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).

The presence of occult hepatitis C virus infection is determined by finding HCV RNA in the liver and peripheral blood mononuclear cells, with no HCV RNA in the serum. Researchers have shown that the presence of occult HCV infection (OCI) was correlated with unfavorable polymorphisms near interferon lambda-3/4 (IFNL3/4), which has been associated with spontaneous HCV clearance.

This study was conducted to assess the frequency of OCI in 450 hemophilia patients in Iran with negative HCV markers, and to evaluate the association of three IFNL3 single nucleotide polymorphisms (rs8099917, rs12979860, and rs12980275) and the IFNL4 ss469415590 SNP with OCI positivity.

The estimated OCI rate was 10.2%. Among the 46 OCI patients, 56.5%, 23.9%, and 19.6% were infected with HCV-1b, HCV-1a, and HCV-3a, respectively. The researchers found that, compared with patients without OCI, unfavorable IFNL3 rs12979860, IFNL3 rs8099917, IFNL3 rs12980275, and IFNL4 ss469415590 genotypes were more frequently found in OCI patients. Multivariate analysis showed that ALT, cholesterol, triglyceride, as well as the aforementioned unfavorable interferon SNP geneotypes were associated with OCI positivity.

“10.2% of anti-HCV seronegative Iranian patients with hemophilia had OCI in our study; therefore, risk of this infection should be taken into consideration. We also showed that patients with unfavorable IFNL3 SNPs and IFNL4 ss469415590 genotypes were exposed to a higher risk of OCI, compared to hemophilia patients with other genotypes,” the researchers concluded.

The authors reported that they had no disclosures.

[email protected]

SOURCE: Nafari AH et al. Infect Genet Evol. 2019 Dec 13. doi: 10.1016/j.meegid.2019.104144.

The presence of occult hepatitis C virus infection is determined by finding HCV RNA in the liver and peripheral blood mononuclear cells, with no HCV RNA in the serum. Researchers have shown that the presence of occult HCV infection (OCI) was correlated with unfavorable polymorphisms near interferon lambda-3/4 (IFNL3/4), which has been associated with spontaneous HCV clearance.

This study was conducted to assess the frequency of OCI in 450 hemophilia patients in Iran with negative HCV markers, and to evaluate the association of three IFNL3 single nucleotide polymorphisms (rs8099917, rs12979860, and rs12980275) and the IFNL4 ss469415590 SNP with OCI positivity.

The estimated OCI rate was 10.2%. Among the 46 OCI patients, 56.5%, 23.9%, and 19.6% were infected with HCV-1b, HCV-1a, and HCV-3a, respectively. The researchers found that, compared with patients without OCI, unfavorable IFNL3 rs12979860, IFNL3 rs8099917, IFNL3 rs12980275, and IFNL4 ss469415590 genotypes were more frequently found in OCI patients. Multivariate analysis showed that ALT, cholesterol, triglyceride, as well as the aforementioned unfavorable interferon SNP geneotypes were associated with OCI positivity.

“10.2% of anti-HCV seronegative Iranian patients with hemophilia had OCI in our study; therefore, risk of this infection should be taken into consideration. We also showed that patients with unfavorable IFNL3 SNPs and IFNL4 ss469415590 genotypes were exposed to a higher risk of OCI, compared to hemophilia patients with other genotypes,” the researchers concluded.

The authors reported that they had no disclosures.

[email protected]

SOURCE: Nafari AH et al. Infect Genet Evol. 2019 Dec 13. doi: 10.1016/j.meegid.2019.104144.

The presence of occult hepatitis C virus infection is determined by finding HCV RNA in the liver and peripheral blood mononuclear cells, with no HCV RNA in the serum. Researchers have shown that the presence of occult HCV infection (OCI) was correlated with unfavorable polymorphisms near interferon lambda-3/4 (IFNL3/4), which has been associated with spontaneous HCV clearance.

This study was conducted to assess the frequency of OCI in 450 hemophilia patients in Iran with negative HCV markers, and to evaluate the association of three IFNL3 single nucleotide polymorphisms (rs8099917, rs12979860, and rs12980275) and the IFNL4 ss469415590 SNP with OCI positivity.

The estimated OCI rate was 10.2%. Among the 46 OCI patients, 56.5%, 23.9%, and 19.6% were infected with HCV-1b, HCV-1a, and HCV-3a, respectively. The researchers found that, compared with patients without OCI, unfavorable IFNL3 rs12979860, IFNL3 rs8099917, IFNL3 rs12980275, and IFNL4 ss469415590 genotypes were more frequently found in OCI patients. Multivariate analysis showed that ALT, cholesterol, triglyceride, as well as the aforementioned unfavorable interferon SNP geneotypes were associated with OCI positivity.

“10.2% of anti-HCV seronegative Iranian patients with hemophilia had OCI in our study; therefore, risk of this infection should be taken into consideration. We also showed that patients with unfavorable IFNL3 SNPs and IFNL4 ss469415590 genotypes were exposed to a higher risk of OCI, compared to hemophilia patients with other genotypes,” the researchers concluded.

The authors reported that they had no disclosures.

[email protected]

SOURCE: Nafari AH et al. Infect Genet Evol. 2019 Dec 13. doi: 10.1016/j.meegid.2019.104144.

The plant compounds known as flavonols that are found in many fruits and vegetables may reduce risk of developing Alzheimer’s disease, results of a recent observational study suggest.

Chalffy/Getty Images

Onset of Alzheimer’s disease (AD) was inversely associated with intake of flavonols, a subclass of flavonoids with antioxidant and anti-inflammatory properties, according to the study authors.

The rate of developing AD was reduced by 50% among individuals reporting high intake of kaempferol, a flavonol plentiful in leafy green vegetables, and by 38% for high intake of the flavonols myricetin and isorhamnetin, researchers said in a report published in Neurology.

The findings are from the Rush Memory and Aging Project (MAP), a large, prospective study of older individuals in retirement communities and public housing in the Chicago area that has been ongoing since 1997.

“Although there is more work to be done, the associations that we observed are promising and deserve further study,” said Thomas M. Holland, MD, of the Rush Institute for Healthy Aging in Chicago, and coauthors.

Those associations between flavonol intake and AD help set the stage for U.S. POINTER and other randomized, controlled trials that seek to evaluate the effects of dietary interventions in a more rigorous way, according to Laura D. Baker, PhD, associate professor of internal medicine at Wake Forest University, Winston-Salem, N.C.

Michele G. Sullivan/MDedge News

“This kind of data helps us feel like we are looking in the right direction in the randomized, controlled trials,” Dr. Baker said in an interview.

Dr. Baker is an investigator in the U.S. POINTER study, which will in part evaluate the impact of the MIND diet, which has been shown to slow cognitive decline with age in a previously published MAP study.

However, in the absence of randomized, controlled trial data, Dr. Baker cautioned against “prematurely advocating” for specific dietary approaches when speaking to patients and caregivers now.

“What I say is, we know for sure that the standard American Heart Association diet has been shown in clinical trials to reduce the risk of heart disease, and in terms of brain health, if you can reduce risk of heart disease, you are protecting your brain,” she said in the interview.

The present MAP study linking a reduced rate of AD to flavonol consumption is believed to be the first of its kind, though two previous studies from the early 2000s did find inverse associations between incident AD and intake of flavonoids, of which flavonoids are just one subclass, said Dr. Holland and coinvestigators in their report.

Moreover, in a MAP study published in 2018, Martha Clare Morris, ScD, and coauthors concluded that consuming about a serving per day of green leafy vegetables and foods rich in kaempferol, among other nutrients and bioactive compounds, may help slow cognitive decline associated with aging.

To more specifically study the relationship between kaempferol and other flavonols and the development of AD, Dr. Holland and colleagues evaluated data for MAP participants who had completed a comprehensive food frequency questionnaire and underwent at least two evaluations to assess incidence of disease.

The mean age of the 921 individuals in the present analysis was 81 years, three-quarters were female, and over approximately 6 years of follow-up, 220 developed AD.

The rate of developing AD was 48% lower among participants reporting the highest total dietary intake of flavonols, compared with those reporting the lowest intake, Dr. Holland and coauthors reported.

Intake of the specific flavonols kaempferol, myricetin, and isorhamnetin were associated with incident AD reductions of 50%, 38%, and 38%, respectively. Another flavonol, quercetin, was by contrast not inversely associated with incident AD, according to the report.

Kaempferol was independently associated with AD in subsequent analyses, while there was no such independent association for myricetin, isorhamnetin, or quercetin, according to Dr. Holland and coinvestigators.

Further analyses of the data suggested the linkages between flavonols and AD were independent of lifestyle factors, dietary intakes, or cardiovascular conditions, they said in their report.

“Confirmation of these findings is warranted through other longitudinal epidemiologic studies and clinical trials, in addition to further elucidation of the biologic mechanisms,” they concluded.

The study was funded by grants from the National Institutes of Health and the USDA Agricultural Research Service. Dr. Holland and coauthors said that they had no disclosures relevant to their report.

SOURCE: Holland TM et al. Neurology. 2020 Jan 29. doi: 10.1212/WNL.0000000000008981.

The plant compounds known as flavonols that are found in many fruits and vegetables may reduce risk of developing Alzheimer’s disease, results of a recent observational study suggest.

Chalffy/Getty Images

Onset of Alzheimer’s disease (AD) was inversely associated with intake of flavonols, a subclass of flavonoids with antioxidant and anti-inflammatory properties, according to the study authors.

The rate of developing AD was reduced by 50% among individuals reporting high intake of kaempferol, a flavonol plentiful in leafy green vegetables, and by 38% for high intake of the flavonols myricetin and isorhamnetin, researchers said in a report published in Neurology.

The findings are from the Rush Memory and Aging Project (MAP), a large, prospective study of older individuals in retirement communities and public housing in the Chicago area that has been ongoing since 1997.

“Although there is more work to be done, the associations that we observed are promising and deserve further study,” said Thomas M. Holland, MD, of the Rush Institute for Healthy Aging in Chicago, and coauthors.

Those associations between flavonol intake and AD help set the stage for U.S. POINTER and other randomized, controlled trials that seek to evaluate the effects of dietary interventions in a more rigorous way, according to Laura D. Baker, PhD, associate professor of internal medicine at Wake Forest University, Winston-Salem, N.C.

Michele G. Sullivan/MDedge News

“This kind of data helps us feel like we are looking in the right direction in the randomized, controlled trials,” Dr. Baker said in an interview.

Dr. Baker is an investigator in the U.S. POINTER study, which will in part evaluate the impact of the MIND diet, which has been shown to slow cognitive decline with age in a previously published MAP study.

However, in the absence of randomized, controlled trial data, Dr. Baker cautioned against “prematurely advocating” for specific dietary approaches when speaking to patients and caregivers now.

“What I say is, we know for sure that the standard American Heart Association diet has been shown in clinical trials to reduce the risk of heart disease, and in terms of brain health, if you can reduce risk of heart disease, you are protecting your brain,” she said in the interview.

The present MAP study linking a reduced rate of AD to flavonol consumption is believed to be the first of its kind, though two previous studies from the early 2000s did find inverse associations between incident AD and intake of flavonoids, of which flavonoids are just one subclass, said Dr. Holland and coinvestigators in their report.

Moreover, in a MAP study published in 2018, Martha Clare Morris, ScD, and coauthors concluded that consuming about a serving per day of green leafy vegetables and foods rich in kaempferol, among other nutrients and bioactive compounds, may help slow cognitive decline associated with aging.

To more specifically study the relationship between kaempferol and other flavonols and the development of AD, Dr. Holland and colleagues evaluated data for MAP participants who had completed a comprehensive food frequency questionnaire and underwent at least two evaluations to assess incidence of disease.

The mean age of the 921 individuals in the present analysis was 81 years, three-quarters were female, and over approximately 6 years of follow-up, 220 developed AD.

The rate of developing AD was 48% lower among participants reporting the highest total dietary intake of flavonols, compared with those reporting the lowest intake, Dr. Holland and coauthors reported.

Intake of the specific flavonols kaempferol, myricetin, and isorhamnetin were associated with incident AD reductions of 50%, 38%, and 38%, respectively. Another flavonol, quercetin, was by contrast not inversely associated with incident AD, according to the report.

Kaempferol was independently associated with AD in subsequent analyses, while there was no such independent association for myricetin, isorhamnetin, or quercetin, according to Dr. Holland and coinvestigators.

Further analyses of the data suggested the linkages between flavonols and AD were independent of lifestyle factors, dietary intakes, or cardiovascular conditions, they said in their report.

“Confirmation of these findings is warranted through other longitudinal epidemiologic studies and clinical trials, in addition to further elucidation of the biologic mechanisms,” they concluded.

The study was funded by grants from the National Institutes of Health and the USDA Agricultural Research Service. Dr. Holland and coauthors said that they had no disclosures relevant to their report.

SOURCE: Holland TM et al. Neurology. 2020 Jan 29. doi: 10.1212/WNL.0000000000008981.

