 years, which means that women with the highest risk of diabetes conversion were excluded, Dr. Ratner said.

Age was the only significantly different baseline characteristic between parous women with and without GDM, he noted. Women with a history of GDM who were randomized to placebo had a 71% higher incidence of diabetes than women without such a history – a striking natural history, Dr. Ratner said.

He and Dr. Boggess each reported that they have no financial or other interests that pose a conflict of interest.

WASHINGTON – Metformin’s role in preventing or delaying the onset of type 2 diabetes in women with a history of gestational diabetes mellitus has been firmly established by the Diabetes Prevention Program (DPP) trial – most recently, by 15-year follow-up data reported this year – and the drug should be front and center for clinicians who hope to stave off the “remarkable” incidence of type 2 diabetes after GDM, Robert E. Ratner, MD, maintained at the biennial meeting of the Diabetes in Pregnancy Study Group of North America.

The DPP included “the single largest population of women with a history of GDM that’s been looked at in a randomized controlled trial,” and considering its multiethnic population, the trial offers a reliable representative sample to ponder today when evaluating long-term use of metformin after GDM, said Dr. Ratner, a principal investigator of the National Institutes of Health–sponsored DPP and the DPP Outcomes Study and a former chief scientific & medical officer for the American Diabetes Association.

The drug stacked up equally to lifestyle interventions among DPP participants who had a history of GDM, but it’s important to appreciate that these interventions were intensive and that metformin is inexpensive, well tolerated, and “has a long safety record,” he said.
 

Results of follow-up out to 15 years

Of the more than 3,000 men and women enrolled in the landmark DPP, conducted during 1996-2001, 350 were women with a documented history of GDM and over 1,400 were women who had deliveries but no history of GDM. All participants had impaired glucose tolerance – defined for the trial as having both a fasting plasma glucose value of 95-125 mg/dL and a 2-hour value of 140-199 mg/dL after a 75-g glucose load – and were randomized to placebo, metformin, or intensive lifestyle intervention.

Metformin therapy reduced the incidence of diabetes by approximately 50% in women with a history of GDM, compared with the placebo group – as did lifestyle – over 3 years. The number needed to treat to prevent one case of diabetes was five. Women without a history of GDM, on the other hand, saw only a 14% reduction with metformin when compared with placebo (and a 49% reduction with lifestyle).

“In women with a history of GDM ... one pill twice a day for $4 a month worked as well as intensive lifestyle [change],” Dr. Ratner said, referring to the initial GDM-specific analysis of DPP data published in 2008 (J Clin Endocrinol Metab. 2008;93[12]:4774-9).

In a 10-year postrandomization follow-up, published in 2015, both metformin and lifestyle continued to be equally effective for the GDM group, reducing the progression to diabetes by 40% and 35%, respectively (J Clin Endocrinol Metab. 2015;100:1646-53). The number needed to treat to prevent one case of diabetes was seven. (Among women without a history of GDM, metformin did not reduce progression to diabetes.)

A recent DPP Outcomes Study analysis of metformin’s impact on diabetes prevention at 15 years, moreover, showed a 41% risk reduction among women with a history of GDM (Diabetes Care. 2019;42[4]:601-8).
 

Advice on prescribing metformin prophylactically

Asked after his presentation whether women with a history of GDM and either an elevated fasting plasma glucose value or an elevated 2-hour oral glucose tolerance test (GTT) value – or neither of the two – would benefit from taking metformin, Dr. Ratner said that “we’re stuck with inclusion criteria of the DPP, in which they had to meet both criteria ... What I’d say, though, is that not everyone with a history of GDM needs to be on metformin prophylactically. But [for women who have] prediabetes as defined by the ADA, the cost-benefit analysis points toward metformin.”

And with respect to early initiation and long-term use of the drug, “I would have absolutely no qualms about medicating a 25-year-old who had developed GDM and who in the postpartum period has prediabetes,” Dr. Ratner said during an open discussion. “She’s actually at the highest risk for developing type 2 very early.”

Kim Boggess, MD, who also presented on long-term use of metformin after GDM, said in the discussion period that she is often quick to recommend metformin therapy to her patients who have an elevated fasting plasma glucose value in the postpartum period, even when a 75-g oral GTT has not yet been performed. (The ADA and the American College of Obstetricians and Gynecologists recommend completion of an oral GTT at 4-12 weeks postpartum after GDM.)

“I start them [on metformin] especially if they’ve had a cesarean section. Even 2, 3, 4 weeks of profound hyperglycemia could have potentially deleterious effects,” said Dr. Boggess, professor and maternal-fetal medicine program director at the University of North Carolina, Chapel Hill. “If someone comes in [shortly after] and looks like they have pristine control, then it might be worth stopping the metformin for 3-5 days (and retesting).”

