There was an explosion in the use of telemedicine during the COVID-19 pandemic, but usage has stabilized and varies between specialties. However, telemedicine use is still somewhat high among rheumatologists, according to speakers at the 2023 Rheumatology Winter Clinical Symposium.

Speaking in general about the future of rheumatology, Jack Cush, MD, a rheumatologist based in Dallas and executive editor of RheumNow.com, said it is up to rheumatologists to adapt to the changing winds in the specialty.

FatCamera/Getty Images

“The future is going to happen no matter what, so the question is, are you going to go along with it? Are you going to be a part of it? Are you going to be resistant to it?” Dr. Cush asked attendees. “Your recent experience with COVID would tell you maybe what your path is going to be if you’re dying to get back to the way it once was.”

Rheumatologists can expect changes in where they work, how they’re paid, increases in their workload, and new innovations in connecting with patients, he said.

“You’re going to be integrating a new style of medicine, you’re going to be digitally connected,” he explained. “All these networks are going to be working together to make you supposedly better at what you do, or maybe they’re working together to make you obsolete – and I think you better start protecting your space.”

One major area of change, telemedicine, already occurred as a result of the COVID-19 pandemic and will “begin to dominate” over the next decade, Dr. Cush said. An analysis conducted by consulting firm McKinsey & Company found telehealth usage increased 78-fold between February and April 2020 before leveling off at a 38-fold higher rate, compared with prepandemic levels. In the same analysis, rheumatology ranked third in terms of telehealth usage claims behind psychiatry and substance use disorder treatment, Dr. Cush observed, as other specialties have “fallen off quite a bit.”

“The common denominators are chronic care, cognitive care, nonprocedural care, pattern recognition, and monitoring, and this is what you do,” he said. “This is why, in many ways, for you to abandon telemedicine I think is a gigantic mistake.”
 

Changes to telemedicine

The most immediate change to telemedicine will come when the Biden administration officially ends the COVID-19 public health emergency in May 2023, and temporary telehealth services will be extended for approximately 5 months after the end of the public health emergency. Legislation passed by Congress will ensure some of the flexibilities in telemedicine will be extended until the end of December 2024.

Alvin Wells, MD, PhD, director of the department of rheumatology at Advocate Aurora Health in Franklin, Wisc., said he sees telemedicine as persisting even after the official COVID-19 public health emergency ends. “There’s a lot of push from the American Medical Association, from the American College of Physicians. You’re going to see people – this will not go away because [there’s] also going to be that demand.”

Despite decreased usage since April 2020, telehealth was estimated to be a $60 billion industry in 2022 and will likely increase over the next decade, Dr. Cush noted. “I question [the decline] because I think it still is a major part of your [future in] 2033.”

The number of physicians who have at least three licenses to practice in other U.S. states increased from 50,454 in 2010 to 72,752 in 2020, and that trend will continue, Dr. Wells explained. It is now becoming easier for physicians to become licensed in other states with companies like CompHealth that offer services to simplify obtaining medical licenses with states that participate in the Interstate Medical Licensure Compact.

“It’s a telemedicine easy pass,” Dr. Cush said.
 

Concerns in telemedicine

Commenting on the presentation, Allan Gibofsky, MD, JD, professor of medicine at Weill Cornell Medicine and codirector of the Clinic for Inflammatory Arthritis and Biologic Therapy at the Hospital for Special Surgery (HSS), both in New York, pointed out that because telemedicine is governed by U.S. states, rather than the federal government, a physician needs to be licensed in the state where the patient is located. While many states relaxed their restrictions during COVID-19, as states began tightening their restrictions later, “many physicians didn’t want to have three licenses,” he said.

“There’s an expense in getting three licenses. There’s an expense in obtaining it and maintaining it, and the reimbursement for the telemedicine visit did not reach that expectation,” Dr. Gibofsky explained. With the exception of the orthopedic surgeons at HSS who practice in New York and a satellite office in Florida, none of the surgeons at his center have obtained more than one license to practice telemedicine in other states.

“Our volume of telemedicine at HSS has remained about the same at 30%, but fewer physicians are doing it because they don’t want to maintain multiple licensures,” he said. “So don’t overlook the role of legal concerns in terms of who’s going to be allowed to do what where. Your talk was great in terms of an exuberance of what’s going to be available, but it’s not going to relieve the physician from the burden of being responsible for their use.”

Eric Ruderman, MD, professor of rheumatology at Northwestern University, Chicago, asked the presenters about the balance between seeing patients for virtual and in-person visits. “The question is what’s the sweet spot? Are there people you’re willing to see virtually forever?” he asked, noting that he has patients scheduling telemedicine visits that he hasn’t seen since before the COVID-19 pandemic.

“That’s not going to work for me. At some point, you have to lay hands on people,” he said.

Dr. Wells said his current practice is 40% virtual, and his staff converts potential no-shows into a telemedicine consultation over the phone. “My no-show rate has gone down to zero. Somebody’s scheduled for a visit, they don’t show up, my [medical assistants] get them on the phone, they put them on hold, tee up the refills. I turn them into a telephone call,” he said. “We don’t accept the no-show at all because we can do a telephone [consultation].”

In Dr. Cush’s practice, he alternates telemedicine visits with in-person visits. “If you come back for two videos in a row, you’re catching hell from me for that,” he said. Responding to how Dr. Wells incorporates telemedicine into his practice, Dr. Cush said many rheumatologists “don’t have the setups to support the care, and that’s why it’s hard to do and that’s why we’re not as great as we could be.”

“This is the way we were trained. We’re used to seeing these patients in the clinic that often. Not every single patient needs to be seen that frequently if they’re stable and doing fine,” Dr. Wells countered.

Dr. Cush and Dr. Wells reported having financial relationships with numerous pharmaceutical companies.

There was an explosion in the use of telemedicine during the COVID-19 pandemic, but usage has stabilized and varies between specialties. However, telemedicine use is still somewhat high among rheumatologists, according to speakers at the 2023 Rheumatology Winter Clinical Symposium.

Speaking in general about the future of rheumatology, Jack Cush, MD, a rheumatologist based in Dallas and executive editor of RheumNow.com, said it is up to rheumatologists to adapt to the changing winds in the specialty.

FatCamera/Getty Images

“The future is going to happen no matter what, so the question is, are you going to go along with it? Are you going to be a part of it? Are you going to be resistant to it?” Dr. Cush asked attendees. “Your recent experience with COVID would tell you maybe what your path is going to be if you’re dying to get back to the way it once was.”

Rheumatologists can expect changes in where they work, how they’re paid, increases in their workload, and new innovations in connecting with patients, he said.

“You’re going to be integrating a new style of medicine, you’re going to be digitally connected,” he explained. “All these networks are going to be working together to make you supposedly better at what you do, or maybe they’re working together to make you obsolete – and I think you better start protecting your space.”

One major area of change, telemedicine, already occurred as a result of the COVID-19 pandemic and will “begin to dominate” over the next decade, Dr. Cush said. An analysis conducted by consulting firm McKinsey & Company found telehealth usage increased 78-fold between February and April 2020 before leveling off at a 38-fold higher rate, compared with prepandemic levels. In the same analysis, rheumatology ranked third in terms of telehealth usage claims behind psychiatry and substance use disorder treatment, Dr. Cush observed, as other specialties have “fallen off quite a bit.”

“The common denominators are chronic care, cognitive care, nonprocedural care, pattern recognition, and monitoring, and this is what you do,” he said. “This is why, in many ways, for you to abandon telemedicine I think is a gigantic mistake.”
 

Changes to telemedicine

The most immediate change to telemedicine will come when the Biden administration officially ends the COVID-19 public health emergency in May 2023, and temporary telehealth services will be extended for approximately 5 months after the end of the public health emergency. Legislation passed by Congress will ensure some of the flexibilities in telemedicine will be extended until the end of December 2024.

Alvin Wells, MD, PhD, director of the department of rheumatology at Advocate Aurora Health in Franklin, Wisc., said he sees telemedicine as persisting even after the official COVID-19 public health emergency ends. “There’s a lot of push from the American Medical Association, from the American College of Physicians. You’re going to see people – this will not go away because [there’s] also going to be that demand.”

Despite decreased usage since April 2020, telehealth was estimated to be a $60 billion industry in 2022 and will likely increase over the next decade, Dr. Cush noted. “I question [the decline] because I think it still is a major part of your [future in] 2033.”

The number of physicians who have at least three licenses to practice in other U.S. states increased from 50,454 in 2010 to 72,752 in 2020, and that trend will continue, Dr. Wells explained. It is now becoming easier for physicians to become licensed in other states with companies like CompHealth that offer services to simplify obtaining medical licenses with states that participate in the Interstate Medical Licensure Compact.

“It’s a telemedicine easy pass,” Dr. Cush said.
 

Concerns in telemedicine

Commenting on the presentation, Allan Gibofsky, MD, JD, professor of medicine at Weill Cornell Medicine and codirector of the Clinic for Inflammatory Arthritis and Biologic Therapy at the Hospital for Special Surgery (HSS), both in New York, pointed out that because telemedicine is governed by U.S. states, rather than the federal government, a physician needs to be licensed in the state where the patient is located. While many states relaxed their restrictions during COVID-19, as states began tightening their restrictions later, “many physicians didn’t want to have three licenses,” he said.

“There’s an expense in getting three licenses. There’s an expense in obtaining it and maintaining it, and the reimbursement for the telemedicine visit did not reach that expectation,” Dr. Gibofsky explained. With the exception of the orthopedic surgeons at HSS who practice in New York and a satellite office in Florida, none of the surgeons at his center have obtained more than one license to practice telemedicine in other states.

“Our volume of telemedicine at HSS has remained about the same at 30%, but fewer physicians are doing it because they don’t want to maintain multiple licensures,” he said. “So don’t overlook the role of legal concerns in terms of who’s going to be allowed to do what where. Your talk was great in terms of an exuberance of what’s going to be available, but it’s not going to relieve the physician from the burden of being responsible for their use.”

Eric Ruderman, MD, professor of rheumatology at Northwestern University, Chicago, asked the presenters about the balance between seeing patients for virtual and in-person visits. “The question is what’s the sweet spot? Are there people you’re willing to see virtually forever?” he asked, noting that he has patients scheduling telemedicine visits that he hasn’t seen since before the COVID-19 pandemic.

“That’s not going to work for me. At some point, you have to lay hands on people,” he said.

Dr. Wells said his current practice is 40% virtual, and his staff converts potential no-shows into a telemedicine consultation over the phone. “My no-show rate has gone down to zero. Somebody’s scheduled for a visit, they don’t show up, my [medical assistants] get them on the phone, they put them on hold, tee up the refills. I turn them into a telephone call,” he said. “We don’t accept the no-show at all because we can do a telephone [consultation].”

In Dr. Cush’s practice, he alternates telemedicine visits with in-person visits. “If you come back for two videos in a row, you’re catching hell from me for that,” he said. Responding to how Dr. Wells incorporates telemedicine into his practice, Dr. Cush said many rheumatologists “don’t have the setups to support the care, and that’s why it’s hard to do and that’s why we’re not as great as we could be.”

“This is the way we were trained. We’re used to seeing these patients in the clinic that often. Not every single patient needs to be seen that frequently if they’re stable and doing fine,” Dr. Wells countered.

Dr. Cush and Dr. Wells reported having financial relationships with numerous pharmaceutical companies.

There was an explosion in the use of telemedicine during the COVID-19 pandemic, but usage has stabilized and varies between specialties. However, telemedicine use is still somewhat high among rheumatologists, according to speakers at the 2023 Rheumatology Winter Clinical Symposium.

Speaking in general about the future of rheumatology, Jack Cush, MD, a rheumatologist based in Dallas and executive editor of RheumNow.com, said it is up to rheumatologists to adapt to the changing winds in the specialty.

FatCamera/Getty Images

“The future is going to happen no matter what, so the question is, are you going to go along with it? Are you going to be a part of it? Are you going to be resistant to it?” Dr. Cush asked attendees. “Your recent experience with COVID would tell you maybe what your path is going to be if you’re dying to get back to the way it once was.”

Rheumatologists can expect changes in where they work, how they’re paid, increases in their workload, and new innovations in connecting with patients, he said.

“You’re going to be integrating a new style of medicine, you’re going to be digitally connected,” he explained. “All these networks are going to be working together to make you supposedly better at what you do, or maybe they’re working together to make you obsolete – and I think you better start protecting your space.”

One major area of change, telemedicine, already occurred as a result of the COVID-19 pandemic and will “begin to dominate” over the next decade, Dr. Cush said. An analysis conducted by consulting firm McKinsey & Company found telehealth usage increased 78-fold between February and April 2020 before leveling off at a 38-fold higher rate, compared with prepandemic levels. In the same analysis, rheumatology ranked third in terms of telehealth usage claims behind psychiatry and substance use disorder treatment, Dr. Cush observed, as other specialties have “fallen off quite a bit.”

“The common denominators are chronic care, cognitive care, nonprocedural care, pattern recognition, and monitoring, and this is what you do,” he said. “This is why, in many ways, for you to abandon telemedicine I think is a gigantic mistake.”
 

Changes to telemedicine

The most immediate change to telemedicine will come when the Biden administration officially ends the COVID-19 public health emergency in May 2023, and temporary telehealth services will be extended for approximately 5 months after the end of the public health emergency. Legislation passed by Congress will ensure some of the flexibilities in telemedicine will be extended until the end of December 2024.

Alvin Wells, MD, PhD, director of the department of rheumatology at Advocate Aurora Health in Franklin, Wisc., said he sees telemedicine as persisting even after the official COVID-19 public health emergency ends. “There’s a lot of push from the American Medical Association, from the American College of Physicians. You’re going to see people – this will not go away because [there’s] also going to be that demand.”

Despite decreased usage since April 2020, telehealth was estimated to be a $60 billion industry in 2022 and will likely increase over the next decade, Dr. Cush noted. “I question [the decline] because I think it still is a major part of your [future in] 2033.”

The number of physicians who have at least three licenses to practice in other U.S. states increased from 50,454 in 2010 to 72,752 in 2020, and that trend will continue, Dr. Wells explained. It is now becoming easier for physicians to become licensed in other states with companies like CompHealth that offer services to simplify obtaining medical licenses with states that participate in the Interstate Medical Licensure Compact.

“It’s a telemedicine easy pass,” Dr. Cush said.
 

Concerns in telemedicine

Commenting on the presentation, Allan Gibofsky, MD, JD, professor of medicine at Weill Cornell Medicine and codirector of the Clinic for Inflammatory Arthritis and Biologic Therapy at the Hospital for Special Surgery (HSS), both in New York, pointed out that because telemedicine is governed by U.S. states, rather than the federal government, a physician needs to be licensed in the state where the patient is located. While many states relaxed their restrictions during COVID-19, as states began tightening their restrictions later, “many physicians didn’t want to have three licenses,” he said.

“There’s an expense in getting three licenses. There’s an expense in obtaining it and maintaining it, and the reimbursement for the telemedicine visit did not reach that expectation,” Dr. Gibofsky explained. With the exception of the orthopedic surgeons at HSS who practice in New York and a satellite office in Florida, none of the surgeons at his center have obtained more than one license to practice telemedicine in other states.

“Our volume of telemedicine at HSS has remained about the same at 30%, but fewer physicians are doing it because they don’t want to maintain multiple licensures,” he said. “So don’t overlook the role of legal concerns in terms of who’s going to be allowed to do what where. Your talk was great in terms of an exuberance of what’s going to be available, but it’s not going to relieve the physician from the burden of being responsible for their use.”

Eric Ruderman, MD, professor of rheumatology at Northwestern University, Chicago, asked the presenters about the balance between seeing patients for virtual and in-person visits. “The question is what’s the sweet spot? Are there people you’re willing to see virtually forever?” he asked, noting that he has patients scheduling telemedicine visits that he hasn’t seen since before the COVID-19 pandemic.

“That’s not going to work for me. At some point, you have to lay hands on people,” he said.

Dr. Wells said his current practice is 40% virtual, and his staff converts potential no-shows into a telemedicine consultation over the phone. “My no-show rate has gone down to zero. Somebody’s scheduled for a visit, they don’t show up, my [medical assistants] get them on the phone, they put them on hold, tee up the refills. I turn them into a telephone call,” he said. “We don’t accept the no-show at all because we can do a telephone [consultation].”

In Dr. Cush’s practice, he alternates telemedicine visits with in-person visits. “If you come back for two videos in a row, you’re catching hell from me for that,” he said. Responding to how Dr. Wells incorporates telemedicine into his practice, Dr. Cush said many rheumatologists “don’t have the setups to support the care, and that’s why it’s hard to do and that’s why we’re not as great as we could be.”

“This is the way we were trained. We’re used to seeing these patients in the clinic that often. Not every single patient needs to be seen that frequently if they’re stable and doing fine,” Dr. Wells countered.

Dr. Cush and Dr. Wells reported having financial relationships with numerous pharmaceutical companies.

A diagnostic workup for pulmonary embolism (PE) should be performed in all patients with recent onset of exertional dyspnea, according to the authors of an article published in the Journal of Thrombosis and Haemostasis. That conclusion emerged from an analysis of PE prevalence in 417 patients with recent marked exertional dyspnea performing previously well-tolerated physical activities.

Exertional dyspnea is a frequently encountered complaint in clinical practice. Missteps in both diagnosis and early management, however, have been found to be prevalent in emergency department practices. PE diagnosis can be delayed or altogether missed through nonspecific clinical manifestations or the absence of typical signs and symptoms, with a complicated clinical course or mortality as a consequence, stated the researchers. Also, failure to diagnose PE is a common malpractice allegation.

Noting that the prevalence of PE among patients with dyspnea on exertion has not been reported, the authors hypothesized: “PE might be a frequent underlying condition in patients presenting for care complaining of marked dyspnea on exertion of recent onset.”

In a multicenter prospective, cross-sectional study among 14 university or hospital centers in Italy, patients who were referred for outpatient evaluation with recent (< 1 month) dyspnea on exertion with a severity of 3 or 4 on the modified Medical Research Council dyspnea scale were potentially eligible for the study. Prior deep-vein thrombosis (DVT), PE, and use of therapeutic anticoagulation were among exclusion criteria. All patients aged 75 years or younger with recent (< 1 month) marked exertional dyspnea had a systematic workup for PE, irrespective of concomitant signs or symptoms of venous thromboembolism and alternative explanations for dyspnea. The main study outcome was prevalence of PE in the entire cohort of patients with recent marked dyspnea on exertion.

When about 400 patients had been enrolled after an interim analysis in which the preestablished stopping rule (if the lower limit of the 95% confidence interval of the prevalence of PE exceeds 20%) was met, the study was prematurely terminated. PE was found, after exclusion of 134 patients based on low PE clinical probability and normal D-dimer, in 134 (47.3%) of the remaining 283 patients. The overall PE prevalence was 32.1% (95% confidence interval, 27.8-36.8).

PE was present in 40 of 204 (19.6%) patients without other findings suspicious for PE and in 94 of 213 patients (44.1%) with PE-suspicious findings. PE involved a main pulmonary artery in 37% and multiple lobes in 87% of the patients.

The researchers pointed out that, while the prevalence of PE was highest (44%) in patients who had concomitant signs or symptoms suspicious of PE or underlying DVT, PE was detected in almost 20% of patients without concomitant PE signs and symptoms. Also, the detected pulmonary emboli were deemed significant.

“Our findings suggest that, regardless of the diagnostic algorithm in use, physicians should rule in or out PE in patients who solely report recent onset of marked dyspnea on exertion,” they concluded.

Agreeing with the authors’ conclusions, Mary Jo S. Farmer, MD, PhD, of the department of medicine at University of Massachusetts, Worcester, stated in an interview, “The results of the current study support a diagnostic workup for pulmonary embolus in all patients with recent onset of exertional dyspnea.” She added, “Pulmonary emboli detected were significant as almost all were segmental or more proximal emboli involving multiple lobes. The observed overall prevalence of pulmonary embolus of 32% may seem high when compared with the low prevalence of 7%-13% reported in other studies of patients with suspected pulmonary embolus. However, the prevalence of pulmonary embolus among emergency department cohorts in European countries is generally higher, as is the diagnostic yield from [CT pulmonary angiogram] compared to North American countries. This could be explained by differences in applied thresholds for suspicion of pulmonary embolus. The incidence of COVID-19 and association with thrombosis was not reported.

“It has been reported that nonspecific clinical manifestations and absence of typical signs and symptoms can result in delay in diagnosis of pulmonary embolus or result in pulmonary embolus being missed, an unfortunate situation that could result in malpractice allegation.” Dr. Farmer concluded.

Among limitations of the study, the authors noted that their results are not applicable to patients older than 75 years or patients with chronic (more than 1 month) symptoms of dyspnea or less severe dyspnea (modified Medical Research Council dyspnea score of 2 or lower). Also, no attempt to stratify the clinical relevance of PE was made.

The study was funded by the Arianna Foundation on Anticoagulation, Bologna, Italy. The authors reported that they had no potential conflicts. Dr. Farmer also declared she had no relevant conflicts.

A diagnostic workup for pulmonary embolism (PE) should be performed in all patients with recent onset of exertional dyspnea, according to the authors of an article published in the Journal of Thrombosis and Haemostasis. That conclusion emerged from an analysis of PE prevalence in 417 patients with recent marked exertional dyspnea performing previously well-tolerated physical activities.

Exertional dyspnea is a frequently encountered complaint in clinical practice. Missteps in both diagnosis and early management, however, have been found to be prevalent in emergency department practices. PE diagnosis can be delayed or altogether missed through nonspecific clinical manifestations or the absence of typical signs and symptoms, with a complicated clinical course or mortality as a consequence, stated the researchers. Also, failure to diagnose PE is a common malpractice allegation.

Noting that the prevalence of PE among patients with dyspnea on exertion has not been reported, the authors hypothesized: “PE might be a frequent underlying condition in patients presenting for care complaining of marked dyspnea on exertion of recent onset.”

In a multicenter prospective, cross-sectional study among 14 university or hospital centers in Italy, patients who were referred for outpatient evaluation with recent (< 1 month) dyspnea on exertion with a severity of 3 or 4 on the modified Medical Research Council dyspnea scale were potentially eligible for the study. Prior deep-vein thrombosis (DVT), PE, and use of therapeutic anticoagulation were among exclusion criteria. All patients aged 75 years or younger with recent (< 1 month) marked exertional dyspnea had a systematic workup for PE, irrespective of concomitant signs or symptoms of venous thromboembolism and alternative explanations for dyspnea. The main study outcome was prevalence of PE in the entire cohort of patients with recent marked dyspnea on exertion.

When about 400 patients had been enrolled after an interim analysis in which the preestablished stopping rule (if the lower limit of the 95% confidence interval of the prevalence of PE exceeds 20%) was met, the study was prematurely terminated. PE was found, after exclusion of 134 patients based on low PE clinical probability and normal D-dimer, in 134 (47.3%) of the remaining 283 patients. The overall PE prevalence was 32.1% (95% confidence interval, 27.8-36.8).

PE was present in 40 of 204 (19.6%) patients without other findings suspicious for PE and in 94 of 213 patients (44.1%) with PE-suspicious findings. PE involved a main pulmonary artery in 37% and multiple lobes in 87% of the patients.

The researchers pointed out that, while the prevalence of PE was highest (44%) in patients who had concomitant signs or symptoms suspicious of PE or underlying DVT, PE was detected in almost 20% of patients without concomitant PE signs and symptoms. Also, the detected pulmonary emboli were deemed significant.

“Our findings suggest that, regardless of the diagnostic algorithm in use, physicians should rule in or out PE in patients who solely report recent onset of marked dyspnea on exertion,” they concluded.

Agreeing with the authors’ conclusions, Mary Jo S. Farmer, MD, PhD, of the department of medicine at University of Massachusetts, Worcester, stated in an interview, “The results of the current study support a diagnostic workup for pulmonary embolus in all patients with recent onset of exertional dyspnea.” She added, “Pulmonary emboli detected were significant as almost all were segmental or more proximal emboli involving multiple lobes. The observed overall prevalence of pulmonary embolus of 32% may seem high when compared with the low prevalence of 7%-13% reported in other studies of patients with suspected pulmonary embolus. However, the prevalence of pulmonary embolus among emergency department cohorts in European countries is generally higher, as is the diagnostic yield from [CT pulmonary angiogram] compared to North American countries. This could be explained by differences in applied thresholds for suspicion of pulmonary embolus. The incidence of COVID-19 and association with thrombosis was not reported.

“It has been reported that nonspecific clinical manifestations and absence of typical signs and symptoms can result in delay in diagnosis of pulmonary embolus or result in pulmonary embolus being missed, an unfortunate situation that could result in malpractice allegation.” Dr. Farmer concluded.

Among limitations of the study, the authors noted that their results are not applicable to patients older than 75 years or patients with chronic (more than 1 month) symptoms of dyspnea or less severe dyspnea (modified Medical Research Council dyspnea score of 2 or lower). Also, no attempt to stratify the clinical relevance of PE was made.

The study was funded by the Arianna Foundation on Anticoagulation, Bologna, Italy. The authors reported that they had no potential conflicts. Dr. Farmer also declared she had no relevant conflicts.

A diagnostic workup for pulmonary embolism (PE) should be performed in all patients with recent onset of exertional dyspnea, according to the authors of an article published in the Journal of Thrombosis and Haemostasis. That conclusion emerged from an analysis of PE prevalence in 417 patients with recent marked exertional dyspnea performing previously well-tolerated physical activities.

Exertional dyspnea is a frequently encountered complaint in clinical practice. Missteps in both diagnosis and early management, however, have been found to be prevalent in emergency department practices. PE diagnosis can be delayed or altogether missed through nonspecific clinical manifestations or the absence of typical signs and symptoms, with a complicated clinical course or mortality as a consequence, stated the researchers. Also, failure to diagnose PE is a common malpractice allegation.

Noting that the prevalence of PE among patients with dyspnea on exertion has not been reported, the authors hypothesized: “PE might be a frequent underlying condition in patients presenting for care complaining of marked dyspnea on exertion of recent onset.”

In a multicenter prospective, cross-sectional study among 14 university or hospital centers in Italy, patients who were referred for outpatient evaluation with recent (< 1 month) dyspnea on exertion with a severity of 3 or 4 on the modified Medical Research Council dyspnea scale were potentially eligible for the study. Prior deep-vein thrombosis (DVT), PE, and use of therapeutic anticoagulation were among exclusion criteria. All patients aged 75 years or younger with recent (< 1 month) marked exertional dyspnea had a systematic workup for PE, irrespective of concomitant signs or symptoms of venous thromboembolism and alternative explanations for dyspnea. The main study outcome was prevalence of PE in the entire cohort of patients with recent marked dyspnea on exertion.

When about 400 patients had been enrolled after an interim analysis in which the preestablished stopping rule (if the lower limit of the 95% confidence interval of the prevalence of PE exceeds 20%) was met, the study was prematurely terminated. PE was found, after exclusion of 134 patients based on low PE clinical probability and normal D-dimer, in 134 (47.3%) of the remaining 283 patients. The overall PE prevalence was 32.1% (95% confidence interval, 27.8-36.8).

PE was present in 40 of 204 (19.6%) patients without other findings suspicious for PE and in 94 of 213 patients (44.1%) with PE-suspicious findings. PE involved a main pulmonary artery in 37% and multiple lobes in 87% of the patients.

The researchers pointed out that, while the prevalence of PE was highest (44%) in patients who had concomitant signs or symptoms suspicious of PE or underlying DVT, PE was detected in almost 20% of patients without concomitant PE signs and symptoms. Also, the detected pulmonary emboli were deemed significant.

“Our findings suggest that, regardless of the diagnostic algorithm in use, physicians should rule in or out PE in patients who solely report recent onset of marked dyspnea on exertion,” they concluded.

Agreeing with the authors’ conclusions, Mary Jo S. Farmer, MD, PhD, of the department of medicine at University of Massachusetts, Worcester, stated in an interview, “The results of the current study support a diagnostic workup for pulmonary embolus in all patients with recent onset of exertional dyspnea.” She added, “Pulmonary emboli detected were significant as almost all were segmental or more proximal emboli involving multiple lobes. The observed overall prevalence of pulmonary embolus of 32% may seem high when compared with the low prevalence of 7%-13% reported in other studies of patients with suspected pulmonary embolus. However, the prevalence of pulmonary embolus among emergency department cohorts in European countries is generally higher, as is the diagnostic yield from [CT pulmonary angiogram] compared to North American countries. This could be explained by differences in applied thresholds for suspicion of pulmonary embolus. The incidence of COVID-19 and association with thrombosis was not reported.

“It has been reported that nonspecific clinical manifestations and absence of typical signs and symptoms can result in delay in diagnosis of pulmonary embolus or result in pulmonary embolus being missed, an unfortunate situation that could result in malpractice allegation.” Dr. Farmer concluded.