The plant compounds known as flavonols that are found in many fruits and vegetables may reduce risk of developing Alzheimer’s disease, results of a recent observational study suggest.

Chalffy/Getty Images

Onset of Alzheimer’s disease (AD) was inversely associated with intake of flavonols, a subclass of flavonoids with antioxidant and anti-inflammatory properties, according to the study authors.

The rate of developing AD was reduced by 50% among individuals reporting high intake of kaempferol, a flavonol plentiful in leafy green vegetables, and by 38% for high intake of the flavonols myricetin and isorhamnetin, researchers said in a report published in Neurology.

The findings are from the Rush Memory and Aging Project (MAP), a large, prospective study of older individuals in retirement communities and public housing in the Chicago area that has been ongoing since 1997.

“Although there is more work to be done, the associations that we observed are promising and deserve further study,” said Thomas M. Holland, MD, of the Rush Institute for Healthy Aging in Chicago, and coauthors.

Those associations between flavonol intake and AD help set the stage for U.S. POINTER and other randomized, controlled trials that seek to evaluate the effects of dietary interventions in a more rigorous way, according to Laura D. Baker, PhD, associate professor of internal medicine at Wake Forest University, Winston-Salem, N.C.

Michele G. Sullivan/MDedge News

“This kind of data helps us feel like we are looking in the right direction in the randomized, controlled trials,” Dr. Baker said in an interview.

Dr. Baker is an investigator in the U.S. POINTER study, which will in part evaluate the impact of the MIND diet, which has been shown to slow cognitive decline with age in a previously published MAP study.

However, in the absence of randomized, controlled trial data, Dr. Baker cautioned against “prematurely advocating” for specific dietary approaches when speaking to patients and caregivers now.

“What I say is, we know for sure that the standard American Heart Association diet has been shown in clinical trials to reduce the risk of heart disease, and in terms of brain health, if you can reduce risk of heart disease, you are protecting your brain,” she said in the interview.

The present MAP study linking a reduced rate of AD to flavonol consumption is believed to be the first of its kind, though two previous studies from the early 2000s did find inverse associations between incident AD and intake of flavonoids, of which flavonoids are just one subclass, said Dr. Holland and coinvestigators in their report.

Moreover, in a MAP study published in 2018, Martha Clare Morris, ScD, and coauthors concluded that consuming about a serving per day of green leafy vegetables and foods rich in kaempferol, among other nutrients and bioactive compounds, may help slow cognitive decline associated with aging.

To more specifically study the relationship between kaempferol and other flavonols and the development of AD, Dr. Holland and colleagues evaluated data for MAP participants who had completed a comprehensive food frequency questionnaire and underwent at least two evaluations to assess incidence of disease.

The mean age of the 921 individuals in the present analysis was 81 years, three-quarters were female, and over approximately 6 years of follow-up, 220 developed AD.

The rate of developing AD was 48% lower among participants reporting the highest total dietary intake of flavonols, compared with those reporting the lowest intake, Dr. Holland and coauthors reported.

Intake of the specific flavonols kaempferol, myricetin, and isorhamnetin were associated with incident AD reductions of 50%, 38%, and 38%, respectively. Another flavonol, quercetin, was by contrast not inversely associated with incident AD, according to the report.

Kaempferol was independently associated with AD in subsequent analyses, while there was no such independent association for myricetin, isorhamnetin, or quercetin, according to Dr. Holland and coinvestigators.

Further analyses of the data suggested the linkages between flavonols and AD were independent of lifestyle factors, dietary intakes, or cardiovascular conditions, they said in their report.

“Confirmation of these findings is warranted through other longitudinal epidemiologic studies and clinical trials, in addition to further elucidation of the biologic mechanisms,” they concluded.

The study was funded by grants from the National Institutes of Health and the USDA Agricultural Research Service. Dr. Holland and coauthors said that they had no disclosures relevant to their report.

SOURCE: Holland TM et al. Neurology. 2020 Jan 29. doi: 10.1212/WNL.0000000000008981.

Traditionally, U.S. health care has operated under a fee-for-service payment model, in which health care providers (such as physicians, hospitals, and health care systems) receive a fee for services such as office visits, hospital stays, procedures, and tests. However, reimbursement discussions are increasingly moving from fee-for-service to value-based, in which payments are tied to managing population health and total cost of care.

Because these changes will impact the entire system all the way down to individual providers, in the upcoming Population Management article series in The Hospitalist, we will discuss the nuances and implications that physicians, executives, and hospitals should be aware of. In this first article, we will examine the impetus for the shift toward population management and introduce common terminology to lay the foundation for the future content.
 

The traditional model: Fee for service

Under the traditional fee-for-service payment system, health care providers are paid per unit of service. For example, hospitals receive diagnosis-related group (DRG) payments for inpatient stays, and physicians are paid per patient visit. The more services that hospitals or physicians provide, the more money both get paid, without financial consequences for quality outcomes or total cost of care. Total cost of care includes clinic visits, outpatient procedures and tests, hospital and ED visits, home health, skilled nursing facilities, durable medical equipment, and sometimes drugs during an episode of care (for example, a hospital stay plus 90 days after discharge) or over a period of time (for example, a month or a year).

As a result of the fee-for-service payment system, the United States spends more money on health care than other wealthy countries, yet it lags behind other countries on many quality measures, such as disease burden, overall mortality, premature death, and preventable death.^1,2

In 2007, the Institute for Healthcare Improvement (IHI) developed the Triple Aim framework that focused on the following:

• Improving the patient experience of care (including quality and satisfaction).
• Improving the health of populations.
• Reducing per capita cost of care.

Both public payers like Medicare and Medicaid, as well as private payers, embraced the Triple Aim to reform how health care is delivered and paid for. As such, health care delivery focus and financial incentives are shifting from managing discrete patient encounters for acute illness to managing population health and total cost of care.
 

A new approach: Population management

Before diving into population management, it is important to first understand the terms “population” and “population health.” A population can be defined geographically or may include employees of an organization, members of a health plan, or patients receiving care from a specific physician group or health care system. David A. Kindig, MD, PhD, professor emeritus of population health sciences at the University of Wisconsin–Madison, defined population health as “the health outcomes of a group of individuals, including the distribution of such outcomes within the group.”³ Dr. Kindig noted that population health outcomes have many determinants, such as the following:⁴

• Health care (access, cost, quantity, and quality of health care services).
• Individual behavior (including diet, exercise, and substance abuse).
• Genetics.
• The social environment (education, income, occupation, class, and social support).
• Physical environment (air and water quality, lead exposure, and the design of neighborhoods).

IHI operationally defines population health by measures such as life expectancy, mortality rates, health and functional status, the incidence and/or prevalence of chronic disease, and behavioral and physiological factors such as smoking, physical activity, diet, blood pressure, body mass index, and cholesterol.⁵

On the other hand, population management is primarily concerned with health care determinants of health and, according to IHI, should be clearly distinguished from population health, which focuses on the broader determinants of health.⁵

According to Ron Greeno, MD, MHM, one of the founding members and a past-president of the Society of Hospital Medicine, population management is a “global approach of caring for an entire patient population to deliver safe and equitable care and to more intelligently allocate resources to keep people well.”

Population management requires understanding the patient population, which includes risk stratification and redesigning and delivering services that are guided by integrated clinical and administrative data and enabled by information technology.
 

Cost-sharing payment models

The cornerstone of population management is provider accountability for the cost of care, which can be accomplished through shared-risk models or population-based payments. Let’s take a closer look at each.

Under shared-risk models, providers receive payment based on their performance against cost targets. The goal is to generate cost savings by improving care coordination, engaging patients in shared decision making based on their health goals, and reducing utilization of care that provides little to no value for patients (for example, preventable hospital admissions or unnecessary imaging or procedures).

Cost targets and actual spending are reconciled retrospectively. If providers beat cost targets, they are eligible to keep a share of generated savings based on their performance on selected quality measures. However, if providers’ actual spending exceeds cost targets, they will compensate payers for a portion of the losses. Under one-sided risk models, providers are eligible for shared savings but not financially responsible for losses. Under two-sided risk models, providers are accountable for both savings and losses.

With prospective population-based payments, also known as capitation, providers receive in advance a fixed amount of money per patient per unit of time (for example, per month) that creates a budget to cover the cost of agreed-upon health care services. The prospective payments are risk adjusted and typically tied to performance on selected quality, effectiveness, and patient experience measures.

Professional services capitation arrangements between physician groups and payers cover the cost of physician services including primary care, specialty care, and related laboratory and radiology services. Under global capitation or global payment arrangements, health care systems receive payments that cover the total cost of care for the patient population for a defined period.

Population-based payments create incentives to provide high-quality and efficient care within a set budget.⁶ If actual cost of delivering services to the defined patient population comes under the budget, the providers will realize savings, but otherwise will encounter losses.
 

What is next?

Now that we have explained the impetus for population management and the terminology, in the next article in this series we will discuss the current state of population management. We will also delve into a hospitalist’s role and participation so you can be aware of impending changes and ensure you are set up for success, no matter how the payment models evolve.
 

Dr. Farah is a hospitalist, physician adviser, and Lean Six Sigma Black Belt. She is a performance improvement consultant based in Corvallis, Ore., and a member of The Hospitalist’s editorial advisory board.

References

1. Source: https://www.healthsystemtracker.org/chart-collection/health-spending-u-s-compare-countries/#item-start

2. Source: https://www.healthsystemtracker.org/brief/on-several-indicators-of-healthcare-quality the-u-s-falls-short/

3. Kindig D, Asada Y, Booske B. (2008). A Population Health Framework for Setting National and State Health Goals. JAMA, 299, 2081-2083.

4. Source: https://improvingpopulationhealth.typepad.com/blog/what-are-health-factorsdeterminants.html

5. Source: http://www.ihi.org/communities/blogs/population-health-population-management-terminology-in-us-health-care

6. Source: http://hcp-lan.org/workproducts/apm-refresh-whitepaper-final.pdf

Traditionally, U.S. health care has operated under a fee-for-service payment model, in which health care providers (such as physicians, hospitals, and health care systems) receive a fee for services such as office visits, hospital stays, procedures, and tests. However, reimbursement discussions are increasingly moving from fee-for-service to value-based, in which payments are tied to managing population health and total cost of care.

Because these changes will impact the entire system all the way down to individual providers, in the upcoming Population Management article series in The Hospitalist, we will discuss the nuances and implications that physicians, executives, and hospitals should be aware of. In this first article, we will examine the impetus for the shift toward population management and introduce common terminology to lay the foundation for the future content.
 

The traditional model: Fee for service

Under the traditional fee-for-service payment system, health care providers are paid per unit of service. For example, hospitals receive diagnosis-related group (DRG) payments for inpatient stays, and physicians are paid per patient visit. The more services that hospitals or physicians provide, the more money both get paid, without financial consequences for quality outcomes or total cost of care. Total cost of care includes clinic visits, outpatient procedures and tests, hospital and ED visits, home health, skilled nursing facilities, durable medical equipment, and sometimes drugs during an episode of care (for example, a hospital stay plus 90 days after discharge) or over a period of time (for example, a month or a year).

As a result of the fee-for-service payment system, the United States spends more money on health care than other wealthy countries, yet it lags behind other countries on many quality measures, such as disease burden, overall mortality, premature death, and preventable death.^1,2

In 2007, the Institute for Healthcare Improvement (IHI) developed the Triple Aim framework that focused on the following:

• Improving the patient experience of care (including quality and satisfaction).
• Improving the health of populations.
• Reducing per capita cost of care.

Both public payers like Medicare and Medicaid, as well as private payers, embraced the Triple Aim to reform how health care is delivered and paid for. As such, health care delivery focus and financial incentives are shifting from managing discrete patient encounters for acute illness to managing population health and total cost of care.
 

A new approach: Population management

Before diving into population management, it is important to first understand the terms “population” and “population health.” A population can be defined geographically or may include employees of an organization, members of a health plan, or patients receiving care from a specific physician group or health care system. David A. Kindig, MD, PhD, professor emeritus of population health sciences at the University of Wisconsin–Madison, defined population health as “the health outcomes of a group of individuals, including the distribution of such outcomes within the group.”³ Dr. Kindig noted that population health outcomes have many determinants, such as the following:⁴

• Health care (access, cost, quantity, and quality of health care services).
• Individual behavior (including diet, exercise, and substance abuse).
• Genetics.
• The social environment (education, income, occupation, class, and social support).
• Physical environment (air and water quality, lead exposure, and the design of neighborhoods).

IHI operationally defines population health by measures such as life expectancy, mortality rates, health and functional status, the incidence and/or prevalence of chronic disease, and behavioral and physiological factors such as smoking, physical activity, diet, blood pressure, body mass index, and cholesterol.⁵

On the other hand, population management is primarily concerned with health care determinants of health and, according to IHI, should be clearly distinguished from population health, which focuses on the broader determinants of health.⁵

According to Ron Greeno, MD, MHM, one of the founding members and a past-president of the Society of Hospital Medicine, population management is a “global approach of caring for an entire patient population to deliver safe and equitable care and to more intelligently allocate resources to keep people well.”

