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Environment More Than Genes Impacts Age at Inflammatory Bowel Disease Diagnosis
a large study of IBD patients reported.
Published in Clinical Gastroenterology and Hepatology , the study found that environment influences the onset of both ulcerative colitis (UC) and Crohn’s disease (CD), and exposures typical in Western society lower the age of diagnosis. These factors include birth in a developed nation, delivery by C-section, and more bathrooms in the home, according to Oriana M. Damas, MD, MSCTI, an associate professor of clinical medicine at the University of Miami Miller School of Medicine in Florida and colleagues.
Environmental factors explained 21% of the variance in age of CD diagnosis and 39% of the variance in age of UC diagnosis. In models incorporating both genetic and environmental risk scores, the environment was the only significant factor associated with younger age of IBD diagnosis in all groups.
Several epidemiologic studies have examined environmental culprits in IBD, and others have examined genetic risk factors, Dr. Damas said in an interview. “But we had not seen any studies that examined the influence of both [of] these on age of IBD development.” Her group’s working hypothesis that environment would have a greater effect than genetics was borne out.
“Additionally, very few studies have examined the contribution of genetics or environmental factors in Hispanic individuals, and our study examined the contribution of these factors in this understudied population,” she added.
According to Dr. Damas, the findings’ most immediate clinical relevance is for counseling people with a family history of IBD. “I think it’s important for concerned patients to know that IBD is not solely genetic and that several environmental factors can shape disease risk to a greater extent than genetic predisposition,” she said
Westernization is increasingly considered a contributor to the global increase in IBD, which has been diagnosed in an estimated 2.39 million Americans . In genetically predisposed individuals, environmental culprits in developed countries are thought to negatively shape the intestinal microbiome’s composition into a less tolerant and more proinflammatory state, the authors noted.
According to the “hygiene hypothesis,” the oversanitization of life in the developed world is partly to blame. “A cleaner environment at home, part of the hygiene hypothesis, has been postulated as a theory to help explain the rise of autoimmune diseases in the 21st century and may play an important part in explaining our study findings,” the authors wrote.
Population-based studies have also pointed to antibiotics, nonsteroidal anti-inflammatory drugs, smoking, cesarean delivery, lack of breastfeeding, and nonexposure to farm animals as other risk factors for IBD.
Study Details
To compare the effect of environmental vs genetic risk factors, the questionnaire-based study surveyed 2952 IBD patients from a tertiary care referral center — 58.9% with CD, 45.83% of Hispanic background, and 53.18% of non-Hispanic White (NHW) ethnicity. There were too few available Black and Asian patients to be included in the cohort. Data were collected from 2017 to 2022.
The mean age of patients was 39.71 years, and 34.14% were defined as born outside of the US mainland. Foreign-born patients were further characterized as from developed nations vs developing nations; 81.3% in this subgroup came from the latter. A detailed questionnaire probed 13 potential environmental factors from type of birth to domestic living conditions, medications, and smoking across several different age groups. Blood was drawn to genotype participants and to create a genetic risk score.
Early plastic water bottle use — which has been linked to inflammatory microplastics in the intestines — and residing in homes with more than one bathroom (and presumably less exposure to infections) were also associated with younger age at diagnosis. Susceptibility to environmental exposures was similar in Hispanic and NHW patients.
“It was interesting to find an association between reported plastic water bottle use and younger age of IBD diagnosis,” said Dr. Damas. “Because this is a self-reported intake, we need more studies to confirm this. However, this finding falls in line with other recent studies showing a potential association between microplastics and disease states, including IBD. The next step is to measure for traces of environmental contaminants in human samples of patients with IBD.”
Unlike previous studies, this analysis did not find parasitic infections, pets, and antibiotics to be associated with age of IBD diagnosis.
“This is an interesting and important study,” commented Ashwin Ananthakrishnan, MBBS, MPH, AGAF, director of the Crohn’s and Colitis Center at Massachusetts General Hospital in Boston, who was not involved in the study. “There are few environmental risk factor studies looking at non-White populations and to that end, this is a very large and well-done analysis looking at environmental factors among Hispanic patients with IBD.”
He added that, while most studies have just compared factors between cases and controls, “this is an interesting examination of the impact of such factors on age of onset.”
Dr. Ananthakrishnan stressed, however, that further work is needed to expand on these findings.” The addition of a control group would help determine how these factors actually modify disease risk. It is also intriguing that environmental factors more strongly predict age of onset than genetic risk. That only highlights the fact that IBD is in large part an environmentally influenced disease, suggesting there is exciting opportunity for environmental modification to address disease onset.”
Offering another outsider’s perspective, Manasi Agrawal, MD, MS, an assistant professor of medicine at Icahn School of Medicine at Mount Sinai in New York City and not a participant in the study, agreed that the findings highlight the contribution of early life and childhood environmental factors to IBD risk relative to genetic variants. “The relative importance of the environment compared to genetic risk toward IBD, timing of exposure, and impact on age at IBD diagnosis is a novel and important finding. These data will help contextualize how we communicate disease risk and potential prevention approaches.”
She added that future research should measure various exposures, such as pollutants in preclinical biological samples. “Mechanistic data on their downstream effects are needed to understand IBD pathogenesis and develop prevention efforts.”
According to the authors, theirs is the first study of its kind to examine the contribution of cumulative environmental factors, age-dependent exposures, and genetic predisposition to age of IBD diagnosis in a diverse IBD cohort.
The authors listed no specific funding for this study and had no conflicts of interest to declare. Dr. Ananthakrishnan and Dr. Agrawal had no relevant competing interests.
A version of this article appeared on Medscape.com.
a large study of IBD patients reported.
Published in Clinical Gastroenterology and Hepatology , the study found that environment influences the onset of both ulcerative colitis (UC) and Crohn’s disease (CD), and exposures typical in Western society lower the age of diagnosis. These factors include birth in a developed nation, delivery by C-section, and more bathrooms in the home, according to Oriana M. Damas, MD, MSCTI, an associate professor of clinical medicine at the University of Miami Miller School of Medicine in Florida and colleagues.
Environmental factors explained 21% of the variance in age of CD diagnosis and 39% of the variance in age of UC diagnosis. In models incorporating both genetic and environmental risk scores, the environment was the only significant factor associated with younger age of IBD diagnosis in all groups.
Several epidemiologic studies have examined environmental culprits in IBD, and others have examined genetic risk factors, Dr. Damas said in an interview. “But we had not seen any studies that examined the influence of both [of] these on age of IBD development.” Her group’s working hypothesis that environment would have a greater effect than genetics was borne out.
“Additionally, very few studies have examined the contribution of genetics or environmental factors in Hispanic individuals, and our study examined the contribution of these factors in this understudied population,” she added.
According to Dr. Damas, the findings’ most immediate clinical relevance is for counseling people with a family history of IBD. “I think it’s important for concerned patients to know that IBD is not solely genetic and that several environmental factors can shape disease risk to a greater extent than genetic predisposition,” she said
Westernization is increasingly considered a contributor to the global increase in IBD, which has been diagnosed in an estimated 2.39 million Americans . In genetically predisposed individuals, environmental culprits in developed countries are thought to negatively shape the intestinal microbiome’s composition into a less tolerant and more proinflammatory state, the authors noted.
According to the “hygiene hypothesis,” the oversanitization of life in the developed world is partly to blame. “A cleaner environment at home, part of the hygiene hypothesis, has been postulated as a theory to help explain the rise of autoimmune diseases in the 21st century and may play an important part in explaining our study findings,” the authors wrote.
Population-based studies have also pointed to antibiotics, nonsteroidal anti-inflammatory drugs, smoking, cesarean delivery, lack of breastfeeding, and nonexposure to farm animals as other risk factors for IBD.
Study Details
To compare the effect of environmental vs genetic risk factors, the questionnaire-based study surveyed 2952 IBD patients from a tertiary care referral center — 58.9% with CD, 45.83% of Hispanic background, and 53.18% of non-Hispanic White (NHW) ethnicity. There were too few available Black and Asian patients to be included in the cohort. Data were collected from 2017 to 2022.
The mean age of patients was 39.71 years, and 34.14% were defined as born outside of the US mainland. Foreign-born patients were further characterized as from developed nations vs developing nations; 81.3% in this subgroup came from the latter. A detailed questionnaire probed 13 potential environmental factors from type of birth to domestic living conditions, medications, and smoking across several different age groups. Blood was drawn to genotype participants and to create a genetic risk score.
Early plastic water bottle use — which has been linked to inflammatory microplastics in the intestines — and residing in homes with more than one bathroom (and presumably less exposure to infections) were also associated with younger age at diagnosis. Susceptibility to environmental exposures was similar in Hispanic and NHW patients.
“It was interesting to find an association between reported plastic water bottle use and younger age of IBD diagnosis,” said Dr. Damas. “Because this is a self-reported intake, we need more studies to confirm this. However, this finding falls in line with other recent studies showing a potential association between microplastics and disease states, including IBD. The next step is to measure for traces of environmental contaminants in human samples of patients with IBD.”
Unlike previous studies, this analysis did not find parasitic infections, pets, and antibiotics to be associated with age of IBD diagnosis.
“This is an interesting and important study,” commented Ashwin Ananthakrishnan, MBBS, MPH, AGAF, director of the Crohn’s and Colitis Center at Massachusetts General Hospital in Boston, who was not involved in the study. “There are few environmental risk factor studies looking at non-White populations and to that end, this is a very large and well-done analysis looking at environmental factors among Hispanic patients with IBD.”
He added that, while most studies have just compared factors between cases and controls, “this is an interesting examination of the impact of such factors on age of onset.”
Dr. Ananthakrishnan stressed, however, that further work is needed to expand on these findings.” The addition of a control group would help determine how these factors actually modify disease risk. It is also intriguing that environmental factors more strongly predict age of onset than genetic risk. That only highlights the fact that IBD is in large part an environmentally influenced disease, suggesting there is exciting opportunity for environmental modification to address disease onset.”
Offering another outsider’s perspective, Manasi Agrawal, MD, MS, an assistant professor of medicine at Icahn School of Medicine at Mount Sinai in New York City and not a participant in the study, agreed that the findings highlight the contribution of early life and childhood environmental factors to IBD risk relative to genetic variants. “The relative importance of the environment compared to genetic risk toward IBD, timing of exposure, and impact on age at IBD diagnosis is a novel and important finding. These data will help contextualize how we communicate disease risk and potential prevention approaches.”
She added that future research should measure various exposures, such as pollutants in preclinical biological samples. “Mechanistic data on their downstream effects are needed to understand IBD pathogenesis and develop prevention efforts.”
According to the authors, theirs is the first study of its kind to examine the contribution of cumulative environmental factors, age-dependent exposures, and genetic predisposition to age of IBD diagnosis in a diverse IBD cohort.
The authors listed no specific funding for this study and had no conflicts of interest to declare. Dr. Ananthakrishnan and Dr. Agrawal had no relevant competing interests.
A version of this article appeared on Medscape.com.
a large study of IBD patients reported.
Published in Clinical Gastroenterology and Hepatology , the study found that environment influences the onset of both ulcerative colitis (UC) and Crohn’s disease (CD), and exposures typical in Western society lower the age of diagnosis. These factors include birth in a developed nation, delivery by C-section, and more bathrooms in the home, according to Oriana M. Damas, MD, MSCTI, an associate professor of clinical medicine at the University of Miami Miller School of Medicine in Florida and colleagues.
Environmental factors explained 21% of the variance in age of CD diagnosis and 39% of the variance in age of UC diagnosis. In models incorporating both genetic and environmental risk scores, the environment was the only significant factor associated with younger age of IBD diagnosis in all groups.
Several epidemiologic studies have examined environmental culprits in IBD, and others have examined genetic risk factors, Dr. Damas said in an interview. “But we had not seen any studies that examined the influence of both [of] these on age of IBD development.” Her group’s working hypothesis that environment would have a greater effect than genetics was borne out.
“Additionally, very few studies have examined the contribution of genetics or environmental factors in Hispanic individuals, and our study examined the contribution of these factors in this understudied population,” she added.
According to Dr. Damas, the findings’ most immediate clinical relevance is for counseling people with a family history of IBD. “I think it’s important for concerned patients to know that IBD is not solely genetic and that several environmental factors can shape disease risk to a greater extent than genetic predisposition,” she said
Westernization is increasingly considered a contributor to the global increase in IBD, which has been diagnosed in an estimated 2.39 million Americans . In genetically predisposed individuals, environmental culprits in developed countries are thought to negatively shape the intestinal microbiome’s composition into a less tolerant and more proinflammatory state, the authors noted.
According to the “hygiene hypothesis,” the oversanitization of life in the developed world is partly to blame. “A cleaner environment at home, part of the hygiene hypothesis, has been postulated as a theory to help explain the rise of autoimmune diseases in the 21st century and may play an important part in explaining our study findings,” the authors wrote.
Population-based studies have also pointed to antibiotics, nonsteroidal anti-inflammatory drugs, smoking, cesarean delivery, lack of breastfeeding, and nonexposure to farm animals as other risk factors for IBD.
Study Details
To compare the effect of environmental vs genetic risk factors, the questionnaire-based study surveyed 2952 IBD patients from a tertiary care referral center — 58.9% with CD, 45.83% of Hispanic background, and 53.18% of non-Hispanic White (NHW) ethnicity. There were too few available Black and Asian patients to be included in the cohort. Data were collected from 2017 to 2022.
The mean age of patients was 39.71 years, and 34.14% were defined as born outside of the US mainland. Foreign-born patients were further characterized as from developed nations vs developing nations; 81.3% in this subgroup came from the latter. A detailed questionnaire probed 13 potential environmental factors from type of birth to domestic living conditions, medications, and smoking across several different age groups. Blood was drawn to genotype participants and to create a genetic risk score.
Early plastic water bottle use — which has been linked to inflammatory microplastics in the intestines — and residing in homes with more than one bathroom (and presumably less exposure to infections) were also associated with younger age at diagnosis. Susceptibility to environmental exposures was similar in Hispanic and NHW patients.
“It was interesting to find an association between reported plastic water bottle use and younger age of IBD diagnosis,” said Dr. Damas. “Because this is a self-reported intake, we need more studies to confirm this. However, this finding falls in line with other recent studies showing a potential association between microplastics and disease states, including IBD. The next step is to measure for traces of environmental contaminants in human samples of patients with IBD.”
Unlike previous studies, this analysis did not find parasitic infections, pets, and antibiotics to be associated with age of IBD diagnosis.
“This is an interesting and important study,” commented Ashwin Ananthakrishnan, MBBS, MPH, AGAF, director of the Crohn’s and Colitis Center at Massachusetts General Hospital in Boston, who was not involved in the study. “There are few environmental risk factor studies looking at non-White populations and to that end, this is a very large and well-done analysis looking at environmental factors among Hispanic patients with IBD.”
He added that, while most studies have just compared factors between cases and controls, “this is an interesting examination of the impact of such factors on age of onset.”
Dr. Ananthakrishnan stressed, however, that further work is needed to expand on these findings.” The addition of a control group would help determine how these factors actually modify disease risk. It is also intriguing that environmental factors more strongly predict age of onset than genetic risk. That only highlights the fact that IBD is in large part an environmentally influenced disease, suggesting there is exciting opportunity for environmental modification to address disease onset.”
Offering another outsider’s perspective, Manasi Agrawal, MD, MS, an assistant professor of medicine at Icahn School of Medicine at Mount Sinai in New York City and not a participant in the study, agreed that the findings highlight the contribution of early life and childhood environmental factors to IBD risk relative to genetic variants. “The relative importance of the environment compared to genetic risk toward IBD, timing of exposure, and impact on age at IBD diagnosis is a novel and important finding. These data will help contextualize how we communicate disease risk and potential prevention approaches.”
She added that future research should measure various exposures, such as pollutants in preclinical biological samples. “Mechanistic data on their downstream effects are needed to understand IBD pathogenesis and develop prevention efforts.”
According to the authors, theirs is the first study of its kind to examine the contribution of cumulative environmental factors, age-dependent exposures, and genetic predisposition to age of IBD diagnosis in a diverse IBD cohort.
The authors listed no specific funding for this study and had no conflicts of interest to declare. Dr. Ananthakrishnan and Dr. Agrawal had no relevant competing interests.
A version of this article appeared on Medscape.com.
FROM CLINICAL GASTROENTEROLOGY AND HEPATOLOGY
More Access to Perinatal Mental Healthcare Needed
Despite federal legislation improving healthcare access, concerted efforts are still needed to increase evidence-based treatment for maternal perinatal mental health issues, a large study of commercially insured mothers suggested. It found that federal legislation had variable and suboptimal effect on mental health services use by delivering mothers.
In the cross-sectional study, published in JAMA Network Open, psychotherapy receipt increased somewhat during 2007-2019 among all mothers and among those diagnosed with perinatal mood and anxiety disorders (PMADs). The timeline encompassed periods before and after passage of the Mental Health Parity and Addiction Equity Act (MHPAEA) of 2008 and the Patient Protection and Affordable Care Act (ACA) of 2010.
The investigators, led by Kara Zivin, PhD, MS, MFA, a professor of psychiatry in the University of Michigan’s School of Public Health at Ann Arbor, found the results varied by policy and between the overall delivering population and the PMAD population. “We did not find a statistically significant immediate change associated with the MHPAEA or ACA in the overall delivering population, except for a steady increase in delivering women who received any psychotherapy after ACA,” Dr. Zivin and colleagues wrote.
The researchers looked at private insurance data for 837,316 deliveries among 716,052 women (64.2% White), ages 15-44 (mean 31.2), to assess changes in psychotherapy visits in the year before and after delivery. They also estimated per-visit out-of-pocket costs for the ACA in 2014 and the MHPAEA in 2010.
In the PMAD population, the MHPAEA was associated with an immediate increase in psychotherapy receipt of 0.72% (95% CI, 0.26%-1.18%; P = .002), followed by a sustained decrease of 0.05% (95% CI, 0.09%-0.02%; P = .001).
In both populations, the ACA was associated with immediate and sustained monthly increases in use of 0.77% (95% CI, 0.26%-1.27%; P = .003) and 0.07% (95% CI, 0.02%-0.12%; P = .005), respectively.
Post MHPAEA, both populations experienced a slight decrease in per-visit monthly out-of-pocket costs, while after the ACA they saw an immediate and steady monthly increase in these.
Although both policies expanded access to any psychotherapy, the greater number of people receiving visits coincided with fewer visits per person, the authors noted. “One hypothesis suggests that the number of available mental health clinicians may not have increased enough to meet the new demand; future research should better characterize this trend,” they wrote.
In addition, a lower standard cost per visit may have dampened the incentive to increase the number of mental health clinicians, they conjectured. These factors could explain why the PMAD group appeared to experience a decrease in the proportion receiving any psychotherapy after the MHPAEA’s implementation.
The findings should be reviewed in the context of the current mental health burden, the authors wrote, in which the shortage of mental health professionals means that less than 30% of mental healthcare needs are being met.
They called for more measures to mitigate the excess burden of PMADs.
This study was funded by the National Institutes of Health. Dr. Zivin had no conflicts of interest. Coauthor Dr. Dalton reported personal fees from Merck, the Society of Family Planning, Up to Date, and The Medical Letter outside of the submitted work.
Despite federal legislation improving healthcare access, concerted efforts are still needed to increase evidence-based treatment for maternal perinatal mental health issues, a large study of commercially insured mothers suggested. It found that federal legislation had variable and suboptimal effect on mental health services use by delivering mothers.
In the cross-sectional study, published in JAMA Network Open, psychotherapy receipt increased somewhat during 2007-2019 among all mothers and among those diagnosed with perinatal mood and anxiety disorders (PMADs). The timeline encompassed periods before and after passage of the Mental Health Parity and Addiction Equity Act (MHPAEA) of 2008 and the Patient Protection and Affordable Care Act (ACA) of 2010.