Among limitations of the study, the authors noted that their results are not applicable to patients older than 75 years or patients with chronic (more than 1 month) symptoms of dyspnea or less severe dyspnea (modified Medical Research Council dyspnea score of 2 or lower). Also, no attempt to stratify the clinical relevance of PE was made.

The study was funded by the Arianna Foundation on Anticoagulation, Bologna, Italy. The authors reported that they had no potential conflicts. Dr. Farmer also declared she had no relevant conflicts.

CASE Patient concerned about hormonal contraception’s impact on lactation

A 19-year-old woman (G2P1102) is postpartum day 1 after delivering a baby at 26 weeks’ gestation. When you see her on postpartum rounds, she states that she does not want any hormonal contraception because she heard that it will decrease her milk supply. What are your next steps?
 

The American Academy of Pediatrics recently updated its policy statement on breastfeeding and the use of human milk to recommend exclusive breastfeeding for 6 months and continued breastfeeding, with complementary foods, as mutually desired for 2 years or beyond given evidence of maternal health benefits with breastfeeding longer than 1 year.¹

Breastfeeding prevalence—and challenges

Despite maternal and infant benefits associated with lactation, current breastfeeding prevalence in the United States remains suboptimal. In 2019, 24.9% of infants were exclusively breastfed through 6 months and 35.9% were breastfeeding at 12 months.² Furthermore, disparities in breastfeeding exist, which contribute to health inequities. For example, non-Hispanic Black infants had lower rates of exclusive breastfeeding at 6 months (19.1%) and any breastfeeding at 12 months (24.1%) compared with non-Hispanic White infants (26.9% and 39.4%, respectively).³

While many new mothers intend to breastfeed and initiate breastfeeding in the hospital after delivery, overall and exclusive breastfeeding continuation rates are low, indicating that patients face challenges with breastfeeding after hospital discharge. Many structural and societal barriers to breastfeeding exist, including inadequate social support and parental leave policies.⁴ Suboptimal maternity care practices during the birth hospitalization may lead to challenges with breastfeeding initiation. Health care practitioners may present additional barriers to breastfeeding due to a lack of knowledge of available resources for patients or incomplete training in breastfeeding counseling and support.

To address our case patient’s concerns, clinicians should be aware of how exogenous progestins may affect breastfeeding physiology, risk factors for breastfeeding difficulty, and the available evidence for safety of hormonal contraception use while breastfeeding.

ILLUSTRATION: KIMBERLY MARTENS FOR OBG MANAGEMENT

Physiology of breastfeeding

During the second half of pregnancy, secretory differentiation (lactogenesis I) of mammary alveolar epithelial cells into secretory cells occurs to allow the mammary gland to eventually produce milk.⁵ After delivery of the placenta, progesterone withdrawal triggers secretory activation (lactogenesis II), which refers to the onset of copious milk production within 2 to 3 days postpartum.⁵ Most patients experience secretory activation within 72 hours; however, a delay in secretory activation past 72 hours is associated with cessation of any and exclusive breastfeeding at 4 weeks postpartum.⁶

Impaired lactation can be related to a delay in secretory activation or to insufficient lactation related to low milk supply. Maternal medical comorbidities (for example, diabetes mellitus, thyroid dysfunction, obesity), breast anatomy (such as insufficient glandular tissue, prior breast reduction surgery), pregnancy-related events (preeclampsia, retained placenta, postpartum hemorrhage), and infant conditions (such as multiple gestation, premature birth, congenital anomalies) all contribute to a risk of impaired lactation.⁷

Guidance on breastfeeding and hormonal contraception initiation

Early initiation of hormonal contraception poses theoretical concerns about breastfeeding difficulty if exogenous progestin interferes with endogenous signals for onset of milk production. The Centers for Disease Control and Prevention US Medical Eligibility Criteria (MEC) for Contraceptive Use provide recommendations on the safety of contraceptive use in the setting of various medical conditions or patient characteristics based on available data. The MEC uses 4 categories in assessing the safety of contraceptive method use for individuals with specific medical conditions or characteristics: 1, no restrictions exist for use of the contraceptive method; 2, advantages generally outweigh theoretical or proven risks; 3, theoretical or proven risks usually outweigh the advantages; and 4, conditions that represent an unacceptable health risk if the method is used.⁸

In the 2016 guidelines, combined hormonal contraceptives are considered category 4 at less than 21 days postpartum, regardless of breastfeeding status, due to the increased risk of venous thromboembolism in the immediate postpartum period (TABLE 1).⁸ Progestin-only contraception is considered category 1 in nonbreastfeeding individuals and category 2 in breastfeeding individuals based on overall evidence that found no adverse outcome with breastfeeding or infant outcomes with early initiation of progestin-only contraception (TABLE 1, TABLE 2).⁸

Since the publication of the 2016 MEC guidelines, several studies have continued to examine breastfeeding and infant outcomes with early initiation of hormonal contraception.

• In a noninferiority randomized controlled trial of immediate versus delayed initiation of a levonorgestrel intrauterine device (LNG IUD), any breastfeeding at 8 weeks in the immediate group was 78% (95% confidence interval [CI], 70%–85%), which was lower than but within the specified noninferiority margin of the delayed breastfeeding group (83%; 95% CI, 75%–90%), indicating that breastfeeding outcomes with immediate initiation of an LNG IUD were not worse compared with delayed initiation.⁹
• A secondary analysis of a randomized trial that compared intracesarean versus LNG IUD placement at 6 or more weeks postpartum showed no difference in breastfeeding at 6, 12, and 24 weeks after LNG IUD placement.¹⁰
• A randomized trial of early (up to 48 hours postpartum) versus placement of an etonogestrel (ENG) implant at 6 or more weeks postpartum showed no difference between groups in infant weight at 12 months.¹¹
• A randomized trial of immediate (within 5 days of delivery) or interval placement of the 2-rod LNG implant (not approved in the United States) showed no difference in change in infant weight from birth to 6 months after delivery, onset of secretory activation, or breastfeeding continuation at 3 and 6 months postpartum.¹²
• In a prospective cohort study that compared immediate postpartum initiation of ENG versus a 2-rod LNG implant (approved by the FDA but not marketed in the United States), there were no differences in breastfeeding continuation at 24 months and exclusive breastfeeding at 6 months postpartum.¹³
• In a noninferiority randomized controlled trial that compared ENG implant initiation in the delivery room (0–2 hours postdelivery) versus delayed initiation (24–48 hours postdelivery), the time to secretory activation in those who initiated an ENG implant in the delivery room (66.8 [SD, 25.2] hours) was noninferior to delayed initiation (66.0 [SD, 35.3] hours). There also was no difference in ongoing breastfeeding over the first year after delivery and implant use at 12 months.¹⁴
• A secondary analysis of a randomized controlled trial examined breastfeeding outcomes with receipt of depot medroxyprogesterone acetate (DMPA) prior to discharge in women who delivered infants who weighed 1,500 g or less at 32 weeks’ or less gestation. Time to secretory activation was longer in 29 women who received DMPA (103.7 hours) compared with 141 women who did not (88.6 hours; P = .028); however, there was no difference in daily milk production, lactation duration, or infant consumption of mother’s own milk.¹⁵

While the overall evidence suggests that early initiation of hormonal contraception does not affect breastfeeding or infant outcomes, it is important for clinicians to recognize the limitations of available data with regard to the populations included in these studies. Specifically, most studies did not include individuals with premature, low birth weight, or multiple gestation infants, who are at higher risk of impaired lactation, and individuals with a higher prevalence of breastfeeding were not included to determine whether early initiation of hormonal contraception would impact breastfeeding. Furthermore, while these studies enrolled participants who planned to breastfeed, data indicate that intentions to initiate and continue exclusive breastfeeding can vary.¹⁶ As the reported rates of any and exclusive breastfeeding are consistent with or lower than current US breastfeeding rates, any decrease in breastfeeding exclusivity or duration that may be attributable to hormonal contraception may be unacceptable to those who are strongly motivated to breastfeed.

Continue to: How can clinicians integrate evidence into contraception counseling?...

The American College of Obstetricians and Gynecologists and the Academy of Breastfeeding Medicine offer guidance for how clinicians can address the use of hormonal contraception in breastfeeding patients. Both organizations recommend discussing the risks and benefits of hormonal contraception within the context of each person’s desire to breastfeed, potential for breastfeeding difficulty, and risk of pregnancy so that individuals can make their own informed decisions.^17,18

Obstetric care clinicians have an important role in helping patients make informed infant feeding decisions without coercion or pressure. To start these discussions, clinicians can begin by assessing a patient’s breastfeeding goals by asking open-ended questions, such as:

• What have you heard about breastfeeding?
• What are your plans for returning to work or school after delivery?
• How did breastfeeding go with older children?
• What are your plans for feeding this baby?

In addition to gathering information about the patient’s priorities and goals, clinicians should identify any risk factors for breastfeeding challenges in the medical, surgical, or previous breastfeeding history. Clinicians can engage in a patient-centered approach to infant feeding decisions by anticipating any challenges and working together to develop strategies to address these challenges with the patient’s goals in mind.¹⁷

When counseling about contraception, a spectrum of approaches exists, from a nondirective information-sharing only model to directive counseling by the clinician. The shared decision-making model lies between these 2 approaches and recognizes the expertise of both the clinician and patient.¹⁹ To start these interactions, clinicians can ask about a patient’s reproductive goals by assessing the patient’s needs, values, and preferences for contraception. Potential questions include:

• What kinds of contraceptive methods have you used in the past?
• What is important to you in a contraceptive method?
• How important is it to you to avoid another pregnancy right now?

Clinicians can then share information about different contraceptive methods based on the desired qualities that the patient has identified and how each method fits or does not fit into the patient’s goals and preferences. This collaborative approach facilitates an open dialogue and supports patient autonomy in contraceptive decision-making.

Lastly, clinicians should be cognizant of their own potential biases that could affect their counseling, such as encouraging contraceptive use because of a patient’s young age, parity, or premature delivery, as in our case presentation. Similarly, clinicians also should recognize that breastfeeding and contraceptive decisions are personal and are made with cultural, historical, and social contexts in mind.²⁰ Ultimately, counseling should be patient centered and individualized for each person’s priorities related to infant feeding and pregnancy prevention. ●

CASE Patient concerned about hormonal contraception’s impact on lactation

A 19-year-old woman (G2P1102) is postpartum day 1 after delivering a baby at 26 weeks’ gestation. When you see her on postpartum rounds, she states that she does not want any hormonal contraception because she heard that it will decrease her milk supply. What are your next steps?
 

The American Academy of Pediatrics recently updated its policy statement on breastfeeding and the use of human milk to recommend exclusive breastfeeding for 6 months and continued breastfeeding, with complementary foods, as mutually desired for 2 years or beyond given evidence of maternal health benefits with breastfeeding longer than 1 year.¹

Breastfeeding prevalence—and challenges

Despite maternal and infant benefits associated with lactation, current breastfeeding prevalence in the United States remains suboptimal. In 2019, 24.9% of infants were exclusively breastfed through 6 months and 35.9% were breastfeeding at 12 months.² Furthermore, disparities in breastfeeding exist, which contribute to health inequities. For example, non-Hispanic Black infants had lower rates of exclusive breastfeeding at 6 months (19.1%) and any breastfeeding at 12 months (24.1%) compared with non-Hispanic White infants (26.9% and 39.4%, respectively).³

While many new mothers intend to breastfeed and initiate breastfeeding in the hospital after delivery, overall and exclusive breastfeeding continuation rates are low, indicating that patients face challenges with breastfeeding after hospital discharge. Many structural and societal barriers to breastfeeding exist, including inadequate social support and parental leave policies.⁴ Suboptimal maternity care practices during the birth hospitalization may lead to challenges with breastfeeding initiation. Health care practitioners may present additional barriers to breastfeeding due to a lack of knowledge of available resources for patients or incomplete training in breastfeeding counseling and support.

To address our case patient’s concerns, clinicians should be aware of how exogenous progestins may affect breastfeeding physiology, risk factors for breastfeeding difficulty, and the available evidence for safety of hormonal contraception use while breastfeeding.

ILLUSTRATION: KIMBERLY MARTENS FOR OBG MANAGEMENT

Physiology of breastfeeding

During the second half of pregnancy, secretory differentiation (lactogenesis I) of mammary alveolar epithelial cells into secretory cells occurs to allow the mammary gland to eventually produce milk.⁵ After delivery of the placenta, progesterone withdrawal triggers secretory activation (lactogenesis II), which refers to the onset of copious milk production within 2 to 3 days postpartum.⁵ Most patients experience secretory activation within 72 hours; however, a delay in secretory activation past 72 hours is associated with cessation of any and exclusive breastfeeding at 4 weeks postpartum.⁶

Impaired lactation can be related to a delay in secretory activation or to insufficient lactation related to low milk supply. Maternal medical comorbidities (for example, diabetes mellitus, thyroid dysfunction, obesity), breast anatomy (such as insufficient glandular tissue, prior breast reduction surgery), pregnancy-related events (preeclampsia, retained placenta, postpartum hemorrhage), and infant conditions (such as multiple gestation, premature birth, congenital anomalies) all contribute to a risk of impaired lactation.⁷

Guidance on breastfeeding and hormonal contraception initiation

Early initiation of hormonal contraception poses theoretical concerns about breastfeeding difficulty if exogenous progestin interferes with endogenous signals for onset of milk production. The Centers for Disease Control and Prevention US Medical Eligibility Criteria (MEC) for Contraceptive Use provide recommendations on the safety of contraceptive use in the setting of various medical conditions or patient characteristics based on available data. The MEC uses 4 categories in assessing the safety of contraceptive method use for individuals with specific medical conditions or characteristics: 1, no restrictions exist for use of the contraceptive method; 2, advantages generally outweigh theoretical or proven risks; 3, theoretical or proven risks usually outweigh the advantages; and 4, conditions that represent an unacceptable health risk if the method is used.⁸

In the 2016 guidelines, combined hormonal contraceptives are considered category 4 at less than 21 days postpartum, regardless of breastfeeding status, due to the increased risk of venous thromboembolism in the immediate postpartum period (TABLE 1).⁸ Progestin-only contraception is considered category 1 in nonbreastfeeding individuals and category 2 in breastfeeding individuals based on overall evidence that found no adverse outcome with breastfeeding or infant outcomes with early initiation of progestin-only contraception (TABLE 1, TABLE 2).⁸

Since the publication of the 2016 MEC guidelines, several studies have continued to examine breastfeeding and infant outcomes with early initiation of hormonal contraception.

• In a noninferiority randomized controlled trial of immediate versus delayed initiation of a levonorgestrel intrauterine device (LNG IUD), any breastfeeding at 8 weeks in the immediate group was 78% (95% confidence interval [CI], 70%–85%), which was lower than but within the specified noninferiority margin of the delayed breastfeeding group (83%; 95% CI, 75%–90%), indicating that breastfeeding outcomes with immediate initiation of an LNG IUD were not worse compared with delayed initiation.⁹
• A secondary analysis of a randomized trial that compared intracesarean versus LNG IUD placement at 6 or more weeks postpartum showed no difference in breastfeeding at 6, 12, and 24 weeks after LNG IUD placement.¹⁰
• A randomized trial of early (up to 48 hours postpartum) versus placement of an etonogestrel (ENG) implant at 6 or more weeks postpartum showed no difference between groups in infant weight at 12 months.¹¹
• A randomized trial of immediate (within 5 days of delivery) or interval placement of the 2-rod LNG implant (not approved in the United States) showed no difference in change in infant weight from birth to 6 months after delivery, onset of secretory activation, or breastfeeding continuation at 3 and 6 months postpartum.¹²
• In a prospective cohort study that compared immediate postpartum initiation of ENG versus a 2-rod LNG implant (approved by the FDA but not marketed in the United States), there were no differences in breastfeeding continuation at 24 months and exclusive breastfeeding at 6 months postpartum.¹³
• In a noninferiority randomized controlled trial that compared ENG implant initiation in the delivery room (0–2 hours postdelivery) versus delayed initiation (24–48 hours postdelivery), the time to secretory activation in those who initiated an ENG implant in the delivery room (66.8 [SD, 25.2] hours) was noninferior to delayed initiation (66.0 [SD, 35.3] hours). There also was no difference in ongoing breastfeeding over the first year after delivery and implant use at 12 months.¹⁴
• A secondary analysis of a randomized controlled trial examined breastfeeding outcomes with receipt of depot medroxyprogesterone acetate (DMPA) prior to discharge in women who delivered infants who weighed 1,500 g or less at 32 weeks’ or less gestation. Time to secretory activation was longer in 29 women who received DMPA (103.7 hours) compared with 141 women who did not (88.6 hours; P = .028); however, there was no difference in daily milk production, lactation duration, or infant consumption of mother’s own milk.¹⁵

While the overall evidence suggests that early initiation of hormonal contraception does not affect breastfeeding or infant outcomes, it is important for clinicians to recognize the limitations of available data with regard to the populations included in these studies. Specifically, most studies did not include individuals with premature, low birth weight, or multiple gestation infants, who are at higher risk of impaired lactation, and individuals with a higher prevalence of breastfeeding were not included to determine whether early initiation of hormonal contraception would impact breastfeeding. Furthermore, while these studies enrolled participants who planned to breastfeed, data indicate that intentions to initiate and continue exclusive breastfeeding can vary.¹⁶ As the reported rates of any and exclusive breastfeeding are consistent with or lower than current US breastfeeding rates, any decrease in breastfeeding exclusivity or duration that may be attributable to hormonal contraception may be unacceptable to those who are strongly motivated to breastfeed.

Continue to: How can clinicians integrate evidence into contraception counseling?...

The American College of Obstetricians and Gynecologists and the Academy of Breastfeeding Medicine offer guidance for how clinicians can address the use of hormonal contraception in breastfeeding patients. Both organizations recommend discussing the risks and benefits of hormonal contraception within the context of each person’s desire to breastfeed, potential for breastfeeding difficulty, and risk of pregnancy so that individuals can make their own informed decisions.^17,18

Obstetric care clinicians have an important role in helping patients make informed infant feeding decisions without coercion or pressure. To start these discussions, clinicians can begin by assessing a patient’s breastfeeding goals by asking open-ended questions, such as:

• What have you heard about breastfeeding?
• What are your plans for returning to work or school after delivery?
• How did breastfeeding go with older children?
• What are your plans for feeding this baby?

In addition to gathering information about the patient’s priorities and goals, clinicians should identify any risk factors for breastfeeding challenges in the medical, surgical, or previous breastfeeding history. Clinicians can engage in a patient-centered approach to infant feeding decisions by anticipating any challenges and working together to develop strategies to address these challenges with the patient’s goals in mind.¹⁷

When counseling about contraception, a spectrum of approaches exists, from a nondirective information-sharing only model to directive counseling by the clinician. The shared decision-making model lies between these 2 approaches and recognizes the expertise of both the clinician and patient.¹⁹ To start these interactions, clinicians can ask about a patient’s reproductive goals by assessing the patient’s needs, values, and preferences for contraception. Potential questions include:

• What kinds of contraceptive methods have you used in the past?
• What is important to you in a contraceptive method?
• How important is it to you to avoid another pregnancy right now?

Clinicians can then share information about different contraceptive methods based on the desired qualities that the patient has identified and how each method fits or does not fit into the patient’s goals and preferences. This collaborative approach facilitates an open dialogue and supports patient autonomy in contraceptive decision-making.

Lastly, clinicians should be cognizant of their own potential biases that could affect their counseling, such as encouraging contraceptive use because of a patient’s young age, parity, or premature delivery, as in our case presentation. Similarly, clinicians also should recognize that breastfeeding and contraceptive decisions are personal and are made with cultural, historical, and social contexts in mind.²⁰ Ultimately, counseling should be patient centered and individualized for each person’s priorities related to infant feeding and pregnancy prevention. ●

CASE Patient concerned about hormonal contraception’s impact on lactation

A 19-year-old woman (G2P1102) is postpartum day 1 after delivering a baby at 26 weeks’ gestation. When you see her on postpartum rounds, she states that she does not want any hormonal contraception because she heard that it will decrease her milk supply. What are your next steps?
 

The American Academy of Pediatrics recently updated its policy statement on breastfeeding and the use of human milk to recommend exclusive breastfeeding for 6 months and continued breastfeeding, with complementary foods, as mutually desired for 2 years or beyond given evidence of maternal health benefits with breastfeeding longer than 1 year.¹

Breastfeeding prevalence—and challenges

Despite maternal and infant benefits associated with lactation, current breastfeeding prevalence in the United States remains suboptimal. In 2019, 24.9% of infants were exclusively breastfed through 6 months and 35.9% were breastfeeding at 12 months.² Furthermore, disparities in breastfeeding exist, which contribute to health inequities. For example, non-Hispanic Black infants had lower rates of exclusive breastfeeding at 6 months (19.1%) and any breastfeeding at 12 months (24.1%) compared with non-Hispanic White infants (26.9% and 39.4%, respectively).³

While many new mothers intend to breastfeed and initiate breastfeeding in the hospital after delivery, overall and exclusive breastfeeding continuation rates are low, indicating that patients face challenges with breastfeeding after hospital discharge. Many structural and societal barriers to breastfeeding exist, including inadequate social support and parental leave policies.⁴ Suboptimal maternity care practices during the birth hospitalization may lead to challenges with breastfeeding initiation. Health care practitioners may present additional barriers to breastfeeding due to a lack of knowledge of available resources for patients or incomplete training in breastfeeding counseling and support.

To address our case patient’s concerns, clinicians should be aware of how exogenous progestins may affect breastfeeding physiology, risk factors for breastfeeding difficulty, and the available evidence for safety of hormonal contraception use while breastfeeding.

ILLUSTRATION: KIMBERLY MARTENS FOR OBG MANAGEMENT

Physiology of breastfeeding

During the second half of pregnancy, secretory differentiation (lactogenesis I) of mammary alveolar epithelial cells into secretory cells occurs to allow the mammary gland to eventually produce milk.⁵ After delivery of the placenta, progesterone withdrawal triggers secretory activation (lactogenesis II), which refers to the onset of copious milk production within 2 to 3 days postpartum.⁵ Most patients experience secretory activation within 72 hours; however, a delay in secretory activation past 72 hours is associated with cessation of any and exclusive breastfeeding at 4 weeks postpartum.⁶

Impaired lactation can be related to a delay in secretory activation or to insufficient lactation related to low milk supply. Maternal medical comorbidities (for example, diabetes mellitus, thyroid dysfunction, obesity), breast anatomy (such as insufficient glandular tissue, prior breast reduction surgery), pregnancy-related events (preeclampsia, retained placenta, postpartum hemorrhage), and infant conditions (such as multiple gestation, premature birth, congenital anomalies) all contribute to a risk of impaired lactation.⁷

Guidance on breastfeeding and hormonal contraception initiation

Early initiation of hormonal contraception poses theoretical concerns about breastfeeding difficulty if exogenous progestin interferes with endogenous signals for onset of milk production. The Centers for Disease Control and Prevention US Medical Eligibility Criteria (MEC) for Contraceptive Use provide recommendations on the safety of contraceptive use in the setting of various medical conditions or patient characteristics based on available data. The MEC uses 4 categories in assessing the safety of contraceptive method use for individuals with specific medical conditions or characteristics: 1, no restrictions exist for use of the contraceptive method; 2, advantages generally outweigh theoretical or proven risks; 3, theoretical or proven risks usually outweigh the advantages; and 4, conditions that represent an unacceptable health risk if the method is used.⁸

In the 2016 guidelines, combined hormonal contraceptives are considered category 4 at less than 21 days postpartum, regardless of breastfeeding status, due to the increased risk of venous thromboembolism in the immediate postpartum period (TABLE 1).⁸ Progestin-only contraception is considered category 1 in nonbreastfeeding individuals and category 2 in breastfeeding individuals based on overall evidence that found no adverse outcome with breastfeeding or infant outcomes with early initiation of progestin-only contraception (TABLE 1, TABLE 2).⁸

Since the publication of the 2016 MEC guidelines, several studies have continued to examine breastfeeding and infant outcomes with early initiation of hormonal contraception.

• In a noninferiority randomized controlled trial of immediate versus delayed initiation of a levonorgestrel intrauterine device (LNG IUD), any breastfeeding at 8 weeks in the immediate group was 78% (95% confidence interval [CI], 70%–85%), which was lower than but within the specified noninferiority margin of the delayed breastfeeding group (83%; 95% CI, 75%–90%), indicating that breastfeeding outcomes with immediate initiation of an LNG IUD were not worse compared with delayed initiation.⁹
• A secondary analysis of a randomized trial that compared intracesarean versus LNG IUD placement at 6 or more weeks postpartum showed no difference in breastfeeding at 6, 12, and 24 weeks after LNG IUD placement.¹⁰
• A randomized trial of early (up to 48 hours postpartum) versus placement of an etonogestrel (ENG) implant at 6 or more weeks postpartum showed no difference between groups in infant weight at 12 months.¹¹
• A randomized trial of immediate (within 5 days of delivery) or interval placement of the 2-rod LNG implant (not approved in the United States) showed no difference in change in infant weight from birth to 6 months after delivery, onset of secretory activation, or breastfeeding continuation at 3 and 6 months postpartum.¹²
• In a prospective cohort study that compared immediate postpartum initiation of ENG versus a 2-rod LNG implant (approved by the FDA but not marketed in the United States), there were no differences in breastfeeding continuation at 24 months and exclusive breastfeeding at 6 months postpartum.¹³
• In a noninferiority randomized controlled trial that compared ENG implant initiation in the delivery room (0–2 hours postdelivery) versus delayed initiation (24–48 hours postdelivery), the time to secretory activation in those who initiated an ENG implant in the delivery room (66.8 [SD, 25.2] hours) was noninferior to delayed initiation (66.0 [SD, 35.3] hours). There also was no difference in ongoing breastfeeding over the first year after delivery and implant use at 12 months.¹⁴
• A secondary analysis of a randomized controlled trial examined breastfeeding outcomes with receipt of depot medroxyprogesterone acetate (DMPA) prior to discharge in women who delivered infants who weighed 1,500 g or less at 32 weeks’ or less gestation. Time to secretory activation was longer in 29 women who received DMPA (103.7 hours) compared with 141 women who did not (88.6 hours; P = .028); however, there was no difference in daily milk production, lactation duration, or infant consumption of mother’s own milk.¹⁵

While the overall evidence suggests that early initiation of hormonal contraception does not affect breastfeeding or infant outcomes, it is important for clinicians to recognize the limitations of available data with regard to the populations included in these studies. Specifically, most studies did not include individuals with premature, low birth weight, or multiple gestation infants, who are at higher risk of impaired lactation, and individuals with a higher prevalence of breastfeeding were not included to determine whether early initiation of hormonal contraception would impact breastfeeding. Furthermore, while these studies enrolled participants who planned to breastfeed, data indicate that intentions to initiate and continue exclusive breastfeeding can vary.¹⁶ As the reported rates of any and exclusive breastfeeding are consistent with or lower than current US breastfeeding rates, any decrease in breastfeeding exclusivity or duration that may be attributable to hormonal contraception may be unacceptable to those who are strongly motivated to breastfeed.

Continue to: How can clinicians integrate evidence into contraception counseling?...

The American College of Obstetricians and Gynecologists and the Academy of Breastfeeding Medicine offer guidance for how clinicians can address the use of hormonal contraception in breastfeeding patients. Both organizations recommend discussing the risks and benefits of hormonal contraception within the context of each person’s desire to breastfeed, potential for breastfeeding difficulty, and risk of pregnancy so that individuals can make their own informed decisions.^17,18

Obstetric care clinicians have an important role in helping patients make informed infant feeding decisions without coercion or pressure. To start these discussions, clinicians can begin by assessing a patient’s breastfeeding goals by asking open-ended questions, such as:

• What have you heard about breastfeeding?
• What are your plans for returning to work or school after delivery?
• How did breastfeeding go with older children?
• What are your plans for feeding this baby?

In addition to gathering information about the patient’s priorities and goals, clinicians should identify any risk factors for breastfeeding challenges in the medical, surgical, or previous breastfeeding history. Clinicians can engage in a patient-centered approach to infant feeding decisions by anticipating any challenges and working together to develop strategies to address these challenges with the patient’s goals in mind.¹⁷

When counseling about contraception, a spectrum of approaches exists, from a nondirective information-sharing only model to directive counseling by the clinician. The shared decision-making model lies between these 2 approaches and recognizes the expertise of both the clinician and patient.¹⁹ To start these interactions, clinicians can ask about a patient’s reproductive goals by assessing the patient’s needs, values, and preferences for contraception. Potential questions include:

• What kinds of contraceptive methods have you used in the past?
• What is important to you in a contraceptive method?
• How important is it to you to avoid another pregnancy right now?

