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Pregnancy studies on psoriasis, PsA medications pick up
Christina Chambers, PhD, MPH, who runs the MotherToBaby Pregnancy Studies research center at the University of California, San Diego, has found most pregnant women to be “entirely altruistic” about sharing their experiences with drug treatment during pregnancy.
– but dermatologists, rheumatologists, and their female patients with psoriasis and psoriatic arthritis (PsA) want much more.
And women’s participation in the MotherToBaby studies conducted by the nonprofit Organization of Teratology Information Specialists (OTIS) is key, say physicians who are treating women of reproductive age. OTIS is now listed in drug labeling as the “pregnancy registry” contact for many of the medications they may be discussing with patients.
Dr. Chambers said that most women appreciate “that participating in a study may not help her with her pregnancy, but it can help her sister or her friend or someone else who has these same questions in planning a pregnancy of ‘Can I stay on my treatment?’ or, in the case of an unplanned pregnancy, ‘Should I be concerned?’ ”
OTIS has enrolled women with psoriasis and/or PsA in studies of nine medications, most of them biologics (both TNF-alpha blockers and newer anti-interleukin agents).
Four of the studies – those evaluating etanercept (Enbrel), adalimumab (Humira), abatacept (Orencia), and ustekinumab (Stelara) – are now closed to enrollment with analyses either underway or completed. The other five are currently enrolling patients and involve treatment with certolizumab pegol (Cimzia), tildrakizumab (Ilumya), apremilast (Otezla), guselkumab (Tremfya), and tofacitinib (Xeljanz).
Lisa R. Sammaritano, MD, a rheumatologist at the Hospital for Special Surgery, New York, who led the development of the American College of Rheumatology’s first guideline for the management of reproductive health in rheumatic and musculoskeletal diseases, recommends to some of her patients that they contact OTIS. “Their pregnancy registry studies have added important information to the field over the years,” she said.
Most recently, a study of the anti–TNF-alpha medication adalimumab that began in 2004 in pregnant patients with RA and Crohn’s disease culminated in a 2019 PLOS ONE paper reporting no associations between exposure to the medication and an increased risk of adverse outcomes. The outcomes studied were major structural birth defects, minor defects, spontaneous abortion, preterm delivery, prenatal and postnatal growth deficiency, serious or opportunistic infections, and malignancies.
An analysis is underway of adalimumab exposure in women with PsA – a patient subset that was added after the study started. But in the meantime, Dr. Chambers said, the 2019 research article is relevant to questions of drug safety across indications.
OTIS’s MothertoBaby studies are structured as prospective cohort studies. Dr. Chambers, a perinatal epidemiologist, is president of OTIS, which recruits women who have an exposure to the medication under study – at least one dose, for any length of time. And in most cases, it also recruits women with the underlying condition but no exposure and healthy women without the condition to represent the general population.
It’s the disease-matched comparison group that makes OTIS’s studies different from traditional pregnancy registries involving “a simple exposure series and outcomes that are described in the context of what you’d expect in the general population,” said Dr. Chambers, professor in the department of pediatrics, as well as family and preventative medicine, at UCSD and codirector of the Center for Better Beginnings at that university. “Many maternal conditions themselves [or their comorbidities] carry some risk of adverse outcomes in pregnancy.”
The OTIS studies typically involve at least 100 exposed pregnancies and a similar number of unexposed pregnancies; some have cohorts of 200-300.
The recently published study of adalimumab, for instance, included 257 women with exposure to the drug and 120 women in a disease comparison group with no exposure. In addition to finding no associations between drug exposure and adverse outcomes, the study found that women with RA or Crohn’s were at increased risk of preterm delivery, irrespective of adalimumab exposure.
“There’s insufficient [power with any of these numbers] to come to the conclusion that a drug is safe,” she said. “But what we have been able to say [through our studies] is that we’ve looked carefully at the whole array of outcomes ... and we don’t see anything unusual. That early view can be reassuring” until large population-based studies or claims analyses become possible.
Dr. Sammaritano, also with Weill Cornell Medicine, New York, said that she does not recommend registry participation for patients who stop biologics at the diagnosis of pregnancy. Since “the start of IgG antibody transfer during pregnancy is about 16 weeks,” she worries that including these patients might lead to falsely reassuring findings. “We are most interested in [knowing the outcomes of] patients who must continue the drugs through pregnancy,” she said.
Dr. Chambers, however, said that in her view, placental transfer is not a requirement for a medication to have some effect on the outcome of pregnancy. “The outcome could be influenced by an effect of the medication that doesn’t require placental transfer or require placental transfer in large amounts,” she said. “So it’s relevant to examine exposures that have occurred only in the first trimester, and this is especially true for the outcome of major birth defects, most of which are initiated in the first trimester.”
The MotherToBaby studies typically include both early, short exposures and longer exposures, she said. “And certainly, duration of use is a factor that we do consider in looking at specific outcomes such as growth, preterm delivery, and risk of serious or opportunistic infections.”
(In the published study of adalimumab, 65.3% of women in the medication-exposed cohort used the medication in all three trimesters, 10.5% in the first and second trimesters, and 22.4% in the first trimester only.)
Women participating in the MotherToBaby studies complete two to four interviews during pregnancy and may be interviewed again after delivery. They are asked for their permission to share a copy of their medical records – and their baby’s medical records – and their babies receive a follow-up pediatric exam by a pediatrician with expertise in dysmorphology/genetics (who is blinded to exposure status), most commonly in the participant’s home. Providers are not asked to enter any data.
Eliza Chakravarty, MD, a rheumatologist with the Oklahoma Medical Research Foundation in Oklahoma City who treats patients with PsA who are pregnant or considering pregnancy, said that her referrals for research participation “have been mostly to MothertoBaby.”
“Most drug companies [in the autoimmune space] are now contracting with them [for their pregnancy exposure research],” she said. “I really like that it’s become so centralized.”
She tells patients that many questions can be answered through research, that their experience matters, and that “there are benefits” to the extra pediatric examination. “I give them the information and let them decide whether or not they want to call [MotherToBaby],” she said. “I don’t want to impose. I want to make them aware.”
Dr. Chambers emphasizes to patients and physicians that the studies are strictly observational and do not require any changes in personal or medical regimens. “When people hear the word ‘research’ they think of clinical trials. We’re saying, you and your provider do everything you normally would do, just let us observe what happens during your pregnancy.”
Physicians should assure patients, moreover, that “just because the drug is being studied doesn’t mean there’s a known risk or even a suspected risk,” she said.
The MotherToBaby studies receive funding from the pharmaceutical companies, which are required by the Food and Drug Administration to conduct pregnancy exposure registries for medications used during pregnancy or in women of reproductive age. OTIS has an independent advisory board, however, and independently analyzes and publishes its findings. Progress reports are shared with the pharmaceutical companies, and in turn, the FDA, Dr. Chambers said.
To refer patients for MotherToBaby studies, physicians can use an online referral form found on the MothertoBaby web site, a service of OTIS, or call the pregnancy studies team at 877-311-8972 to provide them with the patient’s name or number. Patients may also be given the number and advised to consider calling. MotherToBaby offers medication fact sheets that answer questions about exposures during pregnancy and breastfeeding, and runs a free and confidential teratogen counseling service: 866-626-6847.
Christina Chambers, PhD, MPH, who runs the MotherToBaby Pregnancy Studies research center at the University of California, San Diego, has found most pregnant women to be “entirely altruistic” about sharing their experiences with drug treatment during pregnancy.
– but dermatologists, rheumatologists, and their female patients with psoriasis and psoriatic arthritis (PsA) want much more.
And women’s participation in the MotherToBaby studies conducted by the nonprofit Organization of Teratology Information Specialists (OTIS) is key, say physicians who are treating women of reproductive age. OTIS is now listed in drug labeling as the “pregnancy registry” contact for many of the medications they may be discussing with patients.
Dr. Chambers said that most women appreciate “that participating in a study may not help her with her pregnancy, but it can help her sister or her friend or someone else who has these same questions in planning a pregnancy of ‘Can I stay on my treatment?’ or, in the case of an unplanned pregnancy, ‘Should I be concerned?’ ”
OTIS has enrolled women with psoriasis and/or PsA in studies of nine medications, most of them biologics (both TNF-alpha blockers and newer anti-interleukin agents).
Four of the studies – those evaluating etanercept (Enbrel), adalimumab (Humira), abatacept (Orencia), and ustekinumab (Stelara) – are now closed to enrollment with analyses either underway or completed. The other five are currently enrolling patients and involve treatment with certolizumab pegol (Cimzia), tildrakizumab (Ilumya), apremilast (Otezla), guselkumab (Tremfya), and tofacitinib (Xeljanz).
Lisa R. Sammaritano, MD, a rheumatologist at the Hospital for Special Surgery, New York, who led the development of the American College of Rheumatology’s first guideline for the management of reproductive health in rheumatic and musculoskeletal diseases, recommends to some of her patients that they contact OTIS. “Their pregnancy registry studies have added important information to the field over the years,” she said.
Most recently, a study of the anti–TNF-alpha medication adalimumab that began in 2004 in pregnant patients with RA and Crohn’s disease culminated in a 2019 PLOS ONE paper reporting no associations between exposure to the medication and an increased risk of adverse outcomes. The outcomes studied were major structural birth defects, minor defects, spontaneous abortion, preterm delivery, prenatal and postnatal growth deficiency, serious or opportunistic infections, and malignancies.
An analysis is underway of adalimumab exposure in women with PsA – a patient subset that was added after the study started. But in the meantime, Dr. Chambers said, the 2019 research article is relevant to questions of drug safety across indications.
OTIS’s MothertoBaby studies are structured as prospective cohort studies. Dr. Chambers, a perinatal epidemiologist, is president of OTIS, which recruits women who have an exposure to the medication under study – at least one dose, for any length of time. And in most cases, it also recruits women with the underlying condition but no exposure and healthy women without the condition to represent the general population.
It’s the disease-matched comparison group that makes OTIS’s studies different from traditional pregnancy registries involving “a simple exposure series and outcomes that are described in the context of what you’d expect in the general population,” said Dr. Chambers, professor in the department of pediatrics, as well as family and preventative medicine, at UCSD and codirector of the Center for Better Beginnings at that university. “Many maternal conditions themselves [or their comorbidities] carry some risk of adverse outcomes in pregnancy.”
The OTIS studies typically involve at least 100 exposed pregnancies and a similar number of unexposed pregnancies; some have cohorts of 200-300.
The recently published study of adalimumab, for instance, included 257 women with exposure to the drug and 120 women in a disease comparison group with no exposure. In addition to finding no associations between drug exposure and adverse outcomes, the study found that women with RA or Crohn’s were at increased risk of preterm delivery, irrespective of adalimumab exposure.
“There’s insufficient [power with any of these numbers] to come to the conclusion that a drug is safe,” she said. “But what we have been able to say [through our studies] is that we’ve looked carefully at the whole array of outcomes ... and we don’t see anything unusual. That early view can be reassuring” until large population-based studies or claims analyses become possible.
Dr. Sammaritano, also with Weill Cornell Medicine, New York, said that she does not recommend registry participation for patients who stop biologics at the diagnosis of pregnancy. Since “the start of IgG antibody transfer during pregnancy is about 16 weeks,” she worries that including these patients might lead to falsely reassuring findings. “We are most interested in [knowing the outcomes of] patients who must continue the drugs through pregnancy,” she said.
Dr. Chambers, however, said that in her view, placental transfer is not a requirement for a medication to have some effect on the outcome of pregnancy. “The outcome could be influenced by an effect of the medication that doesn’t require placental transfer or require placental transfer in large amounts,” she said. “So it’s relevant to examine exposures that have occurred only in the first trimester, and this is especially true for the outcome of major birth defects, most of which are initiated in the first trimester.”
The MotherToBaby studies typically include both early, short exposures and longer exposures, she said. “And certainly, duration of use is a factor that we do consider in looking at specific outcomes such as growth, preterm delivery, and risk of serious or opportunistic infections.”
(In the published study of adalimumab, 65.3% of women in the medication-exposed cohort used the medication in all three trimesters, 10.5% in the first and second trimesters, and 22.4% in the first trimester only.)
Women participating in the MotherToBaby studies complete two to four interviews during pregnancy and may be interviewed again after delivery. They are asked for their permission to share a copy of their medical records – and their baby’s medical records – and their babies receive a follow-up pediatric exam by a pediatrician with expertise in dysmorphology/genetics (who is blinded to exposure status), most commonly in the participant’s home. Providers are not asked to enter any data.
Eliza Chakravarty, MD, a rheumatologist with the Oklahoma Medical Research Foundation in Oklahoma City who treats patients with PsA who are pregnant or considering pregnancy, said that her referrals for research participation “have been mostly to MothertoBaby.”
“Most drug companies [in the autoimmune space] are now contracting with them [for their pregnancy exposure research],” she said. “I really like that it’s become so centralized.”
She tells patients that many questions can be answered through research, that their experience matters, and that “there are benefits” to the extra pediatric examination. “I give them the information and let them decide whether or not they want to call [MotherToBaby],” she said. “I don’t want to impose. I want to make them aware.”
Dr. Chambers emphasizes to patients and physicians that the studies are strictly observational and do not require any changes in personal or medical regimens. “When people hear the word ‘research’ they think of clinical trials. We’re saying, you and your provider do everything you normally would do, just let us observe what happens during your pregnancy.”
Physicians should assure patients, moreover, that “just because the drug is being studied doesn’t mean there’s a known risk or even a suspected risk,” she said.
The MotherToBaby studies receive funding from the pharmaceutical companies, which are required by the Food and Drug Administration to conduct pregnancy exposure registries for medications used during pregnancy or in women of reproductive age. OTIS has an independent advisory board, however, and independently analyzes and publishes its findings. Progress reports are shared with the pharmaceutical companies, and in turn, the FDA, Dr. Chambers said.
To refer patients for MotherToBaby studies, physicians can use an online referral form found on the MothertoBaby web site, a service of OTIS, or call the pregnancy studies team at 877-311-8972 to provide them with the patient’s name or number. Patients may also be given the number and advised to consider calling. MotherToBaby offers medication fact sheets that answer questions about exposures during pregnancy and breastfeeding, and runs a free and confidential teratogen counseling service: 866-626-6847.
Christina Chambers, PhD, MPH, who runs the MotherToBaby Pregnancy Studies research center at the University of California, San Diego, has found most pregnant women to be “entirely altruistic” about sharing their experiences with drug treatment during pregnancy.
– but dermatologists, rheumatologists, and their female patients with psoriasis and psoriatic arthritis (PsA) want much more.
And women’s participation in the MotherToBaby studies conducted by the nonprofit Organization of Teratology Information Specialists (OTIS) is key, say physicians who are treating women of reproductive age. OTIS is now listed in drug labeling as the “pregnancy registry” contact for many of the medications they may be discussing with patients.
Dr. Chambers said that most women appreciate “that participating in a study may not help her with her pregnancy, but it can help her sister or her friend or someone else who has these same questions in planning a pregnancy of ‘Can I stay on my treatment?’ or, in the case of an unplanned pregnancy, ‘Should I be concerned?’ ”
OTIS has enrolled women with psoriasis and/or PsA in studies of nine medications, most of them biologics (both TNF-alpha blockers and newer anti-interleukin agents).
Four of the studies – those evaluating etanercept (Enbrel), adalimumab (Humira), abatacept (Orencia), and ustekinumab (Stelara) – are now closed to enrollment with analyses either underway or completed. The other five are currently enrolling patients and involve treatment with certolizumab pegol (Cimzia), tildrakizumab (Ilumya), apremilast (Otezla), guselkumab (Tremfya), and tofacitinib (Xeljanz).
Lisa R. Sammaritano, MD, a rheumatologist at the Hospital for Special Surgery, New York, who led the development of the American College of Rheumatology’s first guideline for the management of reproductive health in rheumatic and musculoskeletal diseases, recommends to some of her patients that they contact OTIS. “Their pregnancy registry studies have added important information to the field over the years,” she said.
Most recently, a study of the anti–TNF-alpha medication adalimumab that began in 2004 in pregnant patients with RA and Crohn’s disease culminated in a 2019 PLOS ONE paper reporting no associations between exposure to the medication and an increased risk of adverse outcomes. The outcomes studied were major structural birth defects, minor defects, spontaneous abortion, preterm delivery, prenatal and postnatal growth deficiency, serious or opportunistic infections, and malignancies.
An analysis is underway of adalimumab exposure in women with PsA – a patient subset that was added after the study started. But in the meantime, Dr. Chambers said, the 2019 research article is relevant to questions of drug safety across indications.
OTIS’s MothertoBaby studies are structured as prospective cohort studies. Dr. Chambers, a perinatal epidemiologist, is president of OTIS, which recruits women who have an exposure to the medication under study – at least one dose, for any length of time. And in most cases, it also recruits women with the underlying condition but no exposure and healthy women without the condition to represent the general population.
It’s the disease-matched comparison group that makes OTIS’s studies different from traditional pregnancy registries involving “a simple exposure series and outcomes that are described in the context of what you’d expect in the general population,” said Dr. Chambers, professor in the department of pediatrics, as well as family and preventative medicine, at UCSD and codirector of the Center for Better Beginnings at that university. “Many maternal conditions themselves [or their comorbidities] carry some risk of adverse outcomes in pregnancy.”
The OTIS studies typically involve at least 100 exposed pregnancies and a similar number of unexposed pregnancies; some have cohorts of 200-300.
The recently published study of adalimumab, for instance, included 257 women with exposure to the drug and 120 women in a disease comparison group with no exposure. In addition to finding no associations between drug exposure and adverse outcomes, the study found that women with RA or Crohn’s were at increased risk of preterm delivery, irrespective of adalimumab exposure.
“There’s insufficient [power with any of these numbers] to come to the conclusion that a drug is safe,” she said. “But what we have been able to say [through our studies] is that we’ve looked carefully at the whole array of outcomes ... and we don’t see anything unusual. That early view can be reassuring” until large population-based studies or claims analyses become possible.
Dr. Sammaritano, also with Weill Cornell Medicine, New York, said that she does not recommend registry participation for patients who stop biologics at the diagnosis of pregnancy. Since “the start of IgG antibody transfer during pregnancy is about 16 weeks,” she worries that including these patients might lead to falsely reassuring findings. “We are most interested in [knowing the outcomes of] patients who must continue the drugs through pregnancy,” she said.
Dr. Chambers, however, said that in her view, placental transfer is not a requirement for a medication to have some effect on the outcome of pregnancy. “The outcome could be influenced by an effect of the medication that doesn’t require placental transfer or require placental transfer in large amounts,” she said. “So it’s relevant to examine exposures that have occurred only in the first trimester, and this is especially true for the outcome of major birth defects, most of which are initiated in the first trimester.”
The MotherToBaby studies typically include both early, short exposures and longer exposures, she said. “And certainly, duration of use is a factor that we do consider in looking at specific outcomes such as growth, preterm delivery, and risk of serious or opportunistic infections.”
(In the published study of adalimumab, 65.3% of women in the medication-exposed cohort used the medication in all three trimesters, 10.5% in the first and second trimesters, and 22.4% in the first trimester only.)
Women participating in the MotherToBaby studies complete two to four interviews during pregnancy and may be interviewed again after delivery. They are asked for their permission to share a copy of their medical records – and their baby’s medical records – and their babies receive a follow-up pediatric exam by a pediatrician with expertise in dysmorphology/genetics (who is blinded to exposure status), most commonly in the participant’s home. Providers are not asked to enter any data.
Eliza Chakravarty, MD, a rheumatologist with the Oklahoma Medical Research Foundation in Oklahoma City who treats patients with PsA who are pregnant or considering pregnancy, said that her referrals for research participation “have been mostly to MothertoBaby.”
“Most drug companies [in the autoimmune space] are now contracting with them [for their pregnancy exposure research],” she said. “I really like that it’s become so centralized.”
She tells patients that many questions can be answered through research, that their experience matters, and that “there are benefits” to the extra pediatric examination. “I give them the information and let them decide whether or not they want to call [MotherToBaby],” she said. “I don’t want to impose. I want to make them aware.”
Dr. Chambers emphasizes to patients and physicians that the studies are strictly observational and do not require any changes in personal or medical regimens. “When people hear the word ‘research’ they think of clinical trials. We’re saying, you and your provider do everything you normally would do, just let us observe what happens during your pregnancy.”
Physicians should assure patients, moreover, that “just because the drug is being studied doesn’t mean there’s a known risk or even a suspected risk,” she said.
The MotherToBaby studies receive funding from the pharmaceutical companies, which are required by the Food and Drug Administration to conduct pregnancy exposure registries for medications used during pregnancy or in women of reproductive age. OTIS has an independent advisory board, however, and independently analyzes and publishes its findings. Progress reports are shared with the pharmaceutical companies, and in turn, the FDA, Dr. Chambers said.
To refer patients for MotherToBaby studies, physicians can use an online referral form found on the MothertoBaby web site, a service of OTIS, or call the pregnancy studies team at 877-311-8972 to provide them with the patient’s name or number. Patients may also be given the number and advised to consider calling. MotherToBaby offers medication fact sheets that answer questions about exposures during pregnancy and breastfeeding, and runs a free and confidential teratogen counseling service: 866-626-6847.
