Clinical Review

ILLUSTRATION BY KIMBERLY MARTENS FOR OBG MANAGEMENT

David G. Mutch, MD: The cervical cancer screening guidelines, using Pap testing, have changed significantly since the times of yearly Paps and exams. Coupled with vaccination and new management guidelines (recommending HPV testing, etc), we actually hope that we are on the way to eradicating cervical cancer from our environment.

Screening: Current recommendations

Dr. Mutch: Warner, the American Society of Colposcopy and Cervical Pathology (ASCCP)¹ endorses the cervical cancer screening guidelines for several professional organizations, including the American Cancer Society (ACS),² the US Preventive Services Task Force (USPSTF),³ and the American College of Obstetricians and Gynecologists (ACOG).⁴ What are the current screening recommendations, as these organizations have disparate views?

Warner Huh, MD: There was a time, around 2012-2013, when for the first time ever, we had significant harmonization of the guidelines between ACOG and the USPSTF and ACS. But in the last 10 years there has been an explosion of data in terms of how to best screen patients.

The move to primary HPV testing. The USPSTF³ initially had recommended looking into primary HPV screening, which is just using HPV testing by itself as the screening modality. But there was a lot of pushback at that time. I think a lot of people thought that we were not prepared to make that leap. Therefore, they endorsed screening with cytology by itself as well as HPV testing by itself, as well as co-testing; but in their recommendations, they made it very clear that they were leaning toward primary HPV screening.

A new patient age to begin screening. In 2020, the ACS put out their new guidelines,² which are a significant departure from what we are used to—they are recommending that we start screening at 25 years of age. Like you said, Dr. Mutch, it doesn’t seem that long ago when we were screening people at age 18, or within 3 years of sexual intercourse. But the reason for it is that the rate of cervical cancer is extremely low under age 25, and other countries like the United Kingdom already do this.

The other major departure in the ACS guidelines is that they really are asking clinicians and screeners to focus on primary HPV screening. Overall, they have sort of doubled down on why they think primary HPV screening is so important.

ACOG sits sort of in the middle of the other recommendations. ACOG understands the value of primary HPV screening, but I don’t think that they are quite ready to recommend screening at age 25. If you look at their updated guidelines from April 2021,⁴ they state that we should continue a screening-starting age of 21 years. So there are some disparate views, but I am confident, Dr. Mutch, that in the next 2 to 3 years, there will be greater harmonization of these guidelines and less confusion for our providers. The greatest barrier is understanding the science and the comfort level of clinicians to go with just an HPV test, since for the last 40 years the Pap test has anchored gynecologic care in this country. And it took at least 10 years to get to what I consider to be widespread adoption to co-testing. The other thing that readers should recognize is that the Task Force is actually revisiting their cervical cancer screening guidance now, so expect another major revision.

Reimbursement and access are barriers. Reimbursement is a further real issue. We are now using one less test, but insurance companies may not reimburse when just the HPV test is used. The other issue is access to labs that can do the HPV testing.

Dr. Mutch: We used to see patients yearly and picked up a lot of adjunctive or additional illnesses. Now they are not being seen yearly it could impact negatively their overall health care. We need to understand that cervical cancer screening is simply a test, which should not eliminate other health care.

Dr. Huh: Yes, I think the extended interval between recommended HPV screenings scares people. I have been involved in these screening guidelines (and I can only speak for myself, not for my colleagues), but even I do think we made a leap to a longer interval way too quickly in this country. Screening changes are slow, and sometimes a glacial process. I think it can worry providers when we make rapid changes.

But this is a test that should not anchor the yearly visit. There are plenty of other reasons—and ACOG actually states this⁴—why patients should come for a wellness exam on a yearly basis. So I think our ObGyns in the United States need to recognize that, but I understand there are underlying concerns that if you extend intervals too long, (a) will patients come back, and (b), as a consequence, is the interval going to miss something in between? Those are real legitimate concerns.

Continue to: Management guidelines...

 

 

Management guidelines: The latest

Dr. Mutch: The ASCCP issued new management guidelines in 2019.⁵ Can you address what you feel are the most important updates?

Dr. Huh: Going back to 2002, we have revised these guidelines every 5 years. For this one, the revision came out a little bit later for various reasons, but the reason we revised it is because we collect new data that we think markedly changes our understanding of the disease process and natural history and the interventions for women that have preinvasive disease of the cervix.

Briefly, I think the biggest changes based on what we were hearing from our providers and users of our apps and algorithms was that our algorithms were becoming way too complicated, and they were. If you look over the last 10 years, the number of branch points on our algorithms basically quadrupled. If we incorporated the new data this time, the algorithms would be unworkable, and you could not use them on your phone because they would be too complicated.

So, we created a system where, in essence, providers have 5 choices for patients:

• treatment
• colposcopy
• follow-up in 1 year
• follow-up in 3 years
• follow-up in 5 years.

Those recommendations are based on what we call “clinically actionable thresholds”—basically, the percent chance of developing immediate CIN3 or worse. That threshold will probably change over time, but what we did is create a system that (a) makes it easier for the provider, (although they have to trust the system—and they can look under the hood and understand how we did this) and (b) allows us to create a foundation where we can add future technologies that use the same rubric or paradigm so that they still wind up getting the same result without having to go to another algorithm.

This new system is probably the most marked change in the history of the ASCCP management guidelines, but we did it to make it ultimately easier for providers going forward for the next 10 to 20 years. There are real opportunities, Dr. Mutch, in terms of how do we integrate this into the electronic medical record (EMR), and how do we pull data so clinicians don’t have to manually enter it.

The other difference is now there is a web-based application. Back in 2012, there were a lot of people that were not using EMRs. Now the majority of the country is, and so they actually are on a browser more than they are on their phone. We actually have an equally robust web platform that allows them to get the information that they need.

Dr. Mutch: I think that is really important—the utility of utilizing a mobile app, if you will, for triaging your patient with a specific test result so that patients are followed up at the proper interval, and that ultimately becomes cost-effective.

Dr. Huh: Yes, the app now is very different than the app that I think people are used to using for the last almost 10 years. You don’t put inputs, pull up the algorithm, and look at the outcome. This is different. You enter the patient’s age. You add their cytology, their HPV results, the clinical scenario that you are in, and then it puts out a recommendation of what to do next. Over time, we want to get away from an algorithm and for our providers to understand what the risk is and how that risk calculation then translates into a clinical recommendation.

Dr. Mutch: I think to utilize an app is almost necessary given the complexity of the triaging process so that it does become, in fact, the most cost-effective way to screen patients.

Dr. Huh: I would agree with that. There is a learning curve for whenever you see new technology. There was a learning curve for even ASCCP leadership as they tried to educate providers. I think people will ultimately see that this is a much better way of managing patients with cervical abnormalities, and I am hoping actually that we will use a similar platform for many other diseases that we manage in women’s health.

Continue to: Chipping away of the yearly exam...

 

 

Chipping away of the yearly exam

Dr. Mutch: With this moving away from the yearly exam and Pap test, women may not get yearly examinations. Do you feel that this could affect a stage migration to a higher stage at diagnosis, for instance, of a cervical cancer? Or that it might adversely impact other health issues?

Dr. Huh: I think that’s a good question. I am worried about the interval—I think 5 years is a bit long. I am more worried that patients will miss out on visits because they may think that they need to only come back for their Pap, even though they should be re-educated on that.

COVID-19 has made this a little hard for us to analyze because, clearly, we have had access to care issues. But I am a little concerned that we could see an uptick in invasive cancer rates in this country, including an uptick in the stage and more locally advanced cervical cancer because of the changes in the screening paradigms. But we don’t know that to be the case.

As with all screenings, the bottom line is you have to worry about what the false-negative and false-positive rates of screening are, and that affects everything. I want the readers to know that primary HPV should be used for screenings. It is not perfect, but it is much better than cytology alone. We need to think about how to better adapt screening in the age that we live in.

HPV self-sampling

Dr. Mutch: Could self-sampling for HPV testing, which obviously would be easier for the patient, and certainly useful in terms of screening, address some health care disparities with regard to cervical cancer?

Dr. Huh: The short answer is, yes. Self-sampling is not US Food and Drug Administration-approved in this country. It’s not being widely used without that approval. But there are multiple countries, including the United States, that have done lots of studies on this topic. There are many public health experts and champions for HPV self-sampling. I think we have learned, based on some studies, that the sensitivity is reasonable.⁶

I live in a part of the country that is woefully underserved; where you are there are pockets in Missouri that are woefully underserved as well. So the issue is, can we reduce these disparities and access to care with something like self-sampling? My personal feeling is I think that we can make a dent in that, and it is never going to fully replace screening, but it at least will allow us to reallocate our resources and attention to those women that are at highest risk for developing cervical cancer or precancer based on the self-sampling result.

I don’t think it will ever replace screening per se, but if we have an abnormal self-sampling test, we might say to that patient, “You really do need to come in to get re-tested or to get re-evaluated.” So it could be a better resource and use of our health care dollars and investments in terms of trying to reduce the incidence of cervical cancer. Of course the verdict is out, but I think there are a lot of people who would love to see this scenario.

If we screen and treat perfectly in this country, we would not even need the HPV vaccine when it comes to cervical cancer. That is how effective screening is. But, up to 50% to 60% of women in this country now still are underscreened or unscreened. We were talking about that number almost 25-30 years ago, Dr. Mutch. So access to screening is a big problem, but the other problem is how do you get patients in to be seen if they have an abnormal screening test? It’s not just about screening. It’s about screening, evaluation, and treatment; all 3 components are really important.

Continue to: Where do we stand with HPV vaccination?...

 

 

Where do we stand with HPV vaccination?

Dr. Mutch: Those are great points.

You brought up vaccination. We have a long way to go with regard to that, certainly in the United States, because of the various factions opposed to vaccination and so on. But do you think that vaccination has allowed us to decrease the incidence of cervical cancer?

Dr. Huh: Yes. There is clear evidence from the Nordic countries.⁷ There is emerging evidence from Australia.⁸ There is emerging evidence from other industrialized nations that clearly demonstrate vaccination’s positive effect in reducing the incidence of cervical cancer. None of this should be a surprise. Every population-based study that has been published with the HPV vaccine in populations that have a low frequency of vaccination have demonstrated substantial reductions in things like genital warts, abnormal Pap tests, precancer, and now evidence that there is a downward trend in terms of the incidence of cervical cancer.⁹

I don’t think that there is any debate anymore that vaccination is the way to go. Our challenge is about implementation and getting the vaccine to people. We still have a long way to go with that. There are parts of the world that are so affected by invasive cervical cancers; we need to get the vaccine to those parts of the world.

Dr. Mutch: What are the barriers to vaccination? How can we overcome those barriers?

Dr. Huh: There is a lot of criticism that we are not vaccinating more in the United States. However, the rates of vaccination are going up every single year. The pandemic may have blunted that rise a bit, but if you look at the vaccination curves, they are going up, not down. We need to continue to educate patients, parents, and pediatricians on the importance of vaccination.

Boys still get vaccinated less frequently than girls, so we have some work to do there. I think globally it is the issue of getting the vaccine to people, making sure that vaccine is available. The thing that I think will be the game-changer going forward is whether or not we will have evidence to indicate that 1 dose is as effective as 2 doses or 3 doses. If we can vaccinate boys and girls with just 1 dose, then in the next generation or two, we seriously might eradicate not just cervical cancer but a lot of HPV-related malignancies worldwide.

Educating patients, clinicians is key

Dr. Mutch: So it seems education, education, education, with regard to screening guidelines, with regard to the need for continued examinations, and that HPV testing is only a test, it does not supplant overall care. Finally, education regarding eradication of cervical cancer through vaccination.

Dr. Huh: That summarizes it well. We are still going to screen for cervical cancer. We are still going to vaccinate, and providers are still going to manage abnormal Pap tests. It is confusing because we are changing it up it seems every year or 2, so this conversation you and I are having is particularly important for clinicians to understand the basis of that. There has been an explosion of data that has come out in this area in the last decade.

Dr. Mutch: Thank you, Dr. Huh. I really appreciate your thoughts on this. As you all know, Dr. Huh has been President of the ASCCP and is instrumental in writing and disseminating these guidelines, so we are very grateful that he has consented to agree to come and talk with us today.

Dr. Huh: My pleasure. Thank you for inviting me. This was fun, and I have really enjoyed talking to you and participating. ●

ILLUSTRATION BY KIMBERLY MARTENS FOR OBG MANAGEMENT

David G. Mutch, MD: The cervical cancer screening guidelines, using Pap testing, have changed significantly since the times of yearly Paps and exams. Coupled with vaccination and new management guidelines (recommending HPV testing, etc), we actually hope that we are on the way to eradicating cervical cancer from our environment.

Screening: Current recommendations

Dr. Mutch: Warner, the American Society of Colposcopy and Cervical Pathology (ASCCP)¹ endorses the cervical cancer screening guidelines for several professional organizations, including the American Cancer Society (ACS),² the US Preventive Services Task Force (USPSTF),³ and the American College of Obstetricians and Gynecologists (ACOG).⁴ What are the current screening recommendations, as these organizations have disparate views?

Warner Huh, MD: There was a time, around 2012-2013, when for the first time ever, we had significant harmonization of the guidelines between ACOG and the USPSTF and ACS. But in the last 10 years there has been an explosion of data in terms of how to best screen patients.

The move to primary HPV testing. The USPSTF³ initially had recommended looking into primary HPV screening, which is just using HPV testing by itself as the screening modality. But there was a lot of pushback at that time. I think a lot of people thought that we were not prepared to make that leap. Therefore, they endorsed screening with cytology by itself as well as HPV testing by itself, as well as co-testing; but in their recommendations, they made it very clear that they were leaning toward primary HPV screening.

A new patient age to begin screening. In 2020, the ACS put out their new guidelines,² which are a significant departure from what we are used to—they are recommending that we start screening at 25 years of age. Like you said, Dr. Mutch, it doesn’t seem that long ago when we were screening people at age 18, or within 3 years of sexual intercourse. But the reason for it is that the rate of cervical cancer is extremely low under age 25, and other countries like the United Kingdom already do this.

The other major departure in the ACS guidelines is that they really are asking clinicians and screeners to focus on primary HPV screening. Overall, they have sort of doubled down on why they think primary HPV screening is so important.

ACOG sits sort of in the middle of the other recommendations. ACOG understands the value of primary HPV screening, but I don’t think that they are quite ready to recommend screening at age 25. If you look at their updated guidelines from April 2021,⁴ they state that we should continue a screening-starting age of 21 years. So there are some disparate views, but I am confident, Dr. Mutch, that in the next 2 to 3 years, there will be greater harmonization of these guidelines and less confusion for our providers. The greatest barrier is understanding the science and the comfort level of clinicians to go with just an HPV test, since for the last 40 years the Pap test has anchored gynecologic care in this country. And it took at least 10 years to get to what I consider to be widespread adoption to co-testing. The other thing that readers should recognize is that the Task Force is actually revisiting their cervical cancer screening guidance now, so expect another major revision.

Reimbursement and access are barriers. Reimbursement is a further real issue. We are now using one less test, but insurance companies may not reimburse when just the HPV test is used. The other issue is access to labs that can do the HPV testing.

Dr. Mutch: We used to see patients yearly and picked up a lot of adjunctive or additional illnesses. Now they are not being seen yearly it could impact negatively their overall health care. We need to understand that cervical cancer screening is simply a test, which should not eliminate other health care.

Dr. Huh: Yes, I think the extended interval between recommended HPV screenings scares people. I have been involved in these screening guidelines (and I can only speak for myself, not for my colleagues), but even I do think we made a leap to a longer interval way too quickly in this country. Screening changes are slow, and sometimes a glacial process. I think it can worry providers when we make rapid changes.

But this is a test that should not anchor the yearly visit. There are plenty of other reasons—and ACOG actually states this⁴—why patients should come for a wellness exam on a yearly basis. So I think our ObGyns in the United States need to recognize that, but I understand there are underlying concerns that if you extend intervals too long, (a) will patients come back, and (b), as a consequence, is the interval going to miss something in between? Those are real legitimate concerns.

Continue to: Management guidelines...

 

 

Management guidelines: The latest

Dr. Mutch: The ASCCP issued new management guidelines in 2019.⁵ Can you address what you feel are the most important updates?

Dr. Huh: Going back to 2002, we have revised these guidelines every 5 years. For this one, the revision came out a little bit later for various reasons, but the reason we revised it is because we collect new data that we think markedly changes our understanding of the disease process and natural history and the interventions for women that have preinvasive disease of the cervix.

Briefly, I think the biggest changes based on what we were hearing from our providers and users of our apps and algorithms was that our algorithms were becoming way too complicated, and they were. If you look over the last 10 years, the number of branch points on our algorithms basically quadrupled. If we incorporated the new data this time, the algorithms would be unworkable, and you could not use them on your phone because they would be too complicated.

So, we created a system where, in essence, providers have 5 choices for patients:

• treatment
• colposcopy
• follow-up in 1 year
• follow-up in 3 years
• follow-up in 5 years.

Those recommendations are based on what we call “clinically actionable thresholds”—basically, the percent chance of developing immediate CIN3 or worse. That threshold will probably change over time, but what we did is create a system that (a) makes it easier for the provider, (although they have to trust the system—and they can look under the hood and understand how we did this) and (b) allows us to create a foundation where we can add future technologies that use the same rubric or paradigm so that they still wind up getting the same result without having to go to another algorithm.

This new system is probably the most marked change in the history of the ASCCP management guidelines, but we did it to make it ultimately easier for providers going forward for the next 10 to 20 years. There are real opportunities, Dr. Mutch, in terms of how do we integrate this into the electronic medical record (EMR), and how do we pull data so clinicians don’t have to manually enter it.

The other difference is now there is a web-based application. Back in 2012, there were a lot of people that were not using EMRs. Now the majority of the country is, and so they actually are on a browser more than they are on their phone. We actually have an equally robust web platform that allows them to get the information that they need.

Dr. Mutch: I think that is really important—the utility of utilizing a mobile app, if you will, for triaging your patient with a specific test result so that patients are followed up at the proper interval, and that ultimately becomes cost-effective.

Dr. Huh: Yes, the app now is very different than the app that I think people are used to using for the last almost 10 years. You don’t put inputs, pull up the algorithm, and look at the outcome. This is different. You enter the patient’s age. You add their cytology, their HPV results, the clinical scenario that you are in, and then it puts out a recommendation of what to do next. Over time, we want to get away from an algorithm and for our providers to understand what the risk is and how that risk calculation then translates into a clinical recommendation.

Dr. Mutch: I think to utilize an app is almost necessary given the complexity of the triaging process so that it does become, in fact, the most cost-effective way to screen patients.

Dr. Huh: I would agree with that. There is a learning curve for whenever you see new technology. There was a learning curve for even ASCCP leadership as they tried to educate providers. I think people will ultimately see that this is a much better way of managing patients with cervical abnormalities, and I am hoping actually that we will use a similar platform for many other diseases that we manage in women’s health.

Continue to: Chipping away of the yearly exam...

 

 

Chipping away of the yearly exam

Dr. Mutch: With this moving away from the yearly exam and Pap test, women may not get yearly examinations. Do you feel that this could affect a stage migration to a higher stage at diagnosis, for instance, of a cervical cancer? Or that it might adversely impact other health issues?

Dr. Huh: I think that’s a good question. I am worried about the interval—I think 5 years is a bit long. I am more worried that patients will miss out on visits because they may think that they need to only come back for their Pap, even though they should be re-educated on that.

COVID-19 has made this a little hard for us to analyze because, clearly, we have had access to care issues. But I am a little concerned that we could see an uptick in invasive cancer rates in this country, including an uptick in the stage and more locally advanced cervical cancer because of the changes in the screening paradigms. But we don’t know that to be the case.

As with all screenings, the bottom line is you have to worry about what the false-negative and false-positive rates of screening are, and that affects everything. I want the readers to know that primary HPV should be used for screenings. It is not perfect, but it is much better than cytology alone. We need to think about how to better adapt screening in the age that we live in.

HPV self-sampling

Dr. Mutch: Could self-sampling for HPV testing, which obviously would be easier for the patient, and certainly useful in terms of screening, address some health care disparities with regard to cervical cancer?

Dr. Huh: The short answer is, yes. Self-sampling is not US Food and Drug Administration-approved in this country. It’s not being widely used without that approval. But there are multiple countries, including the United States, that have done lots of studies on this topic. There are many public health experts and champions for HPV self-sampling. I think we have learned, based on some studies, that the sensitivity is reasonable.⁶

I live in a part of the country that is woefully underserved; where you are there are pockets in Missouri that are woefully underserved as well. So the issue is, can we reduce these disparities and access to care with something like self-sampling? My personal feeling is I think that we can make a dent in that, and it is never going to fully replace screening, but it at least will allow us to reallocate our resources and attention to those women that are at highest risk for developing cervical cancer or precancer based on the self-sampling result.

I don’t think it will ever replace screening per se, but if we have an abnormal self-sampling test, we might say to that patient, “You really do need to come in to get re-tested or to get re-evaluated.” So it could be a better resource and use of our health care dollars and investments in terms of trying to reduce the incidence of cervical cancer. Of course the verdict is out, but I think there are a lot of people who would love to see this scenario.

If we screen and treat perfectly in this country, we would not even need the HPV vaccine when it comes to cervical cancer. That is how effective screening is. But, up to 50% to 60% of women in this country now still are underscreened or unscreened. We were talking about that number almost 25-30 years ago, Dr. Mutch. So access to screening is a big problem, but the other problem is how do you get patients in to be seen if they have an abnormal screening test? It’s not just about screening. It’s about screening, evaluation, and treatment; all 3 components are really important.

Continue to: Where do we stand with HPV vaccination?...

 

 

Where do we stand with HPV vaccination?

Dr. Mutch: Those are great points.

You brought up vaccination. We have a long way to go with regard to that, certainly in the United States, because of the various factions opposed to vaccination and so on. But do you think that vaccination has allowed us to decrease the incidence of cervical cancer?

Dr. Huh: Yes. There is clear evidence from the Nordic countries.⁷ There is emerging evidence from Australia.⁸ There is emerging evidence from other industrialized nations that clearly demonstrate vaccination’s positive effect in reducing the incidence of cervical cancer. None of this should be a surprise. Every population-based study that has been published with the HPV vaccine in populations that have a low frequency of vaccination have demonstrated substantial reductions in things like genital warts, abnormal Pap tests, precancer, and now evidence that there is a downward trend in terms of the incidence of cervical cancer.⁹

I don’t think that there is any debate anymore that vaccination is the way to go. Our challenge is about implementation and getting the vaccine to people. We still have a long way to go with that. There are parts of the world that are so affected by invasive cervical cancers; we need to get the vaccine to those parts of the world.

Dr. Mutch: What are the barriers to vaccination? How can we overcome those barriers?

Dr. Huh: There is a lot of criticism that we are not vaccinating more in the United States. However, the rates of vaccination are going up every single year. The pandemic may have blunted that rise a bit, but if you look at the vaccination curves, they are going up, not down. We need to continue to educate patients, parents, and pediatricians on the importance of vaccination.

Boys still get vaccinated less frequently than girls, so we have some work to do there. I think globally it is the issue of getting the vaccine to people, making sure that vaccine is available. The thing that I think will be the game-changer going forward is whether or not we will have evidence to indicate that 1 dose is as effective as 2 doses or 3 doses. If we can vaccinate boys and girls with just 1 dose, then in the next generation or two, we seriously might eradicate not just cervical cancer but a lot of HPV-related malignancies worldwide.

Educating patients, clinicians is key

Dr. Mutch: So it seems education, education, education, with regard to screening guidelines, with regard to the need for continued examinations, and that HPV testing is only a test, it does not supplant overall care. Finally, education regarding eradication of cervical cancer through vaccination.

Dr. Huh: That summarizes it well. We are still going to screen for cervical cancer. We are still going to vaccinate, and providers are still going to manage abnormal Pap tests. It is confusing because we are changing it up it seems every year or 2, so this conversation you and I are having is particularly important for clinicians to understand the basis of that. There has been an explosion of data that has come out in this area in the last decade.

Dr. Mutch: Thank you, Dr. Huh. I really appreciate your thoughts on this. As you all know, Dr. Huh has been President of the ASCCP and is instrumental in writing and disseminating these guidelines, so we are very grateful that he has consented to agree to come and talk with us today.

Dr. Huh: My pleasure. Thank you for inviting me. This was fun, and I have really enjoyed talking to you and participating. ●

ILLUSTRATION BY KIMBERLY MARTENS FOR OBG MANAGEMENT

David G. Mutch, MD: The cervical cancer screening guidelines, using Pap testing, have changed significantly since the times of yearly Paps and exams. Coupled with vaccination and new management guidelines (recommending HPV testing, etc), we actually hope that we are on the way to eradicating cervical cancer from our environment.

Screening: Current recommendations

Dr. Mutch: Warner, the American Society of Colposcopy and Cervical Pathology (ASCCP)¹ endorses the cervical cancer screening guidelines for several professional organizations, including the American Cancer Society (ACS),² the US Preventive Services Task Force (USPSTF),³ and the American College of Obstetricians and Gynecologists (ACOG).⁴ What are the current screening recommendations, as these organizations have disparate views?

Warner Huh, MD: There was a time, around 2012-2013, when for the first time ever, we had significant harmonization of the guidelines between ACOG and the USPSTF and ACS. But in the last 10 years there has been an explosion of data in terms of how to best screen patients.

The move to primary HPV testing. The USPSTF³ initially had recommended looking into primary HPV screening, which is just using HPV testing by itself as the screening modality. But there was a lot of pushback at that time. I think a lot of people thought that we were not prepared to make that leap. Therefore, they endorsed screening with cytology by itself as well as HPV testing by itself, as well as co-testing; but in their recommendations, they made it very clear that they were leaning toward primary HPV screening.

A new patient age to begin screening. In 2020, the ACS put out their new guidelines,² which are a significant departure from what we are used to—they are recommending that we start screening at 25 years of age. Like you said, Dr. Mutch, it doesn’t seem that long ago when we were screening people at age 18, or within 3 years of sexual intercourse. But the reason for it is that the rate of cervical cancer is extremely low under age 25, and other countries like the United Kingdom already do this.

The other major departure in the ACS guidelines is that they really are asking clinicians and screeners to focus on primary HPV screening. Overall, they have sort of doubled down on why they think primary HPV screening is so important.

ACOG sits sort of in the middle of the other recommendations. ACOG understands the value of primary HPV screening, but I don’t think that they are quite ready to recommend screening at age 25. If you look at their updated guidelines from April 2021,⁴ they state that we should continue a screening-starting age of 21 years. So there are some disparate views, but I am confident, Dr. Mutch, that in the next 2 to 3 years, there will be greater harmonization of these guidelines and less confusion for our providers. The greatest barrier is understanding the science and the comfort level of clinicians to go with just an HPV test, since for the last 40 years the Pap test has anchored gynecologic care in this country. And it took at least 10 years to get to what I consider to be widespread adoption to co-testing. The other thing that readers should recognize is that the Task Force is actually revisiting their cervical cancer screening guidance now, so expect another major revision.

Reimbursement and access are barriers. Reimbursement is a further real issue. We are now using one less test, but insurance companies may not reimburse when just the HPV test is used. The other issue is access to labs that can do the HPV testing.

Dr. Mutch: We used to see patients yearly and picked up a lot of adjunctive or additional illnesses. Now they are not being seen yearly it could impact negatively their overall health care. We need to understand that cervical cancer screening is simply a test, which should not eliminate other health care.

Dr. Huh: Yes, I think the extended interval between recommended HPV screenings scares people. I have been involved in these screening guidelines (and I can only speak for myself, not for my colleagues), but even I do think we made a leap to a longer interval way too quickly in this country. Screening changes are slow, and sometimes a glacial process. I think it can worry providers when we make rapid changes.

But this is a test that should not anchor the yearly visit. There are plenty of other reasons—and ACOG actually states this⁴—why patients should come for a wellness exam on a yearly basis. So I think our ObGyns in the United States need to recognize that, but I understand there are underlying concerns that if you extend intervals too long, (a) will patients come back, and (b), as a consequence, is the interval going to miss something in between? Those are real legitimate concerns.

Continue to: Management guidelines...

 

 

Management guidelines: The latest

Dr. Mutch: The ASCCP issued new management guidelines in 2019.⁵ Can you address what you feel are the most important updates?

Dr. Huh: Going back to 2002, we have revised these guidelines every 5 years. For this one, the revision came out a little bit later for various reasons, but the reason we revised it is because we collect new data that we think markedly changes our understanding of the disease process and natural history and the interventions for women that have preinvasive disease of the cervix.

Briefly, I think the biggest changes based on what we were hearing from our providers and users of our apps and algorithms was that our algorithms were becoming way too complicated, and they were. If you look over the last 10 years, the number of branch points on our algorithms basically quadrupled. If we incorporated the new data this time, the algorithms would be unworkable, and you could not use them on your phone because they would be too complicated.

So, we created a system where, in essence, providers have 5 choices for patients:

• treatment
• colposcopy
• follow-up in 1 year
• follow-up in 3 years
• follow-up in 5 years.

Those recommendations are based on what we call “clinically actionable thresholds”—basically, the percent chance of developing immediate CIN3 or worse. That threshold will probably change over time, but what we did is create a system that (a) makes it easier for the provider, (although they have to trust the system—and they can look under the hood and understand how we did this) and (b) allows us to create a foundation where we can add future technologies that use the same rubric or paradigm so that they still wind up getting the same result without having to go to another algorithm.