Clinicians can then share information about different contraceptive methods based on the desired qualities that the patient has identified and how each method fits or does not fit into the patient’s goals and preferences. This collaborative approach facilitates an open dialogue and supports patient autonomy in contraceptive decision-making.

Lastly, clinicians should be cognizant of their own potential biases that could affect their counseling, such as encouraging contraceptive use because of a patient’s young age, parity, or premature delivery, as in our case presentation. Similarly, clinicians also should recognize that breastfeeding and contraceptive decisions are personal and are made with cultural, historical, and social contexts in mind.²⁰ Ultimately, counseling should be patient centered and individualized for each person’s priorities related to infant feeding and pregnancy prevention. ●

All obstetrician-gynecologists know that pregnant patients who are Rh negative and exposed to a sufficient quantity of fetal red blood cells expressing Rh D antigen may become sensitized, producing Rh D antibodies that adversely impact future pregnancies with an Rh D-positive fetus, potentially causing hemolytic disease of the fetus and newborn. In countries where Rh D immune globulin is available, there is a consensus recommendation to administer Rh D immune globulin to Rh-negative pregnant patients at approximately 28 weeks’ gestation and at birth in order to decrease the risk of alloimmunization and hemolytic disease of the fetus and newborn in future pregnancies.¹ In contrast to this global consensus, there is no worldwide agreement about how to manage Rh testing and Rh D immune globulin administration in cases of early pregnancy loss or abortion care before 12 weeks’ gestation. This editorial examines the evolving guidelines of major professional societies.

Guidelines consistent with the routine use of Rh D immune globulin in all cases of early pregnancy loss and abortion care

As of the publication date of this editorial, the American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin on prevention of Rh D alloimmunization provides the following guidance based on consensus and expert opinion²:

• “Although the risk of alloimmunization is low, the consequences can be significant, and administration of Rh D immune globulin should be considered in cases of spontaneous first trimester miscarriage, especially those that are later in the first trimester.”
• “Because of the higher risk of alloimmunization, Rh D-negative women who have instrumentation for their miscarriage should receive Rh D immune globulin prophylaxis.”
• “Rh D immune globulin should be given to Rh D-negative women who have pregnancy termination either medical or surgical.”

The Society of Obstetricians and Gynaecologists of Canada (SOGC) recommends that, “After miscarriage or threatened abortion or induced abortion during the first 12 weeks of gestation, non-sensitized D-negative women should be given a minimum anti-D of 120 µg.”³

The liberal use of Rh D immune globulin in all cases of early pregnancy loss and abortion care is based, in part, on the following considerations:

1. the recognized safety of Rh D immune globulin administration^2,3
2. the report that fetal megaloblasts may express Rh antigen as early as 38 days of gestation⁴
3. the observation that 0.1 mL of Rh D-positive red cells may provoke an immune response in some Rh D-negative patients^5-7
4. the estimate that in some patients with threatened miscarriage a significant quantity of fetal blood may enter the maternal circulation.⁸

Guidelines that suggest restricted use of Rh D immune globulin before 7 to 8 weeks’ gestation

The Reproductive Care Program of Nova Scotia guideline from 2022 notes that “the benefits of administering Rh immune globulin before 8 weeks gestation have not been demonstrated.” Given the burden of Rh testing and Rh D immune globulin administration they suggest that clinicians may withhold Rh testing and Rh D immune globulin administration in cases less than 8 weeks’ gestation (less than 56 days) for spontaneous, threatened, or medication abortions if there is reliable pregnancy dating.⁹

The Dutch Association of Abortion Specialists guidelines from 2018 suggest to not provide Rh D immune globulin treatment in the following clinical situations: patients under 10 weeks’ gestation with spontaneous miscarriage or patients under 7 weeks’ gestation having an induced abortion.¹⁰

Continue to: Guidelines that suggest restricted use of Rh D immune globulin before 10 to 12 weeks’ gestation...

There are a growing number of guidelines that recommend restricting the use of Rh testing and Rh D immune globulin treatment in the management of early miscarriage and induced abortion. In 2019, the United Kingdom’s National Institute for Health and Care Excellence (NICE) recommended that for patients having a spontaneous miscarriage, Rh testing and Rh D immune globulin are not necessary before 10 weeks 0 days of gestation.¹¹ In addition, NICE recommends, “Do not offer anti-D prophylaxis to women who are having a medical abortion up to and including 10+0 weeks’ gestation.…Consider anti-D prophylaxis for women who are rhesus D negative and are having a surgical abortion up to and including 10+0 weeks’ gestation.”¹¹

In 2019, the National Abortion Federation (NAF) Clinical Policies Committee recommended that “…it is reasonable to forgo Rh testing and anti-D immunoglobulin for women having any type of induced abortion before 8 weeks from the last menstrual period. Prior to 8 weeks, the likelihood of fetal-maternal hemorrhage adequate to cause sensitization is negligible. Given that medication abortion is more similar to spontaneous abortion with less risk of fetal-maternal hemorrhage, forgoing Rh testing and anti-D immunoglobulin for medication abortion under 10 weeks may be considered.”¹² In 2022, NAF noted, “Emerging epidemiologic and clinical evidence indicates that the risk of maternal-fetal hemorrhage caused by early abortion is negligible and Rh testing and provision of Rh immune globulin may not be necessary. It is reasonable to forego Rh testing and anti-D immunoglobulin for people having any type of abortion before 56 days and medication abortion before 70 days since the last menstrual period. The pregnancy dating at which people need Rh testing and anti-D immunoglobulin is not well established. Foregoing Rh testing and anti-D immunoglobulinfor those using medication abortion through 11 to 12 weeks may be considered.”¹³

In 2020 the International Federation of Gynaecology and Obstetrics (FIGO) Committee for Safe Motherhood and Newborn Health recommended, “The risk for sensitization is most probably extremely low for spontaneous abortions before 10 gestational weeks; however, data are scarce. Based on the clinical expertise of the guideline committee from the UK’s National Institute for Health and Care Excellence (NICE), it is suggested that prophylaxis should be given only to women who are having a spontaneous abortion or medical management of miscarriage after 10 and 0/7 gestational weeks. Moreover, for women who have surgical management, prophylaxis may also be considered before 10 gestational weeks.”¹⁴

In 2022 the Royal College of Obstetricians and Gynaecologists recommended that for induced abortion, medication or surgical, “a determination of Rhesus blood status may be considered if the duration of pregnancy is over 12 weeks and anti-D is available.”¹⁵ “If available, anti-D should be offered to non-sensitised RhD-negative individuals from 12 weeks of pregnancy and provided within 72 hours of the abortion.”¹⁵

In 2022, the Society of Family Planning recommended that “Rh testing and administration are not recommended prior to 12 weeks gestation for patients undergoing spontaneous, medication or uterine aspiration abortion.” “For patients under 12 weeks gestation, although not recommended, Rh testing and Rh D immune globulin administration may be considered at patient request as part of a shared decision making process.”¹⁶

In 2022, the World Health Organization (WHO) reported “There are few studies examining Rh isoimmunization in unsensitized Rh-negative individuals seeking abortion before 12 weeks of gestation.” “The evidence on the effectiveness of the intervention may favor the intervention, because fewer women in the intervention group (anti-D administration) had antibody formation after the initial pregnancy compared to women in the comparison group (no anti-D) and no harms (undesirable effects) of the intervention were noted.”¹⁷ The evidence referenced for these statements are two low-quality studies from 1972.^18,19 The WHO continues, “…after consideration of the resources required, cost-effectiveness and feasibility of administering anti-D, as well as the very low certainty of evidence on effectiveness, the expert panel concluded that overall, the evidence does not favor the intervention and decided to recommend against it for gestational ages < 12 weeks, rather than < 9 weeks, as mentioned in the 2012 guidance.”¹⁷ In conclusion, the WHO recommended that “for both medical and surgical abortion at < 12 weeks: Recommend against anti-D immunoglobulin administration.”¹⁷

Guidelines that recommend restricted use of Rh D immune globulin during the first trimester, are based, in part, on the following considerations:

• there are no high-quality clinical trials demonstrating the benefit of Rh D immune globulin treatment in first trimester miscarriage and abortion care
• the Kleihauer-Betke technique cannot distinguish between maternal red blood cells expressing fetal hemoglobin (maternal F cells) and fetal cells, which has resulted in the over-estimation of the number of fetal cells in the maternal circulation²⁰
• using a dual-label flow cytometry method that distinguishes maternal F cells and fetal red blood cells, maternal F cells usually far outnumber fetal red blood cells in the maternal circulation in the first trimester²⁰
• among women in the first trimester undergoing uterine aspiration, the number of fetal cells in the maternal circulation is very low both before and after the procedure²⁰
• Rh testing and Rh immune globulin administration is burdensome and expensive.¹⁶

Implications for your practice

The fundamental reason for the proliferation of divergent guidelines is that there is no evidence from high-quality randomized clinical trials demonstrating that Rh testing and Rh D immune globulin treatment in early pregnancy miscarriage or induced abortion care reduces the risk of hemolytic disease of the fetus and newborn. The Cochrane review on Rh D immune globulin administration for preventing alloimmunization among patients with spontaneous miscarriage concluded, “There are insufficient data available to evaluate the practice of anti-D administration in an unsensitized Rh-negative mother after spontaneous miscarriage.”²¹

Given divergent guidelines, obstetrician-gynecologists must decide on which guideline to use in their practice. Clinicians may conclude that absent high-quality evidence from clinical trials, they will continue to use the ACOG/SOGC guidelines^2,3 in their practice, providing universal Rh testing and Rh D immune globulin treatment for all miscarriages and abortions, regardless of the gestational age. Other clinicians may conclude that Rh testing and Rh D immune globulin is not warranted before 8 to 12 weeks’ gestation, because the number of fetal red blood cells in the maternal circulation in cases of miscarriage and induced abortion is too low in early pregnancy to induce a maternal immune response.²² Based on recent studies demonstrating a low number of fetal red blood cells in the maternal circulation in the first trimester, family planning specialists are reducing the use of Rh testing and Rh immune globulin administration in both early pregnancy medication abortion and uterine aspiration abortion.¹⁶ With regard to Rh testing and Rh D immune globulin treatment, the future will definitely be different than the past. It is likely that many clinicians will reduce the use of Rh testing and Rh D immune globulin treatment in patients with miscarriage or induced abortion in early pregnancy. ●

All obstetrician-gynecologists know that pregnant patients who are Rh negative and exposed to a sufficient quantity of fetal red blood cells expressing Rh D antigen may become sensitized, producing Rh D antibodies that adversely impact future pregnancies with an Rh D-positive fetus, potentially causing hemolytic disease of the fetus and newborn. In countries where Rh D immune globulin is available, there is a consensus recommendation to administer Rh D immune globulin to Rh-negative pregnant patients at approximately 28 weeks’ gestation and at birth in order to decrease the risk of alloimmunization and hemolytic disease of the fetus and newborn in future pregnancies.¹ In contrast to this global consensus, there is no worldwide agreement about how to manage Rh testing and Rh D immune globulin administration in cases of early pregnancy loss or abortion care before 12 weeks’ gestation. This editorial examines the evolving guidelines of major professional societies.

Guidelines consistent with the routine use of Rh D immune globulin in all cases of early pregnancy loss and abortion care

As of the publication date of this editorial, the American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin on prevention of Rh D alloimmunization provides the following guidance based on consensus and expert opinion²:

• “Although the risk of alloimmunization is low, the consequences can be significant, and administration of Rh D immune globulin should be considered in cases of spontaneous first trimester miscarriage, especially those that are later in the first trimester.”
• “Because of the higher risk of alloimmunization, Rh D-negative women who have instrumentation for their miscarriage should receive Rh D immune globulin prophylaxis.”
• “Rh D immune globulin should be given to Rh D-negative women who have pregnancy termination either medical or surgical.”

The Society of Obstetricians and Gynaecologists of Canada (SOGC) recommends that, “After miscarriage or threatened abortion or induced abortion during the first 12 weeks of gestation, non-sensitized D-negative women should be given a minimum anti-D of 120 µg.”³

The liberal use of Rh D immune globulin in all cases of early pregnancy loss and abortion care is based, in part, on the following considerations:

1. the recognized safety of Rh D immune globulin administration^2,3
2. the report that fetal megaloblasts may express Rh antigen as early as 38 days of gestation⁴
3. the observation that 0.1 mL of Rh D-positive red cells may provoke an immune response in some Rh D-negative patients^5-7
4. the estimate that in some patients with threatened miscarriage a significant quantity of fetal blood may enter the maternal circulation.⁸

Guidelines that suggest restricted use of Rh D immune globulin before 7 to 8 weeks’ gestation

The Reproductive Care Program of Nova Scotia guideline from 2022 notes that “the benefits of administering Rh immune globulin before 8 weeks gestation have not been demonstrated.” Given the burden of Rh testing and Rh D immune globulin administration they suggest that clinicians may withhold Rh testing and Rh D immune globulin administration in cases less than 8 weeks’ gestation (less than 56 days) for spontaneous, threatened, or medication abortions if there is reliable pregnancy dating.⁹

The Dutch Association of Abortion Specialists guidelines from 2018 suggest to not provide Rh D immune globulin treatment in the following clinical situations: patients under 10 weeks’ gestation with spontaneous miscarriage or patients under 7 weeks’ gestation having an induced abortion.¹⁰

Continue to: Guidelines that suggest restricted use of Rh D immune globulin before 10 to 12 weeks’ gestation...

There are a growing number of guidelines that recommend restricting the use of Rh testing and Rh D immune globulin treatment in the management of early miscarriage and induced abortion. In 2019, the United Kingdom’s National Institute for Health and Care Excellence (NICE) recommended that for patients having a spontaneous miscarriage, Rh testing and Rh D immune globulin are not necessary before 10 weeks 0 days of gestation.¹¹ In addition, NICE recommends, “Do not offer anti-D prophylaxis to women who are having a medical abortion up to and including 10+0 weeks’ gestation.…Consider anti-D prophylaxis for women who are rhesus D negative and are having a surgical abortion up to and including 10+0 weeks’ gestation.”¹¹

In 2019, the National Abortion Federation (NAF) Clinical Policies Committee recommended that “…it is reasonable to forgo Rh testing and anti-D immunoglobulin for women having any type of induced abortion before 8 weeks from the last menstrual period. Prior to 8 weeks, the likelihood of fetal-maternal hemorrhage adequate to cause sensitization is negligible. Given that medication abortion is more similar to spontaneous abortion with less risk of fetal-maternal hemorrhage, forgoing Rh testing and anti-D immunoglobulin for medication abortion under 10 weeks may be considered.”¹² In 2022, NAF noted, “Emerging epidemiologic and clinical evidence indicates that the risk of maternal-fetal hemorrhage caused by early abortion is negligible and Rh testing and provision of Rh immune globulin may not be necessary. It is reasonable to forego Rh testing and anti-D immunoglobulin for people having any type of abortion before 56 days and medication abortion before 70 days since the last menstrual period. The pregnancy dating at which people need Rh testing and anti-D immunoglobulin is not well established. Foregoing Rh testing and anti-D immunoglobulinfor those using medication abortion through 11 to 12 weeks may be considered.”¹³

In 2020 the International Federation of Gynaecology and Obstetrics (FIGO) Committee for Safe Motherhood and Newborn Health recommended, “The risk for sensitization is most probably extremely low for spontaneous abortions before 10 gestational weeks; however, data are scarce. Based on the clinical expertise of the guideline committee from the UK’s National Institute for Health and Care Excellence (NICE), it is suggested that prophylaxis should be given only to women who are having a spontaneous abortion or medical management of miscarriage after 10 and 0/7 gestational weeks. Moreover, for women who have surgical management, prophylaxis may also be considered before 10 gestational weeks.”¹⁴

In 2022 the Royal College of Obstetricians and Gynaecologists recommended that for induced abortion, medication or surgical, “a determination of Rhesus blood status may be considered if the duration of pregnancy is over 12 weeks and anti-D is available.”¹⁵ “If available, anti-D should be offered to non-sensitised RhD-negative individuals from 12 weeks of pregnancy and provided within 72 hours of the abortion.”¹⁵

In 2022, the Society of Family Planning recommended that “Rh testing and administration are not recommended prior to 12 weeks gestation for patients undergoing spontaneous, medication or uterine aspiration abortion.” “For patients under 12 weeks gestation, although not recommended, Rh testing and Rh D immune globulin administration may be considered at patient request as part of a shared decision making process.”¹⁶

In 2022, the World Health Organization (WHO) reported “There are few studies examining Rh isoimmunization in unsensitized Rh-negative individuals seeking abortion before 12 weeks of gestation.” “The evidence on the effectiveness of the intervention may favor the intervention, because fewer women in the intervention group (anti-D administration) had antibody formation after the initial pregnancy compared to women in the comparison group (no anti-D) and no harms (undesirable effects) of the intervention were noted.”¹⁷ The evidence referenced for these statements are two low-quality studies from 1972.^18,19 The WHO continues, “…after consideration of the resources required, cost-effectiveness and feasibility of administering anti-D, as well as the very low certainty of evidence on effectiveness, the expert panel concluded that overall, the evidence does not favor the intervention and decided to recommend against it for gestational ages < 12 weeks, rather than < 9 weeks, as mentioned in the 2012 guidance.”¹⁷ In conclusion, the WHO recommended that “for both medical and surgical abortion at < 12 weeks: Recommend against anti-D immunoglobulin administration.”¹⁷

Guidelines that recommend restricted use of Rh D immune globulin during the first trimester, are based, in part, on the following considerations:

• there are no high-quality clinical trials demonstrating the benefit of Rh D immune globulin treatment in first trimester miscarriage and abortion care
• the Kleihauer-Betke technique cannot distinguish between maternal red blood cells expressing fetal hemoglobin (maternal F cells) and fetal cells, which has resulted in the over-estimation of the number of fetal cells in the maternal circulation²⁰
• using a dual-label flow cytometry method that distinguishes maternal F cells and fetal red blood cells, maternal F cells usually far outnumber fetal red blood cells in the maternal circulation in the first trimester²⁰
• among women in the first trimester undergoing uterine aspiration, the number of fetal cells in the maternal circulation is very low both before and after the procedure²⁰
• Rh testing and Rh immune globulin administration is burdensome and expensive.¹⁶

Implications for your practice

The fundamental reason for the proliferation of divergent guidelines is that there is no evidence from high-quality randomized clinical trials demonstrating that Rh testing and Rh D immune globulin treatment in early pregnancy miscarriage or induced abortion care reduces the risk of hemolytic disease of the fetus and newborn. The Cochrane review on Rh D immune globulin administration for preventing alloimmunization among patients with spontaneous miscarriage concluded, “There are insufficient data available to evaluate the practice of anti-D administration in an unsensitized Rh-negative mother after spontaneous miscarriage.”²¹

Given divergent guidelines, obstetrician-gynecologists must decide on which guideline to use in their practice. Clinicians may conclude that absent high-quality evidence from clinical trials, they will continue to use the ACOG/SOGC guidelines^2,3 in their practice, providing universal Rh testing and Rh D immune globulin treatment for all miscarriages and abortions, regardless of the gestational age. Other clinicians may conclude that Rh testing and Rh D immune globulin is not warranted before 8 to 12 weeks’ gestation, because the number of fetal red blood cells in the maternal circulation in cases of miscarriage and induced abortion is too low in early pregnancy to induce a maternal immune response.²² Based on recent studies demonstrating a low number of fetal red blood cells in the maternal circulation in the first trimester, family planning specialists are reducing the use of Rh testing and Rh immune globulin administration in both early pregnancy medication abortion and uterine aspiration abortion.¹⁶ With regard to Rh testing and Rh D immune globulin treatment, the future will definitely be different than the past. It is likely that many clinicians will reduce the use of Rh testing and Rh D immune globulin treatment in patients with miscarriage or induced abortion in early pregnancy. ●

All obstetrician-gynecologists know that pregnant patients who are Rh negative and exposed to a sufficient quantity of fetal red blood cells expressing Rh D antigen may become sensitized, producing Rh D antibodies that adversely impact future pregnancies with an Rh D-positive fetus, potentially causing hemolytic disease of the fetus and newborn. In countries where Rh D immune globulin is available, there is a consensus recommendation to administer Rh D immune globulin to Rh-negative pregnant patients at approximately 28 weeks’ gestation and at birth in order to decrease the risk of alloimmunization and hemolytic disease of the fetus and newborn in future pregnancies.¹ In contrast to this global consensus, there is no worldwide agreement about how to manage Rh testing and Rh D immune globulin administration in cases of early pregnancy loss or abortion care before 12 weeks’ gestation. This editorial examines the evolving guidelines of major professional societies.

Guidelines consistent with the routine use of Rh D immune globulin in all cases of early pregnancy loss and abortion care

As of the publication date of this editorial, the American College of Obstetricians and Gynecologists (ACOG) Practice Bulletin on prevention of Rh D alloimmunization provides the following guidance based on consensus and expert opinion²:

• “Although the risk of alloimmunization is low, the consequences can be significant, and administration of Rh D immune globulin should be considered in cases of spontaneous first trimester miscarriage, especially those that are later in the first trimester.”
• “Because of the higher risk of alloimmunization, Rh D-negative women who have instrumentation for their miscarriage should receive Rh D immune globulin prophylaxis.”
• “Rh D immune globulin should be given to Rh D-negative women who have pregnancy termination either medical or surgical.”

The Society of Obstetricians and Gynaecologists of Canada (SOGC) recommends that, “After miscarriage or threatened abortion or induced abortion during the first 12 weeks of gestation, non-sensitized D-negative women should be given a minimum anti-D of 120 µg.”³

The liberal use of Rh D immune globulin in all cases of early pregnancy loss and abortion care is based, in part, on the following considerations:

1. the recognized safety of Rh D immune globulin administration^2,3
2. the report that fetal megaloblasts may express Rh antigen as early as 38 days of gestation⁴
3. the observation that 0.1 mL of Rh D-positive red cells may provoke an immune response in some Rh D-negative patients^5-7
4. the estimate that in some patients with threatened miscarriage a significant quantity of fetal blood may enter the maternal circulation.⁸

Guidelines that suggest restricted use of Rh D immune globulin before 7 to 8 weeks’ gestation

The Reproductive Care Program of Nova Scotia guideline from 2022 notes that “the benefits of administering Rh immune globulin before 8 weeks gestation have not been demonstrated.” Given the burden of Rh testing and Rh D immune globulin administration they suggest that clinicians may withhold Rh testing and Rh D immune globulin administration in cases less than 8 weeks’ gestation (less than 56 days) for spontaneous, threatened, or medication abortions if there is reliable pregnancy dating.⁹

The Dutch Association of Abortion Specialists guidelines from 2018 suggest to not provide Rh D immune globulin treatment in the following clinical situations: patients under 10 weeks’ gestation with spontaneous miscarriage or patients under 7 weeks’ gestation having an induced abortion.¹⁰

Continue to: Guidelines that suggest restricted use of Rh D immune globulin before 10 to 12 weeks’ gestation...

There are a growing number of guidelines that recommend restricting the use of Rh testing and Rh D immune globulin treatment in the management of early miscarriage and induced abortion. In 2019, the United Kingdom’s National Institute for Health and Care Excellence (NICE) recommended that for patients having a spontaneous miscarriage, Rh testing and Rh D immune globulin are not necessary before 10 weeks 0 days of gestation.¹¹ In addition, NICE recommends, “Do not offer anti-D prophylaxis to women who are having a medical abortion up to and including 10+0 weeks’ gestation.…Consider anti-D prophylaxis for women who are rhesus D negative and are having a surgical abortion up to and including 10+0 weeks’ gestation.”¹¹

In 2019, the National Abortion Federation (NAF) Clinical Policies Committee recommended that “…it is reasonable to forgo Rh testing and anti-D immunoglobulin for women having any type of induced abortion before 8 weeks from the last menstrual period. Prior to 8 weeks, the likelihood of fetal-maternal hemorrhage adequate to cause sensitization is negligible. Given that medication abortion is more similar to spontaneous abortion with less risk of fetal-maternal hemorrhage, forgoing Rh testing and anti-D immunoglobulin for medication abortion under 10 weeks may be considered.”¹² In 2022, NAF noted, “Emerging epidemiologic and clinical evidence indicates that the risk of maternal-fetal hemorrhage caused by early abortion is negligible and Rh testing and provision of Rh immune globulin may not be necessary. It is reasonable to forego Rh testing and anti-D immunoglobulin for people having any type of abortion before 56 days and medication abortion before 70 days since the last menstrual period. The pregnancy dating at which people need Rh testing and anti-D immunoglobulin is not well established. Foregoing Rh testing and anti-D immunoglobulinfor those using medication abortion through 11 to 12 weeks may be considered.”¹³

In 2020 the International Federation of Gynaecology and Obstetrics (FIGO) Committee for Safe Motherhood and Newborn Health recommended, “The risk for sensitization is most probably extremely low for spontaneous abortions before 10 gestational weeks; however, data are scarce. Based on the clinical expertise of the guideline committee from the UK’s National Institute for Health and Care Excellence (NICE), it is suggested that prophylaxis should be given only to women who are having a spontaneous abortion or medical management of miscarriage after 10 and 0/7 gestational weeks. Moreover, for women who have surgical management, prophylaxis may also be considered before 10 gestational weeks.”¹⁴

In 2022 the Royal College of Obstetricians and Gynaecologists recommended that for induced abortion, medication or surgical, “a determination of Rhesus blood status may be considered if the duration of pregnancy is over 12 weeks and anti-D is available.”¹⁵ “If available, anti-D should be offered to non-sensitised RhD-negative individuals from 12 weeks of pregnancy and provided within 72 hours of the abortion.”¹⁵

In 2022, the Society of Family Planning recommended that “Rh testing and administration are not recommended prior to 12 weeks gestation for patients undergoing spontaneous, medication or uterine aspiration abortion.” “For patients under 12 weeks gestation, although not recommended, Rh testing and Rh D immune globulin administration may be considered at patient request as part of a shared decision making process.”¹⁶

In 2022, the World Health Organization (WHO) reported “There are few studies examining Rh isoimmunization in unsensitized Rh-negative individuals seeking abortion before 12 weeks of gestation.” “The evidence on the effectiveness of the intervention may favor the intervention, because fewer women in the intervention group (anti-D administration) had antibody formation after the initial pregnancy compared to women in the comparison group (no anti-D) and no harms (undesirable effects) of the intervention were noted.”¹⁷ The evidence referenced for these statements are two low-quality studies from 1972.^18,19 The WHO continues, “…after consideration of the resources required, cost-effectiveness and feasibility of administering anti-D, as well as the very low certainty of evidence on effectiveness, the expert panel concluded that overall, the evidence does not favor the intervention and decided to recommend against it for gestational ages < 12 weeks, rather than < 9 weeks, as mentioned in the 2012 guidance.”¹⁷ In conclusion, the WHO recommended that “for both medical and surgical abortion at < 12 weeks: Recommend against anti-D immunoglobulin administration.”¹⁷

Guidelines that recommend restricted use of Rh D immune globulin during the first trimester, are based, in part, on the following considerations:

• there are no high-quality clinical trials demonstrating the benefit of Rh D immune globulin treatment in first trimester miscarriage and abortion care
• the Kleihauer-Betke technique cannot distinguish between maternal red blood cells expressing fetal hemoglobin (maternal F cells) and fetal cells, which has resulted in the over-estimation of the number of fetal cells in the maternal circulation²⁰
• using a dual-label flow cytometry method that distinguishes maternal F cells and fetal red blood cells, maternal F cells usually far outnumber fetal red blood cells in the maternal circulation in the first trimester²⁰
• among women in the first trimester undergoing uterine aspiration, the number of fetal cells in the maternal circulation is very low both before and after the procedure²⁰
• Rh testing and Rh immune globulin administration is burdensome and expensive.¹⁶

Implications for your practice

The fundamental reason for the proliferation of divergent guidelines is that there is no evidence from high-quality randomized clinical trials demonstrating that Rh testing and Rh D immune globulin treatment in early pregnancy miscarriage or induced abortion care reduces the risk of hemolytic disease of the fetus and newborn. The Cochrane review on Rh D immune globulin administration for preventing alloimmunization among patients with spontaneous miscarriage concluded, “There are insufficient data available to evaluate the practice of anti-D administration in an unsensitized Rh-negative mother after spontaneous miscarriage.”²¹

Given divergent guidelines, obstetrician-gynecologists must decide on which guideline to use in their practice. Clinicians may conclude that absent high-quality evidence from clinical trials, they will continue to use the ACOG/SOGC guidelines^2,3 in their practice, providing universal Rh testing and Rh D immune globulin treatment for all miscarriages and abortions, regardless of the gestational age. Other clinicians may conclude that Rh testing and Rh D immune globulin is not warranted before 8 to 12 weeks’ gestation, because the number of fetal red blood cells in the maternal circulation in cases of miscarriage and induced abortion is too low in early pregnancy to induce a maternal immune response.²² Based on recent studies demonstrating a low number of fetal red blood cells in the maternal circulation in the first trimester, family planning specialists are reducing the use of Rh testing and Rh immune globulin administration in both early pregnancy medication abortion and uterine aspiration abortion.¹⁶ With regard to Rh testing and Rh D immune globulin treatment, the future will definitely be different than the past. It is likely that many clinicians will reduce the use of Rh testing and Rh D immune globulin treatment in patients with miscarriage or induced abortion in early pregnancy. ●

Meaningful progress has been made in reducing deaths due to breast cancer over the last half century, with a 43% decrease in mortality rate (breast cancer deaths per 100,000 population).¹ Screening mammography (SM) has contributed greatly to that success, accounting for 30% to 70% of the reduced mortality rate, with the remainder due to advancements in breast cancer treatment.² Despite these improvements, invasive breast cancer remains the highest incident cancer in the United States and in the world, is the second leading cause of cancer death in the United States, and results in more years of life lost than any other cancer (TABLE 1).^1,3

While the benefits and harms of SM are reasonably well understood, different guidelines groups have approached the relative value of the risks and benefits differently, which has led to challenges in implementation of shared decision making, particularly around the age to initiate routine screening.^4-6 In this article, we will focus on the data behind the controversy, current gaps in knowledge, challenges related to breast density and screening in diverse groups, and emerging technologies to address these gaps and provide a construct for appropriate counseling of the patient across the risk spectrum.

