Two sets of evidence reports address the primary care physicians’ role in children and adolescents’ oral health and the effectiveness of the fluoride gels and sealants offered at dental offices and schools.

Both were published online in JAMA.

In one report, the United States Preventive Services Task Force (USPSTF) concludes that there is not enough evidence to assess harms versus benefits of routine screening or interventions for oral health conditions, including dental caries, in primary care for asymptomatic children and adolescents aged 5-17 years.

The evidence report on administering fluoride supplements, fluoride gels, sealants and varnish finds evidence that they improve outcomes. The report was done to inform the USPSTF for a new recommendation on primary care screening, dental referral, behavioral counseling, and preventive interventions for oral health in children and adolescents aged 5-17.
 

Primary care physicians’ role

One problem the USPSTF identified in its report was limited evidence on available clinical screening tools or assessments to identify which children have oral health conditions in the primary care setting.

The USPSTF’s team, led by Michael J. Barry, MD, of Harvard Medical School in Boston, calls for more research to fill in the gaps before it can reassess.

Michael S. Reddy, DMD, DMSc, with University of California San Francisco School of Dentistry, Oral Health Affairs, said in an accompanying editorial that the current lack of data should not keep primary care physicians from considering oral health during routine medical exams or keep dentists from finding ways to collaborate with primary care physicians. “Medical primary care must partner with dentistry,” they wrote.

Until there is enough evidence for a USPSTF reevaluation on the topic, primary care clinicians should ask patients about their oral hygiene routines, whether they have any dental symptoms, and when they last saw a dentist, as well as referring to a dentist as necessary, the editorialists wrote.

That works both ways, the editorialists added. “Equally important, oral health professionals are encouraged to collaborate and be a resource for their primary care colleagues. Prevention is one of the best tools clinicians have, and it is promoted by integrated, whole-person health effort, “ wrote Dr. Reddy and colleagues.

When oral health stays separate from medical care, patients are left vulnerable, and referrals between medical and dental offices should be a stronger two-way system, the editorialists said.

“[N]ot every primary care patient has access to a dentist,” they wrote. “Oral health screening and referral by medical primary care clinicians can help ensure that individuals get to the dental chair to receive needed interventions that can benefit both oral and potentially overall health. Likewise, medical challenges and oral mucosal manifestations of chronic health conditions detected at a dental visit should result in medical referral, allowing prompt evaluation and treatment.”
 

Evidence that gels, varnish, sealants are effective

In a companion paper, done to inform the USPSTF, Roger Chou, MD, with Pacific Northwest Evidence-based Practice Center, Department of Medical Informatics and Clinical Epidemiology at Oregon Health & Science University in Portland, and colleagues found that when administered by a dental professional or in school settings, fluoride supplements, gels and varnish, and resin-based sealants improved health outcomes.

The findings were based on three systematic reviews (20,684 participants) and 19 randomized clinical trials; three nonrandomized trials; and one observational study (total 15,026 participants.)

With fluoride versus placebo or no intervention, researchers found a decrease from baseline in the number of decayed, missing, or filled permanent teeth (DMFT index) or decayed or filled permanent teeth (DFT index). The average difference was −0.73 [95% confidence interval [CI], −1.30 to −0.19]) at 1.5 to 3 years (six trials; n = 1,395).

Fluoride gels were associated with a DMFT- or DFT-prevented fraction of 0.18 (95% CI, 0.09-0.27) at outcomes closest to 3 years (four trials; n = 1,525).

Researchers found an association between fluoride varnish and a DMFT- or DFT-prevented fraction of 0.44 (95% CI, 0.11-0.76) at 1 to 4.5 years (five trials; n = 3,902). The sealants tested were associated with decreased risk of caries in first molars (odds ratio, 0.21 [95% CI, 0.16-0.28]) at 48-54 months (four trials; n = 440).

They noted that the feasibility of administering preventive measures in primary care is unknown; the effectiveness shown here was based on administration in dental and supervised school settings.

Barriers in primary care settings may include lack of training and equipment (particularly for sealants), uncertain reimbursement and lack of acceptance and uptake.
 

USPSTF working to close evidence gaps

Wanda Nicholson, MD, MPH, Prevention and Community Health, George Washington Milken Institute of Public Health in Washington, wrote in an accompanying editorial that to speed necessary research to facilitate recommendations, “the USPSTF and its stakeholders need a transparent, easily implementable communication tool that will systematically describe the research necessary to be directly responsive to the evidence gaps.”

The editorialists noted that the USPSTF in trying to update recommendations often has few, if any, high-quality additional studies to consider since its previous recommendation.

To address that, meetings were conducted in November of 2022 involving USPSTF members, Agency for Healthcare Research and Quality (AHRQ) staff, and leadership from the Office of Disease Prevention and the National Institutes of Health. Members formed a working group “to develop a standardized template for communicating research gaps” according to a framework developed by the National Academies of Sciences, Engineering, and Medicine.

Dr. Nicholson and colleagues wrote, “classifying evidence gaps and calling for specific research needs is a prudent, collaborative step in addressing missing evidence,” particularly for underserved populations.

The authors and editorialists declared no relevant conflicts of interest.

Two sets of evidence reports address the primary care physicians’ role in children and adolescents’ oral health and the effectiveness of the fluoride gels and sealants offered at dental offices and schools.

Both were published online in JAMA.

In one report, the United States Preventive Services Task Force (USPSTF) concludes that there is not enough evidence to assess harms versus benefits of routine screening or interventions for oral health conditions, including dental caries, in primary care for asymptomatic children and adolescents aged 5-17 years.

The evidence report on administering fluoride supplements, fluoride gels, sealants and varnish finds evidence that they improve outcomes. The report was done to inform the USPSTF for a new recommendation on primary care screening, dental referral, behavioral counseling, and preventive interventions for oral health in children and adolescents aged 5-17.
 

Primary care physicians’ role

One problem the USPSTF identified in its report was limited evidence on available clinical screening tools or assessments to identify which children have oral health conditions in the primary care setting.

The USPSTF’s team, led by Michael J. Barry, MD, of Harvard Medical School in Boston, calls for more research to fill in the gaps before it can reassess.

Michael S. Reddy, DMD, DMSc, with University of California San Francisco School of Dentistry, Oral Health Affairs, said in an accompanying editorial that the current lack of data should not keep primary care physicians from considering oral health during routine medical exams or keep dentists from finding ways to collaborate with primary care physicians. “Medical primary care must partner with dentistry,” they wrote.

Until there is enough evidence for a USPSTF reevaluation on the topic, primary care clinicians should ask patients about their oral hygiene routines, whether they have any dental symptoms, and when they last saw a dentist, as well as referring to a dentist as necessary, the editorialists wrote.

That works both ways, the editorialists added. “Equally important, oral health professionals are encouraged to collaborate and be a resource for their primary care colleagues. Prevention is one of the best tools clinicians have, and it is promoted by integrated, whole-person health effort, “ wrote Dr. Reddy and colleagues.

When oral health stays separate from medical care, patients are left vulnerable, and referrals between medical and dental offices should be a stronger two-way system, the editorialists said.

“[N]ot every primary care patient has access to a dentist,” they wrote. “Oral health screening and referral by medical primary care clinicians can help ensure that individuals get to the dental chair to receive needed interventions that can benefit both oral and potentially overall health. Likewise, medical challenges and oral mucosal manifestations of chronic health conditions detected at a dental visit should result in medical referral, allowing prompt evaluation and treatment.”
 

Evidence that gels, varnish, sealants are effective

In a companion paper, done to inform the USPSTF, Roger Chou, MD, with Pacific Northwest Evidence-based Practice Center, Department of Medical Informatics and Clinical Epidemiology at Oregon Health & Science University in Portland, and colleagues found that when administered by a dental professional or in school settings, fluoride supplements, gels and varnish, and resin-based sealants improved health outcomes.

The findings were based on three systematic reviews (20,684 participants) and 19 randomized clinical trials; three nonrandomized trials; and one observational study (total 15,026 participants.)

With fluoride versus placebo or no intervention, researchers found a decrease from baseline in the number of decayed, missing, or filled permanent teeth (DMFT index) or decayed or filled permanent teeth (DFT index). The average difference was −0.73 [95% confidence interval [CI], −1.30 to −0.19]) at 1.5 to 3 years (six trials; n = 1,395).

Fluoride gels were associated with a DMFT- or DFT-prevented fraction of 0.18 (95% CI, 0.09-0.27) at outcomes closest to 3 years (four trials; n = 1,525).

Researchers found an association between fluoride varnish and a DMFT- or DFT-prevented fraction of 0.44 (95% CI, 0.11-0.76) at 1 to 4.5 years (five trials; n = 3,902). The sealants tested were associated with decreased risk of caries in first molars (odds ratio, 0.21 [95% CI, 0.16-0.28]) at 48-54 months (four trials; n = 440).

They noted that the feasibility of administering preventive measures in primary care is unknown; the effectiveness shown here was based on administration in dental and supervised school settings.

Barriers in primary care settings may include lack of training and equipment (particularly for sealants), uncertain reimbursement and lack of acceptance and uptake.
 

USPSTF working to close evidence gaps

Wanda Nicholson, MD, MPH, Prevention and Community Health, George Washington Milken Institute of Public Health in Washington, wrote in an accompanying editorial that to speed necessary research to facilitate recommendations, “the USPSTF and its stakeholders need a transparent, easily implementable communication tool that will systematically describe the research necessary to be directly responsive to the evidence gaps.”

The editorialists noted that the USPSTF in trying to update recommendations often has few, if any, high-quality additional studies to consider since its previous recommendation.

To address that, meetings were conducted in November of 2022 involving USPSTF members, Agency for Healthcare Research and Quality (AHRQ) staff, and leadership from the Office of Disease Prevention and the National Institutes of Health. Members formed a working group “to develop a standardized template for communicating research gaps” according to a framework developed by the National Academies of Sciences, Engineering, and Medicine.

Dr. Nicholson and colleagues wrote, “classifying evidence gaps and calling for specific research needs is a prudent, collaborative step in addressing missing evidence,” particularly for underserved populations.

The authors and editorialists declared no relevant conflicts of interest.

Two sets of evidence reports address the primary care physicians’ role in children and adolescents’ oral health and the effectiveness of the fluoride gels and sealants offered at dental offices and schools.

Both were published online in JAMA.

In one report, the United States Preventive Services Task Force (USPSTF) concludes that there is not enough evidence to assess harms versus benefits of routine screening or interventions for oral health conditions, including dental caries, in primary care for asymptomatic children and adolescents aged 5-17 years.

The evidence report on administering fluoride supplements, fluoride gels, sealants and varnish finds evidence that they improve outcomes. The report was done to inform the USPSTF for a new recommendation on primary care screening, dental referral, behavioral counseling, and preventive interventions for oral health in children and adolescents aged 5-17.
 

Primary care physicians’ role

One problem the USPSTF identified in its report was limited evidence on available clinical screening tools or assessments to identify which children have oral health conditions in the primary care setting.

The USPSTF’s team, led by Michael J. Barry, MD, of Harvard Medical School in Boston, calls for more research to fill in the gaps before it can reassess.

Michael S. Reddy, DMD, DMSc, with University of California San Francisco School of Dentistry, Oral Health Affairs, said in an accompanying editorial that the current lack of data should not keep primary care physicians from considering oral health during routine medical exams or keep dentists from finding ways to collaborate with primary care physicians. “Medical primary care must partner with dentistry,” they wrote.

Until there is enough evidence for a USPSTF reevaluation on the topic, primary care clinicians should ask patients about their oral hygiene routines, whether they have any dental symptoms, and when they last saw a dentist, as well as referring to a dentist as necessary, the editorialists wrote.

That works both ways, the editorialists added. “Equally important, oral health professionals are encouraged to collaborate and be a resource for their primary care colleagues. Prevention is one of the best tools clinicians have, and it is promoted by integrated, whole-person health effort, “ wrote Dr. Reddy and colleagues.

When oral health stays separate from medical care, patients are left vulnerable, and referrals between medical and dental offices should be a stronger two-way system, the editorialists said.

“[N]ot every primary care patient has access to a dentist,” they wrote. “Oral health screening and referral by medical primary care clinicians can help ensure that individuals get to the dental chair to receive needed interventions that can benefit both oral and potentially overall health. Likewise, medical challenges and oral mucosal manifestations of chronic health conditions detected at a dental visit should result in medical referral, allowing prompt evaluation and treatment.”
 

Evidence that gels, varnish, sealants are effective

In a companion paper, done to inform the USPSTF, Roger Chou, MD, with Pacific Northwest Evidence-based Practice Center, Department of Medical Informatics and Clinical Epidemiology at Oregon Health & Science University in Portland, and colleagues found that when administered by a dental professional or in school settings, fluoride supplements, gels and varnish, and resin-based sealants improved health outcomes.

The findings were based on three systematic reviews (20,684 participants) and 19 randomized clinical trials; three nonrandomized trials; and one observational study (total 15,026 participants.)

With fluoride versus placebo or no intervention, researchers found a decrease from baseline in the number of decayed, missing, or filled permanent teeth (DMFT index) or decayed or filled permanent teeth (DFT index). The average difference was −0.73 [95% confidence interval [CI], −1.30 to −0.19]) at 1.5 to 3 years (six trials; n = 1,395).

Fluoride gels were associated with a DMFT- or DFT-prevented fraction of 0.18 (95% CI, 0.09-0.27) at outcomes closest to 3 years (four trials; n = 1,525).

Researchers found an association between fluoride varnish and a DMFT- or DFT-prevented fraction of 0.44 (95% CI, 0.11-0.76) at 1 to 4.5 years (five trials; n = 3,902). The sealants tested were associated with decreased risk of caries in first molars (odds ratio, 0.21 [95% CI, 0.16-0.28]) at 48-54 months (four trials; n = 440).

They noted that the feasibility of administering preventive measures in primary care is unknown; the effectiveness shown here was based on administration in dental and supervised school settings.

Barriers in primary care settings may include lack of training and equipment (particularly for sealants), uncertain reimbursement and lack of acceptance and uptake.
 

USPSTF working to close evidence gaps

Wanda Nicholson, MD, MPH, Prevention and Community Health, George Washington Milken Institute of Public Health in Washington, wrote in an accompanying editorial that to speed necessary research to facilitate recommendations, “the USPSTF and its stakeholders need a transparent, easily implementable communication tool that will systematically describe the research necessary to be directly responsive to the evidence gaps.”

The editorialists noted that the USPSTF in trying to update recommendations often has few, if any, high-quality additional studies to consider since its previous recommendation.

To address that, meetings were conducted in November of 2022 involving USPSTF members, Agency for Healthcare Research and Quality (AHRQ) staff, and leadership from the Office of Disease Prevention and the National Institutes of Health. Members formed a working group “to develop a standardized template for communicating research gaps” according to a framework developed by the National Academies of Sciences, Engineering, and Medicine.

Dr. Nicholson and colleagues wrote, “classifying evidence gaps and calling for specific research needs is a prudent, collaborative step in addressing missing evidence,” particularly for underserved populations.

The authors and editorialists declared no relevant conflicts of interest.

Suicide is among the top three causes of death for young people in the United States. According to the Centers for Disease Control and Prevention, the rate of suicide deaths has climbed from 4.4 per 100,000 American 12- to 17-year-olds in 2011 to 6.5 per 100,000 in 2021, an increase of almost 50%. As with accidents and homicides, we hope these are preventable deaths, although the factors contributing to them are complex.

We do know that more than half of the people who die by suicide visit a health care provider within 4 weeks of their death, highlighting an opportunity for screening and intervention.
 

Suicide screening

In 2022, the American Academy of Pediatrics (AAP) recommended that all adolescents get screened for suicide risk annually. Given that less than 1 in 10,000 adolescents commit suicide and that there is no definitive data on how to prevent suicide in any individual, the goal of suicide screening is much broader than preventing suicide. Beyond universal screening, we will review how being open and curious with all of your patients can be the most extraordinary screening instrument.

There is extensive data that tells us that far from causing suicide, asking about suicidal thoughts is protective. When you make suicidal thoughts discussable, you directly counteract the isolation, stigma, and shame that are strong predictors of actual suicide attempts. You model the value of bringing difficult or frightening thoughts to the attention of caring adults, and you model calm listening rather than emotional overreaction for their parents. The resulting connectedness can lower the risk for vulnerable patients and enhance resilience for all of your patients.
 

Who is at greater risk?

We have robust data to guide our understanding of which youth have suicidal ideation, which is distinct from those who attempt suicide, which also may be quite distinct from those who complete. The CDC reports that the rate of suicidal thoughts (“seriously considering suicide”) in high school students climbed from 16% in 2011 to 22% in 2021. In that decade, the number of high schoolers with a suicide plan climbed from 13% to 18%, and those with suicide attempts climbed from 8% to 10%. Girls are at higher risk for suicidal thoughts and attempts, but boys are at greater risk for suicide completion. Black youth were more likely to attempt suicide than were their Asian, Hispanic, or White peers and LGBTQ+ youth are at particular risk; in 2021, they were three times as likely as were their heterosexual peers to have suicidal thoughts and attempts. Youth with psychiatric illness (particularly PTSD, mood or thought disorders), a family history of suicide, a history of risk-taking behavior (including sexual activity, smoking, drinking, and drug use) and those with prior suicide attempts are at the highest risk for suicide. Adding all these risk factors together means that many, if not the majority, of teenagers have risk factors.

Focus on the patient

In your office, though, a public health approach should give way to curiosity about your individual patient. Suicidal thoughts usually follow a substantial stress. Pay attention to exceptional stresses, especially if they have a component of social stigma or isolation. Did your patient report another student for an assault? Are they now being bullied or ostracized by friends? Have they lost an especially important relationship? Some other stresses may seem minor, such as a poor grade on a test. But for a very driven, perfectionistic teenager who believes that a perfect 4.0 GPA is essential to college admission and future success and happiness, one poor grade may feel like a catastrophe.

When your patients tell you about a challenge or setback, slow down and be curious. Listen to the importance they give it. How have they managed it? Are they finding it hard to go to school or back to practice? Do they feel discouraged or even hopeless? Discouragement is a normal response to adversity, but it should be temporary. This approach can make it easy to ask if they have ever wished they were dead, or made a suicide plan or an attempt. When you calmly and supportively learn about their inner experience, it will be easy for young people to be honest with you.