Dr. Ratner said that, in this clinical scenario, he would first ensure that the fasting glucose value “is a true fasting glucose” and “if it’s substantially elevated – I’m talking 100, 105, 110 mg/dL – I’d start metformin, and I’m not even sure I’d do the GTT.” But, he advised, “if you’re going to do the GTT, I’d stop the metformin the day before.”

In her presentation, Dr. Boggess pointed out that metformin wasn’t shown to be superior to lifestyle interventions in the DPP for preventing progression to type 2 DM, and that some women are more motivated for intensive lifestyle change than others. The ADA recommends, in fact, that either metformin or lifestyle interventions be prescribed to women with a history of GDM who are found to have prediabetes.

What is needed, Dr. Boggess said, are more data on the effects of metformin on cardiovascular disease risk, as well as larger studies of metformin in the postpartum period “to help us determine the best dose.” Some research on metformin use in the postpartum period has reported gastrointestinal side effects and dissatisfaction, she noted.

Dr. Ratner said that metformin’s main drawback is the need for occasional testing of B₁₂ levels. Regarding weight loss and what was observed in the DPP, he said, women with a history of GDM who were randomized to intensive lifestyle interventions did not lose as much weight as women without a history of GDM.

Women who entered the DPP with a GDM history, he noted in his presentation, were essentially a “cohort of survivors.” They had an average age of 43 (compared with 52 years in the parous women without GDM) and a mean interval from the index GDM pregnancy of 11 years, which means that women with the highest risk of diabetes conversion were excluded, Dr. Ratner said.

Age was the only significantly different baseline characteristic between parous women with and without GDM, he noted. Women with a history of GDM who were randomized to placebo had a 71% higher incidence of diabetes than women without such a history – a striking natural history, Dr. Ratner said.

He and Dr. Boggess each reported that they have no financial or other interests that pose a conflict of interest.

WASHINGTON – Cardiovascular risk factors may be elevated “as soon as the first postpartum year” in women who have gestational diabetes or hypertensive disorders of pregnancy, recent findings have affirmed, Deborah B. Ehrenthal, MD, MPH, said at the biennial meeting of the Diabetes in Pregnancy Study Group of North America.

FatCamera/E+/Getty Images

Dr. Ehrenthal was one of several researchers who urged innovative strategies and improved care coordination to boost women’s follow-up after gestational diabetes mellitus (GDM) and other adverse pregnancy outcomes and complications. “The metabolic stress of pregnancy can uncover underlying susceptibilities,” she said. “And adverse pregnancy outcomes can have long-lasting residual effects.”

Evidence that adverse pregnancy outcomes – including GDM and hypertensive disorders of pregnancy (HDP) – can elevate cardiovascular risk comes most recently from the Nulliparous Pregnancy Outcomes Study – Monitoring Mothers to be Heart Health Study (nuMoM2b–HHS study), a prospective observational cohort that followed 4,484 women 2-7 years after their first pregnancy. Women had a follow-up exam, with blood pressure and anthropometric measurements and clinical/biological testing, an average of 3 years post partum.

An analysis published in October 2019 in the Journal of the American Heart Association shows that women with HDP (including preeclampsia and gestational hypertension) had a relative risk of hypertension of 2.5 at follow-up, compared with women without HDP. Women who had preeclampsia specifically were 2.3 times as likely as were women who did not have preeclampsia to have incident hypertension at follow-up, said Dr. Ehrenthal, a coinvestigator of the study.

The analysis focused on incident hypertension as the primary outcome, and adjusted for age, body mass index, and other important cardiovascular disease risk factors, she noted. Researchers utilized the diagnostic threshold for hypertension extant at the time of study design: A systolic blood pressure of 140 mm Hg or greater, or a diastolic BP of 90 mm Hg or greater (J Am Heart Assoc. 2019;8:e013092).

HDP was the most common adverse pregnancy outcome in the nuMoM2b–HHS study (14%). Among all participants, 4% had GDM. Approximately 82% had neither HDP nor GDM. Other adverse pregnancy outcomes included in the analysis were preterm birth, small-for-gestational-age birth, and stillbirth.

Additional preliminary estimates presented by Dr. Ehrenthal show that, based on the new (2017) lower threshold for hypertension – 130 mg Hg systolic or 80 mm Hg diastolic – the disorder afflicted 37% of women who had experienced HDP (relative risk 2.1), and 32% of women who had GDM (RR 1.8). Prediabetes/diabetes (using a fasting blood glucose threshold of 100 mg/dL) at follow-up affected an estimated 21% of women who had HDP (RR 1.4) and 38% of women who had GDM (RR 2.5).