Population management requires understanding the patient population, which includes risk stratification and redesigning and delivering services that are guided by integrated clinical and administrative data and enabled by information technology.
 

Cost-sharing payment models

The cornerstone of population management is provider accountability for the cost of care, which can be accomplished through shared-risk models or population-based payments. Let’s take a closer look at each.

Under shared-risk models, providers receive payment based on their performance against cost targets. The goal is to generate cost savings by improving care coordination, engaging patients in shared decision making based on their health goals, and reducing utilization of care that provides little to no value for patients (for example, preventable hospital admissions or unnecessary imaging or procedures).

Cost targets and actual spending are reconciled retrospectively. If providers beat cost targets, they are eligible to keep a share of generated savings based on their performance on selected quality measures. However, if providers’ actual spending exceeds cost targets, they will compensate payers for a portion of the losses. Under one-sided risk models, providers are eligible for shared savings but not financially responsible for losses. Under two-sided risk models, providers are accountable for both savings and losses.

With prospective population-based payments, also known as capitation, providers receive in advance a fixed amount of money per patient per unit of time (for example, per month) that creates a budget to cover the cost of agreed-upon health care services. The prospective payments are risk adjusted and typically tied to performance on selected quality, effectiveness, and patient experience measures.

Professional services capitation arrangements between physician groups and payers cover the cost of physician services including primary care, specialty care, and related laboratory and radiology services. Under global capitation or global payment arrangements, health care systems receive payments that cover the total cost of care for the patient population for a defined period.

Population-based payments create incentives to provide high-quality and efficient care within a set budget.⁶ If actual cost of delivering services to the defined patient population comes under the budget, the providers will realize savings, but otherwise will encounter losses.
 

What is next?

Now that we have explained the impetus for population management and the terminology, in the next article in this series we will discuss the current state of population management. We will also delve into a hospitalist’s role and participation so you can be aware of impending changes and ensure you are set up for success, no matter how the payment models evolve.
 

Dr. Farah is a hospitalist, physician adviser, and Lean Six Sigma Black Belt. She is a performance improvement consultant based in Corvallis, Ore., and a member of The Hospitalist’s editorial advisory board.

References

1. Source: https://www.healthsystemtracker.org/chart-collection/health-spending-u-s-compare-countries/#item-start

2. Source: https://www.healthsystemtracker.org/brief/on-several-indicators-of-healthcare-quality the-u-s-falls-short/

3. Kindig D, Asada Y, Booske B. (2008). A Population Health Framework for Setting National and State Health Goals. JAMA, 299, 2081-2083.

4. Source: https://improvingpopulationhealth.typepad.com/blog/what-are-health-factorsdeterminants.html

5. Source: http://www.ihi.org/communities/blogs/population-health-population-management-terminology-in-us-health-care

6. Source: http://hcp-lan.org/workproducts/apm-refresh-whitepaper-final.pdf

Traditionally, U.S. health care has operated under a fee-for-service payment model, in which health care providers (such as physicians, hospitals, and health care systems) receive a fee for services such as office visits, hospital stays, procedures, and tests. However, reimbursement discussions are increasingly moving from fee-for-service to value-based, in which payments are tied to managing population health and total cost of care.

Because these changes will impact the entire system all the way down to individual providers, in the upcoming Population Management article series in The Hospitalist, we will discuss the nuances and implications that physicians, executives, and hospitals should be aware of. In this first article, we will examine the impetus for the shift toward population management and introduce common terminology to lay the foundation for the future content.
 

The traditional model: Fee for service

Under the traditional fee-for-service payment system, health care providers are paid per unit of service. For example, hospitals receive diagnosis-related group (DRG) payments for inpatient stays, and physicians are paid per patient visit. The more services that hospitals or physicians provide, the more money both get paid, without financial consequences for quality outcomes or total cost of care. Total cost of care includes clinic visits, outpatient procedures and tests, hospital and ED visits, home health, skilled nursing facilities, durable medical equipment, and sometimes drugs during an episode of care (for example, a hospital stay plus 90 days after discharge) or over a period of time (for example, a month or a year).

As a result of the fee-for-service payment system, the United States spends more money on health care than other wealthy countries, yet it lags behind other countries on many quality measures, such as disease burden, overall mortality, premature death, and preventable death.^1,2

In 2007, the Institute for Healthcare Improvement (IHI) developed the Triple Aim framework that focused on the following:

• Improving the patient experience of care (including quality and satisfaction).
• Improving the health of populations.
• Reducing per capita cost of care.

Both public payers like Medicare and Medicaid, as well as private payers, embraced the Triple Aim to reform how health care is delivered and paid for. As such, health care delivery focus and financial incentives are shifting from managing discrete patient encounters for acute illness to managing population health and total cost of care.
 

A new approach: Population management

Before diving into population management, it is important to first understand the terms “population” and “population health.” A population can be defined geographically or may include employees of an organization, members of a health plan, or patients receiving care from a specific physician group or health care system. David A. Kindig, MD, PhD, professor emeritus of population health sciences at the University of Wisconsin–Madison, defined population health as “the health outcomes of a group of individuals, including the distribution of such outcomes within the group.”³ Dr. Kindig noted that population health outcomes have many determinants, such as the following:⁴

• Health care (access, cost, quantity, and quality of health care services).
• Individual behavior (including diet, exercise, and substance abuse).
• Genetics.
• The social environment (education, income, occupation, class, and social support).
• Physical environment (air and water quality, lead exposure, and the design of neighborhoods).

IHI operationally defines population health by measures such as life expectancy, mortality rates, health and functional status, the incidence and/or prevalence of chronic disease, and behavioral and physiological factors such as smoking, physical activity, diet, blood pressure, body mass index, and cholesterol.⁵

On the other hand, population management is primarily concerned with health care determinants of health and, according to IHI, should be clearly distinguished from population health, which focuses on the broader determinants of health.⁵

According to Ron Greeno, MD, MHM, one of the founding members and a past-president of the Society of Hospital Medicine, population management is a “global approach of caring for an entire patient population to deliver safe and equitable care and to more intelligently allocate resources to keep people well.”

Population management requires understanding the patient population, which includes risk stratification and redesigning and delivering services that are guided by integrated clinical and administrative data and enabled by information technology.
 

Cost-sharing payment models

The cornerstone of population management is provider accountability for the cost of care, which can be accomplished through shared-risk models or population-based payments. Let’s take a closer look at each.

Under shared-risk models, providers receive payment based on their performance against cost targets. The goal is to generate cost savings by improving care coordination, engaging patients in shared decision making based on their health goals, and reducing utilization of care that provides little to no value for patients (for example, preventable hospital admissions or unnecessary imaging or procedures).

Cost targets and actual spending are reconciled retrospectively. If providers beat cost targets, they are eligible to keep a share of generated savings based on their performance on selected quality measures. However, if providers’ actual spending exceeds cost targets, they will compensate payers for a portion of the losses. Under one-sided risk models, providers are eligible for shared savings but not financially responsible for losses. Under two-sided risk models, providers are accountable for both savings and losses.

With prospective population-based payments, also known as capitation, providers receive in advance a fixed amount of money per patient per unit of time (for example, per month) that creates a budget to cover the cost of agreed-upon health care services. The prospective payments are risk adjusted and typically tied to performance on selected quality, effectiveness, and patient experience measures.

Professional services capitation arrangements between physician groups and payers cover the cost of physician services including primary care, specialty care, and related laboratory and radiology services. Under global capitation or global payment arrangements, health care systems receive payments that cover the total cost of care for the patient population for a defined period.

Population-based payments create incentives to provide high-quality and efficient care within a set budget.⁶ If actual cost of delivering services to the defined patient population comes under the budget, the providers will realize savings, but otherwise will encounter losses.
 

What is next?

Now that we have explained the impetus for population management and the terminology, in the next article in this series we will discuss the current state of population management. We will also delve into a hospitalist’s role and participation so you can be aware of impending changes and ensure you are set up for success, no matter how the payment models evolve.
 

Dr. Farah is a hospitalist, physician adviser, and Lean Six Sigma Black Belt. She is a performance improvement consultant based in Corvallis, Ore., and a member of The Hospitalist’s editorial advisory board.

References

1. Source: https://www.healthsystemtracker.org/chart-collection/health-spending-u-s-compare-countries/#item-start

2. Source: https://www.healthsystemtracker.org/brief/on-several-indicators-of-healthcare-quality the-u-s-falls-short/

3. Kindig D, Asada Y, Booske B. (2008). A Population Health Framework for Setting National and State Health Goals. JAMA, 299, 2081-2083.

4. Source: https://improvingpopulationhealth.typepad.com/blog/what-are-health-factorsdeterminants.html

5. Source: http://www.ihi.org/communities/blogs/population-health-population-management-terminology-in-us-health-care

6. Source: http://hcp-lan.org/workproducts/apm-refresh-whitepaper-final.pdf

AUSTIN, TEX. – With the increase in the prevalence of inflammatory bowel disease worldwide approaching pandemic proportions, personalized medicine targeting diet and the microbiome may contribute to a halt or even a reversal of the trend, a leading researcher from Israel and proponent of the Mediterranean diet reported at the Crohn’s & Colitis Congress^®, a partnership of the Crohn's & Colitis Foundation and the American Gastroenterological Association.

“Inflammatory bowel disease is turning into a pandemic around the world,” said Iris Dotan, MD, of the Rabin Medical Center in Petah Tikva, Israel, citing research reported at the 2015 meeting of the European Crohn’s & Colitis Organization that showed the prevalence of inflammatory bowel disease (IBD) in Israel increasing almost 400% from 1991 to 2015, up to 460 per 100,000. “The rising incidence highlights the role of environmental factors,” she added.

She reported on her work with the Rabin Medical Center Pouch Cohort, which is studying the ileal pouch as a man-made model of IBD to get answers. “We believe that when patients progress from having a pouch that is normal to having pouchitis it actually resembles Crohn’s disease and can be used as a model to identify processes that are ongoing in these patients,” she said.

The study is following an unspecified number of ileal pouch patients prospectively, evaluating their biomaterial with stool samples and mucosal biopsies, and tracking their diet and psychosocial status to gain insight into what sets off episodes of pouchitis.

Already, the study has provided insight into how antibiotics may contribute to IBD. “Pouch disease is a very antibiotic-responsive disease,” she said in an interview. “Antibiotics are clinically effective. However, as we dive deeper into this and understand the mechanistics of it, we see that antibiotics cause more dysbiosis, which is something that is unwanted in patients with a pouch.”

A similar response has been shown in Crohn’s disease, she said. With antibiotics, “you’re doing something that might be helpful clinically for the short term; however, it might be harmful in the long term.”

When these patients stop antibiotic therapy, their dysbiosis increases and resistance wanes, she said. “These patients are replenished by other bacteria, probably some from the oral cavity, causing this circle so they would need recurrent courses of antibiotics.”

Evidence is accumulating that the Mediterranean diet can break that cycle, Dr. Dotan said, citing unpublished findings from her group that showed pouchitis patients consumed less fruit than counterparts without the disease. Dr. Dotan also cited a study published this year that found the Mediterranean diet is associated with a lower risk of Crohn’s disease later in life (Gut. 2020 Jan 3. doi: 10.1136/gutjnl-2019-319505).

Dr. Dotan’s research has shown that patients don’t have to adhere completely to the Mediterranean diet but can make less-drastic but significant changes. “You don’t need the whole program,” she said. “If you tell patients to start with something – increase fruits and vegetables – that’s not too complex. Then try to change some of the protein with legumes or other protein sources; that also would be helpful.” Another strategy is to direct patients away from processed foods with additives and preservatives.

“Microbial modifications, including antibiotics, probiotics, diet, and fecal microbial transplantation may have variable effects on specific patient populations, so we can’t be too long simplistic about these options,” she said.

Personalization of diet and microbial manipulations may do more than provide short-term treatment for patients, she said. “It might contribute to halting or even reversing the global increase we’ve seen in IBD recurrence over the past few years.”

Dr. Dotan disclosed financial relationships with AbbVie, Takeda, Pfizer, Genentech/Roche, Neopharm, and Gilead.

SOURCE: Dotan I. Crohn’s & Colitis Congress 2020, Presentation Sp75.

AUSTIN, TEX. – With the increase in the prevalence of inflammatory bowel disease worldwide approaching pandemic proportions, personalized medicine targeting diet and the microbiome may contribute to a halt or even a reversal of the trend, a leading researcher from Israel and proponent of the Mediterranean diet reported at the Crohn’s & Colitis Congress^®, a partnership of the Crohn's & Colitis Foundation and the American Gastroenterological Association.

“Inflammatory bowel disease is turning into a pandemic around the world,” said Iris Dotan, MD, of the Rabin Medical Center in Petah Tikva, Israel, citing research reported at the 2015 meeting of the European Crohn’s & Colitis Organization that showed the prevalence of inflammatory bowel disease (IBD) in Israel increasing almost 400% from 1991 to 2015, up to 460 per 100,000. “The rising incidence highlights the role of environmental factors,” she added.