There will be teenagers in your practice who are sensation-seeking and impulsive, and you should pay special attention to this group. They may not be classically depressed, but in the aftermath of a stressful experience that they find humiliating or shameful, they are at risk for an impulsive act that could still be lethal. Be curious with these patients after they feel they have let down their team or their family, or if they have been caught in a crime or cheating, or even if their girlfriend breaks up with them. Find out how they are managing, and where their support comes from. Ask them in a nonjudgmental manner about whether they are having thoughts about death or suicide, and if those thoughts are troubling, frequent, or feel like a relief. What has stopped them from acting on these thoughts? Offer your patient the perspective that such thoughts may be normal in the face of a large stress, but that the pain of stress always subsides, whereas suicide is irreversible.

There will also be patients in your practice who cut themselves. This is sometimes called “nonsuicidal self-injury,” and it often raises concern about suicide risk. While accelerating frequency of self-injury in a teenager who is suicidal can indicate growing risk, this behavior alone is usually a mechanism for regulating emotion. Ask your patient about when they cut themselves. What are the triggers? How do they feel afterward? Are their friends all doing it? Is it only after fighting with their parents? Or does it make their parents worry instead of getting angry? As you learn about the nature of the behavior, you will be able to offer thoughtful guidance about better strategies for stress management or to pursue further assessment and support.
 

Next steps

Speaking comfortably with your patients about suicidal thoughts and behaviors requires that you also feel comfortable with what comes next. As in the ASQ screening instrument recommended by the AAP, you should always follow affirmative answers about suicidal thoughts with more questions. Do they have a plan? Do they have access to lethal means including any guns in the home? Have they ever made an attempt? Are they thinking about killing themselves now? If the thoughts are current, they have access, and they have tried before, it is clear that they need an urgent assessment, probably in an emergency department. But when the thoughts were in the past or have never been connected to plans or intent, there is an opportunity to enhance their connectedness. You can diminish the potential for shame, stigma and isolation by reminding them that such thoughts and feelings are normal in the face of difficulty. They deserve support to help them face and manage their adversity, whether that stress comes from an internal or external source. How do they feel now that they have shared these thoughts with you? Most will describe feeling better, relieved, even hopeful once they are not facing intense thoughts and feelings alone.

You should tell them that you would like to bring their parents into the conversation. You want them to know they can turn to their parents if they are having these thoughts, so they are never alone in facing them. Parents can learn from your model of calm and supportive listening to fully understand the situation before turning together to talk about what might be helpful next steps. It is always prudent to create “speed bumps” between thought and action with impulsive teens, so recommend limiting access to any lethal means (firearms especially). But the strongest protective intervention is for the child to feel confident in and connected to their support network, trusting you and their parents to listen and understand before figuring out together what else is needed to address the situation.

Lastly, recognize that talking about difficult issues with teenagers is among the most stressful and demanding aspects of pediatric primary care. Talk to colleagues, never worry alone, and recognize and manage your own stress. This is among the best ways to model for your patients and their parents that every challenge can be met, but we often need support.
 

Dr. Swick is physician in chief at Ohana, Center for Child and Adolescent Behavioral Health, Community Hospital of the Monterey (Calif.) Peninsula. Dr. Jellinek is professor emeritus of psychiatry and pediatrics, Harvard Medical School, Boston. Email them at [email protected].

Suicide is among the top three causes of death for young people in the United States. According to the Centers for Disease Control and Prevention, the rate of suicide deaths has climbed from 4.4 per 100,000 American 12- to 17-year-olds in 2011 to 6.5 per 100,000 in 2021, an increase of almost 50%. As with accidents and homicides, we hope these are preventable deaths, although the factors contributing to them are complex.

We do know that more than half of the people who die by suicide visit a health care provider within 4 weeks of their death, highlighting an opportunity for screening and intervention.
 

Suicide screening

In 2022, the American Academy of Pediatrics (AAP) recommended that all adolescents get screened for suicide risk annually. Given that less than 1 in 10,000 adolescents commit suicide and that there is no definitive data on how to prevent suicide in any individual, the goal of suicide screening is much broader than preventing suicide. Beyond universal screening, we will review how being open and curious with all of your patients can be the most extraordinary screening instrument.

There is extensive data that tells us that far from causing suicide, asking about suicidal thoughts is protective. When you make suicidal thoughts discussable, you directly counteract the isolation, stigma, and shame that are strong predictors of actual suicide attempts. You model the value of bringing difficult or frightening thoughts to the attention of caring adults, and you model calm listening rather than emotional overreaction for their parents. The resulting connectedness can lower the risk for vulnerable patients and enhance resilience for all of your patients.
 

Who is at greater risk?

We have robust data to guide our understanding of which youth have suicidal ideation, which is distinct from those who attempt suicide, which also may be quite distinct from those who complete. The CDC reports that the rate of suicidal thoughts (“seriously considering suicide”) in high school students climbed from 16% in 2011 to 22% in 2021. In that decade, the number of high schoolers with a suicide plan climbed from 13% to 18%, and those with suicide attempts climbed from 8% to 10%. Girls are at higher risk for suicidal thoughts and attempts, but boys are at greater risk for suicide completion. Black youth were more likely to attempt suicide than were their Asian, Hispanic, or White peers and LGBTQ+ youth are at particular risk; in 2021, they were three times as likely as were their heterosexual peers to have suicidal thoughts and attempts. Youth with psychiatric illness (particularly PTSD, mood or thought disorders), a family history of suicide, a history of risk-taking behavior (including sexual activity, smoking, drinking, and drug use) and those with prior suicide attempts are at the highest risk for suicide. Adding all these risk factors together means that many, if not the majority, of teenagers have risk factors.

Focus on the patient

In your office, though, a public health approach should give way to curiosity about your individual patient. Suicidal thoughts usually follow a substantial stress. Pay attention to exceptional stresses, especially if they have a component of social stigma or isolation. Did your patient report another student for an assault? Are they now being bullied or ostracized by friends? Have they lost an especially important relationship? Some other stresses may seem minor, such as a poor grade on a test. But for a very driven, perfectionistic teenager who believes that a perfect 4.0 GPA is essential to college admission and future success and happiness, one poor grade may feel like a catastrophe.

When your patients tell you about a challenge or setback, slow down and be curious. Listen to the importance they give it. How have they managed it? Are they finding it hard to go to school or back to practice? Do they feel discouraged or even hopeless? Discouragement is a normal response to adversity, but it should be temporary. This approach can make it easy to ask if they have ever wished they were dead, or made a suicide plan or an attempt. When you calmly and supportively learn about their inner experience, it will be easy for young people to be honest with you.

There will be teenagers in your practice who are sensation-seeking and impulsive, and you should pay special attention to this group. They may not be classically depressed, but in the aftermath of a stressful experience that they find humiliating or shameful, they are at risk for an impulsive act that could still be lethal. Be curious with these patients after they feel they have let down their team or their family, or if they have been caught in a crime or cheating, or even if their girlfriend breaks up with them. Find out how they are managing, and where their support comes from. Ask them in a nonjudgmental manner about whether they are having thoughts about death or suicide, and if those thoughts are troubling, frequent, or feel like a relief. What has stopped them from acting on these thoughts? Offer your patient the perspective that such thoughts may be normal in the face of a large stress, but that the pain of stress always subsides, whereas suicide is irreversible.

There will also be patients in your practice who cut themselves. This is sometimes called “nonsuicidal self-injury,” and it often raises concern about suicide risk. While accelerating frequency of self-injury in a teenager who is suicidal can indicate growing risk, this behavior alone is usually a mechanism for regulating emotion. Ask your patient about when they cut themselves. What are the triggers? How do they feel afterward? Are their friends all doing it? Is it only after fighting with their parents? Or does it make their parents worry instead of getting angry? As you learn about the nature of the behavior, you will be able to offer thoughtful guidance about better strategies for stress management or to pursue further assessment and support.
 

Next steps

Speaking comfortably with your patients about suicidal thoughts and behaviors requires that you also feel comfortable with what comes next. As in the ASQ screening instrument recommended by the AAP, you should always follow affirmative answers about suicidal thoughts with more questions. Do they have a plan? Do they have access to lethal means including any guns in the home? Have they ever made an attempt? Are they thinking about killing themselves now? If the thoughts are current, they have access, and they have tried before, it is clear that they need an urgent assessment, probably in an emergency department. But when the thoughts were in the past or have never been connected to plans or intent, there is an opportunity to enhance their connectedness. You can diminish the potential for shame, stigma and isolation by reminding them that such thoughts and feelings are normal in the face of difficulty. They deserve support to help them face and manage their adversity, whether that stress comes from an internal or external source. How do they feel now that they have shared these thoughts with you? Most will describe feeling better, relieved, even hopeful once they are not facing intense thoughts and feelings alone.

You should tell them that you would like to bring their parents into the conversation. You want them to know they can turn to their parents if they are having these thoughts, so they are never alone in facing them. Parents can learn from your model of calm and supportive listening to fully understand the situation before turning together to talk about what might be helpful next steps. It is always prudent to create “speed bumps” between thought and action with impulsive teens, so recommend limiting access to any lethal means (firearms especially). But the strongest protective intervention is for the child to feel confident in and connected to their support network, trusting you and their parents to listen and understand before figuring out together what else is needed to address the situation.

Lastly, recognize that talking about difficult issues with teenagers is among the most stressful and demanding aspects of pediatric primary care. Talk to colleagues, never worry alone, and recognize and manage your own stress. This is among the best ways to model for your patients and their parents that every challenge can be met, but we often need support.
 

Dr. Swick is physician in chief at Ohana, Center for Child and Adolescent Behavioral Health, Community Hospital of the Monterey (Calif.) Peninsula. Dr. Jellinek is professor emeritus of psychiatry and pediatrics, Harvard Medical School, Boston. Email them at [email protected].

Suicide is among the top three causes of death for young people in the United States. According to the Centers for Disease Control and Prevention, the rate of suicide deaths has climbed from 4.4 per 100,000 American 12- to 17-year-olds in 2011 to 6.5 per 100,000 in 2021, an increase of almost 50%. As with accidents and homicides, we hope these are preventable deaths, although the factors contributing to them are complex.

We do know that more than half of the people who die by suicide visit a health care provider within 4 weeks of their death, highlighting an opportunity for screening and intervention.
 

Suicide screening

In 2022, the American Academy of Pediatrics (AAP) recommended that all adolescents get screened for suicide risk annually. Given that less than 1 in 10,000 adolescents commit suicide and that there is no definitive data on how to prevent suicide in any individual, the goal of suicide screening is much broader than preventing suicide. Beyond universal screening, we will review how being open and curious with all of your patients can be the most extraordinary screening instrument.

There is extensive data that tells us that far from causing suicide, asking about suicidal thoughts is protective. When you make suicidal thoughts discussable, you directly counteract the isolation, stigma, and shame that are strong predictors of actual suicide attempts. You model the value of bringing difficult or frightening thoughts to the attention of caring adults, and you model calm listening rather than emotional overreaction for their parents. The resulting connectedness can lower the risk for vulnerable patients and enhance resilience for all of your patients.
 

Who is at greater risk?

We have robust data to guide our understanding of which youth have suicidal ideation, which is distinct from those who attempt suicide, which also may be quite distinct from those who complete. The CDC reports that the rate of suicidal thoughts (“seriously considering suicide”) in high school students climbed from 16% in 2011 to 22% in 2021. In that decade, the number of high schoolers with a suicide plan climbed from 13% to 18%, and those with suicide attempts climbed from 8% to 10%. Girls are at higher risk for suicidal thoughts and attempts, but boys are at greater risk for suicide completion. Black youth were more likely to attempt suicide than were their Asian, Hispanic, or White peers and LGBTQ+ youth are at particular risk; in 2021, they were three times as likely as were their heterosexual peers to have suicidal thoughts and attempts. Youth with psychiatric illness (particularly PTSD, mood or thought disorders), a family history of suicide, a history of risk-taking behavior (including sexual activity, smoking, drinking, and drug use) and those with prior suicide attempts are at the highest risk for suicide. Adding all these risk factors together means that many, if not the majority, of teenagers have risk factors.

Focus on the patient

In your office, though, a public health approach should give way to curiosity about your individual patient. Suicidal thoughts usually follow a substantial stress. Pay attention to exceptional stresses, especially if they have a component of social stigma or isolation. Did your patient report another student for an assault? Are they now being bullied or ostracized by friends? Have they lost an especially important relationship? Some other stresses may seem minor, such as a poor grade on a test. But for a very driven, perfectionistic teenager who believes that a perfect 4.0 GPA is essential to college admission and future success and happiness, one poor grade may feel like a catastrophe.

When your patients tell you about a challenge or setback, slow down and be curious. Listen to the importance they give it. How have they managed it? Are they finding it hard to go to school or back to practice? Do they feel discouraged or even hopeless? Discouragement is a normal response to adversity, but it should be temporary. This approach can make it easy to ask if they have ever wished they were dead, or made a suicide plan or an attempt. When you calmly and supportively learn about their inner experience, it will be easy for young people to be honest with you.

There will be teenagers in your practice who are sensation-seeking and impulsive, and you should pay special attention to this group. They may not be classically depressed, but in the aftermath of a stressful experience that they find humiliating or shameful, they are at risk for an impulsive act that could still be lethal. Be curious with these patients after they feel they have let down their team or their family, or if they have been caught in a crime or cheating, or even if their girlfriend breaks up with them. Find out how they are managing, and where their support comes from. Ask them in a nonjudgmental manner about whether they are having thoughts about death or suicide, and if those thoughts are troubling, frequent, or feel like a relief. What has stopped them from acting on these thoughts? Offer your patient the perspective that such thoughts may be normal in the face of a large stress, but that the pain of stress always subsides, whereas suicide is irreversible.

There will also be patients in your practice who cut themselves. This is sometimes called “nonsuicidal self-injury,” and it often raises concern about suicide risk. While accelerating frequency of self-injury in a teenager who is suicidal can indicate growing risk, this behavior alone is usually a mechanism for regulating emotion. Ask your patient about when they cut themselves. What are the triggers? How do they feel afterward? Are their friends all doing it? Is it only after fighting with their parents? Or does it make their parents worry instead of getting angry? As you learn about the nature of the behavior, you will be able to offer thoughtful guidance about better strategies for stress management or to pursue further assessment and support.
 

Next steps

Speaking comfortably with your patients about suicidal thoughts and behaviors requires that you also feel comfortable with what comes next. As in the ASQ screening instrument recommended by the AAP, you should always follow affirmative answers about suicidal thoughts with more questions. Do they have a plan? Do they have access to lethal means including any guns in the home? Have they ever made an attempt? Are they thinking about killing themselves now? If the thoughts are current, they have access, and they have tried before, it is clear that they need an urgent assessment, probably in an emergency department. But when the thoughts were in the past or have never been connected to plans or intent, there is an opportunity to enhance their connectedness. You can diminish the potential for shame, stigma and isolation by reminding them that such thoughts and feelings are normal in the face of difficulty. They deserve support to help them face and manage their adversity, whether that stress comes from an internal or external source. How do they feel now that they have shared these thoughts with you? Most will describe feeling better, relieved, even hopeful once they are not facing intense thoughts and feelings alone.

You should tell them that you would like to bring their parents into the conversation. You want them to know they can turn to their parents if they are having these thoughts, so they are never alone in facing them. Parents can learn from your model of calm and supportive listening to fully understand the situation before turning together to talk about what might be helpful next steps. It is always prudent to create “speed bumps” between thought and action with impulsive teens, so recommend limiting access to any lethal means (firearms especially). But the strongest protective intervention is for the child to feel confident in and connected to their support network, trusting you and their parents to listen and understand before figuring out together what else is needed to address the situation.

Lastly, recognize that talking about difficult issues with teenagers is among the most stressful and demanding aspects of pediatric primary care. Talk to colleagues, never worry alone, and recognize and manage your own stress. This is among the best ways to model for your patients and their parents that every challenge can be met, but we often need support.
 

Dr. Swick is physician in chief at Ohana, Center for Child and Adolescent Behavioral Health, Community Hospital of the Monterey (Calif.) Peninsula. Dr. Jellinek is professor emeritus of psychiatry and pediatrics, Harvard Medical School, Boston. Email them at [email protected].

I’d like to talk with you about a recent report from the large-scale Black Women’s Health Study, published in the new journal NEJM Evidence.

This study looked at the association between hypertensive disorders of pregnancy, including preeclampsia and gestational hypertension, and the risk for stroke over the next 20 (median, 22) years. Previous studies have linked hypertensive disorders of pregnancy with an increased risk for stroke. However, most of these studies have been done in White women of European ancestry, and evidence in Black women has been very limited, despite a disproportionately high risk of having a hypertensive disorder of pregnancy and also of stroke.

This study, in more than 40,000 U.S. women, found an increased risk for subsequent stroke among women with a prior history of hypertensive disorder of pregnancy – overall, a 66% increased risk, an 80% increased risk with gestational hypertension, and about a 50% increased risk with preeclampsia.

We know that pregnancy itself can lead to some remodeling of the vascular system, but we don’t know whether a direct causal relationship exists between preeclampsia or gestational hypertension and subsequent stroke. Another potential explanation is that these complications of pregnancy serve as a window into a woman’s future cardiometabolic health and a marker of her cardiovascular risk.

Regardless, the clinical implications are the same. First, we would want to prevent these complications of pregnancy whenever possible. Some women will be candidates for the use of aspirin if they are at high risk for preeclampsia, and certainly for monitoring blood pressure very closely during pregnancy. It will also be important to maintain blood pressure control in the postpartum period and during the subsequent years of adulthood to minimize risk for stroke, because hypertension is such a powerful risk factor for stroke.

It will also be tremendously important to intensify lifestyle modifications such as increasing physical activity and having a heart-healthy diet. These complications of pregnancy have also been linked in other studies to an increased risk for subsequent coronary heart disease events and heart failure.

This transcript has been edited for clarity.

Dr. Manson is professor of medicine and the Michael and Lee Bell Professor of Women’s Health, Harvard Medical School, and chief of the division of preventive medicine, Brigham and Women’s Hospital, both in Boston, and past president, North American Menopause Society, 2011-2012. She disclosed receiving study pill donation and infrastructure support from Mars Symbioscience (for the COSMOS trial).