This new system is probably the most marked change in the history of the ASCCP management guidelines, but we did it to make it ultimately easier for providers going forward for the next 10 to 20 years. There are real opportunities, Dr. Mutch, in terms of how do we integrate this into the electronic medical record (EMR), and how do we pull data so clinicians don’t have to manually enter it.

The other difference is now there is a web-based application. Back in 2012, there were a lot of people that were not using EMRs. Now the majority of the country is, and so they actually are on a browser more than they are on their phone. We actually have an equally robust web platform that allows them to get the information that they need.

Dr. Mutch: I think that is really important—the utility of utilizing a mobile app, if you will, for triaging your patient with a specific test result so that patients are followed up at the proper interval, and that ultimately becomes cost-effective.

Dr. Huh: Yes, the app now is very different than the app that I think people are used to using for the last almost 10 years. You don’t put inputs, pull up the algorithm, and look at the outcome. This is different. You enter the patient’s age. You add their cytology, their HPV results, the clinical scenario that you are in, and then it puts out a recommendation of what to do next. Over time, we want to get away from an algorithm and for our providers to understand what the risk is and how that risk calculation then translates into a clinical recommendation.

Dr. Mutch: I think to utilize an app is almost necessary given the complexity of the triaging process so that it does become, in fact, the most cost-effective way to screen patients.

Dr. Huh: I would agree with that. There is a learning curve for whenever you see new technology. There was a learning curve for even ASCCP leadership as they tried to educate providers. I think people will ultimately see that this is a much better way of managing patients with cervical abnormalities, and I am hoping actually that we will use a similar platform for many other diseases that we manage in women’s health.

Continue to: Chipping away of the yearly exam...

 

 

Chipping away of the yearly exam

Dr. Mutch: With this moving away from the yearly exam and Pap test, women may not get yearly examinations. Do you feel that this could affect a stage migration to a higher stage at diagnosis, for instance, of a cervical cancer? Or that it might adversely impact other health issues?

Dr. Huh: I think that’s a good question. I am worried about the interval—I think 5 years is a bit long. I am more worried that patients will miss out on visits because they may think that they need to only come back for their Pap, even though they should be re-educated on that.

COVID-19 has made this a little hard for us to analyze because, clearly, we have had access to care issues. But I am a little concerned that we could see an uptick in invasive cancer rates in this country, including an uptick in the stage and more locally advanced cervical cancer because of the changes in the screening paradigms. But we don’t know that to be the case.

As with all screenings, the bottom line is you have to worry about what the false-negative and false-positive rates of screening are, and that affects everything. I want the readers to know that primary HPV should be used for screenings. It is not perfect, but it is much better than cytology alone. We need to think about how to better adapt screening in the age that we live in.

HPV self-sampling

Dr. Mutch: Could self-sampling for HPV testing, which obviously would be easier for the patient, and certainly useful in terms of screening, address some health care disparities with regard to cervical cancer?

Dr. Huh: The short answer is, yes. Self-sampling is not US Food and Drug Administration-approved in this country. It’s not being widely used without that approval. But there are multiple countries, including the United States, that have done lots of studies on this topic. There are many public health experts and champions for HPV self-sampling. I think we have learned, based on some studies, that the sensitivity is reasonable.⁶

I live in a part of the country that is woefully underserved; where you are there are pockets in Missouri that are woefully underserved as well. So the issue is, can we reduce these disparities and access to care with something like self-sampling? My personal feeling is I think that we can make a dent in that, and it is never going to fully replace screening, but it at least will allow us to reallocate our resources and attention to those women that are at highest risk for developing cervical cancer or precancer based on the self-sampling result.

I don’t think it will ever replace screening per se, but if we have an abnormal self-sampling test, we might say to that patient, “You really do need to come in to get re-tested or to get re-evaluated.” So it could be a better resource and use of our health care dollars and investments in terms of trying to reduce the incidence of cervical cancer. Of course the verdict is out, but I think there are a lot of people who would love to see this scenario.

If we screen and treat perfectly in this country, we would not even need the HPV vaccine when it comes to cervical cancer. That is how effective screening is. But, up to 50% to 60% of women in this country now still are underscreened or unscreened. We were talking about that number almost 25-30 years ago, Dr. Mutch. So access to screening is a big problem, but the other problem is how do you get patients in to be seen if they have an abnormal screening test? It’s not just about screening. It’s about screening, evaluation, and treatment; all 3 components are really important.

Continue to: Where do we stand with HPV vaccination?...

 

 

Where do we stand with HPV vaccination?

Dr. Mutch: Those are great points.

You brought up vaccination. We have a long way to go with regard to that, certainly in the United States, because of the various factions opposed to vaccination and so on. But do you think that vaccination has allowed us to decrease the incidence of cervical cancer?

Dr. Huh: Yes. There is clear evidence from the Nordic countries.⁷ There is emerging evidence from Australia.⁸ There is emerging evidence from other industrialized nations that clearly demonstrate vaccination’s positive effect in reducing the incidence of cervical cancer. None of this should be a surprise. Every population-based study that has been published with the HPV vaccine in populations that have a low frequency of vaccination have demonstrated substantial reductions in things like genital warts, abnormal Pap tests, precancer, and now evidence that there is a downward trend in terms of the incidence of cervical cancer.⁹

I don’t think that there is any debate anymore that vaccination is the way to go. Our challenge is about implementation and getting the vaccine to people. We still have a long way to go with that. There are parts of the world that are so affected by invasive cervical cancers; we need to get the vaccine to those parts of the world.

Dr. Mutch: What are the barriers to vaccination? How can we overcome those barriers?

Dr. Huh: There is a lot of criticism that we are not vaccinating more in the United States. However, the rates of vaccination are going up every single year. The pandemic may have blunted that rise a bit, but if you look at the vaccination curves, they are going up, not down. We need to continue to educate patients, parents, and pediatricians on the importance of vaccination.

Boys still get vaccinated less frequently than girls, so we have some work to do there. I think globally it is the issue of getting the vaccine to people, making sure that vaccine is available. The thing that I think will be the game-changer going forward is whether or not we will have evidence to indicate that 1 dose is as effective as 2 doses or 3 doses. If we can vaccinate boys and girls with just 1 dose, then in the next generation or two, we seriously might eradicate not just cervical cancer but a lot of HPV-related malignancies worldwide.

Educating patients, clinicians is key

Dr. Mutch: So it seems education, education, education, with regard to screening guidelines, with regard to the need for continued examinations, and that HPV testing is only a test, it does not supplant overall care. Finally, education regarding eradication of cervical cancer through vaccination.

Dr. Huh: That summarizes it well. We are still going to screen for cervical cancer. We are still going to vaccinate, and providers are still going to manage abnormal Pap tests. It is confusing because we are changing it up it seems every year or 2, so this conversation you and I are having is particularly important for clinicians to understand the basis of that. There has been an explosion of data that has come out in this area in the last decade.

Dr. Mutch: Thank you, Dr. Huh. I really appreciate your thoughts on this. As you all know, Dr. Huh has been President of the ASCCP and is instrumental in writing and disseminating these guidelines, so we are very grateful that he has consented to agree to come and talk with us today.

Dr. Huh: My pleasure. Thank you for inviting me. This was fun, and I have really enjoyed talking to you and participating. ●

Children who have greater acute appendicitis pain may be less likely to improve if they’re treated with antibiotics alone, according to a secondary analysis of a nonrandomized clinical trial.

“While approximately 35% of families chose nonoperative management, a high pain score between 7-10 on a 10-point scale nearly doubled in-hospital treatment failure,” Rebecca M. Rentea, MD, a pediatric surgeon and the director of the Comprehensive Colorectal Center at Children’s Mercy Kansas City, Mo., told this news organization in an email.

“Even if nonoperative management of pediatric appendicitis did not work – resulting in the need to remove the appendix in 34% of cases – families were happy with their decisions 1 year later,” added Dr. Rentea, who coauthored an invited commentary about the study.

Lead study author Peter C. Minneci, MD, MHSc, a pediatric surgeon at Nationwide Children’s Hospital, Columbus, Ohio, and colleagues analyzed a subgroup of patients from a larger study in 10 tertiary children’s hospitals in the Midwest Pediatric Surgery Consortium.

As they reported in JAMA Network Open, the larger prospective, nonrandomized clinical trial enrolled 1,068 children between 2015 and 2018. The children ranged in age from 7 to 17 years, and they had imaging-confirmed appendicitis with an appendix diameter of 1.1 cm or less, no abscess, no appendicolith, and no phlegmon. White blood cell count was between 5,000 and 18,000 cells/μL, and abdominal pain began less than 48 hours before they received antibiotic therapy.

Caregivers chose either surgery or nonoperative antibiotic management. Patients who were treated first with antibiotics alone and who did not undergo appendectomy within 1 year were considered to have successfully completed nonoperative treatment.

The secondary analysis included the 370 children enrolled in the nonoperative group. Of these, 229 were boys, and the median age was 12.3 years. In this subgroup, the researchers compared outcomes after nonoperative, antibiotic management vs. surgery.

At 1 year, treatment failure had occurred in 125 patients, with 53 having undergone appendectomy during their first hospitalization, and 72 having experienced delayed treatment failure after being discharged.

• Higher patient-reported pain at presentation was linked to higher risk for in-hospital treatment failure (relative risk, 2.1; 95% confidence interval, 1.0-4.4) but not for delayed treatment failure (RR, 1.3; 95% CI, 0.7-2.3) or overall treatment failure at 1 year (RR, 1.5; 95% CI, 1.0-2.2).
• Pain lasting longer than 24 hours was linked to lower risk for delayed treatment failure (RR, 0.3; 95% CI, 0.1-1.0) but not for in-hospital treatment failure (RR, 1.2; 95% CI, 0.5-2.7) or treatment failure at 1 year (RR, 0.7; 95% CI, 0.4-1.2).
• Satisfaction with the decision was higher with successful nonoperative management at 30 days (28.0 vs. 27.0; difference, 1.0; 95% CI, 0.01-2.0) and at 1 year (28.1 vs 27.0; difference, 1.1; 95% CI, 0.2-2.0).

The researchers found no increased risk for treatment failure based on age, sex, race, ethnicity, white blood cell count, primary language, insurance status, transfer status, presentation symptoms, or imaging results.

Antibiotics-only is a safe option for children

“This study suggests that pediatric patients with uncomplicated acute appendicitis should be offered treatment options, including nonoperative management,” the authors write. “Treatment with antibiotics alone is a safe and equitable option for children, with no increased risk of treatment failure based on sociodemographic or objective clinical characteristics at presentation.”

But, the authors advise: “Families need to be made aware that treatment failure is not uncommon, and they should be provided with anticipatory guidance on how to proceed should symptoms recur.”

The investigators acknowledged limitations to the study, including the nonrandomized design that may have introduced bias, the loss to follow-up, and the study population being U.S. Midwest children, who may differ from children elsewhere in the country.

Shawn D. St Peter, MD, a pediatric surgeon, medical chair, and a senior vice president at Children’s Mercy Kansas City told this news organization in an email that having a nonoperative alternative to surgical appendectomy is important.

“Antibiotics are the initial treatment for appendicitis and can be the definitive treatment,” he said.

“Surprisingly, no sociodemographic or clinical characteristics were associated with an increased risk of nonoperative appendicitis treatment failure,” added Dr. St Peter, who coauthored the commentary with Dr. Rentea.

Howard C. Jen, MD, a pediatric surgeon at University of California, Los Angeles, Mattel Children’s Hospital, was not surprised by the findings.

“Nonoperative management for acute noncomplicated appendicitis in children continues to be safe and effective in highly selected patients,” he said in an email. “This alternative to surgery should be offered routinely to patients with early acute appendicitis.” 

Dr. Jen, who was not involved with the current study, noted that it did not address the impact and costs to families of nonoperative management vs. surgery.

“For the most vulnerable children who had difficulties accessing medical care, what is the best treatment option? What factors are important to the families when making this decision?” he asked.

All study and editorial authors report no relevant financial relationships. The study was funded by the Patient-Centered Outcomes Research Institute and the National Center for Advancing Translational Sciences.

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

Children who have greater acute appendicitis pain may be less likely to improve if they’re treated with antibiotics alone, according to a secondary analysis of a nonrandomized clinical trial.

“While approximately 35% of families chose nonoperative management, a high pain score between 7-10 on a 10-point scale nearly doubled in-hospital treatment failure,” Rebecca M. Rentea, MD, a pediatric surgeon and the director of the Comprehensive Colorectal Center at Children’s Mercy Kansas City, Mo., told this news organization in an email.

“Even if nonoperative management of pediatric appendicitis did not work – resulting in the need to remove the appendix in 34% of cases – families were happy with their decisions 1 year later,” added Dr. Rentea, who coauthored an invited commentary about the study.

Lead study author Peter C. Minneci, MD, MHSc, a pediatric surgeon at Nationwide Children’s Hospital, Columbus, Ohio, and colleagues analyzed a subgroup of patients from a larger study in 10 tertiary children’s hospitals in the Midwest Pediatric Surgery Consortium.

As they reported in JAMA Network Open, the larger prospective, nonrandomized clinical trial enrolled 1,068 children between 2015 and 2018. The children ranged in age from 7 to 17 years, and they had imaging-confirmed appendicitis with an appendix diameter of 1.1 cm or less, no abscess, no appendicolith, and no phlegmon. White blood cell count was between 5,000 and 18,000 cells/μL, and abdominal pain began less than 48 hours before they received antibiotic therapy.

Caregivers chose either surgery or nonoperative antibiotic management. Patients who were treated first with antibiotics alone and who did not undergo appendectomy within 1 year were considered to have successfully completed nonoperative treatment.

The secondary analysis included the 370 children enrolled in the nonoperative group. Of these, 229 were boys, and the median age was 12.3 years. In this subgroup, the researchers compared outcomes after nonoperative, antibiotic management vs. surgery.

At 1 year, treatment failure had occurred in 125 patients, with 53 having undergone appendectomy during their first hospitalization, and 72 having experienced delayed treatment failure after being discharged.

• Higher patient-reported pain at presentation was linked to higher risk for in-hospital treatment failure (relative risk, 2.1; 95% confidence interval, 1.0-4.4) but not for delayed treatment failure (RR, 1.3; 95% CI, 0.7-2.3) or overall treatment failure at 1 year (RR, 1.5; 95% CI, 1.0-2.2).
• Pain lasting longer than 24 hours was linked to lower risk for delayed treatment failure (RR, 0.3; 95% CI, 0.1-1.0) but not for in-hospital treatment failure (RR, 1.2; 95% CI, 0.5-2.7) or treatment failure at 1 year (RR, 0.7; 95% CI, 0.4-1.2).
• Satisfaction with the decision was higher with successful nonoperative management at 30 days (28.0 vs. 27.0; difference, 1.0; 95% CI, 0.01-2.0) and at 1 year (28.1 vs 27.0; difference, 1.1; 95% CI, 0.2-2.0).

The researchers found no increased risk for treatment failure based on age, sex, race, ethnicity, white blood cell count, primary language, insurance status, transfer status, presentation symptoms, or imaging results.

Antibiotics-only is a safe option for children

“This study suggests that pediatric patients with uncomplicated acute appendicitis should be offered treatment options, including nonoperative management,” the authors write. “Treatment with antibiotics alone is a safe and equitable option for children, with no increased risk of treatment failure based on sociodemographic or objective clinical characteristics at presentation.”

But, the authors advise: “Families need to be made aware that treatment failure is not uncommon, and they should be provided with anticipatory guidance on how to proceed should symptoms recur.”

The investigators acknowledged limitations to the study, including the nonrandomized design that may have introduced bias, the loss to follow-up, and the study population being U.S. Midwest children, who may differ from children elsewhere in the country.

Shawn D. St Peter, MD, a pediatric surgeon, medical chair, and a senior vice president at Children’s Mercy Kansas City told this news organization in an email that having a nonoperative alternative to surgical appendectomy is important.

“Antibiotics are the initial treatment for appendicitis and can be the definitive treatment,” he said.

“Surprisingly, no sociodemographic or clinical characteristics were associated with an increased risk of nonoperative appendicitis treatment failure,” added Dr. St Peter, who coauthored the commentary with Dr. Rentea.

Howard C. Jen, MD, a pediatric surgeon at University of California, Los Angeles, Mattel Children’s Hospital, was not surprised by the findings.

“Nonoperative management for acute noncomplicated appendicitis in children continues to be safe and effective in highly selected patients,” he said in an email. “This alternative to surgery should be offered routinely to patients with early acute appendicitis.” 

Dr. Jen, who was not involved with the current study, noted that it did not address the impact and costs to families of nonoperative management vs. surgery.

“For the most vulnerable children who had difficulties accessing medical care, what is the best treatment option? What factors are important to the families when making this decision?” he asked.

All study and editorial authors report no relevant financial relationships. The study was funded by the Patient-Centered Outcomes Research Institute and the National Center for Advancing Translational Sciences.

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

Children who have greater acute appendicitis pain may be less likely to improve if they’re treated with antibiotics alone, according to a secondary analysis of a nonrandomized clinical trial.

“While approximately 35% of families chose nonoperative management, a high pain score between 7-10 on a 10-point scale nearly doubled in-hospital treatment failure,” Rebecca M. Rentea, MD, a pediatric surgeon and the director of the Comprehensive Colorectal Center at Children’s Mercy Kansas City, Mo., told this news organization in an email.

“Even if nonoperative management of pediatric appendicitis did not work – resulting in the need to remove the appendix in 34% of cases – families were happy with their decisions 1 year later,” added Dr. Rentea, who coauthored an invited commentary about the study.

Lead study author Peter C. Minneci, MD, MHSc, a pediatric surgeon at Nationwide Children’s Hospital, Columbus, Ohio, and colleagues analyzed a subgroup of patients from a larger study in 10 tertiary children’s hospitals in the Midwest Pediatric Surgery Consortium.

As they reported in JAMA Network Open, the larger prospective, nonrandomized clinical trial enrolled 1,068 children between 2015 and 2018. The children ranged in age from 7 to 17 years, and they had imaging-confirmed appendicitis with an appendix diameter of 1.1 cm or less, no abscess, no appendicolith, and no phlegmon. White blood cell count was between 5,000 and 18,000 cells/μL, and abdominal pain began less than 48 hours before they received antibiotic therapy.

Caregivers chose either surgery or nonoperative antibiotic management. Patients who were treated first with antibiotics alone and who did not undergo appendectomy within 1 year were considered to have successfully completed nonoperative treatment.

The secondary analysis included the 370 children enrolled in the nonoperative group. Of these, 229 were boys, and the median age was 12.3 years. In this subgroup, the researchers compared outcomes after nonoperative, antibiotic management vs. surgery.

At 1 year, treatment failure had occurred in 125 patients, with 53 having undergone appendectomy during their first hospitalization, and 72 having experienced delayed treatment failure after being discharged.

• Higher patient-reported pain at presentation was linked to higher risk for in-hospital treatment failure (relative risk, 2.1; 95% confidence interval, 1.0-4.4) but not for delayed treatment failure (RR, 1.3; 95% CI, 0.7-2.3) or overall treatment failure at 1 year (RR, 1.5; 95% CI, 1.0-2.2).
• Pain lasting longer than 24 hours was linked to lower risk for delayed treatment failure (RR, 0.3; 95% CI, 0.1-1.0) but not for in-hospital treatment failure (RR, 1.2; 95% CI, 0.5-2.7) or treatment failure at 1 year (RR, 0.7; 95% CI, 0.4-1.2).
• Satisfaction with the decision was higher with successful nonoperative management at 30 days (28.0 vs. 27.0; difference, 1.0; 95% CI, 0.01-2.0) and at 1 year (28.1 vs 27.0; difference, 1.1; 95% CI, 0.2-2.0).

The researchers found no increased risk for treatment failure based on age, sex, race, ethnicity, white blood cell count, primary language, insurance status, transfer status, presentation symptoms, or imaging results.

Antibiotics-only is a safe option for children

“This study suggests that pediatric patients with uncomplicated acute appendicitis should be offered treatment options, including nonoperative management,” the authors write. “Treatment with antibiotics alone is a safe and equitable option for children, with no increased risk of treatment failure based on sociodemographic or objective clinical characteristics at presentation.”

But, the authors advise: “Families need to be made aware that treatment failure is not uncommon, and they should be provided with anticipatory guidance on how to proceed should symptoms recur.”

The investigators acknowledged limitations to the study, including the nonrandomized design that may have introduced bias, the loss to follow-up, and the study population being U.S. Midwest children, who may differ from children elsewhere in the country.

Shawn D. St Peter, MD, a pediatric surgeon, medical chair, and a senior vice president at Children’s Mercy Kansas City told this news organization in an email that having a nonoperative alternative to surgical appendectomy is important.

“Antibiotics are the initial treatment for appendicitis and can be the definitive treatment,” he said.

“Surprisingly, no sociodemographic or clinical characteristics were associated with an increased risk of nonoperative appendicitis treatment failure,” added Dr. St Peter, who coauthored the commentary with Dr. Rentea.

Howard C. Jen, MD, a pediatric surgeon at University of California, Los Angeles, Mattel Children’s Hospital, was not surprised by the findings.

“Nonoperative management for acute noncomplicated appendicitis in children continues to be safe and effective in highly selected patients,” he said in an email. “This alternative to surgery should be offered routinely to patients with early acute appendicitis.” 

Dr. Jen, who was not involved with the current study, noted that it did not address the impact and costs to families of nonoperative management vs. surgery.

“For the most vulnerable children who had difficulties accessing medical care, what is the best treatment option? What factors are important to the families when making this decision?” he asked.

All study and editorial authors report no relevant financial relationships. The study was funded by the Patient-Centered Outcomes Research Institute and the National Center for Advancing Translational Sciences.

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

Muraca GM, Boutin A, Razaz N, et al. Maternal and neonatal trauma following operative vaginal delivery. CMAJ. 2022;194:E1-E12. doi: 10.1503/cmaj.210841.
 

EXPERT COMMENTARY 

Operative vaginal delivery is used to achieve and expedite safe vaginal birth while avoiding CD and its associated morbidities.^1,2 Despite support from the American College of Obstetricians and Gynecologists (ACOG) for the use of OVD as an alternative to CD, OVD was used in only 3% of all US births in 2013, a shift from approximately 30% in 1987.^1,3 Reported complications of OVD are biased by the level of experience of the operator, changes in practice, and by misinterpretation of the counterfactual.¹

Outcomes of OVD should be compared with appropriate reference groups, namely, with second-stage CD births rather than with spontaneous vaginal births.⁴ With decreasing rates of OVD, evidence of contemporary data is needed on appropriately compared perinatal outcomes.⁴
 

Details of the study 

Muraca and colleagues conducted an observational cohort study of births in Canada between 2013 and 2019 to assess the incidence of maternal and neonatal trauma following OVD. They used composites defined a priori— stratified by instrument, region, level of obstetric care, and institutional OVD volume. 

Results. Among 1,326,191 live or stillbirths, 2.9% were attempted forceps deliveries and 8.4% were attempted vacuum deliveries. Following forceps delivery, the maternal trauma rate was 25.3% (95% confidence interval [CI], 24.8%–25.7%), and the neonatal trauma rate was 9.6 per 1,000 live births (95% CI, 8.6–10.6). Following vacuum delivery, maternal and neonatal trauma rates were 13.2% (95% CI, 13.0%–13.4%) and 9.6 per 1,000 live births (95% CI, 9.0–10.2), respectively. Maternal trauma was driven by higher order perineal lacerations. Some association was seen between increased forceps volume and decreased maternal trauma rates. 

The authors concluded that in Canada, rates of maternal and neonatal trauma following OVD are higher than previously reported in consensus statements.

Study strengths and limitations

This large contemporary study uniquely stratified perinatal outcomes following OVD. The outcomes are well defined and meaningful, but some limitations affect the generalizability of the findings. 

First, stillbirths were included for the maternal composite outcome, yet the incidence of this within the study population is not reported. Operative vaginal deliveries that involve stillbirths can be complex; a subgroup analysis excluding these would aid in interpretation.

Second, complicated OVDs, including sequential use of forceps and vacuum and OVDs from midpelvic station, were included; ACOG recommends against both these practices in routine circumstances due to known increases in maternal and neonatal morbidity.¹ As such, the inclusion of these OVDs may bias results away from the null. 

Finally, despite discussing the role of episiotomy, the episiotomy rate in this cohort is not reported.

Despite these limitations, the study by Muraca and colleagues is a positive step forward toward understanding the role of OVD in contemporary obstetric practice, and it uniquely ascertains the impact of OVD volume outcomes that previously had been an elusive exposure ●
 

Muraca GM, Boutin A, Razaz N, et al. Maternal and neonatal trauma following operative vaginal delivery. CMAJ. 2022;194:E1-E12. doi: 10.1503/cmaj.210841.
 

EXPERT COMMENTARY 

Operative vaginal delivery is used to achieve and expedite safe vaginal birth while avoiding CD and its associated morbidities.^1,2 Despite support from the American College of Obstetricians and Gynecologists (ACOG) for the use of OVD as an alternative to CD, OVD was used in only 3% of all US births in 2013, a shift from approximately 30% in 1987.^1,3 Reported complications of OVD are biased by the level of experience of the operator, changes in practice, and by misinterpretation of the counterfactual.¹

Outcomes of OVD should be compared with appropriate reference groups, namely, with second-stage CD births rather than with spontaneous vaginal births.⁴ With decreasing rates of OVD, evidence of contemporary data is needed on appropriately compared perinatal outcomes.⁴
 

Details of the study 

Muraca and colleagues conducted an observational cohort study of births in Canada between 2013 and 2019 to assess the incidence of maternal and neonatal trauma following OVD. They used composites defined a priori— stratified by instrument, region, level of obstetric care, and institutional OVD volume. 

Results. Among 1,326,191 live or stillbirths, 2.9% were attempted forceps deliveries and 8.4% were attempted vacuum deliveries. Following forceps delivery, the maternal trauma rate was 25.3% (95% confidence interval [CI], 24.8%–25.7%), and the neonatal trauma rate was 9.6 per 1,000 live births (95% CI, 8.6–10.6). Following vacuum delivery, maternal and neonatal trauma rates were 13.2% (95% CI, 13.0%–13.4%) and 9.6 per 1,000 live births (95% CI, 9.0–10.2), respectively. Maternal trauma was driven by higher order perineal lacerations. Some association was seen between increased forceps volume and decreased maternal trauma rates. 

The authors concluded that in Canada, rates of maternal and neonatal trauma following OVD are higher than previously reported in consensus statements.

Study strengths and limitations

This large contemporary study uniquely stratified perinatal outcomes following OVD. The outcomes are well defined and meaningful, but some limitations affect the generalizability of the findings. 

First, stillbirths were included for the maternal composite outcome, yet the incidence of this within the study population is not reported. Operative vaginal deliveries that involve stillbirths can be complex; a subgroup analysis excluding these would aid in interpretation.

Second, complicated OVDs, including sequential use of forceps and vacuum and OVDs from midpelvic station, were included; ACOG recommends against both these practices in routine circumstances due to known increases in maternal and neonatal morbidity.¹ As such, the inclusion of these OVDs may bias results away from the null. 

Finally, despite discussing the role of episiotomy, the episiotomy rate in this cohort is not reported.

Despite these limitations, the study by Muraca and colleagues is a positive step forward toward understanding the role of OVD in contemporary obstetric practice, and it uniquely ascertains the impact of OVD volume outcomes that previously had been an elusive exposure ●
 

Muraca GM, Boutin A, Razaz N, et al. Maternal and neonatal trauma following operative vaginal delivery. CMAJ. 2022;194:E1-E12. doi: 10.1503/cmaj.210841.
 

EXPERT COMMENTARY 

Operative vaginal delivery is used to achieve and expedite safe vaginal birth while avoiding CD and its associated morbidities.^1,2 Despite support from the American College of Obstetricians and Gynecologists (ACOG) for the use of OVD as an alternative to CD, OVD was used in only 3% of all US births in 2013, a shift from approximately 30% in 1987.^1,3 Reported complications of OVD are biased by the level of experience of the operator, changes in practice, and by misinterpretation of the counterfactual.¹

Outcomes of OVD should be compared with appropriate reference groups, namely, with second-stage CD births rather than with spontaneous vaginal births.⁴ With decreasing rates of OVD, evidence of contemporary data is needed on appropriately compared perinatal outcomes.⁴
 

Details of the study 

Muraca and colleagues conducted an observational cohort study of births in Canada between 2013 and 2019 to assess the incidence of maternal and neonatal trauma following OVD. They used composites defined a priori— stratified by instrument, region, level of obstetric care, and institutional OVD volume. 

Results. Among 1,326,191 live or stillbirths, 2.9% were attempted forceps deliveries and 8.4% were attempted vacuum deliveries. Following forceps delivery, the maternal trauma rate was 25.3% (95% confidence interval [CI], 24.8%–25.7%), and the neonatal trauma rate was 9.6 per 1,000 live births (95% CI, 8.6–10.6). Following vacuum delivery, maternal and neonatal trauma rates were 13.2% (95% CI, 13.0%–13.4%) and 9.6 per 1,000 live births (95% CI, 9.0–10.2), respectively. Maternal trauma was driven by higher order perineal lacerations. Some association was seen between increased forceps volume and decreased maternal trauma rates. 