The investigators, led by Kara Zivin, PhD, MS, MFA, a professor of psychiatry in the University of Michigan’s School of Public Health at Ann Arbor, found the results varied by policy and between the overall delivering population and the PMAD population. “We did not find a statistically significant immediate change associated with the MHPAEA or ACA in the overall delivering population, except for a steady increase in delivering women who received any psychotherapy after ACA,” Dr. Zivin and colleagues wrote.
The researchers looked at private insurance data for 837,316 deliveries among 716,052 women (64.2% White), ages 15-44 (mean 31.2), to assess changes in psychotherapy visits in the year before and after delivery. They also estimated per-visit out-of-pocket costs for the ACA in 2014 and the MHPAEA in 2010.
In the PMAD population, the MHPAEA was associated with an immediate increase in psychotherapy receipt of 0.72% (95% CI, 0.26%-1.18%; P = .002), followed by a sustained decrease of 0.05% (95% CI, 0.09%-0.02%; P = .001).
In both populations, the ACA was associated with immediate and sustained monthly increases in use of 0.77% (95% CI, 0.26%-1.27%; P = .003) and 0.07% (95% CI, 0.02%-0.12%; P = .005), respectively.
Post MHPAEA, both populations experienced a slight decrease in per-visit monthly out-of-pocket costs, while after the ACA they saw an immediate and steady monthly increase in these.
Although both policies expanded access to any psychotherapy, the greater number of people receiving visits coincided with fewer visits per person, the authors noted. “One hypothesis suggests that the number of available mental health clinicians may not have increased enough to meet the new demand; future research should better characterize this trend,” they wrote.
In addition, a lower standard cost per visit may have dampened the incentive to increase the number of mental health clinicians, they conjectured. These factors could explain why the PMAD group appeared to experience a decrease in the proportion receiving any psychotherapy after the MHPAEA’s implementation.
The findings should be reviewed in the context of the current mental health burden, the authors wrote, in which the shortage of mental health professionals means that less than 30% of mental healthcare needs are being met.
They called for more measures to mitigate the excess burden of PMADs.
This study was funded by the National Institutes of Health. Dr. Zivin had no conflicts of interest. Coauthor Dr. Dalton reported personal fees from Merck, the Society of Family Planning, Up to Date, and The Medical Letter outside of the submitted work.
Despite federal legislation improving healthcare access, concerted efforts are still needed to increase evidence-based treatment for maternal perinatal mental health issues, a large study of commercially insured mothers suggested. It found that federal legislation had variable and suboptimal effect on mental health services use by delivering mothers.
In the cross-sectional study, published in JAMA Network Open, psychotherapy receipt increased somewhat during 2007-2019 among all mothers and among those diagnosed with perinatal mood and anxiety disorders (PMADs). The timeline encompassed periods before and after passage of the Mental Health Parity and Addiction Equity Act (MHPAEA) of 2008 and the Patient Protection and Affordable Care Act (ACA) of 2010.
The investigators, led by Kara Zivin, PhD, MS, MFA, a professor of psychiatry in the University of Michigan’s School of Public Health at Ann Arbor, found the results varied by policy and between the overall delivering population and the PMAD population. “We did not find a statistically significant immediate change associated with the MHPAEA or ACA in the overall delivering population, except for a steady increase in delivering women who received any psychotherapy after ACA,” Dr. Zivin and colleagues wrote.
The researchers looked at private insurance data for 837,316 deliveries among 716,052 women (64.2% White), ages 15-44 (mean 31.2), to assess changes in psychotherapy visits in the year before and after delivery. They also estimated per-visit out-of-pocket costs for the ACA in 2014 and the MHPAEA in 2010.
In the PMAD population, the MHPAEA was associated with an immediate increase in psychotherapy receipt of 0.72% (95% CI, 0.26%-1.18%; P = .002), followed by a sustained decrease of 0.05% (95% CI, 0.09%-0.02%; P = .001).
In both populations, the ACA was associated with immediate and sustained monthly increases in use of 0.77% (95% CI, 0.26%-1.27%; P = .003) and 0.07% (95% CI, 0.02%-0.12%; P = .005), respectively.
Post MHPAEA, both populations experienced a slight decrease in per-visit monthly out-of-pocket costs, while after the ACA they saw an immediate and steady monthly increase in these.
Although both policies expanded access to any psychotherapy, the greater number of people receiving visits coincided with fewer visits per person, the authors noted. “One hypothesis suggests that the number of available mental health clinicians may not have increased enough to meet the new demand; future research should better characterize this trend,” they wrote.
In addition, a lower standard cost per visit may have dampened the incentive to increase the number of mental health clinicians, they conjectured. These factors could explain why the PMAD group appeared to experience a decrease in the proportion receiving any psychotherapy after the MHPAEA’s implementation.
The findings should be reviewed in the context of the current mental health burden, the authors wrote, in which the shortage of mental health professionals means that less than 30% of mental healthcare needs are being met.
They called for more measures to mitigate the excess burden of PMADs.
This study was funded by the National Institutes of Health. Dr. Zivin had no conflicts of interest. Coauthor Dr. Dalton reported personal fees from Merck, the Society of Family Planning, Up to Date, and The Medical Letter outside of the submitted work.
FROM JAMA NETWORK NEWS
Screen for Urinary Incontinence and Manage It in Primary Care
An estimated 25 million adult Americans experience temporary or chronic urinary incontinence.
Although urinary incontinence can occur in both women and men at any age, it is more common in women over age 50. According to Rise for Health, a national survey-based research study on bladder health, up to 40% of girls and women experience urinary problems and it may be as high as 50% or 60%.
“The main known predictors of urinary incontinence are age, obesity, diabetes, and pregnancy and childbirth,” said internist Joan M. Neuner MD, MPH, a professor of women’s health at Medical College of Wisconsin, Milwaukee.
Other causes are urinary tract infections, pelvic surgery, and in men, of course, prostate problems. Medications such as antihypertensives and antidepressants can promote urinary incontinence. Inexplicably, smokers seem to be at higher risk. Childbearing is a prime reason women are at greater risk. “While C-section can be protective against many pelvic floor issues, vaginal delivery, particularly forceps assisted, increases the risk for urinary incontinence,” said Sarah Friedman, MD, director of the Division of Urogynecology at Staten Island University Hospital, New York City.
Urinary incontinence is underrecognized and undertreated in primary care and may not get enough emphasis in medical schools. Dr. Neuner recently coauthored a small pilot study on developing a primary care pathway to manage urinary incontinence. It suggested that a streamlined paradigm from identification and patient self-care through basic medical care and specialty referral might assist primary care providers as first-line providers in urinary incontinence.
Urinary incontinence’s impact on quality of life should not be underestimated. “It depends on severity, but people may limit their physical activities and social activities, including work, going out with friends, and sexual activity, which can in turn increase loneliness and depression,” Dr. Neuner said in an interview. “Incontinence products like pads and adult diapers are costly and often not covered by insurance.”
In fact, urinary incontinence costs US men and women more than $20 billion per year, mostly for management supplies such as pads and laundry.
Primary Care
While primary care practitioners are well positioned to manage urinary incontinence, the majority of patients remain untreated.
The current stepwise approach should start with a knowledge of basic micturition physiology to identify the incontinence type before selecting treatment, said Khaled A. Imam, MD, CMD, a geriatrician at Corewell Health William Beaumont University Hospital in Royal Oak, Michigan. “More important, this working knowledge can prevent the prescription of an inappropriate treatment or drug, thus preventing many adverse effects,”
According to Dr. Imam, urinary incontinence occurs “because the outlet is open when it should be closed, the outlet is closed when it should be open, the detrusor fails to contract, or the detrusor contracts when it should not.”
There are five main types of incontinence: transient, detrusor overactivity (urge), stress, overflow, and functional. The primary care evaluation of urinary incontinence should include history taking, physical examination, post-voiding residual volume measurement, urinalysis, and urine culture, according to Dr. Imam. “The physical examination should include a urine stress test, abdominal examination, pelvic examination in female patients, rectal examination, and neurologic evaluation.”
Screening
“I am always careful before recommending additional screening that hasn’t been backed by a large screening study. Incontinence has not,” said Dr. Neuner. “However, at most preventive visits, PC [primary care] doctors do a review of systems that includes common symptoms. And so if a PC is currently asking a more generic question like ‘any problems with urine?’ I recommend they replace it with the more specific ‘during the last 3 months, have you leaked any urine, even a small amount?’ ”
Added Kathryn E. Flynn, PhD, a professor of medicine at Medical College of Wisconsin and Dr. Neuner’s coauthor on the primary care pilot study: “Routine screening for urinary incontinence in primary care makes a lot of sense because most older women visit a primary care provider regularly, but they often don’t want to bring the topic up to their provider. When providers routinely screen, it can reduce that barrier to disclosure.“
Treatment
For many women, DIY measures such as losing weight, restricting badder irritants such as caffeine or alcohol, scheduled or double voiding, and at-home Kegel exercises are not enough. Fortunately, treatment options are expanding.
“Nonpharmacologic interventions such as pelvic physical therapy can strengthen the pelvic floor muscles and improve incontinence as long as the muscle strength is maintained,” said Dr. Friedman. “Some procedural or surgical effects last long term and some are shorter acting and need to be repeated over time, but a medication’s effect on bladder function lasts only as long as you take it.”
Strengthening pelvic floor muscles. Solutions for stress incontinence – leakage during coughing, sneezing, lifting, or jumping – aim to hold the urethra closed in the face of increased pressure. “Strengthening the pelvic floor muscles can help hold the urethra closed, but many of us do not know how to contract our pelvic floor muscles correctly,” said Heidi Brown, MD, MAS, a clinician researcher at Kaiser Permanente Southern California and a urogynecologist at Kaiser Permanente San Diego Medical Center. “Working with a pelvic floor therapist is not an option for many busy people, so devices that can be used at home to help women confirm they’re contracting their muscles correctly and remind them to do their exercises are becoming more popular.”
These trainers include external thigh exercisers and vaginal Kegel balls or weights. Kegel chairs that electromagnetically stimulate pelvic muscle contractions are another option, if more expensive. Some deliver pelvic therapy in clinic sessions, but there are several portable versions for home use available online.
According to Dr. Neuner, “pelvic exercises can reduce incontinence by 50% or more. “Some women stay completely dry with them but many women will need help to do these and I usually recommend a referral to a pelvic floor physical therapist or someone with extensive experience.”
Drugs. Overactive bladder, or urge urinary incontinence, leads to leakage because the bladder muscle contracts strongly at inappropriate times. Anticholinergics/antimuscarinics such as oxybutynin (Oxytrol, Ditropan) have been used for decades to control these spasms by relaxing the bladder muscle. Because of recent concerns about their association with cognitive impairment after long-term use, these agents are now being used more cautiously, said Dr. Brown. “A newer class of medication, the beta-3-adrenergic agonists, has not been shown to have that association with cognitive impairment and this class is now being used more frequently to treat overactive bladder.”
This class includes the beta-3-adrenergic agonists vibegron (Gemtesa) and mirabegron (Myrbetriq), which a recent Japanese crossover study found to be comparably effective in women with overactive bladder.
“While they have fewer safety concerns, these newer agents can be costly or may require lots of insurance paperwork, and while I hope that will improve soon, it hasn’t yet,” said Dr. Neuner.
Another pharmacologic option is botulinum A toxin (Botox). Injected into the bladder, this neurotoxin can ease urgency and frequency by relaxing the bladder muscle, added Dr. Friedman.
In some cases combination pharmacotherapy may be advisable.
Surgery. Mid-urethral slings are still considered the preferred option for stress urinary incontinence because they are minimally invasive, safe, and very effective, said Dr. Brown. “Single-incisions slings are an emerging treatment for stress incontinence, because they require one incision instead of three, but their effectiveness has not been proven as robustly as that of the traditional mid-urethral slings,” Dr. Brown said.
Urethral bulking. Bulking can reduce incontinence caused by straining as in defecation by thickening the wall of the urethra. This procedure uses a needle to inject a filler material such as collagen. “These injections are gaining more popularity as research uncovers filler materials that are more durable and with fewer potential complications,” Dr. Brown said.
Neuromodulation. This technique works to reprogram communication between the nerves and the bladder. While conventional therapy worked by relaxing the bladder muscle itself, newer approaches target the nerve that controls the muscle. This can be done at home with gentle, acupuncture-like electric stimulation of the S3 sacral nerve.
“Traditional methods of stimulating the S3 nerve involved placing a needle in the ankle and delivering electrical stimulation via that needle in the doctor’s office, or placing a wire in the nerve near the spine and implanting a pacemaker to deliver electrical stimulation,” Dr. Brown explained. “There are now emerging therapies that implant a device in the ankle to allow electrical stimulation of the S3 nerve in the home, providing a minimally invasive option that does not require weekly trips to the office.”
InterStim is a neural pacemaker that is inserted into the fat of the buttocks and patient controlled by a small handheld external device.
Biofeedback is a technique works for some. A patch applied to the skin over the bladder and urethra area and connected to an external monitor allows patients to see the bladder muscle contracting and teaches them to control spasms and prevent leaks.
Dr. Neuner advises primary care doctors to connect with a local incontinence expert and refer patients to a specialist early on if their condition isn’t improving. “There are both surgical and nonsurgical treatments that only those specialists can give and that can be more effective if given before incontinence is severe — or before the patient has been so frustrated with other treatments that she doesn’t want to try anything else.”
When discussing potential outcomes with patients, Dr. Friedman’s advice is to explain that each management option has different success rates. “Patients need to know that urinary incontinence is a very common condition, but it is not a condition you need to live with. There are many treatments available, all with the goal of improving quality of life.”
The primary care pathway pilot study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. Study authors Dr. Neuner and Dr. Flynn disclosed no relevant conflicts of interest. Dr. Friedman, Dr. Imam, and Dr. Brown disclosed no relevant conflicts of interest.
*Story was updated on August 7, 2024.
An estimated 25 million adult Americans experience temporary or chronic urinary incontinence.
Although urinary incontinence can occur in both women and men at any age, it is more common in women over age 50. According to Rise for Health, a national survey-based research study on bladder health, up to 40% of girls and women experience urinary problems and it may be as high as 50% or 60%.
“The main known predictors of urinary incontinence are age, obesity, diabetes, and pregnancy and childbirth,” said internist Joan M. Neuner MD, MPH, a professor of women’s health at Medical College of Wisconsin, Milwaukee.
Other causes are urinary tract infections, pelvic surgery, and in men, of course, prostate problems. Medications such as antihypertensives and antidepressants can promote urinary incontinence. Inexplicably, smokers seem to be at higher risk. Childbearing is a prime reason women are at greater risk. “While C-section can be protective against many pelvic floor issues, vaginal delivery, particularly forceps assisted, increases the risk for urinary incontinence,” said Sarah Friedman, MD, director of the Division of Urogynecology at Staten Island University Hospital, New York City.
Urinary incontinence is underrecognized and undertreated in primary care and may not get enough emphasis in medical schools. Dr. Neuner recently coauthored a small pilot study on developing a primary care pathway to manage urinary incontinence. It suggested that a streamlined paradigm from identification and patient self-care through basic medical care and specialty referral might assist primary care providers as first-line providers in urinary incontinence.
Urinary incontinence’s impact on quality of life should not be underestimated. “It depends on severity, but people may limit their physical activities and social activities, including work, going out with friends, and sexual activity, which can in turn increase loneliness and depression,” Dr. Neuner said in an interview. “Incontinence products like pads and adult diapers are costly and often not covered by insurance.”
In fact, urinary incontinence costs US men and women more than $20 billion per year, mostly for management supplies such as pads and laundry.
Primary Care
While primary care practitioners are well positioned to manage urinary incontinence, the majority of patients remain untreated.
The current stepwise approach should start with a knowledge of basic micturition physiology to identify the incontinence type before selecting treatment, said Khaled A. Imam, MD, CMD, a geriatrician at Corewell Health William Beaumont University Hospital in Royal Oak, Michigan. “More important, this working knowledge can prevent the prescription of an inappropriate treatment or drug, thus preventing many adverse effects,”
According to Dr. Imam, urinary incontinence occurs “because the outlet is open when it should be closed, the outlet is closed when it should be open, the detrusor fails to contract, or the detrusor contracts when it should not.”
There are five main types of incontinence: transient, detrusor overactivity (urge), stress, overflow, and functional. The primary care evaluation of urinary incontinence should include history taking, physical examination, post-voiding residual volume measurement, urinalysis, and urine culture, according to Dr. Imam. “The physical examination should include a urine stress test, abdominal examination, pelvic examination in female patients, rectal examination, and neurologic evaluation.”
Screening
“I am always careful before recommending additional screening that hasn’t been backed by a large screening study. Incontinence has not,” said Dr. Neuner. “However, at most preventive visits, PC [primary care] doctors do a review of systems that includes common symptoms. And so if a PC is currently asking a more generic question like ‘any problems with urine?’ I recommend they replace it with the more specific ‘during the last 3 months, have you leaked any urine, even a small amount?’ ”
Added Kathryn E. Flynn, PhD, a professor of medicine at Medical College of Wisconsin and Dr. Neuner’s coauthor on the primary care pilot study: “Routine screening for urinary incontinence in primary care makes a lot of sense because most older women visit a primary care provider regularly, but they often don’t want to bring the topic up to their provider. When providers routinely screen, it can reduce that barrier to disclosure.“
Treatment
For many women, DIY measures such as losing weight, restricting badder irritants such as caffeine or alcohol, scheduled or double voiding, and at-home Kegel exercises are not enough. Fortunately, treatment options are expanding.
“Nonpharmacologic interventions such as pelvic physical therapy can strengthen the pelvic floor muscles and improve incontinence as long as the muscle strength is maintained,” said Dr. Friedman. “Some procedural or surgical effects last long term and some are shorter acting and need to be repeated over time, but a medication’s effect on bladder function lasts only as long as you take it.”
Strengthening pelvic floor muscles. Solutions for stress incontinence – leakage during coughing, sneezing, lifting, or jumping – aim to hold the urethra closed in the face of increased pressure. “Strengthening the pelvic floor muscles can help hold the urethra closed, but many of us do not know how to contract our pelvic floor muscles correctly,” said Heidi Brown, MD, MAS, a clinician researcher at Kaiser Permanente Southern California and a urogynecologist at Kaiser Permanente San Diego Medical Center. “Working with a pelvic floor therapist is not an option for many busy people, so devices that can be used at home to help women confirm they’re contracting their muscles correctly and remind them to do their exercises are becoming more popular.”
These trainers include external thigh exercisers and vaginal Kegel balls or weights. Kegel chairs that electromagnetically stimulate pelvic muscle contractions are another option, if more expensive. Some deliver pelvic therapy in clinic sessions, but there are several portable versions for home use available online.
According to Dr. Neuner, “pelvic exercises can reduce incontinence by 50% or more. “Some women stay completely dry with them but many women will need help to do these and I usually recommend a referral to a pelvic floor physical therapist or someone with extensive experience.”
Drugs. Overactive bladder, or urge urinary incontinence, leads to leakage because the bladder muscle contracts strongly at inappropriate times. Anticholinergics/antimuscarinics such as oxybutynin (Oxytrol, Ditropan) have been used for decades to control these spasms by relaxing the bladder muscle. Because of recent concerns about their association with cognitive impairment after long-term use, these agents are now being used more cautiously, said Dr. Brown. “A newer class of medication, the beta-3-adrenergic agonists, has not been shown to have that association with cognitive impairment and this class is now being used more frequently to treat overactive bladder.”
This class includes the beta-3-adrenergic agonists vibegron (Gemtesa) and mirabegron (Myrbetriq), which a recent Japanese crossover study found to be comparably effective in women with overactive bladder.