Breast cancer risk

Variables that affect risk

While female sex and older age are the 2 greatest risks for the development of breast cancer, many other factors can either increase or decrease breast cancer risk in a person’s lifetime. The importance of identifying risk factors is 3-fold:

1. to perform risk assessment to determine if individuals would benefit from average-risk versus high-risk breast cancer surveillance
2. to identify persons who might benefit from BRCA genetic counseling and screening, risk reduction medications or procedures, and
3. to allow patients to determine whether any modification in their lifestyle or reproductive choices would make sense to them to reduce their future breast cancer risk.

Most of these risk variables are largely inalterable (for example, family history of breast cancer, carriage of genetic pathogenic variants such as BRCA1 and BRCA2, age of menarche and menopause), but some are potentially modifiable, such as parity, age at first birth, lactation and duration, and dietary factors, among others. TABLE 2 lists common breast cancer risk factors.

Breast cancer risk assessment

Several validated tools have been developed to estimate a person’s breast cancer risk (TABLE 3). These tools combine known risk factors and, depending on the specific tool, can provide estimates of 5-year, 10-year, or lifetime risk of breast cancer. Patients at highest risk can benefit from earlier screening, supplemental screening with breast magnetic resonance imaging (MRI), or risk reduction (see the section, “High-risk screening”). Ideally, a risk assessment should be done by age 30 so that patients at high risk can be identified for earlier or more intensive screening and for possible genetic testing in those at risk for carriage of the BRCA or other breast cancer gene pathogenic variants.^5,7

Continue to: Breast cancer screening: Efficacy and harms...

Breast cancer screening: Efficacy and harms

The earliest studies of breast cancer screening with mammography were randomized controlled trials (RCTs) that compared screened and unscreened patients aged 40 to 74. Nearly all the RCTs and numerous well-designed incidence-based and case-control studies have demonstrated that SM results in a clinically and statistically significant reduction in breast cancer mortality (TABLE 4).^4,6,8 Since the mid-1980s and continuing to the current day, SM programs are routinely recommended in the United States. In addition to the mortality benefit outlined in TABLE 4, SM also is associated with a need for less invasive treatments if breast cancer is diagnosed.^9,10

With several decades of experience, SM programs have demonstrated that multiple harms are associated with SM, including callbacks, false-positive mammograms that result in a benign biopsy, and overdiagnosis of breast cancer (TABLE 4). Overdiagnosis is a mammographic detection of a breast cancer that would not have harmed that woman in her lifetime. Overdiagnosis leads to overtreatment of breast cancers with its attendant side effects, the emotional harms of a breast cancer diagnosis, and the substantial financial cost of cancer treatment. Estimates of overdiagnosis range from 0% to 50%, with the most likely estimate of invasive breast cancer overdiagnosis from SM between 5% and 15%.^11-13 Some of these overdiagnosed cancers are due to very slow growing cancers or breast cancers that may even regress. However, the higher rates of overdiagnosis occur in older persons who are screened and in whom competing causes of mortality become more prevalent. It is estimated that overdiagnosis of invasive breast cancer in patients younger than age 60 is less than 1%, but it exceeds 14% in those older than age 80 (TABLE 4).¹⁴

A structured approach is needed to counsel patients about SM so that they understand both the substantial benefit (earlier-stage diagnosis, reduced need for treatment, reduced breast cancer and all-cause mortality) and the potential harms (callback, false-positive results, and overdiagnosis). Moreover, the relative balance of the benefits and harms are influenced throughout their lifetime by both aging and changes in their personal and family medical history.

Counseling should consider factors beyond just the performance of mammography (sensitivity and specificity), such as the patient’s current health and age (competing causes of mortality), likelihood of developing breast cancer based on risk assessment (more benefit in higher-risk persons), and the individual patient’s values on the importance of the benefits and harms. The differing emphases on mammography performance and the relative value of the benefits and harms have led experts to produce disparate national guideline recommendations (TABLE 5).

Should SM start at age 40, 45, or 50 in average-risk persons?

There is not clear consensus about the age at which to begin to recommend routine SM in patients at average risk. The National Comprehensive Cancer Network (NCCN),⁷ American Cancer Society (ACS),⁴ and the US Preventive Services Task Force (USPSTF)⁵ recommend that those at average risk start SM at age 40, 45, and 50, respectively (TABLE 5). While the guideline groups listed in TABLE 5 agree that there is level 1 evidence that SM reduces breast cancer mortality in the general population for persons starting at age 40, because the incidence of breast cancer is lower in younger persons (TABLE 6),⁴ the net population-based screening benefit is lower in this group, and the number needed to invite to screening to save a single life due to breast cancer varies.

For patients in their 40s, it is estimated that 1,904 individuals need to be invited to SM to save 1 life, whereas for patients in their 50s, it is 1,339.¹⁵ However, for patients in their 40s, the number needed to screen to save 1 life due to breast cancer decreases from 1 in 1,904 if invited to be screened to 1 in 588 if they are actually screened.¹⁶ Furthermore, if a patient is diagnosed with breast cancer at age 40–50, the likelihood of dying is reduced at least 22% and perhaps as high as 48% if her cancer was diagnosed on SM compared with an unscreened individual with a symptomatic presentation (for example, palpable mass).^4,15,17,18 Another benefit of SM in the fifth decade of life (40s) is the decreased need for more extensive treatment, including a higher risk of need for chemotherapy (odds ratio [OR], 2.81; 95% confidence interval [CI], 1.16–6.84); need for mastectomy (OR, 3.41; 95% CI, 1.36–8.52); and need for axillary lymph node dissection (OR, 5.76; 95% CI, 2.40–13.82) in unscreened (compared with screened) patients diagnosed with breast cancer.¹⁰

The harms associated with SM are not inconsequential and include callbacks (approximately 1 in 10), false-positive biopsy (approximately 1 in 100), and overdiagnosis (likely <1% of all breast cancers in persons younger than age 50). Because most patients in their 40s will not develop breast cancer (TABLE 6), the benefit of reduced breast cancer mortality will not be experienced by most in this decade of life, but they are still just as likely to experience a callback, false-positive biopsy, or the possibility of overdiagnosis. Interpretation of this balance on a population level is the crux of the various guideline groups’ development of differing recommendations as to when screening should start. Despite this seeming disagreement, all the guideline groups listed in TABLE 5 concur that persons at average risk for breast cancer should be offered SM if they desire starting at age 40 after a shared decision-making conversation that incorporates the patient’s view on the relative value of the benefits and risks.

Continue to: High-risk screening...

Unlike in screening average-risk patients, there is less disagreement about screening in high-risk groups. TABLE 7 outlines the various categories and recommended strategies that qualify for screening at younger ages or more intensive screening. Adding breast MRI to SM in high-risk individuals results in both higher cancer detection rates and less interval breast cancers (cancers diagnosed between screening rounds) diagnosed compared with SM alone.^19,20 Interval breast cancer tends to be more aggressive and is used as a surrogate marker for more recognized factors, such as breast cancer mortality. In addition to less interval breast cancers, high-risk patients are more likely to be diagnosed with node-negative disease if screening breast MRI is added to SM.

Long-term mortality benefit studies using MRI have not been conducted due to the prolonged follow-up times needed. Expense, lower specificity compared with mammography (that is, more false-positive results), and need for the use of gadolinium limit more widespread use of breast MRI screening in average-risk persons.

Screening in patients with dense breasts

Half of patients undergoing SM in the United States have dense breasts (heterogeneously dense breasts, 40%; extremely dense breasts, 10%). Importantly, increasing breast density is associated with a lower cancer detection rate with SM and is an independent risk factor for developing breast cancer. While most states already require patients to be notified if they have dense breasts identified on SM, the US Food and Drug Administration will soon make breast density patient notification a national standard (see: https://delauro.house.gov/media-center/press-releases/delauro-secures-timeline-fda-rollout-breast-density-notification-rule).

Most of the risk assessment tools listed in TABLE 3 incorporate breast density into their calculation of breast cancer risk. If that calculation places a patient into one of the highest-risk groups (based on additional factors like strong family history of breast cancer, reproductive risk factors, BRCA carriage, and so on), more intensive surveillance should be recommended (TABLE 7).⁷ However, once these risk calculations are done, most persons with dense breasts will remain in an average-risk category.

Because of the frequency and risks associated with dense breasts, different and alternative strategies have been recommended for screening persons who are at average risk with dense breasts. Supplemental screening with MRI, ultrasonography, contrast-enhanced mammography, and molecular breast imaging are all being considered but have not been studied sufficiently to demonstrate mortality benefit or cost-effectiveness.

Of all the supplemental modalities used to screen patients with dense breasts, MRI has been the best studied. A large RCT in the Netherlands evaluated supplemental MRI screening in persons with extremely dense breasts after a negative mammogram.²¹ Compared with no supplemental screening, the MRI group had 17 additional cancers detected per 1,000 screened and a 50% reduction in interval breast cancers; in addition, MRI was associated with a positive predictive value of 26% for biopsies. At present, high cost and limited access to standard breast MRI has not allowed its routine use for persons with dense breasts in the United States, but this may change with more experience and more widespread introduction and experience with abbreviated (or rapid) breast MRI in the future (TABLE 8).

Equitable screening

Black persons who are diagnosed with breast cancer have a 40% higher risk of dying than White patients due to multiple factors, including systemic racial factors (implicit and unconscious bias), reduced access to care, and a lower likelihood of receiving standard of care once diagnosed.^22-24 In addition, Black patients have twice the likelihood of being diagnosed with triple-negative breast cancers, a biologically more aggressive tumor.^22-24 Among Black, Asian, and Hispanic persons diagnosed with breast cancer, one-third are diagnosed younger than age 50, which is higher than for non-Hispanic White persons. Prior to the age of 50, Black, Asian, and Hispanic patients also have a 72% more likelihood of being diagnosed with invasive breast cancer, have a 58% greater risk of advanced-stage disease, and have a 127% higher risk of dying from breast cancer compared with White patients.^25,26 Based on all of these factors, delaying SM until age 50 may adversely affect the Black, Asian, and Hispanic populations.

Persons in the LGBTQ+ community do not present for SM as frequently as the general population, often because they feel threatened or unwelcome.²⁷ Clinicians and breast imaging units should review their inclusivity policies and training to provide a welcoming and respectful environment to all persons in an effort to reduce these barriers. While data are limited and largely depend on expert opinion, current recommendations for screening in the transgender patient depend on sex assigned at birth, the type and duration of hormone use, and surgical history. In patients assigned female sex at birth, average-risk and high-risk screening recommendations are similar to those for the general population unless bilateral mastectomy has been performed.²⁸ In transfeminine patients who have used hormones for longer than 5 years, some groups recommend annual screening starting at age 40, although well-designed studies are lacking.²⁹

Continue to: We have done well, can we do better?...

Screening mammography clearly has been an important and effective tool in the effort to reduce breast cancer mortality, but there are clear limitations. These include moderate sensitivity of mammography, particularly in patients with dense breasts, and a specificity that results in either callbacks (10%), breast biopsies for benign disease (1%), or the reality of overdiagnosis, which becomes increasingly important in older patients.

With the introduction of mammography in the mid-1980s, a one-size-fits-all approach has proved challenging more recently due to an increased recognition of the harms of screening. As a result of this evolving understanding, different recommendations for average-risk screening have emerged. With the advent of breast MRI, risk-based screening is an important but underutilized tool to identify highest-risk individuals, which is associated with improved cancer detection rates, reduced node-positive disease, and fewer diagnosed interval breast cancers. Assuring that nearly all of this highest-risk group is identified through routine breast cancer risk assessment remains a challenge for clinicians.

But what SM recommendations should be offered to persons who fall into an intermediate-risk group (15%–20%), very low-risk groups (<5%), or patients with dense breasts? These are challenges that could be met through novel and individualized approaches (for example, polygenic risk scoring, further research on newer modalities of screening [TABLE 8]), improved screening algorithms for persons with dense breasts, and enhanced clinician engagement to achieve universal breast cancer and BRCA risk assessment of patients by age 25 to 30.

In 2023, best practice and consensus guidelines for intermediate- and low-risk breast cancer groups remain unclear, and one of the many ongoing challenges is to further reduce the impact of breast cancer on the lives of persons affected and the recognized harms of SM.

In the meantime, there is consensus in average-risk patients to provide counseling about SM by age 40. My approach has been to counsel all average-risk patients on the risks and benefits of mammography using the acronym TIP-V:

• Use a Tool to calculate breast cancer risk (TABLE 3). If they are at high risk, provide recommendations for high-risk management (TABLE 7).⁷
• For average-risk patients, counsel that their Incidence of developing breast cancer in the next decade is approximately 1 in 70 (TABLE 6).⁴
• Provide data and guidance on the benefits of SM for patients in their 40s (mortality improvement, decreased treatment) and the likelihood of harm from breast cancer screening (10% callback, 1% benign biopsy, and <1% likelihood of overdiagnosis [TABLE 4]).^4,14,15
• Engage the patient to better understand their relative Values of the benefits and harms and make a shared decision on screening starting at age 40, 45, or 50.

Looking forward

In summary, SM remains an important tool in the effort to decrease the risk of mortality due to breast cancer. Given the limitations of SM, however, newer tools and methods—abbreviated MRI, contrast-enhanced mammography, molecular breast imaging, customized screening intervals depending on individual risk/polygenic risk score, and customized counseling and screening based on risk factors (TABLES 2 and 7)—will play an increased role in recommendations for breast cancer screening in the future. ●

Meaningful progress has been made in reducing deaths due to breast cancer over the last half century, with a 43% decrease in mortality rate (breast cancer deaths per 100,000 population).¹ Screening mammography (SM) has contributed greatly to that success, accounting for 30% to 70% of the reduced mortality rate, with the remainder due to advancements in breast cancer treatment.² Despite these improvements, invasive breast cancer remains the highest incident cancer in the United States and in the world, is the second leading cause of cancer death in the United States, and results in more years of life lost than any other cancer (TABLE 1).^1,3

While the benefits and harms of SM are reasonably well understood, different guidelines groups have approached the relative value of the risks and benefits differently, which has led to challenges in implementation of shared decision making, particularly around the age to initiate routine screening.^4-6 In this article, we will focus on the data behind the controversy, current gaps in knowledge, challenges related to breast density and screening in diverse groups, and emerging technologies to address these gaps and provide a construct for appropriate counseling of the patient across the risk spectrum.

Breast cancer risk

Variables that affect risk

While female sex and older age are the 2 greatest risks for the development of breast cancer, many other factors can either increase or decrease breast cancer risk in a person’s lifetime. The importance of identifying risk factors is 3-fold:

1. to perform risk assessment to determine if individuals would benefit from average-risk versus high-risk breast cancer surveillance
2. to identify persons who might benefit from BRCA genetic counseling and screening, risk reduction medications or procedures, and
3. to allow patients to determine whether any modification in their lifestyle or reproductive choices would make sense to them to reduce their future breast cancer risk.

Most of these risk variables are largely inalterable (for example, family history of breast cancer, carriage of genetic pathogenic variants such as BRCA1 and BRCA2, age of menarche and menopause), but some are potentially modifiable, such as parity, age at first birth, lactation and duration, and dietary factors, among others. TABLE 2 lists common breast cancer risk factors.

Breast cancer risk assessment

Several validated tools have been developed to estimate a person’s breast cancer risk (TABLE 3). These tools combine known risk factors and, depending on the specific tool, can provide estimates of 5-year, 10-year, or lifetime risk of breast cancer. Patients at highest risk can benefit from earlier screening, supplemental screening with breast magnetic resonance imaging (MRI), or risk reduction (see the section, “High-risk screening”). Ideally, a risk assessment should be done by age 30 so that patients at high risk can be identified for earlier or more intensive screening and for possible genetic testing in those at risk for carriage of the BRCA or other breast cancer gene pathogenic variants.^5,7

Continue to: Breast cancer screening: Efficacy and harms...

Breast cancer screening: Efficacy and harms

The earliest studies of breast cancer screening with mammography were randomized controlled trials (RCTs) that compared screened and unscreened patients aged 40 to 74. Nearly all the RCTs and numerous well-designed incidence-based and case-control studies have demonstrated that SM results in a clinically and statistically significant reduction in breast cancer mortality (TABLE 4).^4,6,8 Since the mid-1980s and continuing to the current day, SM programs are routinely recommended in the United States. In addition to the mortality benefit outlined in TABLE 4, SM also is associated with a need for less invasive treatments if breast cancer is diagnosed.^9,10

With several decades of experience, SM programs have demonstrated that multiple harms are associated with SM, including callbacks, false-positive mammograms that result in a benign biopsy, and overdiagnosis of breast cancer (TABLE 4). Overdiagnosis is a mammographic detection of a breast cancer that would not have harmed that woman in her lifetime. Overdiagnosis leads to overtreatment of breast cancers with its attendant side effects, the emotional harms of a breast cancer diagnosis, and the substantial financial cost of cancer treatment. Estimates of overdiagnosis range from 0% to 50%, with the most likely estimate of invasive breast cancer overdiagnosis from SM between 5% and 15%.^11-13 Some of these overdiagnosed cancers are due to very slow growing cancers or breast cancers that may even regress. However, the higher rates of overdiagnosis occur in older persons who are screened and in whom competing causes of mortality become more prevalent. It is estimated that overdiagnosis of invasive breast cancer in patients younger than age 60 is less than 1%, but it exceeds 14% in those older than age 80 (TABLE 4).¹⁴

A structured approach is needed to counsel patients about SM so that they understand both the substantial benefit (earlier-stage diagnosis, reduced need for treatment, reduced breast cancer and all-cause mortality) and the potential harms (callback, false-positive results, and overdiagnosis). Moreover, the relative balance of the benefits and harms are influenced throughout their lifetime by both aging and changes in their personal and family medical history.

Counseling should consider factors beyond just the performance of mammography (sensitivity and specificity), such as the patient’s current health and age (competing causes of mortality), likelihood of developing breast cancer based on risk assessment (more benefit in higher-risk persons), and the individual patient’s values on the importance of the benefits and harms. The differing emphases on mammography performance and the relative value of the benefits and harms have led experts to produce disparate national guideline recommendations (TABLE 5).

Should SM start at age 40, 45, or 50 in average-risk persons?

There is not clear consensus about the age at which to begin to recommend routine SM in patients at average risk. The National Comprehensive Cancer Network (NCCN),⁷ American Cancer Society (ACS),⁴ and the US Preventive Services Task Force (USPSTF)⁵ recommend that those at average risk start SM at age 40, 45, and 50, respectively (TABLE 5). While the guideline groups listed in TABLE 5 agree that there is level 1 evidence that SM reduces breast cancer mortality in the general population for persons starting at age 40, because the incidence of breast cancer is lower in younger persons (TABLE 6),⁴ the net population-based screening benefit is lower in this group, and the number needed to invite to screening to save a single life due to breast cancer varies.

For patients in their 40s, it is estimated that 1,904 individuals need to be invited to SM to save 1 life, whereas for patients in their 50s, it is 1,339.¹⁵ However, for patients in their 40s, the number needed to screen to save 1 life due to breast cancer decreases from 1 in 1,904 if invited to be screened to 1 in 588 if they are actually screened.¹⁶ Furthermore, if a patient is diagnosed with breast cancer at age 40–50, the likelihood of dying is reduced at least 22% and perhaps as high as 48% if her cancer was diagnosed on SM compared with an unscreened individual with a symptomatic presentation (for example, palpable mass).^4,15,17,18 Another benefit of SM in the fifth decade of life (40s) is the decreased need for more extensive treatment, including a higher risk of need for chemotherapy (odds ratio [OR], 2.81; 95% confidence interval [CI], 1.16–6.84); need for mastectomy (OR, 3.41; 95% CI, 1.36–8.52); and need for axillary lymph node dissection (OR, 5.76; 95% CI, 2.40–13.82) in unscreened (compared with screened) patients diagnosed with breast cancer.¹⁰

The harms associated with SM are not inconsequential and include callbacks (approximately 1 in 10), false-positive biopsy (approximately 1 in 100), and overdiagnosis (likely <1% of all breast cancers in persons younger than age 50). Because most patients in their 40s will not develop breast cancer (TABLE 6), the benefit of reduced breast cancer mortality will not be experienced by most in this decade of life, but they are still just as likely to experience a callback, false-positive biopsy, or the possibility of overdiagnosis. Interpretation of this balance on a population level is the crux of the various guideline groups’ development of differing recommendations as to when screening should start. Despite this seeming disagreement, all the guideline groups listed in TABLE 5 concur that persons at average risk for breast cancer should be offered SM if they desire starting at age 40 after a shared decision-making conversation that incorporates the patient’s view on the relative value of the benefits and risks.

Continue to: High-risk screening...

Unlike in screening average-risk patients, there is less disagreement about screening in high-risk groups. TABLE 7 outlines the various categories and recommended strategies that qualify for screening at younger ages or more intensive screening. Adding breast MRI to SM in high-risk individuals results in both higher cancer detection rates and less interval breast cancers (cancers diagnosed between screening rounds) diagnosed compared with SM alone.^19,20 Interval breast cancer tends to be more aggressive and is used as a surrogate marker for more recognized factors, such as breast cancer mortality. In addition to less interval breast cancers, high-risk patients are more likely to be diagnosed with node-negative disease if screening breast MRI is added to SM.

Long-term mortality benefit studies using MRI have not been conducted due to the prolonged follow-up times needed. Expense, lower specificity compared with mammography (that is, more false-positive results), and need for the use of gadolinium limit more widespread use of breast MRI screening in average-risk persons.

Screening in patients with dense breasts

Half of patients undergoing SM in the United States have dense breasts (heterogeneously dense breasts, 40%; extremely dense breasts, 10%). Importantly, increasing breast density is associated with a lower cancer detection rate with SM and is an independent risk factor for developing breast cancer. While most states already require patients to be notified if they have dense breasts identified on SM, the US Food and Drug Administration will soon make breast density patient notification a national standard (see: https://delauro.house.gov/media-center/press-releases/delauro-secures-timeline-fda-rollout-breast-density-notification-rule).

Most of the risk assessment tools listed in TABLE 3 incorporate breast density into their calculation of breast cancer risk. If that calculation places a patient into one of the highest-risk groups (based on additional factors like strong family history of breast cancer, reproductive risk factors, BRCA carriage, and so on), more intensive surveillance should be recommended (TABLE 7).⁷ However, once these risk calculations are done, most persons with dense breasts will remain in an average-risk category.

Because of the frequency and risks associated with dense breasts, different and alternative strategies have been recommended for screening persons who are at average risk with dense breasts. Supplemental screening with MRI, ultrasonography, contrast-enhanced mammography, and molecular breast imaging are all being considered but have not been studied sufficiently to demonstrate mortality benefit or cost-effectiveness.

Of all the supplemental modalities used to screen patients with dense breasts, MRI has been the best studied. A large RCT in the Netherlands evaluated supplemental MRI screening in persons with extremely dense breasts after a negative mammogram.²¹ Compared with no supplemental screening, the MRI group had 17 additional cancers detected per 1,000 screened and a 50% reduction in interval breast cancers; in addition, MRI was associated with a positive predictive value of 26% for biopsies. At present, high cost and limited access to standard breast MRI has not allowed its routine use for persons with dense breasts in the United States, but this may change with more experience and more widespread introduction and experience with abbreviated (or rapid) breast MRI in the future (TABLE 8).

Equitable screening

Black persons who are diagnosed with breast cancer have a 40% higher risk of dying than White patients due to multiple factors, including systemic racial factors (implicit and unconscious bias), reduced access to care, and a lower likelihood of receiving standard of care once diagnosed.^22-24 In addition, Black patients have twice the likelihood of being diagnosed with triple-negative breast cancers, a biologically more aggressive tumor.^22-24 Among Black, Asian, and Hispanic persons diagnosed with breast cancer, one-third are diagnosed younger than age 50, which is higher than for non-Hispanic White persons. Prior to the age of 50, Black, Asian, and Hispanic patients also have a 72% more likelihood of being diagnosed with invasive breast cancer, have a 58% greater risk of advanced-stage disease, and have a 127% higher risk of dying from breast cancer compared with White patients.^25,26 Based on all of these factors, delaying SM until age 50 may adversely affect the Black, Asian, and Hispanic populations.

Persons in the LGBTQ+ community do not present for SM as frequently as the general population, often because they feel threatened or unwelcome.²⁷ Clinicians and breast imaging units should review their inclusivity policies and training to provide a welcoming and respectful environment to all persons in an effort to reduce these barriers. While data are limited and largely depend on expert opinion, current recommendations for screening in the transgender patient depend on sex assigned at birth, the type and duration of hormone use, and surgical history. In patients assigned female sex at birth, average-risk and high-risk screening recommendations are similar to those for the general population unless bilateral mastectomy has been performed.²⁸ In transfeminine patients who have used hormones for longer than 5 years, some groups recommend annual screening starting at age 40, although well-designed studies are lacking.²⁹

Continue to: We have done well, can we do better?...

Screening mammography clearly has been an important and effective tool in the effort to reduce breast cancer mortality, but there are clear limitations. These include moderate sensitivity of mammography, particularly in patients with dense breasts, and a specificity that results in either callbacks (10%), breast biopsies for benign disease (1%), or the reality of overdiagnosis, which becomes increasingly important in older patients.

With the introduction of mammography in the mid-1980s, a one-size-fits-all approach has proved challenging more recently due to an increased recognition of the harms of screening. As a result of this evolving understanding, different recommendations for average-risk screening have emerged. With the advent of breast MRI, risk-based screening is an important but underutilized tool to identify highest-risk individuals, which is associated with improved cancer detection rates, reduced node-positive disease, and fewer diagnosed interval breast cancers. Assuring that nearly all of this highest-risk group is identified through routine breast cancer risk assessment remains a challenge for clinicians.

But what SM recommendations should be offered to persons who fall into an intermediate-risk group (15%–20%), very low-risk groups (<5%), or patients with dense breasts? These are challenges that could be met through novel and individualized approaches (for example, polygenic risk scoring, further research on newer modalities of screening [TABLE 8]), improved screening algorithms for persons with dense breasts, and enhanced clinician engagement to achieve universal breast cancer and BRCA risk assessment of patients by age 25 to 30.

In 2023, best practice and consensus guidelines for intermediate- and low-risk breast cancer groups remain unclear, and one of the many ongoing challenges is to further reduce the impact of breast cancer on the lives of persons affected and the recognized harms of SM.

In the meantime, there is consensus in average-risk patients to provide counseling about SM by age 40. My approach has been to counsel all average-risk patients on the risks and benefits of mammography using the acronym TIP-V:

• Use a Tool to calculate breast cancer risk (TABLE 3). If they are at high risk, provide recommendations for high-risk management (TABLE 7).⁷
• For average-risk patients, counsel that their Incidence of developing breast cancer in the next decade is approximately 1 in 70 (TABLE 6).⁴
• Provide data and guidance on the benefits of SM for patients in their 40s (mortality improvement, decreased treatment) and the likelihood of harm from breast cancer screening (10% callback, 1% benign biopsy, and <1% likelihood of overdiagnosis [TABLE 4]).^4,14,15
• Engage the patient to better understand their relative Values of the benefits and harms and make a shared decision on screening starting at age 40, 45, or 50.