Notably, across the entire study cohort, 20% had hypertension at follow-up, “which is extraordinary” considering the short time frame from pregnancy and the young age of the study population – a mean maternal age of 27 years, said Dr. Ehrenthal, associate professor of population health sciences and obstetrics & gynecology at the University of Wisconsin, Madison.

Also across the cohort, 15% had prediabetes/diabetes at follow-up. “We need to think about women more generally,” she cautioned. “While we recognize the significant elevated risk of HDP and GDM [for the development of subsequent hypertension and cardiovascular risk], we will miss a lot of women [if we focus only on the history of HDP and GDM.]”

The majority of women found to have hypertension or prediabetes/diabetes at follow-up had experienced neither HDP nor GDM, but a good many of them (47% of those who had hypertension and 47% of those found to have prediabetes/diabetes) had a BMI of 30 or above, Dr. Ehrenthal said at the DPSG-NA meeting.
 

Nurses Health Study, hyperglycemia and adverse pregnancy outcome follow-up data

The new findings from the nuMoM2b–HHS study add to a robust and growing body of evidence that pregnancy is an important window to future health, and that follow up and screening after GDM and HDP are crucial.

Regarding GDM specifically, “there’s quite a bit of literature by now demonstrating that GDM history is a risk factor for hypertension, even 1-2 years post partum, and that the risk is elevated as well for dyslipidemia and vascular dysfunction,” Deirdre K. Tobias, D.Sc., an epidemiologist at Brigham and Women’s Hospital and assistant professor of nutrition at Harvard TH Chan School of Public Health, Boston, said at the DPSG meeting.

An analysis of the Nurses Health Study II (NHS II) cohort published in 2017 found a 40% higher relative risk of cardiovascular disease events (largely myocardial infarction) in women who had GDM, compared with women who did not have GDM over a median follow-up of 26 years. This was after adjustments were made for age, time since pregnancy, menopausal status, family history of MI or stroke, hypertension in pregnancy, white race/ethnicity, prepregnancy BMI, and other factors (JAMA Intern Med. 2017;177[12]:1735-42).

The NHS data also have shown, however, that the elevated risk for cardiovascular disease after a GDM pregnancy “can be mitigated by adopting a healthy lifestyle,” said Dr. Tobias, lead author of the 2017 NHS II analysis. Adjustments for postpregnancy weight gain and lifestyle factors attenuated the relative risk of cardiovascular disease events after a GDM pregnancy to a 30% increased risk.

Dr. Tobias and colleagues currently are looking within the NHS cohort for “metabolomic signatures” or signals – various amino acid and lipid metabolites – to identify the progression of GDM to type 2 diabetes. Metabolomics “may help further refine our understanding of the long-term links between GDM and prevention of type 2 diabetes and of cardiovascular disease in mothers,” she said.

The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Follow-Up Study, in the meantime, is documenting associations of maternal glucose levels during pregnancy not only with prediabetes or type 2 diabetes 10-14 years later, but also with measures of cardiovascular risk in mothers 10-14 years later.

Just as perinatal outcomes were strongly associated with glucose as a continuous variable in the original HAPO study, “it’s clear there’s a progressive increase in the risk of [later] disorders of glucose metabolism as [fasting blood glucose levels and 1- and-2-hour glucose values] in pregnancy are higher,” said Boyd E. Metzger, MD, the Tom D. Spies emeritus professor of metabolism and nutrition at Northwestern University, Chicago, and principal investigator of the original HAPO study and its follow up.

“Another message is that the more normal you are in pregnancy, the more normal you will be many years later. Good values [during pregnancy] produce good outcomes.”

Currently unpublished data from the HAPO Follow-Up Study are being analyzed, but it appears thus far that GDM is not associated with hypertension (per the old diagnostic threshold) in this cohort after adjustment for maternal age, BMI, smoking, and family history of hypertension. GDM appears to be a significant risk factor for dyslipidemia, however. HDL cholesterol at follow-up was significantly lower for mothers who had GDM compared with those without, whereas LDL cholesterol and triglycerides at follow-up were significantly higher for mothers with GDM, Dr. Metzger said.
 

Racial/ethnic disparities, postpartum care

Neither long-term study – the NHS II or the HAPO Follow-Up Study – has looked at racial and ethnic differences. The HAPO cohort is racially-ethnically diverse but the NHS II cohort is predominantly white women.