The authors concluded that in Canada, rates of maternal and neonatal trauma following OVD are higher than previously reported in consensus statements.

Study strengths and limitations

This large contemporary study uniquely stratified perinatal outcomes following OVD. The outcomes are well defined and meaningful, but some limitations affect the generalizability of the findings. 

First, stillbirths were included for the maternal composite outcome, yet the incidence of this within the study population is not reported. Operative vaginal deliveries that involve stillbirths can be complex; a subgroup analysis excluding these would aid in interpretation.

Second, complicated OVDs, including sequential use of forceps and vacuum and OVDs from midpelvic station, were included; ACOG recommends against both these practices in routine circumstances due to known increases in maternal and neonatal morbidity.¹ As such, the inclusion of these OVDs may bias results away from the null. 

Finally, despite discussing the role of episiotomy, the episiotomy rate in this cohort is not reported.

Despite these limitations, the study by Muraca and colleagues is a positive step forward toward understanding the role of OVD in contemporary obstetric practice, and it uniquely ascertains the impact of OVD volume outcomes that previously had been an elusive exposure ●
 

Artificial intelligence (AI) in medicine has shown significant promise, particularly in neuroimaging. AI refers to computer systems designed to perform tasks that normally require human intelligence.¹ Machine learning (ML), a field in which computers learn from data without being specifically programmed, is the AI subset responsible for its success in matching or even surpassing humans in certain tasks.²

Supervised learning, a subset of ML, uses an algorithm with annotated data from which to learn.³ The program will use the characteristics of a training data set to predict a specific outcome or target when exposed to a sample data set of the same type. Unsupervised learning finds naturally occurring patterns or groupings within the data.⁴ With deep learning (DL) algorithms, computers learn the features that optimally represent the data for the problem at hand.⁵ Both ML and DL are meant to emulate neural networks in the brain, giving rise to artificial neural networks composed of nodes structured within input, hidden, and output layers.

The DL neural network differs from a conventional one by having many hidden layers instead of just 1 layer that extracts patterns within the data.⁶ Convolutional neural networks (CNNs) are the most prevalent DL architecture used in medical imaging. CNN’s hidden layers apply convolution and pooling operations to break down an image into features containing the most valuable information. The connecting layer applies high-level reasoning before the output layer provides predictions for the image. This framework has applications within radiology, such as predicting a lesion category or condition from an image, determining whether a specific pixel belongs to background or a target class, and predicting the location of lesions.¹

AI promises to increase efficiency and reduces errors. With increased data processing and image interpretation, AI technology may help radiologists improve the quality of patient care.⁶ This article discusses the current applications and future integration of AI in neuroradiology.

Neuroimaging Applications

AI can improve the quality of neuroimaging and reduce the clinical and systemic loads of other imaging modalities. AI can predict patient wait times for computed tomography (CT), magnetic resonance imaging (MRI), ultrasound, and X-ray imaging.⁷ A ML-based AI has detected the variables that most affected patient wait times, including proximity to federal holidays and severity of the patient’s condition, and calculated how long patients would be delayed after their scheduled appointment time. This AI modality could allow more efficient patient scheduling and reveal areas of patient processing that could be changed, potentially improving patient satisfaction and outcomes for time-sensitive neurologic conditions.

AI can save patient and health care practitioner time for repeat MRIs. An estimated 20% of MRI scans require a repeat series—a massive loss of time and funds for both patients and the health care system.⁸ A DL approach can determine whether an MRI is usable clinically or unclear enough to require repetition.⁹ This initial screening measure can prevent patients from making return visits and neuroradiologists from reading inconclusive images. AI offers the opportunity to reduce time and costs incurred by optimizing the health care process before imaging is obtained.

Speeding Up Neuroimaging

AI can reduce the time spent performing imaging. Because MRIs consume time and resources, compressed sensing (CS) is commonly used. CS preferentially maintains in-plane resolution at the expense of through-plane resolution to produce a scan with a single, usable viewpoint that preserves signal-to-noise ratio (SNR). CS, however, limits interpretation to single directions and can create aliasing artifacts. An AI algorithm known as synthetic multi-orientation resolution enhancement works in real time to reduce aliasing and improve resolution in these compressed scans.¹⁰ This AI improved resolution of white matter lesions in patients with multiple sclerosis (MS) on FLAIR (fluid-attenuated inversion recovery) images, and permitted multiview reconstruction from these limited scans.

Tasks of reconstructing and anti-aliasing come with high computational costs that vary inversely with the extent of scanning compression, potentially negating the time and resource savings of CS. DL AI modalities have been developed to reduce operational loads and further improve image resolution in several directions from CS. One such deep residual learning AI was trained with compressed MRIs and used the framelet method to create a CNN that could rapidly remove global and deeply coherent aliasing artifacts.¹¹ This system, compared with synthetic multi-orientation resolution enhancement, uses a pretrained, pretested AI that does not require additional time during scanning for computational analysis, thereby multiplying the time benefit of CS while retaining the benefits of multidirectional reconstruction and increased resolution. This methodology suffers from inherent degradation of perceptual image quality in its reconstructions because of the L2 loss function the CNN uses to reduce mean squared error, which causes blurring by averaging all possible outcomes of signal distribution during reconstruction. To combat this, researchers have developed another AI to reduce reconstruction times that uses a different loss function in a generative adversarial network to retain image quality, while offering reconstruction times several hundred times faster than current CS-MRI structures.¹² So-called sparse-coding methods promise further reduction in reconstruction times, with the possibility of processing completed online with a lightweight architecture rather than on a local system.¹³

Neuroimaging of acute cases benefits most directly from these technologies because MRIs and their high resolution and SNR begin to approach CT imaging time scales. This could have important implications in clinical care, particularly for stroke imaging and evaluating spinal cord compression. CS-MRI optimization represents one of the greatest areas of neuroimaging cost savings and neurologic care improvement in the modern radiology era.

Reducing Contrast and Radiation Doses

AI has the ability to read CT, MRI, and positron emission tomography (PET) with reduced or without contrast without significant loss in sensitivity for detecting lesions. With MRI, gadolinium-based contrast can cause injection site reactions, allergic reactions, metal deposition throughout the body, and nephrogenic systemic fibrosis in the most severe instances.¹⁴ DL has been applied to brain MRIs performed with 10% of a full dose of contrast without significant degradation of image quality. Neuroradiologists did not rate the AI-synthesized images for several MRI indications lower than their full-dose counterparts.¹⁵ Low-dose contrast imaging, regardless of modality, generates greater noise with a significantly reduced signal. However, with AI applied, researchers found that the software suppressed motion and aliasing artifacts and improved image quality, perhaps evidence that this low-dose modality is less vulnerable to the most common pitfalls of MRI.

Recently, low-dose MRI moved into the spotlight when Subtle Medical SubtleGAD software received a National Institutes of Health grant and an expedited pathway to phase 2 clinical trials.¹⁶ SubtleGAD, a DL AI that enables low-dose MRI interpretation, might allow contrast MRI for patients with advanced kidney disease or contrast allergies. At some point, contrast with MRI might not be necessary because DL AI applied to noncontrast MRs for detecting MS lesions was found to be preliminarily effective with 78% lesion detection sensitivity.¹⁷

PET-MRI combines simultaneous PET and MRI and has been used to evaluate neurologic disorders. PET-MRI can detect amyloid plaques in Alzheimer disease 10 to 20 years before clinical signs of dementia emerge.¹⁸ PET-MRI has sparked DL AI development to decrease the dose of the IV radioactive tracer 18F-florbetaben used in imaging to reduce radiation exposure and imaging costs.This reduction is critical if PET-MRI is to become used widely.^19-21

An initial CNN could reconstruct low-dose amyloid scans to full-dose resolution, albeit with a greater susceptibility to some artifacts and motion blurring.²² Similar to the synthetic multi-orientation resolution enhancement CNN, this program showed signal blurring from the L2 loss function, which was corrected in a later AI that used a generative adversarial network to minimize perceptual loss.²³ This new AI demonstrated greater image resolution, feature preservation, and radiologist rating over the previous AI and was capable of reconstructing low-dose PET scans to full-dose resolution without an accompanying MRI. Applications of this algorithm are far-reaching, potentially allowing neuroimaging of brain tumors at more frequent intervals with higher resolution and lower total radiation exposure.

AI also has been applied to neurologic CT to reduce radiation exposure.²⁴ Because it is critical to abide by the principles of ALARA (as low as reasonably achievable), the ability of AI to reduce radiation exposure holds significant promise. A CNN has been used to transform low-dose CTs of anthropomorphic models with calcium inserts and cardiac patients to normal-dose CTs, with the goal of improving the SNR.²⁵ By training a noise-discriminating CNN and a noise-generating CNN together in a generative adversarial network, the AI improved image feature preservation during transformation. This algorithm has a direct application in imaging cerebral vasculature, including calcification that can explain lacunar infarcts and tracking systemic atherosclerosis.²⁶

Another CNN has been applied to remove more complex noise patterns from the phenomena of beam hardening and photon starvation common in low-dose CT. This algorithm extracts the directional components of artifacts and compares them to known artifact patterns, allowing for highly specific suppression of unwanted signals.²⁷ In June 2019, the US Food and Drug Administration (FDA) approved ClariPi, a deep CNN program for advanced denoising and resolution improvement of low- and ultra low-dose CTs.²⁸ Aside from only low-dose settings, this AI could reduce artifacts in all CT imaging modalities and improve therapeutic value of procedures, including cerebral angiograms and emergency cranial scans. As the average CT radiation dose decreased from 12 mSv in 2009 to 1.5 mSv in 2014 and continues to fall, these algorithms will become increasingly necessary to retain the high resolution and diagnostic power expected of neurologic CTs.^29,30

Downstream Applications

Downstream applications refer to AI use after a radiologic study is acquired, mostly image interpretation. More than 70% of FDA-approved AI medical devices are in radiology, and many of these relate to image analysis.^6,31 Although AI is not limited to black-and-white image interpretation, it is hypothesized that one of the reasons radiology is inviting to AI is because gray-scale images lend themselves to standardization.³ Moreover, most radiology departments already use AI-friendly picture archiving and communication systems.^31,32

AI has been applied to a range of radiologic modalities, including MRI, CT, ultrasonography, PET, and mammography.^32-38 AI also has been specifically applied to radiography, including the interpretation of tuberculosis, pneumonia, lung lesions, and COVID-19.^33,39-45 AI also can assist triage, patient screening, providing a “second opinion” rapidly, shortening the time needed for attaining a diagnosis, monitoring disease progression, and predicting prognosis.^{37-39,43,45-47} Downstream applications of AI in neuroradiology and neurology include using CT to aid in detecting hemorrhage or ischemic stroke; using MRI to automatically segment lesions, such as tumors or MS lesions; assisting in early diagnosis and predicting prognosis in MS; assisting in treating paralysis, including from spinal cord injury; determining seizure type and localizing area of seizure onset; and using cameras, wearable devices, and smartphone applications to diagnose and assess treatment response in neurodegenerative disorders, such as Parkinson or Alzheimer diseases (Figure).^37,48-56

Practical and Ethical Considerations

In any discussion of the benefits of AI, it is prudent to address its shortcomings. Chief among these is overfitting, which occurs when an AI is too closely aligned with its training dataset and prone to error when applied to novel cases. Often this is a byproduct of a small training set.⁶⁰ Neuroradiology, particularly with uncommon, advanced imaging methods, has a smaller number of available studies.⁶¹ Even with more prevalent imaging modalities, such as head CT, the work of collecting training scans from patients with the prerequisite disease processes, particularly if these processes are rare, can limit the number of datapoints collected. Neuroradiologists should understand how an AI tool was generated, including the size and variety of the training dataset used, to best gauge the clinical applicability and fitness of the system.

Another point of concern for AI clinical decision support tools’ implementation is automation bias—the tendency for clinicians to favor machine-generated decisions and ignore contrary data or conflicting human decisions.⁶² This situation often arises when radiologists experience overwhelming patient loads or are in underresourced settings, where there is little ability to review every AI-based diagnosis. Although AI might be of benefit in such conditions by reducing physician workload and streamlining the diagnostic process, there is the propensity to improperly rely on a tool meant to augment, not replace, a radiologist’s judgment. Such cases have led to adverse outcomes for patients, and legal precedence shows that this constitutes negligence.⁶³ Maintaining awareness of each tool’s limitations and proper application is the only remedy for such situations.

Ethically, we must consider the opaqueness of ML-developed neuroimaging AIs. For many systems, the specific process by which an AI arrives at its conclusions is unknown. This AI “black box” can conceal potential errors and biases that are masked by overall positive performance metrics. The lack of understanding about how a tool functions in the zero-failure clinical setting understandably gives radiologists pause. The question must be asked: Is it ethical to use a system that is a relatively unknown quantity? Entities, including state governments, Canada, and the European Union, have produced an answer. Each of these governments have implemented policies requiring that health care AIs use some method to display to end users the process by which they arrive at conclusions.^64-68

The 21st Century Cures Act declares that to attain approval, clinical AIs must demonstrate this explainability to clinicians and patients.⁶⁹ The response has been an explosion in the development of explainable AI. Systems that visualize the areas where AI attention most often rests with heatmaps, generate labels for the most heavily weighted features of radiographic images, and create full diagnostic reports to justify AI conclusions aim to meet the goal of transparency and inspiring confidence in clinical end users.⁷⁰ The ability to understand the “thought process” of a system proves useful for error correction and retooling. A trend toward under- or overdetecting conditions, flagging seemingly irrelevant image regions, or low reproducibility can be better addressed when it is clear how the AI is drawing its false conclusions. With an iterative process of testing and redesigning, false positive and negative rates can be reduced, the need for human intervention can be lowered to an appropriate minimum, and patient outcomes can be improved.⁷¹

Data collection raises another ethical concern. To train functional clinical decision support tools, massive amounts of patient demographic, laboratory, and imaging data are required. With incentives to develop the most powerful AI systems, record collection can venture down a path where patient autonomy and privacy are threatened. Radiologists have a duty to ensure data mining serves patients and improves the practice of radiology while protecting patients’ personal information.⁶² Policies have placed similar limits on the access to and use of patient records.^64-69 Patients have the right to request explanation of the AI systems their data have been used to train. Approval for data acquisition requires the use of explainable AI, standardized data security protocol implementation, and adequate proof of communal benefit from the clinical decision support tool. Establishment of state-mandated protections bodes well for a future when developers can access enormous caches of data while patients and health care professionals are assured that no identifying information has escaped a well-regulated space. On the level of the individual radiologist, the knowledge that each datum represents a human life. These are people who has made themselves vulnerable by seeking relief for what ails them, which should serve as a lasting reminder to operate with utmost care when handling sensitive information.

Conclusions

The demonstrated applications of AI in neuroimaging are numerous and varied, and it is reasonable to assume that its implementation will increase as the technology matures. AI use for detecting important neurologic conditions holds promise in combatting ever greater imaging volumes and providing timely diagnoses. As medicine witnesses the continuing adoption of AI, it is important that practitioners possess an understanding of its current and emerging uses.

Artificial intelligence (AI) in medicine has shown significant promise, particularly in neuroimaging. AI refers to computer systems designed to perform tasks that normally require human intelligence.¹ Machine learning (ML), a field in which computers learn from data without being specifically programmed, is the AI subset responsible for its success in matching or even surpassing humans in certain tasks.²

Supervised learning, a subset of ML, uses an algorithm with annotated data from which to learn.³ The program will use the characteristics of a training data set to predict a specific outcome or target when exposed to a sample data set of the same type. Unsupervised learning finds naturally occurring patterns or groupings within the data.⁴ With deep learning (DL) algorithms, computers learn the features that optimally represent the data for the problem at hand.⁵ Both ML and DL are meant to emulate neural networks in the brain, giving rise to artificial neural networks composed of nodes structured within input, hidden, and output layers.

The DL neural network differs from a conventional one by having many hidden layers instead of just 1 layer that extracts patterns within the data.⁶ Convolutional neural networks (CNNs) are the most prevalent DL architecture used in medical imaging. CNN’s hidden layers apply convolution and pooling operations to break down an image into features containing the most valuable information. The connecting layer applies high-level reasoning before the output layer provides predictions for the image. This framework has applications within radiology, such as predicting a lesion category or condition from an image, determining whether a specific pixel belongs to background or a target class, and predicting the location of lesions.¹

AI promises to increase efficiency and reduces errors. With increased data processing and image interpretation, AI technology may help radiologists improve the quality of patient care.⁶ This article discusses the current applications and future integration of AI in neuroradiology.

Neuroimaging Applications

AI can improve the quality of neuroimaging and reduce the clinical and systemic loads of other imaging modalities. AI can predict patient wait times for computed tomography (CT), magnetic resonance imaging (MRI), ultrasound, and X-ray imaging.⁷ A ML-based AI has detected the variables that most affected patient wait times, including proximity to federal holidays and severity of the patient’s condition, and calculated how long patients would be delayed after their scheduled appointment time. This AI modality could allow more efficient patient scheduling and reveal areas of patient processing that could be changed, potentially improving patient satisfaction and outcomes for time-sensitive neurologic conditions.

AI can save patient and health care practitioner time for repeat MRIs. An estimated 20% of MRI scans require a repeat series—a massive loss of time and funds for both patients and the health care system.⁸ A DL approach can determine whether an MRI is usable clinically or unclear enough to require repetition.⁹ This initial screening measure can prevent patients from making return visits and neuroradiologists from reading inconclusive images. AI offers the opportunity to reduce time and costs incurred by optimizing the health care process before imaging is obtained.

Speeding Up Neuroimaging

AI can reduce the time spent performing imaging. Because MRIs consume time and resources, compressed sensing (CS) is commonly used. CS preferentially maintains in-plane resolution at the expense of through-plane resolution to produce a scan with a single, usable viewpoint that preserves signal-to-noise ratio (SNR). CS, however, limits interpretation to single directions and can create aliasing artifacts. An AI algorithm known as synthetic multi-orientation resolution enhancement works in real time to reduce aliasing and improve resolution in these compressed scans.¹⁰ This AI improved resolution of white matter lesions in patients with multiple sclerosis (MS) on FLAIR (fluid-attenuated inversion recovery) images, and permitted multiview reconstruction from these limited scans.

Tasks of reconstructing and anti-aliasing come with high computational costs that vary inversely with the extent of scanning compression, potentially negating the time and resource savings of CS. DL AI modalities have been developed to reduce operational loads and further improve image resolution in several directions from CS. One such deep residual learning AI was trained with compressed MRIs and used the framelet method to create a CNN that could rapidly remove global and deeply coherent aliasing artifacts.¹¹ This system, compared with synthetic multi-orientation resolution enhancement, uses a pretrained, pretested AI that does not require additional time during scanning for computational analysis, thereby multiplying the time benefit of CS while retaining the benefits of multidirectional reconstruction and increased resolution. This methodology suffers from inherent degradation of perceptual image quality in its reconstructions because of the L2 loss function the CNN uses to reduce mean squared error, which causes blurring by averaging all possible outcomes of signal distribution during reconstruction. To combat this, researchers have developed another AI to reduce reconstruction times that uses a different loss function in a generative adversarial network to retain image quality, while offering reconstruction times several hundred times faster than current CS-MRI structures.¹² So-called sparse-coding methods promise further reduction in reconstruction times, with the possibility of processing completed online with a lightweight architecture rather than on a local system.¹³

Neuroimaging of acute cases benefits most directly from these technologies because MRIs and their high resolution and SNR begin to approach CT imaging time scales. This could have important implications in clinical care, particularly for stroke imaging and evaluating spinal cord compression. CS-MRI optimization represents one of the greatest areas of neuroimaging cost savings and neurologic care improvement in the modern radiology era.

Reducing Contrast and Radiation Doses

AI has the ability to read CT, MRI, and positron emission tomography (PET) with reduced or without contrast without significant loss in sensitivity for detecting lesions. With MRI, gadolinium-based contrast can cause injection site reactions, allergic reactions, metal deposition throughout the body, and nephrogenic systemic fibrosis in the most severe instances.¹⁴ DL has been applied to brain MRIs performed with 10% of a full dose of contrast without significant degradation of image quality. Neuroradiologists did not rate the AI-synthesized images for several MRI indications lower than their full-dose counterparts.¹⁵ Low-dose contrast imaging, regardless of modality, generates greater noise with a significantly reduced signal. However, with AI applied, researchers found that the software suppressed motion and aliasing artifacts and improved image quality, perhaps evidence that this low-dose modality is less vulnerable to the most common pitfalls of MRI.

Recently, low-dose MRI moved into the spotlight when Subtle Medical SubtleGAD software received a National Institutes of Health grant and an expedited pathway to phase 2 clinical trials.¹⁶ SubtleGAD, a DL AI that enables low-dose MRI interpretation, might allow contrast MRI for patients with advanced kidney disease or contrast allergies. At some point, contrast with MRI might not be necessary because DL AI applied to noncontrast MRs for detecting MS lesions was found to be preliminarily effective with 78% lesion detection sensitivity.¹⁷

PET-MRI combines simultaneous PET and MRI and has been used to evaluate neurologic disorders. PET-MRI can detect amyloid plaques in Alzheimer disease 10 to 20 years before clinical signs of dementia emerge.¹⁸ PET-MRI has sparked DL AI development to decrease the dose of the IV radioactive tracer 18F-florbetaben used in imaging to reduce radiation exposure and imaging costs.This reduction is critical if PET-MRI is to become used widely.^19-21

An initial CNN could reconstruct low-dose amyloid scans to full-dose resolution, albeit with a greater susceptibility to some artifacts and motion blurring.²² Similar to the synthetic multi-orientation resolution enhancement CNN, this program showed signal blurring from the L2 loss function, which was corrected in a later AI that used a generative adversarial network to minimize perceptual loss.²³ This new AI demonstrated greater image resolution, feature preservation, and radiologist rating over the previous AI and was capable of reconstructing low-dose PET scans to full-dose resolution without an accompanying MRI. Applications of this algorithm are far-reaching, potentially allowing neuroimaging of brain tumors at more frequent intervals with higher resolution and lower total radiation exposure.

AI also has been applied to neurologic CT to reduce radiation exposure.²⁴ Because it is critical to abide by the principles of ALARA (as low as reasonably achievable), the ability of AI to reduce radiation exposure holds significant promise. A CNN has been used to transform low-dose CTs of anthropomorphic models with calcium inserts and cardiac patients to normal-dose CTs, with the goal of improving the SNR.²⁵ By training a noise-discriminating CNN and a noise-generating CNN together in a generative adversarial network, the AI improved image feature preservation during transformation. This algorithm has a direct application in imaging cerebral vasculature, including calcification that can explain lacunar infarcts and tracking systemic atherosclerosis.²⁶

Another CNN has been applied to remove more complex noise patterns from the phenomena of beam hardening and photon starvation common in low-dose CT. This algorithm extracts the directional components of artifacts and compares them to known artifact patterns, allowing for highly specific suppression of unwanted signals.²⁷ In June 2019, the US Food and Drug Administration (FDA) approved ClariPi, a deep CNN program for advanced denoising and resolution improvement of low- and ultra low-dose CTs.²⁸ Aside from only low-dose settings, this AI could reduce artifacts in all CT imaging modalities and improve therapeutic value of procedures, including cerebral angiograms and emergency cranial scans. As the average CT radiation dose decreased from 12 mSv in 2009 to 1.5 mSv in 2014 and continues to fall, these algorithms will become increasingly necessary to retain the high resolution and diagnostic power expected of neurologic CTs.^29,30

Downstream Applications

Downstream applications refer to AI use after a radiologic study is acquired, mostly image interpretation. More than 70% of FDA-approved AI medical devices are in radiology, and many of these relate to image analysis.^6,31 Although AI is not limited to black-and-white image interpretation, it is hypothesized that one of the reasons radiology is inviting to AI is because gray-scale images lend themselves to standardization.³ Moreover, most radiology departments already use AI-friendly picture archiving and communication systems.^31,32

AI has been applied to a range of radiologic modalities, including MRI, CT, ultrasonography, PET, and mammography.^32-38 AI also has been specifically applied to radiography, including the interpretation of tuberculosis, pneumonia, lung lesions, and COVID-19.^33,39-45 AI also can assist triage, patient screening, providing a “second opinion” rapidly, shortening the time needed for attaining a diagnosis, monitoring disease progression, and predicting prognosis.^{37-39,43,45-47} Downstream applications of AI in neuroradiology and neurology include using CT to aid in detecting hemorrhage or ischemic stroke; using MRI to automatically segment lesions, such as tumors or MS lesions; assisting in early diagnosis and predicting prognosis in MS; assisting in treating paralysis, including from spinal cord injury; determining seizure type and localizing area of seizure onset; and using cameras, wearable devices, and smartphone applications to diagnose and assess treatment response in neurodegenerative disorders, such as Parkinson or Alzheimer diseases (Figure).^37,48-56

Practical and Ethical Considerations

In any discussion of the benefits of AI, it is prudent to address its shortcomings. Chief among these is overfitting, which occurs when an AI is too closely aligned with its training dataset and prone to error when applied to novel cases. Often this is a byproduct of a small training set.⁶⁰ Neuroradiology, particularly with uncommon, advanced imaging methods, has a smaller number of available studies.⁶¹ Even with more prevalent imaging modalities, such as head CT, the work of collecting training scans from patients with the prerequisite disease processes, particularly if these processes are rare, can limit the number of datapoints collected. Neuroradiologists should understand how an AI tool was generated, including the size and variety of the training dataset used, to best gauge the clinical applicability and fitness of the system.

Another point of concern for AI clinical decision support tools’ implementation is automation bias—the tendency for clinicians to favor machine-generated decisions and ignore contrary data or conflicting human decisions.⁶² This situation often arises when radiologists experience overwhelming patient loads or are in underresourced settings, where there is little ability to review every AI-based diagnosis. Although AI might be of benefit in such conditions by reducing physician workload and streamlining the diagnostic process, there is the propensity to improperly rely on a tool meant to augment, not replace, a radiologist’s judgment. Such cases have led to adverse outcomes for patients, and legal precedence shows that this constitutes negligence.⁶³ Maintaining awareness of each tool’s limitations and proper application is the only remedy for such situations.

Ethically, we must consider the opaqueness of ML-developed neuroimaging AIs. For many systems, the specific process by which an AI arrives at its conclusions is unknown. This AI “black box” can conceal potential errors and biases that are masked by overall positive performance metrics. The lack of understanding about how a tool functions in the zero-failure clinical setting understandably gives radiologists pause. The question must be asked: Is it ethical to use a system that is a relatively unknown quantity? Entities, including state governments, Canada, and the European Union, have produced an answer. Each of these governments have implemented policies requiring that health care AIs use some method to display to end users the process by which they arrive at conclusions.^64-68

The 21st Century Cures Act declares that to attain approval, clinical AIs must demonstrate this explainability to clinicians and patients.⁶⁹ The response has been an explosion in the development of explainable AI. Systems that visualize the areas where AI attention most often rests with heatmaps, generate labels for the most heavily weighted features of radiographic images, and create full diagnostic reports to justify AI conclusions aim to meet the goal of transparency and inspiring confidence in clinical end users.⁷⁰ The ability to understand the “thought process” of a system proves useful for error correction and retooling. A trend toward under- or overdetecting conditions, flagging seemingly irrelevant image regions, or low reproducibility can be better addressed when it is clear how the AI is drawing its false conclusions. With an iterative process of testing and redesigning, false positive and negative rates can be reduced, the need for human intervention can be lowered to an appropriate minimum, and patient outcomes can be improved.⁷¹

Data collection raises another ethical concern. To train functional clinical decision support tools, massive amounts of patient demographic, laboratory, and imaging data are required. With incentives to develop the most powerful AI systems, record collection can venture down a path where patient autonomy and privacy are threatened. Radiologists have a duty to ensure data mining serves patients and improves the practice of radiology while protecting patients’ personal information.⁶² Policies have placed similar limits on the access to and use of patient records.^64-69 Patients have the right to request explanation of the AI systems their data have been used to train. Approval for data acquisition requires the use of explainable AI, standardized data security protocol implementation, and adequate proof of communal benefit from the clinical decision support tool. Establishment of state-mandated protections bodes well for a future when developers can access enormous caches of data while patients and health care professionals are assured that no identifying information has escaped a well-regulated space. On the level of the individual radiologist, the knowledge that each datum represents a human life. These are people who has made themselves vulnerable by seeking relief for what ails them, which should serve as a lasting reminder to operate with utmost care when handling sensitive information.

Conclusions

The demonstrated applications of AI in neuroimaging are numerous and varied, and it is reasonable to assume that its implementation will increase as the technology matures. AI use for detecting important neurologic conditions holds promise in combatting ever greater imaging volumes and providing timely diagnoses. As medicine witnesses the continuing adoption of AI, it is important that practitioners possess an understanding of its current and emerging uses.

Artificial intelligence (AI) in medicine has shown significant promise, particularly in neuroimaging. AI refers to computer systems designed to perform tasks that normally require human intelligence.¹ Machine learning (ML), a field in which computers learn from data without being specifically programmed, is the AI subset responsible for its success in matching or even surpassing humans in certain tasks.²

Supervised learning, a subset of ML, uses an algorithm with annotated data from which to learn.³ The program will use the characteristics of a training data set to predict a specific outcome or target when exposed to a sample data set of the same type. Unsupervised learning finds naturally occurring patterns or groupings within the data.⁴ With deep learning (DL) algorithms, computers learn the features that optimally represent the data for the problem at hand.⁵ Both ML and DL are meant to emulate neural networks in the brain, giving rise to artificial neural networks composed of nodes structured within input, hidden, and output layers.