A version of this article appeared on Medscape.com.

I’d like to talk with you about a recent report from the large-scale Black Women’s Health Study, published in the new journal NEJM Evidence.

This study looked at the association between hypertensive disorders of pregnancy, including preeclampsia and gestational hypertension, and the risk for stroke over the next 20 (median, 22) years. Previous studies have linked hypertensive disorders of pregnancy with an increased risk for stroke. However, most of these studies have been done in White women of European ancestry, and evidence in Black women has been very limited, despite a disproportionately high risk of having a hypertensive disorder of pregnancy and also of stroke.

This study, in more than 40,000 U.S. women, found an increased risk for subsequent stroke among women with a prior history of hypertensive disorder of pregnancy – overall, a 66% increased risk, an 80% increased risk with gestational hypertension, and about a 50% increased risk with preeclampsia.

We know that pregnancy itself can lead to some remodeling of the vascular system, but we don’t know whether a direct causal relationship exists between preeclampsia or gestational hypertension and subsequent stroke. Another potential explanation is that these complications of pregnancy serve as a window into a woman’s future cardiometabolic health and a marker of her cardiovascular risk.

Regardless, the clinical implications are the same. First, we would want to prevent these complications of pregnancy whenever possible. Some women will be candidates for the use of aspirin if they are at high risk for preeclampsia, and certainly for monitoring blood pressure very closely during pregnancy. It will also be important to maintain blood pressure control in the postpartum period and during the subsequent years of adulthood to minimize risk for stroke, because hypertension is such a powerful risk factor for stroke.

It will also be tremendously important to intensify lifestyle modifications such as increasing physical activity and having a heart-healthy diet. These complications of pregnancy have also been linked in other studies to an increased risk for subsequent coronary heart disease events and heart failure.

This transcript has been edited for clarity.

Dr. Manson is professor of medicine and the Michael and Lee Bell Professor of Women’s Health, Harvard Medical School, and chief of the division of preventive medicine, Brigham and Women’s Hospital, both in Boston, and past president, North American Menopause Society, 2011-2012. She disclosed receiving study pill donation and infrastructure support from Mars Symbioscience (for the COSMOS trial).

A version of this article appeared on Medscape.com.

I’d like to talk with you about a recent report from the large-scale Black Women’s Health Study, published in the new journal NEJM Evidence.

This study looked at the association between hypertensive disorders of pregnancy, including preeclampsia and gestational hypertension, and the risk for stroke over the next 20 (median, 22) years. Previous studies have linked hypertensive disorders of pregnancy with an increased risk for stroke. However, most of these studies have been done in White women of European ancestry, and evidence in Black women has been very limited, despite a disproportionately high risk of having a hypertensive disorder of pregnancy and also of stroke.

This study, in more than 40,000 U.S. women, found an increased risk for subsequent stroke among women with a prior history of hypertensive disorder of pregnancy – overall, a 66% increased risk, an 80% increased risk with gestational hypertension, and about a 50% increased risk with preeclampsia.

We know that pregnancy itself can lead to some remodeling of the vascular system, but we don’t know whether a direct causal relationship exists between preeclampsia or gestational hypertension and subsequent stroke. Another potential explanation is that these complications of pregnancy serve as a window into a woman’s future cardiometabolic health and a marker of her cardiovascular risk.

Regardless, the clinical implications are the same. First, we would want to prevent these complications of pregnancy whenever possible. Some women will be candidates for the use of aspirin if they are at high risk for preeclampsia, and certainly for monitoring blood pressure very closely during pregnancy. It will also be important to maintain blood pressure control in the postpartum period and during the subsequent years of adulthood to minimize risk for stroke, because hypertension is such a powerful risk factor for stroke.

It will also be tremendously important to intensify lifestyle modifications such as increasing physical activity and having a heart-healthy diet. These complications of pregnancy have also been linked in other studies to an increased risk for subsequent coronary heart disease events and heart failure.

This transcript has been edited for clarity.

Dr. Manson is professor of medicine and the Michael and Lee Bell Professor of Women’s Health, Harvard Medical School, and chief of the division of preventive medicine, Brigham and Women’s Hospital, both in Boston, and past president, North American Menopause Society, 2011-2012. She disclosed receiving study pill donation and infrastructure support from Mars Symbioscience (for the COSMOS trial).

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

As a consulting nephrologist, I go all over the hospital. Medicine floors, surgical floors, the ICU – I’ve even done consults in the operating room. And more and more, I do consults in the emergency department.

The reason I am doing more consults in the ED is not because the ED docs are getting gun shy with creatinine increases; it’s because patients are staying for extended periods in the ED despite being formally admitted to the hospital. It’s a phenomenon known as boarding, because there are simply not enough beds. You know the scene if you have ever been to a busy hospital: The ED is full to breaking, with patients on stretchers in hallways. It can often feel more like a warzone than a place for healing.

This is a huge problem.

The Joint Commission specifies that admitted patients should spend no more than 4 hours in the ED waiting for a bed in the hospital.

That is, based on what I’ve seen, hugely ambitious. But I should point out that I work in a hospital that runs near capacity all the time, and studies – from some of my Yale colleagues, actually – have shown that once hospital capacity exceeds 85%, boarding rates skyrocket.

I want to discuss some of the causes of extended boarding and some solutions. But before that, I should prove to you that this really matters, and for that we are going to dig in to a new study which suggests that ED boarding kills.

To put some hard numbers to the boarding problem, we turn to this paper out of France, appearing in JAMA Internal Medicine.

This is a unique study design. Basically, on a single day – Dec. 12, 2022 – researchers fanned out across France to 97 EDs and started counting patients. The study focused on those older than age 75 who were admitted to a hospital ward from the ED. The researchers then defined two groups: those who were sent up to the hospital floor before midnight, and those who spent at least from midnight until 8 AM in the ED (basically, people forced to sleep in the ED for a night). The middle-ground people who were sent up between midnight and 8 AM were excluded.

courtesy JAMA

courtesy Dr. F. Perry Wilson

F. Perry Wilson, MD, MSCE, is an associate professor of medicine and public health and director of Yale’s Clinical and Translational Research Accelerator. He reported no conflicts of interest.

A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity.

As a consulting nephrologist, I go all over the hospital. Medicine floors, surgical floors, the ICU – I’ve even done consults in the operating room. And more and more, I do consults in the emergency department.

The reason I am doing more consults in the ED is not because the ED docs are getting gun shy with creatinine increases; it’s because patients are staying for extended periods in the ED despite being formally admitted to the hospital. It’s a phenomenon known as boarding, because there are simply not enough beds. You know the scene if you have ever been to a busy hospital: The ED is full to breaking, with patients on stretchers in hallways. It can often feel more like a warzone than a place for healing.

This is a huge problem.

The Joint Commission specifies that admitted patients should spend no more than 4 hours in the ED waiting for a bed in the hospital.

That is, based on what I’ve seen, hugely ambitious. But I should point out that I work in a hospital that runs near capacity all the time, and studies – from some of my Yale colleagues, actually – have shown that once hospital capacity exceeds 85%, boarding rates skyrocket.

I want to discuss some of the causes of extended boarding and some solutions. But before that, I should prove to you that this really matters, and for that we are going to dig in to a new study which suggests that ED boarding kills.

To put some hard numbers to the boarding problem, we turn to this paper out of France, appearing in JAMA Internal Medicine.

This is a unique study design. Basically, on a single day – Dec. 12, 2022 – researchers fanned out across France to 97 EDs and started counting patients. The study focused on those older than age 75 who were admitted to a hospital ward from the ED. The researchers then defined two groups: those who were sent up to the hospital floor before midnight, and those who spent at least from midnight until 8 AM in the ED (basically, people forced to sleep in the ED for a night). The middle-ground people who were sent up between midnight and 8 AM were excluded.

courtesy JAMA

courtesy Dr. F. Perry Wilson

F. Perry Wilson, MD, MSCE, is an associate professor of medicine and public health and director of Yale’s Clinical and Translational Research Accelerator. He reported no conflicts of interest.

A version of this article first appeared on Medscape.com.

This transcript has been edited for clarity.

As a consulting nephrologist, I go all over the hospital. Medicine floors, surgical floors, the ICU – I’ve even done consults in the operating room. And more and more, I do consults in the emergency department.

The reason I am doing more consults in the ED is not because the ED docs are getting gun shy with creatinine increases; it’s because patients are staying for extended periods in the ED despite being formally admitted to the hospital. It’s a phenomenon known as boarding, because there are simply not enough beds. You know the scene if you have ever been to a busy hospital: The ED is full to breaking, with patients on stretchers in hallways. It can often feel more like a warzone than a place for healing.

This is a huge problem.

The Joint Commission specifies that admitted patients should spend no more than 4 hours in the ED waiting for a bed in the hospital.

That is, based on what I’ve seen, hugely ambitious. But I should point out that I work in a hospital that runs near capacity all the time, and studies – from some of my Yale colleagues, actually – have shown that once hospital capacity exceeds 85%, boarding rates skyrocket.

I want to discuss some of the causes of extended boarding and some solutions. But before that, I should prove to you that this really matters, and for that we are going to dig in to a new study which suggests that ED boarding kills.

To put some hard numbers to the boarding problem, we turn to this paper out of France, appearing in JAMA Internal Medicine.

This is a unique study design. Basically, on a single day – Dec. 12, 2022 – researchers fanned out across France to 97 EDs and started counting patients. The study focused on those older than age 75 who were admitted to a hospital ward from the ED. The researchers then defined two groups: those who were sent up to the hospital floor before midnight, and those who spent at least from midnight until 8 AM in the ED (basically, people forced to sleep in the ED for a night). The middle-ground people who were sent up between midnight and 8 AM were excluded.

courtesy JAMA

courtesy Dr. F. Perry Wilson

F. Perry Wilson, MD, MSCE, is an associate professor of medicine and public health and director of Yale’s Clinical and Translational Research Accelerator. He reported no conflicts of interest.

A version of this article first appeared on Medscape.com.

New evidence points to an association between exposure to “forever chemicals” and an increased risk for thyroid cancer.

The study suggests that higher exposure to per- and polyfluoroalkyl substances (PFAS), specifically perfluorooctanesulfonic acid (n-PFOS), may increase a person’s risk for thyroid cancer by 56%.

Several news outlets played up the findings, published online in eBioMedicine. “Dangerous ‘Forever Chemicals’ in Your Everyday Items Are Causing Cancer,” Newsweek reported.

But Gideon Meyerowitz-Katz, PhD, an epidemiologist at the University of Wollongong (Australia), voiced his skepticism.

“While it’s possible that PFAS might be causing thyroid cancer, the evidence thus far is unconvincing and probably not worth worrying about,” said Dr. Meyerowitz-Katz, who was not involved in the research.
 

PFAS and thyroid cancer

PFAS are a class of widely used synthetic chemicals found in many consumer and industrial products, including nonstick cookware, stain-repellent carpets, waterproof rain gear, microwave popcorn bags, and firefighting foam.

These substances have been dubbed “forever chemicals” because they do not degrade and are ubiquitous in the environment.

Exposure to endocrine-disrupting chemicals, including PFAS, has been identified as a potential risk factor for thyroid cancer, with some research linking PFAS exposure to thyroid dysfunction and carcinogenesis.

To investigate further, the researchers performed a nested case-control study of 86 patients with thyroid cancer using plasma samples collected at or before diagnosis and 86 controls without cancer who were matched on age, sex, race/ethnicity, body weight, smoking status, and year of sample collection. 

Eighteen individual PFAS were measured in plasma samples; 10 were undetectable and were therefore excluded from the analysis. Of the remaining eight PFAS, only one showed a statistically significant correlation with thyroid cancer. 

Specifically, the researchers found that exposure to n-PFOS was associated with a 56% increased risk for thyroid cancer among people who had a high level of the chemical in their blood (adjusted odds ratio, 1.56; P = .004). The results were similar when patients with papillary thyroid cancer only were included (aOR, 1.56; P = .009).

A separate longitudinal analysis of 31 patients diagnosed with thyroid cancer 1 year or more after plasma sample collection and 31 controls confirmed the positive association between n-PFOS and thyroid cancer (aOR, 2.67; P < .001). The longitudinal analysis also suggested correlations for a few other PFAS.

“This study supports the hypothesis that PFAS exposure may be associated with increased risk of thyroid cancer,” the authors concluded.

But in a Substack post, Dr. Meyerowitz-Katz said that it’s important to put the findings into “proper context before getting terrified about this all-new cancer risk.”

First, this study was “genuinely tiny,” with data on just 88 people with thyroid cancer and 88 controls, a limitation the researchers also acknowledged.

“That’s really not enough to do any sort of robust epidemiological analysis – you can generate interesting correlations, but what those correlations mean is anyone’s guess,” Dr. Meyerowitz-Katz said.

Even more importantly, one could easily argue that the results of this study show that most PFAS aren’t associated with thyroid cancer, given that there was no strong association for seven of the eight PFAS measured, he explained.

“There are no serious methodological concerns here, but equally there’s just not much you can reasonably gather from finding a single correlation among a vast ocean of possibilities,” Dr. Meyerowitz-Katz wrote. “Maybe there’s a correlation there, but you’d need to investigate this in much bigger samples, with more controls, and better data, to understand what that correlation means.”

Bottom line, Dr. Meyerowitz-Katz explained, is that “the link between PFAS and thyroid cancer is, at best, incredibly weak.”

Funding for the study was provided by the National Institutes of Health and The Andrea and Charles Bronfman Philanthropies. One coauthor is cofounder of Linus Biotechnology and is owner of a license agreement with NIES (Japan); received honoraria and travel compensation for lectures for the Bio-Echo and Brin foundations; and has 22 patents at various stages. Dr. Meyerowitz-Katz has no relevant disclosures.

A version of this article appeared on Medscape.com.

New evidence points to an association between exposure to “forever chemicals” and an increased risk for thyroid cancer.

The study suggests that higher exposure to per- and polyfluoroalkyl substances (PFAS), specifically perfluorooctanesulfonic acid (n-PFOS), may increase a person’s risk for thyroid cancer by 56%.

Several news outlets played up the findings, published online in eBioMedicine. “Dangerous ‘Forever Chemicals’ in Your Everyday Items Are Causing Cancer,” Newsweek reported.

But Gideon Meyerowitz-Katz, PhD, an epidemiologist at the University of Wollongong (Australia), voiced his skepticism.

“While it’s possible that PFAS might be causing thyroid cancer, the evidence thus far is unconvincing and probably not worth worrying about,” said Dr. Meyerowitz-Katz, who was not involved in the research.
 

PFAS and thyroid cancer

PFAS are a class of widely used synthetic chemicals found in many consumer and industrial products, including nonstick cookware, stain-repellent carpets, waterproof rain gear, microwave popcorn bags, and firefighting foam.

These substances have been dubbed “forever chemicals” because they do not degrade and are ubiquitous in the environment.

Exposure to endocrine-disrupting chemicals, including PFAS, has been identified as a potential risk factor for thyroid cancer, with some research linking PFAS exposure to thyroid dysfunction and carcinogenesis.

To investigate further, the researchers performed a nested case-control study of 86 patients with thyroid cancer using plasma samples collected at or before diagnosis and 86 controls without cancer who were matched on age, sex, race/ethnicity, body weight, smoking status, and year of sample collection. 

Eighteen individual PFAS were measured in plasma samples; 10 were undetectable and were therefore excluded from the analysis. Of the remaining eight PFAS, only one showed a statistically significant correlation with thyroid cancer. 

Specifically, the researchers found that exposure to n-PFOS was associated with a 56% increased risk for thyroid cancer among people who had a high level of the chemical in their blood (adjusted odds ratio, 1.56; P = .004). The results were similar when patients with papillary thyroid cancer only were included (aOR, 1.56; P = .009).

A separate longitudinal analysis of 31 patients diagnosed with thyroid cancer 1 year or more after plasma sample collection and 31 controls confirmed the positive association between n-PFOS and thyroid cancer (aOR, 2.67; P < .001). The longitudinal analysis also suggested correlations for a few other PFAS.

“This study supports the hypothesis that PFAS exposure may be associated with increased risk of thyroid cancer,” the authors concluded.

But in a Substack post, Dr. Meyerowitz-Katz said that it’s important to put the findings into “proper context before getting terrified about this all-new cancer risk.”

First, this study was “genuinely tiny,” with data on just 88 people with thyroid cancer and 88 controls, a limitation the researchers also acknowledged.

“That’s really not enough to do any sort of robust epidemiological analysis – you can generate interesting correlations, but what those correlations mean is anyone’s guess,” Dr. Meyerowitz-Katz said.

Even more importantly, one could easily argue that the results of this study show that most PFAS aren’t associated with thyroid cancer, given that there was no strong association for seven of the eight PFAS measured, he explained.

“There are no serious methodological concerns here, but equally there’s just not much you can reasonably gather from finding a single correlation among a vast ocean of possibilities,” Dr. Meyerowitz-Katz wrote. “Maybe there’s a correlation there, but you’d need to investigate this in much bigger samples, with more controls, and better data, to understand what that correlation means.”

Bottom line, Dr. Meyerowitz-Katz explained, is that “the link between PFAS and thyroid cancer is, at best, incredibly weak.”

Funding for the study was provided by the National Institutes of Health and The Andrea and Charles Bronfman Philanthropies. One coauthor is cofounder of Linus Biotechnology and is owner of a license agreement with NIES (Japan); received honoraria and travel compensation for lectures for the Bio-Echo and Brin foundations; and has 22 patents at various stages. Dr. Meyerowitz-Katz has no relevant disclosures.

A version of this article appeared on Medscape.com.

New evidence points to an association between exposure to “forever chemicals” and an increased risk for thyroid cancer.

The study suggests that higher exposure to per- and polyfluoroalkyl substances (PFAS), specifically perfluorooctanesulfonic acid (n-PFOS), may increase a person’s risk for thyroid cancer by 56%.

Several news outlets played up the findings, published online in eBioMedicine. “Dangerous ‘Forever Chemicals’ in Your Everyday Items Are Causing Cancer,” Newsweek reported.

But Gideon Meyerowitz-Katz, PhD, an epidemiologist at the University of Wollongong (Australia), voiced his skepticism.