Research suggests that GDM is a heterogeneous condition with some unique phenotypes in subgroups that vary by race and ethnicity. And just as there appear to be racial-ethnic differences in the pathophysiology of GDM, there appear to be racial-ethnic differences in the progression to type 2 diabetes – a known risk factor for cardiovascular disease, said Monique Henderson, PhD, a research scientist at Kaiser Permanente Northern California (KPNC).

On the broadest level, while Asian Americans have the highest prevalence of GDM, African Americans have the highest rates of progressing to type 2 diabetes, Dr. Henderson said. Disparities “may [stem from] metabolic differences in terms of insulin resistance and secretion that are different between pregnancy and the postpartum period, and that might vary [across racial-ethnic subgroups],” she said. Lifestyle differences and variation in postpartum screening rates also may play a role.

At KPNC, where women with GDM receive calls and letters reminding them of the need for postpartum screening, only 48% overall completed an oral glucose tolerance test at 4-12 weeks post partum, as recommended by both the American Diabetes Association and the American College of Obstetricians and Gynecologists. Both before and after adjustment for education, attendance at a postpartum visit, and other variables, Chinese women were most likely to have screening, and black women were least likely, said Dr. Henderson, referring to ongoing research.

A study Dr. Ehrenthal led of women with GDM or HDP recruited from the postpartum service of a large community-based, academic obstetrical hospital in Delaware showed that while nearly all women attended a 6-week postpartum visit with their ob.gyns., 59% of women with GDM had not yet completed diabetes screening when they were interviewed 3 months post partum. Most women with HDP indicated they had follow-up blood pressure testing, and just over half of women with either diagnosis recalled having ever had lipid testing (J Women’s Health 2014;23[9]:760-4).

Women least likely to complete screening tests were those who had no college education, those who had less than a high school level of health literacy, and those who were not privately insured, Dr. Ehrenthal said.

A large national study of privately insured women also found low rates of follow-up testing, however. While the majority of women with GDM had a postpartum visit with an obstetrician or primary care physician within a year after delivery, only a minority of women had a glycemic screening test completed (Obstet Gynecol. 2016;128[1]:159-67).

“We can’t place the blame on women,” Dr. Ehrenthal said. “We need increased attention to screening,” including screening for cardiovascular disease risk factors, and a “deliberate hand-off to primary care.”

For follow-up cardiovascular disease risk factor assessment after HDP, ACOG recommends periodic (perhaps annually) assessment and referral for treatment as needed, and the cardiology professional organizations recommend that pregnancy history be considered when assessing risk in order to decide on lipid treatment, she noted.

Each of the speakers reported that they have no financial or other interests that pose a conflict of interest. The HAPO Follow-Up Study is funded by the National Institute of Diabetes and Digestive and Kidney Diseases, and the nuMoM2b–HHS study has been funded by several National Institutes of Health institutes and other programs and initiatives.

WASHINGTON – Cardiovascular risk factors may be elevated “as soon as the first postpartum year” in women who have gestational diabetes or hypertensive disorders of pregnancy, recent findings have affirmed, Deborah B. Ehrenthal, MD, MPH, said at the biennial meeting of the Diabetes in Pregnancy Study Group of North America.

FatCamera/E+/Getty Images

Dr. Ehrenthal was one of several researchers who urged innovative strategies and improved care coordination to boost women’s follow-up after gestational diabetes mellitus (GDM) and other adverse pregnancy outcomes and complications. “The metabolic stress of pregnancy can uncover underlying susceptibilities,” she said. “And adverse pregnancy outcomes can have long-lasting residual effects.”

Evidence that adverse pregnancy outcomes – including GDM and hypertensive disorders of pregnancy (HDP) – can elevate cardiovascular risk comes most recently from the Nulliparous Pregnancy Outcomes Study – Monitoring Mothers to be Heart Health Study (nuMoM2b–HHS study), a prospective observational cohort that followed 4,484 women 2-7 years after their first pregnancy. Women had a follow-up exam, with blood pressure and anthropometric measurements and clinical/biological testing, an average of 3 years post partum.

An analysis published in October 2019 in the Journal of the American Heart Association shows that women with HDP (including preeclampsia and gestational hypertension) had a relative risk of hypertension of 2.5 at follow-up, compared with women without HDP. Women who had preeclampsia specifically were 2.3 times as likely as were women who did not have preeclampsia to have incident hypertension at follow-up, said Dr. Ehrenthal, a coinvestigator of the study.