The DL neural network differs from a conventional one by having many hidden layers instead of just 1 layer that extracts patterns within the data.⁶ Convolutional neural networks (CNNs) are the most prevalent DL architecture used in medical imaging. CNN’s hidden layers apply convolution and pooling operations to break down an image into features containing the most valuable information. The connecting layer applies high-level reasoning before the output layer provides predictions for the image. This framework has applications within radiology, such as predicting a lesion category or condition from an image, determining whether a specific pixel belongs to background or a target class, and predicting the location of lesions.¹

AI promises to increase efficiency and reduces errors. With increased data processing and image interpretation, AI technology may help radiologists improve the quality of patient care.⁶ This article discusses the current applications and future integration of AI in neuroradiology.

Neuroimaging Applications

AI can improve the quality of neuroimaging and reduce the clinical and systemic loads of other imaging modalities. AI can predict patient wait times for computed tomography (CT), magnetic resonance imaging (MRI), ultrasound, and X-ray imaging.⁷ A ML-based AI has detected the variables that most affected patient wait times, including proximity to federal holidays and severity of the patient’s condition, and calculated how long patients would be delayed after their scheduled appointment time. This AI modality could allow more efficient patient scheduling and reveal areas of patient processing that could be changed, potentially improving patient satisfaction and outcomes for time-sensitive neurologic conditions.

AI can save patient and health care practitioner time for repeat MRIs. An estimated 20% of MRI scans require a repeat series—a massive loss of time and funds for both patients and the health care system.⁸ A DL approach can determine whether an MRI is usable clinically or unclear enough to require repetition.⁹ This initial screening measure can prevent patients from making return visits and neuroradiologists from reading inconclusive images. AI offers the opportunity to reduce time and costs incurred by optimizing the health care process before imaging is obtained.

Speeding Up Neuroimaging

AI can reduce the time spent performing imaging. Because MRIs consume time and resources, compressed sensing (CS) is commonly used. CS preferentially maintains in-plane resolution at the expense of through-plane resolution to produce a scan with a single, usable viewpoint that preserves signal-to-noise ratio (SNR). CS, however, limits interpretation to single directions and can create aliasing artifacts. An AI algorithm known as synthetic multi-orientation resolution enhancement works in real time to reduce aliasing and improve resolution in these compressed scans.¹⁰ This AI improved resolution of white matter lesions in patients with multiple sclerosis (MS) on FLAIR (fluid-attenuated inversion recovery) images, and permitted multiview reconstruction from these limited scans.

Tasks of reconstructing and anti-aliasing come with high computational costs that vary inversely with the extent of scanning compression, potentially negating the time and resource savings of CS. DL AI modalities have been developed to reduce operational loads and further improve image resolution in several directions from CS. One such deep residual learning AI was trained with compressed MRIs and used the framelet method to create a CNN that could rapidly remove global and deeply coherent aliasing artifacts.¹¹ This system, compared with synthetic multi-orientation resolution enhancement, uses a pretrained, pretested AI that does not require additional time during scanning for computational analysis, thereby multiplying the time benefit of CS while retaining the benefits of multidirectional reconstruction and increased resolution. This methodology suffers from inherent degradation of perceptual image quality in its reconstructions because of the L2 loss function the CNN uses to reduce mean squared error, which causes blurring by averaging all possible outcomes of signal distribution during reconstruction. To combat this, researchers have developed another AI to reduce reconstruction times that uses a different loss function in a generative adversarial network to retain image quality, while offering reconstruction times several hundred times faster than current CS-MRI structures.¹² So-called sparse-coding methods promise further reduction in reconstruction times, with the possibility of processing completed online with a lightweight architecture rather than on a local system.¹³

Neuroimaging of acute cases benefits most directly from these technologies because MRIs and their high resolution and SNR begin to approach CT imaging time scales. This could have important implications in clinical care, particularly for stroke imaging and evaluating spinal cord compression. CS-MRI optimization represents one of the greatest areas of neuroimaging cost savings and neurologic care improvement in the modern radiology era.

Reducing Contrast and Radiation Doses

AI has the ability to read CT, MRI, and positron emission tomography (PET) with reduced or without contrast without significant loss in sensitivity for detecting lesions. With MRI, gadolinium-based contrast can cause injection site reactions, allergic reactions, metal deposition throughout the body, and nephrogenic systemic fibrosis in the most severe instances.¹⁴ DL has been applied to brain MRIs performed with 10% of a full dose of contrast without significant degradation of image quality. Neuroradiologists did not rate the AI-synthesized images for several MRI indications lower than their full-dose counterparts.¹⁵ Low-dose contrast imaging, regardless of modality, generates greater noise with a significantly reduced signal. However, with AI applied, researchers found that the software suppressed motion and aliasing artifacts and improved image quality, perhaps evidence that this low-dose modality is less vulnerable to the most common pitfalls of MRI.

Recently, low-dose MRI moved into the spotlight when Subtle Medical SubtleGAD software received a National Institutes of Health grant and an expedited pathway to phase 2 clinical trials.¹⁶ SubtleGAD, a DL AI that enables low-dose MRI interpretation, might allow contrast MRI for patients with advanced kidney disease or contrast allergies. At some point, contrast with MRI might not be necessary because DL AI applied to noncontrast MRs for detecting MS lesions was found to be preliminarily effective with 78% lesion detection sensitivity.¹⁷

PET-MRI combines simultaneous PET and MRI and has been used to evaluate neurologic disorders. PET-MRI can detect amyloid plaques in Alzheimer disease 10 to 20 years before clinical signs of dementia emerge.¹⁸ PET-MRI has sparked DL AI development to decrease the dose of the IV radioactive tracer 18F-florbetaben used in imaging to reduce radiation exposure and imaging costs.This reduction is critical if PET-MRI is to become used widely.^19-21

An initial CNN could reconstruct low-dose amyloid scans to full-dose resolution, albeit with a greater susceptibility to some artifacts and motion blurring.²² Similar to the synthetic multi-orientation resolution enhancement CNN, this program showed signal blurring from the L2 loss function, which was corrected in a later AI that used a generative adversarial network to minimize perceptual loss.²³ This new AI demonstrated greater image resolution, feature preservation, and radiologist rating over the previous AI and was capable of reconstructing low-dose PET scans to full-dose resolution without an accompanying MRI. Applications of this algorithm are far-reaching, potentially allowing neuroimaging of brain tumors at more frequent intervals with higher resolution and lower total radiation exposure.

AI also has been applied to neurologic CT to reduce radiation exposure.²⁴ Because it is critical to abide by the principles of ALARA (as low as reasonably achievable), the ability of AI to reduce radiation exposure holds significant promise. A CNN has been used to transform low-dose CTs of anthropomorphic models with calcium inserts and cardiac patients to normal-dose CTs, with the goal of improving the SNR.²⁵ By training a noise-discriminating CNN and a noise-generating CNN together in a generative adversarial network, the AI improved image feature preservation during transformation. This algorithm has a direct application in imaging cerebral vasculature, including calcification that can explain lacunar infarcts and tracking systemic atherosclerosis.²⁶

Another CNN has been applied to remove more complex noise patterns from the phenomena of beam hardening and photon starvation common in low-dose CT. This algorithm extracts the directional components of artifacts and compares them to known artifact patterns, allowing for highly specific suppression of unwanted signals.²⁷ In June 2019, the US Food and Drug Administration (FDA) approved ClariPi, a deep CNN program for advanced denoising and resolution improvement of low- and ultra low-dose CTs.²⁸ Aside from only low-dose settings, this AI could reduce artifacts in all CT imaging modalities and improve therapeutic value of procedures, including cerebral angiograms and emergency cranial scans. As the average CT radiation dose decreased from 12 mSv in 2009 to 1.5 mSv in 2014 and continues to fall, these algorithms will become increasingly necessary to retain the high resolution and diagnostic power expected of neurologic CTs.^29,30

Downstream Applications

Downstream applications refer to AI use after a radiologic study is acquired, mostly image interpretation. More than 70% of FDA-approved AI medical devices are in radiology, and many of these relate to image analysis.^6,31 Although AI is not limited to black-and-white image interpretation, it is hypothesized that one of the reasons radiology is inviting to AI is because gray-scale images lend themselves to standardization.³ Moreover, most radiology departments already use AI-friendly picture archiving and communication systems.^31,32

AI has been applied to a range of radiologic modalities, including MRI, CT, ultrasonography, PET, and mammography.^32-38 AI also has been specifically applied to radiography, including the interpretation of tuberculosis, pneumonia, lung lesions, and COVID-19.^33,39-45 AI also can assist triage, patient screening, providing a “second opinion” rapidly, shortening the time needed for attaining a diagnosis, monitoring disease progression, and predicting prognosis.^{37-39,43,45-47} Downstream applications of AI in neuroradiology and neurology include using CT to aid in detecting hemorrhage or ischemic stroke; using MRI to automatically segment lesions, such as tumors or MS lesions; assisting in early diagnosis and predicting prognosis in MS; assisting in treating paralysis, including from spinal cord injury; determining seizure type and localizing area of seizure onset; and using cameras, wearable devices, and smartphone applications to diagnose and assess treatment response in neurodegenerative disorders, such as Parkinson or Alzheimer diseases (Figure).^37,48-56

Practical and Ethical Considerations

In any discussion of the benefits of AI, it is prudent to address its shortcomings. Chief among these is overfitting, which occurs when an AI is too closely aligned with its training dataset and prone to error when applied to novel cases. Often this is a byproduct of a small training set.⁶⁰ Neuroradiology, particularly with uncommon, advanced imaging methods, has a smaller number of available studies.⁶¹ Even with more prevalent imaging modalities, such as head CT, the work of collecting training scans from patients with the prerequisite disease processes, particularly if these processes are rare, can limit the number of datapoints collected. Neuroradiologists should understand how an AI tool was generated, including the size and variety of the training dataset used, to best gauge the clinical applicability and fitness of the system.

Another point of concern for AI clinical decision support tools’ implementation is automation bias—the tendency for clinicians to favor machine-generated decisions and ignore contrary data or conflicting human decisions.⁶² This situation often arises when radiologists experience overwhelming patient loads or are in underresourced settings, where there is little ability to review every AI-based diagnosis. Although AI might be of benefit in such conditions by reducing physician workload and streamlining the diagnostic process, there is the propensity to improperly rely on a tool meant to augment, not replace, a radiologist’s judgment. Such cases have led to adverse outcomes for patients, and legal precedence shows that this constitutes negligence.⁶³ Maintaining awareness of each tool’s limitations and proper application is the only remedy for such situations.

Ethically, we must consider the opaqueness of ML-developed neuroimaging AIs. For many systems, the specific process by which an AI arrives at its conclusions is unknown. This AI “black box” can conceal potential errors and biases that are masked by overall positive performance metrics. The lack of understanding about how a tool functions in the zero-failure clinical setting understandably gives radiologists pause. The question must be asked: Is it ethical to use a system that is a relatively unknown quantity? Entities, including state governments, Canada, and the European Union, have produced an answer. Each of these governments have implemented policies requiring that health care AIs use some method to display to end users the process by which they arrive at conclusions.^64-68

The 21st Century Cures Act declares that to attain approval, clinical AIs must demonstrate this explainability to clinicians and patients.⁶⁹ The response has been an explosion in the development of explainable AI. Systems that visualize the areas where AI attention most often rests with heatmaps, generate labels for the most heavily weighted features of radiographic images, and create full diagnostic reports to justify AI conclusions aim to meet the goal of transparency and inspiring confidence in clinical end users.⁷⁰ The ability to understand the “thought process” of a system proves useful for error correction and retooling. A trend toward under- or overdetecting conditions, flagging seemingly irrelevant image regions, or low reproducibility can be better addressed when it is clear how the AI is drawing its false conclusions. With an iterative process of testing and redesigning, false positive and negative rates can be reduced, the need for human intervention can be lowered to an appropriate minimum, and patient outcomes can be improved.⁷¹

Data collection raises another ethical concern. To train functional clinical decision support tools, massive amounts of patient demographic, laboratory, and imaging data are required. With incentives to develop the most powerful AI systems, record collection can venture down a path where patient autonomy and privacy are threatened. Radiologists have a duty to ensure data mining serves patients and improves the practice of radiology while protecting patients’ personal information.⁶² Policies have placed similar limits on the access to and use of patient records.^64-69 Patients have the right to request explanation of the AI systems their data have been used to train. Approval for data acquisition requires the use of explainable AI, standardized data security protocol implementation, and adequate proof of communal benefit from the clinical decision support tool. Establishment of state-mandated protections bodes well for a future when developers can access enormous caches of data while patients and health care professionals are assured that no identifying information has escaped a well-regulated space. On the level of the individual radiologist, the knowledge that each datum represents a human life. These are people who has made themselves vulnerable by seeking relief for what ails them, which should serve as a lasting reminder to operate with utmost care when handling sensitive information.

Conclusions

The demonstrated applications of AI in neuroimaging are numerous and varied, and it is reasonable to assume that its implementation will increase as the technology matures. AI use for detecting important neurologic conditions holds promise in combatting ever greater imaging volumes and providing timely diagnoses. As medicine witnesses the continuing adoption of AI, it is important that practitioners possess an understanding of its current and emerging uses.

Selective estrogen receptor modulators (SERMs) are unique synthetic compounds that bind to the estrogen receptor and initiate either estrogenic agonistic or antagonistic activity, depending on the confirmational change they produce on binding to the receptor. Many SERMs have come to market, others have not. Unlike estrogens, which regardless of dose or route of administration all carry risks as a boxed warning on the label, referred to as class labeling,¹ various SERMs exert various effects in some tissues (uterus, vagina) while they have apparent class properties in others (bone, breast).²

The first SERM, for all practical purposes, was tamoxifen (although clomiphene citrate is often considered a SERM). Tamoxifen was approved by the US Food and Drug Administration (FDA) in 1978 for the treatment of breast cancer and, subsequently, for breast cancer risk reduction. It became the most widely prescribed anticancer drug worldwide.

Subsequently, when data showed that tamoxifen could produce a small number of endometrial cancers and a larger number of endometrial polyps,^3,4 there was renewed interest in raloxifene. In preclinical animal studies, raloxifene behaved differently than tamoxifen in the uterus. After clinical trials with raloxifene showed uterine safety,⁵ the drug was FDA approved for prevention of osteoporosis in 1997, for treatment of osteoporosis in 1999, and for breast cancer risk reduction in 2009. Most clinicians are familiar with these 2 SERMs, which have been in clinical use for more than 4 and 2 decades, respectively.

Ospemifene: A third-generation SERM and its indications

Hormone deficiency from menopause causes vulvovaginal and urogenital changes as well as a multitude of symptoms and signs, including vulvar and vaginal thinning, loss of rugal folds, diminished elasticity, increased pH, and most notably dyspareunia. The nomenclature that previously described vulvovaginal atrophy (VVA) has been expanded to include genitourinary syndrome of menopause (GSM).⁶ Unfortunately, many health care providers do not ask patients about GSM symptoms, and few women report their symptoms to their clinician.⁷ Furthermore, although low-dose local estrogens applied vaginally have been the mainstay of therapy for VVA/GSM, only 7% of symptomatic women use any pharmacologic agent,⁸ mainly because of fear of estrogens due to the class labeling mentioned above.

Ospemifene, a newer SERM, improved superficial cells and reduced parabasal cells as seen on a maturation index compared with placebo, according to results of multiple phase 3 clinical trials^9,10; it also lowered vaginal pH and improved most bothersome symptoms (original studies were for dyspareunia). As a result, the FDA approved ospemifene for treatment of moderate to severe dyspareunia from VVA of menopause.

Subsequent studies allowed for a broadened indication to include treatment of moderate to severe dryness due to menopause.¹¹ The ospemifene label contains a boxed warning that states, “In the endometrium, [ospemifene] has estrogen agonistic effects.”¹² Although ospemifene is not an estrogen (it’s a SERM), the label goes on to state, “There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens.” This statement caused The Medical Letter to initially suggest that patients who receive ospemifene also should receive a progestational agent—a suggestion they later retracted.^13,14

To understand why the ospemifene labeling might be worded in such a way, one must review the data regarding the poorly named entity “weakly proliferative endometrium.” The package labeling combines any proliferative endometrium (“weakly” plus “actively” plus “disordered”) that occurred in the clinical trial. Thus, 86.1 per 1,000 of the ospemifene-treated patients (vs 13.3 per 1,000 of those taking placebo) had any one of the proliferative types. The problem is that “actively proliferative” endometrial glands will have mitotic activity in virtually every nucleus of the gland as well as abundant glandular progression (FIGURE 1), whereas “weakly proliferative” is actually closer to inactive or atrophic endometrium with an occasional mitotic figure in only a few nuclei of each gland (FIGURE 2).

In addition, at 1 year, the incidence of active proliferation with ospemifene was 1%.¹⁵ In examining the uterine safety study for raloxifene, both doses of that agent had an active proliferation incidence of 3% at 1 year.⁵ Furthermore, that study had an estrogen-only arm in which, at end point, the incidence of endometrial proliferation was 39%, and hyperplasia, 23%!⁵ It therefore is evident that, in the endometrium, ospemifene is much more like the SERM raloxifene than it is like estrogen. The American College of Obstetricians and Gynecologists (ACOG) endorsed ospemifene (level A evidence) as a first-line therapy for dyspareunia, noting absent endometrial stimulation.¹⁶

Continue to: Ospemifene effects on breast and bone...

 

 

Ospemifene effects on breast and bone

Although ospemifene is approved for treatment of moderate to severe VVA/GSM, it has other SERM effects typical of its class. The label currently states that ospemifene “has not been adequately studied in women with breast cancer; therefore, it should not be used in women with known or suspected breast cancer.”¹² We know that tamoxifen reduced breast cancer 49% in high-risk women in the Breast Cancer Prevention Trial (BCPT).¹⁷ We also know that in the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, raloxifene reduced breast cancer 77% in osteoporotic women,¹⁸ and in the Study of Tamoxifen and Raloxifene (STAR) trial, it performed virtually identically to tamoxifen in breast cancer prevention.¹⁹ Previous studies demonstrated that ospemifene inhibits breast cancer cell growth in in vitro cultures as well as in animal studies²⁰ and inhibits proliferation of human breast tissue epithelial cells,²¹ with breast effects similar to those seen with tamoxifen and raloxifene.

Thus, although one would not choose ospemifene as a primary treatment or risk-reducing agent for a patient with breast cancer, the direction of its activity in breast tissue is indisputable and is likely the reason that in the European Union (unlike in the United States) it is approved to treat dyspareunia from VVA/GSM in women with a prior history of breast cancer.

Virtually all SERMs have estrogen agonistic activity in bone. Bone is a dynamic organ, constantly being laid down and taken away (resorption). Estrogen and SERMs are potent antiresorptives in bone metabolism. Ospemifene effectively reduced bone loss in ovariectomized rats, with activity comparable to that of estradiol and raloxifene.²² Clinical data from 3 phase 1 or 2 clinical trials found 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.²³ Actual fracture or bone mineral density (BMD) data in postmenopausal women are lacking, but there is a good correlation between biochemical markers for bone turnover and the occurrence of fracture.²⁴ Once again, women who need treatment for osteoporosis should not be treated primarily with ospemifene, but women who use ospemifene for dyspareunia can expect positive activity on bone metabolism.

Clinical application

Ospemifene is an oral SERM approved for the treatment of moderate to severe dyspareunia as well as dryness from VVA due to menopause. In addition, it appears one can safely surmise that the direction of ospemifene’s activity in bone and breast is virtually indisputable. The magnitude of that activity, however, is unstudied. Therefore, in selecting an agent to treat women with dyspareunia or vaginal dryness from VVA of menopause, determining any potential add-on benefit for that particular patient in either bone and/or breast is clinically appropriate.

The SERM bazedoxifene

A meta-analysis of 4 randomized, placebo-controlled trials showed that another SERM, bazedoxifene, can significantly decrease the incidence of vertebral fracture in postmenopausal women at follow-up of 3 and 7 years.²⁵ That meta-analysis also confirmed the long-term favorable safety and tolerability of bazedoxifene, with no increase in adverse events, serious adverse events, myocardial infarction, stroke, venous thromboembolic events, or breast carcinoma in patients using bazedoxifene. However, bazedoxifene use did result in an increased incidence of hot flushes and leg cramps across 7 years.²⁵ Bazedoxifene is available in a 20-mg dose for treatment of postmenopausal osteoporosis in Israel and a number of European Union countries.

Continue to: Enter the concept of tissue-selective estrogen complex (TSEC)...

 

 

Enter the concept of tissue-selective estrogen complex (TSEC)

Some postmenopausal women are extremely intolerant of any progestogen added to estrogen therapy to confer endometrial protection in those with a uterus. According to the results of a clinical trial of postmenopausal women, bazedoxifene is the only SERM shown to decrease endometrial thickness compared with placebo.²⁶ This is the basis for thinking that perhaps a SERM like bazedoxifene, instead of a progestogen, could be used to confer endometrial protection.

A further consideration comes out of the evaluation of data derived from the 2 arms of the Women’s Health Initiative (WHI).²⁷ In the arm that combined conjugated estrogen with medroxyprogesterone acetate through 11.3 years, there was a 25% increase in the incidence of invasive breast cancer, which was statistically significant. Contrast that with the arm in hysterectomized women who received only conjugated estrogen (often inaccurately referred to as the “estrogen only” arm of the WHI). In that study arm, the relative risk of invasive breast cancer was reduced 23%, also statistically significant. Thus, the culprit in the breast cancer incidence difference in these 2 arms appears to be the addition of the progestogen medroxyprogesterone acetate.²⁷

Since the progestogen was used only for endometrial protection, could such endometrial protection be provided by a SERM like bazedoxifene? Preclinical trials showed that a combination of bazedoxifene and conjugated estrogen (in various estrogen doses) resulted in uterine wet weight in an ovariectomized rat model that was no different than that with placebo.²⁸

In terms of effects on breast, preclinical models showed that conjugated estrogen use resulted in less mammary duct elongation and end bud proliferation than estradiol by itself, and that the combination of conjugated estrogen and bazedoxifene resulted in mammary duct elongation and end bud proliferation that was similar to that in the ovariectomized animals and considerably less than a combination of estradiol with bazedoxifene.²⁹

Five phase 3 studies known as the SMART (Selective estrogens, Menopause, And Response to Therapy) trials were then conducted. Collectively, these studies examined the frequency and severity of vasomotor symptoms (VMS), BMD, bone turnover markers, lipid profiles, sleep, quality of life, breast density, and endometrial safety with conjugated estrogen/bazedoxifene treatment.³⁰ Based on these trials with more than 7,500 women, in 2013 the FDA approved a compound of conjugated estrogen 0.45 mg and bazedoxifene 20 mg (Duavee in the United States and Duavive outside the United States).

The incidence of endometrial hyperplasia at 12 months was consistently less than 1%, which is the FDA guidance for approval of hormone therapies. The incidence of bleeding or spotting with conjugated estrogen/bazedoxifene (FIGURE 3) in each 4-week interval over 12 months mirror-imaged that of placebo and ranged from 3.9% in the first 4-week interval to 1.7% in the last 4 weeks, compared with conjugated estrogen 0.45 mg/medroxyprogesterone acetate 1.5 mg, which had a 20.8% incidence of bleeding or spotting in the first 4-week interval and was still at an 8.8% incidence in the last 4 weeks.³¹ This is extremely relevant in clinical practice. There was no difference from placebo in breast cancer incidence, breast pain or tenderness, abnormal mammograms, or breast density at month 12.³²

In terms of frequency of VMS, there was a 74% reduction from baseline at 12 weeks compared with placebo (P<.001), as well as a 37% reduction in the VMS severity score (P<.001).³² Statistically significant improvements occurred in lumbar spine and hip BMD (P<.01) for women who were 1 to 5 years since menopause as well as for those who were more than 5 years since menopause.³³

Packaging issue puts TSEC on back order

In May 2020, Pfizer voluntarily recalled its conjugated estrogen/bazedoxifene product after identifying a “flaw in the drug’s foil laminate pouch that introduced oxygen and lowered the dissolution rate of active pharmaceutical ingredient bazedoxifene acetate.”³⁴ The manufacturer then wrote a letter to health care professionals in September 2021 stating, “Duavee continues to be out of stock due to an unexpected and complex packaging issue, resulting in manufacturing delays. This has nothing to do with the safety or quality of the product itself but could affect product stability throughout its shelf life… Given regulatory approval timelines for any new packaging, it is unlikely that Duavee will return to stock in 2022.”³⁵

Other TSECs?

The conjugated estrogen/bazedoxifene combination is the first FDA-approved TSEC. Other attempts have been made to achieve similar results with combined raloxifene and 17β-estradiol.³⁶ That study was meant to be a 52-week treatment trial with either raloxifene 60 mg alone or in combination with 17β-estradiol 1 mg per day to assess effects on VMS and endometrial safety. The study was stopped early because signs of endometrial stimulation were observed in the raloxifene plus estradiol group. Thus, one cannot combine any estrogen with any SERM and assume similar results.

Clinical application

The combination of conjugated estrogen/bazedoxifene is approved for treatment of VMS of menopause as well as prevention of osteoporosis. Although it is not approved for treatment of moderate to severe VVA, in younger women who initiate treatment it should prevent the development of moderate to severe symptoms of VVA.

Finally, this drug should be protective of the breast. Conjugated estrogen has clearly shown a reduction in breast cancer incidence and mortality, and bazedoxifene is a SERM. All SERMs have, as a class effect, been shown to be antiestrogens in breast tissue, and abundant preclinical data point in that direction.

This combination of conjugated estrogen/bazedoxifene, when it is once again clinically available, may well provide a new paradigm of hormone therapy that is progestogen free and has a benefit/risk ratio that tilts toward its benefits.

Potential for wider therapeutic benefits

Newer SERMs like ospemifene, approved for treatment of VVA/GSM, and bazedoxifene/conjugated estrogen combination, approved for treatment of VMS and prevention of bone loss, have other beneficial properties that can and should result in their more widespread use. ●

Selective estrogen receptor modulators (SERMs) are unique synthetic compounds that bind to the estrogen receptor and initiate either estrogenic agonistic or antagonistic activity, depending on the confirmational change they produce on binding to the receptor. Many SERMs have come to market, others have not. Unlike estrogens, which regardless of dose or route of administration all carry risks as a boxed warning on the label, referred to as class labeling,¹ various SERMs exert various effects in some tissues (uterus, vagina) while they have apparent class properties in others (bone, breast).²

The first SERM, for all practical purposes, was tamoxifen (although clomiphene citrate is often considered a SERM). Tamoxifen was approved by the US Food and Drug Administration (FDA) in 1978 for the treatment of breast cancer and, subsequently, for breast cancer risk reduction. It became the most widely prescribed anticancer drug worldwide.

Subsequently, when data showed that tamoxifen could produce a small number of endometrial cancers and a larger number of endometrial polyps,^3,4 there was renewed interest in raloxifene. In preclinical animal studies, raloxifene behaved differently than tamoxifen in the uterus. After clinical trials with raloxifene showed uterine safety,⁵ the drug was FDA approved for prevention of osteoporosis in 1997, for treatment of osteoporosis in 1999, and for breast cancer risk reduction in 2009. Most clinicians are familiar with these 2 SERMs, which have been in clinical use for more than 4 and 2 decades, respectively.

Ospemifene: A third-generation SERM and its indications

Hormone deficiency from menopause causes vulvovaginal and urogenital changes as well as a multitude of symptoms and signs, including vulvar and vaginal thinning, loss of rugal folds, diminished elasticity, increased pH, and most notably dyspareunia. The nomenclature that previously described vulvovaginal atrophy (VVA) has been expanded to include genitourinary syndrome of menopause (GSM).⁶ Unfortunately, many health care providers do not ask patients about GSM symptoms, and few women report their symptoms to their clinician.⁷ Furthermore, although low-dose local estrogens applied vaginally have been the mainstay of therapy for VVA/GSM, only 7% of symptomatic women use any pharmacologic agent,⁸ mainly because of fear of estrogens due to the class labeling mentioned above.

Ospemifene, a newer SERM, improved superficial cells and reduced parabasal cells as seen on a maturation index compared with placebo, according to results of multiple phase 3 clinical trials^9,10; it also lowered vaginal pH and improved most bothersome symptoms (original studies were for dyspareunia). As a result, the FDA approved ospemifene for treatment of moderate to severe dyspareunia from VVA of menopause.

Subsequent studies allowed for a broadened indication to include treatment of moderate to severe dryness due to menopause.¹¹ The ospemifene label contains a boxed warning that states, “In the endometrium, [ospemifene] has estrogen agonistic effects.”¹² Although ospemifene is not an estrogen (it’s a SERM), the label goes on to state, “There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens.” This statement caused The Medical Letter to initially suggest that patients who receive ospemifene also should receive a progestational agent—a suggestion they later retracted.^13,14

To understand why the ospemifene labeling might be worded in such a way, one must review the data regarding the poorly named entity “weakly proliferative endometrium.” The package labeling combines any proliferative endometrium (“weakly” plus “actively” plus “disordered”) that occurred in the clinical trial. Thus, 86.1 per 1,000 of the ospemifene-treated patients (vs 13.3 per 1,000 of those taking placebo) had any one of the proliferative types. The problem is that “actively proliferative” endometrial glands will have mitotic activity in virtually every nucleus of the gland as well as abundant glandular progression (FIGURE 1), whereas “weakly proliferative” is actually closer to inactive or atrophic endometrium with an occasional mitotic figure in only a few nuclei of each gland (FIGURE 2).