“While it’s possible that PFAS might be causing thyroid cancer, the evidence thus far is unconvincing and probably not worth worrying about,” said Dr. Meyerowitz-Katz, who was not involved in the research.
 

PFAS and thyroid cancer

PFAS are a class of widely used synthetic chemicals found in many consumer and industrial products, including nonstick cookware, stain-repellent carpets, waterproof rain gear, microwave popcorn bags, and firefighting foam.

These substances have been dubbed “forever chemicals” because they do not degrade and are ubiquitous in the environment.

Exposure to endocrine-disrupting chemicals, including PFAS, has been identified as a potential risk factor for thyroid cancer, with some research linking PFAS exposure to thyroid dysfunction and carcinogenesis.

To investigate further, the researchers performed a nested case-control study of 86 patients with thyroid cancer using plasma samples collected at or before diagnosis and 86 controls without cancer who were matched on age, sex, race/ethnicity, body weight, smoking status, and year of sample collection. 

Eighteen individual PFAS were measured in plasma samples; 10 were undetectable and were therefore excluded from the analysis. Of the remaining eight PFAS, only one showed a statistically significant correlation with thyroid cancer. 

Specifically, the researchers found that exposure to n-PFOS was associated with a 56% increased risk for thyroid cancer among people who had a high level of the chemical in their blood (adjusted odds ratio, 1.56; P = .004). The results were similar when patients with papillary thyroid cancer only were included (aOR, 1.56; P = .009).

A separate longitudinal analysis of 31 patients diagnosed with thyroid cancer 1 year or more after plasma sample collection and 31 controls confirmed the positive association between n-PFOS and thyroid cancer (aOR, 2.67; P < .001). The longitudinal analysis also suggested correlations for a few other PFAS.

“This study supports the hypothesis that PFAS exposure may be associated with increased risk of thyroid cancer,” the authors concluded.

But in a Substack post, Dr. Meyerowitz-Katz said that it’s important to put the findings into “proper context before getting terrified about this all-new cancer risk.”

First, this study was “genuinely tiny,” with data on just 88 people with thyroid cancer and 88 controls, a limitation the researchers also acknowledged.

“That’s really not enough to do any sort of robust epidemiological analysis – you can generate interesting correlations, but what those correlations mean is anyone’s guess,” Dr. Meyerowitz-Katz said.

Even more importantly, one could easily argue that the results of this study show that most PFAS aren’t associated with thyroid cancer, given that there was no strong association for seven of the eight PFAS measured, he explained.

“There are no serious methodological concerns here, but equally there’s just not much you can reasonably gather from finding a single correlation among a vast ocean of possibilities,” Dr. Meyerowitz-Katz wrote. “Maybe there’s a correlation there, but you’d need to investigate this in much bigger samples, with more controls, and better data, to understand what that correlation means.”

Bottom line, Dr. Meyerowitz-Katz explained, is that “the link between PFAS and thyroid cancer is, at best, incredibly weak.”

Funding for the study was provided by the National Institutes of Health and The Andrea and Charles Bronfman Philanthropies. One coauthor is cofounder of Linus Biotechnology and is owner of a license agreement with NIES (Japan); received honoraria and travel compensation for lectures for the Bio-Echo and Brin foundations; and has 22 patents at various stages. Dr. Meyerowitz-Katz has no relevant disclosures.

A version of this article appeared on Medscape.com.

As I noted in my last column, I recently had a generic cold.

One of the more irritating aspects is that I usually get a cough that lasts a few weeks afterwards, and, like most people, I try to do something about it. So I load up on various over-the-counter remedies.

I have no idea if they work, or if I’m shelling out for a placebo. I’m not alone in buying these, or they wouldn’t be on the market, or making money, at all.

But the placebo effect is pretty strong. Phenylephrine has been around since 1938. It’s sold on its own and is an ingredient in almost every anti-cough/cold combination medication out there (NyQuil, DayQuil, Robitussin Multi-Symptom, and their many generic store brands). Millions of people use it every year.

Yet, after sifting through piles of accumulated data, the Food and Drug Administration announced earlier this year that phenylephrine ... doesn’t do anything. Zip. Zero. Nada. When compared with a placebo in controlled trials, you couldn’t tell the difference between them. So now the use of it is being questioned. CVS has started pulling it off their shelves, and I suspect other pharmacies will follow.

But back to my cough. A time-honored tradition in American childhood is having to cram down Robitussin and gagging from its nasty taste (the cherry and orange flavoring don’t make a difference, it tastes terrible no matter what you do). So that gets ingrained into us, and to this day I, and most adults, reach for a bottle of dextromethorphan when they have a cough.

But the evidence for that is spotty, too. Several studies have shown equivocal, if any, evidence to suggest it helps with coughs, though others have shown some. Nothing really amazing though.

But we still buy it by the gallon when we’re sick, because we want something, anything, that will make us better. Even if we’re doing so more from hope than conviction.

There’s also the old standby of cough drops, which have been used for more than 3,000 years. Ingredients vary, but menthol is probably the most common one. I go through those, too. I keep a bag in my desk at work. In medical school, during cold season, it was in my backpack. I remember sitting in the Creighton library to study, quietly sucking on a lozenge to keep my cough from disturbing other students.

But even then, the evidence is iffy as to whether they do anything. In fact, one interesting (though small) study in 2018 suggested they may actually prolong coughs.

The fact is that we are all susceptible to the placebo effect, regardless of how much we know about illness and medication. Maybe these things work, maybe they don’t, but it’s a valid question. How often do we let wishful thinking beat objective data?

Probably more often than we want to admit.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

As I noted in my last column, I recently had a generic cold.

One of the more irritating aspects is that I usually get a cough that lasts a few weeks afterwards, and, like most people, I try to do something about it. So I load up on various over-the-counter remedies.

I have no idea if they work, or if I’m shelling out for a placebo. I’m not alone in buying these, or they wouldn’t be on the market, or making money, at all.

But the placebo effect is pretty strong. Phenylephrine has been around since 1938. It’s sold on its own and is an ingredient in almost every anti-cough/cold combination medication out there (NyQuil, DayQuil, Robitussin Multi-Symptom, and their many generic store brands). Millions of people use it every year.

Yet, after sifting through piles of accumulated data, the Food and Drug Administration announced earlier this year that phenylephrine ... doesn’t do anything. Zip. Zero. Nada. When compared with a placebo in controlled trials, you couldn’t tell the difference between them. So now the use of it is being questioned. CVS has started pulling it off their shelves, and I suspect other pharmacies will follow.

But back to my cough. A time-honored tradition in American childhood is having to cram down Robitussin and gagging from its nasty taste (the cherry and orange flavoring don’t make a difference, it tastes terrible no matter what you do). So that gets ingrained into us, and to this day I, and most adults, reach for a bottle of dextromethorphan when they have a cough.

But the evidence for that is spotty, too. Several studies have shown equivocal, if any, evidence to suggest it helps with coughs, though others have shown some. Nothing really amazing though.

But we still buy it by the gallon when we’re sick, because we want something, anything, that will make us better. Even if we’re doing so more from hope than conviction.

There’s also the old standby of cough drops, which have been used for more than 3,000 years. Ingredients vary, but menthol is probably the most common one. I go through those, too. I keep a bag in my desk at work. In medical school, during cold season, it was in my backpack. I remember sitting in the Creighton library to study, quietly sucking on a lozenge to keep my cough from disturbing other students.

But even then, the evidence is iffy as to whether they do anything. In fact, one interesting (though small) study in 2018 suggested they may actually prolong coughs.

The fact is that we are all susceptible to the placebo effect, regardless of how much we know about illness and medication. Maybe these things work, maybe they don’t, but it’s a valid question. How often do we let wishful thinking beat objective data?

Probably more often than we want to admit.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

As I noted in my last column, I recently had a generic cold.

One of the more irritating aspects is that I usually get a cough that lasts a few weeks afterwards, and, like most people, I try to do something about it. So I load up on various over-the-counter remedies.

I have no idea if they work, or if I’m shelling out for a placebo. I’m not alone in buying these, or they wouldn’t be on the market, or making money, at all.

But the placebo effect is pretty strong. Phenylephrine has been around since 1938. It’s sold on its own and is an ingredient in almost every anti-cough/cold combination medication out there (NyQuil, DayQuil, Robitussin Multi-Symptom, and their many generic store brands). Millions of people use it every year.

Yet, after sifting through piles of accumulated data, the Food and Drug Administration announced earlier this year that phenylephrine ... doesn’t do anything. Zip. Zero. Nada. When compared with a placebo in controlled trials, you couldn’t tell the difference between them. So now the use of it is being questioned. CVS has started pulling it off their shelves, and I suspect other pharmacies will follow.

But back to my cough. A time-honored tradition in American childhood is having to cram down Robitussin and gagging from its nasty taste (the cherry and orange flavoring don’t make a difference, it tastes terrible no matter what you do). So that gets ingrained into us, and to this day I, and most adults, reach for a bottle of dextromethorphan when they have a cough.

But the evidence for that is spotty, too. Several studies have shown equivocal, if any, evidence to suggest it helps with coughs, though others have shown some. Nothing really amazing though.

But we still buy it by the gallon when we’re sick, because we want something, anything, that will make us better. Even if we’re doing so more from hope than conviction.

There’s also the old standby of cough drops, which have been used for more than 3,000 years. Ingredients vary, but menthol is probably the most common one. I go through those, too. I keep a bag in my desk at work. In medical school, during cold season, it was in my backpack. I remember sitting in the Creighton library to study, quietly sucking on a lozenge to keep my cough from disturbing other students.

But even then, the evidence is iffy as to whether they do anything. In fact, one interesting (though small) study in 2018 suggested they may actually prolong coughs.

The fact is that we are all susceptible to the placebo effect, regardless of how much we know about illness and medication. Maybe these things work, maybe they don’t, but it’s a valid question. How often do we let wishful thinking beat objective data?

Probably more often than we want to admit.

Dr. Block has a solo neurology practice in Scottsdale, Ariz.

Veronica Brady and her team at the University of Texas Health Science Center, Houston, sat down with 37 people diagnosed with HIV or AIDS to ask them what that felt like.

“The results were really eye-opening and sad,” says Brady, PhD, RN, from the Cizik School of Nursing with UTHealth, Houston.

Many of the people Dr. Brady and her team spoke with were diagnosed through routine or random testing. They ranged in age from 21 years to 65 and said they did not know how they had been infected and felt shocked, freaked out, scared, and in a state of disbelief.

Their conversations about being diagnosed with HIV, presented at the annual meeting of the Association of Nurses in AIDS Care in New Orleans, also described how symptoms of the disease or side effects from treatment can have a huge impact on the daily lives of those affected.

Jesse Milan Jr., president of AIDS United, an HIV advocacy organization based in Washington, D.C., says he recognizes all of these feelings from his own experience with HIV after being diagnosed more than 40 years ago.

“All of those have come up over the years,” he says. “They are all relevant and important at different times.”

For Mr. Milan, less was known about the virus at the time of his diagnosis, and he watched loved ones die. He lived to see the introduction of antiretroviral therapies and receive treatment when his partner and many of his friends did not.
 

Effective treatments

There is a marked difference between the reaction of people diagnosed with HIV years ago and those diagnosed more recently, Dr. Brady explains. Those diagnosed before much was known about the virus and before there were effective treatments were more frightened, she says, whereas people hearing the news recently are much less worried and understand that if they take their medication, they will be fine.

Still, Mr. Milan says when he talks to people diagnosed now, they seem to experience more shame and embarrassment than before. Because it is long known how to prevent HIV infection, they often worry what people will think if they disclose their status. “It makes things harder for people diagnosed today,” says Mr. Milan. “There is a different level of embarrassment tinged with, ‘Why was I so stupid?’ ”

Diagnosis can also be hard on health care professionals, says Dr. Brady. “You never want to tell anyone they’re sick with a chronic disease, especially younger people,” she adds. “You know you’re adding a burden to someone’s life.”

Symptoms and side effects of treatment also had an important impact on the people in this report, with most aspects of their lives affected, including work, relationships, mood, and daily activities.

Clinicians should be supportive and spend some time sitting with patients as they come to terms with the diagnosis and its implications. They should help them understand what to expect and talk about how – or whether – to talk about their status with family and friends. “You need to show you care about the person and that they are not alone,” Dr. Brady says.

And most of all, clinicians need to explain that patients can live a long and healthy life and go on to become whoever they want to be. “Twenty years ago, we wouldn’t have as hopeful a message as we do now,” she says.

Hope is the most important thing for doctors and nurses to communicate to their patients. “There are medications available, and it will be okay. You don’t have to die,” Mr. Milan says. “That’s the core message that everyone needs to hear, whether they were diagnosed 30 years ago or 30 minutes ago.”

A version of this article appeared on Medscape.com.

Veronica Brady and her team at the University of Texas Health Science Center, Houston, sat down with 37 people diagnosed with HIV or AIDS to ask them what that felt like.

“The results were really eye-opening and sad,” says Brady, PhD, RN, from the Cizik School of Nursing with UTHealth, Houston.

Many of the people Dr. Brady and her team spoke with were diagnosed through routine or random testing. They ranged in age from 21 years to 65 and said they did not know how they had been infected and felt shocked, freaked out, scared, and in a state of disbelief.

Their conversations about being diagnosed with HIV, presented at the annual meeting of the Association of Nurses in AIDS Care in New Orleans, also described how symptoms of the disease or side effects from treatment can have a huge impact on the daily lives of those affected.

Jesse Milan Jr., president of AIDS United, an HIV advocacy organization based in Washington, D.C., says he recognizes all of these feelings from his own experience with HIV after being diagnosed more than 40 years ago.

“All of those have come up over the years,” he says. “They are all relevant and important at different times.”

For Mr. Milan, less was known about the virus at the time of his diagnosis, and he watched loved ones die. He lived to see the introduction of antiretroviral therapies and receive treatment when his partner and many of his friends did not.
 

Effective treatments

There is a marked difference between the reaction of people diagnosed with HIV years ago and those diagnosed more recently, Dr. Brady explains. Those diagnosed before much was known about the virus and before there were effective treatments were more frightened, she says, whereas people hearing the news recently are much less worried and understand that if they take their medication, they will be fine.

Still, Mr. Milan says when he talks to people diagnosed now, they seem to experience more shame and embarrassment than before. Because it is long known how to prevent HIV infection, they often worry what people will think if they disclose their status. “It makes things harder for people diagnosed today,” says Mr. Milan. “There is a different level of embarrassment tinged with, ‘Why was I so stupid?’ ”

Diagnosis can also be hard on health care professionals, says Dr. Brady. “You never want to tell anyone they’re sick with a chronic disease, especially younger people,” she adds. “You know you’re adding a burden to someone’s life.”

Symptoms and side effects of treatment also had an important impact on the people in this report, with most aspects of their lives affected, including work, relationships, mood, and daily activities.

Clinicians should be supportive and spend some time sitting with patients as they come to terms with the diagnosis and its implications. They should help them understand what to expect and talk about how – or whether – to talk about their status with family and friends. “You need to show you care about the person and that they are not alone,” Dr. Brady says.

And most of all, clinicians need to explain that patients can live a long and healthy life and go on to become whoever they want to be. “Twenty years ago, we wouldn’t have as hopeful a message as we do now,” she says.

Hope is the most important thing for doctors and nurses to communicate to their patients. “There are medications available, and it will be okay. You don’t have to die,” Mr. Milan says. “That’s the core message that everyone needs to hear, whether they were diagnosed 30 years ago or 30 minutes ago.”

A version of this article appeared on Medscape.com.

Veronica Brady and her team at the University of Texas Health Science Center, Houston, sat down with 37 people diagnosed with HIV or AIDS to ask them what that felt like.

“The results were really eye-opening and sad,” says Brady, PhD, RN, from the Cizik School of Nursing with UTHealth, Houston.

Many of the people Dr. Brady and her team spoke with were diagnosed through routine or random testing. They ranged in age from 21 years to 65 and said they did not know how they had been infected and felt shocked, freaked out, scared, and in a state of disbelief.

Their conversations about being diagnosed with HIV, presented at the annual meeting of the Association of Nurses in AIDS Care in New Orleans, also described how symptoms of the disease or side effects from treatment can have a huge impact on the daily lives of those affected.

Jesse Milan Jr., president of AIDS United, an HIV advocacy organization based in Washington, D.C., says he recognizes all of these feelings from his own experience with HIV after being diagnosed more than 40 years ago.

“All of those have come up over the years,” he says. “They are all relevant and important at different times.”

For Mr. Milan, less was known about the virus at the time of his diagnosis, and he watched loved ones die. He lived to see the introduction of antiretroviral therapies and receive treatment when his partner and many of his friends did not.
 

Effective treatments

There is a marked difference between the reaction of people diagnosed with HIV years ago and those diagnosed more recently, Dr. Brady explains. Those diagnosed before much was known about the virus and before there were effective treatments were more frightened, she says, whereas people hearing the news recently are much less worried and understand that if they take their medication, they will be fine.

Still, Mr. Milan says when he talks to people diagnosed now, they seem to experience more shame and embarrassment than before. Because it is long known how to prevent HIV infection, they often worry what people will think if they disclose their status. “It makes things harder for people diagnosed today,” says Mr. Milan. “There is a different level of embarrassment tinged with, ‘Why was I so stupid?’ ”

Diagnosis can also be hard on health care professionals, says Dr. Brady. “You never want to tell anyone they’re sick with a chronic disease, especially younger people,” she adds. “You know you’re adding a burden to someone’s life.”

Symptoms and side effects of treatment also had an important impact on the people in this report, with most aspects of their lives affected, including work, relationships, mood, and daily activities.

Clinicians should be supportive and spend some time sitting with patients as they come to terms with the diagnosis and its implications. They should help them understand what to expect and talk about how – or whether – to talk about their status with family and friends. “You need to show you care about the person and that they are not alone,” Dr. Brady says.

And most of all, clinicians need to explain that patients can live a long and healthy life and go on to become whoever they want to be. “Twenty years ago, we wouldn’t have as hopeful a message as we do now,” she says.

Hope is the most important thing for doctors and nurses to communicate to their patients. “There are medications available, and it will be okay. You don’t have to die,” Mr. Milan says. “That’s the core message that everyone needs to hear, whether they were diagnosed 30 years ago or 30 minutes ago.”