Study validates OSA phenotypes in Latinos
Three previously described clinical phenotypes of obstructive sleep apnea (OSA) have been validated in a large and diverse Hispanic/Latino community-based population for the first time, according to findings presented at the virtual annual meeting of the Associated Professional Sleep Societies.
The three OSA symptom profiles present in this population – labeled “minimally symptomatic,” “disturbed sleep,” and “daytime sleepiness” – are consistent with recent findings from the Sleep Apnea Global Interdisciplinary Consortium, which were published in Sleep, but there are notable differences in the prevalence of these clusters, with the minimally symptomatic cluster much more prevalent than in prior research, reported Kevin Gonzalez, of the University of California, San Diego.
“Other biopsychosocial factors may be contributing to OSA phenotypes among Hispanics and Latinos,” Mr. Gonzalez said in his presentation. Prior research to characterize the heterogeneity of sleep apnea has not included a diverse Latino population, he emphasized.
The adults studied were aged 18-74 years and participants in the multisite Hispanic Community Health Study/Study of Latinos (HCHS/SOL), a comprehensive study of Hispanic/Latino health and disease in the United States. Their respiratory events were measured overnight in HCHS/SOL sleep reading centers with an ARES Unicorder 5.2, B-Alert. Sleep patterns and risk factors were assessed using the Sleep Heart Health Study Sleep Habits Questionnaire and the Epworth Sleepiness Scale.
Participants meeting the criteria for moderate to severe OSA (with an Apnea Hypopnea Index of 15 or above) were included in the analysis (n = 1,623). Their average age was 52.4 ± 13.9 years, and 34.1% were female.
To identify phenotype clusters, investigators performed a latent class analysis using 15 common OSA symptoms and a survey weighted to adjust for selection bias. The three clusters offering the “best” fit for the data aligned with the previously reported phenotypes and identified daytime sleepiness in 15.3%, disturbed sleep (insomnia-like symptoms) in 37.7%, and minimally symptomatic (a low symptom profile) in 46.9%.
These phenotypes were reported in the European Respiratory Journal in 2014 in a cluster analysis of data from a sleep apnea cohort in Iceland and later replicated in the analysis of data from the Sleep Apnea Global Interdisciplinary Consortium published in Sleep in 2018. The consortium study also added two additional phenotypes, labeled “upper airway symptoms dominant” and “sleepiness dominant.”
The prevalence of a “minimally symptomatic group” in the new analysis of the Hispanics/Latinos in the United States is much higher than reported in these prior studies, at least partly, the investigators believed, because the “prior studies were clinical samples, and the people who were minimally symptomatic didn’t get to the sleep centers,” Mr. Gonzalez said in an interview after the meeting.
Patients with a phenotype of daytime sleepiness – the most common phenotype in prior research – constituted only a minority in the Hispanic/Latino population, he said.
Alberto Ramos, MD, of the University of Miami and the principal investigator, said in an interview that the research team is currently analyzing “if and how these different [phenotypic] clusters could affect the incidence of comorbidities” recorded in the HCHS/SOL study, such as hypertension, diabetes, cardiovascular disease, and cognitive decline.
For now, he said, the findings suggest that OSA may be especially underrecognized in Hispanics and Latinos and that there is more research to be done to better identify and stratify patients with varying symptomatology for more personalized treatment and for clinical trial selection. “Maybe we should expand our criteria ... broaden our [recognition] of the presentation of sleep apnea and the symptoms associated with it, not only in Hispanics but maybe in the general population,” Dr. Ramos said.
In commenting on the study, Krishna M. Sundar, MD, FCCP, director of the Sleep-Wake Center at the University of Utah, Salt Lake City, said that insomnia and daytime sleepiness are “key associations with obstructive sleep apnea and may predict different outcomes with untreated OSA.” Such heterogeneity is “only beginning to be appreciated,” he said. “The expression of OSA with these symptoms points to how OSA impacts quality of life” and how symptomatology in addition to Apnea Hypopnea Index “may be an important determinant of treatment benefit and compliance.”
The investigators reported no relevant disclosures. Dr. Sundar said that he is cofounder of Hypnoscure, software for population management of sleep apnea, but with no monies received.
Three previously described clinical phenotypes of obstructive sleep apnea (OSA) have been validated in a large and diverse Hispanic/Latino community-based population for the first time, according to findings presented at the virtual annual meeting of the Associated Professional Sleep Societies.
The three OSA symptom profiles present in this population – labeled “minimally symptomatic,” “disturbed sleep,” and “daytime sleepiness” – are consistent with recent findings from the Sleep Apnea Global Interdisciplinary Consortium, which were published in Sleep, but there are notable differences in the prevalence of these clusters, with the minimally symptomatic cluster much more prevalent than in prior research, reported Kevin Gonzalez, of the University of California, San Diego.
“Other biopsychosocial factors may be contributing to OSA phenotypes among Hispanics and Latinos,” Mr. Gonzalez said in his presentation. Prior research to characterize the heterogeneity of sleep apnea has not included a diverse Latino population, he emphasized.
The adults studied were aged 18-74 years and participants in the multisite Hispanic Community Health Study/Study of Latinos (HCHS/SOL), a comprehensive study of Hispanic/Latino health and disease in the United States. Their respiratory events were measured overnight in HCHS/SOL sleep reading centers with an ARES Unicorder 5.2, B-Alert. Sleep patterns and risk factors were assessed using the Sleep Heart Health Study Sleep Habits Questionnaire and the Epworth Sleepiness Scale.
Participants meeting the criteria for moderate to severe OSA (with an Apnea Hypopnea Index of 15 or above) were included in the analysis (n = 1,623). Their average age was 52.4 ± 13.9 years, and 34.1% were female.
To identify phenotype clusters, investigators performed a latent class analysis using 15 common OSA symptoms and a survey weighted to adjust for selection bias. The three clusters offering the “best” fit for the data aligned with the previously reported phenotypes and identified daytime sleepiness in 15.3%, disturbed sleep (insomnia-like symptoms) in 37.7%, and minimally symptomatic (a low symptom profile) in 46.9%.
These phenotypes were reported in the European Respiratory Journal in 2014 in a cluster analysis of data from a sleep apnea cohort in Iceland and later replicated in the analysis of data from the Sleep Apnea Global Interdisciplinary Consortium published in Sleep in 2018. The consortium study also added two additional phenotypes, labeled “upper airway symptoms dominant” and “sleepiness dominant.”
The prevalence of a “minimally symptomatic group” in the new analysis of the Hispanics/Latinos in the United States is much higher than reported in these prior studies, at least partly, the investigators believed, because the “prior studies were clinical samples, and the people who were minimally symptomatic didn’t get to the sleep centers,” Mr. Gonzalez said in an interview after the meeting.
Patients with a phenotype of daytime sleepiness – the most common phenotype in prior research – constituted only a minority in the Hispanic/Latino population, he said.
Alberto Ramos, MD, of the University of Miami and the principal investigator, said in an interview that the research team is currently analyzing “if and how these different [phenotypic] clusters could affect the incidence of comorbidities” recorded in the HCHS/SOL study, such as hypertension, diabetes, cardiovascular disease, and cognitive decline.
For now, he said, the findings suggest that OSA may be especially underrecognized in Hispanics and Latinos and that there is more research to be done to better identify and stratify patients with varying symptomatology for more personalized treatment and for clinical trial selection. “Maybe we should expand our criteria ... broaden our [recognition] of the presentation of sleep apnea and the symptoms associated with it, not only in Hispanics but maybe in the general population,” Dr. Ramos said.
In commenting on the study, Krishna M. Sundar, MD, FCCP, director of the Sleep-Wake Center at the University of Utah, Salt Lake City, said that insomnia and daytime sleepiness are “key associations with obstructive sleep apnea and may predict different outcomes with untreated OSA.” Such heterogeneity is “only beginning to be appreciated,” he said. “The expression of OSA with these symptoms points to how OSA impacts quality of life” and how symptomatology in addition to Apnea Hypopnea Index “may be an important determinant of treatment benefit and compliance.”
The investigators reported no relevant disclosures. Dr. Sundar said that he is cofounder of Hypnoscure, software for population management of sleep apnea, but with no monies received.
Three previously described clinical phenotypes of obstructive sleep apnea (OSA) have been validated in a large and diverse Hispanic/Latino community-based population for the first time, according to findings presented at the virtual annual meeting of the Associated Professional Sleep Societies.
The three OSA symptom profiles present in this population – labeled “minimally symptomatic,” “disturbed sleep,” and “daytime sleepiness” – are consistent with recent findings from the Sleep Apnea Global Interdisciplinary Consortium, which were published in Sleep, but there are notable differences in the prevalence of these clusters, with the minimally symptomatic cluster much more prevalent than in prior research, reported Kevin Gonzalez, of the University of California, San Diego.
“Other biopsychosocial factors may be contributing to OSA phenotypes among Hispanics and Latinos,” Mr. Gonzalez said in his presentation. Prior research to characterize the heterogeneity of sleep apnea has not included a diverse Latino population, he emphasized.
The adults studied were aged 18-74 years and participants in the multisite Hispanic Community Health Study/Study of Latinos (HCHS/SOL), a comprehensive study of Hispanic/Latino health and disease in the United States. Their respiratory events were measured overnight in HCHS/SOL sleep reading centers with an ARES Unicorder 5.2, B-Alert. Sleep patterns and risk factors were assessed using the Sleep Heart Health Study Sleep Habits Questionnaire and the Epworth Sleepiness Scale.
Participants meeting the criteria for moderate to severe OSA (with an Apnea Hypopnea Index of 15 or above) were included in the analysis (n = 1,623). Their average age was 52.4 ± 13.9 years, and 34.1% were female.
To identify phenotype clusters, investigators performed a latent class analysis using 15 common OSA symptoms and a survey weighted to adjust for selection bias. The three clusters offering the “best” fit for the data aligned with the previously reported phenotypes and identified daytime sleepiness in 15.3%, disturbed sleep (insomnia-like symptoms) in 37.7%, and minimally symptomatic (a low symptom profile) in 46.9%.
These phenotypes were reported in the European Respiratory Journal in 2014 in a cluster analysis of data from a sleep apnea cohort in Iceland and later replicated in the analysis of data from the Sleep Apnea Global Interdisciplinary Consortium published in Sleep in 2018. The consortium study also added two additional phenotypes, labeled “upper airway symptoms dominant” and “sleepiness dominant.”
The prevalence of a “minimally symptomatic group” in the new analysis of the Hispanics/Latinos in the United States is much higher than reported in these prior studies, at least partly, the investigators believed, because the “prior studies were clinical samples, and the people who were minimally symptomatic didn’t get to the sleep centers,” Mr. Gonzalez said in an interview after the meeting.
Patients with a phenotype of daytime sleepiness – the most common phenotype in prior research – constituted only a minority in the Hispanic/Latino population, he said.
Alberto Ramos, MD, of the University of Miami and the principal investigator, said in an interview that the research team is currently analyzing “if and how these different [phenotypic] clusters could affect the incidence of comorbidities” recorded in the HCHS/SOL study, such as hypertension, diabetes, cardiovascular disease, and cognitive decline.
For now, he said, the findings suggest that OSA may be especially underrecognized in Hispanics and Latinos and that there is more research to be done to better identify and stratify patients with varying symptomatology for more personalized treatment and for clinical trial selection. “Maybe we should expand our criteria ... broaden our [recognition] of the presentation of sleep apnea and the symptoms associated with it, not only in Hispanics but maybe in the general population,” Dr. Ramos said.
In commenting on the study, Krishna M. Sundar, MD, FCCP, director of the Sleep-Wake Center at the University of Utah, Salt Lake City, said that insomnia and daytime sleepiness are “key associations with obstructive sleep apnea and may predict different outcomes with untreated OSA.” Such heterogeneity is “only beginning to be appreciated,” he said. “The expression of OSA with these symptoms points to how OSA impacts quality of life” and how symptomatology in addition to Apnea Hypopnea Index “may be an important determinant of treatment benefit and compliance.”
The investigators reported no relevant disclosures. Dr. Sundar said that he is cofounder of Hypnoscure, software for population management of sleep apnea, but with no monies received.
REPORTING FROM SLEEP 2020
Insomnia may have a role in generation of stressful life events
Insomnia disorder appears to play a causal role in the development of new stressful life events, especially “dependent” events for which individuals are at least partly responsible, said the investigators of an ongoing longitudinal study of people who have experienced involuntary job loss.
The “stress-generation hypothesis” has been applied for several decades in the context of depression. It posits that depressed individuals generate more stressful life events – events that create family conflict or disrupt careers, for instance – than individuals who are not depressed.
The new analysis of individuals with involuntary job loss suggests that the same can be said of insomnia. “Insomnia disorder is associated with fatigue, daytime sleepiness, impaired concentration, and difficulties in emotional regulation,” Iva Skobic, MSPH, MA, a PhD student at the University of Arizona, Tucson, said at the virtual annual meeting of the Associated Professional Sleep Societies.
“These may lead to impaired decision-making, interpersonal conflicts, difficulty meeting deadlines and keeping commitments, and other sources [of stressful life events],” she said. “This extension of the stress-generation hypothesis has important implications for harm reduction interventions for insomnia disorder.”
Investigators conducted a cross-lagged panel analysis using baseline and 3-month follow-up data from 137 individuals who completed a standardized, textual life event measure called the Life Events and Difficulties Schedule after having lost their jobs involuntarily. Participants were interviewed and their events were rated for severity by a consensus panel using operationalized criteria. The analysis employed linear regression controlling for covariates (age, gender, and race) and logistic regression that controlled for insomnia at baseline. Insomnia disorder was defined as meeting ICSD-2/3 criteria using the Duke Structured Interview for Sleep Disorders.
The findings: Insomnia disorder at baseline predicted the number of stressful life events (either dependent or interpersonal) generated within 3 months (beta, 0.70; standard error, 0.31; Tscore, 2.27; P = .03). Conversely, the number of stressful events at baseline did not predict insomnia (odds ratio, 0.97; 95% confidence interval, 0.73-1.29). There also was a trend toward increased generation of dependent events specifically among those with insomnia disorder.
Participants were a mean age of 42 years, and all had been in their previous place of employment for at least 6 months. Nearly 60% met the diagnostic threshold for insomnia at baseline. They were part of a larger ongoing study examining the linkages between job loss and sleep disturbances, obesity, and mental health – the Assessing Daily Activity Patterns through Occupational Transitions (ADAPT) study, supported by the National Heart, Lung, and Blood Institute.
This analysis on insomnia was completed before the COVID-19 pandemic began, but it and other analyses soon to be reported are highly relevant to the economic climate, said Patricia Haynes, PhD, principal investigator of ADAPT and a coauthor of the insomnia study, in an interview after the meeting.
Insomnia is a frequent comorbidity of depression and shares many of its symptoms, from increased fatigue to emotional dysregulation and an increased risk of maladaptive coping strategies. “Interestingly, the literature on the stress-generation hypothesis posits that these very symptoms are on the casual pathway between depression and stressful life events,” said Ms. Skobic at the meeting.
In commenting on the study, Krishna M. Sundar, MD, medical director of the Sleep-Wake Center at the University of Utah, Salt Lake City, noted that the analysis did not include any measure of the severity of insomnia. Still, he said, “finding an association [with stress generation] at [just] 3 months with the presence of insomnia disorder is quite interesting.”
There were higher rates of insomnia in the sample than depression, Dr. Haynes said, but the analysis did not control for depression or take it into account.
“We know [from prior research] that stress clearly leads to insomnia. The big [takeaway] here is that insomnia can also lead to more stress,” she said. “It’s important to think of it as a reciprocal relationship. If we can potentially treat insomnia, we may be able to stop that cycle of other stressful events that affect both [the individuals] and others as well.”
Ms. Skobic had no disclosures.
Insomnia disorder appears to play a causal role in the development of new stressful life events, especially “dependent” events for which individuals are at least partly responsible, said the investigators of an ongoing longitudinal study of people who have experienced involuntary job loss.
The “stress-generation hypothesis” has been applied for several decades in the context of depression. It posits that depressed individuals generate more stressful life events – events that create family conflict or disrupt careers, for instance – than individuals who are not depressed.
The new analysis of individuals with involuntary job loss suggests that the same can be said of insomnia. “Insomnia disorder is associated with fatigue, daytime sleepiness, impaired concentration, and difficulties in emotional regulation,” Iva Skobic, MSPH, MA, a PhD student at the University of Arizona, Tucson, said at the virtual annual meeting of the Associated Professional Sleep Societies.
“These may lead to impaired decision-making, interpersonal conflicts, difficulty meeting deadlines and keeping commitments, and other sources [of stressful life events],” she said. “This extension of the stress-generation hypothesis has important implications for harm reduction interventions for insomnia disorder.”
Investigators conducted a cross-lagged panel analysis using baseline and 3-month follow-up data from 137 individuals who completed a standardized, textual life event measure called the Life Events and Difficulties Schedule after having lost their jobs involuntarily. Participants were interviewed and their events were rated for severity by a consensus panel using operationalized criteria. The analysis employed linear regression controlling for covariates (age, gender, and race) and logistic regression that controlled for insomnia at baseline. Insomnia disorder was defined as meeting ICSD-2/3 criteria using the Duke Structured Interview for Sleep Disorders.
The findings: Insomnia disorder at baseline predicted the number of stressful life events (either dependent or interpersonal) generated within 3 months (beta, 0.70; standard error, 0.31; Tscore, 2.27; P = .03). Conversely, the number of stressful events at baseline did not predict insomnia (odds ratio, 0.97; 95% confidence interval, 0.73-1.29). There also was a trend toward increased generation of dependent events specifically among those with insomnia disorder.
Participants were a mean age of 42 years, and all had been in their previous place of employment for at least 6 months. Nearly 60% met the diagnostic threshold for insomnia at baseline. They were part of a larger ongoing study examining the linkages between job loss and sleep disturbances, obesity, and mental health – the Assessing Daily Activity Patterns through Occupational Transitions (ADAPT) study, supported by the National Heart, Lung, and Blood Institute.
This analysis on insomnia was completed before the COVID-19 pandemic began, but it and other analyses soon to be reported are highly relevant to the economic climate, said Patricia Haynes, PhD, principal investigator of ADAPT and a coauthor of the insomnia study, in an interview after the meeting.
Insomnia is a frequent comorbidity of depression and shares many of its symptoms, from increased fatigue to emotional dysregulation and an increased risk of maladaptive coping strategies. “Interestingly, the literature on the stress-generation hypothesis posits that these very symptoms are on the casual pathway between depression and stressful life events,” said Ms. Skobic at the meeting.
In commenting on the study, Krishna M. Sundar, MD, medical director of the Sleep-Wake Center at the University of Utah, Salt Lake City, noted that the analysis did not include any measure of the severity of insomnia. Still, he said, “finding an association [with stress generation] at [just] 3 months with the presence of insomnia disorder is quite interesting.”
There were higher rates of insomnia in the sample than depression, Dr. Haynes said, but the analysis did not control for depression or take it into account.
“We know [from prior research] that stress clearly leads to insomnia. The big [takeaway] here is that insomnia can also lead to more stress,” she said. “It’s important to think of it as a reciprocal relationship. If we can potentially treat insomnia, we may be able to stop that cycle of other stressful events that affect both [the individuals] and others as well.”
Ms. Skobic had no disclosures.
Insomnia disorder appears to play a causal role in the development of new stressful life events, especially “dependent” events for which individuals are at least partly responsible, said the investigators of an ongoing longitudinal study of people who have experienced involuntary job loss.
The “stress-generation hypothesis” has been applied for several decades in the context of depression. It posits that depressed individuals generate more stressful life events – events that create family conflict or disrupt careers, for instance – than individuals who are not depressed.
The new analysis of individuals with involuntary job loss suggests that the same can be said of insomnia. “Insomnia disorder is associated with fatigue, daytime sleepiness, impaired concentration, and difficulties in emotional regulation,” Iva Skobic, MSPH, MA, a PhD student at the University of Arizona, Tucson, said at the virtual annual meeting of the Associated Professional Sleep Societies.
“These may lead to impaired decision-making, interpersonal conflicts, difficulty meeting deadlines and keeping commitments, and other sources [of stressful life events],” she said. “This extension of the stress-generation hypothesis has important implications for harm reduction interventions for insomnia disorder.”
Investigators conducted a cross-lagged panel analysis using baseline and 3-month follow-up data from 137 individuals who completed a standardized, textual life event measure called the Life Events and Difficulties Schedule after having lost their jobs involuntarily. Participants were interviewed and their events were rated for severity by a consensus panel using operationalized criteria. The analysis employed linear regression controlling for covariates (age, gender, and race) and logistic regression that controlled for insomnia at baseline. Insomnia disorder was defined as meeting ICSD-2/3 criteria using the Duke Structured Interview for Sleep Disorders.
The findings: Insomnia disorder at baseline predicted the number of stressful life events (either dependent or interpersonal) generated within 3 months (beta, 0.70; standard error, 0.31; Tscore, 2.27; P = .03). Conversely, the number of stressful events at baseline did not predict insomnia (odds ratio, 0.97; 95% confidence interval, 0.73-1.29). There also was a trend toward increased generation of dependent events specifically among those with insomnia disorder.