She reported on her work with the Rabin Medical Center Pouch Cohort, which is studying the ileal pouch as a man-made model of IBD to get answers. “We believe that when patients progress from having a pouch that is normal to having pouchitis it actually resembles Crohn’s disease and can be used as a model to identify processes that are ongoing in these patients,” she said.

The study is following an unspecified number of ileal pouch patients prospectively, evaluating their biomaterial with stool samples and mucosal biopsies, and tracking their diet and psychosocial status to gain insight into what sets off episodes of pouchitis.

Already, the study has provided insight into how antibiotics may contribute to IBD. “Pouch disease is a very antibiotic-responsive disease,” she said in an interview. “Antibiotics are clinically effective. However, as we dive deeper into this and understand the mechanistics of it, we see that antibiotics cause more dysbiosis, which is something that is unwanted in patients with a pouch.”

A similar response has been shown in Crohn’s disease, she said. With antibiotics, “you’re doing something that might be helpful clinically for the short term; however, it might be harmful in the long term.”

When these patients stop antibiotic therapy, their dysbiosis increases and resistance wanes, she said. “These patients are replenished by other bacteria, probably some from the oral cavity, causing this circle so they would need recurrent courses of antibiotics.”

Evidence is accumulating that the Mediterranean diet can break that cycle, Dr. Dotan said, citing unpublished findings from her group that showed pouchitis patients consumed less fruit than counterparts without the disease. Dr. Dotan also cited a study published this year that found the Mediterranean diet is associated with a lower risk of Crohn’s disease later in life (Gut. 2020 Jan 3. doi: 10.1136/gutjnl-2019-319505).

Dr. Dotan’s research has shown that patients don’t have to adhere completely to the Mediterranean diet but can make less-drastic but significant changes. “You don’t need the whole program,” she said. “If you tell patients to start with something – increase fruits and vegetables – that’s not too complex. Then try to change some of the protein with legumes or other protein sources; that also would be helpful.” Another strategy is to direct patients away from processed foods with additives and preservatives.

“Microbial modifications, including antibiotics, probiotics, diet, and fecal microbial transplantation may have variable effects on specific patient populations, so we can’t be too long simplistic about these options,” she said.

Personalization of diet and microbial manipulations may do more than provide short-term treatment for patients, she said. “It might contribute to halting or even reversing the global increase we’ve seen in IBD recurrence over the past few years.”

Dr. Dotan disclosed financial relationships with AbbVie, Takeda, Pfizer, Genentech/Roche, Neopharm, and Gilead.

SOURCE: Dotan I. Crohn’s & Colitis Congress 2020, Presentation Sp75.

AUSTIN, TEX. – With the increase in the prevalence of inflammatory bowel disease worldwide approaching pandemic proportions, personalized medicine targeting diet and the microbiome may contribute to a halt or even a reversal of the trend, a leading researcher from Israel and proponent of the Mediterranean diet reported at the Crohn’s & Colitis Congress^®, a partnership of the Crohn's & Colitis Foundation and the American Gastroenterological Association.

“Inflammatory bowel disease is turning into a pandemic around the world,” said Iris Dotan, MD, of the Rabin Medical Center in Petah Tikva, Israel, citing research reported at the 2015 meeting of the European Crohn’s & Colitis Organization that showed the prevalence of inflammatory bowel disease (IBD) in Israel increasing almost 400% from 1991 to 2015, up to 460 per 100,000. “The rising incidence highlights the role of environmental factors,” she added.

She reported on her work with the Rabin Medical Center Pouch Cohort, which is studying the ileal pouch as a man-made model of IBD to get answers. “We believe that when patients progress from having a pouch that is normal to having pouchitis it actually resembles Crohn’s disease and can be used as a model to identify processes that are ongoing in these patients,” she said.

The study is following an unspecified number of ileal pouch patients prospectively, evaluating their biomaterial with stool samples and mucosal biopsies, and tracking their diet and psychosocial status to gain insight into what sets off episodes of pouchitis.

Already, the study has provided insight into how antibiotics may contribute to IBD. “Pouch disease is a very antibiotic-responsive disease,” she said in an interview. “Antibiotics are clinically effective. However, as we dive deeper into this and understand the mechanistics of it, we see that antibiotics cause more dysbiosis, which is something that is unwanted in patients with a pouch.”

A similar response has been shown in Crohn’s disease, she said. With antibiotics, “you’re doing something that might be helpful clinically for the short term; however, it might be harmful in the long term.”

When these patients stop antibiotic therapy, their dysbiosis increases and resistance wanes, she said. “These patients are replenished by other bacteria, probably some from the oral cavity, causing this circle so they would need recurrent courses of antibiotics.”

Evidence is accumulating that the Mediterranean diet can break that cycle, Dr. Dotan said, citing unpublished findings from her group that showed pouchitis patients consumed less fruit than counterparts without the disease. Dr. Dotan also cited a study published this year that found the Mediterranean diet is associated with a lower risk of Crohn’s disease later in life (Gut. 2020 Jan 3. doi: 10.1136/gutjnl-2019-319505).

Dr. Dotan’s research has shown that patients don’t have to adhere completely to the Mediterranean diet but can make less-drastic but significant changes. “You don’t need the whole program,” she said. “If you tell patients to start with something – increase fruits and vegetables – that’s not too complex. Then try to change some of the protein with legumes or other protein sources; that also would be helpful.” Another strategy is to direct patients away from processed foods with additives and preservatives.

“Microbial modifications, including antibiotics, probiotics, diet, and fecal microbial transplantation may have variable effects on specific patient populations, so we can’t be too long simplistic about these options,” she said.

Personalization of diet and microbial manipulations may do more than provide short-term treatment for patients, she said. “It might contribute to halting or even reversing the global increase we’ve seen in IBD recurrence over the past few years.”

Dr. Dotan disclosed financial relationships with AbbVie, Takeda, Pfizer, Genentech/Roche, Neopharm, and Gilead.

SOURCE: Dotan I. Crohn’s & Colitis Congress 2020, Presentation Sp75.

AUSTIN, TEX. – Early results from a cohort study that aims to characterize the brain-gut relationship in ulcerative colitis (UC) have identified potential structural and functional brain changes consistent with the effect chronic bowel inflammation has on the brain and found two subgroups of patients that differed in how they respond to stress. These findings may provide further insight into the role of the brain in symptom flares, the study leader reported the Crohn’s & Colitis Congress^®, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.

So far, the study has shown that, based on validated measures of perceived stress or neuroticism, patients with UC in clinical remission are clustered on two ends of the stress spectrum, with high and low stress responsiveness, said Emeran A. Mayer, MD, who is coprincipal investigator of the study with Jenny Sauk, MD, both of the University of California, Los Angeles.

The goal of the longitudinal follow-up study is to identify brain, gut microbiome, and stress signatures that predict the risk of flares for up to 2 years in UC patients in clinical remission, he said. Patients’ clinical, microbiome, and stress-psychological measures are evaluated quarterly. The intent is to enroll 100- 120 patients between ages 18 years and 65 years. Questionnaire and symptom data on 70 patients have been analyzed so far.

“What we found so far is that, at baseline using the questionnaire data and clustering analysis, you can identify two distinct subgroups: one characterized by stress hyperresponsiveness and one that does not have that feature,” Dr. Mayer said in an interview. “Then we found in the stress hyperresponsive group there are more flares reported and documented during a mean follow-up of 8.1 months.”

The findings so far have also determined that the differences in stress responsiveness and flare frequency don’t seem to be related to baseline fecal calprotectin levels, said Dr. Mayer, who is director of the G. Oppenheimer Center for Neurobiology of Stress and Resilience (CNSR) and codirector of the CURE: Digestive Diseases Research Center.

Early findings show the incidence of clinical flares in the high stress responsiveness group was 27.4% vs. 9.3% in the low-stress group, and the rate of symptomatic flares was 11.8% vs. 4.6%, respectively.

With regard to baseline biological measures, there were no significant differences in cardiovagal tone or morning salivary cortisol measures between the two clusters, Dr. Mayer noted, although the high stress responsiveness cluster had higher sympathetic tone before, during, and after a brief psychological stress.

He noted that the same clustering into low and high stress responsiveness was confirmed in a different data set of 66 UC subjects and that the two clusters showed significant differences in anatomical connectivity of the default mode network in the brain, a set of regions involved in chronic pain and emotion regulation.

By identifying factors that contribute to inflammatory bowel disease, the study may ultimately simplify the process of identifying IBD patients in remission who are at highest risk of flares, Dr. Mayer said. “Patients won’t need to undergo brain imaging or assessment of microbiome parameters; they can just answer a short questionnaire,” he said. Another potential benefit of the study would be to identify changes in the brain–gut microbiome interactions associated with flares, he said.

Full study results would be available in about 2 years, Dr. Mayer said, with more data on biological parameters expected next year.

The study is funded with a Crohn’s & Colitis Foundation grant. Dr. Mayer disclosed financial relationships with Amare, Axial Biotherapeutics, Bloom Science, Danone, Mahana Therapeutics, Pendulum, Ubiome, and Viome.

SOURCE: Mayer EA et al. Crohn’s & Colitis Congress 2020, Session Sp74.

AUSTIN, TEX. – Early results from a cohort study that aims to characterize the brain-gut relationship in ulcerative colitis (UC) have identified potential structural and functional brain changes consistent with the effect chronic bowel inflammation has on the brain and found two subgroups of patients that differed in how they respond to stress. These findings may provide further insight into the role of the brain in symptom flares, the study leader reported the Crohn’s & Colitis Congress^®, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.

So far, the study has shown that, based on validated measures of perceived stress or neuroticism, patients with UC in clinical remission are clustered on two ends of the stress spectrum, with high and low stress responsiveness, said Emeran A. Mayer, MD, who is coprincipal investigator of the study with Jenny Sauk, MD, both of the University of California, Los Angeles.

The goal of the longitudinal follow-up study is to identify brain, gut microbiome, and stress signatures that predict the risk of flares for up to 2 years in UC patients in clinical remission, he said. Patients’ clinical, microbiome, and stress-psychological measures are evaluated quarterly. The intent is to enroll 100- 120 patients between ages 18 years and 65 years. Questionnaire and symptom data on 70 patients have been analyzed so far.

“What we found so far is that, at baseline using the questionnaire data and clustering analysis, you can identify two distinct subgroups: one characterized by stress hyperresponsiveness and one that does not have that feature,” Dr. Mayer said in an interview. “Then we found in the stress hyperresponsive group there are more flares reported and documented during a mean follow-up of 8.1 months.”

The findings so far have also determined that the differences in stress responsiveness and flare frequency don’t seem to be related to baseline fecal calprotectin levels, said Dr. Mayer, who is director of the G. Oppenheimer Center for Neurobiology of Stress and Resilience (CNSR) and codirector of the CURE: Digestive Diseases Research Center.

Early findings show the incidence of clinical flares in the high stress responsiveness group was 27.4% vs. 9.3% in the low-stress group, and the rate of symptomatic flares was 11.8% vs. 4.6%, respectively.

With regard to baseline biological measures, there were no significant differences in cardiovagal tone or morning salivary cortisol measures between the two clusters, Dr. Mayer noted, although the high stress responsiveness cluster had higher sympathetic tone before, during, and after a brief psychological stress.

He noted that the same clustering into low and high stress responsiveness was confirmed in a different data set of 66 UC subjects and that the two clusters showed significant differences in anatomical connectivity of the default mode network in the brain, a set of regions involved in chronic pain and emotion regulation.

By identifying factors that contribute to inflammatory bowel disease, the study may ultimately simplify the process of identifying IBD patients in remission who are at highest risk of flares, Dr. Mayer said. “Patients won’t need to undergo brain imaging or assessment of microbiome parameters; they can just answer a short questionnaire,” he said. Another potential benefit of the study would be to identify changes in the brain–gut microbiome interactions associated with flares, he said.

Full study results would be available in about 2 years, Dr. Mayer said, with more data on biological parameters expected next year.

The study is funded with a Crohn’s & Colitis Foundation grant. Dr. Mayer disclosed financial relationships with Amare, Axial Biotherapeutics, Bloom Science, Danone, Mahana Therapeutics, Pendulum, Ubiome, and Viome.

SOURCE: Mayer EA et al. Crohn’s & Colitis Congress 2020, Session Sp74.

AUSTIN, TEX. – Early results from a cohort study that aims to characterize the brain-gut relationship in ulcerative colitis (UC) have identified potential structural and functional brain changes consistent with the effect chronic bowel inflammation has on the brain and found two subgroups of patients that differed in how they respond to stress. These findings may provide further insight into the role of the brain in symptom flares, the study leader reported the Crohn’s & Colitis Congress^®, a partnership of the Crohn’s & Colitis Foundation and the American Gastroenterological Association.