The analysis focused on incident hypertension as the primary outcome, and adjusted for age, body mass index, and other important cardiovascular disease risk factors, she noted. Researchers utilized the diagnostic threshold for hypertension extant at the time of study design: A systolic blood pressure of 140 mm Hg or greater, or a diastolic BP of 90 mm Hg or greater (J Am Heart Assoc. 2019;8:e013092).

HDP was the most common adverse pregnancy outcome in the nuMoM2b–HHS study (14%). Among all participants, 4% had GDM. Approximately 82% had neither HDP nor GDM. Other adverse pregnancy outcomes included in the analysis were preterm birth, small-for-gestational-age birth, and stillbirth.

Additional preliminary estimates presented by Dr. Ehrenthal show that, based on the new (2017) lower threshold for hypertension – 130 mg Hg systolic or 80 mm Hg diastolic – the disorder afflicted 37% of women who had experienced HDP (relative risk 2.1), and 32% of women who had GDM (RR 1.8). Prediabetes/diabetes (using a fasting blood glucose threshold of 100 mg/dL) at follow-up affected an estimated 21% of women who had HDP (RR 1.4) and 38% of women who had GDM (RR 2.5).

Notably, across the entire study cohort, 20% had hypertension at follow-up, “which is extraordinary” considering the short time frame from pregnancy and the young age of the study population – a mean maternal age of 27 years, said Dr. Ehrenthal, associate professor of population health sciences and obstetrics & gynecology at the University of Wisconsin, Madison.

Also across the cohort, 15% had prediabetes/diabetes at follow-up. “We need to think about women more generally,” she cautioned. “While we recognize the significant elevated risk of HDP and GDM [for the development of subsequent hypertension and cardiovascular risk], we will miss a lot of women [if we focus only on the history of HDP and GDM.]”

The majority of women found to have hypertension or prediabetes/diabetes at follow-up had experienced neither HDP nor GDM, but a good many of them (47% of those who had hypertension and 47% of those found to have prediabetes/diabetes) had a BMI of 30 or above, Dr. Ehrenthal said at the DPSG-NA meeting.
 

Nurses Health Study, hyperglycemia and adverse pregnancy outcome follow-up data

The new findings from the nuMoM2b–HHS study add to a robust and growing body of evidence that pregnancy is an important window to future health, and that follow up and screening after GDM and HDP are crucial.

Regarding GDM specifically, “there’s quite a bit of literature by now demonstrating that GDM history is a risk factor for hypertension, even 1-2 years post partum, and that the risk is elevated as well for dyslipidemia and vascular dysfunction,” Deirdre K. Tobias, D.Sc., an epidemiologist at Brigham and Women’s Hospital and assistant professor of nutrition at Harvard TH Chan School of Public Health, Boston, said at the DPSG meeting.

An analysis of the Nurses Health Study II (NHS II) cohort published in 2017 found a 40% higher relative risk of cardiovascular disease events (largely myocardial infarction) in women who had GDM, compared with women who did not have GDM over a median follow-up of 26 years. This was after adjustments were made for age, time since pregnancy, menopausal status, family history of MI or stroke, hypertension in pregnancy, white race/ethnicity, prepregnancy BMI, and other factors (JAMA Intern Med. 2017;177[12]:1735-42).

The NHS data also have shown, however, that the elevated risk for cardiovascular disease after a GDM pregnancy “can be mitigated by adopting a healthy lifestyle,” said Dr. Tobias, lead author of the 2017 NHS II analysis. Adjustments for postpregnancy weight gain and lifestyle factors attenuated the relative risk of cardiovascular disease events after a GDM pregnancy to a 30% increased risk.

Dr. Tobias and colleagues currently are looking within the NHS cohort for “metabolomic signatures” or signals – various amino acid and lipid metabolites – to identify the progression of GDM to type 2 diabetes. Metabolomics “may help further refine our understanding of the long-term links between GDM and prevention of type 2 diabetes and of cardiovascular disease in mothers,” she said.

The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Follow-Up Study, in the meantime, is documenting associations of maternal glucose levels during pregnancy not only with prediabetes or type 2 diabetes 10-14 years later, but also with measures of cardiovascular risk in mothers 10-14 years later.

Just as perinatal outcomes were strongly associated with glucose as a continuous variable in the original HAPO study, “it’s clear there’s a progressive increase in the risk of [later] disorders of glucose metabolism as [fasting blood glucose levels and 1- and-2-hour glucose values] in pregnancy are higher,” said Boyd E. Metzger, MD, the Tom D. Spies emeritus professor of metabolism and nutrition at Northwestern University, Chicago, and principal investigator of the original HAPO study and its follow up.