Participants were a mean age of 42 years, and all had been in their previous place of employment for at least 6 months. Nearly 60% met the diagnostic threshold for insomnia at baseline. They were part of a larger ongoing study examining the linkages between job loss and sleep disturbances, obesity, and mental health – the Assessing Daily Activity Patterns through Occupational Transitions (ADAPT) study, supported by the National Heart, Lung, and Blood Institute.
This analysis on insomnia was completed before the COVID-19 pandemic began, but it and other analyses soon to be reported are highly relevant to the economic climate, said Patricia Haynes, PhD, principal investigator of ADAPT and a coauthor of the insomnia study, in an interview after the meeting.
Insomnia is a frequent comorbidity of depression and shares many of its symptoms, from increased fatigue to emotional dysregulation and an increased risk of maladaptive coping strategies. “Interestingly, the literature on the stress-generation hypothesis posits that these very symptoms are on the casual pathway between depression and stressful life events,” said Ms. Skobic at the meeting.
In commenting on the study, Krishna M. Sundar, MD, medical director of the Sleep-Wake Center at the University of Utah, Salt Lake City, noted that the analysis did not include any measure of the severity of insomnia. Still, he said, “finding an association [with stress generation] at [just] 3 months with the presence of insomnia disorder is quite interesting.”
There were higher rates of insomnia in the sample than depression, Dr. Haynes said, but the analysis did not control for depression or take it into account.
“We know [from prior research] that stress clearly leads to insomnia. The big [takeaway] here is that insomnia can also lead to more stress,” she said. “It’s important to think of it as a reciprocal relationship. If we can potentially treat insomnia, we may be able to stop that cycle of other stressful events that affect both [the individuals] and others as well.”
Ms. Skobic had no disclosures.
FROM SLEEP 2020
Study confirms link between PAP apnea treatment and dementia onset
Obstructive sleep apnea (OSA) treatment with positive airway pressure (PAP) therapy was associated with a lower odds of incident Alzheimer’s disease and other dementia in a large retrospective cohort study of Medicare patients with the sleep disorder.
The study builds on research linking OSA to poor cognitive outcomes and dementia syndromes. With use of a 5% random sample of Medicare beneficiaries (more than 2.7 million) and their claims data, investigators identified approximately 53,000 who had an OSA diagnosis prior to 2011.
Of these Medicare beneficiaries, 78% with OSA were identified as “PAP-treated” based on having at least one durable medical equipment claim for PAP equipment. And of those treated, 74% were identified as “PAP adherent” based on having more than two PAP equipment claims separated by at least a month, said Galit Levi Dunietz, PhD, MPH, at the virtual annual meeting of the Associated Professional Sleep Societies.
Dr. Dunietz and her coinvestigators used logistic regression to examine the associations between PAP treatment and PAP treatment adherence, and incident ICD-9 diagnoses of Alzheimer’s disease (AD), mild cognitive impairment (MCI), and dementia not otherwise specified (DNOS) over the period 2011-2013.
After adjustments for potential confounders (age, sex, race, stroke, hypertension, cardiovascular disease, and depression), OSA treatment was associated with a significantly lower odds of a diagnosis of AD (odds ratio, 0.78; 95% confidence interval 0.69-0.89) or DNOS (OR, 0.69; 95% CI, 0.55-0.85), as well as nonsignificantly lower odds of MCI diagnosis (OR, 0.82; 95% CI, 0.66-1.02).
“People who are treated for OSA have a 22% reduced odds of being diagnosed with AD and a 31% reduced odds of getting DNOS,” said Dr. Dunietz, from the University of Michigan in Ann Arbor, in an interview after the meeting. “The 18% reduced odds of mild cognitive disorder is not really significant because the upper bound is 1.02, but we consider it approaching significance.”
Adherence to treatment was significantly associated with lower odds of AD, but not with significantly lower odds of DNOS or MCI, she said. OSA was confirmed by ICD-9 diagnosis codes plus the presence of relevant polysomnography current procedural terminology code.
All told, the findings “suggest that PAP therapy for OSA may lower short-term risk for dementia in older persons,” Dr. Dunietz and her co-nvestigators said in their poster presentation. “If a causal pathway exists between OSA and dementia, treatment of OSA may offer new opportunities to improve cognitive outcomes in older adults with OSA.”
Andrew W. Varga, MD, of the division of pulmonary, critical care, and sleep medicine at the Icahn School of Medicine at Mount Sinai and the Mount Sinai Integrative Sleep Center, both in New York, said that cognitive impairment is now a recognized clinical consequence of OSA and that OSA treatment could be a target for the prevention of cognitive impairment and Alzheimer’s disease in particular.
“I absolutely bring it up with patients in their 60s and 70s. I’m honest – I say, there seems to be more and more evidence for links between apnea and Alzheimer’s in particular. I tell them we don’t know 100% whether PAP reverses any of this, but it stands to reason that it does,” said Dr. Varga, who was asked to comment on the study and related research.
An analysis published several years ago in Neurology from the Alzheimer’s Disease Neuroimaging Initiative cohort found that patients with self-reported sleep apnea had a younger age of MCI or AD onset (about 10 years) and that patients who used continuous positive airway pressure had a delayed age of onset. “Those who had a subjective diagnosis of sleep apnea and who also reported using CPAP as treatment seemed to go in the opposite direction,” said Dr. Varga, a coauthor of that study. “They had an onset of AD that looked just like people who had no sleep apnea.”
While this study was limited by sleep apnea being self-reported – and by the lack of severity data – the newly reported study may be limited by the use of ICD codes and the fact that OSA is often entered into patient’s chart before diagnosis is confirmed through a sleep study, Dr. Varga said.
“The field is mature enough that we should be thinking of doing honest and rigorous clinical trials for sleep apnea with cognitive outcomes being a main measure of interest,” he said. “The issue we’re struggling with in the field is that such a trial would not be short.”
There are several theories for the link between OSA and cognitive impairment, he said, including disruptions in sleep architecture leading to increased production of amyloid and tau and/or decreased “clearance” of extracellular amyloid, neuronal sensitivity to hypoxia, and cardiovascular comorbidities.
Dr. Dunietz’s study was supported by The American Academy of Sleep Medicine Foundation. She reported having no disclosures. Dr. Varga said he has no relevant disclosures.
Obstructive sleep apnea (OSA) treatment with positive airway pressure (PAP) therapy was associated with a lower odds of incident Alzheimer’s disease and other dementia in a large retrospective cohort study of Medicare patients with the sleep disorder.
The study builds on research linking OSA to poor cognitive outcomes and dementia syndromes. With use of a 5% random sample of Medicare beneficiaries (more than 2.7 million) and their claims data, investigators identified approximately 53,000 who had an OSA diagnosis prior to 2011.
Of these Medicare beneficiaries, 78% with OSA were identified as “PAP-treated” based on having at least one durable medical equipment claim for PAP equipment. And of those treated, 74% were identified as “PAP adherent” based on having more than two PAP equipment claims separated by at least a month, said Galit Levi Dunietz, PhD, MPH, at the virtual annual meeting of the Associated Professional Sleep Societies.
Dr. Dunietz and her coinvestigators used logistic regression to examine the associations between PAP treatment and PAP treatment adherence, and incident ICD-9 diagnoses of Alzheimer’s disease (AD), mild cognitive impairment (MCI), and dementia not otherwise specified (DNOS) over the period 2011-2013.
After adjustments for potential confounders (age, sex, race, stroke, hypertension, cardiovascular disease, and depression), OSA treatment was associated with a significantly lower odds of a diagnosis of AD (odds ratio, 0.78; 95% confidence interval 0.69-0.89) or DNOS (OR, 0.69; 95% CI, 0.55-0.85), as well as nonsignificantly lower odds of MCI diagnosis (OR, 0.82; 95% CI, 0.66-1.02).
“People who are treated for OSA have a 22% reduced odds of being diagnosed with AD and a 31% reduced odds of getting DNOS,” said Dr. Dunietz, from the University of Michigan in Ann Arbor, in an interview after the meeting. “The 18% reduced odds of mild cognitive disorder is not really significant because the upper bound is 1.02, but we consider it approaching significance.”
Adherence to treatment was significantly associated with lower odds of AD, but not with significantly lower odds of DNOS or MCI, she said. OSA was confirmed by ICD-9 diagnosis codes plus the presence of relevant polysomnography current procedural terminology code.
All told, the findings “suggest that PAP therapy for OSA may lower short-term risk for dementia in older persons,” Dr. Dunietz and her co-nvestigators said in their poster presentation. “If a causal pathway exists between OSA and dementia, treatment of OSA may offer new opportunities to improve cognitive outcomes in older adults with OSA.”
Andrew W. Varga, MD, of the division of pulmonary, critical care, and sleep medicine at the Icahn School of Medicine at Mount Sinai and the Mount Sinai Integrative Sleep Center, both in New York, said that cognitive impairment is now a recognized clinical consequence of OSA and that OSA treatment could be a target for the prevention of cognitive impairment and Alzheimer’s disease in particular.
“I absolutely bring it up with patients in their 60s and 70s. I’m honest – I say, there seems to be more and more evidence for links between apnea and Alzheimer’s in particular. I tell them we don’t know 100% whether PAP reverses any of this, but it stands to reason that it does,” said Dr. Varga, who was asked to comment on the study and related research.
An analysis published several years ago in Neurology from the Alzheimer’s Disease Neuroimaging Initiative cohort found that patients with self-reported sleep apnea had a younger age of MCI or AD onset (about 10 years) and that patients who used continuous positive airway pressure had a delayed age of onset. “Those who had a subjective diagnosis of sleep apnea and who also reported using CPAP as treatment seemed to go in the opposite direction,” said Dr. Varga, a coauthor of that study. “They had an onset of AD that looked just like people who had no sleep apnea.”
While this study was limited by sleep apnea being self-reported – and by the lack of severity data – the newly reported study may be limited by the use of ICD codes and the fact that OSA is often entered into patient’s chart before diagnosis is confirmed through a sleep study, Dr. Varga said.
“The field is mature enough that we should be thinking of doing honest and rigorous clinical trials for sleep apnea with cognitive outcomes being a main measure of interest,” he said. “The issue we’re struggling with in the field is that such a trial would not be short.”
There are several theories for the link between OSA and cognitive impairment, he said, including disruptions in sleep architecture leading to increased production of amyloid and tau and/or decreased “clearance” of extracellular amyloid, neuronal sensitivity to hypoxia, and cardiovascular comorbidities.
Dr. Dunietz’s study was supported by The American Academy of Sleep Medicine Foundation. She reported having no disclosures. Dr. Varga said he has no relevant disclosures.
Obstructive sleep apnea (OSA) treatment with positive airway pressure (PAP) therapy was associated with a lower odds of incident Alzheimer’s disease and other dementia in a large retrospective cohort study of Medicare patients with the sleep disorder.
The study builds on research linking OSA to poor cognitive outcomes and dementia syndromes. With use of a 5% random sample of Medicare beneficiaries (more than 2.7 million) and their claims data, investigators identified approximately 53,000 who had an OSA diagnosis prior to 2011.
Of these Medicare beneficiaries, 78% with OSA were identified as “PAP-treated” based on having at least one durable medical equipment claim for PAP equipment. And of those treated, 74% were identified as “PAP adherent” based on having more than two PAP equipment claims separated by at least a month, said Galit Levi Dunietz, PhD, MPH, at the virtual annual meeting of the Associated Professional Sleep Societies.
Dr. Dunietz and her coinvestigators used logistic regression to examine the associations between PAP treatment and PAP treatment adherence, and incident ICD-9 diagnoses of Alzheimer’s disease (AD), mild cognitive impairment (MCI), and dementia not otherwise specified (DNOS) over the period 2011-2013.
After adjustments for potential confounders (age, sex, race, stroke, hypertension, cardiovascular disease, and depression), OSA treatment was associated with a significantly lower odds of a diagnosis of AD (odds ratio, 0.78; 95% confidence interval 0.69-0.89) or DNOS (OR, 0.69; 95% CI, 0.55-0.85), as well as nonsignificantly lower odds of MCI diagnosis (OR, 0.82; 95% CI, 0.66-1.02).
“People who are treated for OSA have a 22% reduced odds of being diagnosed with AD and a 31% reduced odds of getting DNOS,” said Dr. Dunietz, from the University of Michigan in Ann Arbor, in an interview after the meeting. “The 18% reduced odds of mild cognitive disorder is not really significant because the upper bound is 1.02, but we consider it approaching significance.”
Adherence to treatment was significantly associated with lower odds of AD, but not with significantly lower odds of DNOS or MCI, she said. OSA was confirmed by ICD-9 diagnosis codes plus the presence of relevant polysomnography current procedural terminology code.
All told, the findings “suggest that PAP therapy for OSA may lower short-term risk for dementia in older persons,” Dr. Dunietz and her co-nvestigators said in their poster presentation. “If a causal pathway exists between OSA and dementia, treatment of OSA may offer new opportunities to improve cognitive outcomes in older adults with OSA.”
Andrew W. Varga, MD, of the division of pulmonary, critical care, and sleep medicine at the Icahn School of Medicine at Mount Sinai and the Mount Sinai Integrative Sleep Center, both in New York, said that cognitive impairment is now a recognized clinical consequence of OSA and that OSA treatment could be a target for the prevention of cognitive impairment and Alzheimer’s disease in particular.
“I absolutely bring it up with patients in their 60s and 70s. I’m honest – I say, there seems to be more and more evidence for links between apnea and Alzheimer’s in particular. I tell them we don’t know 100% whether PAP reverses any of this, but it stands to reason that it does,” said Dr. Varga, who was asked to comment on the study and related research.
An analysis published several years ago in Neurology from the Alzheimer’s Disease Neuroimaging Initiative cohort found that patients with self-reported sleep apnea had a younger age of MCI or AD onset (about 10 years) and that patients who used continuous positive airway pressure had a delayed age of onset. “Those who had a subjective diagnosis of sleep apnea and who also reported using CPAP as treatment seemed to go in the opposite direction,” said Dr. Varga, a coauthor of that study. “They had an onset of AD that looked just like people who had no sleep apnea.”
While this study was limited by sleep apnea being self-reported – and by the lack of severity data – the newly reported study may be limited by the use of ICD codes and the fact that OSA is often entered into patient’s chart before diagnosis is confirmed through a sleep study, Dr. Varga said.
“The field is mature enough that we should be thinking of doing honest and rigorous clinical trials for sleep apnea with cognitive outcomes being a main measure of interest,” he said. “The issue we’re struggling with in the field is that such a trial would not be short.”
There are several theories for the link between OSA and cognitive impairment, he said, including disruptions in sleep architecture leading to increased production of amyloid and tau and/or decreased “clearance” of extracellular amyloid, neuronal sensitivity to hypoxia, and cardiovascular comorbidities.
Dr. Dunietz’s study was supported by The American Academy of Sleep Medicine Foundation. She reported having no disclosures. Dr. Varga said he has no relevant disclosures.
FROM SLEEP 2020
Social distancing impacts other infectious diseases
Diagnoses of 12 common pediatric infectious diseases in a large pediatric primary care network declined significantly in the weeks after COVID-19 social distancing (SD) was enacted in Massachusetts, compared with the same time period in 2019, an analysis of EHR data has shown.
While declines in infectious disease transmission with SD are not surprising, “these data demonstrate the extent to which transmission of common pediatric infections can be altered when close contact with other children is eliminated,” Jonathan Hatoun, MD, MPH of the Pediatric Physicians’ Organization at Children’s in Brookline, Mass., and coauthors wrote in Pediatrics . “Notably, three of the studied diseases, namely, influenza, croup, and bronchiolitis, essentially disappeared with [social distancing].”
The researchers analyzed the weekly incidence of each diagnosis for similar calendar periods in 2019 and 2020. A pre-SD period was defined as week 1-9, starting on Jan. 1, and a post-SD period was defined as week 13-18. (The several-week gap represented an implementation period as social distancing was enacted in the state earlier in 2020, from a declared statewide state of emergency through school closures and stay-at-home advisories.)
To isolate the effect of widespread SD, they performed a “difference-in-differences regression analysis, with diagnosis count as a function of calendar year, time period (pre-SD versus post-SD) and the interaction between the two.” The Massachusetts pediatric network provides care for approximately 375,000 children in 100 locations around the state.
In their research brief, Dr. Hatoun and coauthors presented weekly rates expressed as diagnoses per 100,000 patients per day. The rate of bronchiolitis, for instance, was 18 and 8 in the pre- and post-SD–equivalent weeks of 2019, respectively, and 20 and 0.6 in the pre- and post-SD weeks of 2020. Their analysis showed the rate in the 2020 post-SD period to be 10 diagnoses per 100,000 patients per day lower than they would have expected based on the 2019 trend.
Rates of pneumonia, acute otitis media, and streptococcal pharyngitis were similarly 14, 85, and 31 diagnoses per 100,000 patients per day lower, respectively. The prevalence of each of the other conditions analyzed – the common cold, croup, gastroenteritis, nonstreptococcal pharyngitis, sinusitis, skin and soft tissue infections, and urinary tract infection (UTI) – also was significantly lower in the 2020 post-SD period than would be expected based on 2019 data (P < .001 for all diagnoses).
Putting things in perspective
“This study puts numbers to the sense that we have all had in pediatrics – that social distancing appears to have had a dramatic impact on the transmission of common childhood infectious diseases, especially other respiratory viral pathogens,” Audrey R. John, MD, PhD, chief of the division of pediatric infectious disease at Children’s Hospital of Philadelphia, said in an interview.
The authors acknowledged the possible role of families not seeking care, but said that a smaller decrease in diagnoses of UTI – generally not a contagious disease – “suggests that changes in care-seeking behavior had a relatively modest effect on the other observed declines.” (The rate of UTI for the pre- and post-SD periods was 3.3 and 3.7 per 100,000 patients per day in 2019, and 3.4 and 2.4 in 2020, for a difference in differences of –1.5).
In an accompanying editorial, David W. Kimberlin, MD and Erica C. Bjornstad, MD, PhD, MPH, of the University of Alabama at Birmingham, called the report “provocative” and wrote that similar observations of infections dropping during periods of isolation – namely, dramatic declines in influenza and other respiratory viruses in Seattle after a record snowstorm in 2019 – combined with findings from other modeling studies “suggest that the decline [reported in Boston] is indeed real” (Pediatrics 2020. doi: 10.1542/peds.2020-019232).
However, “we also now know that immunization rates for American children have plummeted since the onset of the SARS-CoV-2 pandemic [because of a] ... dramatic decrease in the use of health care during the first months of the pandemic,” they wrote. “Viewed through this lens,” the declines reported in Boston may reflect inflections going “undiagnosed and untreated.”
Ultimately, Dr. Kimberlin and Dr. Bjornstad said, “the verdict remains out.”
Dr. John said that she and others are “concerned about children not seeking care in a timely manner, and [concerned] that reductions in reported infections might be due to a lack of recognition rather than a lack of transmission.”
In Philadelphia, however, declines in admissions for asthma exacerbations, “which are often caused by respiratory viral infections, suggests that this may not be the case,” said Dr. John, who was asked to comment on the study.
In addition, she said, the Massachusetts data showing that UTI diagnoses “are nearly as common this year as in 2019” are “reassuring.”
Are there lessons for the future?
Coauthor Louis Vernacchio, MD, MSc, chief medical officer of the Pediatric Physicians’ Organization at Children’s network, said in an interview that beyond the pandemic, it’s likely that “more careful attention to proven infection control practices in daycares and schools could reduce the burden of common infectious diseases in children.”
Dr. John similarly sees a long-term value of quantifying the impact of social distancing. “We’ve always known [for instance] that bronchiolitis is the result of viral infection.” Findings like the Massachusetts data “will help us advise families who might be trying to protect their premature infants (at risk for severe bronchiolitis) through social distancing.”
The analysis covered both in-person and telemedicine encounters occurring on weekdays.
The authors of the research brief indicated they have no relevant financial disclosures and there was no external funding. The authors of the commentary also reported they have no relevant financial disclosures, and Dr. John said she had no relevant financial disclosures.
SOURCE: Hatoun J et al. Pediatrics. 2020. doi: 10.1542/peds.2020-006460.
Diagnoses of 12 common pediatric infectious diseases in a large pediatric primary care network declined significantly in the weeks after COVID-19 social distancing (SD) was enacted in Massachusetts, compared with the same time period in 2019, an analysis of EHR data has shown.
While declines in infectious disease transmission with SD are not surprising, “these data demonstrate the extent to which transmission of common pediatric infections can be altered when close contact with other children is eliminated,” Jonathan Hatoun, MD, MPH of the Pediatric Physicians’ Organization at Children’s in Brookline, Mass., and coauthors wrote in Pediatrics . “Notably, three of the studied diseases, namely, influenza, croup, and bronchiolitis, essentially disappeared with [social distancing].”
The researchers analyzed the weekly incidence of each diagnosis for similar calendar periods in 2019 and 2020. A pre-SD period was defined as week 1-9, starting on Jan. 1, and a post-SD period was defined as week 13-18. (The several-week gap represented an implementation period as social distancing was enacted in the state earlier in 2020, from a declared statewide state of emergency through school closures and stay-at-home advisories.)