A version of this article appeared on Medscape.com.

MADRID – Cancer-related fatigue is common but often undertreated. Similarly, its impact is underestimated. These were the messages delivered by speakers at the annual meeting of the European Society for Medical Oncology during a session titled “The Multiple Faces of Fatigue in the Cancer Ecosystem.”

Cancer-related fatigue is said to affect 40% of patients at the time of cancer diagnosis, 65% of patients during active or maintenance treatment, 21%-52% of patients in the 5 years following cancer diagnosis, and even one quarter of patients who are between 5 and 30 years post diagnosis, said Florian Scotté, MD, PhD, head of the interdisciplinary department for the Organization of Patient Pathways at Gustave Roussy Institute in Villejuif, France.

However, he underlines that “up to 50% of cancer survivors report never having discussed their cancer-related fatigue or received advice or support on how to manage it.”

What exactly is this fatigue? According to the definition set out in the ESMO 2020 recommendations and repeated word for word in the latest recommendations issued by the National Comprehensive Cancer Network published on Oct. 6, cancer-related fatigue is “a distressing, persistent, subjective sense of physical, emotional, and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning.”
 

Mechanisms at play

The mechanisms at play in cancer-related fatigue are clinical, molecular, and psychological, stated Dr. Scotté.

In terms of the clinical factors responsible for patients’ fatigue, comorbidities such as anemia, diabetes, heart disease, and even psychological conditions are significant elements. In addition, taking medicinal products such as antidepressants or beta-blockers can also cause fatigue. Furthermore, cancer treatment itself has many possible side effects, such as anemia, hypothyroidism, insomnia, pain, and hypopituitarism.

In terms of molecular and physiologic factors, central nervous system dysfunction (inflammation, hypothalamic-pituitary-adrenal axis) leads to perceived reduced physical and mental capacity with no clear motor or cognitive deficiencies. Changes in the peripheral nervous system also cause reduced energy metabolism, which hampers the response of muscles to stimuli, possibly even limiting endurance. Finally, several studies have shown that systemic inflammation is involved in the onset of fatigue.

Dr. Scotté also highlighted the importance of psychological factors, citing depression, psychosocial stress before treatment, negative attention to symptoms, and fear of relapse as key features in the development of cancer-related fatigue.

Among the risk factors for developing cancer-related fatigue, the speaker mentioned a combination of genetic, psychological, and biobehavioral factors (such as preexisting risk factors, depression, sleep disorders, physical inactivity, BMI, smoking, alcohol consumption, and adaptability).
 

Screen and diagnose

“Cancer-related fatigue is one of the most underestimated and least researched side effects,” said Christina Ruhlmann, MD, PhD, an oncology consultant at Odense (Denmark) University Hospital. “It is important to screen for fatigue in cancer patients.”

There are several tools available to enable this screening, she noted. The EORTC Core Quality of Life Questionnaire (EORTC QLQ-C30) is a three-item subscale evaluating the symptoms of fatigue, weakness, and lack of energy. The MD Anderson Symptom Inventory (13 items) assesses fatigue, sleep disorders, and drowsiness. The numeric rating scale (NRS) for fatigue is an 11-point visual self-assessment scale comprising a single element, with 0 representing no fatigue and 10 representing intense fatigue.

When screening for cancer-related fatigue, whenever a score of 4 or more is obtained on the NRS, a diagnostic assessment is needed based on clinical history-taking, fatigue assessment, and evaluation of comorbidities.

When taking the clinical history, information should be obtained on the type of condition, its stage, any relapse or progression, metastases, the date of diagnosis, length of treatment, any cancer or surgical treatments carried out, other treatments administered, and the risk for drug interactions.

In addition, to assess fatigue, the diagnostic process consists of documenting the start, type, and duration of the fatigue, as well as the presence of attenuating factors and interference with activities of daily living and leisure activities.

Seeking information regarding environmental factors such as availability of a support network of family and friends or financial resources is also paramount, said Dr. Ruhlmann.

Finally, contributory factors that may require treatment must be assessed. They include pain, emotional distress, anemia, sleep disorders, nutritional deficiencies, inactivity, smoking and alcohol consumption, and comorbidities (such as cardiac, endocrine, gastrointestinal, hepatic, infectious, and renal conditions).

The following two simple questions can be used to screen for symptoms of depression quickly:

• Over the past month, have you often felt despondent, sad, depressed, or in despair?
• Over the past month, have you found less pleasure than usual in doing the things you normally enjoy doing?

How to treat?

“All of the elements associated with fatigue that can be taken into account ought to be,” stressed Dr. Ruhlmann before insisting on the key role played by physical activity in combating the feeling of exhaustion.

The ESMO recommendations indicate that, according to the results of randomized clinical trials and systematic literature reviews, physical exercise can be recommended in patients with cancer who do not have cachexia (level of evidence I, B).

The type of physical activity recommended is moderate, aerobic, and functional strength exercises (I, B). Walking, aerobic exercises at home, and strength exercises are recommended to improve cancer-related fatigue and quality of life (II, B). “They help with fatigue and also with side effects such as depression, anxiety, pain, and muscle strength,” said Dr. Ruhlmann.

Alongside exercise, and with a lower level of evidence, pharmacologic treatments can sometimes be used (II, B; II, D). Short-term use of dexamethasone or methylprednisolone is recommended for managing fatigue linked to metastatic cancer except during the course of immunotherapy (II, B).

The ESMO expert group did not reach a consensus on the use of methylphenidate, dexmethylphenidate, slow-release methylphenidate, and dexamphetamine.

Modafinil and armodafinil, antidepressants (especially paroxetine), donepezil and eszopiclone, megestrol acetate, and melatonin are not recommended (II, D).

No consensus could be reached on nutraceuticals, and they are not recommended, said Dr. Ruhlmann (II, C; II, D).

Finally, psychosocial interventions in the form of information, advice, psychoeducation, and cognitive-behavioral therapy are useful tools (II, B).

Another area being explored is the gut microbiota. “Research into the microbiota and its role in systemic inflammation is underway and could pave the way for future strategies for managing cancer-related fatigue,” said Dr. Ruhlmann. “Fatigue is a subjective experience, unlike other symptoms. It’s what those people suffering from it say it is!”

This article was translated from the Medscape French edition.

MADRID – Cancer-related fatigue is common but often undertreated. Similarly, its impact is underestimated. These were the messages delivered by speakers at the annual meeting of the European Society for Medical Oncology during a session titled “The Multiple Faces of Fatigue in the Cancer Ecosystem.”

Cancer-related fatigue is said to affect 40% of patients at the time of cancer diagnosis, 65% of patients during active or maintenance treatment, 21%-52% of patients in the 5 years following cancer diagnosis, and even one quarter of patients who are between 5 and 30 years post diagnosis, said Florian Scotté, MD, PhD, head of the interdisciplinary department for the Organization of Patient Pathways at Gustave Roussy Institute in Villejuif, France.

However, he underlines that “up to 50% of cancer survivors report never having discussed their cancer-related fatigue or received advice or support on how to manage it.”

What exactly is this fatigue? According to the definition set out in the ESMO 2020 recommendations and repeated word for word in the latest recommendations issued by the National Comprehensive Cancer Network published on Oct. 6, cancer-related fatigue is “a distressing, persistent, subjective sense of physical, emotional, and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning.”
 

Mechanisms at play

The mechanisms at play in cancer-related fatigue are clinical, molecular, and psychological, stated Dr. Scotté.

In terms of the clinical factors responsible for patients’ fatigue, comorbidities such as anemia, diabetes, heart disease, and even psychological conditions are significant elements. In addition, taking medicinal products such as antidepressants or beta-blockers can also cause fatigue. Furthermore, cancer treatment itself has many possible side effects, such as anemia, hypothyroidism, insomnia, pain, and hypopituitarism.

In terms of molecular and physiologic factors, central nervous system dysfunction (inflammation, hypothalamic-pituitary-adrenal axis) leads to perceived reduced physical and mental capacity with no clear motor or cognitive deficiencies. Changes in the peripheral nervous system also cause reduced energy metabolism, which hampers the response of muscles to stimuli, possibly even limiting endurance. Finally, several studies have shown that systemic inflammation is involved in the onset of fatigue.

Dr. Scotté also highlighted the importance of psychological factors, citing depression, psychosocial stress before treatment, negative attention to symptoms, and fear of relapse as key features in the development of cancer-related fatigue.

Among the risk factors for developing cancer-related fatigue, the speaker mentioned a combination of genetic, psychological, and biobehavioral factors (such as preexisting risk factors, depression, sleep disorders, physical inactivity, BMI, smoking, alcohol consumption, and adaptability).
 

Screen and diagnose

“Cancer-related fatigue is one of the most underestimated and least researched side effects,” said Christina Ruhlmann, MD, PhD, an oncology consultant at Odense (Denmark) University Hospital. “It is important to screen for fatigue in cancer patients.”

There are several tools available to enable this screening, she noted. The EORTC Core Quality of Life Questionnaire (EORTC QLQ-C30) is a three-item subscale evaluating the symptoms of fatigue, weakness, and lack of energy. The MD Anderson Symptom Inventory (13 items) assesses fatigue, sleep disorders, and drowsiness. The numeric rating scale (NRS) for fatigue is an 11-point visual self-assessment scale comprising a single element, with 0 representing no fatigue and 10 representing intense fatigue.

When screening for cancer-related fatigue, whenever a score of 4 or more is obtained on the NRS, a diagnostic assessment is needed based on clinical history-taking, fatigue assessment, and evaluation of comorbidities.

When taking the clinical history, information should be obtained on the type of condition, its stage, any relapse or progression, metastases, the date of diagnosis, length of treatment, any cancer or surgical treatments carried out, other treatments administered, and the risk for drug interactions.

In addition, to assess fatigue, the diagnostic process consists of documenting the start, type, and duration of the fatigue, as well as the presence of attenuating factors and interference with activities of daily living and leisure activities.

Seeking information regarding environmental factors such as availability of a support network of family and friends or financial resources is also paramount, said Dr. Ruhlmann.

Finally, contributory factors that may require treatment must be assessed. They include pain, emotional distress, anemia, sleep disorders, nutritional deficiencies, inactivity, smoking and alcohol consumption, and comorbidities (such as cardiac, endocrine, gastrointestinal, hepatic, infectious, and renal conditions).

The following two simple questions can be used to screen for symptoms of depression quickly:

• Over the past month, have you often felt despondent, sad, depressed, or in despair?
• Over the past month, have you found less pleasure than usual in doing the things you normally enjoy doing?

How to treat?

“All of the elements associated with fatigue that can be taken into account ought to be,” stressed Dr. Ruhlmann before insisting on the key role played by physical activity in combating the feeling of exhaustion.

The ESMO recommendations indicate that, according to the results of randomized clinical trials and systematic literature reviews, physical exercise can be recommended in patients with cancer who do not have cachexia (level of evidence I, B).

The type of physical activity recommended is moderate, aerobic, and functional strength exercises (I, B). Walking, aerobic exercises at home, and strength exercises are recommended to improve cancer-related fatigue and quality of life (II, B). “They help with fatigue and also with side effects such as depression, anxiety, pain, and muscle strength,” said Dr. Ruhlmann.

Alongside exercise, and with a lower level of evidence, pharmacologic treatments can sometimes be used (II, B; II, D). Short-term use of dexamethasone or methylprednisolone is recommended for managing fatigue linked to metastatic cancer except during the course of immunotherapy (II, B).

The ESMO expert group did not reach a consensus on the use of methylphenidate, dexmethylphenidate, slow-release methylphenidate, and dexamphetamine.

Modafinil and armodafinil, antidepressants (especially paroxetine), donepezil and eszopiclone, megestrol acetate, and melatonin are not recommended (II, D).

No consensus could be reached on nutraceuticals, and they are not recommended, said Dr. Ruhlmann (II, C; II, D).

Finally, psychosocial interventions in the form of information, advice, psychoeducation, and cognitive-behavioral therapy are useful tools (II, B).

Another area being explored is the gut microbiota. “Research into the microbiota and its role in systemic inflammation is underway and could pave the way for future strategies for managing cancer-related fatigue,” said Dr. Ruhlmann. “Fatigue is a subjective experience, unlike other symptoms. It’s what those people suffering from it say it is!”

This article was translated from the Medscape French edition.

MADRID – Cancer-related fatigue is common but often undertreated. Similarly, its impact is underestimated. These were the messages delivered by speakers at the annual meeting of the European Society for Medical Oncology during a session titled “The Multiple Faces of Fatigue in the Cancer Ecosystem.”

Cancer-related fatigue is said to affect 40% of patients at the time of cancer diagnosis, 65% of patients during active or maintenance treatment, 21%-52% of patients in the 5 years following cancer diagnosis, and even one quarter of patients who are between 5 and 30 years post diagnosis, said Florian Scotté, MD, PhD, head of the interdisciplinary department for the Organization of Patient Pathways at Gustave Roussy Institute in Villejuif, France.

However, he underlines that “up to 50% of cancer survivors report never having discussed their cancer-related fatigue or received advice or support on how to manage it.”

What exactly is this fatigue? According to the definition set out in the ESMO 2020 recommendations and repeated word for word in the latest recommendations issued by the National Comprehensive Cancer Network published on Oct. 6, cancer-related fatigue is “a distressing, persistent, subjective sense of physical, emotional, and/or cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning.”
 

Mechanisms at play

The mechanisms at play in cancer-related fatigue are clinical, molecular, and psychological, stated Dr. Scotté.

In terms of the clinical factors responsible for patients’ fatigue, comorbidities such as anemia, diabetes, heart disease, and even psychological conditions are significant elements. In addition, taking medicinal products such as antidepressants or beta-blockers can also cause fatigue. Furthermore, cancer treatment itself has many possible side effects, such as anemia, hypothyroidism, insomnia, pain, and hypopituitarism.

In terms of molecular and physiologic factors, central nervous system dysfunction (inflammation, hypothalamic-pituitary-adrenal axis) leads to perceived reduced physical and mental capacity with no clear motor or cognitive deficiencies. Changes in the peripheral nervous system also cause reduced energy metabolism, which hampers the response of muscles to stimuli, possibly even limiting endurance. Finally, several studies have shown that systemic inflammation is involved in the onset of fatigue.

Dr. Scotté also highlighted the importance of psychological factors, citing depression, psychosocial stress before treatment, negative attention to symptoms, and fear of relapse as key features in the development of cancer-related fatigue.

Among the risk factors for developing cancer-related fatigue, the speaker mentioned a combination of genetic, psychological, and biobehavioral factors (such as preexisting risk factors, depression, sleep disorders, physical inactivity, BMI, smoking, alcohol consumption, and adaptability).
 

Screen and diagnose

“Cancer-related fatigue is one of the most underestimated and least researched side effects,” said Christina Ruhlmann, MD, PhD, an oncology consultant at Odense (Denmark) University Hospital. “It is important to screen for fatigue in cancer patients.”

There are several tools available to enable this screening, she noted. The EORTC Core Quality of Life Questionnaire (EORTC QLQ-C30) is a three-item subscale evaluating the symptoms of fatigue, weakness, and lack of energy. The MD Anderson Symptom Inventory (13 items) assesses fatigue, sleep disorders, and drowsiness. The numeric rating scale (NRS) for fatigue is an 11-point visual self-assessment scale comprising a single element, with 0 representing no fatigue and 10 representing intense fatigue.

When screening for cancer-related fatigue, whenever a score of 4 or more is obtained on the NRS, a diagnostic assessment is needed based on clinical history-taking, fatigue assessment, and evaluation of comorbidities.

When taking the clinical history, information should be obtained on the type of condition, its stage, any relapse or progression, metastases, the date of diagnosis, length of treatment, any cancer or surgical treatments carried out, other treatments administered, and the risk for drug interactions.

In addition, to assess fatigue, the diagnostic process consists of documenting the start, type, and duration of the fatigue, as well as the presence of attenuating factors and interference with activities of daily living and leisure activities.

Seeking information regarding environmental factors such as availability of a support network of family and friends or financial resources is also paramount, said Dr. Ruhlmann.

Finally, contributory factors that may require treatment must be assessed. They include pain, emotional distress, anemia, sleep disorders, nutritional deficiencies, inactivity, smoking and alcohol consumption, and comorbidities (such as cardiac, endocrine, gastrointestinal, hepatic, infectious, and renal conditions).

The following two simple questions can be used to screen for symptoms of depression quickly:

• Over the past month, have you often felt despondent, sad, depressed, or in despair?
• Over the past month, have you found less pleasure than usual in doing the things you normally enjoy doing?

How to treat?

“All of the elements associated with fatigue that can be taken into account ought to be,” stressed Dr. Ruhlmann before insisting on the key role played by physical activity in combating the feeling of exhaustion.

The ESMO recommendations indicate that, according to the results of randomized clinical trials and systematic literature reviews, physical exercise can be recommended in patients with cancer who do not have cachexia (level of evidence I, B).

The type of physical activity recommended is moderate, aerobic, and functional strength exercises (I, B). Walking, aerobic exercises at home, and strength exercises are recommended to improve cancer-related fatigue and quality of life (II, B). “They help with fatigue and also with side effects such as depression, anxiety, pain, and muscle strength,” said Dr. Ruhlmann.

Alongside exercise, and with a lower level of evidence, pharmacologic treatments can sometimes be used (II, B; II, D). Short-term use of dexamethasone or methylprednisolone is recommended for managing fatigue linked to metastatic cancer except during the course of immunotherapy (II, B).

The ESMO expert group did not reach a consensus on the use of methylphenidate, dexmethylphenidate, slow-release methylphenidate, and dexamphetamine.

Modafinil and armodafinil, antidepressants (especially paroxetine), donepezil and eszopiclone, megestrol acetate, and melatonin are not recommended (II, D).

No consensus could be reached on nutraceuticals, and they are not recommended, said Dr. Ruhlmann (II, C; II, D).

Finally, psychosocial interventions in the form of information, advice, psychoeducation, and cognitive-behavioral therapy are useful tools (II, B).