“While they have fewer safety concerns, these newer agents can be costly or may require lots of insurance paperwork, and while I hope that will improve soon, it hasn’t yet,” said Dr. Neuner.
Another pharmacologic option is botulinum A toxin (Botox). Injected into the bladder, this neurotoxin can ease urgency and frequency by relaxing the bladder muscle, added Dr. Friedman.
In some cases combination pharmacotherapy may be advisable.
Surgery. Mid-urethral slings are still considered the preferred option for stress urinary incontinence because they are minimally invasive, safe, and very effective, said Dr. Brown. “Single-incisions slings are an emerging treatment for stress incontinence, because they require one incision instead of three, but their effectiveness has not been proven as robustly as that of the traditional mid-urethral slings,” Dr. Brown said.
Urethral bulking. Bulking can reduce incontinence caused by straining as in defecation by thickening the wall of the urethra. This procedure uses a needle to inject a filler material such as collagen. “These injections are gaining more popularity as research uncovers filler materials that are more durable and with fewer potential complications,” Dr. Brown said.
Neuromodulation. This technique works to reprogram communication between the nerves and the bladder. While conventional therapy worked by relaxing the bladder muscle itself, newer approaches target the nerve that controls the muscle. This can be done at home with gentle, acupuncture-like electric stimulation of the S3 sacral nerve.
“Traditional methods of stimulating the S3 nerve involved placing a needle in the ankle and delivering electrical stimulation via that needle in the doctor’s office, or placing a wire in the nerve near the spine and implanting a pacemaker to deliver electrical stimulation,” Dr. Brown explained. “There are now emerging therapies that implant a device in the ankle to allow electrical stimulation of the S3 nerve in the home, providing a minimally invasive option that does not require weekly trips to the office.”
InterStim is a neural pacemaker that is inserted into the fat of the buttocks and patient controlled by a small handheld external device.
Biofeedback is a technique works for some. A patch applied to the skin over the bladder and urethra area and connected to an external monitor allows patients to see the bladder muscle contracting and teaches them to control spasms and prevent leaks.
Dr. Neuner advises primary care doctors to connect with a local incontinence expert and refer patients to a specialist early on if their condition isn’t improving. “There are both surgical and nonsurgical treatments that only those specialists can give and that can be more effective if given before incontinence is severe — or before the patient has been so frustrated with other treatments that she doesn’t want to try anything else.”
When discussing potential outcomes with patients, Dr. Friedman’s advice is to explain that each management option has different success rates. “Patients need to know that urinary incontinence is a very common condition, but it is not a condition you need to live with. There are many treatments available, all with the goal of improving quality of life.”
The primary care pathway pilot study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. Study authors Dr. Neuner and Dr. Flynn disclosed no relevant conflicts of interest. Dr. Friedman, Dr. Imam, and Dr. Brown disclosed no relevant conflicts of interest.
*Story was updated on August 7, 2024.
An estimated 25 million adult Americans experience temporary or chronic urinary incontinence.
Although urinary incontinence can occur in both women and men at any age, it is more common in women over age 50. According to Rise for Health, a national survey-based research study on bladder health, up to 40% of girls and women experience urinary problems and it may be as high as 50% or 60%.
“The main known predictors of urinary incontinence are age, obesity, diabetes, and pregnancy and childbirth,” said internist Joan M. Neuner MD, MPH, a professor of women’s health at Medical College of Wisconsin, Milwaukee.
Other causes are urinary tract infections, pelvic surgery, and in men, of course, prostate problems. Medications such as antihypertensives and antidepressants can promote urinary incontinence. Inexplicably, smokers seem to be at higher risk. Childbearing is a prime reason women are at greater risk. “While C-section can be protective against many pelvic floor issues, vaginal delivery, particularly forceps assisted, increases the risk for urinary incontinence,” said Sarah Friedman, MD, director of the Division of Urogynecology at Staten Island University Hospital, New York City.
Urinary incontinence is underrecognized and undertreated in primary care and may not get enough emphasis in medical schools. Dr. Neuner recently coauthored a small pilot study on developing a primary care pathway to manage urinary incontinence. It suggested that a streamlined paradigm from identification and patient self-care through basic medical care and specialty referral might assist primary care providers as first-line providers in urinary incontinence.
Urinary incontinence’s impact on quality of life should not be underestimated. “It depends on severity, but people may limit their physical activities and social activities, including work, going out with friends, and sexual activity, which can in turn increase loneliness and depression,” Dr. Neuner said in an interview. “Incontinence products like pads and adult diapers are costly and often not covered by insurance.”
In fact, urinary incontinence costs US men and women more than $20 billion per year, mostly for management supplies such as pads and laundry.
Primary Care
While primary care practitioners are well positioned to manage urinary incontinence, the majority of patients remain untreated.
The current stepwise approach should start with a knowledge of basic micturition physiology to identify the incontinence type before selecting treatment, said Khaled A. Imam, MD, CMD, a geriatrician at Corewell Health William Beaumont University Hospital in Royal Oak, Michigan. “More important, this working knowledge can prevent the prescription of an inappropriate treatment or drug, thus preventing many adverse effects,”
According to Dr. Imam, urinary incontinence occurs “because the outlet is open when it should be closed, the outlet is closed when it should be open, the detrusor fails to contract, or the detrusor contracts when it should not.”
There are five main types of incontinence: transient, detrusor overactivity (urge), stress, overflow, and functional. The primary care evaluation of urinary incontinence should include history taking, physical examination, post-voiding residual volume measurement, urinalysis, and urine culture, according to Dr. Imam. “The physical examination should include a urine stress test, abdominal examination, pelvic examination in female patients, rectal examination, and neurologic evaluation.”
Screening
“I am always careful before recommending additional screening that hasn’t been backed by a large screening study. Incontinence has not,” said Dr. Neuner. “However, at most preventive visits, PC [primary care] doctors do a review of systems that includes common symptoms. And so if a PC is currently asking a more generic question like ‘any problems with urine?’ I recommend they replace it with the more specific ‘during the last 3 months, have you leaked any urine, even a small amount?’ ”
Added Kathryn E. Flynn, PhD, a professor of medicine at Medical College of Wisconsin and Dr. Neuner’s coauthor on the primary care pilot study: “Routine screening for urinary incontinence in primary care makes a lot of sense because most older women visit a primary care provider regularly, but they often don’t want to bring the topic up to their provider. When providers routinely screen, it can reduce that barrier to disclosure.“
Treatment
For many women, DIY measures such as losing weight, restricting badder irritants such as caffeine or alcohol, scheduled or double voiding, and at-home Kegel exercises are not enough. Fortunately, treatment options are expanding.
“Nonpharmacologic interventions such as pelvic physical therapy can strengthen the pelvic floor muscles and improve incontinence as long as the muscle strength is maintained,” said Dr. Friedman. “Some procedural or surgical effects last long term and some are shorter acting and need to be repeated over time, but a medication’s effect on bladder function lasts only as long as you take it.”
Strengthening pelvic floor muscles. Solutions for stress incontinence – leakage during coughing, sneezing, lifting, or jumping – aim to hold the urethra closed in the face of increased pressure. “Strengthening the pelvic floor muscles can help hold the urethra closed, but many of us do not know how to contract our pelvic floor muscles correctly,” said Heidi Brown, MD, MAS, a clinician researcher at Kaiser Permanente Southern California and a urogynecologist at Kaiser Permanente San Diego Medical Center. “Working with a pelvic floor therapist is not an option for many busy people, so devices that can be used at home to help women confirm they’re contracting their muscles correctly and remind them to do their exercises are becoming more popular.”
These trainers include external thigh exercisers and vaginal Kegel balls or weights. Kegel chairs that electromagnetically stimulate pelvic muscle contractions are another option, if more expensive. Some deliver pelvic therapy in clinic sessions, but there are several portable versions for home use available online.
According to Dr. Neuner, “pelvic exercises can reduce incontinence by 50% or more. “Some women stay completely dry with them but many women will need help to do these and I usually recommend a referral to a pelvic floor physical therapist or someone with extensive experience.”
Drugs. Overactive bladder, or urge urinary incontinence, leads to leakage because the bladder muscle contracts strongly at inappropriate times. Anticholinergics/antimuscarinics such as oxybutynin (Oxytrol, Ditropan) have been used for decades to control these spasms by relaxing the bladder muscle. Because of recent concerns about their association with cognitive impairment after long-term use, these agents are now being used more cautiously, said Dr. Brown. “A newer class of medication, the beta-3-adrenergic agonists, has not been shown to have that association with cognitive impairment and this class is now being used more frequently to treat overactive bladder.”
This class includes the beta-3-adrenergic agonists vibegron (Gemtesa) and mirabegron (Myrbetriq), which a recent Japanese crossover study found to be comparably effective in women with overactive bladder.
“While they have fewer safety concerns, these newer agents can be costly or may require lots of insurance paperwork, and while I hope that will improve soon, it hasn’t yet,” said Dr. Neuner.
Another pharmacologic option is botulinum A toxin (Botox). Injected into the bladder, this neurotoxin can ease urgency and frequency by relaxing the bladder muscle, added Dr. Friedman.
In some cases combination pharmacotherapy may be advisable.
Surgery. Mid-urethral slings are still considered the preferred option for stress urinary incontinence because they are minimally invasive, safe, and very effective, said Dr. Brown. “Single-incisions slings are an emerging treatment for stress incontinence, because they require one incision instead of three, but their effectiveness has not been proven as robustly as that of the traditional mid-urethral slings,” Dr. Brown said.
Urethral bulking. Bulking can reduce incontinence caused by straining as in defecation by thickening the wall of the urethra. This procedure uses a needle to inject a filler material such as collagen. “These injections are gaining more popularity as research uncovers filler materials that are more durable and with fewer potential complications,” Dr. Brown said.
Neuromodulation. This technique works to reprogram communication between the nerves and the bladder. While conventional therapy worked by relaxing the bladder muscle itself, newer approaches target the nerve that controls the muscle. This can be done at home with gentle, acupuncture-like electric stimulation of the S3 sacral nerve.
“Traditional methods of stimulating the S3 nerve involved placing a needle in the ankle and delivering electrical stimulation via that needle in the doctor’s office, or placing a wire in the nerve near the spine and implanting a pacemaker to deliver electrical stimulation,” Dr. Brown explained. “There are now emerging therapies that implant a device in the ankle to allow electrical stimulation of the S3 nerve in the home, providing a minimally invasive option that does not require weekly trips to the office.”
InterStim is a neural pacemaker that is inserted into the fat of the buttocks and patient controlled by a small handheld external device.
Biofeedback is a technique works for some. A patch applied to the skin over the bladder and urethra area and connected to an external monitor allows patients to see the bladder muscle contracting and teaches them to control spasms and prevent leaks.
Dr. Neuner advises primary care doctors to connect with a local incontinence expert and refer patients to a specialist early on if their condition isn’t improving. “There are both surgical and nonsurgical treatments that only those specialists can give and that can be more effective if given before incontinence is severe — or before the patient has been so frustrated with other treatments that she doesn’t want to try anything else.”
When discussing potential outcomes with patients, Dr. Friedman’s advice is to explain that each management option has different success rates. “Patients need to know that urinary incontinence is a very common condition, but it is not a condition you need to live with. There are many treatments available, all with the goal of improving quality of life.”
The primary care pathway pilot study was supported by the National Institute of Diabetes and Digestive and Kidney Diseases of the National Institutes of Health. Study authors Dr. Neuner and Dr. Flynn disclosed no relevant conflicts of interest. Dr. Friedman, Dr. Imam, and Dr. Brown disclosed no relevant conflicts of interest.
*Story was updated on August 7, 2024.
Endometriosis, Especially Severe Types, Boosts Ovarian Cancer Risk
Ovarian cancer risk was higher in women with endometriosis overall and markedly increased in those with severe forms, a large population-based cohort study found.
The findings, published in JAMA, suggest these women may benefit from counseling on ovarian cancer risk and prevention and potentially from targeted screening, according to a group led by Mollie E. Barnard, ScD, of the Huntsman Cancer Institute at the University of Utah in Salt Lake City.
While the absolute increase in number of cases was small, endometriosis patients overall had a more than fourfold higher risk for any type of ovarian cancer. Those with more severe forms, such as ovarian endometriomas or deep infiltrating endometriosis, had a nearly 10-fold higher risk of any type of ovarian cancer. In addition, those with more severe endometriosis had a 19-fold higher risk of type 1 (slow-growing) ovarian cancer and almost three times the risk of the more aggressive type 2.
“Given the rarity of ovarian cancer, the excess risk was relatively small, with 10-20 additional cases per 10,000 women. Nevertheless, women with endometriosis, notably the more severe subtypes, may be an important population for targeted cancer screening and prevention studies,” said corresponding author Karen C. Schliep, PhD, MSPH, associate professor in the university’s Division of Public Health.
Prior studies have shown modest associations between endometriosis and ovarian cancer, Dr. Schliep said in an interview. A 2021 systematic review and meta-analysis found endometriosis conferred nearly double the risk of ovarian cancer, although associations varied by ovarian cancer histotype. Few studies have been large enough to assess associations between endometriosis types — including superficial or peritoneal endometriosis vs ovarian endometriomas or deep infiltrating endometriosis and ovarian cancer histotypes such as low-grade serous, endometrioid, clear cell, and mucinous carcinomas (type 1), and the most aggressive and lethal form, high-grade serous type 2, she said in an interview. “Our large health administrative database of over 11 million individuals with linked electronic health and cancer registry data allowed us to answer this as yet poorly studied research question.”
Study Details
Drawing on Utah electronic health records from 1992 to 2019, the investigators matched 78,893 women with endometriosis in a 1:5 ratio to unaffected women. Cases were categorized as superficial endometriosis, ovarian endometriomas, deep infiltrating endometriosis, or other, and the types of endometriosis were matched to ovarian cancer histotypes.
The mean age of patients at first endometriosis diagnosis was 36 and the mean follow-up was 12 years. Compared with controls, endometriosis patients were more likely to be nulliparous (31% vs 24%) and to have had a hysterectomy (39% vs 6%) during follow-up.
There were 596 reported cases of ovarian cancer in the cohort. Those with incident endometriosis were 4.2 times more likely to develop ovarian cancer (95% CI, 3.59-4.91), 7.48 times more likely to develop type 1 ovarian cancer (95% CI, 5.80-9.65), and 2.70 times more likely to develop type 2 ovarian cancer (95% CI, 2.09-3.49) compared with those without endometriosis.
The magnitudes of these associations varied by endometriosis subtype. Individuals diagnosed with deep infiltrating endometriosis and/or ovarian endometriomas had 9.66 times the risk of ovarian cancer vs individuals without endometriosis (95% CI, 7.77-12.00). “Women with, compared to without, more severe endometriosis had a 19-fold higher risk of type 1 ovarian cancer, including endometrioid, clear cell, mucinous, and low-grade serous,” Dr. Schliep said, with associated risk highest for malignant subtypes such as clear cell and endometrioid carcinoma (adjusted hazard ratios, 11.15 and 7.96, respectively.
According to Dr. Schliep, physicians should encourage endometriosis patients to be aware of but not worry about ovarian cancer risk because the likelihood of developing it remains low. For their part, patients can reduce their risk of cancer through a balanced diet with low intake of alcohol, regular exercise, a healthy weight, and abstention from smoking.
Her message for researchers is as follows: “We need more studies that explore how different types of endometriosis impact different types of ovarian cancer risk. These studies will guide improved ovarian cancer screening and prevention strategies among women with severe endometriosis, with or without other important ovarian cancer risk factors such as BRCA 1/2 variations.”
An accompanying editorial called the Utah study “eloquent” and noted its distinguishing contribution of observing associations between subtypes of endometriosis with overall risk for ovarian cancer as well as histologic subtypes of epithelial ovarian cancer.
Nevertheless, Michael T. McHale, MD, of the Department of Obstetrics, Gynecology, and Reproductive Sciences at Moores Cancer Center, UC San Diego Health, University of California, expressed some methodological concerns. Although the authors attempted to control for key confounders, he noted, the dataset could not provide details on the medical management of endometriosis, such as oral contraceptives or gonadotropin-releasing hormone agonists. “Additionally, there is a possibility that women in the control cohort could have had undiagnosed endometriosis,” he wrote.
Furthermore, making clinical recommendations from these reported observations, particularly with respect to deep infiltrating endometriosis, would require a clear and consistent definition of this type in the dataset over the entire study interval from 1992 to 2019 and for the state of Utah, which the authors did not provide.
“Despite this potential challenge, the increased risk associated with deep infiltrating and/or ovarian endometriosis was clearly significant,” Dr. McHale wrote.
And although the absolute number of ovarian cancers is limited, in his view, the increased risk is sufficiently significant to advise women who have completed childbearing or have alternative fertility options to consider “more definitive surgery.”
This study was supported by multiple not-for-profit agencies, including the National Cancer Institute, the University of Utah, the National Center for Research Resources, the Utah Department of Health and Human Services, the Utah Cancer Registry, the US Centers for Disease Control and Prevention, the Huntsman Cancer Foundation, the National Institutes of Health, and Doris Duke Foundation. Dr. Barnard reported grants from the National Cancer Institute during the conduct of the study and personal fees from Epi Excellence LLC outside the submitted work. Other coauthors reported similar funding from nonprofit agencies or private research organizations. Dr Schliep disclosed no competing interests. Dr McHale reported educational consulting for Eisai Training outside the submitted work.
Ovarian cancer risk was higher in women with endometriosis overall and markedly increased in those with severe forms, a large population-based cohort study found.
The findings, published in JAMA, suggest these women may benefit from counseling on ovarian cancer risk and prevention and potentially from targeted screening, according to a group led by Mollie E. Barnard, ScD, of the Huntsman Cancer Institute at the University of Utah in Salt Lake City.
While the absolute increase in number of cases was small, endometriosis patients overall had a more than fourfold higher risk for any type of ovarian cancer. Those with more severe forms, such as ovarian endometriomas or deep infiltrating endometriosis, had a nearly 10-fold higher risk of any type of ovarian cancer. In addition, those with more severe endometriosis had a 19-fold higher risk of type 1 (slow-growing) ovarian cancer and almost three times the risk of the more aggressive type 2.
“Given the rarity of ovarian cancer, the excess risk was relatively small, with 10-20 additional cases per 10,000 women. Nevertheless, women with endometriosis, notably the more severe subtypes, may be an important population for targeted cancer screening and prevention studies,” said corresponding author Karen C. Schliep, PhD, MSPH, associate professor in the university’s Division of Public Health.
Prior studies have shown modest associations between endometriosis and ovarian cancer, Dr. Schliep said in an interview. A 2021 systematic review and meta-analysis found endometriosis conferred nearly double the risk of ovarian cancer, although associations varied by ovarian cancer histotype. Few studies have been large enough to assess associations between endometriosis types — including superficial or peritoneal endometriosis vs ovarian endometriomas or deep infiltrating endometriosis and ovarian cancer histotypes such as low-grade serous, endometrioid, clear cell, and mucinous carcinomas (type 1), and the most aggressive and lethal form, high-grade serous type 2, she said in an interview. “Our large health administrative database of over 11 million individuals with linked electronic health and cancer registry data allowed us to answer this as yet poorly studied research question.”
Study Details
Drawing on Utah electronic health records from 1992 to 2019, the investigators matched 78,893 women with endometriosis in a 1:5 ratio to unaffected women. Cases were categorized as superficial endometriosis, ovarian endometriomas, deep infiltrating endometriosis, or other, and the types of endometriosis were matched to ovarian cancer histotypes.
The mean age of patients at first endometriosis diagnosis was 36 and the mean follow-up was 12 years. Compared with controls, endometriosis patients were more likely to be nulliparous (31% vs 24%) and to have had a hysterectomy (39% vs 6%) during follow-up.