To isolate the effect of widespread SD, they performed a “difference-in-differences regression analysis, with diagnosis count as a function of calendar year, time period (pre-SD versus post-SD) and the interaction between the two.” The Massachusetts pediatric network provides care for approximately 375,000 children in 100 locations around the state.
In their research brief, Dr. Hatoun and coauthors presented weekly rates expressed as diagnoses per 100,000 patients per day. The rate of bronchiolitis, for instance, was 18 and 8 in the pre- and post-SD–equivalent weeks of 2019, respectively, and 20 and 0.6 in the pre- and post-SD weeks of 2020. Their analysis showed the rate in the 2020 post-SD period to be 10 diagnoses per 100,000 patients per day lower than they would have expected based on the 2019 trend.
Rates of pneumonia, acute otitis media, and streptococcal pharyngitis were similarly 14, 85, and 31 diagnoses per 100,000 patients per day lower, respectively. The prevalence of each of the other conditions analyzed – the common cold, croup, gastroenteritis, nonstreptococcal pharyngitis, sinusitis, skin and soft tissue infections, and urinary tract infection (UTI) – also was significantly lower in the 2020 post-SD period than would be expected based on 2019 data (P < .001 for all diagnoses).
Putting things in perspective
“This study puts numbers to the sense that we have all had in pediatrics – that social distancing appears to have had a dramatic impact on the transmission of common childhood infectious diseases, especially other respiratory viral pathogens,” Audrey R. John, MD, PhD, chief of the division of pediatric infectious disease at Children’s Hospital of Philadelphia, said in an interview.
The authors acknowledged the possible role of families not seeking care, but said that a smaller decrease in diagnoses of UTI – generally not a contagious disease – “suggests that changes in care-seeking behavior had a relatively modest effect on the other observed declines.” (The rate of UTI for the pre- and post-SD periods was 3.3 and 3.7 per 100,000 patients per day in 2019, and 3.4 and 2.4 in 2020, for a difference in differences of –1.5).
In an accompanying editorial, David W. Kimberlin, MD and Erica C. Bjornstad, MD, PhD, MPH, of the University of Alabama at Birmingham, called the report “provocative” and wrote that similar observations of infections dropping during periods of isolation – namely, dramatic declines in influenza and other respiratory viruses in Seattle after a record snowstorm in 2019 – combined with findings from other modeling studies “suggest that the decline [reported in Boston] is indeed real” (Pediatrics 2020. doi: 10.1542/peds.2020-019232).
However, “we also now know that immunization rates for American children have plummeted since the onset of the SARS-CoV-2 pandemic [because of a] ... dramatic decrease in the use of health care during the first months of the pandemic,” they wrote. “Viewed through this lens,” the declines reported in Boston may reflect inflections going “undiagnosed and untreated.”
Ultimately, Dr. Kimberlin and Dr. Bjornstad said, “the verdict remains out.”
Dr. John said that she and others are “concerned about children not seeking care in a timely manner, and [concerned] that reductions in reported infections might be due to a lack of recognition rather than a lack of transmission.”
In Philadelphia, however, declines in admissions for asthma exacerbations, “which are often caused by respiratory viral infections, suggests that this may not be the case,” said Dr. John, who was asked to comment on the study.
In addition, she said, the Massachusetts data showing that UTI diagnoses “are nearly as common this year as in 2019” are “reassuring.”
Are there lessons for the future?
Coauthor Louis Vernacchio, MD, MSc, chief medical officer of the Pediatric Physicians’ Organization at Children’s network, said in an interview that beyond the pandemic, it’s likely that “more careful attention to proven infection control practices in daycares and schools could reduce the burden of common infectious diseases in children.”
Dr. John similarly sees a long-term value of quantifying the impact of social distancing. “We’ve always known [for instance] that bronchiolitis is the result of viral infection.” Findings like the Massachusetts data “will help us advise families who might be trying to protect their premature infants (at risk for severe bronchiolitis) through social distancing.”
The analysis covered both in-person and telemedicine encounters occurring on weekdays.
The authors of the research brief indicated they have no relevant financial disclosures and there was no external funding. The authors of the commentary also reported they have no relevant financial disclosures, and Dr. John said she had no relevant financial disclosures.
SOURCE: Hatoun J et al. Pediatrics. 2020. doi: 10.1542/peds.2020-006460.
Diagnoses of 12 common pediatric infectious diseases in a large pediatric primary care network declined significantly in the weeks after COVID-19 social distancing (SD) was enacted in Massachusetts, compared with the same time period in 2019, an analysis of EHR data has shown.
While declines in infectious disease transmission with SD are not surprising, “these data demonstrate the extent to which transmission of common pediatric infections can be altered when close contact with other children is eliminated,” Jonathan Hatoun, MD, MPH of the Pediatric Physicians’ Organization at Children’s in Brookline, Mass., and coauthors wrote in Pediatrics . “Notably, three of the studied diseases, namely, influenza, croup, and bronchiolitis, essentially disappeared with [social distancing].”
The researchers analyzed the weekly incidence of each diagnosis for similar calendar periods in 2019 and 2020. A pre-SD period was defined as week 1-9, starting on Jan. 1, and a post-SD period was defined as week 13-18. (The several-week gap represented an implementation period as social distancing was enacted in the state earlier in 2020, from a declared statewide state of emergency through school closures and stay-at-home advisories.)
To isolate the effect of widespread SD, they performed a “difference-in-differences regression analysis, with diagnosis count as a function of calendar year, time period (pre-SD versus post-SD) and the interaction between the two.” The Massachusetts pediatric network provides care for approximately 375,000 children in 100 locations around the state.
In their research brief, Dr. Hatoun and coauthors presented weekly rates expressed as diagnoses per 100,000 patients per day. The rate of bronchiolitis, for instance, was 18 and 8 in the pre- and post-SD–equivalent weeks of 2019, respectively, and 20 and 0.6 in the pre- and post-SD weeks of 2020. Their analysis showed the rate in the 2020 post-SD period to be 10 diagnoses per 100,000 patients per day lower than they would have expected based on the 2019 trend.
Rates of pneumonia, acute otitis media, and streptococcal pharyngitis were similarly 14, 85, and 31 diagnoses per 100,000 patients per day lower, respectively. The prevalence of each of the other conditions analyzed – the common cold, croup, gastroenteritis, nonstreptococcal pharyngitis, sinusitis, skin and soft tissue infections, and urinary tract infection (UTI) – also was significantly lower in the 2020 post-SD period than would be expected based on 2019 data (P < .001 for all diagnoses).
Putting things in perspective
“This study puts numbers to the sense that we have all had in pediatrics – that social distancing appears to have had a dramatic impact on the transmission of common childhood infectious diseases, especially other respiratory viral pathogens,” Audrey R. John, MD, PhD, chief of the division of pediatric infectious disease at Children’s Hospital of Philadelphia, said in an interview.
The authors acknowledged the possible role of families not seeking care, but said that a smaller decrease in diagnoses of UTI – generally not a contagious disease – “suggests that changes in care-seeking behavior had a relatively modest effect on the other observed declines.” (The rate of UTI for the pre- and post-SD periods was 3.3 and 3.7 per 100,000 patients per day in 2019, and 3.4 and 2.4 in 2020, for a difference in differences of –1.5).
In an accompanying editorial, David W. Kimberlin, MD and Erica C. Bjornstad, MD, PhD, MPH, of the University of Alabama at Birmingham, called the report “provocative” and wrote that similar observations of infections dropping during periods of isolation – namely, dramatic declines in influenza and other respiratory viruses in Seattle after a record snowstorm in 2019 – combined with findings from other modeling studies “suggest that the decline [reported in Boston] is indeed real” (Pediatrics 2020. doi: 10.1542/peds.2020-019232).
However, “we also now know that immunization rates for American children have plummeted since the onset of the SARS-CoV-2 pandemic [because of a] ... dramatic decrease in the use of health care during the first months of the pandemic,” they wrote. “Viewed through this lens,” the declines reported in Boston may reflect inflections going “undiagnosed and untreated.”
Ultimately, Dr. Kimberlin and Dr. Bjornstad said, “the verdict remains out.”
Dr. John said that she and others are “concerned about children not seeking care in a timely manner, and [concerned] that reductions in reported infections might be due to a lack of recognition rather than a lack of transmission.”
In Philadelphia, however, declines in admissions for asthma exacerbations, “which are often caused by respiratory viral infections, suggests that this may not be the case,” said Dr. John, who was asked to comment on the study.
In addition, she said, the Massachusetts data showing that UTI diagnoses “are nearly as common this year as in 2019” are “reassuring.”
Are there lessons for the future?
Coauthor Louis Vernacchio, MD, MSc, chief medical officer of the Pediatric Physicians’ Organization at Children’s network, said in an interview that beyond the pandemic, it’s likely that “more careful attention to proven infection control practices in daycares and schools could reduce the burden of common infectious diseases in children.”
Dr. John similarly sees a long-term value of quantifying the impact of social distancing. “We’ve always known [for instance] that bronchiolitis is the result of viral infection.” Findings like the Massachusetts data “will help us advise families who might be trying to protect their premature infants (at risk for severe bronchiolitis) through social distancing.”
The analysis covered both in-person and telemedicine encounters occurring on weekdays.
The authors of the research brief indicated they have no relevant financial disclosures and there was no external funding. The authors of the commentary also reported they have no relevant financial disclosures, and Dr. John said she had no relevant financial disclosures.
SOURCE: Hatoun J et al. Pediatrics. 2020. doi: 10.1542/peds.2020-006460.
FROM PEDIATRICS
Obesity-related hypoventilation increased morbidity risk after bariatric surgery
Patients with obesity-associated sleep hypoventilation had a heightened risk of postoperative morbidities after bariatric surgery, according to a retrospective study.
Reena Mehra, MD, director of sleep disorders research for the Sleep Disorders Center at the Cleveland Clinic, led the team and the findings were presented at the virtual annual meeting of the Associated Professional Sleep Societies. Her research team examined the outcomes of 1,665 patients who underwent polysomnography prior to bariatric surgery performed at the Cleveland Clinic from 2011 to 2018.
More than two-thirds – 68.5% – had obesity-associated sleep hypoventilation as defined by body mass index (BMI) of ≥30 kg/m2 and either polysomnography-based end-tidal CO2 ≥45 mm Hg or serum bicarbonate ≥27 mEq/L.
These patients represent “a subset, if you will, of obesity hypoventilation syndrome – a subset that we were able to capture from our sleep studies … [because] we do CO2 monitoring during sleep studies uniformly,” Dr. Mehra said in an interview after the meeting.
Pornprapa Chindamporn, MD, a former fellow at the center and first author on the abstract, presented the findings. Patients in the study had a mean age of 45.2 ± 12.0 years and a BMI of 48.7 ± 9.0. Approximately 20% were male and 63.6% were White.
Those with obesity-associated sleep hypoventilation were more likely to be male and have a higher BMI and higher hemoglobin A1c than those without the condition. They also had a significantly higher apnea-hypopnea index (17.0 vs. 13.8) in those without the condition, she reported.
A number of outcomes (ICU stay, intubation, tracheostomy, discharge disposition, and 30-day readmission) were compared individually and as a composite outcome between those with and without obesity-associated sleep hypoventilation. While some of these postoperative morbidities were more common in patients with the condition, the differences between those with and without OHS were not statistically significant for intubation (1.5% vs. 1.3%, P = .81) and 30-day readmission (13.8% vs. 11.3%, P = .16). However, the composite outcome was significantly higher: 18.9% vs. 14.3% (P = .021), including in multivariable analysis that considered age, gender, BMI, Apnea Hypopnea Index, and diabetes.
All-cause mortality was not significantly different between the groups, likely because of its low overall rate (hazard ratio, 1.39; 95% confidence interval, 0.56-3.42).
“In this largest sample to date of systematically phenotyped obesity-associated sleep hypoventilation in patients undergoing bariatric surgery, we identified increased postoperative morbidity,” said Dr. Chindamporn, now a pulmonologist and sleep specialist practicing in Bangkok.
Dr. Mehra said in the interview that patients considering bariatric surgery are typically assessed for obstructive sleep apnea, but “not so much obesity hypoventilation syndrome or obesity-associated sleep-related hypoventilation syndrome.” The findings, “support the notion that we should be closely examining sleep-related hypoventilation in these patients.”
At the Cleveland Clinic, “clinically, we make sure we’re identifying these individuals and communicating the findings to bariatric surgery colleagues and to anesthesia,” said Dr. Mehra, also professor of medicine at Case Western Reserve University, Cleveland.
OHS is defined, according to the 2019 American Thoracic Society clinical practice guideline on evaluation and management of OHS, by the combination of obesity, sleep-disordered breathing, and awake daytime hypercapnia, after excluding other causes for hypoventilation (Am J Respir Crit Care Med. 2019;200[3]:e6-24).
A European Respiratory Society task force has proposed severity grading for OHS, with early stages defined by sleep-related hypoventilation and the highest grade of severity defined by morbidity-associated daytime hypercapnia (Eur Respir Rev. 2019;28:180097). However, Dr. Mehra said she is “not sure that we know enough [from long-term studies of OHS] to say definitively that there’s such an evolution.”
Certainly, she said, future research on OHS should consider its heterogeneity. It is possible that a subset of patients with OHS, “maybe these individuals with sleep-related hypoventilation,” are most likely to have adverse postsurgical outcomes.
Atul Malhotra, MD, professor of medicine at the University of California, San Diego, who was asked to comment on the study, said that OHS is understudied in general and particularly in the perioperative setting. “With the obesity pandemic, issues around OHS are likely to be [increasingly] important. And with increasing [use of] bariatric surgery, strategies to minimize risks are clearly needed,” he said, adding that the potential risks of nonbariatric surgery in patients with OHS require further study.
He noted that mortality rates in good hospitals “have become quite low for many elective surgeries, making it hard to show mortality benefit to most interventions.”
The ATS guideline on OHS states that it is the most severe form of obesity-induced respiratory compromise and leads to serious sequelae, including increased rates of mortality, chronic heart failure, pulmonary hypertension, and hospitalization caused by acute-on-chronic hypercapnic respiratory failure.
Dr. Chindamporn said in her presentation that she had no disclosures. Dr. Mehra’s research program is funded by the National Institute of Health, but she has also procured funding from the American College of Chest Physicians, American Heart Association, Clinical Translational Science Collaborative, and Central Society of Clinical Research. Dr. Malhotra disclosed that he is funded by the NIH and has received income from Merck and LIvanova related to medical education.
CORRECTION 9/15/2020: The original story misstated the presenter of the study. Dr. Chindamporn presented the findings.
Patients with obesity-associated sleep hypoventilation had a heightened risk of postoperative morbidities after bariatric surgery, according to a retrospective study.
Reena Mehra, MD, director of sleep disorders research for the Sleep Disorders Center at the Cleveland Clinic, led the team and the findings were presented at the virtual annual meeting of the Associated Professional Sleep Societies. Her research team examined the outcomes of 1,665 patients who underwent polysomnography prior to bariatric surgery performed at the Cleveland Clinic from 2011 to 2018.
More than two-thirds – 68.5% – had obesity-associated sleep hypoventilation as defined by body mass index (BMI) of ≥30 kg/m2 and either polysomnography-based end-tidal CO2 ≥45 mm Hg or serum bicarbonate ≥27 mEq/L.
These patients represent “a subset, if you will, of obesity hypoventilation syndrome – a subset that we were able to capture from our sleep studies … [because] we do CO2 monitoring during sleep studies uniformly,” Dr. Mehra said in an interview after the meeting.
Pornprapa Chindamporn, MD, a former fellow at the center and first author on the abstract, presented the findings. Patients in the study had a mean age of 45.2 ± 12.0 years and a BMI of 48.7 ± 9.0. Approximately 20% were male and 63.6% were White.
Those with obesity-associated sleep hypoventilation were more likely to be male and have a higher BMI and higher hemoglobin A1c than those without the condition. They also had a significantly higher apnea-hypopnea index (17.0 vs. 13.8) in those without the condition, she reported.
A number of outcomes (ICU stay, intubation, tracheostomy, discharge disposition, and 30-day readmission) were compared individually and as a composite outcome between those with and without obesity-associated sleep hypoventilation. While some of these postoperative morbidities were more common in patients with the condition, the differences between those with and without OHS were not statistically significant for intubation (1.5% vs. 1.3%, P = .81) and 30-day readmission (13.8% vs. 11.3%, P = .16). However, the composite outcome was significantly higher: 18.9% vs. 14.3% (P = .021), including in multivariable analysis that considered age, gender, BMI, Apnea Hypopnea Index, and diabetes.
All-cause mortality was not significantly different between the groups, likely because of its low overall rate (hazard ratio, 1.39; 95% confidence interval, 0.56-3.42).
“In this largest sample to date of systematically phenotyped obesity-associated sleep hypoventilation in patients undergoing bariatric surgery, we identified increased postoperative morbidity,” said Dr. Chindamporn, now a pulmonologist and sleep specialist practicing in Bangkok.
Dr. Mehra said in the interview that patients considering bariatric surgery are typically assessed for obstructive sleep apnea, but “not so much obesity hypoventilation syndrome or obesity-associated sleep-related hypoventilation syndrome.” The findings, “support the notion that we should be closely examining sleep-related hypoventilation in these patients.”
At the Cleveland Clinic, “clinically, we make sure we’re identifying these individuals and communicating the findings to bariatric surgery colleagues and to anesthesia,” said Dr. Mehra, also professor of medicine at Case Western Reserve University, Cleveland.
OHS is defined, according to the 2019 American Thoracic Society clinical practice guideline on evaluation and management of OHS, by the combination of obesity, sleep-disordered breathing, and awake daytime hypercapnia, after excluding other causes for hypoventilation (Am J Respir Crit Care Med. 2019;200[3]:e6-24).
A European Respiratory Society task force has proposed severity grading for OHS, with early stages defined by sleep-related hypoventilation and the highest grade of severity defined by morbidity-associated daytime hypercapnia (Eur Respir Rev. 2019;28:180097). However, Dr. Mehra said she is “not sure that we know enough [from long-term studies of OHS] to say definitively that there’s such an evolution.”
Certainly, she said, future research on OHS should consider its heterogeneity. It is possible that a subset of patients with OHS, “maybe these individuals with sleep-related hypoventilation,” are most likely to have adverse postsurgical outcomes.
Atul Malhotra, MD, professor of medicine at the University of California, San Diego, who was asked to comment on the study, said that OHS is understudied in general and particularly in the perioperative setting. “With the obesity pandemic, issues around OHS are likely to be [increasingly] important. And with increasing [use of] bariatric surgery, strategies to minimize risks are clearly needed,” he said, adding that the potential risks of nonbariatric surgery in patients with OHS require further study.
He noted that mortality rates in good hospitals “have become quite low for many elective surgeries, making it hard to show mortality benefit to most interventions.”
The ATS guideline on OHS states that it is the most severe form of obesity-induced respiratory compromise and leads to serious sequelae, including increased rates of mortality, chronic heart failure, pulmonary hypertension, and hospitalization caused by acute-on-chronic hypercapnic respiratory failure.
Dr. Chindamporn said in her presentation that she had no disclosures. Dr. Mehra’s research program is funded by the National Institute of Health, but she has also procured funding from the American College of Chest Physicians, American Heart Association, Clinical Translational Science Collaborative, and Central Society of Clinical Research. Dr. Malhotra disclosed that he is funded by the NIH and has received income from Merck and LIvanova related to medical education.
CORRECTION 9/15/2020: The original story misstated the presenter of the study. Dr. Chindamporn presented the findings.
Patients with obesity-associated sleep hypoventilation had a heightened risk of postoperative morbidities after bariatric surgery, according to a retrospective study.
Reena Mehra, MD, director of sleep disorders research for the Sleep Disorders Center at the Cleveland Clinic, led the team and the findings were presented at the virtual annual meeting of the Associated Professional Sleep Societies. Her research team examined the outcomes of 1,665 patients who underwent polysomnography prior to bariatric surgery performed at the Cleveland Clinic from 2011 to 2018.
More than two-thirds – 68.5% – had obesity-associated sleep hypoventilation as defined by body mass index (BMI) of ≥30 kg/m2 and either polysomnography-based end-tidal CO2 ≥45 mm Hg or serum bicarbonate ≥27 mEq/L.
These patients represent “a subset, if you will, of obesity hypoventilation syndrome – a subset that we were able to capture from our sleep studies … [because] we do CO2 monitoring during sleep studies uniformly,” Dr. Mehra said in an interview after the meeting.
Pornprapa Chindamporn, MD, a former fellow at the center and first author on the abstract, presented the findings. Patients in the study had a mean age of 45.2 ± 12.0 years and a BMI of 48.7 ± 9.0. Approximately 20% were male and 63.6% were White.
Those with obesity-associated sleep hypoventilation were more likely to be male and have a higher BMI and higher hemoglobin A1c than those without the condition. They also had a significantly higher apnea-hypopnea index (17.0 vs. 13.8) in those without the condition, she reported.