Another area being explored is the gut microbiota. “Research into the microbiota and its role in systemic inflammation is underway and could pave the way for future strategies for managing cancer-related fatigue,” said Dr. Ruhlmann. “Fatigue is a subjective experience, unlike other symptoms. It’s what those people suffering from it say it is!”

This article was translated from the Medscape French edition.

This patient's symptoms go beyond just memory problems: She has difficulty with daily tasks, shows behavioral changes, and has significant communication difficulties — symptoms not found in mild cognitive impairment. While the patient has some behavioral changes, she does not exhibit the pronounced personality changes typical of frontotemporal dementia. Finally, the patient's cognitive decline is gradual and consistent without the stepwise progression typical of vascular dementia. Given the comprehensive presentation of the patient's symptoms and the results of her clinical investigations, middle-stage Alzheimer's disease is the most fitting diagnosis.

Alzheimer's disease is a progressive and irreversible brain disorder that affects memory, behavior, and cognitive skills. This condition causes the degeneration and death of brain cells, leading to various cognitive issues. Alzheimer's disease is the most common cause of dementia and accounts for 60%-80% of dementia cases. Although the exact cause is unknown, it is believed to result from genetic, lifestyle, and environmental factors. Alzheimer's disease progresses through stages — mild (early stage), moderate (middle stage), and severe (late stage) — and each stage has different signs and symptoms.

Alzheimer's disease is commonly observed in individuals 65 years or older, as age is the most significant risk factor. Another risk factor for Alzheimer's disease is family history; individuals who have parents or siblings with Alzheimer's disease are more likely to develop the disease. The risk increases with the number of family members diagnosed with the disease. Genetics also contribute to the development of Alzheimer's disease. Genes for developing Alzheimer's disease have been classified as deterministic and risk genes, which imply that they can cause the disease or increase the risk of developing it; however, the deterministic gene, which almost guarantees the occurrence of Alzheimer's, is rare and is found in less than 1% of cases. Experiencing a head injury is also a possible risk factor for Alzheimer's disease.

Accurate diagnosis of Alzheimer's disease requires a thorough history and physical examination. Gathering information from the patient's family and caregivers is important because some patients may not be aware of their condition. It is common for Alzheimer's disease patients to experience "sundowning," which causes confusion, agitation, and behavioral issues in the evening. A comprehensive physical examination, including a detailed neurologic and mental status exam, is necessary to determine the stage of the disease and rule out other conditions. Typically, the neurologic exam of Alzheimer's disease patients is normal.

Volumetric MRI is a recent technique that allows precise measurement of changes in brain volume. In Alzheimer's disease, shrinkage in the medial temporal lobe is visible through volumetric MRI. However, hippocampal atrophy is also a normal part of age-related memory decline, which raises doubts about the appropriateness of using volumetric MRI for early detection of Alzheimer's disease. The full potential of volumetric MRI in aiding the diagnosis of Alzheimer's disease is yet to be fully established.

Alzheimer's disease has no known cure, and treatment options are limited to addressing symptoms. Currently, three types of drugs are approved for treating the moderate or severe stages of the disease: cholinesterase inhibitors, partial N-methyl D-aspartate (NMDA) antagonists, and amyloid-directed antibodies. Cholinesterase inhibitors increase acetylcholine levels, a chemical crucial for cognitive functions such as memory and learning. NMDA antagonists (memantine) blocks NMDA receptors whose overactivation is implicated in Alzheimer's disease and related to synaptic dysfunction. Antiamyloid monoclonal antibodies bind to and promote the clearance of amyloid-beta peptides, thereby reducing amyloid plaques in the brain, which are associated with Alzheimer's disease.

Jasvinder Chawla, MD, Professor of Neurology, Loyola University Medical Center, Maywood; Director, Clinical Neurophysiology Lab, Department of Neurology, Hines VA Hospital, Hines, IL.

Jasvinder Chawla, MD, has disclosed no relevant financial relationships.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

This patient's symptoms go beyond just memory problems: She has difficulty with daily tasks, shows behavioral changes, and has significant communication difficulties — symptoms not found in mild cognitive impairment. While the patient has some behavioral changes, she does not exhibit the pronounced personality changes typical of frontotemporal dementia. Finally, the patient's cognitive decline is gradual and consistent without the stepwise progression typical of vascular dementia. Given the comprehensive presentation of the patient's symptoms and the results of her clinical investigations, middle-stage Alzheimer's disease is the most fitting diagnosis.

Alzheimer's disease is a progressive and irreversible brain disorder that affects memory, behavior, and cognitive skills. This condition causes the degeneration and death of brain cells, leading to various cognitive issues. Alzheimer's disease is the most common cause of dementia and accounts for 60%-80% of dementia cases. Although the exact cause is unknown, it is believed to result from genetic, lifestyle, and environmental factors. Alzheimer's disease progresses through stages — mild (early stage), moderate (middle stage), and severe (late stage) — and each stage has different signs and symptoms.

Alzheimer's disease is commonly observed in individuals 65 years or older, as age is the most significant risk factor. Another risk factor for Alzheimer's disease is family history; individuals who have parents or siblings with Alzheimer's disease are more likely to develop the disease. The risk increases with the number of family members diagnosed with the disease. Genetics also contribute to the development of Alzheimer's disease. Genes for developing Alzheimer's disease have been classified as deterministic and risk genes, which imply that they can cause the disease or increase the risk of developing it; however, the deterministic gene, which almost guarantees the occurrence of Alzheimer's, is rare and is found in less than 1% of cases. Experiencing a head injury is also a possible risk factor for Alzheimer's disease.

Accurate diagnosis of Alzheimer's disease requires a thorough history and physical examination. Gathering information from the patient's family and caregivers is important because some patients may not be aware of their condition. It is common for Alzheimer's disease patients to experience "sundowning," which causes confusion, agitation, and behavioral issues in the evening. A comprehensive physical examination, including a detailed neurologic and mental status exam, is necessary to determine the stage of the disease and rule out other conditions. Typically, the neurologic exam of Alzheimer's disease patients is normal.

Volumetric MRI is a recent technique that allows precise measurement of changes in brain volume. In Alzheimer's disease, shrinkage in the medial temporal lobe is visible through volumetric MRI. However, hippocampal atrophy is also a normal part of age-related memory decline, which raises doubts about the appropriateness of using volumetric MRI for early detection of Alzheimer's disease. The full potential of volumetric MRI in aiding the diagnosis of Alzheimer's disease is yet to be fully established.

Alzheimer's disease has no known cure, and treatment options are limited to addressing symptoms. Currently, three types of drugs are approved for treating the moderate or severe stages of the disease: cholinesterase inhibitors, partial N-methyl D-aspartate (NMDA) antagonists, and amyloid-directed antibodies. Cholinesterase inhibitors increase acetylcholine levels, a chemical crucial for cognitive functions such as memory and learning. NMDA antagonists (memantine) blocks NMDA receptors whose overactivation is implicated in Alzheimer's disease and related to synaptic dysfunction. Antiamyloid monoclonal antibodies bind to and promote the clearance of amyloid-beta peptides, thereby reducing amyloid plaques in the brain, which are associated with Alzheimer's disease.

Jasvinder Chawla, MD, Professor of Neurology, Loyola University Medical Center, Maywood; Director, Clinical Neurophysiology Lab, Department of Neurology, Hines VA Hospital, Hines, IL.

Jasvinder Chawla, MD, has disclosed no relevant financial relationships.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

This patient's symptoms go beyond just memory problems: She has difficulty with daily tasks, shows behavioral changes, and has significant communication difficulties — symptoms not found in mild cognitive impairment. While the patient has some behavioral changes, she does not exhibit the pronounced personality changes typical of frontotemporal dementia. Finally, the patient's cognitive decline is gradual and consistent without the stepwise progression typical of vascular dementia. Given the comprehensive presentation of the patient's symptoms and the results of her clinical investigations, middle-stage Alzheimer's disease is the most fitting diagnosis.

Alzheimer's disease is a progressive and irreversible brain disorder that affects memory, behavior, and cognitive skills. This condition causes the degeneration and death of brain cells, leading to various cognitive issues. Alzheimer's disease is the most common cause of dementia and accounts for 60%-80% of dementia cases. Although the exact cause is unknown, it is believed to result from genetic, lifestyle, and environmental factors. Alzheimer's disease progresses through stages — mild (early stage), moderate (middle stage), and severe (late stage) — and each stage has different signs and symptoms.

Alzheimer's disease is commonly observed in individuals 65 years or older, as age is the most significant risk factor. Another risk factor for Alzheimer's disease is family history; individuals who have parents or siblings with Alzheimer's disease are more likely to develop the disease. The risk increases with the number of family members diagnosed with the disease. Genetics also contribute to the development of Alzheimer's disease. Genes for developing Alzheimer's disease have been classified as deterministic and risk genes, which imply that they can cause the disease or increase the risk of developing it; however, the deterministic gene, which almost guarantees the occurrence of Alzheimer's, is rare and is found in less than 1% of cases. Experiencing a head injury is also a possible risk factor for Alzheimer's disease.

Accurate diagnosis of Alzheimer's disease requires a thorough history and physical examination. Gathering information from the patient's family and caregivers is important because some patients may not be aware of their condition. It is common for Alzheimer's disease patients to experience "sundowning," which causes confusion, agitation, and behavioral issues in the evening. A comprehensive physical examination, including a detailed neurologic and mental status exam, is necessary to determine the stage of the disease and rule out other conditions. Typically, the neurologic exam of Alzheimer's disease patients is normal.

Volumetric MRI is a recent technique that allows precise measurement of changes in brain volume. In Alzheimer's disease, shrinkage in the medial temporal lobe is visible through volumetric MRI. However, hippocampal atrophy is also a normal part of age-related memory decline, which raises doubts about the appropriateness of using volumetric MRI for early detection of Alzheimer's disease. The full potential of volumetric MRI in aiding the diagnosis of Alzheimer's disease is yet to be fully established.

Alzheimer's disease has no known cure, and treatment options are limited to addressing symptoms. Currently, three types of drugs are approved for treating the moderate or severe stages of the disease: cholinesterase inhibitors, partial N-methyl D-aspartate (NMDA) antagonists, and amyloid-directed antibodies. Cholinesterase inhibitors increase acetylcholine levels, a chemical crucial for cognitive functions such as memory and learning. NMDA antagonists (memantine) blocks NMDA receptors whose overactivation is implicated in Alzheimer's disease and related to synaptic dysfunction. Antiamyloid monoclonal antibodies bind to and promote the clearance of amyloid-beta peptides, thereby reducing amyloid plaques in the brain, which are associated with Alzheimer's disease.

Jasvinder Chawla, MD, Professor of Neurology, Loyola University Medical Center, Maywood; Director, Clinical Neurophysiology Lab, Department of Neurology, Hines VA Hospital, Hines, IL.

Jasvinder Chawla, MD, has disclosed no relevant financial relationships.

Image Quizzes are fictional or fictionalized clinical scenarios intended to provide evidence-based educational takeaways.

CASE Anomalous findings on fetal anatomic survey

A 27-year-old previously healthy primigravid woman is at 18 weeks’ gestation. She is a first-grade schoolteacher. On her fetal anatomic survey, the estimated fetal weight was in the eighth percentile. Echogenic bowel and a small amount of ascitic fluid were noted in the fetal abdomen. The lateral and third ventricles were mildly dilated, the head circumference was 2 standard deviations below normal, and the placenta was slightly thickened and edematous.

What is the most likely diagnosis?

What diagnostic tests are indicated?

What management options are available for this patient?
 

Cytomegalovirus (CMV) is the most common of the perinatally transmitted infections, affecting 1% to 4% of all pregnancies. Although the virus typically causes either asymptomatic infection or only mild illness in immunocompetent individuals, it can cause life-threatening disease in immunocompromised persons and in the developing fetus. In this article, we review the virology and epidemiology of CMV infection and then focus on the key methods to diagnose infection in the mother and fetus. We conclude by considering measures that may be of at least modest value in treating CMV in pregnancy.

Virology of CMV infection

Cytomegalovirus is a double-stranded DNA virus in the Herpesviridae family. This ubiquitous virus is present in virtually all secretions and excretions of an infected host, including blood, urine, saliva, breast milk, genital secretions, and tissues and organs used for donation. Infection is transmitted through direct contact with any of the substances listed; contact with infected urine or saliva is the most common mode of transmission. Disease occurrence does not show seasonal variation.

After exposure, an incubation period of 28 to 60 days ensues, followed by development of viremia and clinical symptoms. In the majority of exposed individuals, CMV establishes a lifelong latent infection, and recurrent episodes of illness can occur as a result of reactivation of latent virus (also known as secondary infection) or, more rarely, infection with a new viral strain. In fact, most CMV illness episodes in pregnancy represent a reactivation of a previous infection rather than a new infection.

Following initial infection, both IgM (immunoglobulin M) and IgG (immunoglobulin G) antibodies develop rapidly and can be detected in blood within 1 to 2 weeks. IgM levels typically wane within 30 to 60 days, although persistence for several months is not unusual, and levels also can increase with viral reactivation (secondary infection). IgG antibodies typically persist for many years after a primary infection.

Intrauterine CMV infection occurs through hematogenous transplacental passage during maternal viremia. The risk of transmission and severity of fetal effects depend on whether or not the infection is primary or secondary in nature as well as the gestational age at fetal exposure.^1,2

Additionally, postnatal vertical transmission can occur through exposure to viral particles in genital secretions as well as breast milk. CMV acquired in the postnatal period rarely produces severe sequelae in a healthy term neonate, but it has been associated with an increased rate of complications in very low birth weight and premature newborns.³

Continue to: Who is at risk...

Who is at risk

Congenital CMV, which occurs in 2.1 to 7.7 per 10,000 live births in the United States, is both the most common congenital infection and the leading cause of nonhereditary congenital hearing loss in children.^4,5 The main reservoir of CMV in the United States is young children in day care settings, with approximately 50% of this population showing evidence of viral shedding in saliva.¹ Adult populations in North America have a high prevalence of CMV IgG antibodies indicative of prior infection, with rates reaching 50% to 80%. Among seronegative individuals aged 12 to 49, the rate of seroconversion is approximately 1 in 60 annually.⁶ Significant racial disparities have been noted in rates of seroprevalence and seroconversion, with higher rates of infection in non-Hispanic Black and Mexican American individuals.⁶ Overall, the rate of new CMV infection among pregnant women in the United States is 0.7% to 4%.⁷

Clinical manifestations

Manifestations of infection differ depending on whether or not infection is primary or recurrent (secondary) and whether or not the host is immunocompetent or has a compromised immune system. Unique manifestations develop in the fetus.

CMV infection in children and adults. Among individuals with a normal immune response, the typical course of CMV is either no symptoms or a mononucleosis-like illness. In symptomatic patients, the most common symptoms include malaise, fever, and night sweats, and the most common associated laboratory abnormalities are elevation in liver function tests and a decreased white blood cell count, with a predominance of lymphocytes.⁸

Immunocompromised individuals are at risk for significant morbidity and mortality resulting from CMV. Illness may be the result of reactivation of latent infection due to decreased immune function or may be acquired as a result of treatment such as transplantation of CMV-positive organs or tissues, including bone marrow. Virtually any organ system can be affected, with potential for permanent organ damage and death. Severe systemic infection also can occur.

CMV infection in the fetus and neonate. As noted previously, fetal infection develops as a result of transplacental passage coincident with maternal infection. The risk of CMV transmission to the fetus and the severity of fetal injury vary based on gestational age at fetal infection and whether or not maternal infection is primary or secondary.

In most studies, primary maternal infections are associated with higher rates of fetal infection and more severe fetal and neonatal disease manifestations.^2,7,9,10 Primary infections carry an overall 30% to 40% risk of transmission to the fetus.^7,11 The risk of fetal transmission is much lower with a recurrent infection and is usually less than 2%.¹¹ Due to their greater overall incidence, secondary infections account for the majority of cases of fetal and neonatal CMV disease.⁷ Importantly, although secondary infections generally have been regarded as having a lower risk and lower severity of fetal and neonatal disease, several recent studies have demonstrated rates of complications similar to, and even exceeding, those of primary infections.^12-15 The TABLE provides a summary of the risks of fetal transmission and symptomatic fetal infection based on trimester of pregnancy.^2,11,16-18

In the fetus, CMV may affect multiple organ systems. Among sonographic and magnetic resonance imaging (MRI) findings, central nervous system (CNS) anomalies are the most common.^19,20 These can include microcephaly, ventriculomegaly, and periventricular calcifications. The gastrointestinal system also is frequently affected, and findings include echogenic bowel, hepatosplenomegaly, and liver calcifications. Lastly, isolated effusions, placentomegaly, fetal growth restriction, and even frank hydrops can develop. More favorable neurologic outcomes have been demonstrated in infants with no prenatal brain imaging abnormalities.^20,21 However, the role of MRI in prenatal prognosis currently is not well defined.

FIGURE 1 illustrates selected sonographic findings associated with fetal CMV infection.

Continue to: Diagnosing CMV infection...

Diagnosing CMV infection

Maternal infection

If maternal CMV infection is suspected based on a symptomatic illness or an abnormal fetal ultrasound exam, the first diagnostic test should be an assessment of IgM and IgG serology. If the former test results are positive and the latter negative, the diagnosis of acute CMV infection is confirmed. A positive serum CMV DNA polymerase chain reaction (PCR) test adds additional assurance that the diagnosis is correct. Primary infection, as noted above, poses the greatest risk of serious injury to the fetus.¹

A frequent diagnostic dilemma arises when both the IgM and IgG antibody are positive. Remember that CMV IgM antibody can remain positive for 9 to 12 months after a primary infection and can reappear in the maternal serum in the face of a recurrent or reactivated infection. When confronted by both a positive IgM and positive IgG result, the clinician should then order IgG avidity testing. If the avidity is low to moderate, which reflects poor binding of antibody to the virus, the patient likely has an acute infection. If the avidity is high, which reflects enhanced binding of antibody to virus, the patient probably has a recurrent or reactivated infection; this scenario poses less danger to the developing fetus. The presence of CMV DNA in serum is also more consistent with acute infection, although viremia still can occur with recurrent infection. FIGURE 2 presents a suggested algorithm for the diagnosis of CMV in the pregnant patient.¹

If a diagnosis of maternal CMV infection is confirmed, liver function tests should be obtained to determine if CMV hepatitis is present. If the liver function tests are abnormal, a coagulation profile also should be performed to identify the mother who might be at risk for peripartum hemorrhage.