There were 596 reported cases of ovarian cancer in the cohort. Those with incident endometriosis were 4.2 times more likely to develop ovarian cancer (95% CI, 3.59-4.91), 7.48 times more likely to develop type 1 ovarian cancer (95% CI, 5.80-9.65), and 2.70 times more likely to develop type 2 ovarian cancer (95% CI, 2.09-3.49) compared with those without endometriosis.
The magnitudes of these associations varied by endometriosis subtype. Individuals diagnosed with deep infiltrating endometriosis and/or ovarian endometriomas had 9.66 times the risk of ovarian cancer vs individuals without endometriosis (95% CI, 7.77-12.00). “Women with, compared to without, more severe endometriosis had a 19-fold higher risk of type 1 ovarian cancer, including endometrioid, clear cell, mucinous, and low-grade serous,” Dr. Schliep said, with associated risk highest for malignant subtypes such as clear cell and endometrioid carcinoma (adjusted hazard ratios, 11.15 and 7.96, respectively.
According to Dr. Schliep, physicians should encourage endometriosis patients to be aware of but not worry about ovarian cancer risk because the likelihood of developing it remains low. For their part, patients can reduce their risk of cancer through a balanced diet with low intake of alcohol, regular exercise, a healthy weight, and abstention from smoking.
Her message for researchers is as follows: “We need more studies that explore how different types of endometriosis impact different types of ovarian cancer risk. These studies will guide improved ovarian cancer screening and prevention strategies among women with severe endometriosis, with or without other important ovarian cancer risk factors such as BRCA 1/2 variations.”
An accompanying editorial called the Utah study “eloquent” and noted its distinguishing contribution of observing associations between subtypes of endometriosis with overall risk for ovarian cancer as well as histologic subtypes of epithelial ovarian cancer.
Nevertheless, Michael T. McHale, MD, of the Department of Obstetrics, Gynecology, and Reproductive Sciences at Moores Cancer Center, UC San Diego Health, University of California, expressed some methodological concerns. Although the authors attempted to control for key confounders, he noted, the dataset could not provide details on the medical management of endometriosis, such as oral contraceptives or gonadotropin-releasing hormone agonists. “Additionally, there is a possibility that women in the control cohort could have had undiagnosed endometriosis,” he wrote.
Furthermore, making clinical recommendations from these reported observations, particularly with respect to deep infiltrating endometriosis, would require a clear and consistent definition of this type in the dataset over the entire study interval from 1992 to 2019 and for the state of Utah, which the authors did not provide.
“Despite this potential challenge, the increased risk associated with deep infiltrating and/or ovarian endometriosis was clearly significant,” Dr. McHale wrote.
And although the absolute number of ovarian cancers is limited, in his view, the increased risk is sufficiently significant to advise women who have completed childbearing or have alternative fertility options to consider “more definitive surgery.”
This study was supported by multiple not-for-profit agencies, including the National Cancer Institute, the University of Utah, the National Center for Research Resources, the Utah Department of Health and Human Services, the Utah Cancer Registry, the US Centers for Disease Control and Prevention, the Huntsman Cancer Foundation, the National Institutes of Health, and Doris Duke Foundation. Dr. Barnard reported grants from the National Cancer Institute during the conduct of the study and personal fees from Epi Excellence LLC outside the submitted work. Other coauthors reported similar funding from nonprofit agencies or private research organizations. Dr Schliep disclosed no competing interests. Dr McHale reported educational consulting for Eisai Training outside the submitted work.
Ovarian cancer risk was higher in women with endometriosis overall and markedly increased in those with severe forms, a large population-based cohort study found.
The findings, published in JAMA, suggest these women may benefit from counseling on ovarian cancer risk and prevention and potentially from targeted screening, according to a group led by Mollie E. Barnard, ScD, of the Huntsman Cancer Institute at the University of Utah in Salt Lake City.
While the absolute increase in number of cases was small, endometriosis patients overall had a more than fourfold higher risk for any type of ovarian cancer. Those with more severe forms, such as ovarian endometriomas or deep infiltrating endometriosis, had a nearly 10-fold higher risk of any type of ovarian cancer. In addition, those with more severe endometriosis had a 19-fold higher risk of type 1 (slow-growing) ovarian cancer and almost three times the risk of the more aggressive type 2.
“Given the rarity of ovarian cancer, the excess risk was relatively small, with 10-20 additional cases per 10,000 women. Nevertheless, women with endometriosis, notably the more severe subtypes, may be an important population for targeted cancer screening and prevention studies,” said corresponding author Karen C. Schliep, PhD, MSPH, associate professor in the university’s Division of Public Health.
Prior studies have shown modest associations between endometriosis and ovarian cancer, Dr. Schliep said in an interview. A 2021 systematic review and meta-analysis found endometriosis conferred nearly double the risk of ovarian cancer, although associations varied by ovarian cancer histotype. Few studies have been large enough to assess associations between endometriosis types — including superficial or peritoneal endometriosis vs ovarian endometriomas or deep infiltrating endometriosis and ovarian cancer histotypes such as low-grade serous, endometrioid, clear cell, and mucinous carcinomas (type 1), and the most aggressive and lethal form, high-grade serous type 2, she said in an interview. “Our large health administrative database of over 11 million individuals with linked electronic health and cancer registry data allowed us to answer this as yet poorly studied research question.”
Study Details
Drawing on Utah electronic health records from 1992 to 2019, the investigators matched 78,893 women with endometriosis in a 1:5 ratio to unaffected women. Cases were categorized as superficial endometriosis, ovarian endometriomas, deep infiltrating endometriosis, or other, and the types of endometriosis were matched to ovarian cancer histotypes.
The mean age of patients at first endometriosis diagnosis was 36 and the mean follow-up was 12 years. Compared with controls, endometriosis patients were more likely to be nulliparous (31% vs 24%) and to have had a hysterectomy (39% vs 6%) during follow-up.
There were 596 reported cases of ovarian cancer in the cohort. Those with incident endometriosis were 4.2 times more likely to develop ovarian cancer (95% CI, 3.59-4.91), 7.48 times more likely to develop type 1 ovarian cancer (95% CI, 5.80-9.65), and 2.70 times more likely to develop type 2 ovarian cancer (95% CI, 2.09-3.49) compared with those without endometriosis.
The magnitudes of these associations varied by endometriosis subtype. Individuals diagnosed with deep infiltrating endometriosis and/or ovarian endometriomas had 9.66 times the risk of ovarian cancer vs individuals without endometriosis (95% CI, 7.77-12.00). “Women with, compared to without, more severe endometriosis had a 19-fold higher risk of type 1 ovarian cancer, including endometrioid, clear cell, mucinous, and low-grade serous,” Dr. Schliep said, with associated risk highest for malignant subtypes such as clear cell and endometrioid carcinoma (adjusted hazard ratios, 11.15 and 7.96, respectively.
According to Dr. Schliep, physicians should encourage endometriosis patients to be aware of but not worry about ovarian cancer risk because the likelihood of developing it remains low. For their part, patients can reduce their risk of cancer through a balanced diet with low intake of alcohol, regular exercise, a healthy weight, and abstention from smoking.
Her message for researchers is as follows: “We need more studies that explore how different types of endometriosis impact different types of ovarian cancer risk. These studies will guide improved ovarian cancer screening and prevention strategies among women with severe endometriosis, with or without other important ovarian cancer risk factors such as BRCA 1/2 variations.”
An accompanying editorial called the Utah study “eloquent” and noted its distinguishing contribution of observing associations between subtypes of endometriosis with overall risk for ovarian cancer as well as histologic subtypes of epithelial ovarian cancer.
Nevertheless, Michael T. McHale, MD, of the Department of Obstetrics, Gynecology, and Reproductive Sciences at Moores Cancer Center, UC San Diego Health, University of California, expressed some methodological concerns. Although the authors attempted to control for key confounders, he noted, the dataset could not provide details on the medical management of endometriosis, such as oral contraceptives or gonadotropin-releasing hormone agonists. “Additionally, there is a possibility that women in the control cohort could have had undiagnosed endometriosis,” he wrote.
Furthermore, making clinical recommendations from these reported observations, particularly with respect to deep infiltrating endometriosis, would require a clear and consistent definition of this type in the dataset over the entire study interval from 1992 to 2019 and for the state of Utah, which the authors did not provide.
“Despite this potential challenge, the increased risk associated with deep infiltrating and/or ovarian endometriosis was clearly significant,” Dr. McHale wrote.
And although the absolute number of ovarian cancers is limited, in his view, the increased risk is sufficiently significant to advise women who have completed childbearing or have alternative fertility options to consider “more definitive surgery.”
This study was supported by multiple not-for-profit agencies, including the National Cancer Institute, the University of Utah, the National Center for Research Resources, the Utah Department of Health and Human Services, the Utah Cancer Registry, the US Centers for Disease Control and Prevention, the Huntsman Cancer Foundation, the National Institutes of Health, and Doris Duke Foundation. Dr. Barnard reported grants from the National Cancer Institute during the conduct of the study and personal fees from Epi Excellence LLC outside the submitted work. Other coauthors reported similar funding from nonprofit agencies or private research organizations. Dr Schliep disclosed no competing interests. Dr McHale reported educational consulting for Eisai Training outside the submitted work.
FROM JAMA
Benefit of Massage Therapy for Pain Unclear
The effectiveness of massage therapy for a range of painful adult health conditions remains uncertain. Despite hundreds of randomized clinical trials and dozens of systematic reviews, few studies have offered conclusions based on more than low-certainty evidence, a systematic review in JAMA Network Open has shown (doi: 10.1001/jamanetworkopen.2024.22259).
Some moderate-certainty evidence, however, suggested massage therapy may alleviate pain related to such conditions as low-back problems, labor, and breast cancer surgery, concluded a group led by Selene Mak, PhD, MPH, program manager in the Evidence Synthesis Program at the Veterans Health Administration Greater Los Angeles Healthcare System in Los Angeles, California.
“More high-quality randomized clinical trials are needed to provide a stronger evidence base to assess the effect of massage therapy on pain,” Dr. Mak and colleagues wrote.
The review updates a previous Veterans Affairs evidence map covering reviews of massage therapy for pain published through 2018.
To categorize the evidence base for decision-making by policymakers and practitioners, the VA requested an updated evidence map of reviews to answer the question: “What is the certainty of evidence in systematic reviews of massage therapy for pain?”
The Analysis
The current review included studies published from 2018 to 2023 with formal ratings of evidence quality or certainty, excluding other nonpharmacologic techniques such as sports massage therapy, osteopathy, dry cupping, dry needling, and internal massage therapy, and self-administered techniques such as foam rolling.
Of 129 systematic reviews, only 41 formally rated evidence quality, and 17 were evidence-mapped for pain across 13 health states: cancer, back, neck and mechanical neck issues, fibromyalgia, labor, myofascial, palliative care need, plantar fasciitis, postoperative, post breast cancer surgery, and post cesarean/postpartum.
The investigators found no conclusions based on a high certainty of evidence, while seven based conclusions on moderate-certainty evidence. All remaining conclusions were rated as having low- or very-low-certainty evidence.
The priority, they added, should be studies comparing massage therapy with other recommended, accepted, and active therapies for pain and should have sufficiently long follow-up to allow any nonspecific outcomes to dissipate, At least 6 months’ follow-up has been suggested for studies of chronic pain.
While massage therapy is considered safe, in patients with central sensitizations more aggressive treatments may cause a flare of myofascial pain.
This study was funded by the Department of Veterans Affairs Health Services Research and Development. The authors had no conflicts of interest to disclose.
The effectiveness of massage therapy for a range of painful adult health conditions remains uncertain. Despite hundreds of randomized clinical trials and dozens of systematic reviews, few studies have offered conclusions based on more than low-certainty evidence, a systematic review in JAMA Network Open has shown (doi: 10.1001/jamanetworkopen.2024.22259).
Some moderate-certainty evidence, however, suggested massage therapy may alleviate pain related to such conditions as low-back problems, labor, and breast cancer surgery, concluded a group led by Selene Mak, PhD, MPH, program manager in the Evidence Synthesis Program at the Veterans Health Administration Greater Los Angeles Healthcare System in Los Angeles, California.
“More high-quality randomized clinical trials are needed to provide a stronger evidence base to assess the effect of massage therapy on pain,” Dr. Mak and colleagues wrote.
The review updates a previous Veterans Affairs evidence map covering reviews of massage therapy for pain published through 2018.
To categorize the evidence base for decision-making by policymakers and practitioners, the VA requested an updated evidence map of reviews to answer the question: “What is the certainty of evidence in systematic reviews of massage therapy for pain?”
The Analysis
The current review included studies published from 2018 to 2023 with formal ratings of evidence quality or certainty, excluding other nonpharmacologic techniques such as sports massage therapy, osteopathy, dry cupping, dry needling, and internal massage therapy, and self-administered techniques such as foam rolling.
Of 129 systematic reviews, only 41 formally rated evidence quality, and 17 were evidence-mapped for pain across 13 health states: cancer, back, neck and mechanical neck issues, fibromyalgia, labor, myofascial, palliative care need, plantar fasciitis, postoperative, post breast cancer surgery, and post cesarean/postpartum.
The investigators found no conclusions based on a high certainty of evidence, while seven based conclusions on moderate-certainty evidence. All remaining conclusions were rated as having low- or very-low-certainty evidence.
The priority, they added, should be studies comparing massage therapy with other recommended, accepted, and active therapies for pain and should have sufficiently long follow-up to allow any nonspecific outcomes to dissipate, At least 6 months’ follow-up has been suggested for studies of chronic pain.
While massage therapy is considered safe, in patients with central sensitizations more aggressive treatments may cause a flare of myofascial pain.
This study was funded by the Department of Veterans Affairs Health Services Research and Development. The authors had no conflicts of interest to disclose.
The effectiveness of massage therapy for a range of painful adult health conditions remains uncertain. Despite hundreds of randomized clinical trials and dozens of systematic reviews, few studies have offered conclusions based on more than low-certainty evidence, a systematic review in JAMA Network Open has shown (doi: 10.1001/jamanetworkopen.2024.22259).
Some moderate-certainty evidence, however, suggested massage therapy may alleviate pain related to such conditions as low-back problems, labor, and breast cancer surgery, concluded a group led by Selene Mak, PhD, MPH, program manager in the Evidence Synthesis Program at the Veterans Health Administration Greater Los Angeles Healthcare System in Los Angeles, California.
“More high-quality randomized clinical trials are needed to provide a stronger evidence base to assess the effect of massage therapy on pain,” Dr. Mak and colleagues wrote.
The review updates a previous Veterans Affairs evidence map covering reviews of massage therapy for pain published through 2018.
To categorize the evidence base for decision-making by policymakers and practitioners, the VA requested an updated evidence map of reviews to answer the question: “What is the certainty of evidence in systematic reviews of massage therapy for pain?”
The Analysis
The current review included studies published from 2018 to 2023 with formal ratings of evidence quality or certainty, excluding other nonpharmacologic techniques such as sports massage therapy, osteopathy, dry cupping, dry needling, and internal massage therapy, and self-administered techniques such as foam rolling.
Of 129 systematic reviews, only 41 formally rated evidence quality, and 17 were evidence-mapped for pain across 13 health states: cancer, back, neck and mechanical neck issues, fibromyalgia, labor, myofascial, palliative care need, plantar fasciitis, postoperative, post breast cancer surgery, and post cesarean/postpartum.
The investigators found no conclusions based on a high certainty of evidence, while seven based conclusions on moderate-certainty evidence. All remaining conclusions were rated as having low- or very-low-certainty evidence.
The priority, they added, should be studies comparing massage therapy with other recommended, accepted, and active therapies for pain and should have sufficiently long follow-up to allow any nonspecific outcomes to dissipate, At least 6 months’ follow-up has been suggested for studies of chronic pain.
While massage therapy is considered safe, in patients with central sensitizations more aggressive treatments may cause a flare of myofascial pain.
This study was funded by the Department of Veterans Affairs Health Services Research and Development. The authors had no conflicts of interest to disclose.
FROM JAMA NETWORK OPEN
Combination Therapy Looks Promising for Hepatitis D
, a multinational phase 2b open-label study in Europe found.
The combination resulted in higher rates of HDV RNA suppression levels at 24 weeks after end of treatment, especially at a higher, 10-mg dose of bulevirtide, according to researchers led by Tarik Asselah, MD. PhD, a professor of medicine and hepatology at Hôpital Beaujon, APHP, Clichy, France, and the University of Paris.
“This response appeared to be maintained from 24-48 weeks after the end of treatment — a finding that supports the concept that sustained undetectable HDV RNA for at least 1 year after treatment is possible in patients with chronic hepatitis D who have been treated with a finite duration of therapy of at least 96 weeks, including 48 weeks of peginterferon alfa-2a therapy,” the investigators wrote in The New England Journal of Medicine.
“As of today, there is no approved treatment for chronic HDV infection in the United States. Pegylated interferon alfa-2a, which is not approved for treatment of HDV, is the only option recommended by US treatment guidelines,” said study corresponding author Fabien Zoulim, MD, PhD, a hepatologist at the Lyon Hepatology Institute and a professor of medicine at the University of Lyon in France, in comments to GI & Hepatology News. “Bulevirtide 2 mg is approved for treating chronic HDV and compensated liver disease, and both bulevirtide and peginterferon are recommended options by the European treatment guidelines.”
The study found that most patients with undetectable HDV RNA levels during treatment-free follow-up showed no reduction in HepB surface antigen (HBsAg), suggesting an undetectable HDV RNA level can be achieved and sustained without HBsAg loss, the authors wrote.
While very small numbers in the combo groups and the higher-dose bulevirtide arm cleared HBsAg, “the study was not powered to evaluate the HBsAg response,” Dr. Zoulim said.
HDV is a defective virus that requires HBsAg for assembly and propagation, the authors noted. It affects as many as 20 million persons worldwide, and as the most severe form of chronic viral hepatitis, is associated with 2-6 times the risk of hepatocellular carcinoma and 2-3 times the risk of death associated with HBV monoinfection.
Though not common in the United States, it affects an estimated 10 to 20 million people worldwide (J Hepatol. 2020 Apr. doi: 10.1016/j.jhep.2020.04.008). One US database study found HepD in 4.6% of patients with HepB infection.
Commenting on the study but not a participant in it, Ahmet O. Gurakar, MD, AGAF, a professor of medicine in the sections of gastroenterology and hepatology at Johns Hopkins School of Medicine in Baltimore, Maryland, said the study findings look promising for the future treatment of HepD, but cautioned that it will be “a slow process to get approval for combination therapy with bulevirtide since the FDA has previously said it needs to see more studies. The findings need to be confirmed in larger groups, but it’s difficult to recruit enough patients in the United States for a trial since hepatitis D is not common in this country — it’s more common in the Mediterranean basin Eastern European populations.”
The Trial
The investigators randomly assigned 174, largely male, patients ages 18-65 (mean, about 41) years to receive one of four treatments:
- Pegylated interferon alfa-2a alone at 180 μg per week) for 48 weeks (n = 24).
- Bulevirtide at a daily dose of 2 mg plus peginterferon alfa-2a at 180 μg per week for 48 weeks, followed by the same daily dose of bulevirtide for 48 weeks (n = 50).
- Bulevirtide at 10 mg plus peginterferon alfa-2a at 180 μg per week for 48 weeks, followed by the same daily dose of bulevirtide for 48 weeks (n = 50).
- Bulevirtide at a daily dose of 10 mg alone for 96 weeks (n = 50).
All were followed for 48 weeks after treatment. The primary comparison was between the 10-mg bulevirtide plus peginterferon alfa-2a group and the 10-mg bulevirtide monotherapy group.
At 24 weeks post-treatment, HDV RNA was undetectable in 17% of patients in the peginterferon alfa-2a group. In the other arms, HDV RNA was undetectable in 32% in the 2-mg bulevirtide plus peginterferon alfa-2a group, in 46% of the 10-mg bulevirtide plus peginterferon alfa-2a group, and in 12% of the 10-mg bulevirtide group.