A number of outcomes (ICU stay, intubation, tracheostomy, discharge disposition, and 30-day readmission) were compared individually and as a composite outcome between those with and without obesity-associated sleep hypoventilation. While some of these postoperative morbidities were more common in patients with the condition, the differences between those with and without OHS were not statistically significant for intubation (1.5% vs. 1.3%, P = .81) and 30-day readmission (13.8% vs. 11.3%, P = .16). However, the composite outcome was significantly higher: 18.9% vs. 14.3% (P = .021), including in multivariable analysis that considered age, gender, BMI, Apnea Hypopnea Index, and diabetes.
All-cause mortality was not significantly different between the groups, likely because of its low overall rate (hazard ratio, 1.39; 95% confidence interval, 0.56-3.42).
“In this largest sample to date of systematically phenotyped obesity-associated sleep hypoventilation in patients undergoing bariatric surgery, we identified increased postoperative morbidity,” said Dr. Chindamporn, now a pulmonologist and sleep specialist practicing in Bangkok.
Dr. Mehra said in the interview that patients considering bariatric surgery are typically assessed for obstructive sleep apnea, but “not so much obesity hypoventilation syndrome or obesity-associated sleep-related hypoventilation syndrome.” The findings, “support the notion that we should be closely examining sleep-related hypoventilation in these patients.”
At the Cleveland Clinic, “clinically, we make sure we’re identifying these individuals and communicating the findings to bariatric surgery colleagues and to anesthesia,” said Dr. Mehra, also professor of medicine at Case Western Reserve University, Cleveland.
OHS is defined, according to the 2019 American Thoracic Society clinical practice guideline on evaluation and management of OHS, by the combination of obesity, sleep-disordered breathing, and awake daytime hypercapnia, after excluding other causes for hypoventilation (Am J Respir Crit Care Med. 2019;200[3]:e6-24).
A European Respiratory Society task force has proposed severity grading for OHS, with early stages defined by sleep-related hypoventilation and the highest grade of severity defined by morbidity-associated daytime hypercapnia (Eur Respir Rev. 2019;28:180097). However, Dr. Mehra said she is “not sure that we know enough [from long-term studies of OHS] to say definitively that there’s such an evolution.”
Certainly, she said, future research on OHS should consider its heterogeneity. It is possible that a subset of patients with OHS, “maybe these individuals with sleep-related hypoventilation,” are most likely to have adverse postsurgical outcomes.
Atul Malhotra, MD, professor of medicine at the University of California, San Diego, who was asked to comment on the study, said that OHS is understudied in general and particularly in the perioperative setting. “With the obesity pandemic, issues around OHS are likely to be [increasingly] important. And with increasing [use of] bariatric surgery, strategies to minimize risks are clearly needed,” he said, adding that the potential risks of nonbariatric surgery in patients with OHS require further study.
He noted that mortality rates in good hospitals “have become quite low for many elective surgeries, making it hard to show mortality benefit to most interventions.”
The ATS guideline on OHS states that it is the most severe form of obesity-induced respiratory compromise and leads to serious sequelae, including increased rates of mortality, chronic heart failure, pulmonary hypertension, and hospitalization caused by acute-on-chronic hypercapnic respiratory failure.
Dr. Chindamporn said in her presentation that she had no disclosures. Dr. Mehra’s research program is funded by the National Institute of Health, but she has also procured funding from the American College of Chest Physicians, American Heart Association, Clinical Translational Science Collaborative, and Central Society of Clinical Research. Dr. Malhotra disclosed that he is funded by the NIH and has received income from Merck and LIvanova related to medical education.
CORRECTION 9/15/2020: The original story misstated the presenter of the study. Dr. Chindamporn presented the findings.
FROM SLEEP 2020
Insomnia + COPD linked to more outpatient, ED visits
Insomnia is “highly prevalent” in veterans with chronic pulmonary obstructive disease and is significantly associated with greater COPD-related health care utilization, according to an analysis of national Veterans Health Administration data.
“The study highlights the importance of exploring potential sleep disturbances and disorders in this population and suggests that a targeted treatment for insomnia may help to improve COPD outcomes in veterans with COPD and insomnia,” said Faith Luyster, PhD, assistant professor at the University of Pittsburgh, in an interview after the virtual annual meeting of the Associated Professional Sleep Societies, where she presented the findings.
Dr. Luyster and coinvestigators used an administrative database from the Veterans Affairs Corporate Data Warehouse to identify more than 1.5 million patients with COPD who used VHA services over a 6-year period (fiscal years 2011-2017). Insomnia was defined by ICD-9/10 diagnostic codes and/or a sedative-hypnotic prescription for at least 30 doses during any of these years.
Insomnia with COPD was prevalent in this sample of veterans at 37.3%. Compared with veterans without comorbid insomnia, those who had both COPD and insomnia (575,539 of the total 1,542,642) were older (69 vs. 64 years), more likely to be female (6.3% vs. 3.7%), more likely to be Black (14% vs. 11%) and more likely to be a current smoker (46.1% vs. 35.5%).
Those with both COPD and insomnia were also more likely to have a service-connected disability rating of 50% of greater; use supplemental oxygen; be divorced, widowed, or separated; have a higher body mass index; or have other medical or psychiatric conditions – in particular obstructive sleep apnea (39% vs. 7%), depression (21% vs. 5%), and PTSD (33% vs. 3%).
P values were < .001 for all of these demographic and clinical variables, Dr. Luyster reported at the meeting.
Comorbid insomnia clearly impacted health care utilization, she said. Veterans with insomnia in addition to COPD had more outpatient and ED visits (10.5 vs 6.9, and 1.6 vs. 1.4, respectively) and more hospitalizations (2.2 vs. 1.8) with a primary diagnostic code for COPD or COPD exacerbation (P < .001).
A negative binomial regression analysis (P < .001) showed that “even after controlling for demographic and other medical conditions, COPD patients with insomnia had greater rates of health care utilization relative to COPD patients without insomnia,” Dr. Luyster said in the interview.
Prior studies have suggested that disturbed sleep is a predictor of poorer longitudinal outcomes in COPD, even after controlling for COPD severity, but have not looked specifically at insomnia, she said.
Commenting on the study Octavian C. Ioachimescu, MD, PhD, of Emory University, Atlanta, and the Atlanta VA Medical Center in Decatur, said the criteria used to define insomnia – unadjudicated ICD diagnoses as well as sedative-hypnotic prescriptions – may explain part of the reported prevalence of insomnia. Even so, the findings add to existing literature demonstrating that COPD and insomnia are both common disorders among VHA patients, and that their frequent coexistence “could have adverse consequences on the overall health, functional status, long-term outcomes, and quality of life of these patients.”
Questions of causation are yet to be answered, he said. “Is it that uncontrolled or severe airflow obstruction causing frequent nocturnal arousals, dyspnea, orthopnea, overuse of inhaled sympathomimetics and heightened anxiety leads to insomnia? Or is it that insomnia – possibly in a cluster with other affective disorders such as depression, anxiety disorders, or PTSD – elicits more frequent or more severe symptoms of shortness of breath in those with smoking-induced airway and parenchymal lung disease, making the latter diagnosis more overt than in others?
“My bet is on a bidirectional causal relationship,” said Dr. Ioachimescu, an editorial board advisor of CHEST Physician.
“Regardless of the etiology [of insomnia in veterans with COPD],” Dr. Luyster said, “it’s important that [insomnia] be addressed and treated appropriately, whether that be through pharmacological treatment, or probably more ideally through [cognitive behavioral therapy] for insomnia.”
The study did not control for COPD severity, she said, because of the difficulty of extracting this data from the VA Corporate Data Warehouse. The study was funded by the VA Competitive Career Development Fund.Dr. Luyster reported that she had no disclosures. Dr. Ioachimescu also said he had no relevant disclosures.
Insomnia is “highly prevalent” in veterans with chronic pulmonary obstructive disease and is significantly associated with greater COPD-related health care utilization, according to an analysis of national Veterans Health Administration data.
“The study highlights the importance of exploring potential sleep disturbances and disorders in this population and suggests that a targeted treatment for insomnia may help to improve COPD outcomes in veterans with COPD and insomnia,” said Faith Luyster, PhD, assistant professor at the University of Pittsburgh, in an interview after the virtual annual meeting of the Associated Professional Sleep Societies, where she presented the findings.
Dr. Luyster and coinvestigators used an administrative database from the Veterans Affairs Corporate Data Warehouse to identify more than 1.5 million patients with COPD who used VHA services over a 6-year period (fiscal years 2011-2017). Insomnia was defined by ICD-9/10 diagnostic codes and/or a sedative-hypnotic prescription for at least 30 doses during any of these years.
Insomnia with COPD was prevalent in this sample of veterans at 37.3%. Compared with veterans without comorbid insomnia, those who had both COPD and insomnia (575,539 of the total 1,542,642) were older (69 vs. 64 years), more likely to be female (6.3% vs. 3.7%), more likely to be Black (14% vs. 11%) and more likely to be a current smoker (46.1% vs. 35.5%).
Those with both COPD and insomnia were also more likely to have a service-connected disability rating of 50% of greater; use supplemental oxygen; be divorced, widowed, or separated; have a higher body mass index; or have other medical or psychiatric conditions – in particular obstructive sleep apnea (39% vs. 7%), depression (21% vs. 5%), and PTSD (33% vs. 3%).
P values were < .001 for all of these demographic and clinical variables, Dr. Luyster reported at the meeting.
Comorbid insomnia clearly impacted health care utilization, she said. Veterans with insomnia in addition to COPD had more outpatient and ED visits (10.5 vs 6.9, and 1.6 vs. 1.4, respectively) and more hospitalizations (2.2 vs. 1.8) with a primary diagnostic code for COPD or COPD exacerbation (P < .001).
A negative binomial regression analysis (P < .001) showed that “even after controlling for demographic and other medical conditions, COPD patients with insomnia had greater rates of health care utilization relative to COPD patients without insomnia,” Dr. Luyster said in the interview.
Prior studies have suggested that disturbed sleep is a predictor of poorer longitudinal outcomes in COPD, even after controlling for COPD severity, but have not looked specifically at insomnia, she said.
Commenting on the study Octavian C. Ioachimescu, MD, PhD, of Emory University, Atlanta, and the Atlanta VA Medical Center in Decatur, said the criteria used to define insomnia – unadjudicated ICD diagnoses as well as sedative-hypnotic prescriptions – may explain part of the reported prevalence of insomnia. Even so, the findings add to existing literature demonstrating that COPD and insomnia are both common disorders among VHA patients, and that their frequent coexistence “could have adverse consequences on the overall health, functional status, long-term outcomes, and quality of life of these patients.”
Questions of causation are yet to be answered, he said. “Is it that uncontrolled or severe airflow obstruction causing frequent nocturnal arousals, dyspnea, orthopnea, overuse of inhaled sympathomimetics and heightened anxiety leads to insomnia? Or is it that insomnia – possibly in a cluster with other affective disorders such as depression, anxiety disorders, or PTSD – elicits more frequent or more severe symptoms of shortness of breath in those with smoking-induced airway and parenchymal lung disease, making the latter diagnosis more overt than in others?
“My bet is on a bidirectional causal relationship,” said Dr. Ioachimescu, an editorial board advisor of CHEST Physician.
“Regardless of the etiology [of insomnia in veterans with COPD],” Dr. Luyster said, “it’s important that [insomnia] be addressed and treated appropriately, whether that be through pharmacological treatment, or probably more ideally through [cognitive behavioral therapy] for insomnia.”
The study did not control for COPD severity, she said, because of the difficulty of extracting this data from the VA Corporate Data Warehouse. The study was funded by the VA Competitive Career Development Fund.Dr. Luyster reported that she had no disclosures. Dr. Ioachimescu also said he had no relevant disclosures.
Insomnia is “highly prevalent” in veterans with chronic pulmonary obstructive disease and is significantly associated with greater COPD-related health care utilization, according to an analysis of national Veterans Health Administration data.
“The study highlights the importance of exploring potential sleep disturbances and disorders in this population and suggests that a targeted treatment for insomnia may help to improve COPD outcomes in veterans with COPD and insomnia,” said Faith Luyster, PhD, assistant professor at the University of Pittsburgh, in an interview after the virtual annual meeting of the Associated Professional Sleep Societies, where she presented the findings.
Dr. Luyster and coinvestigators used an administrative database from the Veterans Affairs Corporate Data Warehouse to identify more than 1.5 million patients with COPD who used VHA services over a 6-year period (fiscal years 2011-2017). Insomnia was defined by ICD-9/10 diagnostic codes and/or a sedative-hypnotic prescription for at least 30 doses during any of these years.
Insomnia with COPD was prevalent in this sample of veterans at 37.3%. Compared with veterans without comorbid insomnia, those who had both COPD and insomnia (575,539 of the total 1,542,642) were older (69 vs. 64 years), more likely to be female (6.3% vs. 3.7%), more likely to be Black (14% vs. 11%) and more likely to be a current smoker (46.1% vs. 35.5%).
Those with both COPD and insomnia were also more likely to have a service-connected disability rating of 50% of greater; use supplemental oxygen; be divorced, widowed, or separated; have a higher body mass index; or have other medical or psychiatric conditions – in particular obstructive sleep apnea (39% vs. 7%), depression (21% vs. 5%), and PTSD (33% vs. 3%).
P values were < .001 for all of these demographic and clinical variables, Dr. Luyster reported at the meeting.
Comorbid insomnia clearly impacted health care utilization, she said. Veterans with insomnia in addition to COPD had more outpatient and ED visits (10.5 vs 6.9, and 1.6 vs. 1.4, respectively) and more hospitalizations (2.2 vs. 1.8) with a primary diagnostic code for COPD or COPD exacerbation (P < .001).
A negative binomial regression analysis (P < .001) showed that “even after controlling for demographic and other medical conditions, COPD patients with insomnia had greater rates of health care utilization relative to COPD patients without insomnia,” Dr. Luyster said in the interview.
Prior studies have suggested that disturbed sleep is a predictor of poorer longitudinal outcomes in COPD, even after controlling for COPD severity, but have not looked specifically at insomnia, she said.
Commenting on the study Octavian C. Ioachimescu, MD, PhD, of Emory University, Atlanta, and the Atlanta VA Medical Center in Decatur, said the criteria used to define insomnia – unadjudicated ICD diagnoses as well as sedative-hypnotic prescriptions – may explain part of the reported prevalence of insomnia. Even so, the findings add to existing literature demonstrating that COPD and insomnia are both common disorders among VHA patients, and that their frequent coexistence “could have adverse consequences on the overall health, functional status, long-term outcomes, and quality of life of these patients.”
Questions of causation are yet to be answered, he said. “Is it that uncontrolled or severe airflow obstruction causing frequent nocturnal arousals, dyspnea, orthopnea, overuse of inhaled sympathomimetics and heightened anxiety leads to insomnia? Or is it that insomnia – possibly in a cluster with other affective disorders such as depression, anxiety disorders, or PTSD – elicits more frequent or more severe symptoms of shortness of breath in those with smoking-induced airway and parenchymal lung disease, making the latter diagnosis more overt than in others?
“My bet is on a bidirectional causal relationship,” said Dr. Ioachimescu, an editorial board advisor of CHEST Physician.
“Regardless of the etiology [of insomnia in veterans with COPD],” Dr. Luyster said, “it’s important that [insomnia] be addressed and treated appropriately, whether that be through pharmacological treatment, or probably more ideally through [cognitive behavioral therapy] for insomnia.”
The study did not control for COPD severity, she said, because of the difficulty of extracting this data from the VA Corporate Data Warehouse. The study was funded by the VA Competitive Career Development Fund.Dr. Luyster reported that she had no disclosures. Dr. Ioachimescu also said he had no relevant disclosures.
FROM SLEEP 2020
Psoriasis, PsA, and pregnancy: Tailoring treatment with increasing data
With an average age of diagnosis of 28 years, and one of two incidence peaks occurring at 15-30 years, psoriasis affects many women in the midst of their reproductive years. The prospect of pregnancy – or the reality of a surprise pregnancy – drives questions about heritability of the disease in offspring, the impact of the disease on pregnancy outcomes and breastfeeding, and how to best balance risks of treatments with risks of uncontrolled psoriasis and/or psoriatic arthritis (PsA).
While answers to these questions are not always clear, discussions about pregnancy and psoriasis management “shouldn’t be scary,” said Jenny E. Murase, MD, a dermatologist who speaks and writes widely about her research and experience with psoriasis and pregnancy. “We have access to information and data and educational resources to [work with] and reassure our patients – we just need to use it. Right now, there’s unnecessary suffering [with some patients unnecessarily stopping all treatment].”
Much has been learned in the past 2 decades about the course of psoriasis in pregnancy, and pregnancy outcomes data on the safety of biologics during pregnancy are increasingly emerging – particularly for tumor necrosis factor (TNF)–alpha inhibitors.
Ideally, since half of all pregnancies are unplanned, the implications of therapeutic options should be discussed with all women with psoriasis who are of reproductive age, whether they are sexually active or not. “The onus is on us to make sure that we’re considering the possibility [that our patient] could become pregnant without consulting us first,” said Dr. Murase, associate professor of dermatology at the University of California, San Francisco, and director of medical consultative dermatology for the Palo Alto Foundation Medical Group in Mountain View, Calif.
Lisa R. Sammaritano, MD, associate professor of clinical medicine at Weill Cornell Medicine and a rheumatologist at the Hospital for Special Surgery, both in New York, urges similar attention for PsA. “Pregnancy is best planned while patients have quiescent disease on pregnancy-compatible medications,” she said. “We encourage [more] rheumatologists to be actively involved in pregnancy planning [in order] to guide therapy.”
The impact of estrogen
Dr. Murase was inspired to study psoriasis and pregnancy in part by a patient she met as a medical student. “She had severe psoriasis covering her body, and she said that the only times her psoriasis cleared was during her three pregnancies,” Dr. Murase recalled. “I wondered: What about the pregnancies resulted in such a substantial reduction of her psoriasis?”
She subsequently led a study, published in 2005, of 47 pregnant and 27 nonpregnant patients with psoriasis. More than half of the patients – 55% – reported improvements in their psoriasis during pregnancy, 21% reported no change, and 23% reported worsening. Among the 16 patients who had 10% or greater psoriatic body surface area (BSA) involvement and reported improvements, lesions decreased by 84%.
In the postpartum period, only 9% reported improvement, 26% reported no change, and 65% reported worsening. The increased BSA values observed 6 weeks postpartum did not exceed those of the first trimester, suggesting a return to the patients’ baseline status.
Earlier and smaller retrospective studies had also shown that approximately half of patients improve during pregnancy, and it was believed that progesterone was most likely responsible for this improvement. Dr. Murase’s study moved the needle in that it examined BSA in pregnancy and the postpartum period. It also turned the spotlight on estrogen: Patients who had higher levels of improvement also had higher levels of estradiol, estrone, and the ratio of estrogen to progesterone. However, there was no correlation between psoriatic change and levels of progesterone.
To promote fetal survival, pregnancy triggers a shift from Th1 cell–mediated immunity – and Th17 immunity – to Th2 immunity. While there’s no proof of a causative effect, increased estrogen appears to play a role in this shift and in the reduced production of Th1 and Th17 cytokines. Psoriasis is believed to be primarily a Th17-mediated disease, with some Th1 involvement, so this down-regulation can result in improved disease status, Dr. Murase said. (A host of other autoimmune diseases categorized as Th1 mediated similarly tend to improve during pregnancy, she added.)
Information on the effect of pregnancy on PsA is “conflicting,” Dr. Sammaritano said. “Some [of a limited number of studies] suggest a beneficial effect as is generally seen for rheumatoid arthritis. Others, however, have found an increased risk of disease activity during pregnancy ... It may be that psoriatic arthritis can be quite variable from patient to patient in its clinical presentation.”
At least one study, Dr. Sammaritano added, “has shown that the arthritis in pregnancy patients with PsA did not improve, compared to control nonpregnant patients, while the psoriasis rash did improve.”
The mixed findings don’t surprise Dr. Murase. “It harder to quantify joint disease in general,” she said. “And during pregnancy, physiologic changes relating to the pregnancy itself can cause discomfort – your joints ache. The numbers [of improved] cases aren’t as high with PsA, but it’s a more complex question.”
In the postpartum period, however, research findings “all suggest an increased risk of flare” of PsA, Dr. Sammaritano said, just as with psoriasis.
Assessing risk of treatment
Understanding the immunologic effects of pregnancy on psoriasis and PsA – and appreciating the concept of a hormonal component – is an important part of treatment decision making. So is understanding pregnancy outcomes data.
Researchers have looked at a host of pregnancy outcomes – including congenital malformations, preterm birth, spontaneous abortion, low birth weight, macrosomia, and gestational diabetes and hypertension – in women with psoriasis or psoriasis/PsA, compared with control groups. Some studies have suggested a link between disease activity and pregnancy complications or adverse pregnancy outcomes, “just as a result of having moderate to severe disease,” while others have found no evidence of increased risk, Dr. Murase said.
“It’s a bit unclear and a difficult question to answer; it depends on what study you look at and what data you believe. It would be nice to have some clarity, but basically the jury is still out,” said Dr. Murase, who, with coauthors Alice B. Gottlieb, MD, PhD, of the department of dermatology at the Icahn School of Medicine at Mount Sinai, New York, and Caitriona Ryan, MD, of the Blackrock Clinic and Charles Institute of Dermatology, University College Dublin, discussed the pregnancy outcomes data in a recently published review of psoriasis in women.