So far, the study has shown that, based on validated measures of perceived stress or neuroticism, patients with UC in clinical remission are clustered on two ends of the stress spectrum, with high and low stress responsiveness, said Emeran A. Mayer, MD, who is coprincipal investigator of the study with Jenny Sauk, MD, both of the University of California, Los Angeles.

The goal of the longitudinal follow-up study is to identify brain, gut microbiome, and stress signatures that predict the risk of flares for up to 2 years in UC patients in clinical remission, he said. Patients’ clinical, microbiome, and stress-psychological measures are evaluated quarterly. The intent is to enroll 100- 120 patients between ages 18 years and 65 years. Questionnaire and symptom data on 70 patients have been analyzed so far.

“What we found so far is that, at baseline using the questionnaire data and clustering analysis, you can identify two distinct subgroups: one characterized by stress hyperresponsiveness and one that does not have that feature,” Dr. Mayer said in an interview. “Then we found in the stress hyperresponsive group there are more flares reported and documented during a mean follow-up of 8.1 months.”

The findings so far have also determined that the differences in stress responsiveness and flare frequency don’t seem to be related to baseline fecal calprotectin levels, said Dr. Mayer, who is director of the G. Oppenheimer Center for Neurobiology of Stress and Resilience (CNSR) and codirector of the CURE: Digestive Diseases Research Center.

Early findings show the incidence of clinical flares in the high stress responsiveness group was 27.4% vs. 9.3% in the low-stress group, and the rate of symptomatic flares was 11.8% vs. 4.6%, respectively.

With regard to baseline biological measures, there were no significant differences in cardiovagal tone or morning salivary cortisol measures between the two clusters, Dr. Mayer noted, although the high stress responsiveness cluster had higher sympathetic tone before, during, and after a brief psychological stress.

He noted that the same clustering into low and high stress responsiveness was confirmed in a different data set of 66 UC subjects and that the two clusters showed significant differences in anatomical connectivity of the default mode network in the brain, a set of regions involved in chronic pain and emotion regulation.

By identifying factors that contribute to inflammatory bowel disease, the study may ultimately simplify the process of identifying IBD patients in remission who are at highest risk of flares, Dr. Mayer said. “Patients won’t need to undergo brain imaging or assessment of microbiome parameters; they can just answer a short questionnaire,” he said. Another potential benefit of the study would be to identify changes in the brain–gut microbiome interactions associated with flares, he said.

Full study results would be available in about 2 years, Dr. Mayer said, with more data on biological parameters expected next year.

The study is funded with a Crohn’s & Colitis Foundation grant. Dr. Mayer disclosed financial relationships with Amare, Axial Biotherapeutics, Bloom Science, Danone, Mahana Therapeutics, Pendulum, Ubiome, and Viome.

SOURCE: Mayer EA et al. Crohn’s & Colitis Congress 2020, Session Sp74.

Picosecond and Q-switched (QS) lasers are safe and effective for removing tattoos from the oral mucosa, according to results of two recent cases, researchers reported.

Mucocutaneous tattoos are relatively rare, and lasers have been used for their removal, but cases and results have not been well documented, wrote Hao Feng, MD, then of the Laser & Skin Surgery Center of New York, and the department of dermatology, New York University, and coauthors.

In a report published in Lasers in Surgery and Medicine, the clinicians noted significant improvement with no scarring or dyspigmentation at 1 month after the last treatment session in two patients, with mucosal tattoos that had not been previously treated.

In one case, a healthy 19-year-old woman with Fitzpatrick skin type II presented for removal of a 6‐month‐old, black tattoo on the mucosal surface of her lower lip. She received six treatment sessions at months 0, 1, 3, 5, 7, and 12 with a QS 694‐nm ruby laser at settings of 6-mm spot size, 20-nanosecond pulse duration, and 3.0-3.5 J/cm².

In a second case, a 30‐year‐old man with Fitzpatrick skin type IV presented for removal of a 10‐year‐old black tattoo on his left buccal mucosa. He received one treatment with 755-nm alexandrite picosecond lasers at settings of 2.5-mm spot size, 500-picosecond pulse duration, and 3.36 J/cm².

Both patients experienced local mild discomfort, erythema, and edema after treatment.

“Older tattoos respond better and quicker on the skin to laser treatments, and it is likely the reason why the buccal mucosa tattoo (10 years) resolved with a single treatment whereas the lower lip tattoo (6 months) required six treatments,” the authors noted.

Mucosal tattoos, they added, “tend to respond better, faster, and with less unwanted side effects than tattoos on the skin. This may relate to the fact that mucosal skin is thinner, non-keratinized, well‐vascularized, and contains less melanin content.”

As to which laser is the best choice for removing mucosal tattoos, the authors noted that it is unclear, but while they said they have been using picosecond lasers for tattoo removals, QS lasers “remain excellent treatment modalities,” they wrote.

“Given the excellent clinical response combined with lack of scarring and dyspigmentation in our highly satisfied patients, it is the authors’ opinion that laser treatment should be considered as the first‐line treatment in removing unwanted cosmetic mucosal tattoos. This can be accomplished with various wavelengths in the picosecond and nanosecond domains,” they concluded.

Dr. Feng, who is now director of laser surgery and cosmetic dermatology at the University of Connecticut Health Center, Farmington, disclosed serving as a consultant and medical monitor for Cytrellis Biosystems. Another author disclosed serving on the advisory boards for Cytrellis, Syneron Candela, and Cynosure; owning stocks or having stock options with Cytrellis; and investing in Syneron Candela, Cynosure, and Cytrellis. The remaining two authors had no disclosures.

SOURCE: Feng H et al. Lasers Surg Med. 2019 Dec 30. doi: 10.1002/lsm.23207.

Picosecond and Q-switched (QS) lasers are safe and effective for removing tattoos from the oral mucosa, according to results of two recent cases, researchers reported.

Mucocutaneous tattoos are relatively rare, and lasers have been used for their removal, but cases and results have not been well documented, wrote Hao Feng, MD, then of the Laser & Skin Surgery Center of New York, and the department of dermatology, New York University, and coauthors.

In a report published in Lasers in Surgery and Medicine, the clinicians noted significant improvement with no scarring or dyspigmentation at 1 month after the last treatment session in two patients, with mucosal tattoos that had not been previously treated.

In one case, a healthy 19-year-old woman with Fitzpatrick skin type II presented for removal of a 6‐month‐old, black tattoo on the mucosal surface of her lower lip. She received six treatment sessions at months 0, 1, 3, 5, 7, and 12 with a QS 694‐nm ruby laser at settings of 6-mm spot size, 20-nanosecond pulse duration, and 3.0-3.5 J/cm².

In a second case, a 30‐year‐old man with Fitzpatrick skin type IV presented for removal of a 10‐year‐old black tattoo on his left buccal mucosa. He received one treatment with 755-nm alexandrite picosecond lasers at settings of 2.5-mm spot size, 500-picosecond pulse duration, and 3.36 J/cm².

Both patients experienced local mild discomfort, erythema, and edema after treatment.

“Older tattoos respond better and quicker on the skin to laser treatments, and it is likely the reason why the buccal mucosa tattoo (10 years) resolved with a single treatment whereas the lower lip tattoo (6 months) required six treatments,” the authors noted.

Mucosal tattoos, they added, “tend to respond better, faster, and with less unwanted side effects than tattoos on the skin. This may relate to the fact that mucosal skin is thinner, non-keratinized, well‐vascularized, and contains less melanin content.”

As to which laser is the best choice for removing mucosal tattoos, the authors noted that it is unclear, but while they said they have been using picosecond lasers for tattoo removals, QS lasers “remain excellent treatment modalities,” they wrote.

“Given the excellent clinical response combined with lack of scarring and dyspigmentation in our highly satisfied patients, it is the authors’ opinion that laser treatment should be considered as the first‐line treatment in removing unwanted cosmetic mucosal tattoos. This can be accomplished with various wavelengths in the picosecond and nanosecond domains,” they concluded.

Dr. Feng, who is now director of laser surgery and cosmetic dermatology at the University of Connecticut Health Center, Farmington, disclosed serving as a consultant and medical monitor for Cytrellis Biosystems. Another author disclosed serving on the advisory boards for Cytrellis, Syneron Candela, and Cynosure; owning stocks or having stock options with Cytrellis; and investing in Syneron Candela, Cynosure, and Cytrellis. The remaining two authors had no disclosures.

SOURCE: Feng H et al. Lasers Surg Med. 2019 Dec 30. doi: 10.1002/lsm.23207.

Picosecond and Q-switched (QS) lasers are safe and effective for removing tattoos from the oral mucosa, according to results of two recent cases, researchers reported.

Mucocutaneous tattoos are relatively rare, and lasers have been used for their removal, but cases and results have not been well documented, wrote Hao Feng, MD, then of the Laser & Skin Surgery Center of New York, and the department of dermatology, New York University, and coauthors.

In a report published in Lasers in Surgery and Medicine, the clinicians noted significant improvement with no scarring or dyspigmentation at 1 month after the last treatment session in two patients, with mucosal tattoos that had not been previously treated.

In one case, a healthy 19-year-old woman with Fitzpatrick skin type II presented for removal of a 6‐month‐old, black tattoo on the mucosal surface of her lower lip. She received six treatment sessions at months 0, 1, 3, 5, 7, and 12 with a QS 694‐nm ruby laser at settings of 6-mm spot size, 20-nanosecond pulse duration, and 3.0-3.5 J/cm².

In a second case, a 30‐year‐old man with Fitzpatrick skin type IV presented for removal of a 10‐year‐old black tattoo on his left buccal mucosa. He received one treatment with 755-nm alexandrite picosecond lasers at settings of 2.5-mm spot size, 500-picosecond pulse duration, and 3.36 J/cm².

Both patients experienced local mild discomfort, erythema, and edema after treatment.

“Older tattoos respond better and quicker on the skin to laser treatments, and it is likely the reason why the buccal mucosa tattoo (10 years) resolved with a single treatment whereas the lower lip tattoo (6 months) required six treatments,” the authors noted.

Mucosal tattoos, they added, “tend to respond better, faster, and with less unwanted side effects than tattoos on the skin. This may relate to the fact that mucosal skin is thinner, non-keratinized, well‐vascularized, and contains less melanin content.”

As to which laser is the best choice for removing mucosal tattoos, the authors noted that it is unclear, but while they said they have been using picosecond lasers for tattoo removals, QS lasers “remain excellent treatment modalities,” they wrote.

“Given the excellent clinical response combined with lack of scarring and dyspigmentation in our highly satisfied patients, it is the authors’ opinion that laser treatment should be considered as the first‐line treatment in removing unwanted cosmetic mucosal tattoos. This can be accomplished with various wavelengths in the picosecond and nanosecond domains,” they concluded.

Dr. Feng, who is now director of laser surgery and cosmetic dermatology at the University of Connecticut Health Center, Farmington, disclosed serving as a consultant and medical monitor for Cytrellis Biosystems. Another author disclosed serving on the advisory boards for Cytrellis, Syneron Candela, and Cynosure; owning stocks or having stock options with Cytrellis; and investing in Syneron Candela, Cynosure, and Cytrellis. The remaining two authors had no disclosures.

SOURCE: Feng H et al. Lasers Surg Med. 2019 Dec 30. doi: 10.1002/lsm.23207.

ORLANDO – Dermatologists should be well versed in addressing common concerns that patients, family members, and the media have about photoprotection, Adam Friedman, MD, advised at the ODAC Dermatology, Aesthetic, & Surgical Conference.

“Know the controversies. Be armed and ready when these patients come to your office with questions,” Dr. Friedman, professor and interim chair of dermatology at George Washington University, Washington, said in an interview at the meeting, where he presented on issues related to photoprotection.

Which SPF to choose and the impact of sunscreen on vitamin D are among the issues patients may be asking about.

Sunscreen SPFs above 50 don’t technically provide a “meaningful” increase in ultraviolet protection, given that this value relates to filtering about 98% of UVB, but they still can provide some benefit, which has to do with real-world human error, Dr. Friedman said.

“Most people don’t use sunscreens the right way,” meaning they don’t apply enough to achieve the SPF listed, he added in the interview. “A higher SPF is meaningful, because if they apply less [sunscreen], they actually still are in that safety window,” with the higher SPF sunscreen. (The American Academy of Dermatology recommends an SPF of 30 or higher.) Several studies have shown that a SPF of 70 or 100 is superior to 50, likely because of this “dilutional” effect.

Patients may have concerns about the effects of sunscreen on vitamin D production, the environment, and hair loss, and whether they have endocrine disrupting effects, added Dr. Friedman, who is also the medical director of the meeting.

Inhibition of cutaneous vitamin D synthesis after using sunscreen can vary, based on whether a person has properly applied sunscreen, the season, latitude, and an individual’s age and obesity level. Patients with low vitamin D levels can use a vitamin D supplement to achieve sufficient levels, and patients concerned about the impact of sunscreen and vitamin D can be advised to take 600 IU of vitamin D3 a day, according to Dr. Friedman. Some studies have suggested that UVB exposure and risk of certain cancers are inversely correlated, implicating cutaneous vitamin D synthesis (J Clin Transl Endocrinol. 2014 Oct 5;1[4]:179-86). But correlation does not equal causation, he pointed out.