In addition, at 1 year, the incidence of active proliferation with ospemifene was 1%.¹⁵ In examining the uterine safety study for raloxifene, both doses of that agent had an active proliferation incidence of 3% at 1 year.⁵ Furthermore, that study had an estrogen-only arm in which, at end point, the incidence of endometrial proliferation was 39%, and hyperplasia, 23%!⁵ It therefore is evident that, in the endometrium, ospemifene is much more like the SERM raloxifene than it is like estrogen. The American College of Obstetricians and Gynecologists (ACOG) endorsed ospemifene (level A evidence) as a first-line therapy for dyspareunia, noting absent endometrial stimulation.¹⁶

Continue to: Ospemifene effects on breast and bone...

 

 

Ospemifene effects on breast and bone

Although ospemifene is approved for treatment of moderate to severe VVA/GSM, it has other SERM effects typical of its class. The label currently states that ospemifene “has not been adequately studied in women with breast cancer; therefore, it should not be used in women with known or suspected breast cancer.”¹² We know that tamoxifen reduced breast cancer 49% in high-risk women in the Breast Cancer Prevention Trial (BCPT).¹⁷ We also know that in the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, raloxifene reduced breast cancer 77% in osteoporotic women,¹⁸ and in the Study of Tamoxifen and Raloxifene (STAR) trial, it performed virtually identically to tamoxifen in breast cancer prevention.¹⁹ Previous studies demonstrated that ospemifene inhibits breast cancer cell growth in in vitro cultures as well as in animal studies²⁰ and inhibits proliferation of human breast tissue epithelial cells,²¹ with breast effects similar to those seen with tamoxifen and raloxifene.

Thus, although one would not choose ospemifene as a primary treatment or risk-reducing agent for a patient with breast cancer, the direction of its activity in breast tissue is indisputable and is likely the reason that in the European Union (unlike in the United States) it is approved to treat dyspareunia from VVA/GSM in women with a prior history of breast cancer.

Virtually all SERMs have estrogen agonistic activity in bone. Bone is a dynamic organ, constantly being laid down and taken away (resorption). Estrogen and SERMs are potent antiresorptives in bone metabolism. Ospemifene effectively reduced bone loss in ovariectomized rats, with activity comparable to that of estradiol and raloxifene.²² Clinical data from 3 phase 1 or 2 clinical trials found 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.²³ Actual fracture or bone mineral density (BMD) data in postmenopausal women are lacking, but there is a good correlation between biochemical markers for bone turnover and the occurrence of fracture.²⁴ Once again, women who need treatment for osteoporosis should not be treated primarily with ospemifene, but women who use ospemifene for dyspareunia can expect positive activity on bone metabolism.

Clinical application

Ospemifene is an oral SERM approved for the treatment of moderate to severe dyspareunia as well as dryness from VVA due to menopause. In addition, it appears one can safely surmise that the direction of ospemifene’s activity in bone and breast is virtually indisputable. The magnitude of that activity, however, is unstudied. Therefore, in selecting an agent to treat women with dyspareunia or vaginal dryness from VVA of menopause, determining any potential add-on benefit for that particular patient in either bone and/or breast is clinically appropriate.

The SERM bazedoxifene

A meta-analysis of 4 randomized, placebo-controlled trials showed that another SERM, bazedoxifene, can significantly decrease the incidence of vertebral fracture in postmenopausal women at follow-up of 3 and 7 years.²⁵ That meta-analysis also confirmed the long-term favorable safety and tolerability of bazedoxifene, with no increase in adverse events, serious adverse events, myocardial infarction, stroke, venous thromboembolic events, or breast carcinoma in patients using bazedoxifene. However, bazedoxifene use did result in an increased incidence of hot flushes and leg cramps across 7 years.²⁵ Bazedoxifene is available in a 20-mg dose for treatment of postmenopausal osteoporosis in Israel and a number of European Union countries.

Continue to: Enter the concept of tissue-selective estrogen complex (TSEC)...

 

 

Enter the concept of tissue-selective estrogen complex (TSEC)

Some postmenopausal women are extremely intolerant of any progestogen added to estrogen therapy to confer endometrial protection in those with a uterus. According to the results of a clinical trial of postmenopausal women, bazedoxifene is the only SERM shown to decrease endometrial thickness compared with placebo.²⁶ This is the basis for thinking that perhaps a SERM like bazedoxifene, instead of a progestogen, could be used to confer endometrial protection.

A further consideration comes out of the evaluation of data derived from the 2 arms of the Women’s Health Initiative (WHI).²⁷ In the arm that combined conjugated estrogen with medroxyprogesterone acetate through 11.3 years, there was a 25% increase in the incidence of invasive breast cancer, which was statistically significant. Contrast that with the arm in hysterectomized women who received only conjugated estrogen (often inaccurately referred to as the “estrogen only” arm of the WHI). In that study arm, the relative risk of invasive breast cancer was reduced 23%, also statistically significant. Thus, the culprit in the breast cancer incidence difference in these 2 arms appears to be the addition of the progestogen medroxyprogesterone acetate.²⁷

Since the progestogen was used only for endometrial protection, could such endometrial protection be provided by a SERM like bazedoxifene? Preclinical trials showed that a combination of bazedoxifene and conjugated estrogen (in various estrogen doses) resulted in uterine wet weight in an ovariectomized rat model that was no different than that with placebo.²⁸

In terms of effects on breast, preclinical models showed that conjugated estrogen use resulted in less mammary duct elongation and end bud proliferation than estradiol by itself, and that the combination of conjugated estrogen and bazedoxifene resulted in mammary duct elongation and end bud proliferation that was similar to that in the ovariectomized animals and considerably less than a combination of estradiol with bazedoxifene.²⁹

Five phase 3 studies known as the SMART (Selective estrogens, Menopause, And Response to Therapy) trials were then conducted. Collectively, these studies examined the frequency and severity of vasomotor symptoms (VMS), BMD, bone turnover markers, lipid profiles, sleep, quality of life, breast density, and endometrial safety with conjugated estrogen/bazedoxifene treatment.³⁰ Based on these trials with more than 7,500 women, in 2013 the FDA approved a compound of conjugated estrogen 0.45 mg and bazedoxifene 20 mg (Duavee in the United States and Duavive outside the United States).

The incidence of endometrial hyperplasia at 12 months was consistently less than 1%, which is the FDA guidance for approval of hormone therapies. The incidence of bleeding or spotting with conjugated estrogen/bazedoxifene (FIGURE 3) in each 4-week interval over 12 months mirror-imaged that of placebo and ranged from 3.9% in the first 4-week interval to 1.7% in the last 4 weeks, compared with conjugated estrogen 0.45 mg/medroxyprogesterone acetate 1.5 mg, which had a 20.8% incidence of bleeding or spotting in the first 4-week interval and was still at an 8.8% incidence in the last 4 weeks.³¹ This is extremely relevant in clinical practice. There was no difference from placebo in breast cancer incidence, breast pain or tenderness, abnormal mammograms, or breast density at month 12.³²

In terms of frequency of VMS, there was a 74% reduction from baseline at 12 weeks compared with placebo (P<.001), as well as a 37% reduction in the VMS severity score (P<.001).³² Statistically significant improvements occurred in lumbar spine and hip BMD (P<.01) for women who were 1 to 5 years since menopause as well as for those who were more than 5 years since menopause.³³

Packaging issue puts TSEC on back order

In May 2020, Pfizer voluntarily recalled its conjugated estrogen/bazedoxifene product after identifying a “flaw in the drug’s foil laminate pouch that introduced oxygen and lowered the dissolution rate of active pharmaceutical ingredient bazedoxifene acetate.”³⁴ The manufacturer then wrote a letter to health care professionals in September 2021 stating, “Duavee continues to be out of stock due to an unexpected and complex packaging issue, resulting in manufacturing delays. This has nothing to do with the safety or quality of the product itself but could affect product stability throughout its shelf life… Given regulatory approval timelines for any new packaging, it is unlikely that Duavee will return to stock in 2022.”³⁵

Other TSECs?

The conjugated estrogen/bazedoxifene combination is the first FDA-approved TSEC. Other attempts have been made to achieve similar results with combined raloxifene and 17β-estradiol.³⁶ That study was meant to be a 52-week treatment trial with either raloxifene 60 mg alone or in combination with 17β-estradiol 1 mg per day to assess effects on VMS and endometrial safety. The study was stopped early because signs of endometrial stimulation were observed in the raloxifene plus estradiol group. Thus, one cannot combine any estrogen with any SERM and assume similar results.

Clinical application

The combination of conjugated estrogen/bazedoxifene is approved for treatment of VMS of menopause as well as prevention of osteoporosis. Although it is not approved for treatment of moderate to severe VVA, in younger women who initiate treatment it should prevent the development of moderate to severe symptoms of VVA.

Finally, this drug should be protective of the breast. Conjugated estrogen has clearly shown a reduction in breast cancer incidence and mortality, and bazedoxifene is a SERM. All SERMs have, as a class effect, been shown to be antiestrogens in breast tissue, and abundant preclinical data point in that direction.

This combination of conjugated estrogen/bazedoxifene, when it is once again clinically available, may well provide a new paradigm of hormone therapy that is progestogen free and has a benefit/risk ratio that tilts toward its benefits.

Potential for wider therapeutic benefits

Newer SERMs like ospemifene, approved for treatment of VVA/GSM, and bazedoxifene/conjugated estrogen combination, approved for treatment of VMS and prevention of bone loss, have other beneficial properties that can and should result in their more widespread use. ●

Selective estrogen receptor modulators (SERMs) are unique synthetic compounds that bind to the estrogen receptor and initiate either estrogenic agonistic or antagonistic activity, depending on the confirmational change they produce on binding to the receptor. Many SERMs have come to market, others have not. Unlike estrogens, which regardless of dose or route of administration all carry risks as a boxed warning on the label, referred to as class labeling,¹ various SERMs exert various effects in some tissues (uterus, vagina) while they have apparent class properties in others (bone, breast).²

The first SERM, for all practical purposes, was tamoxifen (although clomiphene citrate is often considered a SERM). Tamoxifen was approved by the US Food and Drug Administration (FDA) in 1978 for the treatment of breast cancer and, subsequently, for breast cancer risk reduction. It became the most widely prescribed anticancer drug worldwide.

Subsequently, when data showed that tamoxifen could produce a small number of endometrial cancers and a larger number of endometrial polyps,^3,4 there was renewed interest in raloxifene. In preclinical animal studies, raloxifene behaved differently than tamoxifen in the uterus. After clinical trials with raloxifene showed uterine safety,⁵ the drug was FDA approved for prevention of osteoporosis in 1997, for treatment of osteoporosis in 1999, and for breast cancer risk reduction in 2009. Most clinicians are familiar with these 2 SERMs, which have been in clinical use for more than 4 and 2 decades, respectively.

Ospemifene: A third-generation SERM and its indications

Hormone deficiency from menopause causes vulvovaginal and urogenital changes as well as a multitude of symptoms and signs, including vulvar and vaginal thinning, loss of rugal folds, diminished elasticity, increased pH, and most notably dyspareunia. The nomenclature that previously described vulvovaginal atrophy (VVA) has been expanded to include genitourinary syndrome of menopause (GSM).⁶ Unfortunately, many health care providers do not ask patients about GSM symptoms, and few women report their symptoms to their clinician.⁷ Furthermore, although low-dose local estrogens applied vaginally have been the mainstay of therapy for VVA/GSM, only 7% of symptomatic women use any pharmacologic agent,⁸ mainly because of fear of estrogens due to the class labeling mentioned above.

Ospemifene, a newer SERM, improved superficial cells and reduced parabasal cells as seen on a maturation index compared with placebo, according to results of multiple phase 3 clinical trials^9,10; it also lowered vaginal pH and improved most bothersome symptoms (original studies were for dyspareunia). As a result, the FDA approved ospemifene for treatment of moderate to severe dyspareunia from VVA of menopause.

Subsequent studies allowed for a broadened indication to include treatment of moderate to severe dryness due to menopause.¹¹ The ospemifene label contains a boxed warning that states, “In the endometrium, [ospemifene] has estrogen agonistic effects.”¹² Although ospemifene is not an estrogen (it’s a SERM), the label goes on to state, “There is an increased risk of endometrial cancer in a woman with a uterus who uses unopposed estrogens.” This statement caused The Medical Letter to initially suggest that patients who receive ospemifene also should receive a progestational agent—a suggestion they later retracted.^13,14

To understand why the ospemifene labeling might be worded in such a way, one must review the data regarding the poorly named entity “weakly proliferative endometrium.” The package labeling combines any proliferative endometrium (“weakly” plus “actively” plus “disordered”) that occurred in the clinical trial. Thus, 86.1 per 1,000 of the ospemifene-treated patients (vs 13.3 per 1,000 of those taking placebo) had any one of the proliferative types. The problem is that “actively proliferative” endometrial glands will have mitotic activity in virtually every nucleus of the gland as well as abundant glandular progression (FIGURE 1), whereas “weakly proliferative” is actually closer to inactive or atrophic endometrium with an occasional mitotic figure in only a few nuclei of each gland (FIGURE 2).

In addition, at 1 year, the incidence of active proliferation with ospemifene was 1%.¹⁵ In examining the uterine safety study for raloxifene, both doses of that agent had an active proliferation incidence of 3% at 1 year.⁵ Furthermore, that study had an estrogen-only arm in which, at end point, the incidence of endometrial proliferation was 39%, and hyperplasia, 23%!⁵ It therefore is evident that, in the endometrium, ospemifene is much more like the SERM raloxifene than it is like estrogen. The American College of Obstetricians and Gynecologists (ACOG) endorsed ospemifene (level A evidence) as a first-line therapy for dyspareunia, noting absent endometrial stimulation.¹⁶

Continue to: Ospemifene effects on breast and bone...

 

 

Ospemifene effects on breast and bone

Although ospemifene is approved for treatment of moderate to severe VVA/GSM, it has other SERM effects typical of its class. The label currently states that ospemifene “has not been adequately studied in women with breast cancer; therefore, it should not be used in women with known or suspected breast cancer.”¹² We know that tamoxifen reduced breast cancer 49% in high-risk women in the Breast Cancer Prevention Trial (BCPT).¹⁷ We also know that in the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, raloxifene reduced breast cancer 77% in osteoporotic women,¹⁸ and in the Study of Tamoxifen and Raloxifene (STAR) trial, it performed virtually identically to tamoxifen in breast cancer prevention.¹⁹ Previous studies demonstrated that ospemifene inhibits breast cancer cell growth in in vitro cultures as well as in animal studies²⁰ and inhibits proliferation of human breast tissue epithelial cells,²¹ with breast effects similar to those seen with tamoxifen and raloxifene.

Thus, although one would not choose ospemifene as a primary treatment or risk-reducing agent for a patient with breast cancer, the direction of its activity in breast tissue is indisputable and is likely the reason that in the European Union (unlike in the United States) it is approved to treat dyspareunia from VVA/GSM in women with a prior history of breast cancer.

Virtually all SERMs have estrogen agonistic activity in bone. Bone is a dynamic organ, constantly being laid down and taken away (resorption). Estrogen and SERMs are potent antiresorptives in bone metabolism. Ospemifene effectively reduced bone loss in ovariectomized rats, with activity comparable to that of estradiol and raloxifene.²² Clinical data from 3 phase 1 or 2 clinical trials found 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.²³ Actual fracture or bone mineral density (BMD) data in postmenopausal women are lacking, but there is a good correlation between biochemical markers for bone turnover and the occurrence of fracture.²⁴ Once again, women who need treatment for osteoporosis should not be treated primarily with ospemifene, but women who use ospemifene for dyspareunia can expect positive activity on bone metabolism.

Clinical application

Ospemifene is an oral SERM approved for the treatment of moderate to severe dyspareunia as well as dryness from VVA due to menopause. In addition, it appears one can safely surmise that the direction of ospemifene’s activity in bone and breast is virtually indisputable. The magnitude of that activity, however, is unstudied. Therefore, in selecting an agent to treat women with dyspareunia or vaginal dryness from VVA of menopause, determining any potential add-on benefit for that particular patient in either bone and/or breast is clinically appropriate.

The SERM bazedoxifene

A meta-analysis of 4 randomized, placebo-controlled trials showed that another SERM, bazedoxifene, can significantly decrease the incidence of vertebral fracture in postmenopausal women at follow-up of 3 and 7 years.²⁵ That meta-analysis also confirmed the long-term favorable safety and tolerability of bazedoxifene, with no increase in adverse events, serious adverse events, myocardial infarction, stroke, venous thromboembolic events, or breast carcinoma in patients using bazedoxifene. However, bazedoxifene use did result in an increased incidence of hot flushes and leg cramps across 7 years.²⁵ Bazedoxifene is available in a 20-mg dose for treatment of postmenopausal osteoporosis in Israel and a number of European Union countries.

Continue to: Enter the concept of tissue-selective estrogen complex (TSEC)...

 

 

Enter the concept of tissue-selective estrogen complex (TSEC)

Some postmenopausal women are extremely intolerant of any progestogen added to estrogen therapy to confer endometrial protection in those with a uterus. According to the results of a clinical trial of postmenopausal women, bazedoxifene is the only SERM shown to decrease endometrial thickness compared with placebo.²⁶ This is the basis for thinking that perhaps a SERM like bazedoxifene, instead of a progestogen, could be used to confer endometrial protection.

A further consideration comes out of the evaluation of data derived from the 2 arms of the Women’s Health Initiative (WHI).²⁷ In the arm that combined conjugated estrogen with medroxyprogesterone acetate through 11.3 years, there was a 25% increase in the incidence of invasive breast cancer, which was statistically significant. Contrast that with the arm in hysterectomized women who received only conjugated estrogen (often inaccurately referred to as the “estrogen only” arm of the WHI). In that study arm, the relative risk of invasive breast cancer was reduced 23%, also statistically significant. Thus, the culprit in the breast cancer incidence difference in these 2 arms appears to be the addition of the progestogen medroxyprogesterone acetate.²⁷

Since the progestogen was used only for endometrial protection, could such endometrial protection be provided by a SERM like bazedoxifene? Preclinical trials showed that a combination of bazedoxifene and conjugated estrogen (in various estrogen doses) resulted in uterine wet weight in an ovariectomized rat model that was no different than that with placebo.²⁸

In terms of effects on breast, preclinical models showed that conjugated estrogen use resulted in less mammary duct elongation and end bud proliferation than estradiol by itself, and that the combination of conjugated estrogen and bazedoxifene resulted in mammary duct elongation and end bud proliferation that was similar to that in the ovariectomized animals and considerably less than a combination of estradiol with bazedoxifene.²⁹

Five phase 3 studies known as the SMART (Selective estrogens, Menopause, And Response to Therapy) trials were then conducted. Collectively, these studies examined the frequency and severity of vasomotor symptoms (VMS), BMD, bone turnover markers, lipid profiles, sleep, quality of life, breast density, and endometrial safety with conjugated estrogen/bazedoxifene treatment.³⁰ Based on these trials with more than 7,500 women, in 2013 the FDA approved a compound of conjugated estrogen 0.45 mg and bazedoxifene 20 mg (Duavee in the United States and Duavive outside the United States).

The incidence of endometrial hyperplasia at 12 months was consistently less than 1%, which is the FDA guidance for approval of hormone therapies. The incidence of bleeding or spotting with conjugated estrogen/bazedoxifene (FIGURE 3) in each 4-week interval over 12 months mirror-imaged that of placebo and ranged from 3.9% in the first 4-week interval to 1.7% in the last 4 weeks, compared with conjugated estrogen 0.45 mg/medroxyprogesterone acetate 1.5 mg, which had a 20.8% incidence of bleeding or spotting in the first 4-week interval and was still at an 8.8% incidence in the last 4 weeks.³¹ This is extremely relevant in clinical practice. There was no difference from placebo in breast cancer incidence, breast pain or tenderness, abnormal mammograms, or breast density at month 12.³²

In terms of frequency of VMS, there was a 74% reduction from baseline at 12 weeks compared with placebo (P<.001), as well as a 37% reduction in the VMS severity score (P<.001).³² Statistically significant improvements occurred in lumbar spine and hip BMD (P<.01) for women who were 1 to 5 years since menopause as well as for those who were more than 5 years since menopause.³³

Packaging issue puts TSEC on back order

In May 2020, Pfizer voluntarily recalled its conjugated estrogen/bazedoxifene product after identifying a “flaw in the drug’s foil laminate pouch that introduced oxygen and lowered the dissolution rate of active pharmaceutical ingredient bazedoxifene acetate.”³⁴ The manufacturer then wrote a letter to health care professionals in September 2021 stating, “Duavee continues to be out of stock due to an unexpected and complex packaging issue, resulting in manufacturing delays. This has nothing to do with the safety or quality of the product itself but could affect product stability throughout its shelf life… Given regulatory approval timelines for any new packaging, it is unlikely that Duavee will return to stock in 2022.”³⁵

Other TSECs?

The conjugated estrogen/bazedoxifene combination is the first FDA-approved TSEC. Other attempts have been made to achieve similar results with combined raloxifene and 17β-estradiol.³⁶ That study was meant to be a 52-week treatment trial with either raloxifene 60 mg alone or in combination with 17β-estradiol 1 mg per day to assess effects on VMS and endometrial safety. The study was stopped early because signs of endometrial stimulation were observed in the raloxifene plus estradiol group. Thus, one cannot combine any estrogen with any SERM and assume similar results.

Clinical application

The combination of conjugated estrogen/bazedoxifene is approved for treatment of VMS of menopause as well as prevention of osteoporosis. Although it is not approved for treatment of moderate to severe VVA, in younger women who initiate treatment it should prevent the development of moderate to severe symptoms of VVA.

Finally, this drug should be protective of the breast. Conjugated estrogen has clearly shown a reduction in breast cancer incidence and mortality, and bazedoxifene is a SERM. All SERMs have, as a class effect, been shown to be antiestrogens in breast tissue, and abundant preclinical data point in that direction.

This combination of conjugated estrogen/bazedoxifene, when it is once again clinically available, may well provide a new paradigm of hormone therapy that is progestogen free and has a benefit/risk ratio that tilts toward its benefits.

Potential for wider therapeutic benefits

Newer SERMs like ospemifene, approved for treatment of VVA/GSM, and bazedoxifene/conjugated estrogen combination, approved for treatment of VMS and prevention of bone loss, have other beneficial properties that can and should result in their more widespread use. ●

ILLUSTRATION BY KIMBERLY MARTENS FOR OBG MANAGEMENT

While its etiology remains uncertain, cesarean scar niche (CSN) is well publicized, as are its pathological clinical manifestations. In a future pregnancy, they include cesarean scar pregnancy (CSP), which in turn can lead to placenta accreta spectrum, and possible uterine rupture/dehiscence of a residual thin myometrial layer. CSP refers to the implantation of an early pregnancy on the scar or in the niche at the site of a prior cesarean delivery (CD); it has an incidence of 1 per 1,000 pregnancies. An estimated 52% of CSPs occur after even just one CD.¹ CSP has been linked to placenta accreta spectrum and has been shown to be its precursor.² Both CSP and placenta accreta spectrum can be consequences of CD and share a common histology of villous or placental attachment/invasion into the cesarean scar.³ The incidence of placenta accreta spectrum has risen from about 1 in 4,000 live births in the 1970s to 1 in 2,500 in the 1980s; in 2016, the incidence of placenta accreta spectrum was reported as 1 per 272 live births.⁴

Placenta accreta spectrum denotes the attachment of the placenta into and through the myometrium,⁵ and it can result in severe complications, including hemorrhage, hysterectomy, and intensive care treatment. The increasing rate of placenta accreta spectrum parallels the increasing CD rate, which rose from 5.8% in 1970 to 31.9% in 2016.⁶ Multiple repeat CDs are increasing in frequency as well. At the beginning of the century, placenta accreta spectrum mainly occurred after manual removal of the placenta, uterine curettage, or endometritis. Recently, experts are in agreement that the main determinant of placenta accreta spectrum is the uterine scar and niche formation after a previous CD.⁵ Larger niches are associated with an increased incidence of uterine rupture or dehiscence in a subsequent pregnancy.⁷

In the nonpregnant state, such niches are associated with intermenstrual bleeding, pelvic pain, painful intercourse, painful menses, and subfertility, becoming increasingly more severe in women with greater numbers of CDs.^8-10 Conception rate with assisted reproductive treatment is notably reduced.¹¹

Understanding its etiology

Monteagudo and colleagues first described a “niche” in 100% of 44 women evaluated for postmenopausal bleeding who had a prior CD.¹² CSN has been the subject of well over 3,000 publications over the past 30 years. While the topic generates much interest among researchers, it is garnering little traction among practicing obstetricians. Such “niches,” also referred to as isthmocele, cesarean scar defect, or a diverticulum, was first described in 1961¹³ and later defined on ultrasonography as a hypoechoic triangular-shaped uterine defect outlined by saline instillation sonohysterogram (SIS), reflecting a discontinuation of the myometrium at the site of a previous CD.¹² In 2019, a European task force further defined a CSN as an “indentation at the site in the cesarean section scar with a depth of at least 2 mm” and extended the classification to include branches as extensions toward the anterior uterine serosa.¹⁴ Using this criterion, sonographic postoperative evaluation after one CD revealed a CSN in 68.9% of women with one single-layer uterine closure and in 73.6% of women after a double-layer closure.¹⁵ Larger niche sizes with thinner residual myometrial thickness appeared more frequently when a single-layer closure technique was used, without closure of the peritoneum. Its prevalence varies from 56% to 84%.^16,17

Etiology of CSN formation: Our hypotheses

The precise pathophysiology of CSN remains elusive. Speculations attributed niche formation to numerous factors: timing of surgery, cervical incision, incomplete closure of the uterine incision, adhesion formation between the CD scar and the abdominal wall, and inherent maternal conditions which may impair healing, such as smoking, obesity, diabetes, maternal age, and labor status.^18-20 Retroflexion of the uterus is reportedly associated with increased incidence and size of the niche, with CSN 50% more likely to develop in women with a retroflexed versus an anteverted uterus.²¹ We demonstrated the origin of niche formation in real-time from the start to the completion of uterine closure by a video capture of a single-layer closure followed by an immediate SIS of the ex vivo hysterectomized uterus, and histopathologic proof of the presence of endometrial cells defining the “niche.”²² This case exposes the misalignment of the uterine wall, while including the endometrium in the closure (FIGURE 1). Similarly, pathologic studies of hysteroscopy-resected isthmocele ridges of symptomatic women with niche-related subfertility revealed the tissue edges lined by endocervical, endometrial, or isthmic mucosa either combined or isolated in the scar.²³ The presence of endometrial/cervical tissue in the myometrial closure has been debated for over a century.^24,25

Continue to: Uterine closure techniques...

 

 

Uterine closure techniques: Historical perspective

In 1882, Max Sanger introduced a vertical uterine closure of a classical cesarean operation in response to hysterectomy as the contemporaneous alternative to prevent infection, bleeding, and death.²⁴ Dr. Sanger emphasized layer approximation, suturing, and the avoidance of decidua in the first layer (FIGURE 2). This became the teaching of the classical CD until the 1970s. In 1926, Munro Kerr addressed uterine rupture with labor after a classical CD by introducing the lower uterine segment transverse incision. He cautioned to maintain the decidua inside the uterine 2-layer closure of the cavity.²⁵ These pioneers were joined by others to rally for endometrium exclusion while promoting layer approximation. These techniques became universally standard and were taught across teaching medical centers in the United States and abroad until about 50 years ago.

In the 1970s, newer developments brought significant changes to uterine closure techniques. Initiated by Joel-Cohen,²⁶ blunt dissection of the abdominal incision was adapted by Michael Stark, creating what came to be known as the Misgav-Ladach cesarean technique.²⁷ Stark emphasized blunt dissection and introduced single-layer closure. Thereby the exclusion of the endometrium, used for more than 70 years, was abandoned by the present-day single- or double-layer uterine closure in favor of cost and time savings. Systematic reviews and meta-analyses comparing the two contrasting techniques were inconclusive, noting that the niche prevalence and size were similar in both groups. These studies did not take into account the variety of individual techniques or the position of the endometrium in the final closures.²⁸

Endometrium and uterine closure

Our recent study examining uterine scar defect in women after one primary CD by SIS concluded that a specific endometrium-free closure technique (EFCT) (FIGURE 3) is associated with fewer and less severe defects and a thicker residual myometrial thickness when compared with closures with unknown or endometrium inclusion.²⁹ The study found non-specific closure techniques to be 6 times more likely to form a niche of 2-mm deep or greater than the EFCT.

Furthermore, we surveyed the diversity of uterine closures and the location of the endometrium among obstetricians in one institution.³⁰ Presence of endometrium on the surface of the final uterine closure was reported by 20% of respondents (see Figure 1). When asked for their opinion on the impact of CD techniques on placenta accreta spectrum, without available evidence 80% of the survey respondents reported no relationship to techniques, and only 20% suggested an association. This particular study demonstrates that the surgical techniques just described are random, unfettered, and applied without consideration of clinical outcomes.