“In my opinion, because we have therapies that are so low risk and well tolerated, it’s better to make sure that the inflammatory cascade and inflammation created by psoriasis is under control,” she said. “So whether or not the pregnancy itself causes the patient to go into remission, or whether you have to use therapy to help the patient stay in remission, it’s important to control the inflammation.”
Contraindicated in pregnancy are oral psoralen, methotrexate, and acitretin, the latter of which should be avoided for several years before pregnancy and “therefore shouldn’t be used in a woman of childbearing age,” said Dr. Murase. Methotrexate, said Dr. Sammaritano, should generally be stopped 1-3 months prior to conception.
For psoriasis, the therapy that’s “classically considered the safest in pregnancy is UVB light therapy, specifically the 300-nm wavelength of light, which works really well as an anti-inflammatory,” Dr. Murase said. Because of the potential for maternal folate degradation with phototherapy and the long-known association of folate deficiency with neural tube defects, women of childbearing age who are receiving light therapy should take daily folic acid supplementation. (She prescribes a daily prenatal vitamin containing at least 1 mg of folic acid for women who are utilizing light therapy.)
Many topical agents can be used during pregnancy, Dr. Murase said. Topical corticosteroids, she noted, have the most safety-affirming data of any topical medication.
Regarding oral therapies, Dr. Murase recommends against the use of apremilast (Otezla) for her patients. “It’s not contraindicated, but the animal studies don’t look promising, so I don’t use that one in women of childbearing age just in case. There’s just very little data to support the safety of this medication [in pregnancy].”
There are no therapeutic guidelines in the United States for guiding the management of psoriasis in women who are considering pregnancy. In 2012, the medical board of the National Psoriasis Foundation published a review of treatment options for psoriasis in pregnant or lactating women, the “closest thing to guidelines that we’ve had,” said Dr. Murase. (Now almost a decade old, the review addresses TNF inhibitors but does not cover the anti-interleukin agents more recently approved for moderate to severe psoriasis and PsA.)
For treating PsA, rheumatologists now have the American College of Rheumatology’s first guideline for the management of reproductive health in rheumatic and musculoskeletal diseases to reference. The 2020 guideline does not address PsA specifically, but its section on pregnancy and lactation includes recommendations on biologic and other therapies used to treat the disease.
Guidelines aside, physician-patient discussions over drug safety have the potential to be much more meaningful now that drug labels offer clinical summaries, data, and risk summaries regarding potential use in pregnancy. The labels have “more of a narrative, which is a more useful way to counsel patients and make risk-benefit decisions” than the former system of five-letter categories, said Dr. Murase. (The changes were made per the Pregnancy and Lactation Labeling Rule of 2015.)
MothertoBaby, a service of the nonprofit Organization of Teratology Information Specialists, also provides good evidence-based information to physicians and mothers, Dr. Sammaritano noted.
The use of biologic therapies
In a 2017 review of biologic safety for patients with psoriasis during pregnancy, Alexa B. Kimball, MD, MPH, professor of dermatology at Harvard Medical School, Boston; Martina L. Porter, MD, currently with the department of dermatology at Beth Israel Deaconess Medical Center, Boston; and Stephen J. Lockwood, MD, MPH, of the department of dermatology at Harvard Medical School, concluded that an increasing body of literature suggests that biologic agents can be used during pregnancy and breastfeeding. Anti-TNF agents “should be considered over IL-12/23 and IL-17 inhibitors due to the increased availability of long-term data,” they wrote.
“In general,” said Dr. Murase, “there’s more and more data coming out from gastroenterology and rheumatology to reassure patients and prescribing physicians that the TNF-blocker class is likely safe to use in pregnancy,” particularly during the first trimester and early second trimester, when the transport of maternal antibodies across the placenta is “essentially nonexistent.” In the third trimester, the active transport of IgG antibodies increases rapidly.
If possible, said Dr. Sammaritano, who served as lead author of the ACR’s reproductive health guideline, TNF inhibitors “will be stopped prior to the third trimester to avoid [the possibility of] high drug levels in the infant at birth, which raises concern for immunosuppression in the newborn. If disease is very active, however, they can be continued throughout the pregnancy.”
The TNF inhibitor certolizumab pegol (Cimzia) has the advantage of being transported only minimally across the placenta, if at all, she and Dr. Murase both explained. “To be actively carried across, antibodies need what’s called an Fc region for the placenta to grab onto,” Dr. Murase said. Certolizumab – a pegylated anti–binding fragment antibody – lacks this Fc region.
Two recent studies – CRIB and a UCB Pharma safety database analysis – showed “essentially no medication crossing – there were barely detectable levels,” Dr. Murase said. Certolizumab’s label contains this information and other clinical trial data as well as findings from safety database analyses/surveillance registries.
“Before we had much data for the biologics, I’d advise transitioning patients to light therapy from their biologics and a lot of times their psoriasis would improve, but it was more of a dance,” she said. “Now we tend to look at [certolizumab] when they’re of childbearing age and keep them on the treatment. I know that the baby is not being immunosuppressed.”
Consideration of the use of certolizumab when treatment with biologic agents is required throughout the pregnancy is a recommendation included in Dr. Kimball’s 2017 review.
As newer anti-interleukin agents – the IL-12/23 and IL-17 inhibitors – play a growing role in the treatment of psoriasis and PsA, questions loom about their safety profile. Dr. Murase and Dr. Sammaritano are waiting for more data. “In general,” Dr. Sammaritano said, “we recommend stopping them at the time pregnancy is detected, based on a lack of data at this time.”
Small-molecule drugs are also less well studied, she noted. “Because of their low molecular weight, we anticipate they will easily cross the placenta, so we recommend avoiding use during pregnancy until more information is available.”
Postpartum care
The good news, both experts say, is that the vast majority of medications, including biologics, are safe to use during breastfeeding. Methotrexate should be avoided, Dr. Sammaritano pointed out, and the impact of novel small-molecule therapies on breast milk has not been studied.
In her 2019 review of psoriasis in women, Dr. Murase and coauthors wrote that too many dermatologists believe that breastfeeding women should either not be on biologics or are uncertain about biologic use during breastfeeding. However, “biologics are considered compatible for use while breastfeeding due to their large molecular size and the proteolytic environment in the neonatal gastrointestinal tract,” they added.
Counseling and support for breastfeeding is especially important for women with psoriasis, Dr. Murase emphasized. “Breastfeeding is very traumatizing to the skin, and psoriasis can form in skin that’s injured. I have my patients set up an office visit very soon after the pregnancy to make sure they’re doing alright with their breastfeeding and that they’re coating their nipple area with some type of moisturizer and keeping the health of their nipples in good shape.”
Timely reviews of therapy and adjustments are also a priority, she said. “We need to prepare for 6 weeks post partum” when psoriasis will often flare without treatment.
Dr. Murase disclosed that she is a consultant for Dermira, UCB Pharma, Sanofi, Ferndale, and Regeneron. She is also coeditor in chief of the International Journal of Women’s Dermatology. Dr. Sammaritano reported that she has no disclosures relating to the treatment of PsA.
With an average age of diagnosis of 28 years, and one of two incidence peaks occurring at 15-30 years, psoriasis affects many women in the midst of their reproductive years. The prospect of pregnancy – or the reality of a surprise pregnancy – drives questions about heritability of the disease in offspring, the impact of the disease on pregnancy outcomes and breastfeeding, and how to best balance risks of treatments with risks of uncontrolled psoriasis and/or psoriatic arthritis (PsA).
While answers to these questions are not always clear, discussions about pregnancy and psoriasis management “shouldn’t be scary,” said Jenny E. Murase, MD, a dermatologist who speaks and writes widely about her research and experience with psoriasis and pregnancy. “We have access to information and data and educational resources to [work with] and reassure our patients – we just need to use it. Right now, there’s unnecessary suffering [with some patients unnecessarily stopping all treatment].”
Much has been learned in the past 2 decades about the course of psoriasis in pregnancy, and pregnancy outcomes data on the safety of biologics during pregnancy are increasingly emerging – particularly for tumor necrosis factor (TNF)–alpha inhibitors.
Ideally, since half of all pregnancies are unplanned, the implications of therapeutic options should be discussed with all women with psoriasis who are of reproductive age, whether they are sexually active or not. “The onus is on us to make sure that we’re considering the possibility [that our patient] could become pregnant without consulting us first,” said Dr. Murase, associate professor of dermatology at the University of California, San Francisco, and director of medical consultative dermatology for the Palo Alto Foundation Medical Group in Mountain View, Calif.
Lisa R. Sammaritano, MD, associate professor of clinical medicine at Weill Cornell Medicine and a rheumatologist at the Hospital for Special Surgery, both in New York, urges similar attention for PsA. “Pregnancy is best planned while patients have quiescent disease on pregnancy-compatible medications,” she said. “We encourage [more] rheumatologists to be actively involved in pregnancy planning [in order] to guide therapy.”
The impact of estrogen
Dr. Murase was inspired to study psoriasis and pregnancy in part by a patient she met as a medical student. “She had severe psoriasis covering her body, and she said that the only times her psoriasis cleared was during her three pregnancies,” Dr. Murase recalled. “I wondered: What about the pregnancies resulted in such a substantial reduction of her psoriasis?”
She subsequently led a study, published in 2005, of 47 pregnant and 27 nonpregnant patients with psoriasis. More than half of the patients – 55% – reported improvements in their psoriasis during pregnancy, 21% reported no change, and 23% reported worsening. Among the 16 patients who had 10% or greater psoriatic body surface area (BSA) involvement and reported improvements, lesions decreased by 84%.
In the postpartum period, only 9% reported improvement, 26% reported no change, and 65% reported worsening. The increased BSA values observed 6 weeks postpartum did not exceed those of the first trimester, suggesting a return to the patients’ baseline status.
Earlier and smaller retrospective studies had also shown that approximately half of patients improve during pregnancy, and it was believed that progesterone was most likely responsible for this improvement. Dr. Murase’s study moved the needle in that it examined BSA in pregnancy and the postpartum period. It also turned the spotlight on estrogen: Patients who had higher levels of improvement also had higher levels of estradiol, estrone, and the ratio of estrogen to progesterone. However, there was no correlation between psoriatic change and levels of progesterone.
To promote fetal survival, pregnancy triggers a shift from Th1 cell–mediated immunity – and Th17 immunity – to Th2 immunity. While there’s no proof of a causative effect, increased estrogen appears to play a role in this shift and in the reduced production of Th1 and Th17 cytokines. Psoriasis is believed to be primarily a Th17-mediated disease, with some Th1 involvement, so this down-regulation can result in improved disease status, Dr. Murase said. (A host of other autoimmune diseases categorized as Th1 mediated similarly tend to improve during pregnancy, she added.)
Information on the effect of pregnancy on PsA is “conflicting,” Dr. Sammaritano said. “Some [of a limited number of studies] suggest a beneficial effect as is generally seen for rheumatoid arthritis. Others, however, have found an increased risk of disease activity during pregnancy ... It may be that psoriatic arthritis can be quite variable from patient to patient in its clinical presentation.”
At least one study, Dr. Sammaritano added, “has shown that the arthritis in pregnancy patients with PsA did not improve, compared to control nonpregnant patients, while the psoriasis rash did improve.”
The mixed findings don’t surprise Dr. Murase. “It harder to quantify joint disease in general,” she said. “And during pregnancy, physiologic changes relating to the pregnancy itself can cause discomfort – your joints ache. The numbers [of improved] cases aren’t as high with PsA, but it’s a more complex question.”
In the postpartum period, however, research findings “all suggest an increased risk of flare” of PsA, Dr. Sammaritano said, just as with psoriasis.
Assessing risk of treatment
Understanding the immunologic effects of pregnancy on psoriasis and PsA – and appreciating the concept of a hormonal component – is an important part of treatment decision making. So is understanding pregnancy outcomes data.
Researchers have looked at a host of pregnancy outcomes – including congenital malformations, preterm birth, spontaneous abortion, low birth weight, macrosomia, and gestational diabetes and hypertension – in women with psoriasis or psoriasis/PsA, compared with control groups. Some studies have suggested a link between disease activity and pregnancy complications or adverse pregnancy outcomes, “just as a result of having moderate to severe disease,” while others have found no evidence of increased risk, Dr. Murase said.
“It’s a bit unclear and a difficult question to answer; it depends on what study you look at and what data you believe. It would be nice to have some clarity, but basically the jury is still out,” said Dr. Murase, who, with coauthors Alice B. Gottlieb, MD, PhD, of the department of dermatology at the Icahn School of Medicine at Mount Sinai, New York, and Caitriona Ryan, MD, of the Blackrock Clinic and Charles Institute of Dermatology, University College Dublin, discussed the pregnancy outcomes data in a recently published review of psoriasis in women.
“In my opinion, because we have therapies that are so low risk and well tolerated, it’s better to make sure that the inflammatory cascade and inflammation created by psoriasis is under control,” she said. “So whether or not the pregnancy itself causes the patient to go into remission, or whether you have to use therapy to help the patient stay in remission, it’s important to control the inflammation.”
Contraindicated in pregnancy are oral psoralen, methotrexate, and acitretin, the latter of which should be avoided for several years before pregnancy and “therefore shouldn’t be used in a woman of childbearing age,” said Dr. Murase. Methotrexate, said Dr. Sammaritano, should generally be stopped 1-3 months prior to conception.
For psoriasis, the therapy that’s “classically considered the safest in pregnancy is UVB light therapy, specifically the 300-nm wavelength of light, which works really well as an anti-inflammatory,” Dr. Murase said. Because of the potential for maternal folate degradation with phototherapy and the long-known association of folate deficiency with neural tube defects, women of childbearing age who are receiving light therapy should take daily folic acid supplementation. (She prescribes a daily prenatal vitamin containing at least 1 mg of folic acid for women who are utilizing light therapy.)
Many topical agents can be used during pregnancy, Dr. Murase said. Topical corticosteroids, she noted, have the most safety-affirming data of any topical medication.
Regarding oral therapies, Dr. Murase recommends against the use of apremilast (Otezla) for her patients. “It’s not contraindicated, but the animal studies don’t look promising, so I don’t use that one in women of childbearing age just in case. There’s just very little data to support the safety of this medication [in pregnancy].”
There are no therapeutic guidelines in the United States for guiding the management of psoriasis in women who are considering pregnancy. In 2012, the medical board of the National Psoriasis Foundation published a review of treatment options for psoriasis in pregnant or lactating women, the “closest thing to guidelines that we’ve had,” said Dr. Murase. (Now almost a decade old, the review addresses TNF inhibitors but does not cover the anti-interleukin agents more recently approved for moderate to severe psoriasis and PsA.)
For treating PsA, rheumatologists now have the American College of Rheumatology’s first guideline for the management of reproductive health in rheumatic and musculoskeletal diseases to reference. The 2020 guideline does not address PsA specifically, but its section on pregnancy and lactation includes recommendations on biologic and other therapies used to treat the disease.
Guidelines aside, physician-patient discussions over drug safety have the potential to be much more meaningful now that drug labels offer clinical summaries, data, and risk summaries regarding potential use in pregnancy. The labels have “more of a narrative, which is a more useful way to counsel patients and make risk-benefit decisions” than the former system of five-letter categories, said Dr. Murase. (The changes were made per the Pregnancy and Lactation Labeling Rule of 2015.)
MothertoBaby, a service of the nonprofit Organization of Teratology Information Specialists, also provides good evidence-based information to physicians and mothers, Dr. Sammaritano noted.
The use of biologic therapies
In a 2017 review of biologic safety for patients with psoriasis during pregnancy, Alexa B. Kimball, MD, MPH, professor of dermatology at Harvard Medical School, Boston; Martina L. Porter, MD, currently with the department of dermatology at Beth Israel Deaconess Medical Center, Boston; and Stephen J. Lockwood, MD, MPH, of the department of dermatology at Harvard Medical School, concluded that an increasing body of literature suggests that biologic agents can be used during pregnancy and breastfeeding. Anti-TNF agents “should be considered over IL-12/23 and IL-17 inhibitors due to the increased availability of long-term data,” they wrote.
“In general,” said Dr. Murase, “there’s more and more data coming out from gastroenterology and rheumatology to reassure patients and prescribing physicians that the TNF-blocker class is likely safe to use in pregnancy,” particularly during the first trimester and early second trimester, when the transport of maternal antibodies across the placenta is “essentially nonexistent.” In the third trimester, the active transport of IgG antibodies increases rapidly.
If possible, said Dr. Sammaritano, who served as lead author of the ACR’s reproductive health guideline, TNF inhibitors “will be stopped prior to the third trimester to avoid [the possibility of] high drug levels in the infant at birth, which raises concern for immunosuppression in the newborn. If disease is very active, however, they can be continued throughout the pregnancy.”
The TNF inhibitor certolizumab pegol (Cimzia) has the advantage of being transported only minimally across the placenta, if at all, she and Dr. Murase both explained. “To be actively carried across, antibodies need what’s called an Fc region for the placenta to grab onto,” Dr. Murase said. Certolizumab – a pegylated anti–binding fragment antibody – lacks this Fc region.
Two recent studies – CRIB and a UCB Pharma safety database analysis – showed “essentially no medication crossing – there were barely detectable levels,” Dr. Murase said. Certolizumab’s label contains this information and other clinical trial data as well as findings from safety database analyses/surveillance registries.
“Before we had much data for the biologics, I’d advise transitioning patients to light therapy from their biologics and a lot of times their psoriasis would improve, but it was more of a dance,” she said. “Now we tend to look at [certolizumab] when they’re of childbearing age and keep them on the treatment. I know that the baby is not being immunosuppressed.”
Consideration of the use of certolizumab when treatment with biologic agents is required throughout the pregnancy is a recommendation included in Dr. Kimball’s 2017 review.
As newer anti-interleukin agents – the IL-12/23 and IL-17 inhibitors – play a growing role in the treatment of psoriasis and PsA, questions loom about their safety profile. Dr. Murase and Dr. Sammaritano are waiting for more data. “In general,” Dr. Sammaritano said, “we recommend stopping them at the time pregnancy is detected, based on a lack of data at this time.”
Small-molecule drugs are also less well studied, she noted. “Because of their low molecular weight, we anticipate they will easily cross the placenta, so we recommend avoiding use during pregnancy until more information is available.”
Postpartum care
The good news, both experts say, is that the vast majority of medications, including biologics, are safe to use during breastfeeding. Methotrexate should be avoided, Dr. Sammaritano pointed out, and the impact of novel small-molecule therapies on breast milk has not been studied.
In her 2019 review of psoriasis in women, Dr. Murase and coauthors wrote that too many dermatologists believe that breastfeeding women should either not be on biologics or are uncertain about biologic use during breastfeeding. However, “biologics are considered compatible for use while breastfeeding due to their large molecular size and the proteolytic environment in the neonatal gastrointestinal tract,” they added.
Counseling and support for breastfeeding is especially important for women with psoriasis, Dr. Murase emphasized. “Breastfeeding is very traumatizing to the skin, and psoriasis can form in skin that’s injured. I have my patients set up an office visit very soon after the pregnancy to make sure they’re doing alright with their breastfeeding and that they’re coating their nipple area with some type of moisturizer and keeping the health of their nipples in good shape.”
Timely reviews of therapy and adjustments are also a priority, she said. “We need to prepare for 6 weeks post partum” when psoriasis will often flare without treatment.
Dr. Murase disclosed that she is a consultant for Dermira, UCB Pharma, Sanofi, Ferndale, and Regeneron. She is also coeditor in chief of the International Journal of Women’s Dermatology. Dr. Sammaritano reported that she has no disclosures relating to the treatment of PsA.
With an average age of diagnosis of 28 years, and one of two incidence peaks occurring at 15-30 years, psoriasis affects many women in the midst of their reproductive years. The prospect of pregnancy – or the reality of a surprise pregnancy – drives questions about heritability of the disease in offspring, the impact of the disease on pregnancy outcomes and breastfeeding, and how to best balance risks of treatments with risks of uncontrolled psoriasis and/or psoriatic arthritis (PsA).
While answers to these questions are not always clear, discussions about pregnancy and psoriasis management “shouldn’t be scary,” said Jenny E. Murase, MD, a dermatologist who speaks and writes widely about her research and experience with psoriasis and pregnancy. “We have access to information and data and educational resources to [work with] and reassure our patients – we just need to use it. Right now, there’s unnecessary suffering [with some patients unnecessarily stopping all treatment].”
Much has been learned in the past 2 decades about the course of psoriasis in pregnancy, and pregnancy outcomes data on the safety of biologics during pregnancy are increasingly emerging – particularly for tumor necrosis factor (TNF)–alpha inhibitors.
Ideally, since half of all pregnancies are unplanned, the implications of therapeutic options should be discussed with all women with psoriasis who are of reproductive age, whether they are sexually active or not. “The onus is on us to make sure that we’re considering the possibility [that our patient] could become pregnant without consulting us first,” said Dr. Murase, associate professor of dermatology at the University of California, San Francisco, and director of medical consultative dermatology for the Palo Alto Foundation Medical Group in Mountain View, Calif.