Looking forward

In summary, SM remains an important tool in the effort to decrease the risk of mortality due to breast cancer. Given the limitations of SM, however, newer tools and methods—abbreviated MRI, contrast-enhanced mammography, molecular breast imaging, customized screening intervals depending on individual risk/polygenic risk score, and customized counseling and screening based on risk factors (TABLES 2 and 7)—will play an increased role in recommendations for breast cancer screening in the future. ●

Meaningful progress has been made in reducing deaths due to breast cancer over the last half century, with a 43% decrease in mortality rate (breast cancer deaths per 100,000 population).¹ Screening mammography (SM) has contributed greatly to that success, accounting for 30% to 70% of the reduced mortality rate, with the remainder due to advancements in breast cancer treatment.² Despite these improvements, invasive breast cancer remains the highest incident cancer in the United States and in the world, is the second leading cause of cancer death in the United States, and results in more years of life lost than any other cancer (TABLE 1).^1,3

While the benefits and harms of SM are reasonably well understood, different guidelines groups have approached the relative value of the risks and benefits differently, which has led to challenges in implementation of shared decision making, particularly around the age to initiate routine screening.^4-6 In this article, we will focus on the data behind the controversy, current gaps in knowledge, challenges related to breast density and screening in diverse groups, and emerging technologies to address these gaps and provide a construct for appropriate counseling of the patient across the risk spectrum.

Breast cancer risk

Variables that affect risk

While female sex and older age are the 2 greatest risks for the development of breast cancer, many other factors can either increase or decrease breast cancer risk in a person’s lifetime. The importance of identifying risk factors is 3-fold:

1. to perform risk assessment to determine if individuals would benefit from average-risk versus high-risk breast cancer surveillance
2. to identify persons who might benefit from BRCA genetic counseling and screening, risk reduction medications or procedures, and
3. to allow patients to determine whether any modification in their lifestyle or reproductive choices would make sense to them to reduce their future breast cancer risk.

Most of these risk variables are largely inalterable (for example, family history of breast cancer, carriage of genetic pathogenic variants such as BRCA1 and BRCA2, age of menarche and menopause), but some are potentially modifiable, such as parity, age at first birth, lactation and duration, and dietary factors, among others. TABLE 2 lists common breast cancer risk factors.

Breast cancer risk assessment

Several validated tools have been developed to estimate a person’s breast cancer risk (TABLE 3). These tools combine known risk factors and, depending on the specific tool, can provide estimates of 5-year, 10-year, or lifetime risk of breast cancer. Patients at highest risk can benefit from earlier screening, supplemental screening with breast magnetic resonance imaging (MRI), or risk reduction (see the section, “High-risk screening”). Ideally, a risk assessment should be done by age 30 so that patients at high risk can be identified for earlier or more intensive screening and for possible genetic testing in those at risk for carriage of the BRCA or other breast cancer gene pathogenic variants.^5,7

Continue to: Breast cancer screening: Efficacy and harms...

Breast cancer screening: Efficacy and harms

The earliest studies of breast cancer screening with mammography were randomized controlled trials (RCTs) that compared screened and unscreened patients aged 40 to 74. Nearly all the RCTs and numerous well-designed incidence-based and case-control studies have demonstrated that SM results in a clinically and statistically significant reduction in breast cancer mortality (TABLE 4).^4,6,8 Since the mid-1980s and continuing to the current day, SM programs are routinely recommended in the United States. In addition to the mortality benefit outlined in TABLE 4, SM also is associated with a need for less invasive treatments if breast cancer is diagnosed.^9,10

With several decades of experience, SM programs have demonstrated that multiple harms are associated with SM, including callbacks, false-positive mammograms that result in a benign biopsy, and overdiagnosis of breast cancer (TABLE 4). Overdiagnosis is a mammographic detection of a breast cancer that would not have harmed that woman in her lifetime. Overdiagnosis leads to overtreatment of breast cancers with its attendant side effects, the emotional harms of a breast cancer diagnosis, and the substantial financial cost of cancer treatment. Estimates of overdiagnosis range from 0% to 50%, with the most likely estimate of invasive breast cancer overdiagnosis from SM between 5% and 15%.^11-13 Some of these overdiagnosed cancers are due to very slow growing cancers or breast cancers that may even regress. However, the higher rates of overdiagnosis occur in older persons who are screened and in whom competing causes of mortality become more prevalent. It is estimated that overdiagnosis of invasive breast cancer in patients younger than age 60 is less than 1%, but it exceeds 14% in those older than age 80 (TABLE 4).¹⁴

A structured approach is needed to counsel patients about SM so that they understand both the substantial benefit (earlier-stage diagnosis, reduced need for treatment, reduced breast cancer and all-cause mortality) and the potential harms (callback, false-positive results, and overdiagnosis). Moreover, the relative balance of the benefits and harms are influenced throughout their lifetime by both aging and changes in their personal and family medical history.

Counseling should consider factors beyond just the performance of mammography (sensitivity and specificity), such as the patient’s current health and age (competing causes of mortality), likelihood of developing breast cancer based on risk assessment (more benefit in higher-risk persons), and the individual patient’s values on the importance of the benefits and harms. The differing emphases on mammography performance and the relative value of the benefits and harms have led experts to produce disparate national guideline recommendations (TABLE 5).

Should SM start at age 40, 45, or 50 in average-risk persons?

There is not clear consensus about the age at which to begin to recommend routine SM in patients at average risk. The National Comprehensive Cancer Network (NCCN),⁷ American Cancer Society (ACS),⁴ and the US Preventive Services Task Force (USPSTF)⁵ recommend that those at average risk start SM at age 40, 45, and 50, respectively (TABLE 5). While the guideline groups listed in TABLE 5 agree that there is level 1 evidence that SM reduces breast cancer mortality in the general population for persons starting at age 40, because the incidence of breast cancer is lower in younger persons (TABLE 6),⁴ the net population-based screening benefit is lower in this group, and the number needed to invite to screening to save a single life due to breast cancer varies.

For patients in their 40s, it is estimated that 1,904 individuals need to be invited to SM to save 1 life, whereas for patients in their 50s, it is 1,339.¹⁵ However, for patients in their 40s, the number needed to screen to save 1 life due to breast cancer decreases from 1 in 1,904 if invited to be screened to 1 in 588 if they are actually screened.¹⁶ Furthermore, if a patient is diagnosed with breast cancer at age 40–50, the likelihood of dying is reduced at least 22% and perhaps as high as 48% if her cancer was diagnosed on SM compared with an unscreened individual with a symptomatic presentation (for example, palpable mass).^4,15,17,18 Another benefit of SM in the fifth decade of life (40s) is the decreased need for more extensive treatment, including a higher risk of need for chemotherapy (odds ratio [OR], 2.81; 95% confidence interval [CI], 1.16–6.84); need for mastectomy (OR, 3.41; 95% CI, 1.36–8.52); and need for axillary lymph node dissection (OR, 5.76; 95% CI, 2.40–13.82) in unscreened (compared with screened) patients diagnosed with breast cancer.¹⁰

The harms associated with SM are not inconsequential and include callbacks (approximately 1 in 10), false-positive biopsy (approximately 1 in 100), and overdiagnosis (likely <1% of all breast cancers in persons younger than age 50). Because most patients in their 40s will not develop breast cancer (TABLE 6), the benefit of reduced breast cancer mortality will not be experienced by most in this decade of life, but they are still just as likely to experience a callback, false-positive biopsy, or the possibility of overdiagnosis. Interpretation of this balance on a population level is the crux of the various guideline groups’ development of differing recommendations as to when screening should start. Despite this seeming disagreement, all the guideline groups listed in TABLE 5 concur that persons at average risk for breast cancer should be offered SM if they desire starting at age 40 after a shared decision-making conversation that incorporates the patient’s view on the relative value of the benefits and risks.

Continue to: High-risk screening...

Unlike in screening average-risk patients, there is less disagreement about screening in high-risk groups. TABLE 7 outlines the various categories and recommended strategies that qualify for screening at younger ages or more intensive screening. Adding breast MRI to SM in high-risk individuals results in both higher cancer detection rates and less interval breast cancers (cancers diagnosed between screening rounds) diagnosed compared with SM alone.^19,20 Interval breast cancer tends to be more aggressive and is used as a surrogate marker for more recognized factors, such as breast cancer mortality. In addition to less interval breast cancers, high-risk patients are more likely to be diagnosed with node-negative disease if screening breast MRI is added to SM.

Long-term mortality benefit studies using MRI have not been conducted due to the prolonged follow-up times needed. Expense, lower specificity compared with mammography (that is, more false-positive results), and need for the use of gadolinium limit more widespread use of breast MRI screening in average-risk persons.

Screening in patients with dense breasts

Half of patients undergoing SM in the United States have dense breasts (heterogeneously dense breasts, 40%; extremely dense breasts, 10%). Importantly, increasing breast density is associated with a lower cancer detection rate with SM and is an independent risk factor for developing breast cancer. While most states already require patients to be notified if they have dense breasts identified on SM, the US Food and Drug Administration will soon make breast density patient notification a national standard (see: https://delauro.house.gov/media-center/press-releases/delauro-secures-timeline-fda-rollout-breast-density-notification-rule).

Most of the risk assessment tools listed in TABLE 3 incorporate breast density into their calculation of breast cancer risk. If that calculation places a patient into one of the highest-risk groups (based on additional factors like strong family history of breast cancer, reproductive risk factors, BRCA carriage, and so on), more intensive surveillance should be recommended (TABLE 7).⁷ However, once these risk calculations are done, most persons with dense breasts will remain in an average-risk category.

Because of the frequency and risks associated with dense breasts, different and alternative strategies have been recommended for screening persons who are at average risk with dense breasts. Supplemental screening with MRI, ultrasonography, contrast-enhanced mammography, and molecular breast imaging are all being considered but have not been studied sufficiently to demonstrate mortality benefit or cost-effectiveness.

Of all the supplemental modalities used to screen patients with dense breasts, MRI has been the best studied. A large RCT in the Netherlands evaluated supplemental MRI screening in persons with extremely dense breasts after a negative mammogram.²¹ Compared with no supplemental screening, the MRI group had 17 additional cancers detected per 1,000 screened and a 50% reduction in interval breast cancers; in addition, MRI was associated with a positive predictive value of 26% for biopsies. At present, high cost and limited access to standard breast MRI has not allowed its routine use for persons with dense breasts in the United States, but this may change with more experience and more widespread introduction and experience with abbreviated (or rapid) breast MRI in the future (TABLE 8).

Equitable screening

Black persons who are diagnosed with breast cancer have a 40% higher risk of dying than White patients due to multiple factors, including systemic racial factors (implicit and unconscious bias), reduced access to care, and a lower likelihood of receiving standard of care once diagnosed.^22-24 In addition, Black patients have twice the likelihood of being diagnosed with triple-negative breast cancers, a biologically more aggressive tumor.^22-24 Among Black, Asian, and Hispanic persons diagnosed with breast cancer, one-third are diagnosed younger than age 50, which is higher than for non-Hispanic White persons. Prior to the age of 50, Black, Asian, and Hispanic patients also have a 72% more likelihood of being diagnosed with invasive breast cancer, have a 58% greater risk of advanced-stage disease, and have a 127% higher risk of dying from breast cancer compared with White patients.^25,26 Based on all of these factors, delaying SM until age 50 may adversely affect the Black, Asian, and Hispanic populations.

Persons in the LGBTQ+ community do not present for SM as frequently as the general population, often because they feel threatened or unwelcome.²⁷ Clinicians and breast imaging units should review their inclusivity policies and training to provide a welcoming and respectful environment to all persons in an effort to reduce these barriers. While data are limited and largely depend on expert opinion, current recommendations for screening in the transgender patient depend on sex assigned at birth, the type and duration of hormone use, and surgical history. In patients assigned female sex at birth, average-risk and high-risk screening recommendations are similar to those for the general population unless bilateral mastectomy has been performed.²⁸ In transfeminine patients who have used hormones for longer than 5 years, some groups recommend annual screening starting at age 40, although well-designed studies are lacking.²⁹

Continue to: We have done well, can we do better?...

Screening mammography clearly has been an important and effective tool in the effort to reduce breast cancer mortality, but there are clear limitations. These include moderate sensitivity of mammography, particularly in patients with dense breasts, and a specificity that results in either callbacks (10%), breast biopsies for benign disease (1%), or the reality of overdiagnosis, which becomes increasingly important in older patients.

With the introduction of mammography in the mid-1980s, a one-size-fits-all approach has proved challenging more recently due to an increased recognition of the harms of screening. As a result of this evolving understanding, different recommendations for average-risk screening have emerged. With the advent of breast MRI, risk-based screening is an important but underutilized tool to identify highest-risk individuals, which is associated with improved cancer detection rates, reduced node-positive disease, and fewer diagnosed interval breast cancers. Assuring that nearly all of this highest-risk group is identified through routine breast cancer risk assessment remains a challenge for clinicians.

But what SM recommendations should be offered to persons who fall into an intermediate-risk group (15%–20%), very low-risk groups (<5%), or patients with dense breasts? These are challenges that could be met through novel and individualized approaches (for example, polygenic risk scoring, further research on newer modalities of screening [TABLE 8]), improved screening algorithms for persons with dense breasts, and enhanced clinician engagement to achieve universal breast cancer and BRCA risk assessment of patients by age 25 to 30.

In 2023, best practice and consensus guidelines for intermediate- and low-risk breast cancer groups remain unclear, and one of the many ongoing challenges is to further reduce the impact of breast cancer on the lives of persons affected and the recognized harms of SM.

In the meantime, there is consensus in average-risk patients to provide counseling about SM by age 40. My approach has been to counsel all average-risk patients on the risks and benefits of mammography using the acronym TIP-V:

• Use a Tool to calculate breast cancer risk (TABLE 3). If they are at high risk, provide recommendations for high-risk management (TABLE 7).⁷
• For average-risk patients, counsel that their Incidence of developing breast cancer in the next decade is approximately 1 in 70 (TABLE 6).⁴
• Provide data and guidance on the benefits of SM for patients in their 40s (mortality improvement, decreased treatment) and the likelihood of harm from breast cancer screening (10% callback, 1% benign biopsy, and <1% likelihood of overdiagnosis [TABLE 4]).^4,14,15
• Engage the patient to better understand their relative Values of the benefits and harms and make a shared decision on screening starting at age 40, 45, or 50.

Looking forward

In summary, SM remains an important tool in the effort to decrease the risk of mortality due to breast cancer. Given the limitations of SM, however, newer tools and methods—abbreviated MRI, contrast-enhanced mammography, molecular breast imaging, customized screening intervals depending on individual risk/polygenic risk score, and customized counseling and screening based on risk factors (TABLES 2 and 7)—will play an increased role in recommendations for breast cancer screening in the future. ●

I recently heard a lecture where the speaker quoted this statistic: “A 50-year-old woman who does not currently have heart disease or cancer has a life expectancy of 91.” Hopefully, anyone reading this article already is aware of the fact that as our patients age, hip fracture results in greater morbidity and mortality than early breast cancer. It should be well known to clinicians (and, ultimately, to our patients) that localized breast cancer has a survival rate of 99%,¹ whereas hip fracture carries a 21% mortality in the first year after the event.² In addition, approximately one-third of women who fracture their hip do not have osteoporosis.³ Furthermore, the role of muscle mass, strength, and performance in bone health has become well established.⁴

With this in mind, a recent encounter with a patient in my clinical practice illustrates what I believe is an increasing problem today. The patient had been on long-term prednisone systemically for polymyalgia rheumatica. Her dual energy x-ray absorptiometry (DXA) bone mass measurements were among the worst osteoporotic numbers I have witnessed. She related to me the “argument” that occurred between her rheumatologist and endocrinologist. One wanted her to use injectable parathyroid hormone analog daily, while the other advised yearly infusion of zoledronic acid. She chose the yearly infusion. I inquired if either physician had mentioned anything to her about using nonskid rugs in the bathroom, grab bars, being careful of black ice, a calcium-rich diet, vitamin D supplementation, good eyesight, illumination so she does not miss a step, mindful walking, and maintaining optimal balance, muscle mass, strength, and performance-enhancing exercise? She replied, “No, just which drug I should take.”

Realize that the goal for our patients should be to avoid the morbidity and mortality associated especially with hip fracture. The goal is not to have a better bone mass measurement on your DXA scan as you age. This is exactly why the name of this column, years ago, was changed from “Update on osteoporosis” to “Update on bone health.” Similarly, in 2021, the NOF (National Osteoporosis Foundation) became the BHOF (Bone Health and Osteoporosis Foundation). Thus, our understanding and interest in bone health should and must go beyond simply bone mass measurement with DXA technology. The articles highlighted in this year’s Update reflect the importance of this concept.

Know SERMs’ effects on bone health for appropriate prescribing

Goldstein SR. Selective estrogen receptor modulators and bone health. Climacteric. 2022;25:56-59.

Selective estrogen receptor modulators (SERMs) are synthetic molecules that bind to the estrogen receptor and can have agonistic activity in some tissues and antagonistic activity in others. In a recent article, I reviewed the known data regarding the effects of various SERMs on bone health.⁵

A rundown on 4 SERMs and their effects on bone

Tamoxifen is approved by the US Food and Drug Administration (FDA) for the prevention and treatment of breast cancer in women with estrogen receptor–positive tumors. The only prospective study of tamoxifen versus placebo in which fracture risk was studied in women at risk for but not diagnosed with breast cancer was the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 trial. In this study, more than 13,000 women were randomly assigned to treatment with tamoxifen or placebo, with a primary objective of studying the incidence of invasive breast cancer in these high-risk women. With 7 years of follow-up, women receiving tamoxifen had significantly fewer fractures of the hip, radius, and spine (80 vs 116 in the placebo group), resulting in a combined relative risk (RR) of 0.68 (95% confidence interval [CI], 0.51–0.92).⁶

Raloxifene, another SERM, was extensively studied in the MORE (Multiple Outcomes of Raloxifene Evaluation) trial.⁷ This study involved more than 7,700 postmenopausal women with osteoporosis, average age 67. The incidence of first vertebral fracture was decreased from 4.3% with placebo to 1.9% with raloxifene (RR, 0.55; 95% CI, 0.29–0.71), and subsequent vertebral fractures were decreased from 20.2% with placebo to 14.1% with raloxifene (RR, 0.70; 95% CI, 0.60–0.90). In 2007, the FDA approved raloxifene for “reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis” as well as for “postmenopausal women at high risk for invasive breast cancer” based on the Study of Tamoxifen and Raloxifene (STAR) trial that involved almost 20,000 postmenopausal women deemed at high risk for breast cancer.⁸

The concept of combining an estrogen with a SERM, known as a TSEC (tissue selective estrogen complex) was studied and brought to market as conjugated equine estrogen (CEE) 0.45 mg and bazedoxifene (BZA) 20 mg. CEE and BZA individually have been shown to prevent vertebral fracture.^9,10 The combination of BZA and CEE has been shown to improve bone density compared with placebo.¹¹ There are, however, no fracture prevention data for this combination therapy. This was the basis on which the combination agent received regulatory approval for prevention of osteoporosis in postmenopausal women. This combination drug is also FDA approved for treating moderate to severe vasomotor symptoms of menopause.

Ospemifene is yet another SERM that is clinically available, at an oral dose of 60 mg, and is indicated for the treatment of moderate to severe dyspareunia secondary to vulvovaginal atrophy, or genitourinary syndrome of menopause (GSM). Ospemifene effectively reduced bone loss in ovariectomized rats, with activity comparable to estradiol and raloxifene.¹² Clinical data from three phase 1 or phase 2 clinical trials revealed that ospemifene 60 mg/day had a positive effect on biochemical markers for bone turnover in healthy postmenopausal women, with significant improvements relative to placebo and effects comparable to those of raloxifene.¹³ While actual fracture or bone mineral density (BMD) data in postmenopausal women are lacking, there is a good correlation between biochemical markers for bone turnover and occurrence of fracture.¹⁴ Women who need treatment for osteoporosis should not be treated with ospemifene, but women who use ospemifene for dyspareunia can expect positive activity on bone metabolism.

Continue to: Gut microbiome constituents may influence the development of osteoporosis: A potential treatment target?...

Cronin O, Lanham-New SA, Corfe BM, et al. Role of the microbiome in regulating bone metabolism and susceptibility to osteoporosis. Calcif Tissue Int. 2022;110:273-284.

Yang X, Chang T, Yuan Q, et al. Changes in the composition of gut and vaginal microbiota in patients with postmenopausal osteoporosis. Front Immunol. 2022;13:930244.

The role of the microbiome in many arenas is rapidly emerging. Apparently, its relationship in bone metabolism is still in its infancy. A review of PubMed articles showed that 1 paper was published in 2012, none until 2 more in 2015, with a total of 221 published through November 1, 2022. A recent review by Cronin and colleagues on the microbiome’s role in regulating bone metabolism came out of a workshop held by the Osteoporosis and Bone Research Academy of the Royal Osteoporosis Society in the United Kingdom.¹⁵

The gut microbiome’s relationship with bone health

The authors noted that the human microbiota functions at the interface between diet, medication use, lifestyle, host immune development, and health. Hence, it is closely aligned with many of the recognized modifiable factors that influence bone mass accrual in the young and bone maintenance and skeletal decline in older populations. Microbiome research and discovery supports a role of the human gut microbiome in the regulation of bone metabolism and the pathogenesis of osteoporosis as well as its prevention and treatment.

Numerous factors which influence the gut microbiome and the development of osteoporosis overlap. These include body mass index (BMI), vitamin D, alcohol intake, diet, corticosteroid use, physical activity, sex hormone deficiency, genetic variability, and chronic inflammatory disorders.

Cronin and colleagues reviewed a number of clinical studies and concluded that “the available evidence suggests that probiotic supplements can attenuate bone loss in postmenopausal women, although the studies investigating this have been short term and individually have had small sample sizes. Moving forward, it will be important to conduct larger scale studies to evaluate if the skeletal response differs with different types of probiotic and also to determine if the effects are sustained in the longer term.”¹⁵

Composition of the microbiota

A recent study by Yang and colleagues focused on changes in gut and vaginal microbiota composition in patients with postmenopausal osteoporosis. They analyzed data from 132 postmenopausal women with osteoporosis (n = 34), osteopenia (n = 47), and controls (n = 51) based on their T-scores.¹⁶

Significant differences were observed in the microbial compositions of fecal samples between groups (P<.05), with some species enhanced in the control group whereas other species were higher in the osteoporosis group. Similar but less pronounced differences were seen in the vaginal microbiome but of different species.

The authors concluded that “The results show that changes in BMD in postmenopausal women are associated with the changes in gut microbiome and vaginal microbiome; however, changes in gut microbiome are more closely correlated with postmenopausal osteoporosis than vaginal microbiome.”¹⁶

Continue to: Sarcopenia, osteoporosis, and frailty: A fracture risk triple play...

Laskou F, Fuggle NR, Patel HP, et al. Associations of osteoporosis and sarcopenia with frailty and multimorbidity among participants of the Hertfordshire Cohort Study. J Cachexia Sarcopenia Muscle. 2022;13:220-229.

Laskou and colleagues aimed to explore the relationship between sarcopenia, osteoporosis, and frailty in community-dwelling adults participating in a cohort study in the United Kingdom and to determine if the coexistence of osteoporosis and sarcopenia is associated with a significantly heavier health burden.¹⁷

Study details

The authors examined data from 206 women with an average age of 75.5 years. Sarcopenia was defined using the European Working Group on Sarcopenia in Older People (EWGSOP) criteria, which includes low grip strength or slow chair rise and low muscle quantity. Osteoporosis was defined by standard measurements as a T-score of less than or equal to -2.5 standard deviations at the femoral neck or use of any osteoporosis medications. Frailty was defined using the Fried definition, which includes having 3 or more of the following 5 domains: weakness, slowness, exhaustion, low physical activity, and unintentional weight loss. Having 1 or 2 domains is “prefrailty” and no domains signifies nonfrail.

Frailty confers additional risk

The study results showed that among the 206 women, the prevalence of frailty and prefrailty was 9.2% and 60.7%, respectively. Of the 5 Fried frailty components, low walking speed and low physical activity followed by self-reported exhaustion were the most prevalent (96.6%, 87.5%, and 75.8%, respectively) among frail participants. Having sarcopenia only was strongly associated with frailty (odds ratio [OR], 8.28; 95% CI, 1.27–54.03; P=.027]). The likelihood of being frail was substantially higher with the presence of coexisting sarcopenia and osteoporosis (OR, 26.15; 95% CI, 3.31–218.76; P=.003).

Thus, both these conditions confer a high health burden for the individual as well as for health care systems. Osteosarcopenia is the term given when low bone mass and sarcopenia occur in consort. Previous data have shown that when osteoporosis or even osteopenia is combined with sarcopenia, it can result in a 3-fold increase in the risk of falls and a 4-fold increase in the risk of fracture compared with women who have osteopenia or osteoporosis alone.¹⁸

Continue to: Denosumab effective in reducing falls, strengthening muscle...

Rupp T, von Vopelius E, Strahl A, et al. Beneficial effects of denosumab on muscle performance in patients with low BMD: a retrospective, propensity score-matched study. Osteoporos Int. 2022;33:2177-2184.

Results of a previous study showed that denosumab treatment significantly decreased falls and resulted in significant improvement in all sarcopenic measures.¹⁹ Furthermore, 1 year after denosumab was discontinued, a significant worsening occurred in both falls and sarcopenic measures. In that study, the control group, treated with alendronate or zoledronate, also showed improvement on some tests of muscle performance but no improvement in the risk of falls.

Those results agreed with the outcomes of the FREEDOM (Fracture Reduction Evaluation of Denosumab in Osteoporosis) trial.²⁰ This study revealed that denosumab treatment not only reduced the risk of vertebral, nonvertebral, and hip fracture over 36 months but also that the denosumab-treated group had fewer falls compared with the placebo-treated group (4.5% vs 5.7%; P = .02).

Denosumab found to increase muscle strength

More recently, Rupp and colleagues conducted a retrospective cohort study that included women with osteoporosis or osteopenia who received vitamin D only (n = 52), alendronate 70 mg/week (n = 26), or denosumab (n = 52).²¹

After a mean follow-up period of 17.6 (SD, 9.0) months, the authors observed a significantly higher increase in grip force in both the denosumab (P<.001) and bisphosphonate groups (P = .001) compared with the vitamin D group. In addition, the denosumab group showed a significantly higher increase in chair rising test performance compared with the bisphosphonate group (denosumab vs bisphosphonate, P = 0.03). They concluded that denosumab resulted in increased muscle strength in the upper and lower limbs, indicating systemic rather than site-specific effects as compared with the bisphosphonate.

The authors concluded that based on these findings, denosumab might be favored over other osteoporosis treatments in patients with low BMD coexisting with poor muscle strength. ●

I recently heard a lecture where the speaker quoted this statistic: “A 50-year-old woman who does not currently have heart disease or cancer has a life expectancy of 91.” Hopefully, anyone reading this article already is aware of the fact that as our patients age, hip fracture results in greater morbidity and mortality than early breast cancer. It should be well known to clinicians (and, ultimately, to our patients) that localized breast cancer has a survival rate of 99%,¹ whereas hip fracture carries a 21% mortality in the first year after the event.² In addition, approximately one-third of women who fracture their hip do not have osteoporosis.³ Furthermore, the role of muscle mass, strength, and performance in bone health has become well established.⁴

With this in mind, a recent encounter with a patient in my clinical practice illustrates what I believe is an increasing problem today. The patient had been on long-term prednisone systemically for polymyalgia rheumatica. Her dual energy x-ray absorptiometry (DXA) bone mass measurements were among the worst osteoporotic numbers I have witnessed. She related to me the “argument” that occurred between her rheumatologist and endocrinologist. One wanted her to use injectable parathyroid hormone analog daily, while the other advised yearly infusion of zoledronic acid. She chose the yearly infusion. I inquired if either physician had mentioned anything to her about using nonskid rugs in the bathroom, grab bars, being careful of black ice, a calcium-rich diet, vitamin D supplementation, good eyesight, illumination so she does not miss a step, mindful walking, and maintaining optimal balance, muscle mass, strength, and performance-enhancing exercise? She replied, “No, just which drug I should take.”

Realize that the goal for our patients should be to avoid the morbidity and mortality associated especially with hip fracture. The goal is not to have a better bone mass measurement on your DXA scan as you age. This is exactly why the name of this column, years ago, was changed from “Update on osteoporosis” to “Update on bone health.” Similarly, in 2021, the NOF (National Osteoporosis Foundation) became the BHOF (Bone Health and Osteoporosis Foundation). Thus, our understanding and interest in bone health should and must go beyond simply bone mass measurement with DXA technology. The articles highlighted in this year’s Update reflect the importance of this concept.

Know SERMs’ effects on bone health for appropriate prescribing

Goldstein SR. Selective estrogen receptor modulators and bone health. Climacteric. 2022;25:56-59.