For the primary comparison, the between-group difference was 34 percentage points (95% confidence interval, 15-50; P < .001).
At 48 weeks after the end of treatment, HDV RNA was undetectable in 25% in the peginterferon alfa-2a group, 26% in the 2-mg bulevirtide plus peginterferon alfa-2a group, 46% in the 10-mg bulevirtide plus peginterferon alfa-2a group, and 12% in the 10-mg bulevirtide group.
Also calling the findings promising, Anna Lok, MBBS, MD, AGAF, a gastroenterologist at the University of Michigan, Ann Arbor, said that, “Given that the European Medicines Agency’s approval is for bulevirtide alone at 2 mg, results of this study should prompt reassessment whether bulevirtide should be used in combination with pegylated interferon in patients with no contraindications, and if 10 mg is more appropriate than a 2-mg dose.”
As to safety, the most frequent adverse events were leukopenia, neutropenia, and thrombocytopenia, with the majority of adverse events being grade 1 or 2.
In comparison with other research, the current trial found that 70% in the 10-mg bulevirtide plus peginterferon alfa-2a group had an undetectable HDV RNA level at the end of treatment versus results of the Hep-Net International Delta Hepatitis Interventional Trial II (HIDIT-II), in which 33%-48% had undetectable levels after 96 weeks of peginterferon alfa-2a therapy, with or without tenofovir disoproxil. And in the phase 3 MYR301 trial, HDV RNA was undetectable in 20%-36% after 96 weeks of bulevirtide monotherapy.
The authors acknowledged that in addition to the lack of blinding, the trial was not designed to compare the two doses of bulevirtide and therefore lacked an adequate sample size to allow for formal comparisons. And although it included a peginterferon alfa-2a monotherapy group, it was not sufficiently powered to allow for comparison. They are currently considering plans for further studies in this area.
This study was funded by Gilead Sciences. Dr. Asselah disclosed consulting, safety/data monitoring, or travel for Gilead Sciences, AbbVie, Antio Therapeutics, Eiger Biopharmaceutical, Enyo Pharma, GlaxoSmithKline, Johnson & Johnson Healthcare Systems, and Vir Biotechnology. Dr. Zoulim reported consulting or research for multiple pharmaceutical/biotech companies, including Gilead Sciences. Numerous study coauthors declared financial relationships such as consulting, research, or employment with multiple private-sector companies, including Gilead Sciences. Dr. Lok and Dr. Gurakar disclosed no competing interests relevant to their comments.
, a multinational phase 2b open-label study in Europe found.
The combination resulted in higher rates of HDV RNA suppression levels at 24 weeks after end of treatment, especially at a higher, 10-mg dose of bulevirtide, according to researchers led by Tarik Asselah, MD. PhD, a professor of medicine and hepatology at Hôpital Beaujon, APHP, Clichy, France, and the University of Paris.
“This response appeared to be maintained from 24-48 weeks after the end of treatment — a finding that supports the concept that sustained undetectable HDV RNA for at least 1 year after treatment is possible in patients with chronic hepatitis D who have been treated with a finite duration of therapy of at least 96 weeks, including 48 weeks of peginterferon alfa-2a therapy,” the investigators wrote in The New England Journal of Medicine.
“As of today, there is no approved treatment for chronic HDV infection in the United States. Pegylated interferon alfa-2a, which is not approved for treatment of HDV, is the only option recommended by US treatment guidelines,” said study corresponding author Fabien Zoulim, MD, PhD, a hepatologist at the Lyon Hepatology Institute and a professor of medicine at the University of Lyon in France, in comments to GI & Hepatology News. “Bulevirtide 2 mg is approved for treating chronic HDV and compensated liver disease, and both bulevirtide and peginterferon are recommended options by the European treatment guidelines.”
The study found that most patients with undetectable HDV RNA levels during treatment-free follow-up showed no reduction in HepB surface antigen (HBsAg), suggesting an undetectable HDV RNA level can be achieved and sustained without HBsAg loss, the authors wrote.
While very small numbers in the combo groups and the higher-dose bulevirtide arm cleared HBsAg, “the study was not powered to evaluate the HBsAg response,” Dr. Zoulim said.
HDV is a defective virus that requires HBsAg for assembly and propagation, the authors noted. It affects as many as 20 million persons worldwide, and as the most severe form of chronic viral hepatitis, is associated with 2-6 times the risk of hepatocellular carcinoma and 2-3 times the risk of death associated with HBV monoinfection.
Though not common in the United States, it affects an estimated 10 to 20 million people worldwide (J Hepatol. 2020 Apr. doi: 10.1016/j.jhep.2020.04.008). One US database study found HepD in 4.6% of patients with HepB infection.
Commenting on the study but not a participant in it, Ahmet O. Gurakar, MD, AGAF, a professor of medicine in the sections of gastroenterology and hepatology at Johns Hopkins School of Medicine in Baltimore, Maryland, said the study findings look promising for the future treatment of HepD, but cautioned that it will be “a slow process to get approval for combination therapy with bulevirtide since the FDA has previously said it needs to see more studies. The findings need to be confirmed in larger groups, but it’s difficult to recruit enough patients in the United States for a trial since hepatitis D is not common in this country — it’s more common in the Mediterranean basin Eastern European populations.”
The Trial
The investigators randomly assigned 174, largely male, patients ages 18-65 (mean, about 41) years to receive one of four treatments:
- Pegylated interferon alfa-2a alone at 180 μg per week) for 48 weeks (n = 24).
- Bulevirtide at a daily dose of 2 mg plus peginterferon alfa-2a at 180 μg per week for 48 weeks, followed by the same daily dose of bulevirtide for 48 weeks (n = 50).
- Bulevirtide at 10 mg plus peginterferon alfa-2a at 180 μg per week for 48 weeks, followed by the same daily dose of bulevirtide for 48 weeks (n = 50).
- Bulevirtide at a daily dose of 10 mg alone for 96 weeks (n = 50).
All were followed for 48 weeks after treatment. The primary comparison was between the 10-mg bulevirtide plus peginterferon alfa-2a group and the 10-mg bulevirtide monotherapy group.
At 24 weeks post-treatment, HDV RNA was undetectable in 17% of patients in the peginterferon alfa-2a group. In the other arms, HDV RNA was undetectable in 32% in the 2-mg bulevirtide plus peginterferon alfa-2a group, in 46% of the 10-mg bulevirtide plus peginterferon alfa-2a group, and in 12% of the 10-mg bulevirtide group.
For the primary comparison, the between-group difference was 34 percentage points (95% confidence interval, 15-50; P < .001).
At 48 weeks after the end of treatment, HDV RNA was undetectable in 25% in the peginterferon alfa-2a group, 26% in the 2-mg bulevirtide plus peginterferon alfa-2a group, 46% in the 10-mg bulevirtide plus peginterferon alfa-2a group, and 12% in the 10-mg bulevirtide group.
Also calling the findings promising, Anna Lok, MBBS, MD, AGAF, a gastroenterologist at the University of Michigan, Ann Arbor, said that, “Given that the European Medicines Agency’s approval is for bulevirtide alone at 2 mg, results of this study should prompt reassessment whether bulevirtide should be used in combination with pegylated interferon in patients with no contraindications, and if 10 mg is more appropriate than a 2-mg dose.”
As to safety, the most frequent adverse events were leukopenia, neutropenia, and thrombocytopenia, with the majority of adverse events being grade 1 or 2.
In comparison with other research, the current trial found that 70% in the 10-mg bulevirtide plus peginterferon alfa-2a group had an undetectable HDV RNA level at the end of treatment versus results of the Hep-Net International Delta Hepatitis Interventional Trial II (HIDIT-II), in which 33%-48% had undetectable levels after 96 weeks of peginterferon alfa-2a therapy, with or without tenofovir disoproxil. And in the phase 3 MYR301 trial, HDV RNA was undetectable in 20%-36% after 96 weeks of bulevirtide monotherapy.
The authors acknowledged that in addition to the lack of blinding, the trial was not designed to compare the two doses of bulevirtide and therefore lacked an adequate sample size to allow for formal comparisons. And although it included a peginterferon alfa-2a monotherapy group, it was not sufficiently powered to allow for comparison. They are currently considering plans for further studies in this area.
This study was funded by Gilead Sciences. Dr. Asselah disclosed consulting, safety/data monitoring, or travel for Gilead Sciences, AbbVie, Antio Therapeutics, Eiger Biopharmaceutical, Enyo Pharma, GlaxoSmithKline, Johnson & Johnson Healthcare Systems, and Vir Biotechnology. Dr. Zoulim reported consulting or research for multiple pharmaceutical/biotech companies, including Gilead Sciences. Numerous study coauthors declared financial relationships such as consulting, research, or employment with multiple private-sector companies, including Gilead Sciences. Dr. Lok and Dr. Gurakar disclosed no competing interests relevant to their comments.
, a multinational phase 2b open-label study in Europe found.
The combination resulted in higher rates of HDV RNA suppression levels at 24 weeks after end of treatment, especially at a higher, 10-mg dose of bulevirtide, according to researchers led by Tarik Asselah, MD. PhD, a professor of medicine and hepatology at Hôpital Beaujon, APHP, Clichy, France, and the University of Paris.
“This response appeared to be maintained from 24-48 weeks after the end of treatment — a finding that supports the concept that sustained undetectable HDV RNA for at least 1 year after treatment is possible in patients with chronic hepatitis D who have been treated with a finite duration of therapy of at least 96 weeks, including 48 weeks of peginterferon alfa-2a therapy,” the investigators wrote in The New England Journal of Medicine.
“As of today, there is no approved treatment for chronic HDV infection in the United States. Pegylated interferon alfa-2a, which is not approved for treatment of HDV, is the only option recommended by US treatment guidelines,” said study corresponding author Fabien Zoulim, MD, PhD, a hepatologist at the Lyon Hepatology Institute and a professor of medicine at the University of Lyon in France, in comments to GI & Hepatology News. “Bulevirtide 2 mg is approved for treating chronic HDV and compensated liver disease, and both bulevirtide and peginterferon are recommended options by the European treatment guidelines.”
The study found that most patients with undetectable HDV RNA levels during treatment-free follow-up showed no reduction in HepB surface antigen (HBsAg), suggesting an undetectable HDV RNA level can be achieved and sustained without HBsAg loss, the authors wrote.
While very small numbers in the combo groups and the higher-dose bulevirtide arm cleared HBsAg, “the study was not powered to evaluate the HBsAg response,” Dr. Zoulim said.
HDV is a defective virus that requires HBsAg for assembly and propagation, the authors noted. It affects as many as 20 million persons worldwide, and as the most severe form of chronic viral hepatitis, is associated with 2-6 times the risk of hepatocellular carcinoma and 2-3 times the risk of death associated with HBV monoinfection.
Though not common in the United States, it affects an estimated 10 to 20 million people worldwide (J Hepatol. 2020 Apr. doi: 10.1016/j.jhep.2020.04.008). One US database study found HepD in 4.6% of patients with HepB infection.
Commenting on the study but not a participant in it, Ahmet O. Gurakar, MD, AGAF, a professor of medicine in the sections of gastroenterology and hepatology at Johns Hopkins School of Medicine in Baltimore, Maryland, said the study findings look promising for the future treatment of HepD, but cautioned that it will be “a slow process to get approval for combination therapy with bulevirtide since the FDA has previously said it needs to see more studies. The findings need to be confirmed in larger groups, but it’s difficult to recruit enough patients in the United States for a trial since hepatitis D is not common in this country — it’s more common in the Mediterranean basin Eastern European populations.”
The Trial
The investigators randomly assigned 174, largely male, patients ages 18-65 (mean, about 41) years to receive one of four treatments:
- Pegylated interferon alfa-2a alone at 180 μg per week) for 48 weeks (n = 24).
- Bulevirtide at a daily dose of 2 mg plus peginterferon alfa-2a at 180 μg per week for 48 weeks, followed by the same daily dose of bulevirtide for 48 weeks (n = 50).
- Bulevirtide at 10 mg plus peginterferon alfa-2a at 180 μg per week for 48 weeks, followed by the same daily dose of bulevirtide for 48 weeks (n = 50).
- Bulevirtide at a daily dose of 10 mg alone for 96 weeks (n = 50).
All were followed for 48 weeks after treatment. The primary comparison was between the 10-mg bulevirtide plus peginterferon alfa-2a group and the 10-mg bulevirtide monotherapy group.
At 24 weeks post-treatment, HDV RNA was undetectable in 17% of patients in the peginterferon alfa-2a group. In the other arms, HDV RNA was undetectable in 32% in the 2-mg bulevirtide plus peginterferon alfa-2a group, in 46% of the 10-mg bulevirtide plus peginterferon alfa-2a group, and in 12% of the 10-mg bulevirtide group.
For the primary comparison, the between-group difference was 34 percentage points (95% confidence interval, 15-50; P < .001).
At 48 weeks after the end of treatment, HDV RNA was undetectable in 25% in the peginterferon alfa-2a group, 26% in the 2-mg bulevirtide plus peginterferon alfa-2a group, 46% in the 10-mg bulevirtide plus peginterferon alfa-2a group, and 12% in the 10-mg bulevirtide group.
Also calling the findings promising, Anna Lok, MBBS, MD, AGAF, a gastroenterologist at the University of Michigan, Ann Arbor, said that, “Given that the European Medicines Agency’s approval is for bulevirtide alone at 2 mg, results of this study should prompt reassessment whether bulevirtide should be used in combination with pegylated interferon in patients with no contraindications, and if 10 mg is more appropriate than a 2-mg dose.”
As to safety, the most frequent adverse events were leukopenia, neutropenia, and thrombocytopenia, with the majority of adverse events being grade 1 or 2.
In comparison with other research, the current trial found that 70% in the 10-mg bulevirtide plus peginterferon alfa-2a group had an undetectable HDV RNA level at the end of treatment versus results of the Hep-Net International Delta Hepatitis Interventional Trial II (HIDIT-II), in which 33%-48% had undetectable levels after 96 weeks of peginterferon alfa-2a therapy, with or without tenofovir disoproxil. And in the phase 3 MYR301 trial, HDV RNA was undetectable in 20%-36% after 96 weeks of bulevirtide monotherapy.
The authors acknowledged that in addition to the lack of blinding, the trial was not designed to compare the two doses of bulevirtide and therefore lacked an adequate sample size to allow for formal comparisons. And although it included a peginterferon alfa-2a monotherapy group, it was not sufficiently powered to allow for comparison. They are currently considering plans for further studies in this area.
This study was funded by Gilead Sciences. Dr. Asselah disclosed consulting, safety/data monitoring, or travel for Gilead Sciences, AbbVie, Antio Therapeutics, Eiger Biopharmaceutical, Enyo Pharma, GlaxoSmithKline, Johnson & Johnson Healthcare Systems, and Vir Biotechnology. Dr. Zoulim reported consulting or research for multiple pharmaceutical/biotech companies, including Gilead Sciences. Numerous study coauthors declared financial relationships such as consulting, research, or employment with multiple private-sector companies, including Gilead Sciences. Dr. Lok and Dr. Gurakar disclosed no competing interests relevant to their comments.
FROM NEW ENGLAND JOURNAL OF MEDICINE
Don’t Forget Adult Hepatitis Vaccinations
Hepatitis B (Hep B) is a liver infection against which vaccination was previously recommended for certain eligible risk groups. However, in 2022, the Centers for Disease Control and Prevention (CDC) switched from recommending vaccination for at-risk persons to recommending universal vaccination for children and adults.
That includes infants, children 18 years of age and younger, adults aged 19-59, and people aged 60 and up with risk factors for this viral infection. Even those aged 60 and older without known risk factors for hepatitis B may receive Hep B vaccines.
Risk factors under prior recommendations included potential criminal or stigmatizing behaviors such as injection-drug use, incarceration, or multiple sex partners, which limited risk assessment by providers. The CDC points out that universal adult Hep B vaccination through age 59 obviates the need for the previous approach of risk-factor screening and sensitive disclosures to determine eligibility and could increase vaccination coverage and reduce cases.
“A universal recommendation for Hep B vaccination could increase the number of persons who receive vaccination before the onset of chronic liver disease and other comorbidities (e.g., obesity or diabetes) that might make vaccination less effective,” the CDC stated, noting that patients with chronic liver disease have a reduced immune response to Hep B vaccination. Hep B vaccination also protects against hepatitis D.
“Most people born in the US are vaccinated during infancy, beginning on the first day of life,” Lauren D. Block, MD, an internist at Northwell Health and an assistant professor in the Institute of Health System Science at the Feinstein Institutes for Medical Research at sites in metropolitan New York City, said in an interview.
Typically, Dr. Block added, at-risk persons will have titers drawn to make sure they are immune to Hep B. “Titers can wane over the decades in healthy people, in which case a booster shot may be needed, or a restart of the three-part vaccination series if a person is not sure if they were vaccinated previously.” Those at greater risk include people with weakened immune systems, people with diabetes or on immunosuppressives, healthcare workers, travelers to higher-risk countries, people with multiple sexual partners, and IV drug users.
Although Hep B vaccines have demonstrated safety, immunogenicity, and efficacy during the past four decades, coverage among US adults has been suboptimal, limiting further reduction in infections, the CDC noted.
Hepatitis A
Though not widely endemic to North America, Hep A can be acquired during travel abroad, particularly to developing countries, or through exposure to unsanitary conditions and contaminated food or water.
The CDC recommends routine Hep A vaccination for all children aged 12-23 months, all unvaccinated children and adolescents 2-18 years, and all persons, including those who are pregnant, with increased risk factors for this orally and fecally transmitted infection or at risk for severe disease from it. At-risk groups include international travelers to affected regions, men who have sex with men, incarcerated individuals or group-home residents, injection and non-injection drug users, and homeless persons.
Hepatitis C and E
There is no vaccine for Hep C, and no FDA-approved vaccine in the United States for hepatitis E, although a vaccine for the latter was approved in China in 2012.
As with Hep A, observing strict water, food, and sanitation standards is essential for preventing infection with hepatitis E.
Dr. Block disclosed no competing interests relevant to her comments.
Hepatitis B (Hep B) is a liver infection against which vaccination was previously recommended for certain eligible risk groups. However, in 2022, the Centers for Disease Control and Prevention (CDC) switched from recommending vaccination for at-risk persons to recommending universal vaccination for children and adults.
That includes infants, children 18 years of age and younger, adults aged 19-59, and people aged 60 and up with risk factors for this viral infection. Even those aged 60 and older without known risk factors for hepatitis B may receive Hep B vaccines.
Risk factors under prior recommendations included potential criminal or stigmatizing behaviors such as injection-drug use, incarceration, or multiple sex partners, which limited risk assessment by providers. The CDC points out that universal adult Hep B vaccination through age 59 obviates the need for the previous approach of risk-factor screening and sensitive disclosures to determine eligibility and could increase vaccination coverage and reduce cases.
“A universal recommendation for Hep B vaccination could increase the number of persons who receive vaccination before the onset of chronic liver disease and other comorbidities (e.g., obesity or diabetes) that might make vaccination less effective,” the CDC stated, noting that patients with chronic liver disease have a reduced immune response to Hep B vaccination. Hep B vaccination also protects against hepatitis D.
“Most people born in the US are vaccinated during infancy, beginning on the first day of life,” Lauren D. Block, MD, an internist at Northwell Health and an assistant professor in the Institute of Health System Science at the Feinstein Institutes for Medical Research at sites in metropolitan New York City, said in an interview.
Typically, Dr. Block added, at-risk persons will have titers drawn to make sure they are immune to Hep B. “Titers can wane over the decades in healthy people, in which case a booster shot may be needed, or a restart of the three-part vaccination series if a person is not sure if they were vaccinated previously.” Those at greater risk include people with weakened immune systems, people with diabetes or on immunosuppressives, healthcare workers, travelers to higher-risk countries, people with multiple sexual partners, and IV drug users.