Lisa R. Sammaritano, MD, associate professor of clinical medicine at Weill Cornell Medicine and a rheumatologist at the Hospital for Special Surgery, both in New York, urges similar attention for PsA. “Pregnancy is best planned while patients have quiescent disease on pregnancy-compatible medications,” she said. “We encourage [more] rheumatologists to be actively involved in pregnancy planning [in order] to guide therapy.”
The impact of estrogen
Dr. Murase was inspired to study psoriasis and pregnancy in part by a patient she met as a medical student. “She had severe psoriasis covering her body, and she said that the only times her psoriasis cleared was during her three pregnancies,” Dr. Murase recalled. “I wondered: What about the pregnancies resulted in such a substantial reduction of her psoriasis?”
She subsequently led a study, published in 2005, of 47 pregnant and 27 nonpregnant patients with psoriasis. More than half of the patients – 55% – reported improvements in their psoriasis during pregnancy, 21% reported no change, and 23% reported worsening. Among the 16 patients who had 10% or greater psoriatic body surface area (BSA) involvement and reported improvements, lesions decreased by 84%.
In the postpartum period, only 9% reported improvement, 26% reported no change, and 65% reported worsening. The increased BSA values observed 6 weeks postpartum did not exceed those of the first trimester, suggesting a return to the patients’ baseline status.
Earlier and smaller retrospective studies had also shown that approximately half of patients improve during pregnancy, and it was believed that progesterone was most likely responsible for this improvement. Dr. Murase’s study moved the needle in that it examined BSA in pregnancy and the postpartum period. It also turned the spotlight on estrogen: Patients who had higher levels of improvement also had higher levels of estradiol, estrone, and the ratio of estrogen to progesterone. However, there was no correlation between psoriatic change and levels of progesterone.
To promote fetal survival, pregnancy triggers a shift from Th1 cell–mediated immunity – and Th17 immunity – to Th2 immunity. While there’s no proof of a causative effect, increased estrogen appears to play a role in this shift and in the reduced production of Th1 and Th17 cytokines. Psoriasis is believed to be primarily a Th17-mediated disease, with some Th1 involvement, so this down-regulation can result in improved disease status, Dr. Murase said. (A host of other autoimmune diseases categorized as Th1 mediated similarly tend to improve during pregnancy, she added.)
Information on the effect of pregnancy on PsA is “conflicting,” Dr. Sammaritano said. “Some [of a limited number of studies] suggest a beneficial effect as is generally seen for rheumatoid arthritis. Others, however, have found an increased risk of disease activity during pregnancy ... It may be that psoriatic arthritis can be quite variable from patient to patient in its clinical presentation.”
At least one study, Dr. Sammaritano added, “has shown that the arthritis in pregnancy patients with PsA did not improve, compared to control nonpregnant patients, while the psoriasis rash did improve.”
The mixed findings don’t surprise Dr. Murase. “It harder to quantify joint disease in general,” she said. “And during pregnancy, physiologic changes relating to the pregnancy itself can cause discomfort – your joints ache. The numbers [of improved] cases aren’t as high with PsA, but it’s a more complex question.”
In the postpartum period, however, research findings “all suggest an increased risk of flare” of PsA, Dr. Sammaritano said, just as with psoriasis.
Assessing risk of treatment
Understanding the immunologic effects of pregnancy on psoriasis and PsA – and appreciating the concept of a hormonal component – is an important part of treatment decision making. So is understanding pregnancy outcomes data.
Researchers have looked at a host of pregnancy outcomes – including congenital malformations, preterm birth, spontaneous abortion, low birth weight, macrosomia, and gestational diabetes and hypertension – in women with psoriasis or psoriasis/PsA, compared with control groups. Some studies have suggested a link between disease activity and pregnancy complications or adverse pregnancy outcomes, “just as a result of having moderate to severe disease,” while others have found no evidence of increased risk, Dr. Murase said.
“It’s a bit unclear and a difficult question to answer; it depends on what study you look at and what data you believe. It would be nice to have some clarity, but basically the jury is still out,” said Dr. Murase, who, with coauthors Alice B. Gottlieb, MD, PhD, of the department of dermatology at the Icahn School of Medicine at Mount Sinai, New York, and Caitriona Ryan, MD, of the Blackrock Clinic and Charles Institute of Dermatology, University College Dublin, discussed the pregnancy outcomes data in a recently published review of psoriasis in women.
“In my opinion, because we have therapies that are so low risk and well tolerated, it’s better to make sure that the inflammatory cascade and inflammation created by psoriasis is under control,” she said. “So whether or not the pregnancy itself causes the patient to go into remission, or whether you have to use therapy to help the patient stay in remission, it’s important to control the inflammation.”
Contraindicated in pregnancy are oral psoralen, methotrexate, and acitretin, the latter of which should be avoided for several years before pregnancy and “therefore shouldn’t be used in a woman of childbearing age,” said Dr. Murase. Methotrexate, said Dr. Sammaritano, should generally be stopped 1-3 months prior to conception.
For psoriasis, the therapy that’s “classically considered the safest in pregnancy is UVB light therapy, specifically the 300-nm wavelength of light, which works really well as an anti-inflammatory,” Dr. Murase said. Because of the potential for maternal folate degradation with phototherapy and the long-known association of folate deficiency with neural tube defects, women of childbearing age who are receiving light therapy should take daily folic acid supplementation. (She prescribes a daily prenatal vitamin containing at least 1 mg of folic acid for women who are utilizing light therapy.)
Many topical agents can be used during pregnancy, Dr. Murase said. Topical corticosteroids, she noted, have the most safety-affirming data of any topical medication.
Regarding oral therapies, Dr. Murase recommends against the use of apremilast (Otezla) for her patients. “It’s not contraindicated, but the animal studies don’t look promising, so I don’t use that one in women of childbearing age just in case. There’s just very little data to support the safety of this medication [in pregnancy].”
There are no therapeutic guidelines in the United States for guiding the management of psoriasis in women who are considering pregnancy. In 2012, the medical board of the National Psoriasis Foundation published a review of treatment options for psoriasis in pregnant or lactating women, the “closest thing to guidelines that we’ve had,” said Dr. Murase. (Now almost a decade old, the review addresses TNF inhibitors but does not cover the anti-interleukin agents more recently approved for moderate to severe psoriasis and PsA.)
For treating PsA, rheumatologists now have the American College of Rheumatology’s first guideline for the management of reproductive health in rheumatic and musculoskeletal diseases to reference. The 2020 guideline does not address PsA specifically, but its section on pregnancy and lactation includes recommendations on biologic and other therapies used to treat the disease.
Guidelines aside, physician-patient discussions over drug safety have the potential to be much more meaningful now that drug labels offer clinical summaries, data, and risk summaries regarding potential use in pregnancy. The labels have “more of a narrative, which is a more useful way to counsel patients and make risk-benefit decisions” than the former system of five-letter categories, said Dr. Murase. (The changes were made per the Pregnancy and Lactation Labeling Rule of 2015.)
MothertoBaby, a service of the nonprofit Organization of Teratology Information Specialists, also provides good evidence-based information to physicians and mothers, Dr. Sammaritano noted.
The use of biologic therapies
In a 2017 review of biologic safety for patients with psoriasis during pregnancy, Alexa B. Kimball, MD, MPH, professor of dermatology at Harvard Medical School, Boston; Martina L. Porter, MD, currently with the department of dermatology at Beth Israel Deaconess Medical Center, Boston; and Stephen J. Lockwood, MD, MPH, of the department of dermatology at Harvard Medical School, concluded that an increasing body of literature suggests that biologic agents can be used during pregnancy and breastfeeding. Anti-TNF agents “should be considered over IL-12/23 and IL-17 inhibitors due to the increased availability of long-term data,” they wrote.
“In general,” said Dr. Murase, “there’s more and more data coming out from gastroenterology and rheumatology to reassure patients and prescribing physicians that the TNF-blocker class is likely safe to use in pregnancy,” particularly during the first trimester and early second trimester, when the transport of maternal antibodies across the placenta is “essentially nonexistent.” In the third trimester, the active transport of IgG antibodies increases rapidly.
If possible, said Dr. Sammaritano, who served as lead author of the ACR’s reproductive health guideline, TNF inhibitors “will be stopped prior to the third trimester to avoid [the possibility of] high drug levels in the infant at birth, which raises concern for immunosuppression in the newborn. If disease is very active, however, they can be continued throughout the pregnancy.”
The TNF inhibitor certolizumab pegol (Cimzia) has the advantage of being transported only minimally across the placenta, if at all, she and Dr. Murase both explained. “To be actively carried across, antibodies need what’s called an Fc region for the placenta to grab onto,” Dr. Murase said. Certolizumab – a pegylated anti–binding fragment antibody – lacks this Fc region.
Two recent studies – CRIB and a UCB Pharma safety database analysis – showed “essentially no medication crossing – there were barely detectable levels,” Dr. Murase said. Certolizumab’s label contains this information and other clinical trial data as well as findings from safety database analyses/surveillance registries.
“Before we had much data for the biologics, I’d advise transitioning patients to light therapy from their biologics and a lot of times their psoriasis would improve, but it was more of a dance,” she said. “Now we tend to look at [certolizumab] when they’re of childbearing age and keep them on the treatment. I know that the baby is not being immunosuppressed.”
Consideration of the use of certolizumab when treatment with biologic agents is required throughout the pregnancy is a recommendation included in Dr. Kimball’s 2017 review.
As newer anti-interleukin agents – the IL-12/23 and IL-17 inhibitors – play a growing role in the treatment of psoriasis and PsA, questions loom about their safety profile. Dr. Murase and Dr. Sammaritano are waiting for more data. “In general,” Dr. Sammaritano said, “we recommend stopping them at the time pregnancy is detected, based on a lack of data at this time.”
Small-molecule drugs are also less well studied, she noted. “Because of their low molecular weight, we anticipate they will easily cross the placenta, so we recommend avoiding use during pregnancy until more information is available.”
Postpartum care
The good news, both experts say, is that the vast majority of medications, including biologics, are safe to use during breastfeeding. Methotrexate should be avoided, Dr. Sammaritano pointed out, and the impact of novel small-molecule therapies on breast milk has not been studied.
In her 2019 review of psoriasis in women, Dr. Murase and coauthors wrote that too many dermatologists believe that breastfeeding women should either not be on biologics or are uncertain about biologic use during breastfeeding. However, “biologics are considered compatible for use while breastfeeding due to their large molecular size and the proteolytic environment in the neonatal gastrointestinal tract,” they added.
Counseling and support for breastfeeding is especially important for women with psoriasis, Dr. Murase emphasized. “Breastfeeding is very traumatizing to the skin, and psoriasis can form in skin that’s injured. I have my patients set up an office visit very soon after the pregnancy to make sure they’re doing alright with their breastfeeding and that they’re coating their nipple area with some type of moisturizer and keeping the health of their nipples in good shape.”
Timely reviews of therapy and adjustments are also a priority, she said. “We need to prepare for 6 weeks post partum” when psoriasis will often flare without treatment.
Dr. Murase disclosed that she is a consultant for Dermira, UCB Pharma, Sanofi, Ferndale, and Regeneron. She is also coeditor in chief of the International Journal of Women’s Dermatology. Dr. Sammaritano reported that she has no disclosures relating to the treatment of PsA.
Study highlights role of structural racism in delayed autism diagnoses
An analysis of a large cohort of African American children with autism spectrum disorder (ASD) reveals a more than 3-year time lag between parental recognition of a development delay and an ASD diagnosis, reported John N. Constantino, MD, of the department of psychiatry at Washington University, St. Louis, and coauthors.
The analysis also highlights the need to further understand – and act on – the disproportionate burden of intellectual disability comorbidity among these children, the investigators say.
Their analysis, published in Pediatrics, builds on national community surveillance data from the Centers for Disease Control and Prevention published in 2018 showing near-equal rates of identification of ASD among African American (and other minorities) and non-Hispanic white children, but greater delays in diagnosis for African American children as well as twice the rate of comorbid intellectual disability, compared with non-Hispanic white children (44% vs. 22%).
To explore potential drivers of both diagnostic delays and the intellectual disability disparity, the investigators tapped into a repository of data on 584 African American children with ASD and their first-degree relatives who were consecutively enrolled in the National Institutes of Health–funded Autism Genetic Resource Exchange across four academic sites. The program aims to improve the representation of families of self-reported African ancestry in ASD genetics research.
The mean age of diagnosis was 65 months, which came at an average of more than 3 years after parents reported having concerns about their child’s language, behavior or development – and “the period when early developmental therapies (typically delivered through part C interventions in the United States) are initiated to ameliorate the disability associated with ASD,” Dr. Constantino and associates said.
Approximately 42% reported seeing multiple professionals before receiving an ASD diagnosis (14% saw six or more), and 31% said that a lack of available professionals had contributed to the delay. Almost all families – 98% – reported having some type of health insurance at the time of their first concerns (49% private, 46% public, and 5% others).
The data also show that excess intellectual disability comorbidity seen in African American children cannot be explained by familial or sociodemographic factors that have traditionally been associated with variation in IQ in the general population. Nor can it be explained by overclassification of intellectual disability, the authors said.
they wrote.
The NIH-funded program involved parental completion of “Diagnostic Odyssey” interviews (characterizing service-seeking experiences and obstacles to diagnosis, treatment, and care) and several in-person cognitive assessments and measurements of adaptive functioning. “These were in-depth [highly validated] intellectual assessments based on IQ measures that were tailored to the level of functioning of the children and backed by extensive assessments of adaptive functioning,” Dr. Constantino said in an interview.
Historically, autism has been underdiagnosed among minority children. Now that this is no longer the case, as demonstrated in the CDC’s 2018 report from its Autism and Developmental Disabilities Monitoring Network, the thought that higher rates of intellectual disability comorbidity among minority children are due to ascertainment bias – to “our only diagnosing the most serious cases” – “is no longer true,” he said.
And now, with use of data from the largest-available repository of diagnostic and phenotypic information on African American children with ASD, “we’ve dispelled other misperceptions, other factors that might be used to dismiss or explain away why Black children might have a high rate of intellectual disability,” Dr. Constantino said in the interview, referring to the absence of association between the IQ scores of children with ASD and those of their first-degree relatives as well as the lack of significant associations between the IQ of children with ASD and factors such as family income (above versus below the median income of the cohort), the mother having or not having a college degree, and the estimated gestational age at birth (before versus after 37 weeks).
“This kind of complication of autism lasts for the life of a child and profoundly impairs their functioning,” he said. “If anyone thinks there isn’t an opportunity to improve the timing of diagnosis and to improve access to services and appropriate developmental therapies, that’s wrong. There is opportunity – parents are raising the alarm, and we are not coming to these children’s rescue.”
In an accompanying editorial, Sarabeth Broder-Fingert, MD, MPH, of Boston University and Boston Medical Center, and associates wrote that the “confluence of findings [in this study] are suggestive of structural racism leading to inequity.”
For example, they said, “although the causes of delays from first parental concern to ASD diagnosis are complex, they can result from a number of issues, including racial bias and discrimination experienced by families, a lack of diversity in health professionals (impacting patient-provider relationships), and/or concentration of specialists in geographic areas with fewer minority residents.” Each of these issues, they wrote, can be linked to racism, both structural and individual.
Combined with previous research on inequity in ASD, the new data “necessitate an immediate evaluation of how issues of structural racism have impacted ASD diagnosis and, more importantly, an action plan to address inequity,” they said.
Issues of workforce capacity for ASD diagnosis need to be addressed by evaluating Medicaid reimbursement rates for ASD diagnosis, for instance, and removing restrictions on who is qualified to make a diagnosis, increasing adherence to evidence-based practices, “increasing workforce cultural humility, and recruiting a workforce that reflects the diverse communities they serve,” Dr. Broder-Fingert and associates said.
Jeremiah Dickerson, MD, a child and adolescent psychiatrist at the University of Vermont, Burlington, said he is hopeful that the inequities and structural obstacles that he sees in his patients are “being informed more and more by science” and that “we’re taking steps in exploring our own cultural humility and focusing on problems ... that have been under the surface for decades.”
Years of diagnostic delay and missed intervention for ASD can lead to increasing lifelong functional difficulties, which in turn can be compounded by enduring inequities and stigma, he said when asked to comment on the study.
“Diagnosing and teasing apart ID [intellectual disability] versus ASD, and ID co-occurring with ASD, can be very complicated, particularly in young children with significant language impairments,” he added. “If indeed there is a higher proportion of African American children with co-occurring ASD and ID ... we have to do a much better job with identifying those children earlier and providing longitudinal follow-up/assessment that can help provide diagnostic clarity and inform recommendations.”
Understanding better why this occurs “without repeating the history of assigning cause based upon racist thinking” is also important, said Dr. Dickerson, who directs the autism assessment clinic at the university’s Vermont Center for Children, Youth & Families.
Dr. Constantino, who has been involved in the CDC’s 11-site ASD surveillance network, said it is unclear to what extent broad implementation of early and high-quality interventions can reduce the proportion of African American children with autism and comorbid intellectual disability. “We may be only half-successful in closing the gap, or there may be other factors involved that we don’t understand yet,” he said. “But we haven’t even attempted to close the gap [through] reasonable application of an intervention strategy that is available and that we know can improve cognitive outcomes.”
“Some primary care doctors are reluctant to make the diagnosis in the first place because they have nothing to offer the families,” Dr. Constantino noted.
Continued research on the interactions between genetic background and specific biological susceptibilities to autism is an ongoing objective of the Autism Genetic Resource Exchange.
The CDC recently published its latest report on the prevalence of ASD in children aged 8 years, concluding again that continued efforts are needed for “early and equitable identification of ASD and timely enrollment in services.
The study was supported by grants from the National Institutes of Health and from the Intellectual and Developmental Disabilities Research Center at Washington University. Dr. Constantino is author of the Social Responsiveness Scale-2, from which he receives royalties. A coauthor helped author the Vineland-3 and receives royalties, and this coauthor and another associate also have ties to pharmaceutical companies or other organizations; the remaining authors of the study said they had no relevant financial disclosures. Dr. Broder-Fingert and associates said they have no relevant financial relationships; the editorial was funded by the National Institutes of Health. Dr. Dickerson said he had no relevant financial disclosures.
SOURCE: Constantino JN et al. Pediatrics. 2020. doi: 10.1542/peds.2019-3629.
An analysis of a large cohort of African American children with autism spectrum disorder (ASD) reveals a more than 3-year time lag between parental recognition of a development delay and an ASD diagnosis, reported John N. Constantino, MD, of the department of psychiatry at Washington University, St. Louis, and coauthors.
The analysis also highlights the need to further understand – and act on – the disproportionate burden of intellectual disability comorbidity among these children, the investigators say.
Their analysis, published in Pediatrics, builds on national community surveillance data from the Centers for Disease Control and Prevention published in 2018 showing near-equal rates of identification of ASD among African American (and other minorities) and non-Hispanic white children, but greater delays in diagnosis for African American children as well as twice the rate of comorbid intellectual disability, compared with non-Hispanic white children (44% vs. 22%).
To explore potential drivers of both diagnostic delays and the intellectual disability disparity, the investigators tapped into a repository of data on 584 African American children with ASD and their first-degree relatives who were consecutively enrolled in the National Institutes of Health–funded Autism Genetic Resource Exchange across four academic sites. The program aims to improve the representation of families of self-reported African ancestry in ASD genetics research.
The mean age of diagnosis was 65 months, which came at an average of more than 3 years after parents reported having concerns about their child’s language, behavior or development – and “the period when early developmental therapies (typically delivered through part C interventions in the United States) are initiated to ameliorate the disability associated with ASD,” Dr. Constantino and associates said.
Approximately 42% reported seeing multiple professionals before receiving an ASD diagnosis (14% saw six or more), and 31% said that a lack of available professionals had contributed to the delay. Almost all families – 98% – reported having some type of health insurance at the time of their first concerns (49% private, 46% public, and 5% others).
The data also show that excess intellectual disability comorbidity seen in African American children cannot be explained by familial or sociodemographic factors that have traditionally been associated with variation in IQ in the general population. Nor can it be explained by overclassification of intellectual disability, the authors said.
they wrote.
The NIH-funded program involved parental completion of “Diagnostic Odyssey” interviews (characterizing service-seeking experiences and obstacles to diagnosis, treatment, and care) and several in-person cognitive assessments and measurements of adaptive functioning. “These were in-depth [highly validated] intellectual assessments based on IQ measures that were tailored to the level of functioning of the children and backed by extensive assessments of adaptive functioning,” Dr. Constantino said in an interview.
Historically, autism has been underdiagnosed among minority children. Now that this is no longer the case, as demonstrated in the CDC’s 2018 report from its Autism and Developmental Disabilities Monitoring Network, the thought that higher rates of intellectual disability comorbidity among minority children are due to ascertainment bias – to “our only diagnosing the most serious cases” – “is no longer true,” he said.