Our recent retrospective study that spanned 30 years and examined the EFCT—per­formed anywhere between 3 to 9 consecutive CDs—revealed no abnormal placentation in any subsequent pregnancies.³¹ This was one of the few clinical studies of the long-term consequences of a uterine closure technique. In this study, the endometrium was excluded during the uterine closure, allowing its free edges to abut and heal. This step avoids scarring the endometrial-myometrial (EM) interface and unintentional inclusion of endometrium in the closed uterine wall. In this context, Jauniaux and colleagues cited the destruction of the EM interface as the main factor for placenta-adherent disorders.³² Sholapurkar and others highlight the need to further examine intrinsic details of uterine closure beyond single- and double-layer techniques to better understand the etiology of cesarean scar formation.¹⁹ The search for the pathophysiology of CSN continues to present significant challenges imposed by the variety of currently practiced uterine closures.

Continue to: Focus on prevention...

 

 

Research: Focus on prevention

Our research aims to address the endometrium, a specific layer that was the topic of concern in nascent CD techniques, as a renewed and contemporary one. The presence of the endometrium in ectopic locations or its destruction from intrauterine surgeries or infections has been implicated in abnormal placentation.^13,24 Our approach, in theory, is to limit the position of the endometrium to its innermost location and avoid its iatrogenic suturing and inclusion into the uterine wall closure. The rationale of sparing the endometrium in a layer-by-layer approximation is to allow for a closer restoration to normal anatomy and physiology than a random “en masse” uterine wall closure would permit. For this reason, the EM junction, the perimetrium, and the serosa must be identified and realigned for a more effective closure that incorporates the entire myometrial thickness. As evidence supports technical impact on the development of uterine scar defect in women after one CD, future studies are needed to evaluate uterine integrity by saline infusion sonohysterography in multiparous women with a prior random closure technique or a prior EFCT.

The potential long-term risks of blunt dissection for opening the uterus have not been studied. There are no physiologic lines in the uterine wall to facilitate a regular-bordered uterine stretch. The tissue stretch, which depends on the individual surgeon’s strength applied during the procedure and patient’s labor status, may result in an irregular tear and a difficult repair. The EFCT technique shows a more optimized risk-benefit ratio for an anatomical repair and is replicable. The safety of uterine layer re-approximation has been demonstrated and can be studied in large populations using strict uniform criteria.

Current and future challenges

Residency training

Most recently, teachers of resident trainees are mostly familiar with blunt dissection, techniques of which are passed on unchallenged from resident to resident. The endometrium and peritoneum are neither identified nor treated as separate layers, thus becoming obsolete as surgical and anatomical landmarks.

Standardization of CD techniques

Front-line obstetricians are persuaded to practice a standardized approach that relies on the benefits of cost related to operating room turnover as well as surgeons’ time savings without consideration of outcomes in subsequent pregnancies. Sholapurkar has warned that “wrong standardization” is far worse than no standardization, worse for the training of junior obstetricians, as it can inhibit critical reasoning about safe surgical techniques that can optimize outcomes of the condition of the lower uterine segment.³³

Emergence of cost and time savings in clinical practice

A time-cost savings argument is relatively negligeable in an estimated 40-minute CD. By contrast, deliberate surgical technique and carrying out the appropriate steps for the particular condition at hand to achieve the best outcomes assume more weight.³² Furthermore, this short-term cost benefit is challenged by the comparatively larger costs associated with the diagnosis, the treatment of post-CD adverse consequences (outlined above), as well as the emotional impact on women and their families. Additionally, the emphasis on time savings creates a generation of surgeons fixated with total operative time without consideration of long-term risks and adverse maternal outcomes.

Physician autonomy has led to the unmonitored freedom of obstetricians to choose their own technique for a CD, with some employing the commonly practiced culture of fastest turnaround even in nonurgent circumstances.

Documentation and terminology

Current documenting systems are not detail-oriented enough to assist in a thorough correlation between surgical techniques and outcomes. The use of single- or double-layer closure terminology is insufficient and has proven to be flawed, without describing the handling of the endometrium in terms of its inclusion or exclusion in the closure.

Quality improvement feedback

Long-term post-CD complications are often not reported to the physician or institution involved in the prior CD. In our opinion, some sort of registry would be of value. Perhaps then subsequent CD outcomes could be traced back and reported to the prior institution and surgeon. Feedback is critical to understanding the correlation between techniques and outcomes and more specifically to gathering learning points and using data for quality improvement of future cases.

Patient education

While women continue to have complications following the presently used surgical techniques, they often have expectations not discussed with their obstetricians. Women should be educated and empowered to realize the different approaches to all aspects and consequences of CDs.

Conclusion

The technique of excluding the endometrium in closing the uterine incision appears to reduce subsequent abnormal placentation and diminish the frequency and size of post-CD scar defect. The revival of the endometrium-free closure technique may allow significant change in the postoperative results. Currently, standardization of CD technique is being promoted on the basis of time- and cost-savings rather than clinical outcomes. Simultaneously, inroads are being made to better understand the risks and consequences of CD.

Emerging evidence suggests that a post-CD niche is the result of poor layer approximation as well as inclusion of the endometrium, which prevent healing of the uterine wall and often enables faulty implantation of the fertilized oocyte in the next pregnancy, potentially giving rise to placenta accreta spectrum. The prevalence and size of the defect can be minimized by techniques aimed at restoring the anatomy of the uterine wall and the physiology of the endometrium. Specialized training and education are necessary to stress the importance of anatomical assessment and decision making at the time of uterine closure. ●

ILLUSTRATION BY KIMBERLY MARTENS FOR OBG MANAGEMENT

While its etiology remains uncertain, cesarean scar niche (CSN) is well publicized, as are its pathological clinical manifestations. In a future pregnancy, they include cesarean scar pregnancy (CSP), which in turn can lead to placenta accreta spectrum, and possible uterine rupture/dehiscence of a residual thin myometrial layer. CSP refers to the implantation of an early pregnancy on the scar or in the niche at the site of a prior cesarean delivery (CD); it has an incidence of 1 per 1,000 pregnancies. An estimated 52% of CSPs occur after even just one CD.¹ CSP has been linked to placenta accreta spectrum and has been shown to be its precursor.² Both CSP and placenta accreta spectrum can be consequences of CD and share a common histology of villous or placental attachment/invasion into the cesarean scar.³ The incidence of placenta accreta spectrum has risen from about 1 in 4,000 live births in the 1970s to 1 in 2,500 in the 1980s; in 2016, the incidence of placenta accreta spectrum was reported as 1 per 272 live births.⁴

Placenta accreta spectrum denotes the attachment of the placenta into and through the myometrium,⁵ and it can result in severe complications, including hemorrhage, hysterectomy, and intensive care treatment. The increasing rate of placenta accreta spectrum parallels the increasing CD rate, which rose from 5.8% in 1970 to 31.9% in 2016.⁶ Multiple repeat CDs are increasing in frequency as well. At the beginning of the century, placenta accreta spectrum mainly occurred after manual removal of the placenta, uterine curettage, or endometritis. Recently, experts are in agreement that the main determinant of placenta accreta spectrum is the uterine scar and niche formation after a previous CD.⁵ Larger niches are associated with an increased incidence of uterine rupture or dehiscence in a subsequent pregnancy.⁷

In the nonpregnant state, such niches are associated with intermenstrual bleeding, pelvic pain, painful intercourse, painful menses, and subfertility, becoming increasingly more severe in women with greater numbers of CDs.^8-10 Conception rate with assisted reproductive treatment is notably reduced.¹¹

Understanding its etiology

Monteagudo and colleagues first described a “niche” in 100% of 44 women evaluated for postmenopausal bleeding who had a prior CD.¹² CSN has been the subject of well over 3,000 publications over the past 30 years. While the topic generates much interest among researchers, it is garnering little traction among practicing obstetricians. Such “niches,” also referred to as isthmocele, cesarean scar defect, or a diverticulum, was first described in 1961¹³ and later defined on ultrasonography as a hypoechoic triangular-shaped uterine defect outlined by saline instillation sonohysterogram (SIS), reflecting a discontinuation of the myometrium at the site of a previous CD.¹² In 2019, a European task force further defined a CSN as an “indentation at the site in the cesarean section scar with a depth of at least 2 mm” and extended the classification to include branches as extensions toward the anterior uterine serosa.¹⁴ Using this criterion, sonographic postoperative evaluation after one CD revealed a CSN in 68.9% of women with one single-layer uterine closure and in 73.6% of women after a double-layer closure.¹⁵ Larger niche sizes with thinner residual myometrial thickness appeared more frequently when a single-layer closure technique was used, without closure of the peritoneum. Its prevalence varies from 56% to 84%.^16,17

Etiology of CSN formation: Our hypotheses

The precise pathophysiology of CSN remains elusive. Speculations attributed niche formation to numerous factors: timing of surgery, cervical incision, incomplete closure of the uterine incision, adhesion formation between the CD scar and the abdominal wall, and inherent maternal conditions which may impair healing, such as smoking, obesity, diabetes, maternal age, and labor status.^18-20 Retroflexion of the uterus is reportedly associated with increased incidence and size of the niche, with CSN 50% more likely to develop in women with a retroflexed versus an anteverted uterus.²¹ We demonstrated the origin of niche formation in real-time from the start to the completion of uterine closure by a video capture of a single-layer closure followed by an immediate SIS of the ex vivo hysterectomized uterus, and histopathologic proof of the presence of endometrial cells defining the “niche.”²² This case exposes the misalignment of the uterine wall, while including the endometrium in the closure (FIGURE 1). Similarly, pathologic studies of hysteroscopy-resected isthmocele ridges of symptomatic women with niche-related subfertility revealed the tissue edges lined by endocervical, endometrial, or isthmic mucosa either combined or isolated in the scar.²³ The presence of endometrial/cervical tissue in the myometrial closure has been debated for over a century.^24,25

Continue to: Uterine closure techniques...

 

 

Uterine closure techniques: Historical perspective

In 1882, Max Sanger introduced a vertical uterine closure of a classical cesarean operation in response to hysterectomy as the contemporaneous alternative to prevent infection, bleeding, and death.²⁴ Dr. Sanger emphasized layer approximation, suturing, and the avoidance of decidua in the first layer (FIGURE 2). This became the teaching of the classical CD until the 1970s. In 1926, Munro Kerr addressed uterine rupture with labor after a classical CD by introducing the lower uterine segment transverse incision. He cautioned to maintain the decidua inside the uterine 2-layer closure of the cavity.²⁵ These pioneers were joined by others to rally for endometrium exclusion while promoting layer approximation. These techniques became universally standard and were taught across teaching medical centers in the United States and abroad until about 50 years ago.

In the 1970s, newer developments brought significant changes to uterine closure techniques. Initiated by Joel-Cohen,²⁶ blunt dissection of the abdominal incision was adapted by Michael Stark, creating what came to be known as the Misgav-Ladach cesarean technique.²⁷ Stark emphasized blunt dissection and introduced single-layer closure. Thereby the exclusion of the endometrium, used for more than 70 years, was abandoned by the present-day single- or double-layer uterine closure in favor of cost and time savings. Systematic reviews and meta-analyses comparing the two contrasting techniques were inconclusive, noting that the niche prevalence and size were similar in both groups. These studies did not take into account the variety of individual techniques or the position of the endometrium in the final closures.²⁸

Endometrium and uterine closure

Our recent study examining uterine scar defect in women after one primary CD by SIS concluded that a specific endometrium-free closure technique (EFCT) (FIGURE 3) is associated with fewer and less severe defects and a thicker residual myometrial thickness when compared with closures with unknown or endometrium inclusion.²⁹ The study found non-specific closure techniques to be 6 times more likely to form a niche of 2-mm deep or greater than the EFCT.

Furthermore, we surveyed the diversity of uterine closures and the location of the endometrium among obstetricians in one institution.³⁰ Presence of endometrium on the surface of the final uterine closure was reported by 20% of respondents (see Figure 1). When asked for their opinion on the impact of CD techniques on placenta accreta spectrum, without available evidence 80% of the survey respondents reported no relationship to techniques, and only 20% suggested an association. This particular study demonstrates that the surgical techniques just described are random, unfettered, and applied without consideration of clinical outcomes.

Our recent retrospective study that spanned 30 years and examined the EFCT—per­formed anywhere between 3 to 9 consecutive CDs—revealed no abnormal placentation in any subsequent pregnancies.³¹ This was one of the few clinical studies of the long-term consequences of a uterine closure technique. In this study, the endometrium was excluded during the uterine closure, allowing its free edges to abut and heal. This step avoids scarring the endometrial-myometrial (EM) interface and unintentional inclusion of endometrium in the closed uterine wall. In this context, Jauniaux and colleagues cited the destruction of the EM interface as the main factor for placenta-adherent disorders.³² Sholapurkar and others highlight the need to further examine intrinsic details of uterine closure beyond single- and double-layer techniques to better understand the etiology of cesarean scar formation.¹⁹ The search for the pathophysiology of CSN continues to present significant challenges imposed by the variety of currently practiced uterine closures.

Continue to: Focus on prevention...

 

 

Research: Focus on prevention

Our research aims to address the endometrium, a specific layer that was the topic of concern in nascent CD techniques, as a renewed and contemporary one. The presence of the endometrium in ectopic locations or its destruction from intrauterine surgeries or infections has been implicated in abnormal placentation.^13,24 Our approach, in theory, is to limit the position of the endometrium to its innermost location and avoid its iatrogenic suturing and inclusion into the uterine wall closure. The rationale of sparing the endometrium in a layer-by-layer approximation is to allow for a closer restoration to normal anatomy and physiology than a random “en masse” uterine wall closure would permit. For this reason, the EM junction, the perimetrium, and the serosa must be identified and realigned for a more effective closure that incorporates the entire myometrial thickness. As evidence supports technical impact on the development of uterine scar defect in women after one CD, future studies are needed to evaluate uterine integrity by saline infusion sonohysterography in multiparous women with a prior random closure technique or a prior EFCT.

The potential long-term risks of blunt dissection for opening the uterus have not been studied. There are no physiologic lines in the uterine wall to facilitate a regular-bordered uterine stretch. The tissue stretch, which depends on the individual surgeon’s strength applied during the procedure and patient’s labor status, may result in an irregular tear and a difficult repair. The EFCT technique shows a more optimized risk-benefit ratio for an anatomical repair and is replicable. The safety of uterine layer re-approximation has been demonstrated and can be studied in large populations using strict uniform criteria.

Current and future challenges

Residency training

Most recently, teachers of resident trainees are mostly familiar with blunt dissection, techniques of which are passed on unchallenged from resident to resident. The endometrium and peritoneum are neither identified nor treated as separate layers, thus becoming obsolete as surgical and anatomical landmarks.

Standardization of CD techniques

Front-line obstetricians are persuaded to practice a standardized approach that relies on the benefits of cost related to operating room turnover as well as surgeons’ time savings without consideration of outcomes in subsequent pregnancies. Sholapurkar has warned that “wrong standardization” is far worse than no standardization, worse for the training of junior obstetricians, as it can inhibit critical reasoning about safe surgical techniques that can optimize outcomes of the condition of the lower uterine segment.³³

Emergence of cost and time savings in clinical practice

A time-cost savings argument is relatively negligeable in an estimated 40-minute CD. By contrast, deliberate surgical technique and carrying out the appropriate steps for the particular condition at hand to achieve the best outcomes assume more weight.³² Furthermore, this short-term cost benefit is challenged by the comparatively larger costs associated with the diagnosis, the treatment of post-CD adverse consequences (outlined above), as well as the emotional impact on women and their families. Additionally, the emphasis on time savings creates a generation of surgeons fixated with total operative time without consideration of long-term risks and adverse maternal outcomes.

Physician autonomy has led to the unmonitored freedom of obstetricians to choose their own technique for a CD, with some employing the commonly practiced culture of fastest turnaround even in nonurgent circumstances.

Documentation and terminology

Current documenting systems are not detail-oriented enough to assist in a thorough correlation between surgical techniques and outcomes. The use of single- or double-layer closure terminology is insufficient and has proven to be flawed, without describing the handling of the endometrium in terms of its inclusion or exclusion in the closure.

Quality improvement feedback

Long-term post-CD complications are often not reported to the physician or institution involved in the prior CD. In our opinion, some sort of registry would be of value. Perhaps then subsequent CD outcomes could be traced back and reported to the prior institution and surgeon. Feedback is critical to understanding the correlation between techniques and outcomes and more specifically to gathering learning points and using data for quality improvement of future cases.

Patient education

While women continue to have complications following the presently used surgical techniques, they often have expectations not discussed with their obstetricians. Women should be educated and empowered to realize the different approaches to all aspects and consequences of CDs.

Conclusion

The technique of excluding the endometrium in closing the uterine incision appears to reduce subsequent abnormal placentation and diminish the frequency and size of post-CD scar defect. The revival of the endometrium-free closure technique may allow significant change in the postoperative results. Currently, standardization of CD technique is being promoted on the basis of time- and cost-savings rather than clinical outcomes. Simultaneously, inroads are being made to better understand the risks and consequences of CD.

Emerging evidence suggests that a post-CD niche is the result of poor layer approximation as well as inclusion of the endometrium, which prevent healing of the uterine wall and often enables faulty implantation of the fertilized oocyte in the next pregnancy, potentially giving rise to placenta accreta spectrum. The prevalence and size of the defect can be minimized by techniques aimed at restoring the anatomy of the uterine wall and the physiology of the endometrium. Specialized training and education are necessary to stress the importance of anatomical assessment and decision making at the time of uterine closure. ●

ILLUSTRATION BY KIMBERLY MARTENS FOR OBG MANAGEMENT

While its etiology remains uncertain, cesarean scar niche (CSN) is well publicized, as are its pathological clinical manifestations. In a future pregnancy, they include cesarean scar pregnancy (CSP), which in turn can lead to placenta accreta spectrum, and possible uterine rupture/dehiscence of a residual thin myometrial layer. CSP refers to the implantation of an early pregnancy on the scar or in the niche at the site of a prior cesarean delivery (CD); it has an incidence of 1 per 1,000 pregnancies. An estimated 52% of CSPs occur after even just one CD.¹ CSP has been linked to placenta accreta spectrum and has been shown to be its precursor.² Both CSP and placenta accreta spectrum can be consequences of CD and share a common histology of villous or placental attachment/invasion into the cesarean scar.³ The incidence of placenta accreta spectrum has risen from about 1 in 4,000 live births in the 1970s to 1 in 2,500 in the 1980s; in 2016, the incidence of placenta accreta spectrum was reported as 1 per 272 live births.⁴

Placenta accreta spectrum denotes the attachment of the placenta into and through the myometrium,⁵ and it can result in severe complications, including hemorrhage, hysterectomy, and intensive care treatment. The increasing rate of placenta accreta spectrum parallels the increasing CD rate, which rose from 5.8% in 1970 to 31.9% in 2016.⁶ Multiple repeat CDs are increasing in frequency as well. At the beginning of the century, placenta accreta spectrum mainly occurred after manual removal of the placenta, uterine curettage, or endometritis. Recently, experts are in agreement that the main determinant of placenta accreta spectrum is the uterine scar and niche formation after a previous CD.⁵ Larger niches are associated with an increased incidence of uterine rupture or dehiscence in a subsequent pregnancy.⁷

In the nonpregnant state, such niches are associated with intermenstrual bleeding, pelvic pain, painful intercourse, painful menses, and subfertility, becoming increasingly more severe in women with greater numbers of CDs.^8-10 Conception rate with assisted reproductive treatment is notably reduced.¹¹

Understanding its etiology

Monteagudo and colleagues first described a “niche” in 100% of 44 women evaluated for postmenopausal bleeding who had a prior CD.¹² CSN has been the subject of well over 3,000 publications over the past 30 years. While the topic generates much interest among researchers, it is garnering little traction among practicing obstetricians. Such “niches,” also referred to as isthmocele, cesarean scar defect, or a diverticulum, was first described in 1961¹³ and later defined on ultrasonography as a hypoechoic triangular-shaped uterine defect outlined by saline instillation sonohysterogram (SIS), reflecting a discontinuation of the myometrium at the site of a previous CD.¹² In 2019, a European task force further defined a CSN as an “indentation at the site in the cesarean section scar with a depth of at least 2 mm” and extended the classification to include branches as extensions toward the anterior uterine serosa.¹⁴ Using this criterion, sonographic postoperative evaluation after one CD revealed a CSN in 68.9% of women with one single-layer uterine closure and in 73.6% of women after a double-layer closure.¹⁵ Larger niche sizes with thinner residual myometrial thickness appeared more frequently when a single-layer closure technique was used, without closure of the peritoneum. Its prevalence varies from 56% to 84%.^16,17

Etiology of CSN formation: Our hypotheses

The precise pathophysiology of CSN remains elusive. Speculations attributed niche formation to numerous factors: timing of surgery, cervical incision, incomplete closure of the uterine incision, adhesion formation between the CD scar and the abdominal wall, and inherent maternal conditions which may impair healing, such as smoking, obesity, diabetes, maternal age, and labor status.^18-20 Retroflexion of the uterus is reportedly associated with increased incidence and size of the niche, with CSN 50% more likely to develop in women with a retroflexed versus an anteverted uterus.²¹ We demonstrated the origin of niche formation in real-time from the start to the completion of uterine closure by a video capture of a single-layer closure followed by an immediate SIS of the ex vivo hysterectomized uterus, and histopathologic proof of the presence of endometrial cells defining the “niche.”²² This case exposes the misalignment of the uterine wall, while including the endometrium in the closure (FIGURE 1). Similarly, pathologic studies of hysteroscopy-resected isthmocele ridges of symptomatic women with niche-related subfertility revealed the tissue edges lined by endocervical, endometrial, or isthmic mucosa either combined or isolated in the scar.²³ The presence of endometrial/cervical tissue in the myometrial closure has been debated for over a century.^24,25

Continue to: Uterine closure techniques...

 

 

Uterine closure techniques: Historical perspective

In 1882, Max Sanger introduced a vertical uterine closure of a classical cesarean operation in response to hysterectomy as the contemporaneous alternative to prevent infection, bleeding, and death.²⁴ Dr. Sanger emphasized layer approximation, suturing, and the avoidance of decidua in the first layer (FIGURE 2). This became the teaching of the classical CD until the 1970s. In 1926, Munro Kerr addressed uterine rupture with labor after a classical CD by introducing the lower uterine segment transverse incision. He cautioned to maintain the decidua inside the uterine 2-layer closure of the cavity.²⁵ These pioneers were joined by others to rally for endometrium exclusion while promoting layer approximation. These techniques became universally standard and were taught across teaching medical centers in the United States and abroad until about 50 years ago.

In the 1970s, newer developments brought significant changes to uterine closure techniques. Initiated by Joel-Cohen,²⁶ blunt dissection of the abdominal incision was adapted by Michael Stark, creating what came to be known as the Misgav-Ladach cesarean technique.²⁷ Stark emphasized blunt dissection and introduced single-layer closure. Thereby the exclusion of the endometrium, used for more than 70 years, was abandoned by the present-day single- or double-layer uterine closure in favor of cost and time savings. Systematic reviews and meta-analyses comparing the two contrasting techniques were inconclusive, noting that the niche prevalence and size were similar in both groups. These studies did not take into account the variety of individual techniques or the position of the endometrium in the final closures.²⁸

Endometrium and uterine closure

Our recent study examining uterine scar defect in women after one primary CD by SIS concluded that a specific endometrium-free closure technique (EFCT) (FIGURE 3) is associated with fewer and less severe defects and a thicker residual myometrial thickness when compared with closures with unknown or endometrium inclusion.²⁹ The study found non-specific closure techniques to be 6 times more likely to form a niche of 2-mm deep or greater than the EFCT.

Furthermore, we surveyed the diversity of uterine closures and the location of the endometrium among obstetricians in one institution.³⁰ Presence of endometrium on the surface of the final uterine closure was reported by 20% of respondents (see Figure 1). When asked for their opinion on the impact of CD techniques on placenta accreta spectrum, without available evidence 80% of the survey respondents reported no relationship to techniques, and only 20% suggested an association. This particular study demonstrates that the surgical techniques just described are random, unfettered, and applied without consideration of clinical outcomes.

Our recent retrospective study that spanned 30 years and examined the EFCT—per­formed anywhere between 3 to 9 consecutive CDs—revealed no abnormal placentation in any subsequent pregnancies.³¹ This was one of the few clinical studies of the long-term consequences of a uterine closure technique. In this study, the endometrium was excluded during the uterine closure, allowing its free edges to abut and heal. This step avoids scarring the endometrial-myometrial (EM) interface and unintentional inclusion of endometrium in the closed uterine wall. In this context, Jauniaux and colleagues cited the destruction of the EM interface as the main factor for placenta-adherent disorders.³² Sholapurkar and others highlight the need to further examine intrinsic details of uterine closure beyond single- and double-layer techniques to better understand the etiology of cesarean scar formation.¹⁹ The search for the pathophysiology of CSN continues to present significant challenges imposed by the variety of currently practiced uterine closures.

Continue to: Focus on prevention...

 

 

Research: Focus on prevention

Our research aims to address the endometrium, a specific layer that was the topic of concern in nascent CD techniques, as a renewed and contemporary one. The presence of the endometrium in ectopic locations or its destruction from intrauterine surgeries or infections has been implicated in abnormal placentation.^13,24 Our approach, in theory, is to limit the position of the endometrium to its innermost location and avoid its iatrogenic suturing and inclusion into the uterine wall closure. The rationale of sparing the endometrium in a layer-by-layer approximation is to allow for a closer restoration to normal anatomy and physiology than a random “en masse” uterine wall closure would permit. For this reason, the EM junction, the perimetrium, and the serosa must be identified and realigned for a more effective closure that incorporates the entire myometrial thickness. As evidence supports technical impact on the development of uterine scar defect in women after one CD, future studies are needed to evaluate uterine integrity by saline infusion sonohysterography in multiparous women with a prior random closure technique or a prior EFCT.

The potential long-term risks of blunt dissection for opening the uterus have not been studied. There are no physiologic lines in the uterine wall to facilitate a regular-bordered uterine stretch. The tissue stretch, which depends on the individual surgeon’s strength applied during the procedure and patient’s labor status, may result in an irregular tear and a difficult repair. The EFCT technique shows a more optimized risk-benefit ratio for an anatomical repair and is replicable. The safety of uterine layer re-approximation has been demonstrated and can be studied in large populations using strict uniform criteria.

Current and future challenges

Residency training

Most recently, teachers of resident trainees are mostly familiar with blunt dissection, techniques of which are passed on unchallenged from resident to resident. The endometrium and peritoneum are neither identified nor treated as separate layers, thus becoming obsolete as surgical and anatomical landmarks.

Standardization of CD techniques

Front-line obstetricians are persuaded to practice a standardized approach that relies on the benefits of cost related to operating room turnover as well as surgeons’ time savings without consideration of outcomes in subsequent pregnancies. Sholapurkar has warned that “wrong standardization” is far worse than no standardization, worse for the training of junior obstetricians, as it can inhibit critical reasoning about safe surgical techniques that can optimize outcomes of the condition of the lower uterine segment.³³

Emergence of cost and time savings in clinical practice

A time-cost savings argument is relatively negligeable in an estimated 40-minute CD. By contrast, deliberate surgical technique and carrying out the appropriate steps for the particular condition at hand to achieve the best outcomes assume more weight.³² Furthermore, this short-term cost benefit is challenged by the comparatively larger costs associated with the diagnosis, the treatment of post-CD adverse consequences (outlined above), as well as the emotional impact on women and their families. Additionally, the emphasis on time savings creates a generation of surgeons fixated with total operative time without consideration of long-term risks and adverse maternal outcomes.

Physician autonomy has led to the unmonitored freedom of obstetricians to choose their own technique for a CD, with some employing the commonly practiced culture of fastest turnaround even in nonurgent circumstances.

Documentation and terminology

Current documenting systems are not detail-oriented enough to assist in a thorough correlation between surgical techniques and outcomes. The use of single- or double-layer closure terminology is insufficient and has proven to be flawed, without describing the handling of the endometrium in terms of its inclusion or exclusion in the closure.

Quality improvement feedback

Long-term post-CD complications are often not reported to the physician or institution involved in the prior CD. In our opinion, some sort of registry would be of value. Perhaps then subsequent CD outcomes could be traced back and reported to the prior institution and surgeon. Feedback is critical to understanding the correlation between techniques and outcomes and more specifically to gathering learning points and using data for quality improvement of future cases.

Patient education

While women continue to have complications following the presently used surgical techniques, they often have expectations not discussed with their obstetricians. Women should be educated and empowered to realize the different approaches to all aspects and consequences of CDs.

Conclusion

The technique of excluding the endometrium in closing the uterine incision appears to reduce subsequent abnormal placentation and diminish the frequency and size of post-CD scar defect. The revival of the endometrium-free closure technique may allow significant change in the postoperative results. Currently, standardization of CD technique is being promoted on the basis of time- and cost-savings rather than clinical outcomes. Simultaneously, inroads are being made to better understand the risks and consequences of CD.