Although Hep B vaccines have demonstrated safety, immunogenicity, and efficacy during the past four decades, coverage among US adults has been suboptimal, limiting further reduction in infections, the CDC noted.
Hepatitis A
Though not widely endemic to North America, Hep A can be acquired during travel abroad, particularly to developing countries, or through exposure to unsanitary conditions and contaminated food or water.
The CDC recommends routine Hep A vaccination for all children aged 12-23 months, all unvaccinated children and adolescents 2-18 years, and all persons, including those who are pregnant, with increased risk factors for this orally and fecally transmitted infection or at risk for severe disease from it. At-risk groups include international travelers to affected regions, men who have sex with men, incarcerated individuals or group-home residents, injection and non-injection drug users, and homeless persons.
Hepatitis C and E
There is no vaccine for Hep C, and no FDA-approved vaccine in the United States for hepatitis E, although a vaccine for the latter was approved in China in 2012.
As with Hep A, observing strict water, food, and sanitation standards is essential for preventing infection with hepatitis E.
Dr. Block disclosed no competing interests relevant to her comments.
Hepatitis B (Hep B) is a liver infection against which vaccination was previously recommended for certain eligible risk groups. However, in 2022, the Centers for Disease Control and Prevention (CDC) switched from recommending vaccination for at-risk persons to recommending universal vaccination for children and adults.
That includes infants, children 18 years of age and younger, adults aged 19-59, and people aged 60 and up with risk factors for this viral infection. Even those aged 60 and older without known risk factors for hepatitis B may receive Hep B vaccines.
Risk factors under prior recommendations included potential criminal or stigmatizing behaviors such as injection-drug use, incarceration, or multiple sex partners, which limited risk assessment by providers. The CDC points out that universal adult Hep B vaccination through age 59 obviates the need for the previous approach of risk-factor screening and sensitive disclosures to determine eligibility and could increase vaccination coverage and reduce cases.
“A universal recommendation for Hep B vaccination could increase the number of persons who receive vaccination before the onset of chronic liver disease and other comorbidities (e.g., obesity or diabetes) that might make vaccination less effective,” the CDC stated, noting that patients with chronic liver disease have a reduced immune response to Hep B vaccination. Hep B vaccination also protects against hepatitis D.
“Most people born in the US are vaccinated during infancy, beginning on the first day of life,” Lauren D. Block, MD, an internist at Northwell Health and an assistant professor in the Institute of Health System Science at the Feinstein Institutes for Medical Research at sites in metropolitan New York City, said in an interview.
Typically, Dr. Block added, at-risk persons will have titers drawn to make sure they are immune to Hep B. “Titers can wane over the decades in healthy people, in which case a booster shot may be needed, or a restart of the three-part vaccination series if a person is not sure if they were vaccinated previously.” Those at greater risk include people with weakened immune systems, people with diabetes or on immunosuppressives, healthcare workers, travelers to higher-risk countries, people with multiple sexual partners, and IV drug users.
Although Hep B vaccines have demonstrated safety, immunogenicity, and efficacy during the past four decades, coverage among US adults has been suboptimal, limiting further reduction in infections, the CDC noted.
Hepatitis A
Though not widely endemic to North America, Hep A can be acquired during travel abroad, particularly to developing countries, or through exposure to unsanitary conditions and contaminated food or water.
The CDC recommends routine Hep A vaccination for all children aged 12-23 months, all unvaccinated children and adolescents 2-18 years, and all persons, including those who are pregnant, with increased risk factors for this orally and fecally transmitted infection or at risk for severe disease from it. At-risk groups include international travelers to affected regions, men who have sex with men, incarcerated individuals or group-home residents, injection and non-injection drug users, and homeless persons.
Hepatitis C and E
There is no vaccine for Hep C, and no FDA-approved vaccine in the United States for hepatitis E, although a vaccine for the latter was approved in China in 2012.
As with Hep A, observing strict water, food, and sanitation standards is essential for preventing infection with hepatitis E.
Dr. Block disclosed no competing interests relevant to her comments.
Dupilumab Effective in PPI-Refractory Pediatric EoE
Good news for younger children suffering from the uncommon but debilitating gastrointestinal condition eosinophilic esophagitis (EoE): Data from this trial led to a January US Food and Drug Administration (FDA) approval of the anti-inflammatory biologic for patients aged 1-11 years weighing at least 15 kg.
In addition, the trial, published in The New England Journal of Medicine, found that a higher-exposure dupilumab regimen (approximating the trough concentration of a 300-mg dose administered once weekly versus every 2 weeks) improved key secondary end points, according to gastroenterologist Mirna Chehade, MD, MPH, AGAF, a professor of pediatrics at Icahn School of Medicine at Mount Sinai and Mount Sinai Kravis Children’s Hospital in New York City, and colleagues.
In 2022, the FDA approved the drug for those aged 12 or older weighing at least 40 kg.
“Left untreated or inadequately treated, EoE can progress to esophageal narrowing and strictures, leading to increased risk of food impactions and the need for esophageal dilations,” Dr. Chehade said in an interview. “Therefore, it’s important that children with EoE have the FDA-approved treatment option based on our study that can address their underlying disease starting at a young age.”
She added that dupilumab has the exciting potential to transform the standard of care for many young children living with EoE. “There are, however, factors to consider before switching a child to dupilumab — all related to the child’s specific medical history and therefore the perceived potential benefits from the drug.”
Commenting on the study but not involved in it, Toni Webster, DO, a pediatric gastroenterologist at Cohen Children’s Medical Center in Queens, New York, and an assistant professor at the Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York, said, “Like many allergic diseases, EoE is on the rise and, unfortunately, is affecting our children at alarming rates and at earlier ages. Given its efficacy and side-effect profile, dupilumab will vastly change our ability to treat EoE, especially for families who find diet and daily medication to be a challenge.”
Dr. Webster noted that an elimination diet is a rigorous choice that is often difficult to navigate. And the oral administration of off-label choices, proton pump inhibitors, and swallowed topical steroids, as well as the newly FDA-approved oral budesonide therapy (Eohilia), may also be challenging because many children have precluding aversions to oral therapy. “Regardless of age, treatment choice for EoE should be a good fit that is a plausible addition to a family’s lifestyle,” she said.
Blocking interleukin 4 and interleukin 13 inflammatory pathways, dupilumab has shown efficacy in other atopic diseases such as eczema. It broadly inhibits most aspects of type 2 inflammation and that action is reflected in its histologic and transcriptomic effects in affected tissues, Dr. Chehade and associates explained.
The Trial
Conducted at one Canadian and 26 US sites, the two-part phase 3 study randomly assigned 102 EoE patients aged 1-11 years who were refractory to proton pump inhibition in a 2:2:1:1 ratio.
Part A enrolled 102 patients and evaluated dupilumab at a weight-tiered higher-dose or lower-dose regimen vs placebo (two groups) for 16 weeks.
Part B was a 36-week extended active treatment period in which eligible dupilumab recipients from part A maintained their weight-tiered higher- or lower-dose regimen, whereas those in the placebo groups switched to weight-tiered higher- or lower-dose dupilumab.
The primary end point was histologic remission (peak esophageal intraepithelial eosinophil count, ≤ 6 per high-power field) at week 16. Continued dupilumab treatment appeared to maintain its effect through week 52.
During part A, histologic remission occurred in 25 of the 37 higher-exposure patients (68%), 18 of the 31 lower-exposure patients (58%), and one of the 34 placebo patients (3%).
The difference between the higher-exposure regimen and placebo was 65 percentage points (95% confidence interval [CI], 48-81; P < .001), whereas that between the lower-exposure regimen and placebo was 55 percentage points (95% CI, 37-73; P < .001).
Higher exposure led to significant improvements in histologic, endoscopic, and transcriptomic measures over placebo. Improvements between baseline and week 52 in all patients were generally similar to those between baseline and week 16 in patients who received dupilumab in part A.
As for adverse events, in part A, the incidence of coronavirus disease, nausea, injection-site pain, and headache was at least 10 percentage points higher among dupilumab recipients at either dose than among placebo recipients. Serious adverse events were reported in three dupilumab patients during part A and in six patients overall during part B.
A Balanced Approach
On a cautionary note, Eric H. Chiou, MD, an assistant professor of pediatrics at Baylor College of Medicine and a pediatric gastroenterologist at Texas Children’s Hospital in Houston, said that while dupilumab shows great promise, further research is needed on its cost-effectiveness in EoE.
“The cost of treatment will need to be compared relative to potential long-term savings from reduced hospitalizations, fewer complications, and improved quality of life,” said Dr. Chiou, who was not involved in the study. “A balanced approach that considers clinical efficacy, patient well-being, cost-effectiveness, and equity is essential.”
He added that despite the study’s encouraging results, long-term safety and efficacy data are needed to fully understand the impact of dupilumab on pediatric patients with EoE. “Dupilumab will need to be compared with existing treatments for EoE such as dietary management and swallowed topical corticosteroids in terms of efficacy, safety, and quality of life improvements.”
Additionally, further research is required to identify which patients are most likely to benefit from this therapy and to explore any potential complications associated with its long-term use. “Understanding the optimal dosing and duration of treatment will also be crucial for maximizing benefits while minimizing risks,” Dr. Chiou said.
Dr. Chehade agreed. “While it’s that great that young children finally have an FDA-approved drug to treat their EoE, more research is needed to learn which patient subsets would derive maximum benefit from dupilumab and at which specific steps in their medical management journey should dupilumab be used.”
This study was supported by Sanofi and Regeneron Pharmaceuticals. Dr. Chehade disclosed research funding from and consulting for numerous private sector companies, among others, Sanofi and Regeneron Pharmaceuticals, AstraZeneca, Shire-Takeda, and Bristol-Myers Squibb. Multiple study coauthors disclosed various relationships with private-sector companies, including Sanofi and Regeneron Pharmaceuticals, for research funding, consulting, travel, employment, and stock or intellectual ownership. Dr. Webster and Dr. Chiou disclosed no competing interests relevant to their comments.
A version of this article first appeared on Medscape.com.
Good news for younger children suffering from the uncommon but debilitating gastrointestinal condition eosinophilic esophagitis (EoE): Data from this trial led to a January US Food and Drug Administration (FDA) approval of the anti-inflammatory biologic for patients aged 1-11 years weighing at least 15 kg.
In addition, the trial, published in The New England Journal of Medicine, found that a higher-exposure dupilumab regimen (approximating the trough concentration of a 300-mg dose administered once weekly versus every 2 weeks) improved key secondary end points, according to gastroenterologist Mirna Chehade, MD, MPH, AGAF, a professor of pediatrics at Icahn School of Medicine at Mount Sinai and Mount Sinai Kravis Children’s Hospital in New York City, and colleagues.
In 2022, the FDA approved the drug for those aged 12 or older weighing at least 40 kg.
“Left untreated or inadequately treated, EoE can progress to esophageal narrowing and strictures, leading to increased risk of food impactions and the need for esophageal dilations,” Dr. Chehade said in an interview. “Therefore, it’s important that children with EoE have the FDA-approved treatment option based on our study that can address their underlying disease starting at a young age.”
She added that dupilumab has the exciting potential to transform the standard of care for many young children living with EoE. “There are, however, factors to consider before switching a child to dupilumab — all related to the child’s specific medical history and therefore the perceived potential benefits from the drug.”
Commenting on the study but not involved in it, Toni Webster, DO, a pediatric gastroenterologist at Cohen Children’s Medical Center in Queens, New York, and an assistant professor at the Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York, said, “Like many allergic diseases, EoE is on the rise and, unfortunately, is affecting our children at alarming rates and at earlier ages. Given its efficacy and side-effect profile, dupilumab will vastly change our ability to treat EoE, especially for families who find diet and daily medication to be a challenge.”
Dr. Webster noted that an elimination diet is a rigorous choice that is often difficult to navigate. And the oral administration of off-label choices, proton pump inhibitors, and swallowed topical steroids, as well as the newly FDA-approved oral budesonide therapy (Eohilia), may also be challenging because many children have precluding aversions to oral therapy. “Regardless of age, treatment choice for EoE should be a good fit that is a plausible addition to a family’s lifestyle,” she said.
Blocking interleukin 4 and interleukin 13 inflammatory pathways, dupilumab has shown efficacy in other atopic diseases such as eczema. It broadly inhibits most aspects of type 2 inflammation and that action is reflected in its histologic and transcriptomic effects in affected tissues, Dr. Chehade and associates explained.
The Trial
Conducted at one Canadian and 26 US sites, the two-part phase 3 study randomly assigned 102 EoE patients aged 1-11 years who were refractory to proton pump inhibition in a 2:2:1:1 ratio.
Part A enrolled 102 patients and evaluated dupilumab at a weight-tiered higher-dose or lower-dose regimen vs placebo (two groups) for 16 weeks.
Part B was a 36-week extended active treatment period in which eligible dupilumab recipients from part A maintained their weight-tiered higher- or lower-dose regimen, whereas those in the placebo groups switched to weight-tiered higher- or lower-dose dupilumab.
The primary end point was histologic remission (peak esophageal intraepithelial eosinophil count, ≤ 6 per high-power field) at week 16. Continued dupilumab treatment appeared to maintain its effect through week 52.
During part A, histologic remission occurred in 25 of the 37 higher-exposure patients (68%), 18 of the 31 lower-exposure patients (58%), and one of the 34 placebo patients (3%).
The difference between the higher-exposure regimen and placebo was 65 percentage points (95% confidence interval [CI], 48-81; P < .001), whereas that between the lower-exposure regimen and placebo was 55 percentage points (95% CI, 37-73; P < .001).
Higher exposure led to significant improvements in histologic, endoscopic, and transcriptomic measures over placebo. Improvements between baseline and week 52 in all patients were generally similar to those between baseline and week 16 in patients who received dupilumab in part A.
As for adverse events, in part A, the incidence of coronavirus disease, nausea, injection-site pain, and headache was at least 10 percentage points higher among dupilumab recipients at either dose than among placebo recipients. Serious adverse events were reported in three dupilumab patients during part A and in six patients overall during part B.
A Balanced Approach
On a cautionary note, Eric H. Chiou, MD, an assistant professor of pediatrics at Baylor College of Medicine and a pediatric gastroenterologist at Texas Children’s Hospital in Houston, said that while dupilumab shows great promise, further research is needed on its cost-effectiveness in EoE.
“The cost of treatment will need to be compared relative to potential long-term savings from reduced hospitalizations, fewer complications, and improved quality of life,” said Dr. Chiou, who was not involved in the study. “A balanced approach that considers clinical efficacy, patient well-being, cost-effectiveness, and equity is essential.”
He added that despite the study’s encouraging results, long-term safety and efficacy data are needed to fully understand the impact of dupilumab on pediatric patients with EoE. “Dupilumab will need to be compared with existing treatments for EoE such as dietary management and swallowed topical corticosteroids in terms of efficacy, safety, and quality of life improvements.”
Additionally, further research is required to identify which patients are most likely to benefit from this therapy and to explore any potential complications associated with its long-term use. “Understanding the optimal dosing and duration of treatment will also be crucial for maximizing benefits while minimizing risks,” Dr. Chiou said.
Dr. Chehade agreed. “While it’s that great that young children finally have an FDA-approved drug to treat their EoE, more research is needed to learn which patient subsets would derive maximum benefit from dupilumab and at which specific steps in their medical management journey should dupilumab be used.”
This study was supported by Sanofi and Regeneron Pharmaceuticals. Dr. Chehade disclosed research funding from and consulting for numerous private sector companies, among others, Sanofi and Regeneron Pharmaceuticals, AstraZeneca, Shire-Takeda, and Bristol-Myers Squibb. Multiple study coauthors disclosed various relationships with private-sector companies, including Sanofi and Regeneron Pharmaceuticals, for research funding, consulting, travel, employment, and stock or intellectual ownership. Dr. Webster and Dr. Chiou disclosed no competing interests relevant to their comments.
A version of this article first appeared on Medscape.com.
Good news for younger children suffering from the uncommon but debilitating gastrointestinal condition eosinophilic esophagitis (EoE): Data from this trial led to a January US Food and Drug Administration (FDA) approval of the anti-inflammatory biologic for patients aged 1-11 years weighing at least 15 kg.
In addition, the trial, published in The New England Journal of Medicine, found that a higher-exposure dupilumab regimen (approximating the trough concentration of a 300-mg dose administered once weekly versus every 2 weeks) improved key secondary end points, according to gastroenterologist Mirna Chehade, MD, MPH, AGAF, a professor of pediatrics at Icahn School of Medicine at Mount Sinai and Mount Sinai Kravis Children’s Hospital in New York City, and colleagues.
In 2022, the FDA approved the drug for those aged 12 or older weighing at least 40 kg.
“Left untreated or inadequately treated, EoE can progress to esophageal narrowing and strictures, leading to increased risk of food impactions and the need for esophageal dilations,” Dr. Chehade said in an interview. “Therefore, it’s important that children with EoE have the FDA-approved treatment option based on our study that can address their underlying disease starting at a young age.”
She added that dupilumab has the exciting potential to transform the standard of care for many young children living with EoE. “There are, however, factors to consider before switching a child to dupilumab — all related to the child’s specific medical history and therefore the perceived potential benefits from the drug.”
Commenting on the study but not involved in it, Toni Webster, DO, a pediatric gastroenterologist at Cohen Children’s Medical Center in Queens, New York, and an assistant professor at the Zucker School of Medicine at Hofstra/Northwell in Hempstead, New York, said, “Like many allergic diseases, EoE is on the rise and, unfortunately, is affecting our children at alarming rates and at earlier ages. Given its efficacy and side-effect profile, dupilumab will vastly change our ability to treat EoE, especially for families who find diet and daily medication to be a challenge.”
Dr. Webster noted that an elimination diet is a rigorous choice that is often difficult to navigate. And the oral administration of off-label choices, proton pump inhibitors, and swallowed topical steroids, as well as the newly FDA-approved oral budesonide therapy (Eohilia), may also be challenging because many children have precluding aversions to oral therapy. “Regardless of age, treatment choice for EoE should be a good fit that is a plausible addition to a family’s lifestyle,” she said.
Blocking interleukin 4 and interleukin 13 inflammatory pathways, dupilumab has shown efficacy in other atopic diseases such as eczema. It broadly inhibits most aspects of type 2 inflammation and that action is reflected in its histologic and transcriptomic effects in affected tissues, Dr. Chehade and associates explained.
The Trial
Conducted at one Canadian and 26 US sites, the two-part phase 3 study randomly assigned 102 EoE patients aged 1-11 years who were refractory to proton pump inhibition in a 2:2:1:1 ratio.
Part A enrolled 102 patients and evaluated dupilumab at a weight-tiered higher-dose or lower-dose regimen vs placebo (two groups) for 16 weeks.
Part B was a 36-week extended active treatment period in which eligible dupilumab recipients from part A maintained their weight-tiered higher- or lower-dose regimen, whereas those in the placebo groups switched to weight-tiered higher- or lower-dose dupilumab.
The primary end point was histologic remission (peak esophageal intraepithelial eosinophil count, ≤ 6 per high-power field) at week 16. Continued dupilumab treatment appeared to maintain its effect through week 52.
During part A, histologic remission occurred in 25 of the 37 higher-exposure patients (68%), 18 of the 31 lower-exposure patients (58%), and one of the 34 placebo patients (3%).
The difference between the higher-exposure regimen and placebo was 65 percentage points (95% confidence interval [CI], 48-81; P < .001), whereas that between the lower-exposure regimen and placebo was 55 percentage points (95% CI, 37-73; P < .001).
Higher exposure led to significant improvements in histologic, endoscopic, and transcriptomic measures over placebo. Improvements between baseline and week 52 in all patients were generally similar to those between baseline and week 16 in patients who received dupilumab in part A.