“Another message is that the more normal you are in pregnancy, the more normal you will be many years later. Good values [during pregnancy] produce good outcomes.”

Currently unpublished data from the HAPO Follow-Up Study are being analyzed, but it appears thus far that GDM is not associated with hypertension (per the old diagnostic threshold) in this cohort after adjustment for maternal age, BMI, smoking, and family history of hypertension. GDM appears to be a significant risk factor for dyslipidemia, however. HDL cholesterol at follow-up was significantly lower for mothers who had GDM compared with those without, whereas LDL cholesterol and triglycerides at follow-up were significantly higher for mothers with GDM, Dr. Metzger said.
 

Racial/ethnic disparities, postpartum care

Neither long-term study – the NHS II or the HAPO Follow-Up Study – has looked at racial and ethnic differences. The HAPO cohort is racially-ethnically diverse but the NHS II cohort is predominantly white women.

Research suggests that GDM is a heterogeneous condition with some unique phenotypes in subgroups that vary by race and ethnicity. And just as there appear to be racial-ethnic differences in the pathophysiology of GDM, there appear to be racial-ethnic differences in the progression to type 2 diabetes – a known risk factor for cardiovascular disease, said Monique Henderson, PhD, a research scientist at Kaiser Permanente Northern California (KPNC).

On the broadest level, while Asian Americans have the highest prevalence of GDM, African Americans have the highest rates of progressing to type 2 diabetes, Dr. Henderson said. Disparities “may [stem from] metabolic differences in terms of insulin resistance and secretion that are different between pregnancy and the postpartum period, and that might vary [across racial-ethnic subgroups],” she said. Lifestyle differences and variation in postpartum screening rates also may play a role.

At KPNC, where women with GDM receive calls and letters reminding them of the need for postpartum screening, only 48% overall completed an oral glucose tolerance test at 4-12 weeks post partum, as recommended by both the American Diabetes Association and the American College of Obstetricians and Gynecologists. Both before and after adjustment for education, attendance at a postpartum visit, and other variables, Chinese women were most likely to have screening, and black women were least likely, said Dr. Henderson, referring to ongoing research.

A study Dr. Ehrenthal led of women with GDM or HDP recruited from the postpartum service of a large community-based, academic obstetrical hospital in Delaware showed that while nearly all women attended a 6-week postpartum visit with their ob.gyns., 59% of women with GDM had not yet completed diabetes screening when they were interviewed 3 months post partum. Most women with HDP indicated they had follow-up blood pressure testing, and just over half of women with either diagnosis recalled having ever had lipid testing (J Women’s Health 2014;23[9]:760-4).

Women least likely to complete screening tests were those who had no college education, those who had less than a high school level of health literacy, and those who were not privately insured, Dr. Ehrenthal said.

A large national study of privately insured women also found low rates of follow-up testing, however. While the majority of women with GDM had a postpartum visit with an obstetrician or primary care physician within a year after delivery, only a minority of women had a glycemic screening test completed (Obstet Gynecol. 2016;128[1]:159-67).

“We can’t place the blame on women,” Dr. Ehrenthal said. “We need increased attention to screening,” including screening for cardiovascular disease risk factors, and a “deliberate hand-off to primary care.”

For follow-up cardiovascular disease risk factor assessment after HDP, ACOG recommends periodic (perhaps annually) assessment and referral for treatment as needed, and the cardiology professional organizations recommend that pregnancy history be considered when assessing risk in order to decide on lipid treatment, she noted.

Each of the speakers reported that they have no financial or other interests that pose a conflict of interest. The HAPO Follow-Up Study is funded by the National Institute of Diabetes and Digestive and Kidney Diseases, and the nuMoM2b–HHS study has been funded by several National Institutes of Health institutes and other programs and initiatives.

WASHINGTON – Cardiovascular risk factors may be elevated “as soon as the first postpartum year” in women who have gestational diabetes or hypertensive disorders of pregnancy, recent findings have affirmed, Deborah B. Ehrenthal, MD, MPH, said at the biennial meeting of the Diabetes in Pregnancy Study Group of North America.

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Dr. Ehrenthal was one of several researchers who urged innovative strategies and improved care coordination to boost women’s follow-up after gestational diabetes mellitus (GDM) and other adverse pregnancy outcomes and complications. “The metabolic stress of pregnancy can uncover underlying susceptibilities,” she said. “And adverse pregnancy outcomes can have long-lasting residual effects.”