Other concerns stem from the potential for oxybenzone, a UVA/UVB filter in more than 70% of sunscreens, to act as an endocrine disruptor in people and whether it is potentially damaging the environment. The data driving these concerns “stem from the bench, not the real world,” Dr. Friedman said. While topical application of oxybenzone can result in systemic absorption, and even though it’s been detected in waters that are heavily populated or where people go on vacation, there is no evidence demonstrating toxicity to humans or the coral reefs. “At least the information we have to date says they don’t,” he added.

In a randomized clinical trial recently published in JAMA, Food and Drug Administration investigators found that systemic skin absorption with geometric mean plasma concentrations greater than 0.5 ng/mL with six active ingredients in sunscreen that were tested, including oxybenzone (JAMA. 2020;323[3]:256-7). The study was part of an FDA proposed rule requesting additional information on sunscreen ingredients; the plasma concentrations exceeded the level at which further safety studies could potentially be waived.

The study, Dr. Friedman said, “only demonstrated the ability to detect these UV filters at very small concentrations in the blood. They have yet to show any meaningful biologic correlation to these findings.”

For those patients who prefer not to use chemical filters, Dr. Friedman suggests recommending mineral-based sunscreens, of which he said micro- and nanoparticulate formulations offer the best cosmesis by sitting more evenly on the skin, being more amenable to thinner and less-lipophilic vehicles, and limiting visible light scattering (thereby limiting the unsightly white appearance) – while maintaining UV scattering efficacy. However, controversy has emerged as there are past studies that posit the theoretical danger of nanoparticles in sunscreens, given their potential to penetrate the skin and enter cells.

But continually emerging evidence has shown that commercially available nanosunscreens are safe, with no toxicity even at the cellular level when applied to the skin in sunscreen or in cosmetics. “All evidence to date suggests they do not do this,” Dr. Friedman said, noting that, in Europe, the European Commission’s Scientific Committee on Consumer Safety has stated that nanoparticles below a concentration of 25% in sunscreens is safe, “just don’t put them in aerosolized forms.”

Lastly, while some recent studies have detected titanium dioxide on the hair shafts of patients with and without frontal fibrosing alopecia, Dr. Friedman noted more evidence is needed before recommending that these patients avoid using sunscreen (Br J Dermatol. 2019 Jul;181[1]:216-7). “Correlation does not mean causation, and the current dogma is that there’s no connection between these two,” he commented.

Dr. Friedman reported consulting and advisory board relationships with numerous companies; he also reported speaking for Regeneron, Abbvie, and Dermira, and receiving grants with Pfizer and DF Pharma.

ORLANDO – Dermatologists should be well versed in addressing common concerns that patients, family members, and the media have about photoprotection, Adam Friedman, MD, advised at the ODAC Dermatology, Aesthetic, & Surgical Conference.

“Know the controversies. Be armed and ready when these patients come to your office with questions,” Dr. Friedman, professor and interim chair of dermatology at George Washington University, Washington, said in an interview at the meeting, where he presented on issues related to photoprotection.

Which SPF to choose and the impact of sunscreen on vitamin D are among the issues patients may be asking about.

Sunscreen SPFs above 50 don’t technically provide a “meaningful” increase in ultraviolet protection, given that this value relates to filtering about 98% of UVB, but they still can provide some benefit, which has to do with real-world human error, Dr. Friedman said.

“Most people don’t use sunscreens the right way,” meaning they don’t apply enough to achieve the SPF listed, he added in the interview. “A higher SPF is meaningful, because if they apply less [sunscreen], they actually still are in that safety window,” with the higher SPF sunscreen. (The American Academy of Dermatology recommends an SPF of 30 or higher.) Several studies have shown that a SPF of 70 or 100 is superior to 50, likely because of this “dilutional” effect.

Patients may have concerns about the effects of sunscreen on vitamin D production, the environment, and hair loss, and whether they have endocrine disrupting effects, added Dr. Friedman, who is also the medical director of the meeting.

Inhibition of cutaneous vitamin D synthesis after using sunscreen can vary, based on whether a person has properly applied sunscreen, the season, latitude, and an individual’s age and obesity level. Patients with low vitamin D levels can use a vitamin D supplement to achieve sufficient levels, and patients concerned about the impact of sunscreen and vitamin D can be advised to take 600 IU of vitamin D3 a day, according to Dr. Friedman. Some studies have suggested that UVB exposure and risk of certain cancers are inversely correlated, implicating cutaneous vitamin D synthesis (J Clin Transl Endocrinol. 2014 Oct 5;1[4]:179-86). But correlation does not equal causation, he pointed out.

Other concerns stem from the potential for oxybenzone, a UVA/UVB filter in more than 70% of sunscreens, to act as an endocrine disruptor in people and whether it is potentially damaging the environment. The data driving these concerns “stem from the bench, not the real world,” Dr. Friedman said. While topical application of oxybenzone can result in systemic absorption, and even though it’s been detected in waters that are heavily populated or where people go on vacation, there is no evidence demonstrating toxicity to humans or the coral reefs. “At least the information we have to date says they don’t,” he added.

In a randomized clinical trial recently published in JAMA, Food and Drug Administration investigators found that systemic skin absorption with geometric mean plasma concentrations greater than 0.5 ng/mL with six active ingredients in sunscreen that were tested, including oxybenzone (JAMA. 2020;323[3]:256-7). The study was part of an FDA proposed rule requesting additional information on sunscreen ingredients; the plasma concentrations exceeded the level at which further safety studies could potentially be waived.

The study, Dr. Friedman said, “only demonstrated the ability to detect these UV filters at very small concentrations in the blood. They have yet to show any meaningful biologic correlation to these findings.”

For those patients who prefer not to use chemical filters, Dr. Friedman suggests recommending mineral-based sunscreens, of which he said micro- and nanoparticulate formulations offer the best cosmesis by sitting more evenly on the skin, being more amenable to thinner and less-lipophilic vehicles, and limiting visible light scattering (thereby limiting the unsightly white appearance) – while maintaining UV scattering efficacy. However, controversy has emerged as there are past studies that posit the theoretical danger of nanoparticles in sunscreens, given their potential to penetrate the skin and enter cells.

But continually emerging evidence has shown that commercially available nanosunscreens are safe, with no toxicity even at the cellular level when applied to the skin in sunscreen or in cosmetics. “All evidence to date suggests they do not do this,” Dr. Friedman said, noting that, in Europe, the European Commission’s Scientific Committee on Consumer Safety has stated that nanoparticles below a concentration of 25% in sunscreens is safe, “just don’t put them in aerosolized forms.”

Lastly, while some recent studies have detected titanium dioxide on the hair shafts of patients with and without frontal fibrosing alopecia, Dr. Friedman noted more evidence is needed before recommending that these patients avoid using sunscreen (Br J Dermatol. 2019 Jul;181[1]:216-7). “Correlation does not mean causation, and the current dogma is that there’s no connection between these two,” he commented.

Dr. Friedman reported consulting and advisory board relationships with numerous companies; he also reported speaking for Regeneron, Abbvie, and Dermira, and receiving grants with Pfizer and DF Pharma.

ORLANDO – Dermatologists should be well versed in addressing common concerns that patients, family members, and the media have about photoprotection, Adam Friedman, MD, advised at the ODAC Dermatology, Aesthetic, & Surgical Conference.

“Know the controversies. Be armed and ready when these patients come to your office with questions,” Dr. Friedman, professor and interim chair of dermatology at George Washington University, Washington, said in an interview at the meeting, where he presented on issues related to photoprotection.

Which SPF to choose and the impact of sunscreen on vitamin D are among the issues patients may be asking about.

Sunscreen SPFs above 50 don’t technically provide a “meaningful” increase in ultraviolet protection, given that this value relates to filtering about 98% of UVB, but they still can provide some benefit, which has to do with real-world human error, Dr. Friedman said.

“Most people don’t use sunscreens the right way,” meaning they don’t apply enough to achieve the SPF listed, he added in the interview. “A higher SPF is meaningful, because if they apply less [sunscreen], they actually still are in that safety window,” with the higher SPF sunscreen. (The American Academy of Dermatology recommends an SPF of 30 or higher.) Several studies have shown that a SPF of 70 or 100 is superior to 50, likely because of this “dilutional” effect.

Patients may have concerns about the effects of sunscreen on vitamin D production, the environment, and hair loss, and whether they have endocrine disrupting effects, added Dr. Friedman, who is also the medical director of the meeting.

Inhibition of cutaneous vitamin D synthesis after using sunscreen can vary, based on whether a person has properly applied sunscreen, the season, latitude, and an individual’s age and obesity level. Patients with low vitamin D levels can use a vitamin D supplement to achieve sufficient levels, and patients concerned about the impact of sunscreen and vitamin D can be advised to take 600 IU of vitamin D3 a day, according to Dr. Friedman. Some studies have suggested that UVB exposure and risk of certain cancers are inversely correlated, implicating cutaneous vitamin D synthesis (J Clin Transl Endocrinol. 2014 Oct 5;1[4]:179-86). But correlation does not equal causation, he pointed out.

Other concerns stem from the potential for oxybenzone, a UVA/UVB filter in more than 70% of sunscreens, to act as an endocrine disruptor in people and whether it is potentially damaging the environment. The data driving these concerns “stem from the bench, not the real world,” Dr. Friedman said. While topical application of oxybenzone can result in systemic absorption, and even though it’s been detected in waters that are heavily populated or where people go on vacation, there is no evidence demonstrating toxicity to humans or the coral reefs. “At least the information we have to date says they don’t,” he added.

In a randomized clinical trial recently published in JAMA, Food and Drug Administration investigators found that systemic skin absorption with geometric mean plasma concentrations greater than 0.5 ng/mL with six active ingredients in sunscreen that were tested, including oxybenzone (JAMA. 2020;323[3]:256-7). The study was part of an FDA proposed rule requesting additional information on sunscreen ingredients; the plasma concentrations exceeded the level at which further safety studies could potentially be waived.

The study, Dr. Friedman said, “only demonstrated the ability to detect these UV filters at very small concentrations in the blood. They have yet to show any meaningful biologic correlation to these findings.”

For those patients who prefer not to use chemical filters, Dr. Friedman suggests recommending mineral-based sunscreens, of which he said micro- and nanoparticulate formulations offer the best cosmesis by sitting more evenly on the skin, being more amenable to thinner and less-lipophilic vehicles, and limiting visible light scattering (thereby limiting the unsightly white appearance) – while maintaining UV scattering efficacy. However, controversy has emerged as there are past studies that posit the theoretical danger of nanoparticles in sunscreens, given their potential to penetrate the skin and enter cells.

But continually emerging evidence has shown that commercially available nanosunscreens are safe, with no toxicity even at the cellular level when applied to the skin in sunscreen or in cosmetics. “All evidence to date suggests they do not do this,” Dr. Friedman said, noting that, in Europe, the European Commission’s Scientific Committee on Consumer Safety has stated that nanoparticles below a concentration of 25% in sunscreens is safe, “just don’t put them in aerosolized forms.”

Lastly, while some recent studies have detected titanium dioxide on the hair shafts of patients with and without frontal fibrosing alopecia, Dr. Friedman noted more evidence is needed before recommending that these patients avoid using sunscreen (Br J Dermatol. 2019 Jul;181[1]:216-7). “Correlation does not mean causation, and the current dogma is that there’s no connection between these two,” he commented.

Dr. Friedman reported consulting and advisory board relationships with numerous companies; he also reported speaking for Regeneron, Abbvie, and Dermira, and receiving grants with Pfizer and DF Pharma.

High-dose chemotherapy in the adjuvant setting offers a long-term survival advantage for women with very-high-risk stage III breast cancer, but does not improve survival odds for women with lower-risk cancers, an analysis of 20 years of follow-up data shows.

Among 885 women younger than 56 years at the time of treatment who had 4 or more involved axilliary lymph nodes, there was no overall survival difference over 2 decades between the total population of women randomized to receive adjuvant high-dose chemotherapy (HDCT) and those assigned to receive conventional-dose chemotherapy (CDCT).

However, women with 10 or more involved axilliary nodes and those with triple-negative breast cancer had an approximately 15% absolute improvement in 20-year overall survival with high-dose chemotherapy, although the difference for triple-negative disease fell just short of statistical significance, reported Tessa G. Steenbruggen, MD, from the Netherlands Cancer Institute in Amsterdam and colleagues.

“Our analysis confirms earlier results that HDCT has no significant overall survival benefit compared with CDCT for unselected patients with stage III [breast cancer]. However, we found a 14.6%improvement in 20-year OS estimates with HDCT in the predefined subgroup of patients with 10 or more involved [axilliary lymph nodes],” they wrote in JAMA Oncology.