Emerging evidence suggests that a post-CD niche is the result of poor layer approximation as well as inclusion of the endometrium, which prevent healing of the uterine wall and often enables faulty implantation of the fertilized oocyte in the next pregnancy, potentially giving rise to placenta accreta spectrum. The prevalence and size of the defect can be minimized by techniques aimed at restoring the anatomy of the uterine wall and the physiology of the endometrium. Specialized training and education are necessary to stress the importance of anatomical assessment and decision making at the time of uterine closure. ●

In recent years, direct-to-consumer (DTC) teledermatology platforms have gained popularity as telehealth business models, allowing patients to directly initiate visits with physicians and purchase medications from single platforms. A shortage of dermatologists, improved technology, drug patent expirations, and rising health care costs accelerated the growth of DTC dermatology.¹ During the COVID-19 pandemic, teledermatology adoption surged due to the need to provide care while social distancing and minimizing viral exposure. These needs prompted additional federal funding and loosened regulatory provisions.² As the userbase of these companies has grown, so have their valuations.³ Although the DTC model has attracted the attention of patients and investors, its rise provokes many questions about patients acting as consumers in health care. Indeed, DTC telemedicine offers greater autonomy and convenience for patients, but it may impact the quality of care and the nature of physician-patient relationships, perhaps making them more transactional.

Evolution of DTC in Health Care

The DTC model emphasizes individual choice and accessible health care. Although the definition has evolved, the core idea is not new.⁴ Over decades, pharmaceutical companies have spent billions of dollars on DTC advertising, circumventing physicians by directly reaching patients with campaigns on prescription drugs and laboratory tests and shaping public definitions of diseases.⁵

The DTC model of care is fundamentally different from traditional care models in that it changes the roles of the patient and physician. Whereas early telehealth models required a health care provider to initiate teleconsultations with specialists, DTC telemedicine bypasses this step (eg, the patient can consult a dermatologist without needing a primary care provider’s input first). This care can then be provided by dermatologists with whom patients may or may not have pre-established relationships.^4,6

Dermatology was an early adopter of DTC telemedicine. The shortage of dermatologists in the United States created demand for increasing accessibility to dermatologic care. Additionally, the visual nature of diagnosing dermatologic disease was ideal for platforms supporting image sharing.⁷ Early DTC providers were primarily individual companies offering teledermatology. However, many dermatologists can now offer DTC capabilities via companies such as Amwell and Teladoc Health.⁸

Over the last 2 decades, start-ups such as Warby Parker (eyeglasses) and Casper (mattresses) defined the DTC industry using borrowed supply chains, cohesive branding, heavy social media marketing, and web-only retail. Scalability, lack of competition, and abundant venture capital created competition across numerous markets.⁹ Health care capitalized on this DTC model, creating a $700 billion market for products ranging from hearing aids to over-the-counter medications.¹⁰

Borrowing from this DTC playbook, platforms were created to offer delivery of generic prescription drugs to patients’ doorsteps. However, unlike with other products bought online, a consumer cannot simply add prescription drugs to their shopping cart and check out. In all models of American medical practice, physicians still serve as gatekeepers, providing a safeguard for patients to ensure appropriate prescription and avoid negative consequences of unnecessary drug use. This new model effectively streamlines diagnosis, prescription, and drug delivery without the patient ever having to leave home. Combining the prescribing and selling of medications (2 tasks that traditionally have been separated) potentially creates financial conflicts of interest (COIs). Additionally, high utilization of health care, including more prescriptions and visits, does not necessarily equal high quality of care. The companies stand to benefit from extra care regardless of need, and thus these models must be scrutinized for any incentives driving unnecessary care and prescriptions.

Ultimately, DTC has evolved to encompass multiple definitions in health care (Table 1). Although all models provide health care, each offers a different modality of delivery. The primary service may be the sale of prescription drugs or simply telemedicine visits. This review primarily discusses DTC pharmaceutical telemedicine platforms that sell private-label drugs and also offer telemedicine services to streamline care. However, the history, risks, and benefits discussed may apply to all models.

The DTC Landscape

Most DTC companies employ variations on a model with the same 3 main components: a triage questionnaire, telehealth services, and prescription/drug delivery (Figure). The triage questionnaire elicits a history of the patient’s presentation and medical history. Some companies may use artificial intelligence (AI) algorithms to tailor questions to patient needs. There are 2 modalities for patient-provider communication: synchronous and asynchronous. Synchronous communication entails real-time patient-physician conversations via audio only or video call. Asynchronous (or store-and-forward) communication refers to consultations provided via messaging or text-based modality, where a provider may respond to a patient within 24 hours.⁶ Direct-to-consumer platforms primarily use asynchronous visits (Table 2). However, some also use synchronous modalities if the provider deems it necessary or if state laws require it.

Once a provider has consulted with the patient, they can prescribe medication as needed. In certain cases, with adequate history, a prescription may be issued without a full physician visit. Furthermore, DTC companies require purchase of their custom-branded generic drugs. Prescriptions are fulfilled by the company’s pharmacy network and directly shipped to patients; few will allow patients to transfer a prescription to a pharmacy of their choice. Some platforms also sell supplements and over-the-counter medications.

Payment models vary among these companies, and most do not accept insurance (Table 2). Select models may provide free consultations and only require payment for pharmaceuticals. Others charge for consultations but reallocate payment to the cost of medication if prescribed. Another model involves flat rates for consultations and additional charges for drugs but unlimited messaging with providers for the duration of the prescription. Moreover, patients can subscribe to monthly deliveries of their medications.

Foundation of DTC

Technological advances have enabled patients to receive remote treatment from a single platform offering video calls, AI, electronic medical record interoperability, and integration of drug supply chains. Even in its simplest form, AI is increasingly used, as it allows for programs and chatbots to screen and triage patients.¹¹ Technology also has improved at targeted mass marketing through social media platforms and search engines (eg, companies can use age, interests, location, and other parameters to target individuals likely needing acne treatment).

Drug patent expirations are a key catalyst for the rise of DTC companies, creating an attractive business model with generic drugs as the core product. Since 2008, patents for medications treating chronic conditions, such as erectile dysfunction, have expired. These patent expirations are responsible for $198 billion in projected prescription sales between 2019 and 2024.¹ Thus, it follows that DTC companies have seized this opportunity to act as middlemen, taking advantage of these generic medications’ lower costs to create platforms focused on personalization and accessibility.

Rising deductibles have led patients to consider cheaper out-of-pocket alternatives that are not covered by insurance.¹ For example, insurers typically do not cover finasteride treatment for conditions deemed cosmetic, such as androgenetic alopecia.¹² The low cost of generic drugs creates an attractive business model for patients and investors. According to GoodRx, the average retail price for a 30-day supply of brand-name finasteride (Propecia [Merck]) is $135.92, whereas generic finasteride is $75.24.¹³ Direct-to-consumer pharmaceutical companies offer a 30-day supply of generic finasteride ranging from $8.33 to $30.¹⁴ The average wholesale cost for retailers is an estimated $2.31 for 30 days.¹⁵ Although profit margins on generic medications may be lower, more affordable drugs increase the size of the total market. These prescriptions are available as subscription plans, resulting in recurring revenue.

Lax US pharmaceutical marketing regulations allow direct advertising to the general public.¹⁶ In 1997, the US Food and Drug Administration allowed DTC advertisements to replace summaries of serious and common adverse effects with short statements covering important risks or referrals to other sources for complete information. In 2015, the US Food and Drug Administration guidelines preventing encouragement of self-diagnosis and self-treatment were withdrawn.⁵ These changes enable DTC companies to launch large advertising campaigns and to accelerate customer acquisition, as the industry often describes it, with ease.

Rapid Growth and Implications

Increasing generic drug availability and improving telemedicine capabilities have the potential to reduce costs and barriers but also have the potential for financial gain. Venture capital funds have recognized this opportunity, reflected by millions of dollars of investments, and accelerated the growth of DTC health care start-ups. For example, Ro has raised $376 million from venture capital, valuing the company at $1.5 billion.³

Direct-to-consumer companies require a heavy focus on marketing campaigns for customer acquisition. Their aesthetically pleasing websites and aggressive campaigns target specific audiences based on demographics, digital use habits, and purchasing behavior.⁴ Some campaigns celebrate the ease of obtaining prescriptions.¹⁷ Companies have been effective in recruiting so-called millennial and Generation Z patients, known to search the internet for remedies prior to seeking physician consultations.¹⁸ Recognizing these needs, some platforms offer guides on diseases they treat, creating effective customer-acquisition funnels. Recruitment of these technology-friendly patients has proven effective, especially given the largely positive media coverage of DTC platforms––potentially serving as a surrogate for medical credibility for patients.¹⁸

Some DTC companies also market physically; skin care ads may be strategically placed in social media feeds, or even found near mirrors in public bathrooms.¹⁹ Marketing campaigns also involve disease awareness; such efforts serve to increase diagnoses and prescribed treatments while destigmatizing diseases. Although DTC companies argue this strategy empowers patients, these marketing habits have the potential to take advantage of uninformed patients. Campaigns could potentially medicalize normal experiences and expand disease definitions resulting in overdiagnosis, overtreatment, and wasted resources.⁵ For example, off-label propranolol use has been advertised to attract patients who might have “nerves that come creeping before an important presentation.”¹⁷ Disease awareness campaigns also may lead people to falsely believe unproven drug benefits.⁵ According to studies, DTC pharmaceutical advertisements are low in informational quality and result in increased patient visits and prescriptions despite cost-effective alternatives.^5,20-22

Fragmentation of the health care system is another possible complication of DTC teledermatology. These companies operate as for-profit organizations separated from the rest of the health care system, raising concerns about care coordination.⁸ Vital health data may not be conveyed as patients move among different providers and pharmacies. One study found DTC teledermatology rarely offered to provide medical records or facilitate a referral to a local physician.²³ Such a lack of communication is concerning, as medication errors are the leading cause of avoidable harm in health care.²⁴

Direct-to-consumer care models also seemingly redefine the physician-patient relationship by turning patients into consumers. Patient interactions may seem transactional and streamlined toward sales. For these platforms, a visit often is set up as an evaluation of a patient’s suitability for a prescription, not necessarily for the best treatment modality for the problem. These companies primarily make money through the sale of prescription drugs, creating a potential COI that may undermine the patient-physician relationship. Although some companies have made it clear that medical care and pharmaceutical sales are provided by legally separate business entities and that they do not pay physicians on commission, a conflict may still exist given the financial importance of physicians prescribing medication to the success of the business.¹⁶

Even as DTC models advertise upon expanded access and choice, the companies largely prohibit patients from choosing their own pharmacy. Instead, they encourage patients to fill prescriptions with the company’s pharmacy network by claiming lower costs compared with competitors. One DTC company, Hims, is launching a prescription-fulfillment center to further consolidate their business.^17,19,25 The inherent COI of issuing and fulfilling prescriptions raises concerns of patient harm.²⁶ For example, when Dermatology.com launched as a DTC prescription skin medication shop backed by Bausch Health Companies Inc, its model included telemedicine consultation. Although consultations were provided by RxDefine, a third party, only Dermatology.com drugs were prescribed. Given the poor quality of care and obvious financial COI, an uproar in the dermatology community and advocacy by the American Academy of Dermatology led to the shutdown of Dermatology.com’s online prescription services.²⁶

The quality of care among DTC telemedicine platforms has been equivocal. Some studies have reported equivalent care in person and online, while others have reported poor adherence to guidelines, overuse of antibiotics, and misdiagnosis.^8,23 A vital portion of the DTC experience is the history questionnaire, which is geared to diagnosis and risk assessment.²⁵ Resneck et al²³ found diagnostic quality to be adequate for simple dermatologic clinical scenarios but poor for scenarios requiring more than basic histories. Although Ro has reported leveraging data from millions of interactions to ask the right questions and streamline visits, it is still unclear whether history questionnaires are adequate.^17,27 Additionally, consultations may lack sufficient counseling on adverse effects, risks, or pregnancy warnings, as well as discussions on alternative treatments and preventative care.^17,23 Finally, patients often are limited in their choice of dermatologist; the lack of a fully developed relationship increases concerns of follow-up and monitoring practices. Although some DTC platforms offer unlimited interactions with physicians for the duration of a prescription, it is unknown how often these services are utilized or how adequate the quality of these interactions is. This potential for lax follow-up is especially concerning for prescriptions that autorenew on a monthly basis and could result in unnecessary overtreatment.

Postpandemic and Future Outlook

The COVID-19 pandemic dramatically impacted the use of telemedicine. To minimize COVID-19 transmission, the Centers for Medicare & Medicaid Services and private payers expanded telehealth coverage and eliminated reimbursement and licensing barriers.²⁸ A decade’s worth of regulatory changes and consumer adoption was accelerated to weeks, resulting in telemedicine companies reaching record-high visit numbers.²⁹ McKinsey & Company estimated that telehealth visit numbers surged 50- to 175-fold compared with pre–COVID-19 numbers. Additionally, 76% of patients were interested in future telehealth use, and 64% of providers were more comfortable using telehealth than before the pandemic.³⁰ For their part, US dermatologists reported an increase in telemedicine use from 14.1% to 96.9% since COVID-19.³¹

Exactly how much DTC pharmaceutical telemedicine companies are growing is unclear, but private investments may be an indication. A record $14.7 billion was invested in the digital health sector in the first half of 2021; the majority went to telehealth companies.³⁰ Ro, which reported $230 million in revenue in 2020 and has served 6 million visits, raised $200 milllion in July 2020 and $500 million in March 2021.³² Although post–COVID-19 health care will certainly involve increased telemedicine, the extent remains unclear, as telehealth vendors saw decreased usage upon reopening of state economies. Ultimately, the postpandemic regulatory landscape is hard to predict.³⁰

Although COVID-19 appears to have caused rapid growth for DTC platforms, it also may have spurred competition. Telemedicine providers have given independent dermatologists and health care systems the infrastructure to implement custom DTC services.³³ Although systems do not directly sell prescription drugs, the target market is essentially the same: patients looking for instant virtual dermatologic care. Therefore, sustained telemedicine services offered by traditional practices and systems may prove detrimental to DTC companies. However, unlike most telemedicine services, DTC models are less affected by certain changes in regulation since they do not rely on insurance. If regulations are tightened and reimbursements for telehealth are not attractive for dermatologists, teledermatology services may see an overall decrease. If so, patients who appreciate teledermatology may shift to using DTC platforms, even if their insurance does not cover them. Still, a nationwide survey found 56% of respondents felt an established relationship with a physician prior to a telemedicine visit is important, which may create a barrier for DTC adoption.³⁴

Conclusion

Direct-to-consumer teledermatology represents a growing for-profit model of health care that provides patients with seemingly affordable and convenient care. However, there is potential for overtreatment, misdiagnosis, and fragmentation of health care. It will be important to monitor and evaluate the quality of care that DTC teledermatology offers and advocate for appropriate regulations and oversight. Eventually, more patients will have medications prescribed and dermatologic care administered through DTC companies. Dermatologists will benefit from this knowledge of DTC models to properly counsel patients on the risks and benefits of their use.

In recent years, direct-to-consumer (DTC) teledermatology platforms have gained popularity as telehealth business models, allowing patients to directly initiate visits with physicians and purchase medications from single platforms. A shortage of dermatologists, improved technology, drug patent expirations, and rising health care costs accelerated the growth of DTC dermatology.¹ During the COVID-19 pandemic, teledermatology adoption surged due to the need to provide care while social distancing and minimizing viral exposure. These needs prompted additional federal funding and loosened regulatory provisions.² As the userbase of these companies has grown, so have their valuations.³ Although the DTC model has attracted the attention of patients and investors, its rise provokes many questions about patients acting as consumers in health care. Indeed, DTC telemedicine offers greater autonomy and convenience for patients, but it may impact the quality of care and the nature of physician-patient relationships, perhaps making them more transactional.

Evolution of DTC in Health Care

The DTC model emphasizes individual choice and accessible health care. Although the definition has evolved, the core idea is not new.⁴ Over decades, pharmaceutical companies have spent billions of dollars on DTC advertising, circumventing physicians by directly reaching patients with campaigns on prescription drugs and laboratory tests and shaping public definitions of diseases.⁵

The DTC model of care is fundamentally different from traditional care models in that it changes the roles of the patient and physician. Whereas early telehealth models required a health care provider to initiate teleconsultations with specialists, DTC telemedicine bypasses this step (eg, the patient can consult a dermatologist without needing a primary care provider’s input first). This care can then be provided by dermatologists with whom patients may or may not have pre-established relationships.^4,6

Dermatology was an early adopter of DTC telemedicine. The shortage of dermatologists in the United States created demand for increasing accessibility to dermatologic care. Additionally, the visual nature of diagnosing dermatologic disease was ideal for platforms supporting image sharing.⁷ Early DTC providers were primarily individual companies offering teledermatology. However, many dermatologists can now offer DTC capabilities via companies such as Amwell and Teladoc Health.⁸

Over the last 2 decades, start-ups such as Warby Parker (eyeglasses) and Casper (mattresses) defined the DTC industry using borrowed supply chains, cohesive branding, heavy social media marketing, and web-only retail. Scalability, lack of competition, and abundant venture capital created competition across numerous markets.⁹ Health care capitalized on this DTC model, creating a $700 billion market for products ranging from hearing aids to over-the-counter medications.¹⁰

Borrowing from this DTC playbook, platforms were created to offer delivery of generic prescription drugs to patients’ doorsteps. However, unlike with other products bought online, a consumer cannot simply add prescription drugs to their shopping cart and check out. In all models of American medical practice, physicians still serve as gatekeepers, providing a safeguard for patients to ensure appropriate prescription and avoid negative consequences of unnecessary drug use. This new model effectively streamlines diagnosis, prescription, and drug delivery without the patient ever having to leave home. Combining the prescribing and selling of medications (2 tasks that traditionally have been separated) potentially creates financial conflicts of interest (COIs). Additionally, high utilization of health care, including more prescriptions and visits, does not necessarily equal high quality of care. The companies stand to benefit from extra care regardless of need, and thus these models must be scrutinized for any incentives driving unnecessary care and prescriptions.

Ultimately, DTC has evolved to encompass multiple definitions in health care (Table 1). Although all models provide health care, each offers a different modality of delivery. The primary service may be the sale of prescription drugs or simply telemedicine visits. This review primarily discusses DTC pharmaceutical telemedicine platforms that sell private-label drugs and also offer telemedicine services to streamline care. However, the history, risks, and benefits discussed may apply to all models.

The DTC Landscape

Most DTC companies employ variations on a model with the same 3 main components: a triage questionnaire, telehealth services, and prescription/drug delivery (Figure). The triage questionnaire elicits a history of the patient’s presentation and medical history. Some companies may use artificial intelligence (AI) algorithms to tailor questions to patient needs. There are 2 modalities for patient-provider communication: synchronous and asynchronous. Synchronous communication entails real-time patient-physician conversations via audio only or video call. Asynchronous (or store-and-forward) communication refers to consultations provided via messaging or text-based modality, where a provider may respond to a patient within 24 hours.⁶ Direct-to-consumer platforms primarily use asynchronous visits (Table 2). However, some also use synchronous modalities if the provider deems it necessary or if state laws require it.

Once a provider has consulted with the patient, they can prescribe medication as needed. In certain cases, with adequate history, a prescription may be issued without a full physician visit. Furthermore, DTC companies require purchase of their custom-branded generic drugs. Prescriptions are fulfilled by the company’s pharmacy network and directly shipped to patients; few will allow patients to transfer a prescription to a pharmacy of their choice. Some platforms also sell supplements and over-the-counter medications.

Payment models vary among these companies, and most do not accept insurance (Table 2). Select models may provide free consultations and only require payment for pharmaceuticals. Others charge for consultations but reallocate payment to the cost of medication if prescribed. Another model involves flat rates for consultations and additional charges for drugs but unlimited messaging with providers for the duration of the prescription. Moreover, patients can subscribe to monthly deliveries of their medications.

Foundation of DTC

Technological advances have enabled patients to receive remote treatment from a single platform offering video calls, AI, electronic medical record interoperability, and integration of drug supply chains. Even in its simplest form, AI is increasingly used, as it allows for programs and chatbots to screen and triage patients.¹¹ Technology also has improved at targeted mass marketing through social media platforms and search engines (eg, companies can use age, interests, location, and other parameters to target individuals likely needing acne treatment).

Drug patent expirations are a key catalyst for the rise of DTC companies, creating an attractive business model with generic drugs as the core product. Since 2008, patents for medications treating chronic conditions, such as erectile dysfunction, have expired. These patent expirations are responsible for $198 billion in projected prescription sales between 2019 and 2024.¹ Thus, it follows that DTC companies have seized this opportunity to act as middlemen, taking advantage of these generic medications’ lower costs to create platforms focused on personalization and accessibility.

Rising deductibles have led patients to consider cheaper out-of-pocket alternatives that are not covered by insurance.¹ For example, insurers typically do not cover finasteride treatment for conditions deemed cosmetic, such as androgenetic alopecia.¹² The low cost of generic drugs creates an attractive business model for patients and investors. According to GoodRx, the average retail price for a 30-day supply of brand-name finasteride (Propecia [Merck]) is $135.92, whereas generic finasteride is $75.24.¹³ Direct-to-consumer pharmaceutical companies offer a 30-day supply of generic finasteride ranging from $8.33 to $30.¹⁴ The average wholesale cost for retailers is an estimated $2.31 for 30 days.¹⁵ Although profit margins on generic medications may be lower, more affordable drugs increase the size of the total market. These prescriptions are available as subscription plans, resulting in recurring revenue.

Lax US pharmaceutical marketing regulations allow direct advertising to the general public.¹⁶ In 1997, the US Food and Drug Administration allowed DTC advertisements to replace summaries of serious and common adverse effects with short statements covering important risks or referrals to other sources for complete information. In 2015, the US Food and Drug Administration guidelines preventing encouragement of self-diagnosis and self-treatment were withdrawn.⁵ These changes enable DTC companies to launch large advertising campaigns and to accelerate customer acquisition, as the industry often describes it, with ease.

Rapid Growth and Implications

Increasing generic drug availability and improving telemedicine capabilities have the potential to reduce costs and barriers but also have the potential for financial gain. Venture capital funds have recognized this opportunity, reflected by millions of dollars of investments, and accelerated the growth of DTC health care start-ups. For example, Ro has raised $376 million from venture capital, valuing the company at $1.5 billion.³

Direct-to-consumer companies require a heavy focus on marketing campaigns for customer acquisition. Their aesthetically pleasing websites and aggressive campaigns target specific audiences based on demographics, digital use habits, and purchasing behavior.⁴ Some campaigns celebrate the ease of obtaining prescriptions.¹⁷ Companies have been effective in recruiting so-called millennial and Generation Z patients, known to search the internet for remedies prior to seeking physician consultations.¹⁸ Recognizing these needs, some platforms offer guides on diseases they treat, creating effective customer-acquisition funnels. Recruitment of these technology-friendly patients has proven effective, especially given the largely positive media coverage of DTC platforms––potentially serving as a surrogate for medical credibility for patients.¹⁸

Some DTC companies also market physically; skin care ads may be strategically placed in social media feeds, or even found near mirrors in public bathrooms.¹⁹ Marketing campaigns also involve disease awareness; such efforts serve to increase diagnoses and prescribed treatments while destigmatizing diseases. Although DTC companies argue this strategy empowers patients, these marketing habits have the potential to take advantage of uninformed patients. Campaigns could potentially medicalize normal experiences and expand disease definitions resulting in overdiagnosis, overtreatment, and wasted resources.⁵ For example, off-label propranolol use has been advertised to attract patients who might have “nerves that come creeping before an important presentation.”¹⁷ Disease awareness campaigns also may lead people to falsely believe unproven drug benefits.⁵ According to studies, DTC pharmaceutical advertisements are low in informational quality and result in increased patient visits and prescriptions despite cost-effective alternatives.^5,20-22

Fragmentation of the health care system is another possible complication of DTC teledermatology. These companies operate as for-profit organizations separated from the rest of the health care system, raising concerns about care coordination.⁸ Vital health data may not be conveyed as patients move among different providers and pharmacies. One study found DTC teledermatology rarely offered to provide medical records or facilitate a referral to a local physician.²³ Such a lack of communication is concerning, as medication errors are the leading cause of avoidable harm in health care.²⁴

Direct-to-consumer care models also seemingly redefine the physician-patient relationship by turning patients into consumers. Patient interactions may seem transactional and streamlined toward sales. For these platforms, a visit often is set up as an evaluation of a patient’s suitability for a prescription, not necessarily for the best treatment modality for the problem. These companies primarily make money through the sale of prescription drugs, creating a potential COI that may undermine the patient-physician relationship. Although some companies have made it clear that medical care and pharmaceutical sales are provided by legally separate business entities and that they do not pay physicians on commission, a conflict may still exist given the financial importance of physicians prescribing medication to the success of the business.¹⁶

Even as DTC models advertise upon expanded access and choice, the companies largely prohibit patients from choosing their own pharmacy. Instead, they encourage patients to fill prescriptions with the company’s pharmacy network by claiming lower costs compared with competitors. One DTC company, Hims, is launching a prescription-fulfillment center to further consolidate their business.^17,19,25 The inherent COI of issuing and fulfilling prescriptions raises concerns of patient harm.²⁶ For example, when Dermatology.com launched as a DTC prescription skin medication shop backed by Bausch Health Companies Inc, its model included telemedicine consultation. Although consultations were provided by RxDefine, a third party, only Dermatology.com drugs were prescribed. Given the poor quality of care and obvious financial COI, an uproar in the dermatology community and advocacy by the American Academy of Dermatology led to the shutdown of Dermatology.com’s online prescription services.²⁶

The quality of care among DTC telemedicine platforms has been equivocal. Some studies have reported equivalent care in person and online, while others have reported poor adherence to guidelines, overuse of antibiotics, and misdiagnosis.^8,23 A vital portion of the DTC experience is the history questionnaire, which is geared to diagnosis and risk assessment.²⁵ Resneck et al²³ found diagnostic quality to be adequate for simple dermatologic clinical scenarios but poor for scenarios requiring more than basic histories. Although Ro has reported leveraging data from millions of interactions to ask the right questions and streamline visits, it is still unclear whether history questionnaires are adequate.^17,27 Additionally, consultations may lack sufficient counseling on adverse effects, risks, or pregnancy warnings, as well as discussions on alternative treatments and preventative care.^17,23 Finally, patients often are limited in their choice of dermatologist; the lack of a fully developed relationship increases concerns of follow-up and monitoring practices. Although some DTC platforms offer unlimited interactions with physicians for the duration of a prescription, it is unknown how often these services are utilized or how adequate the quality of these interactions is. This potential for lax follow-up is especially concerning for prescriptions that autorenew on a monthly basis and could result in unnecessary overtreatment.

Postpandemic and Future Outlook

The COVID-19 pandemic dramatically impacted the use of telemedicine. To minimize COVID-19 transmission, the Centers for Medicare & Medicaid Services and private payers expanded telehealth coverage and eliminated reimbursement and licensing barriers.²⁸ A decade’s worth of regulatory changes and consumer adoption was accelerated to weeks, resulting in telemedicine companies reaching record-high visit numbers.²⁹ McKinsey & Company estimated that telehealth visit numbers surged 50- to 175-fold compared with pre–COVID-19 numbers. Additionally, 76% of patients were interested in future telehealth use, and 64% of providers were more comfortable using telehealth than before the pandemic.³⁰ For their part, US dermatologists reported an increase in telemedicine use from 14.1% to 96.9% since COVID-19.³¹

Exactly how much DTC pharmaceutical telemedicine companies are growing is unclear, but private investments may be an indication. A record $14.7 billion was invested in the digital health sector in the first half of 2021; the majority went to telehealth companies.³⁰ Ro, which reported $230 million in revenue in 2020 and has served 6 million visits, raised $200 milllion in July 2020 and $500 million in March 2021.³² Although post–COVID-19 health care will certainly involve increased telemedicine, the extent remains unclear, as telehealth vendors saw decreased usage upon reopening of state economies. Ultimately, the postpandemic regulatory landscape is hard to predict.³⁰

Although COVID-19 appears to have caused rapid growth for DTC platforms, it also may have spurred competition. Telemedicine providers have given independent dermatologists and health care systems the infrastructure to implement custom DTC services.³³ Although systems do not directly sell prescription drugs, the target market is essentially the same: patients looking for instant virtual dermatologic care. Therefore, sustained telemedicine services offered by traditional practices and systems may prove detrimental to DTC companies. However, unlike most telemedicine services, DTC models are less affected by certain changes in regulation since they do not rely on insurance. If regulations are tightened and reimbursements for telehealth are not attractive for dermatologists, teledermatology services may see an overall decrease. If so, patients who appreciate teledermatology may shift to using DTC platforms, even if their insurance does not cover them. Still, a nationwide survey found 56% of respondents felt an established relationship with a physician prior to a telemedicine visit is important, which may create a barrier for DTC adoption.³⁴

Conclusion

Direct-to-consumer teledermatology represents a growing for-profit model of health care that provides patients with seemingly affordable and convenient care. However, there is potential for overtreatment, misdiagnosis, and fragmentation of health care. It will be important to monitor and evaluate the quality of care that DTC teledermatology offers and advocate for appropriate regulations and oversight. Eventually, more patients will have medications prescribed and dermatologic care administered through DTC companies. Dermatologists will benefit from this knowledge of DTC models to properly counsel patients on the risks and benefits of their use.

In recent years, direct-to-consumer (DTC) teledermatology platforms have gained popularity as telehealth business models, allowing patients to directly initiate visits with physicians and purchase medications from single platforms. A shortage of dermatologists, improved technology, drug patent expirations, and rising health care costs accelerated the growth of DTC dermatology.¹ During the COVID-19 pandemic, teledermatology adoption surged due to the need to provide care while social distancing and minimizing viral exposure. These needs prompted additional federal funding and loosened regulatory provisions.² As the userbase of these companies has grown, so have their valuations.³ Although the DTC model has attracted the attention of patients and investors, its rise provokes many questions about patients acting as consumers in health care. Indeed, DTC telemedicine offers greater autonomy and convenience for patients, but it may impact the quality of care and the nature of physician-patient relationships, perhaps making them more transactional.