Selective estrogen receptor modulators (SERMs) are synthetic molecules that bind to the estrogen receptor and can have agonistic activity in some tissues and antagonistic activity in others. In a recent article, I reviewed the known data regarding the effects of various SERMs on bone health.⁵

A rundown on 4 SERMs and their effects on bone

Tamoxifen is approved by the US Food and Drug Administration (FDA) for the prevention and treatment of breast cancer in women with estrogen receptor–positive tumors. The only prospective study of tamoxifen versus placebo in which fracture risk was studied in women at risk for but not diagnosed with breast cancer was the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 trial. In this study, more than 13,000 women were randomly assigned to treatment with tamoxifen or placebo, with a primary objective of studying the incidence of invasive breast cancer in these high-risk women. With 7 years of follow-up, women receiving tamoxifen had significantly fewer fractures of the hip, radius, and spine (80 vs 116 in the placebo group), resulting in a combined relative risk (RR) of 0.68 (95% confidence interval [CI], 0.51–0.92).⁶

Raloxifene, another SERM, was extensively studied in the MORE (Multiple Outcomes of Raloxifene Evaluation) trial.⁷ This study involved more than 7,700 postmenopausal women with osteoporosis, average age 67. The incidence of first vertebral fracture was decreased from 4.3% with placebo to 1.9% with raloxifene (RR, 0.55; 95% CI, 0.29–0.71), and subsequent vertebral fractures were decreased from 20.2% with placebo to 14.1% with raloxifene (RR, 0.70; 95% CI, 0.60–0.90). In 2007, the FDA approved raloxifene for “reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis” as well as for “postmenopausal women at high risk for invasive breast cancer” based on the Study of Tamoxifen and Raloxifene (STAR) trial that involved almost 20,000 postmenopausal women deemed at high risk for breast cancer.⁸

The concept of combining an estrogen with a SERM, known as a TSEC (tissue selective estrogen complex) was studied and brought to market as conjugated equine estrogen (CEE) 0.45 mg and bazedoxifene (BZA) 20 mg. CEE and BZA individually have been shown to prevent vertebral fracture.^9,10 The combination of BZA and CEE has been shown to improve bone density compared with placebo.¹¹ There are, however, no fracture prevention data for this combination therapy. This was the basis on which the combination agent received regulatory approval for prevention of osteoporosis in postmenopausal women. This combination drug is also FDA approved for treating moderate to severe vasomotor symptoms of menopause.

Ospemifene is yet another SERM that is clinically available, at an oral dose of 60 mg, and is indicated for the treatment of moderate to severe dyspareunia secondary to vulvovaginal atrophy, or genitourinary syndrome of menopause (GSM). Ospemifene effectively reduced bone loss in ovariectomized rats, with activity comparable to estradiol and raloxifene.¹² Clinical data from three phase 1 or phase 2 clinical trials revealed that ospemifene 60 mg/day had a positive effect on biochemical markers for bone turnover in healthy postmenopausal women, with significant improvements relative to placebo and effects comparable to those of raloxifene.¹³ While actual fracture or bone mineral density (BMD) data in postmenopausal women are lacking, there is a good correlation between biochemical markers for bone turnover and occurrence of fracture.¹⁴ Women who need treatment for osteoporosis should not be treated with ospemifene, but women who use ospemifene for dyspareunia can expect positive activity on bone metabolism.

Continue to: Gut microbiome constituents may influence the development of osteoporosis: A potential treatment target?...

Cronin O, Lanham-New SA, Corfe BM, et al. Role of the microbiome in regulating bone metabolism and susceptibility to osteoporosis. Calcif Tissue Int. 2022;110:273-284.

Yang X, Chang T, Yuan Q, et al. Changes in the composition of gut and vaginal microbiota in patients with postmenopausal osteoporosis. Front Immunol. 2022;13:930244.

The role of the microbiome in many arenas is rapidly emerging. Apparently, its relationship in bone metabolism is still in its infancy. A review of PubMed articles showed that 1 paper was published in 2012, none until 2 more in 2015, with a total of 221 published through November 1, 2022. A recent review by Cronin and colleagues on the microbiome’s role in regulating bone metabolism came out of a workshop held by the Osteoporosis and Bone Research Academy of the Royal Osteoporosis Society in the United Kingdom.¹⁵

The gut microbiome’s relationship with bone health

The authors noted that the human microbiota functions at the interface between diet, medication use, lifestyle, host immune development, and health. Hence, it is closely aligned with many of the recognized modifiable factors that influence bone mass accrual in the young and bone maintenance and skeletal decline in older populations. Microbiome research and discovery supports a role of the human gut microbiome in the regulation of bone metabolism and the pathogenesis of osteoporosis as well as its prevention and treatment.

Numerous factors which influence the gut microbiome and the development of osteoporosis overlap. These include body mass index (BMI), vitamin D, alcohol intake, diet, corticosteroid use, physical activity, sex hormone deficiency, genetic variability, and chronic inflammatory disorders.

Cronin and colleagues reviewed a number of clinical studies and concluded that “the available evidence suggests that probiotic supplements can attenuate bone loss in postmenopausal women, although the studies investigating this have been short term and individually have had small sample sizes. Moving forward, it will be important to conduct larger scale studies to evaluate if the skeletal response differs with different types of probiotic and also to determine if the effects are sustained in the longer term.”¹⁵

Composition of the microbiota

A recent study by Yang and colleagues focused on changes in gut and vaginal microbiota composition in patients with postmenopausal osteoporosis. They analyzed data from 132 postmenopausal women with osteoporosis (n = 34), osteopenia (n = 47), and controls (n = 51) based on their T-scores.¹⁶

Significant differences were observed in the microbial compositions of fecal samples between groups (P<.05), with some species enhanced in the control group whereas other species were higher in the osteoporosis group. Similar but less pronounced differences were seen in the vaginal microbiome but of different species.

The authors concluded that “The results show that changes in BMD in postmenopausal women are associated with the changes in gut microbiome and vaginal microbiome; however, changes in gut microbiome are more closely correlated with postmenopausal osteoporosis than vaginal microbiome.”¹⁶

Continue to: Sarcopenia, osteoporosis, and frailty: A fracture risk triple play...

Laskou F, Fuggle NR, Patel HP, et al. Associations of osteoporosis and sarcopenia with frailty and multimorbidity among participants of the Hertfordshire Cohort Study. J Cachexia Sarcopenia Muscle. 2022;13:220-229.

Laskou and colleagues aimed to explore the relationship between sarcopenia, osteoporosis, and frailty in community-dwelling adults participating in a cohort study in the United Kingdom and to determine if the coexistence of osteoporosis and sarcopenia is associated with a significantly heavier health burden.¹⁷

Study details

The authors examined data from 206 women with an average age of 75.5 years. Sarcopenia was defined using the European Working Group on Sarcopenia in Older People (EWGSOP) criteria, which includes low grip strength or slow chair rise and low muscle quantity. Osteoporosis was defined by standard measurements as a T-score of less than or equal to -2.5 standard deviations at the femoral neck or use of any osteoporosis medications. Frailty was defined using the Fried definition, which includes having 3 or more of the following 5 domains: weakness, slowness, exhaustion, low physical activity, and unintentional weight loss. Having 1 or 2 domains is “prefrailty” and no domains signifies nonfrail.

Frailty confers additional risk

The study results showed that among the 206 women, the prevalence of frailty and prefrailty was 9.2% and 60.7%, respectively. Of the 5 Fried frailty components, low walking speed and low physical activity followed by self-reported exhaustion were the most prevalent (96.6%, 87.5%, and 75.8%, respectively) among frail participants. Having sarcopenia only was strongly associated with frailty (odds ratio [OR], 8.28; 95% CI, 1.27–54.03; P=.027]). The likelihood of being frail was substantially higher with the presence of coexisting sarcopenia and osteoporosis (OR, 26.15; 95% CI, 3.31–218.76; P=.003).

Thus, both these conditions confer a high health burden for the individual as well as for health care systems. Osteosarcopenia is the term given when low bone mass and sarcopenia occur in consort. Previous data have shown that when osteoporosis or even osteopenia is combined with sarcopenia, it can result in a 3-fold increase in the risk of falls and a 4-fold increase in the risk of fracture compared with women who have osteopenia or osteoporosis alone.¹⁸

Continue to: Denosumab effective in reducing falls, strengthening muscle...

Rupp T, von Vopelius E, Strahl A, et al. Beneficial effects of denosumab on muscle performance in patients with low BMD: a retrospective, propensity score-matched study. Osteoporos Int. 2022;33:2177-2184.

Results of a previous study showed that denosumab treatment significantly decreased falls and resulted in significant improvement in all sarcopenic measures.¹⁹ Furthermore, 1 year after denosumab was discontinued, a significant worsening occurred in both falls and sarcopenic measures. In that study, the control group, treated with alendronate or zoledronate, also showed improvement on some tests of muscle performance but no improvement in the risk of falls.

Those results agreed with the outcomes of the FREEDOM (Fracture Reduction Evaluation of Denosumab in Osteoporosis) trial.²⁰ This study revealed that denosumab treatment not only reduced the risk of vertebral, nonvertebral, and hip fracture over 36 months but also that the denosumab-treated group had fewer falls compared with the placebo-treated group (4.5% vs 5.7%; P = .02).

Denosumab found to increase muscle strength

More recently, Rupp and colleagues conducted a retrospective cohort study that included women with osteoporosis or osteopenia who received vitamin D only (n = 52), alendronate 70 mg/week (n = 26), or denosumab (n = 52).²¹

After a mean follow-up period of 17.6 (SD, 9.0) months, the authors observed a significantly higher increase in grip force in both the denosumab (P<.001) and bisphosphonate groups (P = .001) compared with the vitamin D group. In addition, the denosumab group showed a significantly higher increase in chair rising test performance compared with the bisphosphonate group (denosumab vs bisphosphonate, P = 0.03). They concluded that denosumab resulted in increased muscle strength in the upper and lower limbs, indicating systemic rather than site-specific effects as compared with the bisphosphonate.

The authors concluded that based on these findings, denosumab might be favored over other osteoporosis treatments in patients with low BMD coexisting with poor muscle strength. ●

I recently heard a lecture where the speaker quoted this statistic: “A 50-year-old woman who does not currently have heart disease or cancer has a life expectancy of 91.” Hopefully, anyone reading this article already is aware of the fact that as our patients age, hip fracture results in greater morbidity and mortality than early breast cancer. It should be well known to clinicians (and, ultimately, to our patients) that localized breast cancer has a survival rate of 99%,¹ whereas hip fracture carries a 21% mortality in the first year after the event.² In addition, approximately one-third of women who fracture their hip do not have osteoporosis.³ Furthermore, the role of muscle mass, strength, and performance in bone health has become well established.⁴

With this in mind, a recent encounter with a patient in my clinical practice illustrates what I believe is an increasing problem today. The patient had been on long-term prednisone systemically for polymyalgia rheumatica. Her dual energy x-ray absorptiometry (DXA) bone mass measurements were among the worst osteoporotic numbers I have witnessed. She related to me the “argument” that occurred between her rheumatologist and endocrinologist. One wanted her to use injectable parathyroid hormone analog daily, while the other advised yearly infusion of zoledronic acid. She chose the yearly infusion. I inquired if either physician had mentioned anything to her about using nonskid rugs in the bathroom, grab bars, being careful of black ice, a calcium-rich diet, vitamin D supplementation, good eyesight, illumination so she does not miss a step, mindful walking, and maintaining optimal balance, muscle mass, strength, and performance-enhancing exercise? She replied, “No, just which drug I should take.”

Realize that the goal for our patients should be to avoid the morbidity and mortality associated especially with hip fracture. The goal is not to have a better bone mass measurement on your DXA scan as you age. This is exactly why the name of this column, years ago, was changed from “Update on osteoporosis” to “Update on bone health.” Similarly, in 2021, the NOF (National Osteoporosis Foundation) became the BHOF (Bone Health and Osteoporosis Foundation). Thus, our understanding and interest in bone health should and must go beyond simply bone mass measurement with DXA technology. The articles highlighted in this year’s Update reflect the importance of this concept.

Know SERMs’ effects on bone health for appropriate prescribing

Goldstein SR. Selective estrogen receptor modulators and bone health. Climacteric. 2022;25:56-59.

Selective estrogen receptor modulators (SERMs) are synthetic molecules that bind to the estrogen receptor and can have agonistic activity in some tissues and antagonistic activity in others. In a recent article, I reviewed the known data regarding the effects of various SERMs on bone health.⁵

A rundown on 4 SERMs and their effects on bone

Tamoxifen is approved by the US Food and Drug Administration (FDA) for the prevention and treatment of breast cancer in women with estrogen receptor–positive tumors. The only prospective study of tamoxifen versus placebo in which fracture risk was studied in women at risk for but not diagnosed with breast cancer was the National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1 trial. In this study, more than 13,000 women were randomly assigned to treatment with tamoxifen or placebo, with a primary objective of studying the incidence of invasive breast cancer in these high-risk women. With 7 years of follow-up, women receiving tamoxifen had significantly fewer fractures of the hip, radius, and spine (80 vs 116 in the placebo group), resulting in a combined relative risk (RR) of 0.68 (95% confidence interval [CI], 0.51–0.92).⁶

Raloxifene, another SERM, was extensively studied in the MORE (Multiple Outcomes of Raloxifene Evaluation) trial.⁷ This study involved more than 7,700 postmenopausal women with osteoporosis, average age 67. The incidence of first vertebral fracture was decreased from 4.3% with placebo to 1.9% with raloxifene (RR, 0.55; 95% CI, 0.29–0.71), and subsequent vertebral fractures were decreased from 20.2% with placebo to 14.1% with raloxifene (RR, 0.70; 95% CI, 0.60–0.90). In 2007, the FDA approved raloxifene for “reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis” as well as for “postmenopausal women at high risk for invasive breast cancer” based on the Study of Tamoxifen and Raloxifene (STAR) trial that involved almost 20,000 postmenopausal women deemed at high risk for breast cancer.⁸

The concept of combining an estrogen with a SERM, known as a TSEC (tissue selective estrogen complex) was studied and brought to market as conjugated equine estrogen (CEE) 0.45 mg and bazedoxifene (BZA) 20 mg. CEE and BZA individually have been shown to prevent vertebral fracture.^9,10 The combination of BZA and CEE has been shown to improve bone density compared with placebo.¹¹ There are, however, no fracture prevention data for this combination therapy. This was the basis on which the combination agent received regulatory approval for prevention of osteoporosis in postmenopausal women. This combination drug is also FDA approved for treating moderate to severe vasomotor symptoms of menopause.

Ospemifene is yet another SERM that is clinically available, at an oral dose of 60 mg, and is indicated for the treatment of moderate to severe dyspareunia secondary to vulvovaginal atrophy, or genitourinary syndrome of menopause (GSM). Ospemifene effectively reduced bone loss in ovariectomized rats, with activity comparable to estradiol and raloxifene.¹² Clinical data from three phase 1 or phase 2 clinical trials revealed that ospemifene 60 mg/day had a positive effect on biochemical markers for bone turnover in healthy postmenopausal women, with significant improvements relative to placebo and effects comparable to those of raloxifene.¹³ While actual fracture or bone mineral density (BMD) data in postmenopausal women are lacking, there is a good correlation between biochemical markers for bone turnover and occurrence of fracture.¹⁴ Women who need treatment for osteoporosis should not be treated with ospemifene, but women who use ospemifene for dyspareunia can expect positive activity on bone metabolism.

Continue to: Gut microbiome constituents may influence the development of osteoporosis: A potential treatment target?...

Cronin O, Lanham-New SA, Corfe BM, et al. Role of the microbiome in regulating bone metabolism and susceptibility to osteoporosis. Calcif Tissue Int. 2022;110:273-284.

Yang X, Chang T, Yuan Q, et al. Changes in the composition of gut and vaginal microbiota in patients with postmenopausal osteoporosis. Front Immunol. 2022;13:930244.

The role of the microbiome in many arenas is rapidly emerging. Apparently, its relationship in bone metabolism is still in its infancy. A review of PubMed articles showed that 1 paper was published in 2012, none until 2 more in 2015, with a total of 221 published through November 1, 2022. A recent review by Cronin and colleagues on the microbiome’s role in regulating bone metabolism came out of a workshop held by the Osteoporosis and Bone Research Academy of the Royal Osteoporosis Society in the United Kingdom.¹⁵

The gut microbiome’s relationship with bone health

The authors noted that the human microbiota functions at the interface between diet, medication use, lifestyle, host immune development, and health. Hence, it is closely aligned with many of the recognized modifiable factors that influence bone mass accrual in the young and bone maintenance and skeletal decline in older populations. Microbiome research and discovery supports a role of the human gut microbiome in the regulation of bone metabolism and the pathogenesis of osteoporosis as well as its prevention and treatment.

Numerous factors which influence the gut microbiome and the development of osteoporosis overlap. These include body mass index (BMI), vitamin D, alcohol intake, diet, corticosteroid use, physical activity, sex hormone deficiency, genetic variability, and chronic inflammatory disorders.

Cronin and colleagues reviewed a number of clinical studies and concluded that “the available evidence suggests that probiotic supplements can attenuate bone loss in postmenopausal women, although the studies investigating this have been short term and individually have had small sample sizes. Moving forward, it will be important to conduct larger scale studies to evaluate if the skeletal response differs with different types of probiotic and also to determine if the effects are sustained in the longer term.”¹⁵

Composition of the microbiota

A recent study by Yang and colleagues focused on changes in gut and vaginal microbiota composition in patients with postmenopausal osteoporosis. They analyzed data from 132 postmenopausal women with osteoporosis (n = 34), osteopenia (n = 47), and controls (n = 51) based on their T-scores.¹⁶

Significant differences were observed in the microbial compositions of fecal samples between groups (P<.05), with some species enhanced in the control group whereas other species were higher in the osteoporosis group. Similar but less pronounced differences were seen in the vaginal microbiome but of different species.

The authors concluded that “The results show that changes in BMD in postmenopausal women are associated with the changes in gut microbiome and vaginal microbiome; however, changes in gut microbiome are more closely correlated with postmenopausal osteoporosis than vaginal microbiome.”¹⁶

Continue to: Sarcopenia, osteoporosis, and frailty: A fracture risk triple play...

Laskou F, Fuggle NR, Patel HP, et al. Associations of osteoporosis and sarcopenia with frailty and multimorbidity among participants of the Hertfordshire Cohort Study. J Cachexia Sarcopenia Muscle. 2022;13:220-229.

Laskou and colleagues aimed to explore the relationship between sarcopenia, osteoporosis, and frailty in community-dwelling adults participating in a cohort study in the United Kingdom and to determine if the coexistence of osteoporosis and sarcopenia is associated with a significantly heavier health burden.¹⁷

Study details

The authors examined data from 206 women with an average age of 75.5 years. Sarcopenia was defined using the European Working Group on Sarcopenia in Older People (EWGSOP) criteria, which includes low grip strength or slow chair rise and low muscle quantity. Osteoporosis was defined by standard measurements as a T-score of less than or equal to -2.5 standard deviations at the femoral neck or use of any osteoporosis medications. Frailty was defined using the Fried definition, which includes having 3 or more of the following 5 domains: weakness, slowness, exhaustion, low physical activity, and unintentional weight loss. Having 1 or 2 domains is “prefrailty” and no domains signifies nonfrail.

Frailty confers additional risk

The study results showed that among the 206 women, the prevalence of frailty and prefrailty was 9.2% and 60.7%, respectively. Of the 5 Fried frailty components, low walking speed and low physical activity followed by self-reported exhaustion were the most prevalent (96.6%, 87.5%, and 75.8%, respectively) among frail participants. Having sarcopenia only was strongly associated with frailty (odds ratio [OR], 8.28; 95% CI, 1.27–54.03; P=.027]). The likelihood of being frail was substantially higher with the presence of coexisting sarcopenia and osteoporosis (OR, 26.15; 95% CI, 3.31–218.76; P=.003).

Thus, both these conditions confer a high health burden for the individual as well as for health care systems. Osteosarcopenia is the term given when low bone mass and sarcopenia occur in consort. Previous data have shown that when osteoporosis or even osteopenia is combined with sarcopenia, it can result in a 3-fold increase in the risk of falls and a 4-fold increase in the risk of fracture compared with women who have osteopenia or osteoporosis alone.¹⁸

Continue to: Denosumab effective in reducing falls, strengthening muscle...

Rupp T, von Vopelius E, Strahl A, et al. Beneficial effects of denosumab on muscle performance in patients with low BMD: a retrospective, propensity score-matched study. Osteoporos Int. 2022;33:2177-2184.

Results of a previous study showed that denosumab treatment significantly decreased falls and resulted in significant improvement in all sarcopenic measures.¹⁹ Furthermore, 1 year after denosumab was discontinued, a significant worsening occurred in both falls and sarcopenic measures. In that study, the control group, treated with alendronate or zoledronate, also showed improvement on some tests of muscle performance but no improvement in the risk of falls.

Those results agreed with the outcomes of the FREEDOM (Fracture Reduction Evaluation of Denosumab in Osteoporosis) trial.²⁰ This study revealed that denosumab treatment not only reduced the risk of vertebral, nonvertebral, and hip fracture over 36 months but also that the denosumab-treated group had fewer falls compared with the placebo-treated group (4.5% vs 5.7%; P = .02).

Denosumab found to increase muscle strength

More recently, Rupp and colleagues conducted a retrospective cohort study that included women with osteoporosis or osteopenia who received vitamin D only (n = 52), alendronate 70 mg/week (n = 26), or denosumab (n = 52).²¹

After a mean follow-up period of 17.6 (SD, 9.0) months, the authors observed a significantly higher increase in grip force in both the denosumab (P<.001) and bisphosphonate groups (P = .001) compared with the vitamin D group. In addition, the denosumab group showed a significantly higher increase in chair rising test performance compared with the bisphosphonate group (denosumab vs bisphosphonate, P = 0.03). They concluded that denosumab resulted in increased muscle strength in the upper and lower limbs, indicating systemic rather than site-specific effects as compared with the bisphosphonate.

The authors concluded that based on these findings, denosumab might be favored over other osteoporosis treatments in patients with low BMD coexisting with poor muscle strength. ●

SAN FRANCISCO – For patients with metastatic castration-resistant prostate cancer (mCRPC) with a BRCA alteration whose disease had already progressed with an androgen receptor pathway inhibitor (ARPI), imaging-based progression-free survival (PFS) was significantly longer through treatment with rucaparib (Rubraca, Clovis) than with any other drug chosen by their physician.

The finding, which comes from the TRITON3 clinical trial, provides evidence of clinical benefit for an indication for rucaparib that was granted an accelerated approval in May 2020.

“Rucaparib reduced the risk of progression or death by half in patients with BRCA alterations,” said lead author Alan H. Bryce, MD, medical director of the Genomic Oncology Clinic at Mayo Clinic Arizona, in Phoenix.

For the subgroup of patients with BRCA alterations, the median PFS was 11.2 months with rucaparib vs. 6.4 months (hazard ratio, 0.50; P < .001) among those who received physician’s choice of therapy, which included docetaxel or a second-generation ARPI, such as abiraterone or enzalutamide.

In another subgroup of patients whose disease had ATM alterations, the median PFS was 8.1 months with rucaparib vs. 6.8 months with physician’s choice of drug. The difference was not statistically significant.

However, the difference was significant in the intention-to-treat (ITT) population (comprising both subgroups), for whom the median PFS was 10.2 months with rucaparib vs. 6.4 months with physician’s choice of drug (HR, 0.61; P < .001 by log-rank test).

Dr. Bryce pointed out that three-quarters of the patients in the physician’s-choice arm who had progressive disease crossed over to rucaparib upon progression and that overall survival (OS) results are immature. At 62 months, median OS did not significantly differ in the BRCA subgroup (24.3 vs. 20.8 months favoring rucaparib; P = .21) or in the ITT group (23.6 vs. 20.9 months; P = .67).

Importantly, rucaparib was well tolerated. In all treatment groups, the most frequent adverse events were asthenia and fatigue, Bryce said. “There were no cases of myelodysplastic syndrome or acute myeloid leukemia reported.”

These results from the TRITON3 trial were presented at the 2023 ASCO Genitourinary Cancers Symposium and were published simultaneously in the New England Journal of Medicine.
 

Suggested benefit

Rucaparib is the first PARP inhibitor approved for use in patients with mCRPC that harbors deleterious BRCA mutations (germline and/or somatic) who have already been treated with androgen receptor–directed therapy and a taxane-based chemotherapy. This prostate cancer indication was granted an accelerated approval in May 2020 by the U.S. Food and Drug Administration on the basis of response rates and effect on levels of prostate-specific antigen (PSA) from the TRITON2 clinical trial, the forerunner of the current study.

The TRITON2 study was a single-arm clinical trial that involved three cohorts: 62 patients with a BRCA mutation (germline and/or somatic) and measurable disease; 115 patients with a BRCA mutation (germline and/or somatic) and measurable or nonmeasurable disease; and 209 patients with homologous recombination deficiency–positive mCRPC.

In an analysis of 115 patients with a deleterious BRCA mutation (germline and/or somatic) and measurable or nonmeasurable disease, the confirmed PSA response rate was 55%. For the patients with measurable disease and a BRCA mutation, the objective response rate was 44%. The objective response rate was similar for those with a germline BRCA mutation.
 

Study details

The current phase 3 randomized TRITON3 clinical trial was conducted to confirm the earlier findings and to expand upon the data in mCRPC. The participants in this trial were patients with mCRPC who had specific gene alterations, including BRCA and ATM alterations, who had experienced disease progression after androgen receptor–directed therapy but who had not yet received chemotherapy.

A total of 270 men were assigned to receive rucaparib (600 mg twice daily); 135 patients received their physician’s choice of medication. Within the two study arms, 302 patients had a BRCA alteration, and 103 patients had an ATM alteration. The ITT population consisted of all the patients who had been randomly assigned to either of the two groups. A prespecified subgroup included patients with a BRCA alteration.

The primary outcome was the median duration of imaging-based PSF, as determined through independent review. Key secondary outcomes were overall survival and objective response rate.

The most common adverse events in the rucaparib group were fatigue, nausea, and anemia or decreased hemoglobin. In the control group, the most common adverse events were fatigue, diarrhea, and neuropathy. The most common events of grade 3 or higher were anemia or decreased hemoglobin, neutropenia or a decreased neutrophil count, and fatigue in the rucaparib group, and fatigue and neutropenia or a decreased neutrophil count among control patients.
 

No changes in standard of care

In a discussion of the study, Elena Castro, MD, PhD, of the Instituto de Investigación Biomédica de Málaga, Campanillas, Spain, emphasized that there is a clear benefit from the use of PARP inhibitors (such as rucaparib) for patients with BRCA alterations.

However, she highlighted the absence of convincing overall survival data and the absence of a clear benefit on PFS in the subgroup of patients with ATM alterations.

“These data raise several questions,” she noted, “such as, do patients with ATM alterations benefit at all? And should PARP inhibitors [such as rucaparib] precede or follow docetaxel therapy?”

Because of the high crossover rate, it may be possible to evaluate the directionality of docetaxel followed by PARP inhibitors and the other way around, she suggested.

Dr. Castro said that patients with BRCA alterations benefit from PARP inhibitors and are likely to derive more benefit from them than from taxanes.

“But those with ATM alterations are unlikely to benefit from rucaparib more than from taxanes,” she said.

In a comment, Hank Ng, MD, medical oncologist, NYU Langone Perlmutter Cancer Center, New York, said he is not convinced that the findings from TRITON 3 represent a new standard of care in BRCA 1/2 mutations or ATM.

“Currently, we know that, for patients with prostate cancer with BRCA1/2 or ATM, the standard of care is an androgen receptor pathway inhibitor (ARPI), such as abiraterone or enzalutamide, then docetaxel, and then a PARP inhibitor like rucaparib,” he said.

(Currently, rucaparib is indicated for use in patients with mCRPC with BRCA alterations after they have already received an ARPI and taxane-based chemotherapy.)

Dr. Ng also questioned the control arm of the TRITON 3 trial. All the participants in the trial had already experienced disease progression after treatment with a second-generation ARPI. But the physician’s choice of therapy allowed them to move on to another ARPI or to docetaxel.

Dr. NG commented that, “in almost all cases, after progression of one ARPI, switching to another ARPI does not provide much benefit – from what is visible from this abstract – and only 56% patients received docetaxel, and thus 44% received a not-beneficial treatment,” he said.

“I am not sure what the docetaxel subgroup showed, but potentially, if those numbers are convincing, we could move this [rucaparib] ahead of docetaxel,” he speculated.

However, he also pointed out that an overall survival benefit has not yet been shown; so far, the benefit that has been shown is with respect to imaging-based PFS.