And now, with use of data from the largest-available repository of diagnostic and phenotypic information on African American children with ASD, “we’ve dispelled other misperceptions, other factors that might be used to dismiss or explain away why Black children might have a high rate of intellectual disability,” Dr. Constantino said in the interview, referring to the absence of association between the IQ scores of children with ASD and those of their first-degree relatives as well as the lack of significant associations between the IQ of children with ASD and factors such as family income (above versus below the median income of the cohort), the mother having or not having a college degree, and the estimated gestational age at birth (before versus after 37 weeks).
“This kind of complication of autism lasts for the life of a child and profoundly impairs their functioning,” he said. “If anyone thinks there isn’t an opportunity to improve the timing of diagnosis and to improve access to services and appropriate developmental therapies, that’s wrong. There is opportunity – parents are raising the alarm, and we are not coming to these children’s rescue.”
In an accompanying editorial, Sarabeth Broder-Fingert, MD, MPH, of Boston University and Boston Medical Center, and associates wrote that the “confluence of findings [in this study] are suggestive of structural racism leading to inequity.”
For example, they said, “although the causes of delays from first parental concern to ASD diagnosis are complex, they can result from a number of issues, including racial bias and discrimination experienced by families, a lack of diversity in health professionals (impacting patient-provider relationships), and/or concentration of specialists in geographic areas with fewer minority residents.” Each of these issues, they wrote, can be linked to racism, both structural and individual.
Combined with previous research on inequity in ASD, the new data “necessitate an immediate evaluation of how issues of structural racism have impacted ASD diagnosis and, more importantly, an action plan to address inequity,” they said.
Issues of workforce capacity for ASD diagnosis need to be addressed by evaluating Medicaid reimbursement rates for ASD diagnosis, for instance, and removing restrictions on who is qualified to make a diagnosis, increasing adherence to evidence-based practices, “increasing workforce cultural humility, and recruiting a workforce that reflects the diverse communities they serve,” Dr. Broder-Fingert and associates said.
Jeremiah Dickerson, MD, a child and adolescent psychiatrist at the University of Vermont, Burlington, said he is hopeful that the inequities and structural obstacles that he sees in his patients are “being informed more and more by science” and that “we’re taking steps in exploring our own cultural humility and focusing on problems ... that have been under the surface for decades.”
Years of diagnostic delay and missed intervention for ASD can lead to increasing lifelong functional difficulties, which in turn can be compounded by enduring inequities and stigma, he said when asked to comment on the study.
“Diagnosing and teasing apart ID [intellectual disability] versus ASD, and ID co-occurring with ASD, can be very complicated, particularly in young children with significant language impairments,” he added. “If indeed there is a higher proportion of African American children with co-occurring ASD and ID ... we have to do a much better job with identifying those children earlier and providing longitudinal follow-up/assessment that can help provide diagnostic clarity and inform recommendations.”
Understanding better why this occurs “without repeating the history of assigning cause based upon racist thinking” is also important, said Dr. Dickerson, who directs the autism assessment clinic at the university’s Vermont Center for Children, Youth & Families.
Dr. Constantino, who has been involved in the CDC’s 11-site ASD surveillance network, said it is unclear to what extent broad implementation of early and high-quality interventions can reduce the proportion of African American children with autism and comorbid intellectual disability. “We may be only half-successful in closing the gap, or there may be other factors involved that we don’t understand yet,” he said. “But we haven’t even attempted to close the gap [through] reasonable application of an intervention strategy that is available and that we know can improve cognitive outcomes.”
“Some primary care doctors are reluctant to make the diagnosis in the first place because they have nothing to offer the families,” Dr. Constantino noted.
Continued research on the interactions between genetic background and specific biological susceptibilities to autism is an ongoing objective of the Autism Genetic Resource Exchange.
The CDC recently published its latest report on the prevalence of ASD in children aged 8 years, concluding again that continued efforts are needed for “early and equitable identification of ASD and timely enrollment in services.
The study was supported by grants from the National Institutes of Health and from the Intellectual and Developmental Disabilities Research Center at Washington University. Dr. Constantino is author of the Social Responsiveness Scale-2, from which he receives royalties. A coauthor helped author the Vineland-3 and receives royalties, and this coauthor and another associate also have ties to pharmaceutical companies or other organizations; the remaining authors of the study said they had no relevant financial disclosures. Dr. Broder-Fingert and associates said they have no relevant financial relationships; the editorial was funded by the National Institutes of Health. Dr. Dickerson said he had no relevant financial disclosures.
SOURCE: Constantino JN et al. Pediatrics. 2020. doi: 10.1542/peds.2019-3629.
An analysis of a large cohort of African American children with autism spectrum disorder (ASD) reveals a more than 3-year time lag between parental recognition of a development delay and an ASD diagnosis, reported John N. Constantino, MD, of the department of psychiatry at Washington University, St. Louis, and coauthors.
The analysis also highlights the need to further understand – and act on – the disproportionate burden of intellectual disability comorbidity among these children, the investigators say.
Their analysis, published in Pediatrics, builds on national community surveillance data from the Centers for Disease Control and Prevention published in 2018 showing near-equal rates of identification of ASD among African American (and other minorities) and non-Hispanic white children, but greater delays in diagnosis for African American children as well as twice the rate of comorbid intellectual disability, compared with non-Hispanic white children (44% vs. 22%).
To explore potential drivers of both diagnostic delays and the intellectual disability disparity, the investigators tapped into a repository of data on 584 African American children with ASD and their first-degree relatives who were consecutively enrolled in the National Institutes of Health–funded Autism Genetic Resource Exchange across four academic sites. The program aims to improve the representation of families of self-reported African ancestry in ASD genetics research.
The mean age of diagnosis was 65 months, which came at an average of more than 3 years after parents reported having concerns about their child’s language, behavior or development – and “the period when early developmental therapies (typically delivered through part C interventions in the United States) are initiated to ameliorate the disability associated with ASD,” Dr. Constantino and associates said.
Approximately 42% reported seeing multiple professionals before receiving an ASD diagnosis (14% saw six or more), and 31% said that a lack of available professionals had contributed to the delay. Almost all families – 98% – reported having some type of health insurance at the time of their first concerns (49% private, 46% public, and 5% others).
The data also show that excess intellectual disability comorbidity seen in African American children cannot be explained by familial or sociodemographic factors that have traditionally been associated with variation in IQ in the general population. Nor can it be explained by overclassification of intellectual disability, the authors said.
they wrote.
The NIH-funded program involved parental completion of “Diagnostic Odyssey” interviews (characterizing service-seeking experiences and obstacles to diagnosis, treatment, and care) and several in-person cognitive assessments and measurements of adaptive functioning. “These were in-depth [highly validated] intellectual assessments based on IQ measures that were tailored to the level of functioning of the children and backed by extensive assessments of adaptive functioning,” Dr. Constantino said in an interview.
Historically, autism has been underdiagnosed among minority children. Now that this is no longer the case, as demonstrated in the CDC’s 2018 report from its Autism and Developmental Disabilities Monitoring Network, the thought that higher rates of intellectual disability comorbidity among minority children are due to ascertainment bias – to “our only diagnosing the most serious cases” – “is no longer true,” he said.
And now, with use of data from the largest-available repository of diagnostic and phenotypic information on African American children with ASD, “we’ve dispelled other misperceptions, other factors that might be used to dismiss or explain away why Black children might have a high rate of intellectual disability,” Dr. Constantino said in the interview, referring to the absence of association between the IQ scores of children with ASD and those of their first-degree relatives as well as the lack of significant associations between the IQ of children with ASD and factors such as family income (above versus below the median income of the cohort), the mother having or not having a college degree, and the estimated gestational age at birth (before versus after 37 weeks).
“This kind of complication of autism lasts for the life of a child and profoundly impairs their functioning,” he said. “If anyone thinks there isn’t an opportunity to improve the timing of diagnosis and to improve access to services and appropriate developmental therapies, that’s wrong. There is opportunity – parents are raising the alarm, and we are not coming to these children’s rescue.”
In an accompanying editorial, Sarabeth Broder-Fingert, MD, MPH, of Boston University and Boston Medical Center, and associates wrote that the “confluence of findings [in this study] are suggestive of structural racism leading to inequity.”
For example, they said, “although the causes of delays from first parental concern to ASD diagnosis are complex, they can result from a number of issues, including racial bias and discrimination experienced by families, a lack of diversity in health professionals (impacting patient-provider relationships), and/or concentration of specialists in geographic areas with fewer minority residents.” Each of these issues, they wrote, can be linked to racism, both structural and individual.
Combined with previous research on inequity in ASD, the new data “necessitate an immediate evaluation of how issues of structural racism have impacted ASD diagnosis and, more importantly, an action plan to address inequity,” they said.
Issues of workforce capacity for ASD diagnosis need to be addressed by evaluating Medicaid reimbursement rates for ASD diagnosis, for instance, and removing restrictions on who is qualified to make a diagnosis, increasing adherence to evidence-based practices, “increasing workforce cultural humility, and recruiting a workforce that reflects the diverse communities they serve,” Dr. Broder-Fingert and associates said.
Jeremiah Dickerson, MD, a child and adolescent psychiatrist at the University of Vermont, Burlington, said he is hopeful that the inequities and structural obstacles that he sees in his patients are “being informed more and more by science” and that “we’re taking steps in exploring our own cultural humility and focusing on problems ... that have been under the surface for decades.”
Years of diagnostic delay and missed intervention for ASD can lead to increasing lifelong functional difficulties, which in turn can be compounded by enduring inequities and stigma, he said when asked to comment on the study.
“Diagnosing and teasing apart ID [intellectual disability] versus ASD, and ID co-occurring with ASD, can be very complicated, particularly in young children with significant language impairments,” he added. “If indeed there is a higher proportion of African American children with co-occurring ASD and ID ... we have to do a much better job with identifying those children earlier and providing longitudinal follow-up/assessment that can help provide diagnostic clarity and inform recommendations.”
Understanding better why this occurs “without repeating the history of assigning cause based upon racist thinking” is also important, said Dr. Dickerson, who directs the autism assessment clinic at the university’s Vermont Center for Children, Youth & Families.
Dr. Constantino, who has been involved in the CDC’s 11-site ASD surveillance network, said it is unclear to what extent broad implementation of early and high-quality interventions can reduce the proportion of African American children with autism and comorbid intellectual disability. “We may be only half-successful in closing the gap, or there may be other factors involved that we don’t understand yet,” he said. “But we haven’t even attempted to close the gap [through] reasonable application of an intervention strategy that is available and that we know can improve cognitive outcomes.”
“Some primary care doctors are reluctant to make the diagnosis in the first place because they have nothing to offer the families,” Dr. Constantino noted.
Continued research on the interactions between genetic background and specific biological susceptibilities to autism is an ongoing objective of the Autism Genetic Resource Exchange.
The CDC recently published its latest report on the prevalence of ASD in children aged 8 years, concluding again that continued efforts are needed for “early and equitable identification of ASD and timely enrollment in services.
The study was supported by grants from the National Institutes of Health and from the Intellectual and Developmental Disabilities Research Center at Washington University. Dr. Constantino is author of the Social Responsiveness Scale-2, from which he receives royalties. A coauthor helped author the Vineland-3 and receives royalties, and this coauthor and another associate also have ties to pharmaceutical companies or other organizations; the remaining authors of the study said they had no relevant financial disclosures. Dr. Broder-Fingert and associates said they have no relevant financial relationships; the editorial was funded by the National Institutes of Health. Dr. Dickerson said he had no relevant financial disclosures.
SOURCE: Constantino JN et al. Pediatrics. 2020. doi: 10.1542/peds.2019-3629.
FROM PEDIATRICS
New uterine compression technique controls postpartum hemorrhage
A newly described uterine compression technique that uses simple supplies and does not require hysterotomy was successful in controlling postpartum hemorrhage in 16 of 18 (89%) women in two teaching hospitals in Nigeria, averting the need for hysterectomy in these women.
Each of the women had severe postpartum hemorrhage attributable to uterine atony and had undergone local protocols for medical management “to no avail,” Chidi Ochu Uzoma Esike, MD, who developed the technique, wrote in a report published in Obstetrics and Gynecology.
The technique involves placing six polyglactin (Vicryl) #2 or chromic #2 sutures in the lower uterine segment – three anteriorly and three posteriorly – and could be particularly useful in developing countries, where many women die from postpartum hemorrhage “because most of the medical officers who attend the majority of births in health facilities can perform cesarean delivery but cannot perform hysterectomy and find existing compression suture techniques too complex to perform,” Dr. Esike wrote in the case series report.
In addition, “specialized sutures and needles required for some of the known compression techniques are not readily available,” said Dr. Esike of the department of obstetrics and gynecology at Alex Ekwueme Federal University Hospital and Ebyonyi State University in Abakaliki, Nigeria.
Angela Martin, MD, a maternal-fetal medicine specialist at the University of Kansas Medical Center in Kansas City, said that “having a quick and effective surgical technique [for uncontrollable postpartum hemorrhage] is essential.”
“I love that Esike’s technique uses polyglactin (Vicryl) or chromic sutures. These are familiar to most surgeons, cheap, and typically available even in most resource-deficient settings,” said Dr. Martin, who was asked to comment on the report, adding that several of the known surgical techniques for uterine atony require a skilled operator and are indeed not universally feasible.
“If successful,” Dr. Martin said in an interview, “compression sutures can be lifesaving and fertility preserving.”
The technique involves tying the two middle sutures (one placed anteriorly and one posteriorly) at the fundus as an assistant slowly and continuously compresses the uterus. The more laterally placed sutures are tied similarly, with each pair tied at about 4 cm from the lateral edge of the uterus. “As the uterus is compressed, the slack should be taken up by the sutures before tying,” said Dr. Esike, whose report features both diagrammatic and photographic representations of suture insertion and tying.
For patients who delivered vaginally – nine in this case series – the technique involves performing a laparotomy and exteriorizing the uterus. The technique’s “suture placement,” Dr. Esike wrote, “took 11-25 minutes from the onset of laparotomy to completion.” There were no short or long-term complications in any of the 18 patients.
B-Lynch compression sutures are more complex to perform and require a larger curved needle, Dr. Esike wrote, and the Hayman technique similarly requires a longer needle that may not be available in resource-constrained countries. The hysterotomy required in the B-Lynch technique, Dr. Esike added, “leads to the uterus not contracting maximally until it is repaired,” which increases blood loss from the procedure.
Dr. Martin said the small size of the case series is not discouraging. “The B-Lynch suture was widely adopted after it was described in five cases in 1997,” she said. There are no randomized controlled trials to suggest that one method of uterine compression sutures is better than another. “Ultimately,” she said, “the technique chosen will depend on the surgeon’s training and available supplies.”
Dr. Esike had no relevant financial disclosures. Dr. Martin had no relevant financial disclosures.
SOURCE: Esike COU. Obstet Gynecol. 2020. doi: 10.1097/AOG.0000000000003947.
A newly described uterine compression technique that uses simple supplies and does not require hysterotomy was successful in controlling postpartum hemorrhage in 16 of 18 (89%) women in two teaching hospitals in Nigeria, averting the need for hysterectomy in these women.
Each of the women had severe postpartum hemorrhage attributable to uterine atony and had undergone local protocols for medical management “to no avail,” Chidi Ochu Uzoma Esike, MD, who developed the technique, wrote in a report published in Obstetrics and Gynecology.
The technique involves placing six polyglactin (Vicryl) #2 or chromic #2 sutures in the lower uterine segment – three anteriorly and three posteriorly – and could be particularly useful in developing countries, where many women die from postpartum hemorrhage “because most of the medical officers who attend the majority of births in health facilities can perform cesarean delivery but cannot perform hysterectomy and find existing compression suture techniques too complex to perform,” Dr. Esike wrote in the case series report.
In addition, “specialized sutures and needles required for some of the known compression techniques are not readily available,” said Dr. Esike of the department of obstetrics and gynecology at Alex Ekwueme Federal University Hospital and Ebyonyi State University in Abakaliki, Nigeria.
Angela Martin, MD, a maternal-fetal medicine specialist at the University of Kansas Medical Center in Kansas City, said that “having a quick and effective surgical technique [for uncontrollable postpartum hemorrhage] is essential.”
“I love that Esike’s technique uses polyglactin (Vicryl) or chromic sutures. These are familiar to most surgeons, cheap, and typically available even in most resource-deficient settings,” said Dr. Martin, who was asked to comment on the report, adding that several of the known surgical techniques for uterine atony require a skilled operator and are indeed not universally feasible.
“If successful,” Dr. Martin said in an interview, “compression sutures can be lifesaving and fertility preserving.”
The technique involves tying the two middle sutures (one placed anteriorly and one posteriorly) at the fundus as an assistant slowly and continuously compresses the uterus. The more laterally placed sutures are tied similarly, with each pair tied at about 4 cm from the lateral edge of the uterus. “As the uterus is compressed, the slack should be taken up by the sutures before tying,” said Dr. Esike, whose report features both diagrammatic and photographic representations of suture insertion and tying.
For patients who delivered vaginally – nine in this case series – the technique involves performing a laparotomy and exteriorizing the uterus. The technique’s “suture placement,” Dr. Esike wrote, “took 11-25 minutes from the onset of laparotomy to completion.” There were no short or long-term complications in any of the 18 patients.
B-Lynch compression sutures are more complex to perform and require a larger curved needle, Dr. Esike wrote, and the Hayman technique similarly requires a longer needle that may not be available in resource-constrained countries. The hysterotomy required in the B-Lynch technique, Dr. Esike added, “leads to the uterus not contracting maximally until it is repaired,” which increases blood loss from the procedure.
Dr. Martin said the small size of the case series is not discouraging. “The B-Lynch suture was widely adopted after it was described in five cases in 1997,” she said. There are no randomized controlled trials to suggest that one method of uterine compression sutures is better than another. “Ultimately,” she said, “the technique chosen will depend on the surgeon’s training and available supplies.”
Dr. Esike had no relevant financial disclosures. Dr. Martin had no relevant financial disclosures.
SOURCE: Esike COU. Obstet Gynecol. 2020. doi: 10.1097/AOG.0000000000003947.
A newly described uterine compression technique that uses simple supplies and does not require hysterotomy was successful in controlling postpartum hemorrhage in 16 of 18 (89%) women in two teaching hospitals in Nigeria, averting the need for hysterectomy in these women.
Each of the women had severe postpartum hemorrhage attributable to uterine atony and had undergone local protocols for medical management “to no avail,” Chidi Ochu Uzoma Esike, MD, who developed the technique, wrote in a report published in Obstetrics and Gynecology.
The technique involves placing six polyglactin (Vicryl) #2 or chromic #2 sutures in the lower uterine segment – three anteriorly and three posteriorly – and could be particularly useful in developing countries, where many women die from postpartum hemorrhage “because most of the medical officers who attend the majority of births in health facilities can perform cesarean delivery but cannot perform hysterectomy and find existing compression suture techniques too complex to perform,” Dr. Esike wrote in the case series report.
In addition, “specialized sutures and needles required for some of the known compression techniques are not readily available,” said Dr. Esike of the department of obstetrics and gynecology at Alex Ekwueme Federal University Hospital and Ebyonyi State University in Abakaliki, Nigeria.
Angela Martin, MD, a maternal-fetal medicine specialist at the University of Kansas Medical Center in Kansas City, said that “having a quick and effective surgical technique [for uncontrollable postpartum hemorrhage] is essential.”
“I love that Esike’s technique uses polyglactin (Vicryl) or chromic sutures. These are familiar to most surgeons, cheap, and typically available even in most resource-deficient settings,” said Dr. Martin, who was asked to comment on the report, adding that several of the known surgical techniques for uterine atony require a skilled operator and are indeed not universally feasible.
“If successful,” Dr. Martin said in an interview, “compression sutures can be lifesaving and fertility preserving.”
The technique involves tying the two middle sutures (one placed anteriorly and one posteriorly) at the fundus as an assistant slowly and continuously compresses the uterus. The more laterally placed sutures are tied similarly, with each pair tied at about 4 cm from the lateral edge of the uterus. “As the uterus is compressed, the slack should be taken up by the sutures before tying,” said Dr. Esike, whose report features both diagrammatic and photographic representations of suture insertion and tying.
For patients who delivered vaginally – nine in this case series – the technique involves performing a laparotomy and exteriorizing the uterus. The technique’s “suture placement,” Dr. Esike wrote, “took 11-25 minutes from the onset of laparotomy to completion.” There were no short or long-term complications in any of the 18 patients.
B-Lynch compression sutures are more complex to perform and require a larger curved needle, Dr. Esike wrote, and the Hayman technique similarly requires a longer needle that may not be available in resource-constrained countries. The hysterotomy required in the B-Lynch technique, Dr. Esike added, “leads to the uterus not contracting maximally until it is repaired,” which increases blood loss from the procedure.
Dr. Martin said the small size of the case series is not discouraging. “The B-Lynch suture was widely adopted after it was described in five cases in 1997,” she said. There are no randomized controlled trials to suggest that one method of uterine compression sutures is better than another. “Ultimately,” she said, “the technique chosen will depend on the surgeon’s training and available supplies.”
Dr. Esike had no relevant financial disclosures. Dr. Martin had no relevant financial disclosures.
SOURCE: Esike COU. Obstet Gynecol. 2020. doi: 10.1097/AOG.0000000000003947.
FROM OBSTETRICS & GYNECOLOGY