Fetal infection

The single best test for confirmation of congenital CMV infection is detection of viral DNA and quantitation of viral load in the amniotic fluid by PCR. If the amniocentesis is performed prior to 20 weeks’ gestation and is negative, the test should be repeated in approximately 4 weeks.^1,19,24

Detection of viral DNA indicates congenital infection. The ultimate task, however, is to determine if the infection has injured the fetus. Detailed ultrasound examination is the key to identifying fetal injury. As noted previously, the principal ultrasonographic findings that suggest congenital CMV infection include^{2,19,20,21,25}:

• hydropic placenta
• fetal growth restriction
• microcephaly (head circumference more than 3 standard deviations below the mean)
• periventricular calcifications
• enlarged liver
• echogenic bowel
• ascites
• fetal hydrops.

Management: Evidence on CMV hyperimmune globulin, valacyclovir

If the immunocompetent mother has clinical manifestations of infection, she should receive symptomatic treatment. She should be encouraged to rest as much as possible, stay well hydrated, and use acetaminophen (1,000 mg every 6 to 8 hours) as needed for malaise and fever.

However, if the mother is immunocompromised and has signs of serious complications, such as chorioretinitis, hepatitis, or pneumonia, more aggressive therapy is indicated. Drugs used in this setting include foscarnet and ganciclovir and are best prescribed in consultation with a medical infectious disease specialist.

At this time, no consistently effective therapy for congenital infection is available. Therefore, if a patient has primary CMV infection in the first half of pregnancy, particularly in the first trimester, she should be counseled that the risk of fetal infection is approximately 40% and that approximately 5% to 15% of infants will be severely affected at birth. Given this information, some patients may opt for pregnancy termination.

In 2005, a report from Nigro and colleagues stimulated great hope that CMV-specific hyperimmune globulin (CytoGam) might be of value for both treatment and prophylaxis for congenital infection.²⁶ These authors studied 157 women with confirmed primary CMV infection. One-hundred forty-eight women were asymptomatic and were identified by routine serologic screening, 8 had symptomatic infection, and 1 was identified because of abnormal fetal ultrasound findings. Forty-five women had CMV detected in amniotic fluid by PCR or culture more than 6 weeks before study enrollment. Thirty-one of these women were treated with intravenous hyperimmune globulin (200 U or 200 mg/kg maternal body weight); 14 declined treatment. Seven of the latter women had infants who were acutely symptomatic at the time of delivery; only 1 of the 31 treated women had an affected neonate (adjusted odds ratio [OR], 0.02; P<.001). In this same study, 84 women did not have a diagnostic amniocentesis because their infection occurred within 6 weeks of enrollment, their gestational age was less than 20 weeks, or they declined the procedure. Thirty-seven of these women received hyperimmune globulin (100 U or 100 mg/kg) every month until delivery, and 47 declined treatment. Six of the treated women delivered infected infants compared with 19 of the untreated women (adjusted OR, 0.32; P<.04).

Although these results were quite encouraging, several problems existed with the study’s design, as noted in an editorial that accompanied the study’s publication.²⁷ First, the study was not randomized or placebo controlled. Second, patients were not stratified based on the severity of fetal ultrasound abnormalities. Third, the dosing of hyperimmune globulin varied; 9 of the 31 patients in the treatment group received additional infusions of drug into either the amniotic fluid or fetal umbilical vein. Moreover, patients in the prophylaxis group actually received a higher cumulative dose of hyperimmune globulin than patients in the treatment group.

Two subsequent investigations that were better designed were unable to verify the effectiveness of hyperimmune globulin. In 2014, Revello and colleagues reported the results of a prospective, randomized, placebo-controlled, double-blinded study of 124 women at 5 to 26 weeks’ gestation with confirmed primary CMV infection.²⁸ The rate of congenital infection was 30% in the group treated with hyperimmune globulin and 44% in the placebo group (P=.13). There also was no significant difference in the concentration of serum CMV DNA in treated versus untreated mothers. Moreover, the number of adverse obstetric events (preterm delivery, fetal growth restriction, intrahepatic cholestasis of pregnancy, and postpartum preeclampsia) in the treatment group was higher than in the placebo group, 13% versus 2%.

In 2021, Hughes and colleagues published the results of a multicenter, double-blind trial in 399 women who had a diagnosis of primary CMV infection before 23 weeks’ gestation.²⁹ The primary outcome was defined as a composite of congenital CMV infection or fetal/neonatal death. An adverse primary outcome occurred in 22.7% of the patients who received hyperimmune globulin and 19.4% of those who received placebo (relative risk, 1.17; 95% confidence interval [CI], 0.80–1.72; P=.42).
 

Continue to: Jacquemard and colleagues...

Jacquemard and colleagues then proposed a different approach.³⁰ In a small pilot study of 20 patients, these authors used high doses of oral valacylovir (2 g 4 times daily) and documented therapeutic drug concentrations and a decline in CMV viral load in fetal serum. Patients were not stratified by severity of fetal injury at onset of treatment, so the authors were unable to define which fetuses were most likely to benefit from treatment.

In a follow-up investigation, Leruez-Ville and colleagues reported another small series in which high-dose oral valacyclovir (8 g daily) was used for treatment.³¹ They excluded fetuses with severe brain anomalies and fetuses with no sonographic evidence of injury. The median gestational age at diagnosis was 26 weeks. Thirty-four of 43 treated fetuses were free of injury at birth. In addition, the viral load in the neonate’s serum decreased significantly after treatment, and the platelet count increased. The authors then compared these outcomes to a historical cohort and confirmed that treatment increased the proportion of asymptomatic neonates from 43% without treatment to 82% with treatment (P<.05 with no overlapping confidence intervals).

We conclude from these investigations that hyperimmune globulin is unlikely to be of value in treating congenital CMV infection, especially if the fetus already has sonographic findings of severe injury. High-dose oral valacyclovir also is unlikely to be of value in severely affected fetuses, particularly those with evidence of CNS injury. However, antiviral therapy may be of modest value in situations when the fetus is less severely injured.

Preventive measures

Since no definitive treatment is available for congenital CMV infection, our efforts as clinicians should focus on measures that may prevent transmission of infection to the pregnant patient. These measures include:

• Encouraging patients to use careful handwashing techniques when handling infant diapers and toys.
• Encouraging patients to adopt safe sexual practices if not already engaged in a mutually faithful, monogamous relationship.
• Using CMV-negative blood when transfusing a pregnant woman or a fetus.

At the present time, unfortunately, a readily available and highly effective therapy for prevention of CMV infection is not available.

CASE Congenital infection diagnosed

The ultrasound findings are most consistent with congenital CMV infection, especially given the patient’s work as an elementary schoolteacher. The diagnosis of maternal infection is best established by conventional serology (positive IgM, negative IgM) and detection of viral DNA in maternal blood by PCR testing. The diagnosis of congenital infection is best confirmed by documentation of viral DNA in the amniotic fluid by PCR testing. Given that this fetus already has evidence of moderate to severe injury, no treatment is likely to be effective in reversing the abnormal ultrasound findings. Pregnancy termination may be an option, depending upon the patient’s desires and the legal restrictions prevalent in the patient’s geographic area. ●

CASE Anomalous findings on fetal anatomic survey

A 27-year-old previously healthy primigravid woman is at 18 weeks’ gestation. She is a first-grade schoolteacher. On her fetal anatomic survey, the estimated fetal weight was in the eighth percentile. Echogenic bowel and a small amount of ascitic fluid were noted in the fetal abdomen. The lateral and third ventricles were mildly dilated, the head circumference was 2 standard deviations below normal, and the placenta was slightly thickened and edematous.

What is the most likely diagnosis?

What diagnostic tests are indicated?

What management options are available for this patient?
 

Cytomegalovirus (CMV) is the most common of the perinatally transmitted infections, affecting 1% to 4% of all pregnancies. Although the virus typically causes either asymptomatic infection or only mild illness in immunocompetent individuals, it can cause life-threatening disease in immunocompromised persons and in the developing fetus. In this article, we review the virology and epidemiology of CMV infection and then focus on the key methods to diagnose infection in the mother and fetus. We conclude by considering measures that may be of at least modest value in treating CMV in pregnancy.

Virology of CMV infection

Cytomegalovirus is a double-stranded DNA virus in the Herpesviridae family. This ubiquitous virus is present in virtually all secretions and excretions of an infected host, including blood, urine, saliva, breast milk, genital secretions, and tissues and organs used for donation. Infection is transmitted through direct contact with any of the substances listed; contact with infected urine or saliva is the most common mode of transmission. Disease occurrence does not show seasonal variation.

After exposure, an incubation period of 28 to 60 days ensues, followed by development of viremia and clinical symptoms. In the majority of exposed individuals, CMV establishes a lifelong latent infection, and recurrent episodes of illness can occur as a result of reactivation of latent virus (also known as secondary infection) or, more rarely, infection with a new viral strain. In fact, most CMV illness episodes in pregnancy represent a reactivation of a previous infection rather than a new infection.

Following initial infection, both IgM (immunoglobulin M) and IgG (immunoglobulin G) antibodies develop rapidly and can be detected in blood within 1 to 2 weeks. IgM levels typically wane within 30 to 60 days, although persistence for several months is not unusual, and levels also can increase with viral reactivation (secondary infection). IgG antibodies typically persist for many years after a primary infection.

Intrauterine CMV infection occurs through hematogenous transplacental passage during maternal viremia. The risk of transmission and severity of fetal effects depend on whether or not the infection is primary or secondary in nature as well as the gestational age at fetal exposure.^1,2

Additionally, postnatal vertical transmission can occur through exposure to viral particles in genital secretions as well as breast milk. CMV acquired in the postnatal period rarely produces severe sequelae in a healthy term neonate, but it has been associated with an increased rate of complications in very low birth weight and premature newborns.³

Continue to: Who is at risk...

Who is at risk

Congenital CMV, which occurs in 2.1 to 7.7 per 10,000 live births in the United States, is both the most common congenital infection and the leading cause of nonhereditary congenital hearing loss in children.^4,5 The main reservoir of CMV in the United States is young children in day care settings, with approximately 50% of this population showing evidence of viral shedding in saliva.¹ Adult populations in North America have a high prevalence of CMV IgG antibodies indicative of prior infection, with rates reaching 50% to 80%. Among seronegative individuals aged 12 to 49, the rate of seroconversion is approximately 1 in 60 annually.⁶ Significant racial disparities have been noted in rates of seroprevalence and seroconversion, with higher rates of infection in non-Hispanic Black and Mexican American individuals.⁶ Overall, the rate of new CMV infection among pregnant women in the United States is 0.7% to 4%.⁷

Clinical manifestations

Manifestations of infection differ depending on whether or not infection is primary or recurrent (secondary) and whether or not the host is immunocompetent or has a compromised immune system. Unique manifestations develop in the fetus.

CMV infection in children and adults. Among individuals with a normal immune response, the typical course of CMV is either no symptoms or a mononucleosis-like illness. In symptomatic patients, the most common symptoms include malaise, fever, and night sweats, and the most common associated laboratory abnormalities are elevation in liver function tests and a decreased white blood cell count, with a predominance of lymphocytes.⁸

Immunocompromised individuals are at risk for significant morbidity and mortality resulting from CMV. Illness may be the result of reactivation of latent infection due to decreased immune function or may be acquired as a result of treatment such as transplantation of CMV-positive organs or tissues, including bone marrow. Virtually any organ system can be affected, with potential for permanent organ damage and death. Severe systemic infection also can occur.

CMV infection in the fetus and neonate. As noted previously, fetal infection develops as a result of transplacental passage coincident with maternal infection. The risk of CMV transmission to the fetus and the severity of fetal injury vary based on gestational age at fetal infection and whether or not maternal infection is primary or secondary.

In most studies, primary maternal infections are associated with higher rates of fetal infection and more severe fetal and neonatal disease manifestations.^2,7,9,10 Primary infections carry an overall 30% to 40% risk of transmission to the fetus.^7,11 The risk of fetal transmission is much lower with a recurrent infection and is usually less than 2%.¹¹ Due to their greater overall incidence, secondary infections account for the majority of cases of fetal and neonatal CMV disease.⁷ Importantly, although secondary infections generally have been regarded as having a lower risk and lower severity of fetal and neonatal disease, several recent studies have demonstrated rates of complications similar to, and even exceeding, those of primary infections.^12-15 The TABLE provides a summary of the risks of fetal transmission and symptomatic fetal infection based on trimester of pregnancy.^2,11,16-18

In the fetus, CMV may affect multiple organ systems. Among sonographic and magnetic resonance imaging (MRI) findings, central nervous system (CNS) anomalies are the most common.^19,20 These can include microcephaly, ventriculomegaly, and periventricular calcifications. The gastrointestinal system also is frequently affected, and findings include echogenic bowel, hepatosplenomegaly, and liver calcifications. Lastly, isolated effusions, placentomegaly, fetal growth restriction, and even frank hydrops can develop. More favorable neurologic outcomes have been demonstrated in infants with no prenatal brain imaging abnormalities.^20,21 However, the role of MRI in prenatal prognosis currently is not well defined.

FIGURE 1 illustrates selected sonographic findings associated with fetal CMV infection.

Continue to: Diagnosing CMV infection...

Diagnosing CMV infection

Maternal infection

If maternal CMV infection is suspected based on a symptomatic illness or an abnormal fetal ultrasound exam, the first diagnostic test should be an assessment of IgM and IgG serology. If the former test results are positive and the latter negative, the diagnosis of acute CMV infection is confirmed. A positive serum CMV DNA polymerase chain reaction (PCR) test adds additional assurance that the diagnosis is correct. Primary infection, as noted above, poses the greatest risk of serious injury to the fetus.¹

A frequent diagnostic dilemma arises when both the IgM and IgG antibody are positive. Remember that CMV IgM antibody can remain positive for 9 to 12 months after a primary infection and can reappear in the maternal serum in the face of a recurrent or reactivated infection. When confronted by both a positive IgM and positive IgG result, the clinician should then order IgG avidity testing. If the avidity is low to moderate, which reflects poor binding of antibody to the virus, the patient likely has an acute infection. If the avidity is high, which reflects enhanced binding of antibody to virus, the patient probably has a recurrent or reactivated infection; this scenario poses less danger to the developing fetus. The presence of CMV DNA in serum is also more consistent with acute infection, although viremia still can occur with recurrent infection. FIGURE 2 presents a suggested algorithm for the diagnosis of CMV in the pregnant patient.¹

If a diagnosis of maternal CMV infection is confirmed, liver function tests should be obtained to determine if CMV hepatitis is present. If the liver function tests are abnormal, a coagulation profile also should be performed to identify the mother who might be at risk for peripartum hemorrhage.

Fetal infection

The single best test for confirmation of congenital CMV infection is detection of viral DNA and quantitation of viral load in the amniotic fluid by PCR. If the amniocentesis is performed prior to 20 weeks’ gestation and is negative, the test should be repeated in approximately 4 weeks.^1,19,24

Detection of viral DNA indicates congenital infection. The ultimate task, however, is to determine if the infection has injured the fetus. Detailed ultrasound examination is the key to identifying fetal injury. As noted previously, the principal ultrasonographic findings that suggest congenital CMV infection include^{2,19,20,21,25}:

• hydropic placenta
• fetal growth restriction
• microcephaly (head circumference more than 3 standard deviations below the mean)
• periventricular calcifications
• enlarged liver
• echogenic bowel
• ascites
• fetal hydrops.

Management: Evidence on CMV hyperimmune globulin, valacyclovir

If the immunocompetent mother has clinical manifestations of infection, she should receive symptomatic treatment. She should be encouraged to rest as much as possible, stay well hydrated, and use acetaminophen (1,000 mg every 6 to 8 hours) as needed for malaise and fever.

However, if the mother is immunocompromised and has signs of serious complications, such as chorioretinitis, hepatitis, or pneumonia, more aggressive therapy is indicated. Drugs used in this setting include foscarnet and ganciclovir and are best prescribed in consultation with a medical infectious disease specialist.

At this time, no consistently effective therapy for congenital infection is available. Therefore, if a patient has primary CMV infection in the first half of pregnancy, particularly in the first trimester, she should be counseled that the risk of fetal infection is approximately 40% and that approximately 5% to 15% of infants will be severely affected at birth. Given this information, some patients may opt for pregnancy termination.

In 2005, a report from Nigro and colleagues stimulated great hope that CMV-specific hyperimmune globulin (CytoGam) might be of value for both treatment and prophylaxis for congenital infection.²⁶ These authors studied 157 women with confirmed primary CMV infection. One-hundred forty-eight women were asymptomatic and were identified by routine serologic screening, 8 had symptomatic infection, and 1 was identified because of abnormal fetal ultrasound findings. Forty-five women had CMV detected in amniotic fluid by PCR or culture more than 6 weeks before study enrollment. Thirty-one of these women were treated with intravenous hyperimmune globulin (200 U or 200 mg/kg maternal body weight); 14 declined treatment. Seven of the latter women had infants who were acutely symptomatic at the time of delivery; only 1 of the 31 treated women had an affected neonate (adjusted odds ratio [OR], 0.02; P<.001). In this same study, 84 women did not have a diagnostic amniocentesis because their infection occurred within 6 weeks of enrollment, their gestational age was less than 20 weeks, or they declined the procedure. Thirty-seven of these women received hyperimmune globulin (100 U or 100 mg/kg) every month until delivery, and 47 declined treatment. Six of the treated women delivered infected infants compared with 19 of the untreated women (adjusted OR, 0.32; P<.04).

Although these results were quite encouraging, several problems existed with the study’s design, as noted in an editorial that accompanied the study’s publication.²⁷ First, the study was not randomized or placebo controlled. Second, patients were not stratified based on the severity of fetal ultrasound abnormalities. Third, the dosing of hyperimmune globulin varied; 9 of the 31 patients in the treatment group received additional infusions of drug into either the amniotic fluid or fetal umbilical vein. Moreover, patients in the prophylaxis group actually received a higher cumulative dose of hyperimmune globulin than patients in the treatment group.