Dr. Ng does agree that rucaparib is indicated in the second line after progression with one ARPI for patients who are not candidates for chemotherapy. “But this has not yet shown me that we should absolutely be offering rucaparib before docetaxel,” he said.

TRITON3 was supported by Clovis Oncology, manufacturer of rucaparib. Dr. Bryce has relationships with Bayer, Foundation Medicine, Janssen, Merck, Myovant Sciences, and Novartis and holds a patent for therapeutic targeting of cancer patients with NRG1 rearrangements. Dr. Castro has relationships with Astellas Pharma, AstraZeneca, Bayer, Clovis Oncology, Janssen-Cilag, Merck, MSD Oncology, Novartis, Pfizer, and Roche.

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

SAN FRANCISCO – For patients with metastatic castration-resistant prostate cancer (mCRPC) with a BRCA alteration whose disease had already progressed with an androgen receptor pathway inhibitor (ARPI), imaging-based progression-free survival (PFS) was significantly longer through treatment with rucaparib (Rubraca, Clovis) than with any other drug chosen by their physician.

The finding, which comes from the TRITON3 clinical trial, provides evidence of clinical benefit for an indication for rucaparib that was granted an accelerated approval in May 2020.

“Rucaparib reduced the risk of progression or death by half in patients with BRCA alterations,” said lead author Alan H. Bryce, MD, medical director of the Genomic Oncology Clinic at Mayo Clinic Arizona, in Phoenix.

For the subgroup of patients with BRCA alterations, the median PFS was 11.2 months with rucaparib vs. 6.4 months (hazard ratio, 0.50; P < .001) among those who received physician’s choice of therapy, which included docetaxel or a second-generation ARPI, such as abiraterone or enzalutamide.

In another subgroup of patients whose disease had ATM alterations, the median PFS was 8.1 months with rucaparib vs. 6.8 months with physician’s choice of drug. The difference was not statistically significant.

However, the difference was significant in the intention-to-treat (ITT) population (comprising both subgroups), for whom the median PFS was 10.2 months with rucaparib vs. 6.4 months with physician’s choice of drug (HR, 0.61; P < .001 by log-rank test).

Dr. Bryce pointed out that three-quarters of the patients in the physician’s-choice arm who had progressive disease crossed over to rucaparib upon progression and that overall survival (OS) results are immature. At 62 months, median OS did not significantly differ in the BRCA subgroup (24.3 vs. 20.8 months favoring rucaparib; P = .21) or in the ITT group (23.6 vs. 20.9 months; P = .67).

Importantly, rucaparib was well tolerated. In all treatment groups, the most frequent adverse events were asthenia and fatigue, Bryce said. “There were no cases of myelodysplastic syndrome or acute myeloid leukemia reported.”

These results from the TRITON3 trial were presented at the 2023 ASCO Genitourinary Cancers Symposium and were published simultaneously in the New England Journal of Medicine.
 

Suggested benefit

Rucaparib is the first PARP inhibitor approved for use in patients with mCRPC that harbors deleterious BRCA mutations (germline and/or somatic) who have already been treated with androgen receptor–directed therapy and a taxane-based chemotherapy. This prostate cancer indication was granted an accelerated approval in May 2020 by the U.S. Food and Drug Administration on the basis of response rates and effect on levels of prostate-specific antigen (PSA) from the TRITON2 clinical trial, the forerunner of the current study.

The TRITON2 study was a single-arm clinical trial that involved three cohorts: 62 patients with a BRCA mutation (germline and/or somatic) and measurable disease; 115 patients with a BRCA mutation (germline and/or somatic) and measurable or nonmeasurable disease; and 209 patients with homologous recombination deficiency–positive mCRPC.

In an analysis of 115 patients with a deleterious BRCA mutation (germline and/or somatic) and measurable or nonmeasurable disease, the confirmed PSA response rate was 55%. For the patients with measurable disease and a BRCA mutation, the objective response rate was 44%. The objective response rate was similar for those with a germline BRCA mutation.
 

Study details

The current phase 3 randomized TRITON3 clinical trial was conducted to confirm the earlier findings and to expand upon the data in mCRPC. The participants in this trial were patients with mCRPC who had specific gene alterations, including BRCA and ATM alterations, who had experienced disease progression after androgen receptor–directed therapy but who had not yet received chemotherapy.

A total of 270 men were assigned to receive rucaparib (600 mg twice daily); 135 patients received their physician’s choice of medication. Within the two study arms, 302 patients had a BRCA alteration, and 103 patients had an ATM alteration. The ITT population consisted of all the patients who had been randomly assigned to either of the two groups. A prespecified subgroup included patients with a BRCA alteration.

The primary outcome was the median duration of imaging-based PSF, as determined through independent review. Key secondary outcomes were overall survival and objective response rate.

The most common adverse events in the rucaparib group were fatigue, nausea, and anemia or decreased hemoglobin. In the control group, the most common adverse events were fatigue, diarrhea, and neuropathy. The most common events of grade 3 or higher were anemia or decreased hemoglobin, neutropenia or a decreased neutrophil count, and fatigue in the rucaparib group, and fatigue and neutropenia or a decreased neutrophil count among control patients.
 

No changes in standard of care

In a discussion of the study, Elena Castro, MD, PhD, of the Instituto de Investigación Biomédica de Málaga, Campanillas, Spain, emphasized that there is a clear benefit from the use of PARP inhibitors (such as rucaparib) for patients with BRCA alterations.

However, she highlighted the absence of convincing overall survival data and the absence of a clear benefit on PFS in the subgroup of patients with ATM alterations.

“These data raise several questions,” she noted, “such as, do patients with ATM alterations benefit at all? And should PARP inhibitors [such as rucaparib] precede or follow docetaxel therapy?”

Because of the high crossover rate, it may be possible to evaluate the directionality of docetaxel followed by PARP inhibitors and the other way around, she suggested.

Dr. Castro said that patients with BRCA alterations benefit from PARP inhibitors and are likely to derive more benefit from them than from taxanes.

“But those with ATM alterations are unlikely to benefit from rucaparib more than from taxanes,” she said.

In a comment, Hank Ng, MD, medical oncologist, NYU Langone Perlmutter Cancer Center, New York, said he is not convinced that the findings from TRITON 3 represent a new standard of care in BRCA 1/2 mutations or ATM.

“Currently, we know that, for patients with prostate cancer with BRCA1/2 or ATM, the standard of care is an androgen receptor pathway inhibitor (ARPI), such as abiraterone or enzalutamide, then docetaxel, and then a PARP inhibitor like rucaparib,” he said.

(Currently, rucaparib is indicated for use in patients with mCRPC with BRCA alterations after they have already received an ARPI and taxane-based chemotherapy.)

Dr. Ng also questioned the control arm of the TRITON 3 trial. All the participants in the trial had already experienced disease progression after treatment with a second-generation ARPI. But the physician’s choice of therapy allowed them to move on to another ARPI or to docetaxel.

Dr. NG commented that, “in almost all cases, after progression of one ARPI, switching to another ARPI does not provide much benefit – from what is visible from this abstract – and only 56% patients received docetaxel, and thus 44% received a not-beneficial treatment,” he said.

“I am not sure what the docetaxel subgroup showed, but potentially, if those numbers are convincing, we could move this [rucaparib] ahead of docetaxel,” he speculated.

However, he also pointed out that an overall survival benefit has not yet been shown; so far, the benefit that has been shown is with respect to imaging-based PFS.

Dr. Ng does agree that rucaparib is indicated in the second line after progression with one ARPI for patients who are not candidates for chemotherapy. “But this has not yet shown me that we should absolutely be offering rucaparib before docetaxel,” he said.

TRITON3 was supported by Clovis Oncology, manufacturer of rucaparib. Dr. Bryce has relationships with Bayer, Foundation Medicine, Janssen, Merck, Myovant Sciences, and Novartis and holds a patent for therapeutic targeting of cancer patients with NRG1 rearrangements. Dr. Castro has relationships with Astellas Pharma, AstraZeneca, Bayer, Clovis Oncology, Janssen-Cilag, Merck, MSD Oncology, Novartis, Pfizer, and Roche.

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

SAN FRANCISCO – For patients with metastatic castration-resistant prostate cancer (mCRPC) with a BRCA alteration whose disease had already progressed with an androgen receptor pathway inhibitor (ARPI), imaging-based progression-free survival (PFS) was significantly longer through treatment with rucaparib (Rubraca, Clovis) than with any other drug chosen by their physician.

The finding, which comes from the TRITON3 clinical trial, provides evidence of clinical benefit for an indication for rucaparib that was granted an accelerated approval in May 2020.

“Rucaparib reduced the risk of progression or death by half in patients with BRCA alterations,” said lead author Alan H. Bryce, MD, medical director of the Genomic Oncology Clinic at Mayo Clinic Arizona, in Phoenix.

For the subgroup of patients with BRCA alterations, the median PFS was 11.2 months with rucaparib vs. 6.4 months (hazard ratio, 0.50; P < .001) among those who received physician’s choice of therapy, which included docetaxel or a second-generation ARPI, such as abiraterone or enzalutamide.

In another subgroup of patients whose disease had ATM alterations, the median PFS was 8.1 months with rucaparib vs. 6.8 months with physician’s choice of drug. The difference was not statistically significant.

However, the difference was significant in the intention-to-treat (ITT) population (comprising both subgroups), for whom the median PFS was 10.2 months with rucaparib vs. 6.4 months with physician’s choice of drug (HR, 0.61; P < .001 by log-rank test).

Dr. Bryce pointed out that three-quarters of the patients in the physician’s-choice arm who had progressive disease crossed over to rucaparib upon progression and that overall survival (OS) results are immature. At 62 months, median OS did not significantly differ in the BRCA subgroup (24.3 vs. 20.8 months favoring rucaparib; P = .21) or in the ITT group (23.6 vs. 20.9 months; P = .67).

Importantly, rucaparib was well tolerated. In all treatment groups, the most frequent adverse events were asthenia and fatigue, Bryce said. “There were no cases of myelodysplastic syndrome or acute myeloid leukemia reported.”

These results from the TRITON3 trial were presented at the 2023 ASCO Genitourinary Cancers Symposium and were published simultaneously in the New England Journal of Medicine.
 

Suggested benefit

Rucaparib is the first PARP inhibitor approved for use in patients with mCRPC that harbors deleterious BRCA mutations (germline and/or somatic) who have already been treated with androgen receptor–directed therapy and a taxane-based chemotherapy. This prostate cancer indication was granted an accelerated approval in May 2020 by the U.S. Food and Drug Administration on the basis of response rates and effect on levels of prostate-specific antigen (PSA) from the TRITON2 clinical trial, the forerunner of the current study.

The TRITON2 study was a single-arm clinical trial that involved three cohorts: 62 patients with a BRCA mutation (germline and/or somatic) and measurable disease; 115 patients with a BRCA mutation (germline and/or somatic) and measurable or nonmeasurable disease; and 209 patients with homologous recombination deficiency–positive mCRPC.

In an analysis of 115 patients with a deleterious BRCA mutation (germline and/or somatic) and measurable or nonmeasurable disease, the confirmed PSA response rate was 55%. For the patients with measurable disease and a BRCA mutation, the objective response rate was 44%. The objective response rate was similar for those with a germline BRCA mutation.
 

Study details

The current phase 3 randomized TRITON3 clinical trial was conducted to confirm the earlier findings and to expand upon the data in mCRPC. The participants in this trial were patients with mCRPC who had specific gene alterations, including BRCA and ATM alterations, who had experienced disease progression after androgen receptor–directed therapy but who had not yet received chemotherapy.

A total of 270 men were assigned to receive rucaparib (600 mg twice daily); 135 patients received their physician’s choice of medication. Within the two study arms, 302 patients had a BRCA alteration, and 103 patients had an ATM alteration. The ITT population consisted of all the patients who had been randomly assigned to either of the two groups. A prespecified subgroup included patients with a BRCA alteration.

The primary outcome was the median duration of imaging-based PSF, as determined through independent review. Key secondary outcomes were overall survival and objective response rate.

The most common adverse events in the rucaparib group were fatigue, nausea, and anemia or decreased hemoglobin. In the control group, the most common adverse events were fatigue, diarrhea, and neuropathy. The most common events of grade 3 or higher were anemia or decreased hemoglobin, neutropenia or a decreased neutrophil count, and fatigue in the rucaparib group, and fatigue and neutropenia or a decreased neutrophil count among control patients.
 

No changes in standard of care

In a discussion of the study, Elena Castro, MD, PhD, of the Instituto de Investigación Biomédica de Málaga, Campanillas, Spain, emphasized that there is a clear benefit from the use of PARP inhibitors (such as rucaparib) for patients with BRCA alterations.

However, she highlighted the absence of convincing overall survival data and the absence of a clear benefit on PFS in the subgroup of patients with ATM alterations.

“These data raise several questions,” she noted, “such as, do patients with ATM alterations benefit at all? And should PARP inhibitors [such as rucaparib] precede or follow docetaxel therapy?”

Because of the high crossover rate, it may be possible to evaluate the directionality of docetaxel followed by PARP inhibitors and the other way around, she suggested.

Dr. Castro said that patients with BRCA alterations benefit from PARP inhibitors and are likely to derive more benefit from them than from taxanes.

“But those with ATM alterations are unlikely to benefit from rucaparib more than from taxanes,” she said.

In a comment, Hank Ng, MD, medical oncologist, NYU Langone Perlmutter Cancer Center, New York, said he is not convinced that the findings from TRITON 3 represent a new standard of care in BRCA 1/2 mutations or ATM.

“Currently, we know that, for patients with prostate cancer with BRCA1/2 or ATM, the standard of care is an androgen receptor pathway inhibitor (ARPI), such as abiraterone or enzalutamide, then docetaxel, and then a PARP inhibitor like rucaparib,” he said.

(Currently, rucaparib is indicated for use in patients with mCRPC with BRCA alterations after they have already received an ARPI and taxane-based chemotherapy.)

Dr. Ng also questioned the control arm of the TRITON 3 trial. All the participants in the trial had already experienced disease progression after treatment with a second-generation ARPI. But the physician’s choice of therapy allowed them to move on to another ARPI or to docetaxel.

Dr. NG commented that, “in almost all cases, after progression of one ARPI, switching to another ARPI does not provide much benefit – from what is visible from this abstract – and only 56% patients received docetaxel, and thus 44% received a not-beneficial treatment,” he said.

“I am not sure what the docetaxel subgroup showed, but potentially, if those numbers are convincing, we could move this [rucaparib] ahead of docetaxel,” he speculated.

However, he also pointed out that an overall survival benefit has not yet been shown; so far, the benefit that has been shown is with respect to imaging-based PFS.

Dr. Ng does agree that rucaparib is indicated in the second line after progression with one ARPI for patients who are not candidates for chemotherapy. “But this has not yet shown me that we should absolutely be offering rucaparib before docetaxel,” he said.

TRITON3 was supported by Clovis Oncology, manufacturer of rucaparib. Dr. Bryce has relationships with Bayer, Foundation Medicine, Janssen, Merck, Myovant Sciences, and Novartis and holds a patent for therapeutic targeting of cancer patients with NRG1 rearrangements. Dr. Castro has relationships with Astellas Pharma, AstraZeneca, Bayer, Clovis Oncology, Janssen-Cilag, Merck, MSD Oncology, Novartis, Pfizer, and Roche.

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

Patients with intermediate-risk acute myeloid leukemia (AML) who underwent allogeneic hematopoietic cell transplantation (HCT) after their first complete remission showed improvements in disease-free survival but had similar overall survival rates, compared with patients treated with consolidation chemotherapy alone.

Notably, all patients who relapsed after consolidation chemotherapy were able to receive allogeneic HCT, suggesting that transplantation may be safely delayed in some patients until their first relapse.

“The results of this randomized clinical trial indicate that the probability of survival after [allogeneic] HCT is not superior to that of conventional consolidation chemotherapy” among patients 60 years or younger with intermediate-risk AML, the authors concluded.

However, two experts highlighted several caveats to the study, which suggest the results may not translate to current clinical practice.

The study was published online in JAMA Oncology.

Approximately 50%-70% of patients with AML who receive intensive induction chemotherapy for AML and achieve a first complete remission are referred for post-remission therapy.

While consolidation chemotherapy with high-dose cytarabine has shown a benefit for those with a favorable risk profile, patients considered high-risk with adequate performance status may be candidates for allogeneic HCT.

However, determining the optimal post-remission treatment option for patients who fall into the intermediate-risk category can be more challenging.

To compare outcomes among intermediate-risk patients, researchers from Germany conducted a multicenter trial, enrolling 143 adults aged 60 or younger with intermediate-risk AML who had achieved first complete remission or complete remission with incomplete blood cell count recovery following conventional induction therapy.

The patients, who had a mean age of 48.2 years, were randomly assigned to consolidation treatment with allogeneic HCT (n = 76) or chemotherapy with high-dose cytarabine (n = 67), with the option for salvage HCT in the case of relapse. Overall, 12 patients in the HCT group received one consolidation course of high-dose cytarabine after achieving complete remission to bridge until allogeneic HCT, while all other patients in this group received allogeneic HCT directly after induction therapy.

Overall, disease-free survival at 2 years was significantly higher in the allogeneic HCT group (69%), compared with the consolidation therapy group (40%; P = .001). And the cumulative incidence of relapse at 2 years in the allogeneic HCT group was also lower, at 20%, compared with 58% in the consolidation therapy group (P < .001).

The overall survival data, however, painted a slightly more complex picture. In the intention-to-treat analysis, the probability of survival at 2 years was similar between the allogeneic HCT group (74%, or 56 of 76 patients), compared with consolidation chemotherapy (84%, or 56 of 67 patients; P = .22).

In addition, the rates of nonrelapse mortality at 2 years were higher in the allogeneic HCT group (9%) versus chemotherapy (2%; P = .005).

Although the rate of nonrelapse mortality was higher with allogeneic HCT, the relatively low rate with each treatment strategies was “an important and rewarding finding,” the authors noted. “This achievement is clearly due to the availability of less toxic but still effective conditioning therapies and modern antiviral and antifungal prophylaxis.”

In addition, among the 41 patients who relapsed after consolidation chemotherapy, all received allogeneic HCT, and the authors observed no significant differences between the groups in terms of health-related quality of life measures.
 

Results ‘may not translate to real-life clinical practice’

An important caveat is that the findings do not reflect some key updated strategies currently used in clinical practice, said Diego Adrianzen Herrera, MD, from the University of Vermont’s Larner College of Medicine, Burlington, who was not involved in the study.

“A charitable interpretation of the results is that a clear, large survival benefit of transplant in first complete remission is not apparent, which in turn can inform decision-making in certain circumstances for patients meeting the trial criteria, [including] younger patients with a readily available donor,” he told this news organization.

“However, risk stratification strategies currently used were not followed,” he said.

For instance, molecular risk stratification was not universally used, which may have led the researchers to overrepresent the number of patients considered to have favorable risk disease and “could have skewed the results in favor of the chemotherapy arm,” he explained.

In addition, minimal residual disease surveillance by flow cytometry was not used. Plus, Dr. Herrera added, in practice, not all patients can be salvaged and taken to HCT when in their second complete remission, or even achieve complete remission again.

“Unfortunately, these issues make the clinical significance of these results limited,” he concluded.

Margaret Kasner, MD, who was not associated with the research, agreed that aspects of the study design may not translate to real-life clinical practice, particularly in terms of quality-of-life outcomes.

“Although the [study] showed no difference in quality of life in the patient groups, this is likely due to the patient selection,” Dr. Kasner, of the Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, said in an interview. “Most patients do not allow themselves to be randomized between these two very different strategies, so those who are willing to be randomized may be a different population in terms how their quality of life is affected by relapse.”

The authors acknowledged some of these limitations, adding that the routine use of minimal residual disease monitoring in some patients was only established once the trial was underway, and the number of patients with complete minimal residual disease was therefore limited.

In addition, Dr. Herrera explained that because HCT involves significant disruptions to daily life and extensive follow-up and monitoring, decisions to use the strategy are not taken lightly by clinicians or patients.

“This is a major issue,” he said. “HCT remains a therapeutic option which causes significant apprehension to patients.”

Nevertheless, “in my experience most patients would prefer an upfront strategy if there is a definitive need for transplant,” he added. “I think the main question patients have is whether they absolutely need an HCT and how can we better identify up front who will be in the relapse-free group at 2 years.”

The study received grant funding from the Deutsche Forschungsgemeinschaft. The authors’ disclosures are detailed in the original article. Dr. Herrera and Dr. Kasner report no relevant financial relationships.

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

Patients with intermediate-risk acute myeloid leukemia (AML) who underwent allogeneic hematopoietic cell transplantation (HCT) after their first complete remission showed improvements in disease-free survival but had similar overall survival rates, compared with patients treated with consolidation chemotherapy alone.

Notably, all patients who relapsed after consolidation chemotherapy were able to receive allogeneic HCT, suggesting that transplantation may be safely delayed in some patients until their first relapse.

“The results of this randomized clinical trial indicate that the probability of survival after [allogeneic] HCT is not superior to that of conventional consolidation chemotherapy” among patients 60 years or younger with intermediate-risk AML, the authors concluded.

However, two experts highlighted several caveats to the study, which suggest the results may not translate to current clinical practice.

The study was published online in JAMA Oncology.

Approximately 50%-70% of patients with AML who receive intensive induction chemotherapy for AML and achieve a first complete remission are referred for post-remission therapy.

While consolidation chemotherapy with high-dose cytarabine has shown a benefit for those with a favorable risk profile, patients considered high-risk with adequate performance status may be candidates for allogeneic HCT.

However, determining the optimal post-remission treatment option for patients who fall into the intermediate-risk category can be more challenging.

To compare outcomes among intermediate-risk patients, researchers from Germany conducted a multicenter trial, enrolling 143 adults aged 60 or younger with intermediate-risk AML who had achieved first complete remission or complete remission with incomplete blood cell count recovery following conventional induction therapy.

The patients, who had a mean age of 48.2 years, were randomly assigned to consolidation treatment with allogeneic HCT (n = 76) or chemotherapy with high-dose cytarabine (n = 67), with the option for salvage HCT in the case of relapse. Overall, 12 patients in the HCT group received one consolidation course of high-dose cytarabine after achieving complete remission to bridge until allogeneic HCT, while all other patients in this group received allogeneic HCT directly after induction therapy.

Overall, disease-free survival at 2 years was significantly higher in the allogeneic HCT group (69%), compared with the consolidation therapy group (40%; P = .001). And the cumulative incidence of relapse at 2 years in the allogeneic HCT group was also lower, at 20%, compared with 58% in the consolidation therapy group (P < .001).

The overall survival data, however, painted a slightly more complex picture. In the intention-to-treat analysis, the probability of survival at 2 years was similar between the allogeneic HCT group (74%, or 56 of 76 patients), compared with consolidation chemotherapy (84%, or 56 of 67 patients; P = .22).

In addition, the rates of nonrelapse mortality at 2 years were higher in the allogeneic HCT group (9%) versus chemotherapy (2%; P = .005).

Although the rate of nonrelapse mortality was higher with allogeneic HCT, the relatively low rate with each treatment strategies was “an important and rewarding finding,” the authors noted. “This achievement is clearly due to the availability of less toxic but still effective conditioning therapies and modern antiviral and antifungal prophylaxis.”

In addition, among the 41 patients who relapsed after consolidation chemotherapy, all received allogeneic HCT, and the authors observed no significant differences between the groups in terms of health-related quality of life measures.
 

Results ‘may not translate to real-life clinical practice’

An important caveat is that the findings do not reflect some key updated strategies currently used in clinical practice, said Diego Adrianzen Herrera, MD, from the University of Vermont’s Larner College of Medicine, Burlington, who was not involved in the study.

“A charitable interpretation of the results is that a clear, large survival benefit of transplant in first complete remission is not apparent, which in turn can inform decision-making in certain circumstances for patients meeting the trial criteria, [including] younger patients with a readily available donor,” he told this news organization.

“However, risk stratification strategies currently used were not followed,” he said.

For instance, molecular risk stratification was not universally used, which may have led the researchers to overrepresent the number of patients considered to have favorable risk disease and “could have skewed the results in favor of the chemotherapy arm,” he explained.

In addition, minimal residual disease surveillance by flow cytometry was not used. Plus, Dr. Herrera added, in practice, not all patients can be salvaged and taken to HCT when in their second complete remission, or even achieve complete remission again.

“Unfortunately, these issues make the clinical significance of these results limited,” he concluded.

Margaret Kasner, MD, who was not associated with the research, agreed that aspects of the study design may not translate to real-life clinical practice, particularly in terms of quality-of-life outcomes.

“Although the [study] showed no difference in quality of life in the patient groups, this is likely due to the patient selection,” Dr. Kasner, of the Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, said in an interview. “Most patients do not allow themselves to be randomized between these two very different strategies, so those who are willing to be randomized may be a different population in terms how their quality of life is affected by relapse.”

The authors acknowledged some of these limitations, adding that the routine use of minimal residual disease monitoring in some patients was only established once the trial was underway, and the number of patients with complete minimal residual disease was therefore limited.

In addition, Dr. Herrera explained that because HCT involves significant disruptions to daily life and extensive follow-up and monitoring, decisions to use the strategy are not taken lightly by clinicians or patients.

“This is a major issue,” he said. “HCT remains a therapeutic option which causes significant apprehension to patients.”

Nevertheless, “in my experience most patients would prefer an upfront strategy if there is a definitive need for transplant,” he added. “I think the main question patients have is whether they absolutely need an HCT and how can we better identify up front who will be in the relapse-free group at 2 years.”

The study received grant funding from the Deutsche Forschungsgemeinschaft. The authors’ disclosures are detailed in the original article. Dr. Herrera and Dr. Kasner report no relevant financial relationships.

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

Patients with intermediate-risk acute myeloid leukemia (AML) who underwent allogeneic hematopoietic cell transplantation (HCT) after their first complete remission showed improvements in disease-free survival but had similar overall survival rates, compared with patients treated with consolidation chemotherapy alone.

Notably, all patients who relapsed after consolidation chemotherapy were able to receive allogeneic HCT, suggesting that transplantation may be safely delayed in some patients until their first relapse.

“The results of this randomized clinical trial indicate that the probability of survival after [allogeneic] HCT is not superior to that of conventional consolidation chemotherapy” among patients 60 years or younger with intermediate-risk AML, the authors concluded.

However, two experts highlighted several caveats to the study, which suggest the results may not translate to current clinical practice.

The study was published online in JAMA Oncology.

Approximately 50%-70% of patients with AML who receive intensive induction chemotherapy for AML and achieve a first complete remission are referred for post-remission therapy.

While consolidation chemotherapy with high-dose cytarabine has shown a benefit for those with a favorable risk profile, patients considered high-risk with adequate performance status may be candidates for allogeneic HCT.

However, determining the optimal post-remission treatment option for patients who fall into the intermediate-risk category can be more challenging.

To compare outcomes among intermediate-risk patients, researchers from Germany conducted a multicenter trial, enrolling 143 adults aged 60 or younger with intermediate-risk AML who had achieved first complete remission or complete remission with incomplete blood cell count recovery following conventional induction therapy.

The patients, who had a mean age of 48.2 years, were randomly assigned to consolidation treatment with allogeneic HCT (n = 76) or chemotherapy with high-dose cytarabine (n = 67), with the option for salvage HCT in the case of relapse. Overall, 12 patients in the HCT group received one consolidation course of high-dose cytarabine after achieving complete remission to bridge until allogeneic HCT, while all other patients in this group received allogeneic HCT directly after induction therapy.

Overall, disease-free survival at 2 years was significantly higher in the allogeneic HCT group (69%), compared with the consolidation therapy group (40%; P = .001). And the cumulative incidence of relapse at 2 years in the allogeneic HCT group was also lower, at 20%, compared with 58% in the consolidation therapy group (P < .001).

The overall survival data, however, painted a slightly more complex picture. In the intention-to-treat analysis, the probability of survival at 2 years was similar between the allogeneic HCT group (74%, or 56 of 76 patients), compared with consolidation chemotherapy (84%, or 56 of 67 patients; P = .22).

In addition, the rates of nonrelapse mortality at 2 years were higher in the allogeneic HCT group (9%) versus chemotherapy (2%; P = .005).

Although the rate of nonrelapse mortality was higher with allogeneic HCT, the relatively low rate with each treatment strategies was “an important and rewarding finding,” the authors noted. “This achievement is clearly due to the availability of less toxic but still effective conditioning therapies and modern antiviral and antifungal prophylaxis.”

In addition, among the 41 patients who relapsed after consolidation chemotherapy, all received allogeneic HCT, and the authors observed no significant differences between the groups in terms of health-related quality of life measures.
 

Results ‘may not translate to real-life clinical practice’

An important caveat is that the findings do not reflect some key updated strategies currently used in clinical practice, said Diego Adrianzen Herrera, MD, from the University of Vermont’s Larner College of Medicine, Burlington, who was not involved in the study.