And although other studies of chemotherapy regimens containing high doses of alkylating agents have shown increases in risk of late second malignancies and major cardiovascular events, there were no significant increases of either adverse event with HDCT in this study, the authors noted.

They reported 20-year follow-up results for 885 women who were enrolled in a 10-center randomized clinical trial conducted in the Netherlands from August 1, 1993, through July 31, 1999.

The participants were younger than age 56 years with breast cancer involving at least 4 axillary lymph nodes. All patients underwent surgery with complete axillary clearance and were then randomized to receive either conventional chemotherapy, which consisted of five cycles of fluorouracil 500mg/m2, epirubicin 90 mg/m2, and cyclophosphamide 500mg/m2 (FEC), or high-dose chemotherapy, with the first 4 cycles identical to conventional-dose chemotherapy but the fifth cycle consisting of cyclophosphamide 6000 mg/m2, thiotepa 480 mg/m2, and carboplatin 1600 mg/m2, supported with autologous hematopoietic stem cell transplant.

In addition, all patients received radiotherapy according to the local standard and 2 years of adjuvant tamoxifen.

After a median follow-up of 20.4 years, the 20-year overall survival (OS) rates were 45.3% for patients who had received high-dose chemotherapy and 41.5% for those who had received the conventional dose. This translated into a nonsignificant hazard ratio of 0.89.

However, for patients with 10 or more involved axillary nodes, the 20-year OS rates were 44.5% with HDCT and 29.9% with CDCT, translating into an absolute OS advantage for high-dose chemotherapy of 14.6% and an HR of 0.72 (P = .02).

Respective 20-year OS rates for women with triple-negative breast cancer were 52.9% and 37.5%, an absolute difference of 15.4% and a HR of 0.67, which fell just short of statistical significance, possibly because of the small number of patients with triple-negative breast cancer (140).

“In our 20-year follow-up analysis, there was no increase in cumulative risk for a second malignant neoplasm or for incidence of major cardiovascular events after HDCT,” the investigators wrote.

They noted that women randomized to high-dose chemotherapy had more frequent dysrhythmias, hypertension, and hypercholesterolemia, adding that the latter two adverse events may be partly attributable to a higher incidence of menopause induction among women who received HDCT.

The study was sponsored by University Medical Center Groningen and the The Netherlands Cancer Institute. Dr Steenbruggen reported receiving grants from the Dutch Health Insurance Council during the conduct of the study.

SOURCE: Steenbruggen TG et al. JAMA Oncology. 2020 Jan 30. doi: 10.1001/jamaoncol.2019.6276.

High-dose chemotherapy in the adjuvant setting offers a long-term survival advantage for women with very-high-risk stage III breast cancer, but does not improve survival odds for women with lower-risk cancers, an analysis of 20 years of follow-up data shows.

Among 885 women younger than 56 years at the time of treatment who had 4 or more involved axilliary lymph nodes, there was no overall survival difference over 2 decades between the total population of women randomized to receive adjuvant high-dose chemotherapy (HDCT) and those assigned to receive conventional-dose chemotherapy (CDCT).

However, women with 10 or more involved axilliary nodes and those with triple-negative breast cancer had an approximately 15% absolute improvement in 20-year overall survival with high-dose chemotherapy, although the difference for triple-negative disease fell just short of statistical significance, reported Tessa G. Steenbruggen, MD, from the Netherlands Cancer Institute in Amsterdam and colleagues.

“Our analysis confirms earlier results that HDCT has no significant overall survival benefit compared with CDCT for unselected patients with stage III [breast cancer]. However, we found a 14.6%improvement in 20-year OS estimates with HDCT in the predefined subgroup of patients with 10 or more involved [axilliary lymph nodes],” they wrote in JAMA Oncology.

And although other studies of chemotherapy regimens containing high doses of alkylating agents have shown increases in risk of late second malignancies and major cardiovascular events, there were no significant increases of either adverse event with HDCT in this study, the authors noted.

They reported 20-year follow-up results for 885 women who were enrolled in a 10-center randomized clinical trial conducted in the Netherlands from August 1, 1993, through July 31, 1999.

The participants were younger than age 56 years with breast cancer involving at least 4 axillary lymph nodes. All patients underwent surgery with complete axillary clearance and were then randomized to receive either conventional chemotherapy, which consisted of five cycles of fluorouracil 500mg/m2, epirubicin 90 mg/m2, and cyclophosphamide 500mg/m2 (FEC), or high-dose chemotherapy, with the first 4 cycles identical to conventional-dose chemotherapy but the fifth cycle consisting of cyclophosphamide 6000 mg/m2, thiotepa 480 mg/m2, and carboplatin 1600 mg/m2, supported with autologous hematopoietic stem cell transplant.

In addition, all patients received radiotherapy according to the local standard and 2 years of adjuvant tamoxifen.

After a median follow-up of 20.4 years, the 20-year overall survival (OS) rates were 45.3% for patients who had received high-dose chemotherapy and 41.5% for those who had received the conventional dose. This translated into a nonsignificant hazard ratio of 0.89.

However, for patients with 10 or more involved axillary nodes, the 20-year OS rates were 44.5% with HDCT and 29.9% with CDCT, translating into an absolute OS advantage for high-dose chemotherapy of 14.6% and an HR of 0.72 (P = .02).

Respective 20-year OS rates for women with triple-negative breast cancer were 52.9% and 37.5%, an absolute difference of 15.4% and a HR of 0.67, which fell just short of statistical significance, possibly because of the small number of patients with triple-negative breast cancer (140).

“In our 20-year follow-up analysis, there was no increase in cumulative risk for a second malignant neoplasm or for incidence of major cardiovascular events after HDCT,” the investigators wrote.

They noted that women randomized to high-dose chemotherapy had more frequent dysrhythmias, hypertension, and hypercholesterolemia, adding that the latter two adverse events may be partly attributable to a higher incidence of menopause induction among women who received HDCT.

The study was sponsored by University Medical Center Groningen and the The Netherlands Cancer Institute. Dr Steenbruggen reported receiving grants from the Dutch Health Insurance Council during the conduct of the study.

SOURCE: Steenbruggen TG et al. JAMA Oncology. 2020 Jan 30. doi: 10.1001/jamaoncol.2019.6276.

High-dose chemotherapy in the adjuvant setting offers a long-term survival advantage for women with very-high-risk stage III breast cancer, but does not improve survival odds for women with lower-risk cancers, an analysis of 20 years of follow-up data shows.

Among 885 women younger than 56 years at the time of treatment who had 4 or more involved axilliary lymph nodes, there was no overall survival difference over 2 decades between the total population of women randomized to receive adjuvant high-dose chemotherapy (HDCT) and those assigned to receive conventional-dose chemotherapy (CDCT).

However, women with 10 or more involved axilliary nodes and those with triple-negative breast cancer had an approximately 15% absolute improvement in 20-year overall survival with high-dose chemotherapy, although the difference for triple-negative disease fell just short of statistical significance, reported Tessa G. Steenbruggen, MD, from the Netherlands Cancer Institute in Amsterdam and colleagues.

“Our analysis confirms earlier results that HDCT has no significant overall survival benefit compared with CDCT for unselected patients with stage III [breast cancer]. However, we found a 14.6%improvement in 20-year OS estimates with HDCT in the predefined subgroup of patients with 10 or more involved [axilliary lymph nodes],” they wrote in JAMA Oncology.

And although other studies of chemotherapy regimens containing high doses of alkylating agents have shown increases in risk of late second malignancies and major cardiovascular events, there were no significant increases of either adverse event with HDCT in this study, the authors noted.

They reported 20-year follow-up results for 885 women who were enrolled in a 10-center randomized clinical trial conducted in the Netherlands from August 1, 1993, through July 31, 1999.

The participants were younger than age 56 years with breast cancer involving at least 4 axillary lymph nodes. All patients underwent surgery with complete axillary clearance and were then randomized to receive either conventional chemotherapy, which consisted of five cycles of fluorouracil 500mg/m2, epirubicin 90 mg/m2, and cyclophosphamide 500mg/m2 (FEC), or high-dose chemotherapy, with the first 4 cycles identical to conventional-dose chemotherapy but the fifth cycle consisting of cyclophosphamide 6000 mg/m2, thiotepa 480 mg/m2, and carboplatin 1600 mg/m2, supported with autologous hematopoietic stem cell transplant.

In addition, all patients received radiotherapy according to the local standard and 2 years of adjuvant tamoxifen.

After a median follow-up of 20.4 years, the 20-year overall survival (OS) rates were 45.3% for patients who had received high-dose chemotherapy and 41.5% for those who had received the conventional dose. This translated into a nonsignificant hazard ratio of 0.89.

However, for patients with 10 or more involved axillary nodes, the 20-year OS rates were 44.5% with HDCT and 29.9% with CDCT, translating into an absolute OS advantage for high-dose chemotherapy of 14.6% and an HR of 0.72 (P = .02).

Respective 20-year OS rates for women with triple-negative breast cancer were 52.9% and 37.5%, an absolute difference of 15.4% and a HR of 0.67, which fell just short of statistical significance, possibly because of the small number of patients with triple-negative breast cancer (140).

“In our 20-year follow-up analysis, there was no increase in cumulative risk for a second malignant neoplasm or for incidence of major cardiovascular events after HDCT,” the investigators wrote.

They noted that women randomized to high-dose chemotherapy had more frequent dysrhythmias, hypertension, and hypercholesterolemia, adding that the latter two adverse events may be partly attributable to a higher incidence of menopause induction among women who received HDCT.

The study was sponsored by University Medical Center Groningen and the The Netherlands Cancer Institute. Dr Steenbruggen reported receiving grants from the Dutch Health Insurance Council during the conduct of the study.

SOURCE: Steenbruggen TG et al. JAMA Oncology. 2020 Jan 30. doi: 10.1001/jamaoncol.2019.6276.

Although the last decade has brought appropriate increased interest in the diagnosis and treatment of postpartum depression, with screening initiatives across more than 40 states in place and even new medications being brought to market for treatment, far less attention has been given to diagnosis and treatment of a particularly serious psychiatric illness: postpartum psychosis.

Postpartum psychosis is relatively rare, with an incidence of 1 in 1,000 births, but it is one of the most serious complications of modern obstetrics. Clinically, women can experience rapid mood changes, most often with the presentation that is consistent with a manic-like psychosis, with associated symptoms of delusional thinking, hallucinations, paranoia and either depression or elation, or an amalgam of these so-called “mixed symptoms.” Onset of symptoms typically is early, within 72 hours as is classically described, but may have a somewhat later time of onset in some women.

Many investigators have studied risk factors for postpartum psychosis, and it has been well established that a history of mood disorder, particularly bipolar disorder, is one of the strongest predictors of risk for postpartum psychosis. Women with histories of postpartum psychosis are at very high risk of recurrence, with as many as 70%-90% of women experiencing recurrence if not prophylaxed with an appropriate agent. From a clinical point of view, women with postpartum psychosis typically are hospitalized, given that this is both a psychiatric and potential obstetrical emergency. In fact, the data would suggest that although postpartum suicide and infanticide are not common, they can be a tragic concomitant of postpartum psychosis (Am J Psychiatry. 2016 Dec 1;173[12]:1179-88).

A great amount of interest has been placed on the etiology of postpartum psychosis, as it’s a dramatic presentation with very rapid onset in the acute postpartum period. A rich evidence base with respect to an algorithm of treatment that maximizes likelihood of full recovery or sustaining of euthymia after recovery is limited. Few studies have looked systematically at the optimum way to treat postpartum psychosis. Clinical wisdom has dictated that, given the dramatic symptoms with which these patients present, most patients are treated with lithium and an antipsychotic medication as if they have a manic-like psychosis. It may take brief or extended periods of time for patients to stabilize. Once they are stabilized, one of the most challenging questions for clinicians is how long to treat. Again, an evidence base clearly informing this question is lacking.

Over the years, many clinicians have treated patients with postpartum psychosis as if they have bipolar disorder, given the index presentation of the illness, so some of these patients are treated with antimanic drugs indefinitely. However, clinical experience from several centers that treat women with postpartum psychosis suggests that in remitted patients, a proportion of them may be able to taper and discontinue treatment, then sustain well-being for protracted periods.

One obstacle with respect to treatment of postpartum psychosis derives from the short length of stay after delivery for many women. Some women who present with symptoms of postpartum psychosis in the first 24-48 hours frequently are managed with direct admission to an inpatient psychiatric service. But others may not develop symptoms until they are home, which may place both mother and newborn at risk.

Given that the risk for recurrent postpartum psychosis is so great (70%-90%), women with histories of postpartum psychosis invariably are prophylaxed with mood stabilizer prior to delivery in a subsequent pregnancy. In our own center, we have published on the value of such prophylactic intervention, not just in women with postpartum psychosis, but in women with bipolar disorder, who are, as noted, at great risk for developing postpartum psychotic symptoms (Am J Psychiatry. 1995 Nov;152[11]:1641-5.)