Evidence that adverse pregnancy outcomes – including GDM and hypertensive disorders of pregnancy (HDP) – can elevate cardiovascular risk comes most recently from the Nulliparous Pregnancy Outcomes Study – Monitoring Mothers to be Heart Health Study (nuMoM2b–HHS study), a prospective observational cohort that followed 4,484 women 2-7 years after their first pregnancy. Women had a follow-up exam, with blood pressure and anthropometric measurements and clinical/biological testing, an average of 3 years post partum.

An analysis published in October 2019 in the Journal of the American Heart Association shows that women with HDP (including preeclampsia and gestational hypertension) had a relative risk of hypertension of 2.5 at follow-up, compared with women without HDP. Women who had preeclampsia specifically were 2.3 times as likely as were women who did not have preeclampsia to have incident hypertension at follow-up, said Dr. Ehrenthal, a coinvestigator of the study.

The analysis focused on incident hypertension as the primary outcome, and adjusted for age, body mass index, and other important cardiovascular disease risk factors, she noted. Researchers utilized the diagnostic threshold for hypertension extant at the time of study design: A systolic blood pressure of 140 mm Hg or greater, or a diastolic BP of 90 mm Hg or greater (J Am Heart Assoc. 2019;8:e013092).

HDP was the most common adverse pregnancy outcome in the nuMoM2b–HHS study (14%). Among all participants, 4% had GDM. Approximately 82% had neither HDP nor GDM. Other adverse pregnancy outcomes included in the analysis were preterm birth, small-for-gestational-age birth, and stillbirth.

Additional preliminary estimates presented by Dr. Ehrenthal show that, based on the new (2017) lower threshold for hypertension – 130 mg Hg systolic or 80 mm Hg diastolic – the disorder afflicted 37% of women who had experienced HDP (relative risk 2.1), and 32% of women who had GDM (RR 1.8). Prediabetes/diabetes (using a fasting blood glucose threshold of 100 mg/dL) at follow-up affected an estimated 21% of women who had HDP (RR 1.4) and 38% of women who had GDM (RR 2.5).

Notably, across the entire study cohort, 20% had hypertension at follow-up, “which is extraordinary” considering the short time frame from pregnancy and the young age of the study population – a mean maternal age of 27 years, said Dr. Ehrenthal, associate professor of population health sciences and obstetrics & gynecology at the University of Wisconsin, Madison.

Also across the cohort, 15% had prediabetes/diabetes at follow-up. “We need to think about women more generally,” she cautioned. “While we recognize the significant elevated risk of HDP and GDM [for the development of subsequent hypertension and cardiovascular risk], we will miss a lot of women [if we focus only on the history of HDP and GDM.]”

The majority of women found to have hypertension or prediabetes/diabetes at follow-up had experienced neither HDP nor GDM, but a good many of them (47% of those who had hypertension and 47% of those found to have prediabetes/diabetes) had a BMI of 30 or above, Dr. Ehrenthal said at the DPSG-NA meeting.
 

Nurses Health Study, hyperglycemia and adverse pregnancy outcome follow-up data

The new findings from the nuMoM2b–HHS study add to a robust and growing body of evidence that pregnancy is an important window to future health, and that follow up and screening after GDM and HDP are crucial.

Regarding GDM specifically, “there’s quite a bit of literature by now demonstrating that GDM history is a risk factor for hypertension, even 1-2 years post partum, and that the risk is elevated as well for dyslipidemia and vascular dysfunction,” Deirdre K. Tobias, D.Sc., an epidemiologist at Brigham and Women’s Hospital and assistant professor of nutrition at Harvard TH Chan School of Public Health, Boston, said at the DPSG meeting.

An analysis of the Nurses Health Study II (NHS II) cohort published in 2017 found a 40% higher relative risk of cardiovascular disease events (largely myocardial infarction) in women who had GDM, compared with women who did not have GDM over a median follow-up of 26 years. This was after adjustments were made for age, time since pregnancy, menopausal status, family history of MI or stroke, hypertension in pregnancy, white race/ethnicity, prepregnancy BMI, and other factors (JAMA Intern Med. 2017;177[12]:1735-42).

The NHS data also have shown, however, that the elevated risk for cardiovascular disease after a GDM pregnancy “can be mitigated by adopting a healthy lifestyle,” said Dr. Tobias, lead author of the 2017 NHS II analysis. Adjustments for postpregnancy weight gain and lifestyle factors attenuated the relative risk of cardiovascular disease events after a GDM pregnancy to a 30% increased risk.

Dr. Tobias and colleagues currently are looking within the NHS cohort for “metabolomic signatures” or signals – various amino acid and lipid metabolites – to identify the progression of GDM to type 2 diabetes. Metabolomics “may help further refine our understanding of the long-term links between GDM and prevention of type 2 diabetes and of cardiovascular disease in mothers,” she said.

The Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Follow-Up Study, in the meantime, is documenting associations of maternal glucose levels during pregnancy not only with prediabetes or type 2 diabetes 10-14 years later, but also with measures of cardiovascular risk in mothers 10-14 years later.

Just as perinatal outcomes were strongly associated with glucose as a continuous variable in the original HAPO study, “it’s clear there’s a progressive increase in the risk of [later] disorders of glucose metabolism as [fasting blood glucose levels and 1- and-2-hour glucose values] in pregnancy are higher,” said Boyd E. Metzger, MD, the Tom D. Spies emeritus professor of metabolism and nutrition at Northwestern University, Chicago, and principal investigator of the original HAPO study and its follow up.

“Another message is that the more normal you are in pregnancy, the more normal you will be many years later. Good values [during pregnancy] produce good outcomes.”

Currently unpublished data from the HAPO Follow-Up Study are being analyzed, but it appears thus far that GDM is not associated with hypertension (per the old diagnostic threshold) in this cohort after adjustment for maternal age, BMI, smoking, and family history of hypertension. GDM appears to be a significant risk factor for dyslipidemia, however. HDL cholesterol at follow-up was significantly lower for mothers who had GDM compared with those without, whereas LDL cholesterol and triglycerides at follow-up were significantly higher for mothers with GDM, Dr. Metzger said.
 

Racial/ethnic disparities, postpartum care

Neither long-term study – the NHS II or the HAPO Follow-Up Study – has looked at racial and ethnic differences. The HAPO cohort is racially-ethnically diverse but the NHS II cohort is predominantly white women.

Research suggests that GDM is a heterogeneous condition with some unique phenotypes in subgroups that vary by race and ethnicity. And just as there appear to be racial-ethnic differences in the pathophysiology of GDM, there appear to be racial-ethnic differences in the progression to type 2 diabetes – a known risk factor for cardiovascular disease, said Monique Henderson, PhD, a research scientist at Kaiser Permanente Northern California (KPNC).

On the broadest level, while Asian Americans have the highest prevalence of GDM, African Americans have the highest rates of progressing to type 2 diabetes, Dr. Henderson said. Disparities “may [stem from] metabolic differences in terms of insulin resistance and secretion that are different between pregnancy and the postpartum period, and that might vary [across racial-ethnic subgroups],” she said. Lifestyle differences and variation in postpartum screening rates also may play a role.

At KPNC, where women with GDM receive calls and letters reminding them of the need for postpartum screening, only 48% overall completed an oral glucose tolerance test at 4-12 weeks post partum, as recommended by both the American Diabetes Association and the American College of Obstetricians and Gynecologists. Both before and after adjustment for education, attendance at a postpartum visit, and other variables, Chinese women were most likely to have screening, and black women were least likely, said Dr. Henderson, referring to ongoing research.

A study Dr. Ehrenthal led of women with GDM or HDP recruited from the postpartum service of a large community-based, academic obstetrical hospital in Delaware showed that while nearly all women attended a 6-week postpartum visit with their ob.gyns., 59% of women with GDM had not yet completed diabetes screening when they were interviewed 3 months post partum. Most women with HDP indicated they had follow-up blood pressure testing, and just over half of women with either diagnosis recalled having ever had lipid testing (J Women’s Health 2014;23[9]:760-4).

Women least likely to complete screening tests were those who had no college education, those who had less than a high school level of health literacy, and those who were not privately insured, Dr. Ehrenthal said.

A large national study of privately insured women also found low rates of follow-up testing, however. While the majority of women with GDM had a postpartum visit with an obstetrician or primary care physician within a year after delivery, only a minority of women had a glycemic screening test completed (Obstet Gynecol. 2016;128[1]:159-67).

“We can’t place the blame on women,” Dr. Ehrenthal said. “We need increased attention to screening,” including screening for cardiovascular disease risk factors, and a “deliberate hand-off to primary care.”

For follow-up cardiovascular disease risk factor assessment after HDP, ACOG recommends periodic (perhaps annually) assessment and referral for treatment as needed, and the cardiology professional organizations recommend that pregnancy history be considered when assessing risk in order to decide on lipid treatment, she noted.

Each of the speakers reported that they have no financial or other interests that pose a conflict of interest. The HAPO Follow-Up Study is funded by the National Institute of Diabetes and Digestive and Kidney Diseases, and the nuMoM2b–HHS study has been funded by several National Institutes of Health institutes and other programs and initiatives.