“A charitable interpretation of the results is that a clear, large survival benefit of transplant in first complete remission is not apparent, which in turn can inform decision-making in certain circumstances for patients meeting the trial criteria, [including] younger patients with a readily available donor,” he told this news organization.

“However, risk stratification strategies currently used were not followed,” he said.

For instance, molecular risk stratification was not universally used, which may have led the researchers to overrepresent the number of patients considered to have favorable risk disease and “could have skewed the results in favor of the chemotherapy arm,” he explained.

In addition, minimal residual disease surveillance by flow cytometry was not used. Plus, Dr. Herrera added, in practice, not all patients can be salvaged and taken to HCT when in their second complete remission, or even achieve complete remission again.

“Unfortunately, these issues make the clinical significance of these results limited,” he concluded.

Margaret Kasner, MD, who was not associated with the research, agreed that aspects of the study design may not translate to real-life clinical practice, particularly in terms of quality-of-life outcomes.

“Although the [study] showed no difference in quality of life in the patient groups, this is likely due to the patient selection,” Dr. Kasner, of the Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, said in an interview. “Most patients do not allow themselves to be randomized between these two very different strategies, so those who are willing to be randomized may be a different population in terms how their quality of life is affected by relapse.”

The authors acknowledged some of these limitations, adding that the routine use of minimal residual disease monitoring in some patients was only established once the trial was underway, and the number of patients with complete minimal residual disease was therefore limited.

In addition, Dr. Herrera explained that because HCT involves significant disruptions to daily life and extensive follow-up and monitoring, decisions to use the strategy are not taken lightly by clinicians or patients.

“This is a major issue,” he said. “HCT remains a therapeutic option which causes significant apprehension to patients.”

Nevertheless, “in my experience most patients would prefer an upfront strategy if there is a definitive need for transplant,” he added. “I think the main question patients have is whether they absolutely need an HCT and how can we better identify up front who will be in the relapse-free group at 2 years.”

The study received grant funding from the Deutsche Forschungsgemeinschaft. The authors’ disclosures are detailed in the original article. Dr. Herrera and Dr. Kasner report no relevant financial relationships.

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

Educating the next generation of health professionals is 1 of 4 congressionally mandated statutory missions of the US Department of Veterans Affairs (VA).¹ Even before the COVID-19 pandemic, the number of veterans accessing VA health care was increasing, and those veterans are older and more medically complex than those who seek care outside the VA.² Almost half of medical residents reported a decline in the quality of their clinical education since the institution of the 2011 duty hours regulations, and in the past decade, more attention has been paid to the need for structured faculty development programs that focus on clinicians’ roles as medical educators.^3-6 Hospitalists in particular shoulder a large portion of inpatient medicine education.⁷ As a result, hospitalists have adapted known frameworks for medical education to their unique clinical setting and developed novel frameworks to meet the needs of their learners.^8,9

Access to technology and social media have shaped the educational experience of young learners who are accustomed to quick answers and the rapidity of change.¹⁰ The clinical teaching landscape changed again with COVID-19, requiring at least temporary abandonment of traditional in-person teaching methods, which upended well-established educational norms.^11,12 In this evolving field, even seasoned preceptors may feel ill-equipped to manage the nuances of modern clinical education and may struggle to recognize which teaching skills are most critical.^13,14 Baseline core teaching competencies for medical educators have been previously described and are separate from clinical competencies; however, to our knowledge, no needs assessment has previously been performed specifically for VA hospitalist clinician educators.¹⁵

Between May and June of 2020, we distributed an online needs assessment to academic VA hospitalists to identify perceived barriers to effective clinical education and preferred strategies to overcome them. We received 71 responses from 140 hospitalists (50% response rate) on the Veterans Health Administration (VHA) academic hospitalist listserv. Of respondents, 59 (83%) reported teaching health professions trainees every year. VA hospitalists reported educating a diverse group of interprofessional learners, including medical residents and students, physician assistant students, nursing students, pharmacy residents and students, and podiatry students.

Only 14 respondents (20%) were aware of faculty development training available to them through their VA facility, while 53 (75%) were aware of similar resources through academic affiliates or other outside sources. More than 95% of respondents (n = 68) reported interest in receiving VA-specific faculty development to improve skills as clinician educators. The most preferred forms of delivery were in-person or virtual real-time workshops. VA hospitalists reported the least confidence in their ability to support struggling learners, balance supervision and autonomy, and develop individualized learning plans (Table 1).

Teaching the Teacher

Teaching the Teacher began at a single VA institution as a series of in-person, discussion-based faculty development workshops. The series met a local need for collaborative professional development in clinical education for hospitalists and specialists who round with health professions learners on the inpatient wards. Both novice and experienced clinicians participated in the series with positive feedback. Based on the results of the national needs assessment, the program has since expanded to other sites with support from the VHA Hospital Medicine Program Office. The project’s overarching goal was to facilitate sharing of best practices across VA sites and create a network of local and national VA educators that participants could continue to access even after course completion.

Teaching the Teacher is structured into 5 facilitated hour-long sessions that can be completed either daily for 1 week or weekly for 1 month at the discretion of each institution. Each session is dedicated to a subject identified on the needs assessment as being highest yield. The hospitalist needs assessment also identified the preference for targeted faculty development that is relevant specifically to VA clinicians. To meet this need, Teaching the Teacher delivers its content through the unique lens of VA medicine. The educational mission of the VA is threaded throughout all presentations, and tips to maximize teaching in the VA’s unique clinical environments are embedded into each hour. Examples include discussions on how to incorporate veteran patients into bedside teaching, handling challenging patient-practitioner interactions as they pertain to patients, and the use of VA resources to find and teach evidence-based medicine.Each session includes a set of learning objectives; within that framework, facilitators allow participants to guide the nuances of content based on their individual and institutional priorities. The pandemic continues to shape much of the course content, as both hospitalists and their trainees grapple with mental health challenges, decreased bedside teaching, and wide variations in baseline trainee competence due to different institutional responses to teaching during a pandemic.^12,16 Content is regularly updated to incorporate new literature and feedback from participants and prioritize active participation. Continuing medical education/continuing educational units credit is available through the VA for course completion.

In the first session on modern learners, participants discuss the current generation of health professions trainees, including how personality characteristics and COVID-19 have impacted their learning experiences, and strategies to improve our ability to teach them successfully (Table 2).

Program Impact

Ten academically affiliated VA hospital medicine sections across 6 states have participated in Teaching the Teacher and several more are scheduled at other sites. Of the 10, 5 completed the course in collaboration with another VA site. Ninety-seven clinicians completed < 1 session synchronously but given the asynchronous option, this number likely underestimates the total audience. Participants included physicians, nurse practitioners, and physician assistants.

Surveys were conducted before and after the program, with 58 participants completing the presurvey, 32 the postsurvey, and 27 completing both. Of the 32 postsurvey respondents, 31 (97%) would recommend the seminar to colleagues. The live, discussion-based format was the most valued aspect of the course structure, with engaging facilitators and course content also ranking highly. Just over half (n = 17) indicated specific behavioral changes they plan to enact after completing the series, such as connecting with and better understanding learners, prioritizing high-quality feedback more deliberately, and bringing medicine to the bedside. The most common critiques of the course were requests for more time for feedback skills.

Discussion

Teaching the Teacher is a VA-specific faculty development seminar for hospitalists. Participants who responded to a survey reported that it met their needs as VA clinician educators. This is the first published needs assessment of academic VA hospitalists in their roles as clinician educators and the first faculty development initiative to address those specific needs using a collaborative, multisite approach. Although this program is a pilot, the positive response it has received has set a precedent for increased development and growth.

Teaching the Teacher presents a novel approach with a condensed curriculum that is more convenient and accessible to VA clinicians than previous programs with similar goals. Hospitalists have busy and variable work schedules, and it can be difficult to find time to participate in a traditional faculty development program. While these programs are becoming more commonplace, they are often longitudinal and require a significant time and/or financial commitment from participants.¹⁸ In contrast, Teaching the Teacher is only 5 hours long, can be viewed either synchronously or asynchronously, and is no cost to participants. In the future, other specialties may similarly value an efficient faculty development curriculum, and participation from clinicians outside of hospital medicine could augment the richness of content.

Teaching the Teacher’s curriculum is not meant to be exhaustive, but rather to spark conversation among colleagues. According to survey respondents, the most lauded aspect of this program was the facilitated, discussion-based structure, wherein participants are presented with common challenges and encouraged to share their experiences and solutions with colleagues. Of particular interest to the program’s mission of greater community building are the VA facilities that chose to complete the seminar with another hospitalist section from a different institution. Within this structure lies an opportunity for seasoned educators to informally mentor junior colleagues both within and across institutions, and foster connections among educators that continue beyond the completion of the series. We envision this program growing into an enduring professional development course that begins at onboarding and is revisited at regular intervals thereafter.

Another compelling aspect of this project is the interprofessional design, bringing physicians, nurse practitioners, and physician assistants together. Health education, like clinical care, is shifting to a team approach.¹⁹ The curriculum addresses topics previously described as high priority for interprofessional faculty development, such as fostering healthy team leadership, motivating learners, and appraising evidence and online resources.²⁰ A pilot project in VA primary care facilities found that deliberate interprofessional education improved collaboration among health care professionals.²¹ Prior to Teaching the Teacher, no similar faculty development program provided interprofessional learning and collaboration for VA hospitalists.

Limitations and Future Directions

There are several limitations to this preliminary study. Participation at each site was voluntary and did not always reach the full potential audience of hospitalist clinician educators. As one participant stated, future directions include doing “more to involve teachers who need to learn [these skills]. The ones who attended [from our institution] were already the best teachers.” In addition, despite the asynchronous option, lack of protected time for faculty development may be a limiting factor in participation. Support from institutional and national leadership would likely improve participation.

Measured endpoints to date consist primarily of participant satisfaction and do not yet capture objective changes in teaching. Data collection is ongoing to assess immediate and longitudinal changes in confidence and behaviors of attendees and how this might affect their health professions learners.

Last, our initial needs assessment only targeted academic hospitalists, and the needs of VA hospitalists in rural areas or at facilities without academic affiliation may be different. More research is needed to understand the diverse faculty that comprises both urban and rural VA sites, what their professional development needs are, and how those needs can be met.

Conclusions

Teaching the Teacher is a faculty development pilot, tailored to meet the needs of VA hospitalist clinician educators, that has been voluntarily adopted at multiple VA sites. The facilitated discussion format allows participants to guide the conversation and personalize content, thereby promoting a culture of discussing challenges and best practices among colleagues that we hope endures beyond the bounds of the curriculum. The program focuses on elevating the specific teaching mission of the VA and could be incorporated into onboarding and regular VA-sponsored faculty development updates. While Teaching the Teacher was originally developed for VA hospitalists, most of the content is applicable to clinicians outside hospital medicine. This project serves as a model for training clinical educators and has opportunities to expand across VA as a customizable didactic platform.

Acknowledgments

We thank Brian Schneider, MD, for his tireless support of this program, as well as all the VA clinicians who have shared their time, talents, and wisdom with us since this program’s inception.

Educating the next generation of health professionals is 1 of 4 congressionally mandated statutory missions of the US Department of Veterans Affairs (VA).¹ Even before the COVID-19 pandemic, the number of veterans accessing VA health care was increasing, and those veterans are older and more medically complex than those who seek care outside the VA.² Almost half of medical residents reported a decline in the quality of their clinical education since the institution of the 2011 duty hours regulations, and in the past decade, more attention has been paid to the need for structured faculty development programs that focus on clinicians’ roles as medical educators.^3-6 Hospitalists in particular shoulder a large portion of inpatient medicine education.⁷ As a result, hospitalists have adapted known frameworks for medical education to their unique clinical setting and developed novel frameworks to meet the needs of their learners.^8,9

Access to technology and social media have shaped the educational experience of young learners who are accustomed to quick answers and the rapidity of change.¹⁰ The clinical teaching landscape changed again with COVID-19, requiring at least temporary abandonment of traditional in-person teaching methods, which upended well-established educational norms.^11,12 In this evolving field, even seasoned preceptors may feel ill-equipped to manage the nuances of modern clinical education and may struggle to recognize which teaching skills are most critical.^13,14 Baseline core teaching competencies for medical educators have been previously described and are separate from clinical competencies; however, to our knowledge, no needs assessment has previously been performed specifically for VA hospitalist clinician educators.¹⁵

Between May and June of 2020, we distributed an online needs assessment to academic VA hospitalists to identify perceived barriers to effective clinical education and preferred strategies to overcome them. We received 71 responses from 140 hospitalists (50% response rate) on the Veterans Health Administration (VHA) academic hospitalist listserv. Of respondents, 59 (83%) reported teaching health professions trainees every year. VA hospitalists reported educating a diverse group of interprofessional learners, including medical residents and students, physician assistant students, nursing students, pharmacy residents and students, and podiatry students.

Only 14 respondents (20%) were aware of faculty development training available to them through their VA facility, while 53 (75%) were aware of similar resources through academic affiliates or other outside sources. More than 95% of respondents (n = 68) reported interest in receiving VA-specific faculty development to improve skills as clinician educators. The most preferred forms of delivery were in-person or virtual real-time workshops. VA hospitalists reported the least confidence in their ability to support struggling learners, balance supervision and autonomy, and develop individualized learning plans (Table 1).

Teaching the Teacher

Teaching the Teacher began at a single VA institution as a series of in-person, discussion-based faculty development workshops. The series met a local need for collaborative professional development in clinical education for hospitalists and specialists who round with health professions learners on the inpatient wards. Both novice and experienced clinicians participated in the series with positive feedback. Based on the results of the national needs assessment, the program has since expanded to other sites with support from the VHA Hospital Medicine Program Office. The project’s overarching goal was to facilitate sharing of best practices across VA sites and create a network of local and national VA educators that participants could continue to access even after course completion.

Teaching the Teacher is structured into 5 facilitated hour-long sessions that can be completed either daily for 1 week or weekly for 1 month at the discretion of each institution. Each session is dedicated to a subject identified on the needs assessment as being highest yield. The hospitalist needs assessment also identified the preference for targeted faculty development that is relevant specifically to VA clinicians. To meet this need, Teaching the Teacher delivers its content through the unique lens of VA medicine. The educational mission of the VA is threaded throughout all presentations, and tips to maximize teaching in the VA’s unique clinical environments are embedded into each hour. Examples include discussions on how to incorporate veteran patients into bedside teaching, handling challenging patient-practitioner interactions as they pertain to patients, and the use of VA resources to find and teach evidence-based medicine.Each session includes a set of learning objectives; within that framework, facilitators allow participants to guide the nuances of content based on their individual and institutional priorities. The pandemic continues to shape much of the course content, as both hospitalists and their trainees grapple with mental health challenges, decreased bedside teaching, and wide variations in baseline trainee competence due to different institutional responses to teaching during a pandemic.^12,16 Content is regularly updated to incorporate new literature and feedback from participants and prioritize active participation. Continuing medical education/continuing educational units credit is available through the VA for course completion.

In the first session on modern learners, participants discuss the current generation of health professions trainees, including how personality characteristics and COVID-19 have impacted their learning experiences, and strategies to improve our ability to teach them successfully (Table 2).

Program Impact

Ten academically affiliated VA hospital medicine sections across 6 states have participated in Teaching the Teacher and several more are scheduled at other sites. Of the 10, 5 completed the course in collaboration with another VA site. Ninety-seven clinicians completed < 1 session synchronously but given the asynchronous option, this number likely underestimates the total audience. Participants included physicians, nurse practitioners, and physician assistants.

Surveys were conducted before and after the program, with 58 participants completing the presurvey, 32 the postsurvey, and 27 completing both. Of the 32 postsurvey respondents, 31 (97%) would recommend the seminar to colleagues. The live, discussion-based format was the most valued aspect of the course structure, with engaging facilitators and course content also ranking highly. Just over half (n = 17) indicated specific behavioral changes they plan to enact after completing the series, such as connecting with and better understanding learners, prioritizing high-quality feedback more deliberately, and bringing medicine to the bedside. The most common critiques of the course were requests for more time for feedback skills.

Discussion

Teaching the Teacher is a VA-specific faculty development seminar for hospitalists. Participants who responded to a survey reported that it met their needs as VA clinician educators. This is the first published needs assessment of academic VA hospitalists in their roles as clinician educators and the first faculty development initiative to address those specific needs using a collaborative, multisite approach. Although this program is a pilot, the positive response it has received has set a precedent for increased development and growth.

Teaching the Teacher presents a novel approach with a condensed curriculum that is more convenient and accessible to VA clinicians than previous programs with similar goals. Hospitalists have busy and variable work schedules, and it can be difficult to find time to participate in a traditional faculty development program. While these programs are becoming more commonplace, they are often longitudinal and require a significant time and/or financial commitment from participants.¹⁸ In contrast, Teaching the Teacher is only 5 hours long, can be viewed either synchronously or asynchronously, and is no cost to participants. In the future, other specialties may similarly value an efficient faculty development curriculum, and participation from clinicians outside of hospital medicine could augment the richness of content.

Teaching the Teacher’s curriculum is not meant to be exhaustive, but rather to spark conversation among colleagues. According to survey respondents, the most lauded aspect of this program was the facilitated, discussion-based structure, wherein participants are presented with common challenges and encouraged to share their experiences and solutions with colleagues. Of particular interest to the program’s mission of greater community building are the VA facilities that chose to complete the seminar with another hospitalist section from a different institution. Within this structure lies an opportunity for seasoned educators to informally mentor junior colleagues both within and across institutions, and foster connections among educators that continue beyond the completion of the series. We envision this program growing into an enduring professional development course that begins at onboarding and is revisited at regular intervals thereafter.

Another compelling aspect of this project is the interprofessional design, bringing physicians, nurse practitioners, and physician assistants together. Health education, like clinical care, is shifting to a team approach.¹⁹ The curriculum addresses topics previously described as high priority for interprofessional faculty development, such as fostering healthy team leadership, motivating learners, and appraising evidence and online resources.²⁰ A pilot project in VA primary care facilities found that deliberate interprofessional education improved collaboration among health care professionals.²¹ Prior to Teaching the Teacher, no similar faculty development program provided interprofessional learning and collaboration for VA hospitalists.

Limitations and Future Directions

There are several limitations to this preliminary study. Participation at each site was voluntary and did not always reach the full potential audience of hospitalist clinician educators. As one participant stated, future directions include doing “more to involve teachers who need to learn [these skills]. The ones who attended [from our institution] were already the best teachers.” In addition, despite the asynchronous option, lack of protected time for faculty development may be a limiting factor in participation. Support from institutional and national leadership would likely improve participation.

Measured endpoints to date consist primarily of participant satisfaction and do not yet capture objective changes in teaching. Data collection is ongoing to assess immediate and longitudinal changes in confidence and behaviors of attendees and how this might affect their health professions learners.

Last, our initial needs assessment only targeted academic hospitalists, and the needs of VA hospitalists in rural areas or at facilities without academic affiliation may be different. More research is needed to understand the diverse faculty that comprises both urban and rural VA sites, what their professional development needs are, and how those needs can be met.

Conclusions

Teaching the Teacher is a faculty development pilot, tailored to meet the needs of VA hospitalist clinician educators, that has been voluntarily adopted at multiple VA sites. The facilitated discussion format allows participants to guide the conversation and personalize content, thereby promoting a culture of discussing challenges and best practices among colleagues that we hope endures beyond the bounds of the curriculum. The program focuses on elevating the specific teaching mission of the VA and could be incorporated into onboarding and regular VA-sponsored faculty development updates. While Teaching the Teacher was originally developed for VA hospitalists, most of the content is applicable to clinicians outside hospital medicine. This project serves as a model for training clinical educators and has opportunities to expand across VA as a customizable didactic platform.

Acknowledgments

We thank Brian Schneider, MD, for his tireless support of this program, as well as all the VA clinicians who have shared their time, talents, and wisdom with us since this program’s inception.

Educating the next generation of health professionals is 1 of 4 congressionally mandated statutory missions of the US Department of Veterans Affairs (VA).¹ Even before the COVID-19 pandemic, the number of veterans accessing VA health care was increasing, and those veterans are older and more medically complex than those who seek care outside the VA.² Almost half of medical residents reported a decline in the quality of their clinical education since the institution of the 2011 duty hours regulations, and in the past decade, more attention has been paid to the need for structured faculty development programs that focus on clinicians’ roles as medical educators.^3-6 Hospitalists in particular shoulder a large portion of inpatient medicine education.⁷ As a result, hospitalists have adapted known frameworks for medical education to their unique clinical setting and developed novel frameworks to meet the needs of their learners.^8,9

Access to technology and social media have shaped the educational experience of young learners who are accustomed to quick answers and the rapidity of change.¹⁰ The clinical teaching landscape changed again with COVID-19, requiring at least temporary abandonment of traditional in-person teaching methods, which upended well-established educational norms.^11,12 In this evolving field, even seasoned preceptors may feel ill-equipped to manage the nuances of modern clinical education and may struggle to recognize which teaching skills are most critical.^13,14 Baseline core teaching competencies for medical educators have been previously described and are separate from clinical competencies; however, to our knowledge, no needs assessment has previously been performed specifically for VA hospitalist clinician educators.¹⁵

Between May and June of 2020, we distributed an online needs assessment to academic VA hospitalists to identify perceived barriers to effective clinical education and preferred strategies to overcome them. We received 71 responses from 140 hospitalists (50% response rate) on the Veterans Health Administration (VHA) academic hospitalist listserv. Of respondents, 59 (83%) reported teaching health professions trainees every year. VA hospitalists reported educating a diverse group of interprofessional learners, including medical residents and students, physician assistant students, nursing students, pharmacy residents and students, and podiatry students.

Only 14 respondents (20%) were aware of faculty development training available to them through their VA facility, while 53 (75%) were aware of similar resources through academic affiliates or other outside sources. More than 95% of respondents (n = 68) reported interest in receiving VA-specific faculty development to improve skills as clinician educators. The most preferred forms of delivery were in-person or virtual real-time workshops. VA hospitalists reported the least confidence in their ability to support struggling learners, balance supervision and autonomy, and develop individualized learning plans (Table 1).

Teaching the Teacher

Teaching the Teacher began at a single VA institution as a series of in-person, discussion-based faculty development workshops. The series met a local need for collaborative professional development in clinical education for hospitalists and specialists who round with health professions learners on the inpatient wards. Both novice and experienced clinicians participated in the series with positive feedback. Based on the results of the national needs assessment, the program has since expanded to other sites with support from the VHA Hospital Medicine Program Office. The project’s overarching goal was to facilitate sharing of best practices across VA sites and create a network of local and national VA educators that participants could continue to access even after course completion.

Teaching the Teacher is structured into 5 facilitated hour-long sessions that can be completed either daily for 1 week or weekly for 1 month at the discretion of each institution. Each session is dedicated to a subject identified on the needs assessment as being highest yield. The hospitalist needs assessment also identified the preference for targeted faculty development that is relevant specifically to VA clinicians. To meet this need, Teaching the Teacher delivers its content through the unique lens of VA medicine. The educational mission of the VA is threaded throughout all presentations, and tips to maximize teaching in the VA’s unique clinical environments are embedded into each hour. Examples include discussions on how to incorporate veteran patients into bedside teaching, handling challenging patient-practitioner interactions as they pertain to patients, and the use of VA resources to find and teach evidence-based medicine.Each session includes a set of learning objectives; within that framework, facilitators allow participants to guide the nuances of content based on their individual and institutional priorities. The pandemic continues to shape much of the course content, as both hospitalists and their trainees grapple with mental health challenges, decreased bedside teaching, and wide variations in baseline trainee competence due to different institutional responses to teaching during a pandemic.^12,16 Content is regularly updated to incorporate new literature and feedback from participants and prioritize active participation. Continuing medical education/continuing educational units credit is available through the VA for course completion.

In the first session on modern learners, participants discuss the current generation of health professions trainees, including how personality characteristics and COVID-19 have impacted their learning experiences, and strategies to improve our ability to teach them successfully (Table 2).

Program Impact

Ten academically affiliated VA hospital medicine sections across 6 states have participated in Teaching the Teacher and several more are scheduled at other sites. Of the 10, 5 completed the course in collaboration with another VA site. Ninety-seven clinicians completed < 1 session synchronously but given the asynchronous option, this number likely underestimates the total audience. Participants included physicians, nurse practitioners, and physician assistants.

Surveys were conducted before and after the program, with 58 participants completing the presurvey, 32 the postsurvey, and 27 completing both. Of the 32 postsurvey respondents, 31 (97%) would recommend the seminar to colleagues. The live, discussion-based format was the most valued aspect of the course structure, with engaging facilitators and course content also ranking highly. Just over half (n = 17) indicated specific behavioral changes they plan to enact after completing the series, such as connecting with and better understanding learners, prioritizing high-quality feedback more deliberately, and bringing medicine to the bedside. The most common critiques of the course were requests for more time for feedback skills.

Discussion

Teaching the Teacher is a VA-specific faculty development seminar for hospitalists. Participants who responded to a survey reported that it met their needs as VA clinician educators. This is the first published needs assessment of academic VA hospitalists in their roles as clinician educators and the first faculty development initiative to address those specific needs using a collaborative, multisite approach. Although this program is a pilot, the positive response it has received has set a precedent for increased development and growth.

Teaching the Teacher presents a novel approach with a condensed curriculum that is more convenient and accessible to VA clinicians than previous programs with similar goals. Hospitalists have busy and variable work schedules, and it can be difficult to find time to participate in a traditional faculty development program. While these programs are becoming more commonplace, they are often longitudinal and require a significant time and/or financial commitment from participants.¹⁸ In contrast, Teaching the Teacher is only 5 hours long, can be viewed either synchronously or asynchronously, and is no cost to participants. In the future, other specialties may similarly value an efficient faculty development curriculum, and participation from clinicians outside of hospital medicine could augment the richness of content.

Teaching the Teacher’s curriculum is not meant to be exhaustive, but rather to spark conversation among colleagues. According to survey respondents, the most lauded aspect of this program was the facilitated, discussion-based structure, wherein participants are presented with common challenges and encouraged to share their experiences and solutions with colleagues. Of particular interest to the program’s mission of greater community building are the VA facilities that chose to complete the seminar with another hospitalist section from a different institution. Within this structure lies an opportunity for seasoned educators to informally mentor junior colleagues both within and across institutions, and foster connections among educators that continue beyond the completion of the series. We envision this program growing into an enduring professional development course that begins at onboarding and is revisited at regular intervals thereafter.

Another compelling aspect of this project is the interprofessional design, bringing physicians, nurse practitioners, and physician assistants together. Health education, like clinical care, is shifting to a team approach.¹⁹ The curriculum addresses topics previously described as high priority for interprofessional faculty development, such as fostering healthy team leadership, motivating learners, and appraising evidence and online resources.²⁰ A pilot project in VA primary care facilities found that deliberate interprofessional education improved collaboration among health care professionals.²¹ Prior to Teaching the Teacher, no similar faculty development program provided interprofessional learning and collaboration for VA hospitalists.

Limitations and Future Directions

There are several limitations to this preliminary study. Participation at each site was voluntary and did not always reach the full potential audience of hospitalist clinician educators. As one participant stated, future directions include doing “more to involve teachers who need to learn [these skills]. The ones who attended [from our institution] were already the best teachers.” In addition, despite the asynchronous option, lack of protected time for faculty development may be a limiting factor in participation. Support from institutional and national leadership would likely improve participation.

Measured endpoints to date consist primarily of participant satisfaction and do not yet capture objective changes in teaching. Data collection is ongoing to assess immediate and longitudinal changes in confidence and behaviors of attendees and how this might affect their health professions learners.

Last, our initial needs assessment only targeted academic hospitalists, and the needs of VA hospitalists in rural areas or at facilities without academic affiliation may be different. More research is needed to understand the diverse faculty that comprises both urban and rural VA sites, what their professional development needs are, and how those needs can be met.

Conclusions

Teaching the Teacher is a faculty development pilot, tailored to meet the needs of VA hospitalist clinician educators, that has been voluntarily adopted at multiple VA sites. The facilitated discussion format allows participants to guide the conversation and personalize content, thereby promoting a culture of discussing challenges and best practices among colleagues that we hope endures beyond the bounds of the curriculum. The program focuses on elevating the specific teaching mission of the VA and could be incorporated into onboarding and regular VA-sponsored faculty development updates. While Teaching the Teacher was originally developed for VA hospitalists, most of the content is applicable to clinicians outside hospital medicine. This project serves as a model for training clinical educators and has opportunities to expand across VA as a customizable didactic platform.

Acknowledgments

We thank Brian Schneider, MD, for his tireless support of this program, as well as all the VA clinicians who have shared their time, talents, and wisdom with us since this program’s inception.