As for adverse events, in part A, the incidence of coronavirus disease, nausea, injection-site pain, and headache was at least 10 percentage points higher among dupilumab recipients at either dose than among placebo recipients. Serious adverse events were reported in three dupilumab patients during part A and in six patients overall during part B.
A Balanced Approach
On a cautionary note, Eric H. Chiou, MD, an assistant professor of pediatrics at Baylor College of Medicine and a pediatric gastroenterologist at Texas Children’s Hospital in Houston, said that while dupilumab shows great promise, further research is needed on its cost-effectiveness in EoE.
“The cost of treatment will need to be compared relative to potential long-term savings from reduced hospitalizations, fewer complications, and improved quality of life,” said Dr. Chiou, who was not involved in the study. “A balanced approach that considers clinical efficacy, patient well-being, cost-effectiveness, and equity is essential.”
He added that despite the study’s encouraging results, long-term safety and efficacy data are needed to fully understand the impact of dupilumab on pediatric patients with EoE. “Dupilumab will need to be compared with existing treatments for EoE such as dietary management and swallowed topical corticosteroids in terms of efficacy, safety, and quality of life improvements.”
Additionally, further research is required to identify which patients are most likely to benefit from this therapy and to explore any potential complications associated with its long-term use. “Understanding the optimal dosing and duration of treatment will also be crucial for maximizing benefits while minimizing risks,” Dr. Chiou said.
Dr. Chehade agreed. “While it’s that great that young children finally have an FDA-approved drug to treat their EoE, more research is needed to learn which patient subsets would derive maximum benefit from dupilumab and at which specific steps in their medical management journey should dupilumab be used.”
This study was supported by Sanofi and Regeneron Pharmaceuticals. Dr. Chehade disclosed research funding from and consulting for numerous private sector companies, among others, Sanofi and Regeneron Pharmaceuticals, AstraZeneca, Shire-Takeda, and Bristol-Myers Squibb. Multiple study coauthors disclosed various relationships with private-sector companies, including Sanofi and Regeneron Pharmaceuticals, for research funding, consulting, travel, employment, and stock or intellectual ownership. Dr. Webster and Dr. Chiou disclosed no competing interests relevant to their comments.
A version of this article first appeared on Medscape.com.
FROM THE NEW ENGLAND JOURNAL OF MEDICINE
Medicare Advantage Plans Not Always Advantageous
While Medicare Advantage (MA) plans are marketed as providing more generous benefits than traditional Medicare (TM), differences in the financial burden between beneficiaries switching to MA and staying with TM, are minimal, a longitudinal cohort analysis found.
In fact, according to a study by Sungchul Park, PhD, a health economist at Korea University in Seoul, and colleagues, the estimated annual out-of-pocket spending when switching to MA was $168 higher than staying in TM. That amounted to a 10.5% relative increase based on baseline out-of-pocket spending of $1597 annually among switchers, ranging widely, however, from a $133 decrease to a $469 increase. And for some, MA enrollment was associated with a higher likelihood of catastrophic financial burden.
“Our findings contrast with the notion that MA’s apparently more generous health insurance benefits lead to financial savings for enrollees,” Dr. Park and associates wrote in Annals of Internal Medicine.
The study
The analysis looked at costs for 7054 TM stayers and 1544 TM-to-MA switchers from the 2014-2020 Medical Expenditure Panel Survey, focusing on a cohort in which 18% of TM-covered individuals in year 1 switched to MA in year 2.
Comparative financial outcome measures included individual healthcare costs (out-of-pocket spending/cost sharing), financial burden (high/catastrophic), and subjective financial hardship (difficulty paying medical bills).
Although the overall out-of-pocket differences for MA were minimal and amounted to less than 1% of total healthcare expenses, MA was associated with a greater financial burden in vulnerable, especially in low-income populations. For every 100 beneficiaries with family incomes below 200% of the federal poverty level, one to six more switchers faced a catastrophic financial burden, with their out-of-pocket costs consuming more than 40% of household income in the year after switching.
The gap between the perception of lower costs and reality may be caused by a substantially heavier cost-sharing burden for certain services in MA plans, Dr. Park and associates pointed out. While MA enrollees generally paid less in some studies than the Part A hospital deductible for TM for inpatient stays of 3 days, they were more likely to face higher cost sharing for stays exceeding 7 days
Furthermore, whereas TM covers home health services without cost sharing, some MA plans have copayments. In addition, out-of-network health services can cost more. MA enrollees paid an average of $9 more for mental health services than for other in-network services and often encountered limited access to in-network providers. According to a 2021 study, only 18.2% of mental health professionals, 34.4% of cardiologists, 50.0% of psychiatrists, and 57.9% of primary care providers were included in MA networks,
An accompanying editorial noted that private MA plans will reap $83 billion in overpayments from U.S. taxpayers this year, according to Congress’s Medicare Payment Advisory Commission.
And as the data from Dr. Park and colleagues reveal, switchers don’t get much financial protection, according to primary care physician and healthcare researcher Steffi J. Woolhandler, MD, MPH, and internist David U. Himmelstein, MD, both of City University of New York at Hunter College in New York City.
“Medicare Advantage looks good when you’re healthy and don’t need much care. But when you need coverage, it often fails, leaving you with big bills and narrow choices for care,” Dr. Woolhandler said in an interview.
So how do these findings square with insurers’ hard-sell claims and enrollees’ perceptions that MA cuts out-of-pocket costs? “The likeliest explanation is that MA insurers have structured their benefits to advantage low-cost (that is, profitable) enrollees and disadvantage those requiring expensive care,” the editorial commentators wrote. For beneficiaries on inexpensive medications, MA plans would be a financial win. “But for patients requiring expensive chemotherapies, the 20% coinsurance that most MA plans charge could be financially ruinous.”
Commenting on the study but not involved in it, David A. Lipschutz, JD, LLB, associate director of the Center for Medicare Advocacy in Washington, DC, called the study an important one that provides more evidence that significant overpayments to MA plans don’t translate to better financial protections for plan enrollees, particularly lower-income individuals. “While there has been some recent movement to hold plans more accountable for providing necessary care, much more impactful action by policymakers is required to mitigate the harms of the growing privatization of the Medicare program,” he said. “MA overpayments could be redistributed to traditional Medicare in order to enrich all Medicare beneficiaries instead of just insurance companies.”
This study was supported by the National Research Foundation of Korea. Dr. Park disclosed no competing interests. One study coauthor reported support from government and not-for-profit research-funding bodies. Editorialists Dr. Woolhandler and Dr. Himmelstein had no competing interests to declare. Dr. Lipschutz disclosed Medicare advocacy work.
While Medicare Advantage (MA) plans are marketed as providing more generous benefits than traditional Medicare (TM), differences in the financial burden between beneficiaries switching to MA and staying with TM, are minimal, a longitudinal cohort analysis found.
In fact, according to a study by Sungchul Park, PhD, a health economist at Korea University in Seoul, and colleagues, the estimated annual out-of-pocket spending when switching to MA was $168 higher than staying in TM. That amounted to a 10.5% relative increase based on baseline out-of-pocket spending of $1597 annually among switchers, ranging widely, however, from a $133 decrease to a $469 increase. And for some, MA enrollment was associated with a higher likelihood of catastrophic financial burden.
“Our findings contrast with the notion that MA’s apparently more generous health insurance benefits lead to financial savings for enrollees,” Dr. Park and associates wrote in Annals of Internal Medicine.
The study
The analysis looked at costs for 7054 TM stayers and 1544 TM-to-MA switchers from the 2014-2020 Medical Expenditure Panel Survey, focusing on a cohort in which 18% of TM-covered individuals in year 1 switched to MA in year 2.
Comparative financial outcome measures included individual healthcare costs (out-of-pocket spending/cost sharing), financial burden (high/catastrophic), and subjective financial hardship (difficulty paying medical bills).
Although the overall out-of-pocket differences for MA were minimal and amounted to less than 1% of total healthcare expenses, MA was associated with a greater financial burden in vulnerable, especially in low-income populations. For every 100 beneficiaries with family incomes below 200% of the federal poverty level, one to six more switchers faced a catastrophic financial burden, with their out-of-pocket costs consuming more than 40% of household income in the year after switching.
The gap between the perception of lower costs and reality may be caused by a substantially heavier cost-sharing burden for certain services in MA plans, Dr. Park and associates pointed out. While MA enrollees generally paid less in some studies than the Part A hospital deductible for TM for inpatient stays of 3 days, they were more likely to face higher cost sharing for stays exceeding 7 days
Furthermore, whereas TM covers home health services without cost sharing, some MA plans have copayments. In addition, out-of-network health services can cost more. MA enrollees paid an average of $9 more for mental health services than for other in-network services and often encountered limited access to in-network providers. According to a 2021 study, only 18.2% of mental health professionals, 34.4% of cardiologists, 50.0% of psychiatrists, and 57.9% of primary care providers were included in MA networks,
An accompanying editorial noted that private MA plans will reap $83 billion in overpayments from U.S. taxpayers this year, according to Congress’s Medicare Payment Advisory Commission.
And as the data from Dr. Park and colleagues reveal, switchers don’t get much financial protection, according to primary care physician and healthcare researcher Steffi J. Woolhandler, MD, MPH, and internist David U. Himmelstein, MD, both of City University of New York at Hunter College in New York City.
“Medicare Advantage looks good when you’re healthy and don’t need much care. But when you need coverage, it often fails, leaving you with big bills and narrow choices for care,” Dr. Woolhandler said in an interview.
So how do these findings square with insurers’ hard-sell claims and enrollees’ perceptions that MA cuts out-of-pocket costs? “The likeliest explanation is that MA insurers have structured their benefits to advantage low-cost (that is, profitable) enrollees and disadvantage those requiring expensive care,” the editorial commentators wrote. For beneficiaries on inexpensive medications, MA plans would be a financial win. “But for patients requiring expensive chemotherapies, the 20% coinsurance that most MA plans charge could be financially ruinous.”
Commenting on the study but not involved in it, David A. Lipschutz, JD, LLB, associate director of the Center for Medicare Advocacy in Washington, DC, called the study an important one that provides more evidence that significant overpayments to MA plans don’t translate to better financial protections for plan enrollees, particularly lower-income individuals. “While there has been some recent movement to hold plans more accountable for providing necessary care, much more impactful action by policymakers is required to mitigate the harms of the growing privatization of the Medicare program,” he said. “MA overpayments could be redistributed to traditional Medicare in order to enrich all Medicare beneficiaries instead of just insurance companies.”
This study was supported by the National Research Foundation of Korea. Dr. Park disclosed no competing interests. One study coauthor reported support from government and not-for-profit research-funding bodies. Editorialists Dr. Woolhandler and Dr. Himmelstein had no competing interests to declare. Dr. Lipschutz disclosed Medicare advocacy work.
While Medicare Advantage (MA) plans are marketed as providing more generous benefits than traditional Medicare (TM), differences in the financial burden between beneficiaries switching to MA and staying with TM, are minimal, a longitudinal cohort analysis found.
In fact, according to a study by Sungchul Park, PhD, a health economist at Korea University in Seoul, and colleagues, the estimated annual out-of-pocket spending when switching to MA was $168 higher than staying in TM. That amounted to a 10.5% relative increase based on baseline out-of-pocket spending of $1597 annually among switchers, ranging widely, however, from a $133 decrease to a $469 increase. And for some, MA enrollment was associated with a higher likelihood of catastrophic financial burden.
“Our findings contrast with the notion that MA’s apparently more generous health insurance benefits lead to financial savings for enrollees,” Dr. Park and associates wrote in Annals of Internal Medicine.
The study
The analysis looked at costs for 7054 TM stayers and 1544 TM-to-MA switchers from the 2014-2020 Medical Expenditure Panel Survey, focusing on a cohort in which 18% of TM-covered individuals in year 1 switched to MA in year 2.
Comparative financial outcome measures included individual healthcare costs (out-of-pocket spending/cost sharing), financial burden (high/catastrophic), and subjective financial hardship (difficulty paying medical bills).
Although the overall out-of-pocket differences for MA were minimal and amounted to less than 1% of total healthcare expenses, MA was associated with a greater financial burden in vulnerable, especially in low-income populations. For every 100 beneficiaries with family incomes below 200% of the federal poverty level, one to six more switchers faced a catastrophic financial burden, with their out-of-pocket costs consuming more than 40% of household income in the year after switching.
The gap between the perception of lower costs and reality may be caused by a substantially heavier cost-sharing burden for certain services in MA plans, Dr. Park and associates pointed out. While MA enrollees generally paid less in some studies than the Part A hospital deductible for TM for inpatient stays of 3 days, they were more likely to face higher cost sharing for stays exceeding 7 days
Furthermore, whereas TM covers home health services without cost sharing, some MA plans have copayments. In addition, out-of-network health services can cost more. MA enrollees paid an average of $9 more for mental health services than for other in-network services and often encountered limited access to in-network providers. According to a 2021 study, only 18.2% of mental health professionals, 34.4% of cardiologists, 50.0% of psychiatrists, and 57.9% of primary care providers were included in MA networks,
An accompanying editorial noted that private MA plans will reap $83 billion in overpayments from U.S. taxpayers this year, according to Congress’s Medicare Payment Advisory Commission.
And as the data from Dr. Park and colleagues reveal, switchers don’t get much financial protection, according to primary care physician and healthcare researcher Steffi J. Woolhandler, MD, MPH, and internist David U. Himmelstein, MD, both of City University of New York at Hunter College in New York City.
“Medicare Advantage looks good when you’re healthy and don’t need much care. But when you need coverage, it often fails, leaving you with big bills and narrow choices for care,” Dr. Woolhandler said in an interview.
So how do these findings square with insurers’ hard-sell claims and enrollees’ perceptions that MA cuts out-of-pocket costs? “The likeliest explanation is that MA insurers have structured their benefits to advantage low-cost (that is, profitable) enrollees and disadvantage those requiring expensive care,” the editorial commentators wrote. For beneficiaries on inexpensive medications, MA plans would be a financial win. “But for patients requiring expensive chemotherapies, the 20% coinsurance that most MA plans charge could be financially ruinous.”
Commenting on the study but not involved in it, David A. Lipschutz, JD, LLB, associate director of the Center for Medicare Advocacy in Washington, DC, called the study an important one that provides more evidence that significant overpayments to MA plans don’t translate to better financial protections for plan enrollees, particularly lower-income individuals. “While there has been some recent movement to hold plans more accountable for providing necessary care, much more impactful action by policymakers is required to mitigate the harms of the growing privatization of the Medicare program,” he said. “MA overpayments could be redistributed to traditional Medicare in order to enrich all Medicare beneficiaries instead of just insurance companies.”
This study was supported by the National Research Foundation of Korea. Dr. Park disclosed no competing interests. One study coauthor reported support from government and not-for-profit research-funding bodies. Editorialists Dr. Woolhandler and Dr. Himmelstein had no competing interests to declare. Dr. Lipschutz disclosed Medicare advocacy work.
FROM ANNALS OF INTERNAL MEDICINE
Metformin Gets a Reproductive Reprieve — For Diabetic Moms and Dads Alike
For decades it’s been thought that preconception use of the oral antidiabetic metformin by mothers and fathers might result in adverse fetal outcomes, including congenital malformations and stillbirths.
Women with type 2 diabetes (T2D) are often advised to switch to insulin before or during early pregnancy out of concern for fetal safety. But two studies from the Harvard T.H. Chan School of Public Health in Boston, Massachusetts — one in mothers, the other in fathers — report that metformin, a common and cost-effective antidiabetic agent, is not associated with a significant increased risk of teratogenicity and negative perinatal outcomes. The studies appear in Annals of Internal Medicine.
The studies may make it easier for physicians to reassure diabetic parents-to-be about the safety of metformin use before conception and in early pregnancy,
In the context of sparse existing safety data, the maternal analysis looked at Medicaid data on 12,489 mothers (mean age, about 30) receiving metformin for pregestational T2D during the period 2000-2018. “Many women become pregnant while still taking noninsulin oral antidiabetics, mostly metformin, and one safety concern is whether metformin could cause birth defects,” lead author Yu-Han Chiu, MD, ScD, an epidemiologist, said in an interview, commenting on the impetus for the study.
“On the one hand, metformin can cross the placenta and might directly affect the fetus. On the other hand, poor blood sugar control is a risk factor for birth defects,” she continued. “Insulin in combination with metformin might control blood sugar better than using insulin alone, which may lower the risk of birth defects.”
Switched to insulin monotherapy or prescribed additional insulin within 90 days of their last menstrual period, mothers were assessed for nonchromosomal fetal malformations and nonlive births, spontaneous abortion, and termination. Continuing metformin or adding insulin to metformin in early pregnancy resulted in little to no increased risk for major malformations in infants.
The estimated risk for nonlive birth was 32.7% with insulin monotherapy and 34.3% with insulin plus metformin polytherapy, for a risk ratio (RR) of 1.02 (95% confidence interval (CI), 1.01-1.04).
In addition, the estimated risk for live birth with congenital malformations was 8.0% (5.70-10.2) under insulin monotherapy and 5.7% under insulin plus metformin (95% CI, 4.5-7.3), amounting to a risk ratio of 0.72 (0.51-1.09).
While the results may involve residual confounding by participants’ glycemic control and body mass index, Dr. Chiu said, “Our findings suggest that the current clinical recommendations to switch from metformin to insulin before pregnancy, due to concerns about birth defects, may require reconsideration.”
She noted that previous trials showed adding metformin to insulin in mid-late pregnancy also improved blood sugar control with no increase in risk of birth defects. “However, most of these studies started treatment too late — between 10 and 34 weeks of pregnancy — to determine if metformin could cause birth defects.”
Observational studies found that women with pregestational diabetes who used noninsulin antidiabetics (mainly metformin) in the first trimester had a lower risk of birth defects, compared with those who used insulin, Dr. Chiu added. “However, comparing metformin with insulin may have some biases because women who used metformin generally have less severe diabetes than those who used insulin.”
Aligning with these reassuring findings, a randomized, placebo-controlled trial reported that adding metformin to insulin did not lead to a higher incidence of neonatal morbidity and mortality and was associated with better maternal glycemic control and reduced maternal weight gain. Metformin-exposed offspring, however, had lower birth weights and a higher incidence of being small for gestational age.
Similarly, a recent Nordic register study of more than 3.7 million infants also found no evidence of an increased risk of major defects with the use of metformin vs insulin in the first trimester.
Despite such reassuring findings, however, Dr. Chiu stressed the need to study other pregnancy and infant outcomes as well as the safety of other oral antidiabetics during pregnancy.
Metformin in Fathers
Turning to fathers, a much larger cohort study by Harvard T.H. Chan investigators looked at the effect of paternal metformin use and also found it to be safe.
The Harvard investigators analyzed diabetic men in 383,851 live births from 1999 to 2020 in an Israeli health fund cohort, excluding those with diabetic spouses. Across different T2D medication groups, paternal age ranged from about 35 to about 43 years. The data revealed that paternal use of metformin monotherapy in the preconception sperm production period was, after adjustment of crude numbers, not associated with major congenital malformations (MCMs) in newborns.
“While metformin has an overall good safety profile, it can lower androgen levels, and there had been some concerns that its use in fathers could alter the sperm, causing adverse effects to the fetus,” lead author and neuroepidemiologist Ran S. Rotem, MD, ScD, of the Harvard School of Public Health, Boston, Massachusetts, said in interview. “Given the increasing prevalence of diabetes in young individuals, more fathers are conceiving a child while using the medication, which could lead to a substantial population effect even if the individual risk is low. But our study suggests that the medication is safe to use by fathers before conception.”
The prevalence of MCMs in the cohort was 4.7% in children of fathers unexposed to diabetes medications (n = 381,041), compared with 6.2% in children of fathers exposed during preconception spermatogenesis to metformin (n = 1730).