Two subsequent investigations that were better designed were unable to verify the effectiveness of hyperimmune globulin. In 2014, Revello and colleagues reported the results of a prospective, randomized, placebo-controlled, double-blinded study of 124 women at 5 to 26 weeks’ gestation with confirmed primary CMV infection.²⁸ The rate of congenital infection was 30% in the group treated with hyperimmune globulin and 44% in the placebo group (P=.13). There also was no significant difference in the concentration of serum CMV DNA in treated versus untreated mothers. Moreover, the number of adverse obstetric events (preterm delivery, fetal growth restriction, intrahepatic cholestasis of pregnancy, and postpartum preeclampsia) in the treatment group was higher than in the placebo group, 13% versus 2%.

In 2021, Hughes and colleagues published the results of a multicenter, double-blind trial in 399 women who had a diagnosis of primary CMV infection before 23 weeks’ gestation.²⁹ The primary outcome was defined as a composite of congenital CMV infection or fetal/neonatal death. An adverse primary outcome occurred in 22.7% of the patients who received hyperimmune globulin and 19.4% of those who received placebo (relative risk, 1.17; 95% confidence interval [CI], 0.80–1.72; P=.42).
 

Continue to: Jacquemard and colleagues...

Jacquemard and colleagues then proposed a different approach.³⁰ In a small pilot study of 20 patients, these authors used high doses of oral valacylovir (2 g 4 times daily) and documented therapeutic drug concentrations and a decline in CMV viral load in fetal serum. Patients were not stratified by severity of fetal injury at onset of treatment, so the authors were unable to define which fetuses were most likely to benefit from treatment.

In a follow-up investigation, Leruez-Ville and colleagues reported another small series in which high-dose oral valacyclovir (8 g daily) was used for treatment.³¹ They excluded fetuses with severe brain anomalies and fetuses with no sonographic evidence of injury. The median gestational age at diagnosis was 26 weeks. Thirty-four of 43 treated fetuses were free of injury at birth. In addition, the viral load in the neonate’s serum decreased significantly after treatment, and the platelet count increased. The authors then compared these outcomes to a historical cohort and confirmed that treatment increased the proportion of asymptomatic neonates from 43% without treatment to 82% with treatment (P<.05 with no overlapping confidence intervals).

We conclude from these investigations that hyperimmune globulin is unlikely to be of value in treating congenital CMV infection, especially if the fetus already has sonographic findings of severe injury. High-dose oral valacyclovir also is unlikely to be of value in severely affected fetuses, particularly those with evidence of CNS injury. However, antiviral therapy may be of modest value in situations when the fetus is less severely injured.

Preventive measures

Since no definitive treatment is available for congenital CMV infection, our efforts as clinicians should focus on measures that may prevent transmission of infection to the pregnant patient. These measures include:

• Encouraging patients to use careful handwashing techniques when handling infant diapers and toys.
• Encouraging patients to adopt safe sexual practices if not already engaged in a mutually faithful, monogamous relationship.
• Using CMV-negative blood when transfusing a pregnant woman or a fetus.

At the present time, unfortunately, a readily available and highly effective therapy for prevention of CMV infection is not available.

CASE Congenital infection diagnosed

The ultrasound findings are most consistent with congenital CMV infection, especially given the patient’s work as an elementary schoolteacher. The diagnosis of maternal infection is best established by conventional serology (positive IgM, negative IgM) and detection of viral DNA in maternal blood by PCR testing. The diagnosis of congenital infection is best confirmed by documentation of viral DNA in the amniotic fluid by PCR testing. Given that this fetus already has evidence of moderate to severe injury, no treatment is likely to be effective in reversing the abnormal ultrasound findings. Pregnancy termination may be an option, depending upon the patient’s desires and the legal restrictions prevalent in the patient’s geographic area. ●

CASE Anomalous findings on fetal anatomic survey

A 27-year-old previously healthy primigravid woman is at 18 weeks’ gestation. She is a first-grade schoolteacher. On her fetal anatomic survey, the estimated fetal weight was in the eighth percentile. Echogenic bowel and a small amount of ascitic fluid were noted in the fetal abdomen. The lateral and third ventricles were mildly dilated, the head circumference was 2 standard deviations below normal, and the placenta was slightly thickened and edematous.

What is the most likely diagnosis?

What diagnostic tests are indicated?

What management options are available for this patient?
 

Cytomegalovirus (CMV) is the most common of the perinatally transmitted infections, affecting 1% to 4% of all pregnancies. Although the virus typically causes either asymptomatic infection or only mild illness in immunocompetent individuals, it can cause life-threatening disease in immunocompromised persons and in the developing fetus. In this article, we review the virology and epidemiology of CMV infection and then focus on the key methods to diagnose infection in the mother and fetus. We conclude by considering measures that may be of at least modest value in treating CMV in pregnancy.

Virology of CMV infection

Cytomegalovirus is a double-stranded DNA virus in the Herpesviridae family. This ubiquitous virus is present in virtually all secretions and excretions of an infected host, including blood, urine, saliva, breast milk, genital secretions, and tissues and organs used for donation. Infection is transmitted through direct contact with any of the substances listed; contact with infected urine or saliva is the most common mode of transmission. Disease occurrence does not show seasonal variation.

After exposure, an incubation period of 28 to 60 days ensues, followed by development of viremia and clinical symptoms. In the majority of exposed individuals, CMV establishes a lifelong latent infection, and recurrent episodes of illness can occur as a result of reactivation of latent virus (also known as secondary infection) or, more rarely, infection with a new viral strain. In fact, most CMV illness episodes in pregnancy represent a reactivation of a previous infection rather than a new infection.

Following initial infection, both IgM (immunoglobulin M) and IgG (immunoglobulin G) antibodies develop rapidly and can be detected in blood within 1 to 2 weeks. IgM levels typically wane within 30 to 60 days, although persistence for several months is not unusual, and levels also can increase with viral reactivation (secondary infection). IgG antibodies typically persist for many years after a primary infection.

Intrauterine CMV infection occurs through hematogenous transplacental passage during maternal viremia. The risk of transmission and severity of fetal effects depend on whether or not the infection is primary or secondary in nature as well as the gestational age at fetal exposure.^1,2

Additionally, postnatal vertical transmission can occur through exposure to viral particles in genital secretions as well as breast milk. CMV acquired in the postnatal period rarely produces severe sequelae in a healthy term neonate, but it has been associated with an increased rate of complications in very low birth weight and premature newborns.³

Continue to: Who is at risk...

Who is at risk

Congenital CMV, which occurs in 2.1 to 7.7 per 10,000 live births in the United States, is both the most common congenital infection and the leading cause of nonhereditary congenital hearing loss in children.^4,5 The main reservoir of CMV in the United States is young children in day care settings, with approximately 50% of this population showing evidence of viral shedding in saliva.¹ Adult populations in North America have a high prevalence of CMV IgG antibodies indicative of prior infection, with rates reaching 50% to 80%. Among seronegative individuals aged 12 to 49, the rate of seroconversion is approximately 1 in 60 annually.⁶ Significant racial disparities have been noted in rates of seroprevalence and seroconversion, with higher rates of infection in non-Hispanic Black and Mexican American individuals.⁶ Overall, the rate of new CMV infection among pregnant women in the United States is 0.7% to 4%.⁷

Clinical manifestations

Manifestations of infection differ depending on whether or not infection is primary or recurrent (secondary) and whether or not the host is immunocompetent or has a compromised immune system. Unique manifestations develop in the fetus.

CMV infection in children and adults. Among individuals with a normal immune response, the typical course of CMV is either no symptoms or a mononucleosis-like illness. In symptomatic patients, the most common symptoms include malaise, fever, and night sweats, and the most common associated laboratory abnormalities are elevation in liver function tests and a decreased white blood cell count, with a predominance of lymphocytes.⁸

Immunocompromised individuals are at risk for significant morbidity and mortality resulting from CMV. Illness may be the result of reactivation of latent infection due to decreased immune function or may be acquired as a result of treatment such as transplantation of CMV-positive organs or tissues, including bone marrow. Virtually any organ system can be affected, with potential for permanent organ damage and death. Severe systemic infection also can occur.

CMV infection in the fetus and neonate. As noted previously, fetal infection develops as a result of transplacental passage coincident with maternal infection. The risk of CMV transmission to the fetus and the severity of fetal injury vary based on gestational age at fetal infection and whether or not maternal infection is primary or secondary.

In most studies, primary maternal infections are associated with higher rates of fetal infection and more severe fetal and neonatal disease manifestations.^2,7,9,10 Primary infections carry an overall 30% to 40% risk of transmission to the fetus.^7,11 The risk of fetal transmission is much lower with a recurrent infection and is usually less than 2%.¹¹ Due to their greater overall incidence, secondary infections account for the majority of cases of fetal and neonatal CMV disease.⁷ Importantly, although secondary infections generally have been regarded as having a lower risk and lower severity of fetal and neonatal disease, several recent studies have demonstrated rates of complications similar to, and even exceeding, those of primary infections.^12-15 The TABLE provides a summary of the risks of fetal transmission and symptomatic fetal infection based on trimester of pregnancy.^2,11,16-18

In the fetus, CMV may affect multiple organ systems. Among sonographic and magnetic resonance imaging (MRI) findings, central nervous system (CNS) anomalies are the most common.^19,20 These can include microcephaly, ventriculomegaly, and periventricular calcifications. The gastrointestinal system also is frequently affected, and findings include echogenic bowel, hepatosplenomegaly, and liver calcifications. Lastly, isolated effusions, placentomegaly, fetal growth restriction, and even frank hydrops can develop. More favorable neurologic outcomes have been demonstrated in infants with no prenatal brain imaging abnormalities.^20,21 However, the role of MRI in prenatal prognosis currently is not well defined.

FIGURE 1 illustrates selected sonographic findings associated with fetal CMV infection.

Continue to: Diagnosing CMV infection...

Diagnosing CMV infection

Maternal infection

If maternal CMV infection is suspected based on a symptomatic illness or an abnormal fetal ultrasound exam, the first diagnostic test should be an assessment of IgM and IgG serology. If the former test results are positive and the latter negative, the diagnosis of acute CMV infection is confirmed. A positive serum CMV DNA polymerase chain reaction (PCR) test adds additional assurance that the diagnosis is correct. Primary infection, as noted above, poses the greatest risk of serious injury to the fetus.¹

A frequent diagnostic dilemma arises when both the IgM and IgG antibody are positive. Remember that CMV IgM antibody can remain positive for 9 to 12 months after a primary infection and can reappear in the maternal serum in the face of a recurrent or reactivated infection. When confronted by both a positive IgM and positive IgG result, the clinician should then order IgG avidity testing. If the avidity is low to moderate, which reflects poor binding of antibody to the virus, the patient likely has an acute infection. If the avidity is high, which reflects enhanced binding of antibody to virus, the patient probably has a recurrent or reactivated infection; this scenario poses less danger to the developing fetus. The presence of CMV DNA in serum is also more consistent with acute infection, although viremia still can occur with recurrent infection. FIGURE 2 presents a suggested algorithm for the diagnosis of CMV in the pregnant patient.¹

If a diagnosis of maternal CMV infection is confirmed, liver function tests should be obtained to determine if CMV hepatitis is present. If the liver function tests are abnormal, a coagulation profile also should be performed to identify the mother who might be at risk for peripartum hemorrhage.

Fetal infection

The single best test for confirmation of congenital CMV infection is detection of viral DNA and quantitation of viral load in the amniotic fluid by PCR. If the amniocentesis is performed prior to 20 weeks’ gestation and is negative, the test should be repeated in approximately 4 weeks.^1,19,24

Detection of viral DNA indicates congenital infection. The ultimate task, however, is to determine if the infection has injured the fetus. Detailed ultrasound examination is the key to identifying fetal injury. As noted previously, the principal ultrasonographic findings that suggest congenital CMV infection include^{2,19,20,21,25}:

• hydropic placenta
• fetal growth restriction
• microcephaly (head circumference more than 3 standard deviations below the mean)
• periventricular calcifications
• enlarged liver
• echogenic bowel
• ascites
• fetal hydrops.

Management: Evidence on CMV hyperimmune globulin, valacyclovir

If the immunocompetent mother has clinical manifestations of infection, she should receive symptomatic treatment. She should be encouraged to rest as much as possible, stay well hydrated, and use acetaminophen (1,000 mg every 6 to 8 hours) as needed for malaise and fever.

However, if the mother is immunocompromised and has signs of serious complications, such as chorioretinitis, hepatitis, or pneumonia, more aggressive therapy is indicated. Drugs used in this setting include foscarnet and ganciclovir and are best prescribed in consultation with a medical infectious disease specialist.

At this time, no consistently effective therapy for congenital infection is available. Therefore, if a patient has primary CMV infection in the first half of pregnancy, particularly in the first trimester, she should be counseled that the risk of fetal infection is approximately 40% and that approximately 5% to 15% of infants will be severely affected at birth. Given this information, some patients may opt for pregnancy termination.

In 2005, a report from Nigro and colleagues stimulated great hope that CMV-specific hyperimmune globulin (CytoGam) might be of value for both treatment and prophylaxis for congenital infection.²⁶ These authors studied 157 women with confirmed primary CMV infection. One-hundred forty-eight women were asymptomatic and were identified by routine serologic screening, 8 had symptomatic infection, and 1 was identified because of abnormal fetal ultrasound findings. Forty-five women had CMV detected in amniotic fluid by PCR or culture more than 6 weeks before study enrollment. Thirty-one of these women were treated with intravenous hyperimmune globulin (200 U or 200 mg/kg maternal body weight); 14 declined treatment. Seven of the latter women had infants who were acutely symptomatic at the time of delivery; only 1 of the 31 treated women had an affected neonate (adjusted odds ratio [OR], 0.02; P<.001). In this same study, 84 women did not have a diagnostic amniocentesis because their infection occurred within 6 weeks of enrollment, their gestational age was less than 20 weeks, or they declined the procedure. Thirty-seven of these women received hyperimmune globulin (100 U or 100 mg/kg) every month until delivery, and 47 declined treatment. Six of the treated women delivered infected infants compared with 19 of the untreated women (adjusted OR, 0.32; P<.04).

Although these results were quite encouraging, several problems existed with the study’s design, as noted in an editorial that accompanied the study’s publication.²⁷ First, the study was not randomized or placebo controlled. Second, patients were not stratified based on the severity of fetal ultrasound abnormalities. Third, the dosing of hyperimmune globulin varied; 9 of the 31 patients in the treatment group received additional infusions of drug into either the amniotic fluid or fetal umbilical vein. Moreover, patients in the prophylaxis group actually received a higher cumulative dose of hyperimmune globulin than patients in the treatment group.

Two subsequent investigations that were better designed were unable to verify the effectiveness of hyperimmune globulin. In 2014, Revello and colleagues reported the results of a prospective, randomized, placebo-controlled, double-blinded study of 124 women at 5 to 26 weeks’ gestation with confirmed primary CMV infection.²⁸ The rate of congenital infection was 30% in the group treated with hyperimmune globulin and 44% in the placebo group (P=.13). There also was no significant difference in the concentration of serum CMV DNA in treated versus untreated mothers. Moreover, the number of adverse obstetric events (preterm delivery, fetal growth restriction, intrahepatic cholestasis of pregnancy, and postpartum preeclampsia) in the treatment group was higher than in the placebo group, 13% versus 2%.

In 2021, Hughes and colleagues published the results of a multicenter, double-blind trial in 399 women who had a diagnosis of primary CMV infection before 23 weeks’ gestation.²⁹ The primary outcome was defined as a composite of congenital CMV infection or fetal/neonatal death. An adverse primary outcome occurred in 22.7% of the patients who received hyperimmune globulin and 19.4% of those who received placebo (relative risk, 1.17; 95% confidence interval [CI], 0.80–1.72; P=.42).
 

Continue to: Jacquemard and colleagues...

Jacquemard and colleagues then proposed a different approach.³⁰ In a small pilot study of 20 patients, these authors used high doses of oral valacylovir (2 g 4 times daily) and documented therapeutic drug concentrations and a decline in CMV viral load in fetal serum. Patients were not stratified by severity of fetal injury at onset of treatment, so the authors were unable to define which fetuses were most likely to benefit from treatment.

In a follow-up investigation, Leruez-Ville and colleagues reported another small series in which high-dose oral valacyclovir (8 g daily) was used for treatment.³¹ They excluded fetuses with severe brain anomalies and fetuses with no sonographic evidence of injury. The median gestational age at diagnosis was 26 weeks. Thirty-four of 43 treated fetuses were free of injury at birth. In addition, the viral load in the neonate’s serum decreased significantly after treatment, and the platelet count increased. The authors then compared these outcomes to a historical cohort and confirmed that treatment increased the proportion of asymptomatic neonates from 43% without treatment to 82% with treatment (P<.05 with no overlapping confidence intervals).

We conclude from these investigations that hyperimmune globulin is unlikely to be of value in treating congenital CMV infection, especially if the fetus already has sonographic findings of severe injury. High-dose oral valacyclovir also is unlikely to be of value in severely affected fetuses, particularly those with evidence of CNS injury. However, antiviral therapy may be of modest value in situations when the fetus is less severely injured.

Preventive measures

Since no definitive treatment is available for congenital CMV infection, our efforts as clinicians should focus on measures that may prevent transmission of infection to the pregnant patient. These measures include:

• Encouraging patients to use careful handwashing techniques when handling infant diapers and toys.
• Encouraging patients to adopt safe sexual practices if not already engaged in a mutually faithful, monogamous relationship.
• Using CMV-negative blood when transfusing a pregnant woman or a fetus.

At the present time, unfortunately, a readily available and highly effective therapy for prevention of CMV infection is not available.

CASE Congenital infection diagnosed

The ultrasound findings are most consistent with congenital CMV infection, especially given the patient’s work as an elementary schoolteacher. The diagnosis of maternal infection is best established by conventional serology (positive IgM, negative IgM) and detection of viral DNA in maternal blood by PCR testing. The diagnosis of congenital infection is best confirmed by documentation of viral DNA in the amniotic fluid by PCR testing. Given that this fetus already has evidence of moderate to severe injury, no treatment is likely to be effective in reversing the abnormal ultrasound findings. Pregnancy termination may be an option, depending upon the patient’s desires and the legal restrictions prevalent in the patient’s geographic area. ●