Although postpartum psychosis may be rare, over the last 3 decades we have seen a substantial number of women with postpartum psychosis and have been fascinated with the spectrum of symptoms with which some women with postpartum psychotic illness present. We also have been impressed with the time required for some women to recompensate from their illness and the course of their disorder after they have seemingly remitted. Some women appear to be able to discontinue treatment as noted above; others, particularly if there is any history of bipolar disorder, need to be maintained on treatment with mood stabilizer indefinitely.

To better understand the phenomenology of postpartum psychosis, as well as the longitudinal course of the illness, in 2019, the Mass General Hospital Postpartum Psychosis Project (MGHP3) was established. The project is conducted as a hospital-based registry where women with histories of postpartum psychosis over the last decade are invited to participate in an in-depth interview to understand both symptoms and course of underlying illness. This is complemented by obtaining a sample of saliva, which is used for genetic testing to try to identify a genetic underpinning associated with postpartum psychosis, as the question of genetic etiology of postpartum psychosis is still an open one.

As part of the MGHP3 project, clinicians across the country are able to contact perinatal psychiatrists in our center with expertise in the treatment of postpartum psychosis. Our psychiatrists also can counsel clinicians on issues regarding long-term management of postpartum psychosis because for many, knowledge of precisely how to manage this disorder or the follow-up treatment may be incomplete.

From a clinical point of view, the relevant questions really include not only acute treatment, which has already been outlined, but also the issue of duration of treatment. While some patients may be able to taper and discontinue treatment after, for example, a year of being totally well, to date we are unable to know who those patients are. We tend to be more conservative in our own center and treat patients with puerperal psychosis for a more protracted period of time, usually over several years. We also ask women about their family history of bipolar disorder or postpartum psychosis. Depending on the clinical course (if the patient really has sustained euthymia), we consider slow taper and ultimate discontinuation. As always, treatment decisions are tailored to individual clinical history, course, and patient wishes.

Postpartum psychosis remains one of the most serious illnesses that we find in reproductive psychiatry, and incomplete attention has been given to this devastating illness, which we read about periodically in newspapers and magazines. Greater understanding of postpartum psychosis will lead to a more precision-like psychiatric approach, tailoring treatment to the invariable heterogeneity of this illness.

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. Email Dr. Cohen at [email protected].

Although the last decade has brought appropriate increased interest in the diagnosis and treatment of postpartum depression, with screening initiatives across more than 40 states in place and even new medications being brought to market for treatment, far less attention has been given to diagnosis and treatment of a particularly serious psychiatric illness: postpartum psychosis.

Postpartum psychosis is relatively rare, with an incidence of 1 in 1,000 births, but it is one of the most serious complications of modern obstetrics. Clinically, women can experience rapid mood changes, most often with the presentation that is consistent with a manic-like psychosis, with associated symptoms of delusional thinking, hallucinations, paranoia and either depression or elation, or an amalgam of these so-called “mixed symptoms.” Onset of symptoms typically is early, within 72 hours as is classically described, but may have a somewhat later time of onset in some women.

Many investigators have studied risk factors for postpartum psychosis, and it has been well established that a history of mood disorder, particularly bipolar disorder, is one of the strongest predictors of risk for postpartum psychosis. Women with histories of postpartum psychosis are at very high risk of recurrence, with as many as 70%-90% of women experiencing recurrence if not prophylaxed with an appropriate agent. From a clinical point of view, women with postpartum psychosis typically are hospitalized, given that this is both a psychiatric and potential obstetrical emergency. In fact, the data would suggest that although postpartum suicide and infanticide are not common, they can be a tragic concomitant of postpartum psychosis (Am J Psychiatry. 2016 Dec 1;173[12]:1179-88).

A great amount of interest has been placed on the etiology of postpartum psychosis, as it’s a dramatic presentation with very rapid onset in the acute postpartum period. A rich evidence base with respect to an algorithm of treatment that maximizes likelihood of full recovery or sustaining of euthymia after recovery is limited. Few studies have looked systematically at the optimum way to treat postpartum psychosis. Clinical wisdom has dictated that, given the dramatic symptoms with which these patients present, most patients are treated with lithium and an antipsychotic medication as if they have a manic-like psychosis. It may take brief or extended periods of time for patients to stabilize. Once they are stabilized, one of the most challenging questions for clinicians is how long to treat. Again, an evidence base clearly informing this question is lacking.

Over the years, many clinicians have treated patients with postpartum psychosis as if they have bipolar disorder, given the index presentation of the illness, so some of these patients are treated with antimanic drugs indefinitely. However, clinical experience from several centers that treat women with postpartum psychosis suggests that in remitted patients, a proportion of them may be able to taper and discontinue treatment, then sustain well-being for protracted periods.

One obstacle with respect to treatment of postpartum psychosis derives from the short length of stay after delivery for many women. Some women who present with symptoms of postpartum psychosis in the first 24-48 hours frequently are managed with direct admission to an inpatient psychiatric service. But others may not develop symptoms until they are home, which may place both mother and newborn at risk.

Given that the risk for recurrent postpartum psychosis is so great (70%-90%), women with histories of postpartum psychosis invariably are prophylaxed with mood stabilizer prior to delivery in a subsequent pregnancy. In our own center, we have published on the value of such prophylactic intervention, not just in women with postpartum psychosis, but in women with bipolar disorder, who are, as noted, at great risk for developing postpartum psychotic symptoms (Am J Psychiatry. 1995 Nov;152[11]:1641-5.)

Although postpartum psychosis may be rare, over the last 3 decades we have seen a substantial number of women with postpartum psychosis and have been fascinated with the spectrum of symptoms with which some women with postpartum psychotic illness present. We also have been impressed with the time required for some women to recompensate from their illness and the course of their disorder after they have seemingly remitted. Some women appear to be able to discontinue treatment as noted above; others, particularly if there is any history of bipolar disorder, need to be maintained on treatment with mood stabilizer indefinitely.

To better understand the phenomenology of postpartum psychosis, as well as the longitudinal course of the illness, in 2019, the Mass General Hospital Postpartum Psychosis Project (MGHP3) was established. The project is conducted as a hospital-based registry where women with histories of postpartum psychosis over the last decade are invited to participate in an in-depth interview to understand both symptoms and course of underlying illness. This is complemented by obtaining a sample of saliva, which is used for genetic testing to try to identify a genetic underpinning associated with postpartum psychosis, as the question of genetic etiology of postpartum psychosis is still an open one.

As part of the MGHP3 project, clinicians across the country are able to contact perinatal psychiatrists in our center with expertise in the treatment of postpartum psychosis. Our psychiatrists also can counsel clinicians on issues regarding long-term management of postpartum psychosis because for many, knowledge of precisely how to manage this disorder or the follow-up treatment may be incomplete.

From a clinical point of view, the relevant questions really include not only acute treatment, which has already been outlined, but also the issue of duration of treatment. While some patients may be able to taper and discontinue treatment after, for example, a year of being totally well, to date we are unable to know who those patients are. We tend to be more conservative in our own center and treat patients with puerperal psychosis for a more protracted period of time, usually over several years. We also ask women about their family history of bipolar disorder or postpartum psychosis. Depending on the clinical course (if the patient really has sustained euthymia), we consider slow taper and ultimate discontinuation. As always, treatment decisions are tailored to individual clinical history, course, and patient wishes.

Postpartum psychosis remains one of the most serious illnesses that we find in reproductive psychiatry, and incomplete attention has been given to this devastating illness, which we read about periodically in newspapers and magazines. Greater understanding of postpartum psychosis will lead to a more precision-like psychiatric approach, tailoring treatment to the invariable heterogeneity of this illness.

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. Email Dr. Cohen at [email protected].

Although the last decade has brought appropriate increased interest in the diagnosis and treatment of postpartum depression, with screening initiatives across more than 40 states in place and even new medications being brought to market for treatment, far less attention has been given to diagnosis and treatment of a particularly serious psychiatric illness: postpartum psychosis.

Postpartum psychosis is relatively rare, with an incidence of 1 in 1,000 births, but it is one of the most serious complications of modern obstetrics. Clinically, women can experience rapid mood changes, most often with the presentation that is consistent with a manic-like psychosis, with associated symptoms of delusional thinking, hallucinations, paranoia and either depression or elation, or an amalgam of these so-called “mixed symptoms.” Onset of symptoms typically is early, within 72 hours as is classically described, but may have a somewhat later time of onset in some women.

Many investigators have studied risk factors for postpartum psychosis, and it has been well established that a history of mood disorder, particularly bipolar disorder, is one of the strongest predictors of risk for postpartum psychosis. Women with histories of postpartum psychosis are at very high risk of recurrence, with as many as 70%-90% of women experiencing recurrence if not prophylaxed with an appropriate agent. From a clinical point of view, women with postpartum psychosis typically are hospitalized, given that this is both a psychiatric and potential obstetrical emergency. In fact, the data would suggest that although postpartum suicide and infanticide are not common, they can be a tragic concomitant of postpartum psychosis (Am J Psychiatry. 2016 Dec 1;173[12]:1179-88).

A great amount of interest has been placed on the etiology of postpartum psychosis, as it’s a dramatic presentation with very rapid onset in the acute postpartum period. A rich evidence base with respect to an algorithm of treatment that maximizes likelihood of full recovery or sustaining of euthymia after recovery is limited. Few studies have looked systematically at the optimum way to treat postpartum psychosis. Clinical wisdom has dictated that, given the dramatic symptoms with which these patients present, most patients are treated with lithium and an antipsychotic medication as if they have a manic-like psychosis. It may take brief or extended periods of time for patients to stabilize. Once they are stabilized, one of the most challenging questions for clinicians is how long to treat. Again, an evidence base clearly informing this question is lacking.

Over the years, many clinicians have treated patients with postpartum psychosis as if they have bipolar disorder, given the index presentation of the illness, so some of these patients are treated with antimanic drugs indefinitely. However, clinical experience from several centers that treat women with postpartum psychosis suggests that in remitted patients, a proportion of them may be able to taper and discontinue treatment, then sustain well-being for protracted periods.

One obstacle with respect to treatment of postpartum psychosis derives from the short length of stay after delivery for many women. Some women who present with symptoms of postpartum psychosis in the first 24-48 hours frequently are managed with direct admission to an inpatient psychiatric service. But others may not develop symptoms until they are home, which may place both mother and newborn at risk.

Given that the risk for recurrent postpartum psychosis is so great (70%-90%), women with histories of postpartum psychosis invariably are prophylaxed with mood stabilizer prior to delivery in a subsequent pregnancy. In our own center, we have published on the value of such prophylactic intervention, not just in women with postpartum psychosis, but in women with bipolar disorder, who are, as noted, at great risk for developing postpartum psychotic symptoms (Am J Psychiatry. 1995 Nov;152[11]:1641-5.)

Although postpartum psychosis may be rare, over the last 3 decades we have seen a substantial number of women with postpartum psychosis and have been fascinated with the spectrum of symptoms with which some women with postpartum psychotic illness present. We also have been impressed with the time required for some women to recompensate from their illness and the course of their disorder after they have seemingly remitted. Some women appear to be able to discontinue treatment as noted above; others, particularly if there is any history of bipolar disorder, need to be maintained on treatment with mood stabilizer indefinitely.

To better understand the phenomenology of postpartum psychosis, as well as the longitudinal course of the illness, in 2019, the Mass General Hospital Postpartum Psychosis Project (MGHP3) was established. The project is conducted as a hospital-based registry where women with histories of postpartum psychosis over the last decade are invited to participate in an in-depth interview to understand both symptoms and course of underlying illness. This is complemented by obtaining a sample of saliva, which is used for genetic testing to try to identify a genetic underpinning associated with postpartum psychosis, as the question of genetic etiology of postpartum psychosis is still an open one.

As part of the MGHP3 project, clinicians across the country are able to contact perinatal psychiatrists in our center with expertise in the treatment of postpartum psychosis. Our psychiatrists also can counsel clinicians on issues regarding long-term management of postpartum psychosis because for many, knowledge of precisely how to manage this disorder or the follow-up treatment may be incomplete.

From a clinical point of view, the relevant questions really include not only acute treatment, which has already been outlined, but also the issue of duration of treatment. While some patients may be able to taper and discontinue treatment after, for example, a year of being totally well, to date we are unable to know who those patients are. We tend to be more conservative in our own center and treat patients with puerperal psychosis for a more protracted period of time, usually over several years. We also ask women about their family history of bipolar disorder or postpartum psychosis. Depending on the clinical course (if the patient really has sustained euthymia), we consider slow taper and ultimate discontinuation. As always, treatment decisions are tailored to individual clinical history, course, and patient wishes.

Postpartum psychosis remains one of the most serious illnesses that we find in reproductive psychiatry, and incomplete attention has been given to this devastating illness, which we read about periodically in newspapers and magazines. Greater understanding of postpartum psychosis will lead to a more precision-like psychiatric approach, tailoring treatment to the invariable heterogeneity of this illness.

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. Email Dr. Cohen at [email protected].