By these crude numbers, children with preconception paternal metformin exposure had a nearly 30% increased odds of MCMs. But whereas the crude odds ratio (OR) for MCMs with paternal metformin exposure in all formulations was 1.28 (95% CI, 1.01-1.64), the adjusted OR was 1.00 (95% CI, 0.76 -1.31). Within specific regimens, the adjusted OR was 0.86 (95% CI, 0.60-1.23) for metformin in monotherapy and 1.36 (95% CI, 1.00-1.85) for metformin in polytherapy.
At the outset, Dr. Rotem’s group hypothesized that any crude associations between metformin in polytherapy and birth defects could potentially be explained by poorer underlying parental cardiometabolic risk profiles in those taking multiple diabetes medications. Compared with that of unexposed fathers, the prevalence of cardiometabolic morbidity was indeed substantially higher among both fathers who used metformin during spermatogenesis and their spouses.
In addition, these fathers were more likely to be older, to be smokers, and to have fertility problems. Similarly, mothers were more likely to have cardiovascular comorbidity and to have had fertility problems when the father used metformin.
Moreover, children born to men who used diabetes medications before conception were much more likely to have mothers who also had diabetes and other metabolic conditions, Dr. Rotem noted. “This makes sense since we know that many of these conditions are affected by diet and lifestyle factors that are probably shared across individuals living in the same household.”
Recent research has shown that paternal health and behavior before conception can affect offspring development and long-term health. Characteristics including obesity, diabetes, and metabolic syndrome are seen to affect offspring via complex indirect and direct mechanisms, both genetic and nongenetic.
Doing little to dispel safety concerns, a recent Danish national study reported a link between preconception paternal metformin and major birth defects, particularly genital birth defects in boys. That study, however, lacked data on medication adherence and glycemic control.
“These are well-conducted studies, but it would be useful to see them replicated in different populations, as the sample sizes eligible for analysis are relatively small and some of the confidence intervals are wide,” said Robert W. Platt, PhD, a professor in the departments of Pediatrics and of Epidemiology, Biostatistics, and Occupational Health at McGill University in Montreal, Canada. “However, the results suggest that type 2 diabetics can focus on the most effective treatment pathway for their condition. Metformin does not appear to confer an increased risk of congenital malformations.”
According to an accompanying editorial by Sarah Martins da Silva. MBChB, MD, a reproductive medicine specialist at the University of Dundee in Scotland, the Israeli findings highlight the importance of factoring the sometimes overlooked issue of paternal health into reproductive planning and prenatal care. She stressed that individual risks and benefits should always be carefully considered and results interpreted with caution since such studies lack information on glycemic control. “Nonetheless, these recent analyses suggest that metformin is a safe and effective treatment option for T2D for men and women trying to conceive as well as for managing hyperglycemia in pregnant women in the first trimester,” she wrote and agreed that it may be time to reconsider current prenatal care guidelines that advocate switching to insulin therapy.
The studies by Dr. Chiu and Dr. Rotem were funded by the National Institutes of Health. Dr. Chiu and Dr. Rotem had no competing interests to declare. Dr. Hernandez Diaz, a coauthor on both studies, reported funding from Takeda and consulting for Moderna, Johnson & Johnson, and UCB. Several authors reported support from government and not-for-profit research funding agencies. Dr. Platt disclosed no competing interests. Editorial commentator Dr. Martins da Silva disclosed consulting, speaking, travel, and advisory fees from, variously, Dyneval, Ferring Pharmaceutical, Merck, IBSA, and Gedeon Richer.
For decades it’s been thought that preconception use of the oral antidiabetic metformin by mothers and fathers might result in adverse fetal outcomes, including congenital malformations and stillbirths.
Women with type 2 diabetes (T2D) are often advised to switch to insulin before or during early pregnancy out of concern for fetal safety. But two studies from the Harvard T.H. Chan School of Public Health in Boston, Massachusetts — one in mothers, the other in fathers — report that metformin, a common and cost-effective antidiabetic agent, is not associated with a significant increased risk of teratogenicity and negative perinatal outcomes. The studies appear in Annals of Internal Medicine.
The studies may make it easier for physicians to reassure diabetic parents-to-be about the safety of metformin use before conception and in early pregnancy,
In the context of sparse existing safety data, the maternal analysis looked at Medicaid data on 12,489 mothers (mean age, about 30) receiving metformin for pregestational T2D during the period 2000-2018. “Many women become pregnant while still taking noninsulin oral antidiabetics, mostly metformin, and one safety concern is whether metformin could cause birth defects,” lead author Yu-Han Chiu, MD, ScD, an epidemiologist, said in an interview, commenting on the impetus for the study.
“On the one hand, metformin can cross the placenta and might directly affect the fetus. On the other hand, poor blood sugar control is a risk factor for birth defects,” she continued. “Insulin in combination with metformin might control blood sugar better than using insulin alone, which may lower the risk of birth defects.”
Switched to insulin monotherapy or prescribed additional insulin within 90 days of their last menstrual period, mothers were assessed for nonchromosomal fetal malformations and nonlive births, spontaneous abortion, and termination. Continuing metformin or adding insulin to metformin in early pregnancy resulted in little to no increased risk for major malformations in infants.
The estimated risk for nonlive birth was 32.7% with insulin monotherapy and 34.3% with insulin plus metformin polytherapy, for a risk ratio (RR) of 1.02 (95% confidence interval (CI), 1.01-1.04).
In addition, the estimated risk for live birth with congenital malformations was 8.0% (5.70-10.2) under insulin monotherapy and 5.7% under insulin plus metformin (95% CI, 4.5-7.3), amounting to a risk ratio of 0.72 (0.51-1.09).
While the results may involve residual confounding by participants’ glycemic control and body mass index, Dr. Chiu said, “Our findings suggest that the current clinical recommendations to switch from metformin to insulin before pregnancy, due to concerns about birth defects, may require reconsideration.”
She noted that previous trials showed adding metformin to insulin in mid-late pregnancy also improved blood sugar control with no increase in risk of birth defects. “However, most of these studies started treatment too late — between 10 and 34 weeks of pregnancy — to determine if metformin could cause birth defects.”
Observational studies found that women with pregestational diabetes who used noninsulin antidiabetics (mainly metformin) in the first trimester had a lower risk of birth defects, compared with those who used insulin, Dr. Chiu added. “However, comparing metformin with insulin may have some biases because women who used metformin generally have less severe diabetes than those who used insulin.”
Aligning with these reassuring findings, a randomized, placebo-controlled trial reported that adding metformin to insulin did not lead to a higher incidence of neonatal morbidity and mortality and was associated with better maternal glycemic control and reduced maternal weight gain. Metformin-exposed offspring, however, had lower birth weights and a higher incidence of being small for gestational age.
Similarly, a recent Nordic register study of more than 3.7 million infants also found no evidence of an increased risk of major defects with the use of metformin vs insulin in the first trimester.
Despite such reassuring findings, however, Dr. Chiu stressed the need to study other pregnancy and infant outcomes as well as the safety of other oral antidiabetics during pregnancy.
Metformin in Fathers
Turning to fathers, a much larger cohort study by Harvard T.H. Chan investigators looked at the effect of paternal metformin use and also found it to be safe.
The Harvard investigators analyzed diabetic men in 383,851 live births from 1999 to 2020 in an Israeli health fund cohort, excluding those with diabetic spouses. Across different T2D medication groups, paternal age ranged from about 35 to about 43 years. The data revealed that paternal use of metformin monotherapy in the preconception sperm production period was, after adjustment of crude numbers, not associated with major congenital malformations (MCMs) in newborns.
“While metformin has an overall good safety profile, it can lower androgen levels, and there had been some concerns that its use in fathers could alter the sperm, causing adverse effects to the fetus,” lead author and neuroepidemiologist Ran S. Rotem, MD, ScD, of the Harvard School of Public Health, Boston, Massachusetts, said in interview. “Given the increasing prevalence of diabetes in young individuals, more fathers are conceiving a child while using the medication, which could lead to a substantial population effect even if the individual risk is low. But our study suggests that the medication is safe to use by fathers before conception.”
The prevalence of MCMs in the cohort was 4.7% in children of fathers unexposed to diabetes medications (n = 381,041), compared with 6.2% in children of fathers exposed during preconception spermatogenesis to metformin (n = 1730).
By these crude numbers, children with preconception paternal metformin exposure had a nearly 30% increased odds of MCMs. But whereas the crude odds ratio (OR) for MCMs with paternal metformin exposure in all formulations was 1.28 (95% CI, 1.01-1.64), the adjusted OR was 1.00 (95% CI, 0.76 -1.31). Within specific regimens, the adjusted OR was 0.86 (95% CI, 0.60-1.23) for metformin in monotherapy and 1.36 (95% CI, 1.00-1.85) for metformin in polytherapy.
At the outset, Dr. Rotem’s group hypothesized that any crude associations between metformin in polytherapy and birth defects could potentially be explained by poorer underlying parental cardiometabolic risk profiles in those taking multiple diabetes medications. Compared with that of unexposed fathers, the prevalence of cardiometabolic morbidity was indeed substantially higher among both fathers who used metformin during spermatogenesis and their spouses.
In addition, these fathers were more likely to be older, to be smokers, and to have fertility problems. Similarly, mothers were more likely to have cardiovascular comorbidity and to have had fertility problems when the father used metformin.
Moreover, children born to men who used diabetes medications before conception were much more likely to have mothers who also had diabetes and other metabolic conditions, Dr. Rotem noted. “This makes sense since we know that many of these conditions are affected by diet and lifestyle factors that are probably shared across individuals living in the same household.”
Recent research has shown that paternal health and behavior before conception can affect offspring development and long-term health. Characteristics including obesity, diabetes, and metabolic syndrome are seen to affect offspring via complex indirect and direct mechanisms, both genetic and nongenetic.
Doing little to dispel safety concerns, a recent Danish national study reported a link between preconception paternal metformin and major birth defects, particularly genital birth defects in boys. That study, however, lacked data on medication adherence and glycemic control.
“These are well-conducted studies, but it would be useful to see them replicated in different populations, as the sample sizes eligible for analysis are relatively small and some of the confidence intervals are wide,” said Robert W. Platt, PhD, a professor in the departments of Pediatrics and of Epidemiology, Biostatistics, and Occupational Health at McGill University in Montreal, Canada. “However, the results suggest that type 2 diabetics can focus on the most effective treatment pathway for their condition. Metformin does not appear to confer an increased risk of congenital malformations.”
According to an accompanying editorial by Sarah Martins da Silva. MBChB, MD, a reproductive medicine specialist at the University of Dundee in Scotland, the Israeli findings highlight the importance of factoring the sometimes overlooked issue of paternal health into reproductive planning and prenatal care. She stressed that individual risks and benefits should always be carefully considered and results interpreted with caution since such studies lack information on glycemic control. “Nonetheless, these recent analyses suggest that metformin is a safe and effective treatment option for T2D for men and women trying to conceive as well as for managing hyperglycemia in pregnant women in the first trimester,” she wrote and agreed that it may be time to reconsider current prenatal care guidelines that advocate switching to insulin therapy.
The studies by Dr. Chiu and Dr. Rotem were funded by the National Institutes of Health. Dr. Chiu and Dr. Rotem had no competing interests to declare. Dr. Hernandez Diaz, a coauthor on both studies, reported funding from Takeda and consulting for Moderna, Johnson & Johnson, and UCB. Several authors reported support from government and not-for-profit research funding agencies. Dr. Platt disclosed no competing interests. Editorial commentator Dr. Martins da Silva disclosed consulting, speaking, travel, and advisory fees from, variously, Dyneval, Ferring Pharmaceutical, Merck, IBSA, and Gedeon Richer.
For decades it’s been thought that preconception use of the oral antidiabetic metformin by mothers and fathers might result in adverse fetal outcomes, including congenital malformations and stillbirths.
Women with type 2 diabetes (T2D) are often advised to switch to insulin before or during early pregnancy out of concern for fetal safety. But two studies from the Harvard T.H. Chan School of Public Health in Boston, Massachusetts — one in mothers, the other in fathers — report that metformin, a common and cost-effective antidiabetic agent, is not associated with a significant increased risk of teratogenicity and negative perinatal outcomes. The studies appear in Annals of Internal Medicine.
The studies may make it easier for physicians to reassure diabetic parents-to-be about the safety of metformin use before conception and in early pregnancy,
In the context of sparse existing safety data, the maternal analysis looked at Medicaid data on 12,489 mothers (mean age, about 30) receiving metformin for pregestational T2D during the period 2000-2018. “Many women become pregnant while still taking noninsulin oral antidiabetics, mostly metformin, and one safety concern is whether metformin could cause birth defects,” lead author Yu-Han Chiu, MD, ScD, an epidemiologist, said in an interview, commenting on the impetus for the study.
“On the one hand, metformin can cross the placenta and might directly affect the fetus. On the other hand, poor blood sugar control is a risk factor for birth defects,” she continued. “Insulin in combination with metformin might control blood sugar better than using insulin alone, which may lower the risk of birth defects.”
Switched to insulin monotherapy or prescribed additional insulin within 90 days of their last menstrual period, mothers were assessed for nonchromosomal fetal malformations and nonlive births, spontaneous abortion, and termination. Continuing metformin or adding insulin to metformin in early pregnancy resulted in little to no increased risk for major malformations in infants.
The estimated risk for nonlive birth was 32.7% with insulin monotherapy and 34.3% with insulin plus metformin polytherapy, for a risk ratio (RR) of 1.02 (95% confidence interval (CI), 1.01-1.04).
In addition, the estimated risk for live birth with congenital malformations was 8.0% (5.70-10.2) under insulin monotherapy and 5.7% under insulin plus metformin (95% CI, 4.5-7.3), amounting to a risk ratio of 0.72 (0.51-1.09).
While the results may involve residual confounding by participants’ glycemic control and body mass index, Dr. Chiu said, “Our findings suggest that the current clinical recommendations to switch from metformin to insulin before pregnancy, due to concerns about birth defects, may require reconsideration.”
She noted that previous trials showed adding metformin to insulin in mid-late pregnancy also improved blood sugar control with no increase in risk of birth defects. “However, most of these studies started treatment too late — between 10 and 34 weeks of pregnancy — to determine if metformin could cause birth defects.”
Observational studies found that women with pregestational diabetes who used noninsulin antidiabetics (mainly metformin) in the first trimester had a lower risk of birth defects, compared with those who used insulin, Dr. Chiu added. “However, comparing metformin with insulin may have some biases because women who used metformin generally have less severe diabetes than those who used insulin.”
Aligning with these reassuring findings, a randomized, placebo-controlled trial reported that adding metformin to insulin did not lead to a higher incidence of neonatal morbidity and mortality and was associated with better maternal glycemic control and reduced maternal weight gain. Metformin-exposed offspring, however, had lower birth weights and a higher incidence of being small for gestational age.
Similarly, a recent Nordic register study of more than 3.7 million infants also found no evidence of an increased risk of major defects with the use of metformin vs insulin in the first trimester.
Despite such reassuring findings, however, Dr. Chiu stressed the need to study other pregnancy and infant outcomes as well as the safety of other oral antidiabetics during pregnancy.
Metformin in Fathers
Turning to fathers, a much larger cohort study by Harvard T.H. Chan investigators looked at the effect of paternal metformin use and also found it to be safe.
The Harvard investigators analyzed diabetic men in 383,851 live births from 1999 to 2020 in an Israeli health fund cohort, excluding those with diabetic spouses. Across different T2D medication groups, paternal age ranged from about 35 to about 43 years. The data revealed that paternal use of metformin monotherapy in the preconception sperm production period was, after adjustment of crude numbers, not associated with major congenital malformations (MCMs) in newborns.
“While metformin has an overall good safety profile, it can lower androgen levels, and there had been some concerns that its use in fathers could alter the sperm, causing adverse effects to the fetus,” lead author and neuroepidemiologist Ran S. Rotem, MD, ScD, of the Harvard School of Public Health, Boston, Massachusetts, said in interview. “Given the increasing prevalence of diabetes in young individuals, more fathers are conceiving a child while using the medication, which could lead to a substantial population effect even if the individual risk is low. But our study suggests that the medication is safe to use by fathers before conception.”
The prevalence of MCMs in the cohort was 4.7% in children of fathers unexposed to diabetes medications (n = 381,041), compared with 6.2% in children of fathers exposed during preconception spermatogenesis to metformin (n = 1730).
By these crude numbers, children with preconception paternal metformin exposure had a nearly 30% increased odds of MCMs. But whereas the crude odds ratio (OR) for MCMs with paternal metformin exposure in all formulations was 1.28 (95% CI, 1.01-1.64), the adjusted OR was 1.00 (95% CI, 0.76 -1.31). Within specific regimens, the adjusted OR was 0.86 (95% CI, 0.60-1.23) for metformin in monotherapy and 1.36 (95% CI, 1.00-1.85) for metformin in polytherapy.
At the outset, Dr. Rotem’s group hypothesized that any crude associations between metformin in polytherapy and birth defects could potentially be explained by poorer underlying parental cardiometabolic risk profiles in those taking multiple diabetes medications. Compared with that of unexposed fathers, the prevalence of cardiometabolic morbidity was indeed substantially higher among both fathers who used metformin during spermatogenesis and their spouses.
In addition, these fathers were more likely to be older, to be smokers, and to have fertility problems. Similarly, mothers were more likely to have cardiovascular comorbidity and to have had fertility problems when the father used metformin.
Moreover, children born to men who used diabetes medications before conception were much more likely to have mothers who also had diabetes and other metabolic conditions, Dr. Rotem noted. “This makes sense since we know that many of these conditions are affected by diet and lifestyle factors that are probably shared across individuals living in the same household.”
Recent research has shown that paternal health and behavior before conception can affect offspring development and long-term health. Characteristics including obesity, diabetes, and metabolic syndrome are seen to affect offspring via complex indirect and direct mechanisms, both genetic and nongenetic.
Doing little to dispel safety concerns, a recent Danish national study reported a link between preconception paternal metformin and major birth defects, particularly genital birth defects in boys. That study, however, lacked data on medication adherence and glycemic control.
“These are well-conducted studies, but it would be useful to see them replicated in different populations, as the sample sizes eligible for analysis are relatively small and some of the confidence intervals are wide,” said Robert W. Platt, PhD, a professor in the departments of Pediatrics and of Epidemiology, Biostatistics, and Occupational Health at McGill University in Montreal, Canada. “However, the results suggest that type 2 diabetics can focus on the most effective treatment pathway for their condition. Metformin does not appear to confer an increased risk of congenital malformations.”
According to an accompanying editorial by Sarah Martins da Silva. MBChB, MD, a reproductive medicine specialist at the University of Dundee in Scotland, the Israeli findings highlight the importance of factoring the sometimes overlooked issue of paternal health into reproductive planning and prenatal care. She stressed that individual risks and benefits should always be carefully considered and results interpreted with caution since such studies lack information on glycemic control. “Nonetheless, these recent analyses suggest that metformin is a safe and effective treatment option for T2D for men and women trying to conceive as well as for managing hyperglycemia in pregnant women in the first trimester,” she wrote and agreed that it may be time to reconsider current prenatal care guidelines that advocate switching to insulin therapy.
The studies by Dr. Chiu and Dr. Rotem were funded by the National Institutes of Health. Dr. Chiu and Dr. Rotem had no competing interests to declare. Dr. Hernandez Diaz, a coauthor on both studies, reported funding from Takeda and consulting for Moderna, Johnson & Johnson, and UCB. Several authors reported support from government and not-for-profit research funding agencies. Dr. Platt disclosed no competing interests. Editorial commentator Dr. Martins da Silva disclosed consulting, speaking, travel, and advisory fees from, variously, Dyneval, Ferring Pharmaceutical, Merck, IBSA, and Gedeon Richer.