Evolution of DTC in Health Care

The DTC model emphasizes individual choice and accessible health care. Although the definition has evolved, the core idea is not new.⁴ Over decades, pharmaceutical companies have spent billions of dollars on DTC advertising, circumventing physicians by directly reaching patients with campaigns on prescription drugs and laboratory tests and shaping public definitions of diseases.⁵

The DTC model of care is fundamentally different from traditional care models in that it changes the roles of the patient and physician. Whereas early telehealth models required a health care provider to initiate teleconsultations with specialists, DTC telemedicine bypasses this step (eg, the patient can consult a dermatologist without needing a primary care provider’s input first). This care can then be provided by dermatologists with whom patients may or may not have pre-established relationships.^4,6

Dermatology was an early adopter of DTC telemedicine. The shortage of dermatologists in the United States created demand for increasing accessibility to dermatologic care. Additionally, the visual nature of diagnosing dermatologic disease was ideal for platforms supporting image sharing.⁷ Early DTC providers were primarily individual companies offering teledermatology. However, many dermatologists can now offer DTC capabilities via companies such as Amwell and Teladoc Health.⁸

Over the last 2 decades, start-ups such as Warby Parker (eyeglasses) and Casper (mattresses) defined the DTC industry using borrowed supply chains, cohesive branding, heavy social media marketing, and web-only retail. Scalability, lack of competition, and abundant venture capital created competition across numerous markets.⁹ Health care capitalized on this DTC model, creating a $700 billion market for products ranging from hearing aids to over-the-counter medications.¹⁰

Borrowing from this DTC playbook, platforms were created to offer delivery of generic prescription drugs to patients’ doorsteps. However, unlike with other products bought online, a consumer cannot simply add prescription drugs to their shopping cart and check out. In all models of American medical practice, physicians still serve as gatekeepers, providing a safeguard for patients to ensure appropriate prescription and avoid negative consequences of unnecessary drug use. This new model effectively streamlines diagnosis, prescription, and drug delivery without the patient ever having to leave home. Combining the prescribing and selling of medications (2 tasks that traditionally have been separated) potentially creates financial conflicts of interest (COIs). Additionally, high utilization of health care, including more prescriptions and visits, does not necessarily equal high quality of care. The companies stand to benefit from extra care regardless of need, and thus these models must be scrutinized for any incentives driving unnecessary care and prescriptions.

Ultimately, DTC has evolved to encompass multiple definitions in health care (Table 1). Although all models provide health care, each offers a different modality of delivery. The primary service may be the sale of prescription drugs or simply telemedicine visits. This review primarily discusses DTC pharmaceutical telemedicine platforms that sell private-label drugs and also offer telemedicine services to streamline care. However, the history, risks, and benefits discussed may apply to all models.

The DTC Landscape

Most DTC companies employ variations on a model with the same 3 main components: a triage questionnaire, telehealth services, and prescription/drug delivery (Figure). The triage questionnaire elicits a history of the patient’s presentation and medical history. Some companies may use artificial intelligence (AI) algorithms to tailor questions to patient needs. There are 2 modalities for patient-provider communication: synchronous and asynchronous. Synchronous communication entails real-time patient-physician conversations via audio only or video call. Asynchronous (or store-and-forward) communication refers to consultations provided via messaging or text-based modality, where a provider may respond to a patient within 24 hours.⁶ Direct-to-consumer platforms primarily use asynchronous visits (Table 2). However, some also use synchronous modalities if the provider deems it necessary or if state laws require it.

Once a provider has consulted with the patient, they can prescribe medication as needed. In certain cases, with adequate history, a prescription may be issued without a full physician visit. Furthermore, DTC companies require purchase of their custom-branded generic drugs. Prescriptions are fulfilled by the company’s pharmacy network and directly shipped to patients; few will allow patients to transfer a prescription to a pharmacy of their choice. Some platforms also sell supplements and over-the-counter medications.

Payment models vary among these companies, and most do not accept insurance (Table 2). Select models may provide free consultations and only require payment for pharmaceuticals. Others charge for consultations but reallocate payment to the cost of medication if prescribed. Another model involves flat rates for consultations and additional charges for drugs but unlimited messaging with providers for the duration of the prescription. Moreover, patients can subscribe to monthly deliveries of their medications.

Foundation of DTC

Technological advances have enabled patients to receive remote treatment from a single platform offering video calls, AI, electronic medical record interoperability, and integration of drug supply chains. Even in its simplest form, AI is increasingly used, as it allows for programs and chatbots to screen and triage patients.¹¹ Technology also has improved at targeted mass marketing through social media platforms and search engines (eg, companies can use age, interests, location, and other parameters to target individuals likely needing acne treatment).

Drug patent expirations are a key catalyst for the rise of DTC companies, creating an attractive business model with generic drugs as the core product. Since 2008, patents for medications treating chronic conditions, such as erectile dysfunction, have expired. These patent expirations are responsible for $198 billion in projected prescription sales between 2019 and 2024.¹ Thus, it follows that DTC companies have seized this opportunity to act as middlemen, taking advantage of these generic medications’ lower costs to create platforms focused on personalization and accessibility.

Rising deductibles have led patients to consider cheaper out-of-pocket alternatives that are not covered by insurance.¹ For example, insurers typically do not cover finasteride treatment for conditions deemed cosmetic, such as androgenetic alopecia.¹² The low cost of generic drugs creates an attractive business model for patients and investors. According to GoodRx, the average retail price for a 30-day supply of brand-name finasteride (Propecia [Merck]) is $135.92, whereas generic finasteride is $75.24.¹³ Direct-to-consumer pharmaceutical companies offer a 30-day supply of generic finasteride ranging from $8.33 to $30.¹⁴ The average wholesale cost for retailers is an estimated $2.31 for 30 days.¹⁵ Although profit margins on generic medications may be lower, more affordable drugs increase the size of the total market. These prescriptions are available as subscription plans, resulting in recurring revenue.

Lax US pharmaceutical marketing regulations allow direct advertising to the general public.¹⁶ In 1997, the US Food and Drug Administration allowed DTC advertisements to replace summaries of serious and common adverse effects with short statements covering important risks or referrals to other sources for complete information. In 2015, the US Food and Drug Administration guidelines preventing encouragement of self-diagnosis and self-treatment were withdrawn.⁵ These changes enable DTC companies to launch large advertising campaigns and to accelerate customer acquisition, as the industry often describes it, with ease.

Rapid Growth and Implications

Increasing generic drug availability and improving telemedicine capabilities have the potential to reduce costs and barriers but also have the potential for financial gain. Venture capital funds have recognized this opportunity, reflected by millions of dollars of investments, and accelerated the growth of DTC health care start-ups. For example, Ro has raised $376 million from venture capital, valuing the company at $1.5 billion.³

Direct-to-consumer companies require a heavy focus on marketing campaigns for customer acquisition. Their aesthetically pleasing websites and aggressive campaigns target specific audiences based on demographics, digital use habits, and purchasing behavior.⁴ Some campaigns celebrate the ease of obtaining prescriptions.¹⁷ Companies have been effective in recruiting so-called millennial and Generation Z patients, known to search the internet for remedies prior to seeking physician consultations.¹⁸ Recognizing these needs, some platforms offer guides on diseases they treat, creating effective customer-acquisition funnels. Recruitment of these technology-friendly patients has proven effective, especially given the largely positive media coverage of DTC platforms––potentially serving as a surrogate for medical credibility for patients.¹⁸

Some DTC companies also market physically; skin care ads may be strategically placed in social media feeds, or even found near mirrors in public bathrooms.¹⁹ Marketing campaigns also involve disease awareness; such efforts serve to increase diagnoses and prescribed treatments while destigmatizing diseases. Although DTC companies argue this strategy empowers patients, these marketing habits have the potential to take advantage of uninformed patients. Campaigns could potentially medicalize normal experiences and expand disease definitions resulting in overdiagnosis, overtreatment, and wasted resources.⁵ For example, off-label propranolol use has been advertised to attract patients who might have “nerves that come creeping before an important presentation.”¹⁷ Disease awareness campaigns also may lead people to falsely believe unproven drug benefits.⁵ According to studies, DTC pharmaceutical advertisements are low in informational quality and result in increased patient visits and prescriptions despite cost-effective alternatives.^5,20-22

Fragmentation of the health care system is another possible complication of DTC teledermatology. These companies operate as for-profit organizations separated from the rest of the health care system, raising concerns about care coordination.⁸ Vital health data may not be conveyed as patients move among different providers and pharmacies. One study found DTC teledermatology rarely offered to provide medical records or facilitate a referral to a local physician.²³ Such a lack of communication is concerning, as medication errors are the leading cause of avoidable harm in health care.²⁴

Direct-to-consumer care models also seemingly redefine the physician-patient relationship by turning patients into consumers. Patient interactions may seem transactional and streamlined toward sales. For these platforms, a visit often is set up as an evaluation of a patient’s suitability for a prescription, not necessarily for the best treatment modality for the problem. These companies primarily make money through the sale of prescription drugs, creating a potential COI that may undermine the patient-physician relationship. Although some companies have made it clear that medical care and pharmaceutical sales are provided by legally separate business entities and that they do not pay physicians on commission, a conflict may still exist given the financial importance of physicians prescribing medication to the success of the business.¹⁶

Even as DTC models advertise upon expanded access and choice, the companies largely prohibit patients from choosing their own pharmacy. Instead, they encourage patients to fill prescriptions with the company’s pharmacy network by claiming lower costs compared with competitors. One DTC company, Hims, is launching a prescription-fulfillment center to further consolidate their business.^17,19,25 The inherent COI of issuing and fulfilling prescriptions raises concerns of patient harm.²⁶ For example, when Dermatology.com launched as a DTC prescription skin medication shop backed by Bausch Health Companies Inc, its model included telemedicine consultation. Although consultations were provided by RxDefine, a third party, only Dermatology.com drugs were prescribed. Given the poor quality of care and obvious financial COI, an uproar in the dermatology community and advocacy by the American Academy of Dermatology led to the shutdown of Dermatology.com’s online prescription services.²⁶

The quality of care among DTC telemedicine platforms has been equivocal. Some studies have reported equivalent care in person and online, while others have reported poor adherence to guidelines, overuse of antibiotics, and misdiagnosis.^8,23 A vital portion of the DTC experience is the history questionnaire, which is geared to diagnosis and risk assessment.²⁵ Resneck et al²³ found diagnostic quality to be adequate for simple dermatologic clinical scenarios but poor for scenarios requiring more than basic histories. Although Ro has reported leveraging data from millions of interactions to ask the right questions and streamline visits, it is still unclear whether history questionnaires are adequate.^17,27 Additionally, consultations may lack sufficient counseling on adverse effects, risks, or pregnancy warnings, as well as discussions on alternative treatments and preventative care.^17,23 Finally, patients often are limited in their choice of dermatologist; the lack of a fully developed relationship increases concerns of follow-up and monitoring practices. Although some DTC platforms offer unlimited interactions with physicians for the duration of a prescription, it is unknown how often these services are utilized or how adequate the quality of these interactions is. This potential for lax follow-up is especially concerning for prescriptions that autorenew on a monthly basis and could result in unnecessary overtreatment.

Postpandemic and Future Outlook

The COVID-19 pandemic dramatically impacted the use of telemedicine. To minimize COVID-19 transmission, the Centers for Medicare & Medicaid Services and private payers expanded telehealth coverage and eliminated reimbursement and licensing barriers.²⁸ A decade’s worth of regulatory changes and consumer adoption was accelerated to weeks, resulting in telemedicine companies reaching record-high visit numbers.²⁹ McKinsey & Company estimated that telehealth visit numbers surged 50- to 175-fold compared with pre–COVID-19 numbers. Additionally, 76% of patients were interested in future telehealth use, and 64% of providers were more comfortable using telehealth than before the pandemic.³⁰ For their part, US dermatologists reported an increase in telemedicine use from 14.1% to 96.9% since COVID-19.³¹

Exactly how much DTC pharmaceutical telemedicine companies are growing is unclear, but private investments may be an indication. A record $14.7 billion was invested in the digital health sector in the first half of 2021; the majority went to telehealth companies.³⁰ Ro, which reported $230 million in revenue in 2020 and has served 6 million visits, raised $200 milllion in July 2020 and $500 million in March 2021.³² Although post–COVID-19 health care will certainly involve increased telemedicine, the extent remains unclear, as telehealth vendors saw decreased usage upon reopening of state economies. Ultimately, the postpandemic regulatory landscape is hard to predict.³⁰

Although COVID-19 appears to have caused rapid growth for DTC platforms, it also may have spurred competition. Telemedicine providers have given independent dermatologists and health care systems the infrastructure to implement custom DTC services.³³ Although systems do not directly sell prescription drugs, the target market is essentially the same: patients looking for instant virtual dermatologic care. Therefore, sustained telemedicine services offered by traditional practices and systems may prove detrimental to DTC companies. However, unlike most telemedicine services, DTC models are less affected by certain changes in regulation since they do not rely on insurance. If regulations are tightened and reimbursements for telehealth are not attractive for dermatologists, teledermatology services may see an overall decrease. If so, patients who appreciate teledermatology may shift to using DTC platforms, even if their insurance does not cover them. Still, a nationwide survey found 56% of respondents felt an established relationship with a physician prior to a telemedicine visit is important, which may create a barrier for DTC adoption.³⁴

Conclusion

Direct-to-consumer teledermatology represents a growing for-profit model of health care that provides patients with seemingly affordable and convenient care. However, there is potential for overtreatment, misdiagnosis, and fragmentation of health care. It will be important to monitor and evaluate the quality of care that DTC teledermatology offers and advocate for appropriate regulations and oversight. Eventually, more patients will have medications prescribed and dermatologic care administered through DTC companies. Dermatologists will benefit from this knowledge of DTC models to properly counsel patients on the risks and benefits of their use.

Polycythemia vera (PV) is a rare myeloproliferative neoplasm affecting 44 to 57 individuals per 100,000 in the United States.^1,2 It is characterized by somatic mutations in the hematopoietic stem cell, resulting in hyperproliferation of mature myeloid lineage cells.² Sustained erythrocytosis is a hallmark of PV, although many patients also have leukocytosis and thrombocytosis.^2,3 These patients have increased inherent thrombotic risk with arterial events reported to occur at rates of 7 to 21/1000 person-years and venous thrombotic events at 5 to 20/1000 person-years.^4-7 Thrombotic and cardiovascular events are leading causes of morbidity and mortality, resulting in a reduced overall survival of patients with PV compared with the general population.^3,8-10

Blood Cell Counts and Thrombotic Events in PV

Treatment strategies for patients with PV mainly aim to prevent or manage thrombotic and bleeding complications through normalization of blood counts.¹¹ Hematocrit (Hct) control has been reported to be associated with reduced thrombotic risk in patients with PV. This was shown and popularized by the prospective, randomized Cytoreductive Therapy in Polycythemia Vera (CYTO-PV) trial in which participants were randomized 1:1 to maintaining either a low (< 45%) or high (45%-50%) Hct for 5 years to examine the long-term effects of more- or less-intensive cytoreductive therapy.¹² Patients in the low-Hct group were found to have a lower rate of death from cardiovascular events or major thrombosis (1.1/100 person-years in the low-Hct group vs 4.4 in the high-Hct group; hazard ratio [HR], 3.91; 95% confidence interval [CI], 1.45-10.53; P = .007). Likewise, cardiovascular events occurred at a lower rate in patients in the low-Hct group compared with the high-Hct group (4.4% vs 10.9% of patients, respectively; HR, 2.69; 95% CI, 1.19-6.12; P = .02).¹²

Leukocytosis has also been linked to elevated risk for vascular events as shown in several studies, including the real-world European Collaboration on Low-Dose Aspirin in PV (ECLAP) observational study and a post hoc subanalysis of the CYTO-PV study.^13,14 In a multivariate, time-dependent analysis in ECLAP, patients with white blood cell (WBC) counts > 15 × 10⁹/L had a significant increase in the risk of thrombosis compared with those who had lower WBC counts, with higher WBC count more strongly associated with arterial than venous thromboembolism.¹³ In CYTO-PV, a significant correlation between elevated WBC count (≥ 11 × 10⁹/L vs reference level of < 7 × 10⁹/L) and time-dependent risk of major thrombosis was shown (HR, 3.9; 95% CI, 1.24-12.3; P = .02).¹⁴ Likewise, WBC count ≥ 11 × 10⁹/L was found to be a predictor of subsequent venous events in a separate single-center multivariate analysis of patients with PV.⁸

Although CYTO-PV remains one of the largest prospective landmark studies in PV demonstrating the impact of Hct control on thrombosis, it is worthwhile to note that the patients in the high-Hct group who received less frequent myelosuppressive therapy with hydroxyurea than the low-Hct group also had higher WBC counts.^12,15 Work is needed to determine the relative effects of high Hct and high WBC counts on PV independent of each other.

The Veteran Population with PV

Two recently published retrospective analyses from Parasuraman and colleagues used data from the Veterans Health Administration (VHA), the largest integrated health care system in the US, with an aim to replicate findings from CYTO-PV in a real-world population.^16,17 The 2 analyses focused independently on the effects of Hct control and WBC count on the risk of a thrombotic event in patients with PV.

In the first retrospective analysis, 213 patients with PV and no prior thrombosis were placed into groups based on whether Hct levels were consistently either < 45% or ≥ 45% throughout the study period.¹⁷ The mean follow-up time was 2.3 years, during which 44.1% of patients experienced a thrombotic event (Figure 1). Patients with Hct levels < 45% had a lower rate of thrombotic events compared to those with levels ≥ 45% (40.3% vs 54.2%, respectively; HR, 1.61; 95% CI, 1.03-2.51; P = .04). In a sensitivity analysis that included patients with pre-index thrombotic events (N = 342), similar results were noted (55.6% vs 76.9% between the < 45% and ≥ 45% groups, respectively; HR, 1.95; 95% CI, 1.46-2.61; P < .001).

Some limitations to these studies are attributable to their retrospective design, reliance on health records, and the VHA population characteristics, which differ from the general population. For example, in this analysis, patients with PV in the VHA population had significantly increased risk of thrombotic events, even at a lower WBC count threshold (≥ 8.5 × 10⁹/L) compared with those reported in CYTO-PV (≥ 11 × 10⁹/L). Furthermore, approximately one-third of patients had elevated WBC levels, compared with 25.5% in the CYTO-PV study.^14,16 This is most likely due to the unique nature of the VHA patient population, who are predominantly older adult men and generally have a higher comorbidity burden. A notable pre-index comorbidity burden was reported in the VHA population in the Hct analysis, even when compared to patients with PV in the general US population (Charlson Comorbidity Index score, 1.3 vs 0.8).^6,17 Comorbid conditions such as hypertension, diabetes, and tobacco use, which are most common among the VHA population, are independently associated with higher risk of cardiovascular and thrombotic events.^18,19 However, whether these higher levels of comorbidities affected the type of treatments they received was not elucidated, and the effectiveness of treatments to maintain target Hct levels was not addressed in the study.

Current PV Management and Future Implications

The National Comprehensive Cancer Network (NCCN) clinical practice guidelines in oncology in myeloproliferative neoplasms recommend maintaining Hct levels < 45% in patients with PV.¹¹ Patients with high-risk disease (age ≥ 60 years and/or history of thrombosis) are monitored for new thrombosis or bleeding and are managed for their cardiovascular risk factors. In addition, they receive low-dose aspirin (81-100 mg/day), undergo phlebotomy to maintain an Hct < 45%, and are managed with pharmacologic cytoreductive therapy. Cytoreductive therapy primarily consists of hydroxyurea or peginterferon alfa-2a for younger patients. Ruxolitinib, a Janus kinase (JAK1)/JAK2 inhibitor, is now approved by the US Food and Drug Administration as second-line treatment for those with PV that is intolerant or unresponsive to hydroxyurea or peginterferon alfa-2a treatments.^11,20 However, the role of cytoreductive therapy is not clear for patients with low-risk disease (age < 60 years and no history of thrombosis). These patients are managed for their cardiovascular risk factors, undergo phlebotomy to maintain an Hct < 45%, are maintained on low-dose aspirin (81-100 mg/day), and are monitored for indications for cytoreductive therapy, which include any new thrombosis or disease-related major bleeding, frequent or persistent need for phlebotomy with poor tolerance for the procedure, splenomegaly, thrombocytosis, leukocytosis, and disease-related symptoms (eg, aquagenic pruritus, night sweats, fatigue).

Even though the current guidelines recommend maintaining a target Hct of < 45% in patients with high-risk PV, the role of Hct as the main determinant of thrombotic risk in patients with PV is still debated.²¹ In JAK2V617F-positive essential thrombocythemia, Hct levels are usually normal but risk of thrombosis is nevertheless still significant.²² The risk of thrombosis is significantly lower in primary familial and congenital polycythemia and much lower in secondary erythrocytosis such as cyanotic heart disease, long-term native dwellers of high altitude, and those with high-oxygen–affinity hemoglobins.^21,23 In secondary erythrocytosis from hypoxia or upregulated hypoxic pathway such as hypoxia inducible factor-2α (HIF-2α) mutation and Chuvash erythrocytosis, the risk of thrombosis is more associated with the upregulated HIF pathway and its downstream consequences, rather than the elevated Hct level.²⁴

However, most current literature supports the association of increased risk of thrombosis with higher Hct and high WBC count in patients with PV. In addition, the underlying mechanism of thrombogenesis still remains elusive; it is likely a complex process that involves interactions among multiple components, including elevated blood counts arising from clonal hematopoiesis, JAK2V617F allele burden, and platelet and WBC activation and their interaction with endothelial cells and inflammatory cytokines.²⁵

Nevertheless, Hct control and aspirin use are current standard of care for patients with PV to mitigate thrombotic risk, and the results from the 2 analyses by Parasuraman and colleagues, using real-world data from the VHA, support the current practice guidelines to maintain Hct < 45% in these patients. They also provide additional support for considering WBC counts when determining patient risk and treatment plans. Although treatment response criteria from the European LeukemiaNet include achieving normal WBC levels to decrease the risk of thrombosis, current NCCN guidelines do not include WBC counts as a component for establishing patient risk or provide a target WBC count to guide patient management.^11,26,27 Updates to these practice guidelines may be warranted. In addition, further study is needed to understand the mechanism of thrombogenesis in PV and other myeloproliferative disorders in order to develop novel therapeutic targets and improve patient outcomes.

Acknowledgments

Writing assistance was provided by Tania Iqbal, PhD, an employee of ICON (North Wales, PA), and was funded by Incyte Corporation (Wilmington, DE).

Polycythemia vera (PV) is a rare myeloproliferative neoplasm affecting 44 to 57 individuals per 100,000 in the United States.^1,2 It is characterized by somatic mutations in the hematopoietic stem cell, resulting in hyperproliferation of mature myeloid lineage cells.² Sustained erythrocytosis is a hallmark of PV, although many patients also have leukocytosis and thrombocytosis.^2,3 These patients have increased inherent thrombotic risk with arterial events reported to occur at rates of 7 to 21/1000 person-years and venous thrombotic events at 5 to 20/1000 person-years.^4-7 Thrombotic and cardiovascular events are leading causes of morbidity and mortality, resulting in a reduced overall survival of patients with PV compared with the general population.^3,8-10

Blood Cell Counts and Thrombotic Events in PV

Treatment strategies for patients with PV mainly aim to prevent or manage thrombotic and bleeding complications through normalization of blood counts.¹¹ Hematocrit (Hct) control has been reported to be associated with reduced thrombotic risk in patients with PV. This was shown and popularized by the prospective, randomized Cytoreductive Therapy in Polycythemia Vera (CYTO-PV) trial in which participants were randomized 1:1 to maintaining either a low (< 45%) or high (45%-50%) Hct for 5 years to examine the long-term effects of more- or less-intensive cytoreductive therapy.¹² Patients in the low-Hct group were found to have a lower rate of death from cardiovascular events or major thrombosis (1.1/100 person-years in the low-Hct group vs 4.4 in the high-Hct group; hazard ratio [HR], 3.91; 95% confidence interval [CI], 1.45-10.53; P = .007). Likewise, cardiovascular events occurred at a lower rate in patients in the low-Hct group compared with the high-Hct group (4.4% vs 10.9% of patients, respectively; HR, 2.69; 95% CI, 1.19-6.12; P = .02).¹²

Leukocytosis has also been linked to elevated risk for vascular events as shown in several studies, including the real-world European Collaboration on Low-Dose Aspirin in PV (ECLAP) observational study and a post hoc subanalysis of the CYTO-PV study.^13,14 In a multivariate, time-dependent analysis in ECLAP, patients with white blood cell (WBC) counts > 15 × 10⁹/L had a significant increase in the risk of thrombosis compared with those who had lower WBC counts, with higher WBC count more strongly associated with arterial than venous thromboembolism.¹³ In CYTO-PV, a significant correlation between elevated WBC count (≥ 11 × 10⁹/L vs reference level of < 7 × 10⁹/L) and time-dependent risk of major thrombosis was shown (HR, 3.9; 95% CI, 1.24-12.3; P = .02).¹⁴ Likewise, WBC count ≥ 11 × 10⁹/L was found to be a predictor of subsequent venous events in a separate single-center multivariate analysis of patients with PV.⁸

Although CYTO-PV remains one of the largest prospective landmark studies in PV demonstrating the impact of Hct control on thrombosis, it is worthwhile to note that the patients in the high-Hct group who received less frequent myelosuppressive therapy with hydroxyurea than the low-Hct group also had higher WBC counts.^12,15 Work is needed to determine the relative effects of high Hct and high WBC counts on PV independent of each other.

The Veteran Population with PV

Two recently published retrospective analyses from Parasuraman and colleagues used data from the Veterans Health Administration (VHA), the largest integrated health care system in the US, with an aim to replicate findings from CYTO-PV in a real-world population.^16,17 The 2 analyses focused independently on the effects of Hct control and WBC count on the risk of a thrombotic event in patients with PV.

In the first retrospective analysis, 213 patients with PV and no prior thrombosis were placed into groups based on whether Hct levels were consistently either < 45% or ≥ 45% throughout the study period.¹⁷ The mean follow-up time was 2.3 years, during which 44.1% of patients experienced a thrombotic event (Figure 1). Patients with Hct levels < 45% had a lower rate of thrombotic events compared to those with levels ≥ 45% (40.3% vs 54.2%, respectively; HR, 1.61; 95% CI, 1.03-2.51; P = .04). In a sensitivity analysis that included patients with pre-index thrombotic events (N = 342), similar results were noted (55.6% vs 76.9% between the < 45% and ≥ 45% groups, respectively; HR, 1.95; 95% CI, 1.46-2.61; P < .001).

Some limitations to these studies are attributable to their retrospective design, reliance on health records, and the VHA population characteristics, which differ from the general population. For example, in this analysis, patients with PV in the VHA population had significantly increased risk of thrombotic events, even at a lower WBC count threshold (≥ 8.5 × 10⁹/L) compared with those reported in CYTO-PV (≥ 11 × 10⁹/L). Furthermore, approximately one-third of patients had elevated WBC levels, compared with 25.5% in the CYTO-PV study.^14,16 This is most likely due to the unique nature of the VHA patient population, who are predominantly older adult men and generally have a higher comorbidity burden. A notable pre-index comorbidity burden was reported in the VHA population in the Hct analysis, even when compared to patients with PV in the general US population (Charlson Comorbidity Index score, 1.3 vs 0.8).^6,17 Comorbid conditions such as hypertension, diabetes, and tobacco use, which are most common among the VHA population, are independently associated with higher risk of cardiovascular and thrombotic events.^18,19 However, whether these higher levels of comorbidities affected the type of treatments they received was not elucidated, and the effectiveness of treatments to maintain target Hct levels was not addressed in the study.

Current PV Management and Future Implications

The National Comprehensive Cancer Network (NCCN) clinical practice guidelines in oncology in myeloproliferative neoplasms recommend maintaining Hct levels < 45% in patients with PV.¹¹ Patients with high-risk disease (age ≥ 60 years and/or history of thrombosis) are monitored for new thrombosis or bleeding and are managed for their cardiovascular risk factors. In addition, they receive low-dose aspirin (81-100 mg/day), undergo phlebotomy to maintain an Hct < 45%, and are managed with pharmacologic cytoreductive therapy. Cytoreductive therapy primarily consists of hydroxyurea or peginterferon alfa-2a for younger patients. Ruxolitinib, a Janus kinase (JAK1)/JAK2 inhibitor, is now approved by the US Food and Drug Administration as second-line treatment for those with PV that is intolerant or unresponsive to hydroxyurea or peginterferon alfa-2a treatments.^11,20 However, the role of cytoreductive therapy is not clear for patients with low-risk disease (age < 60 years and no history of thrombosis). These patients are managed for their cardiovascular risk factors, undergo phlebotomy to maintain an Hct < 45%, are maintained on low-dose aspirin (81-100 mg/day), and are monitored for indications for cytoreductive therapy, which include any new thrombosis or disease-related major bleeding, frequent or persistent need for phlebotomy with poor tolerance for the procedure, splenomegaly, thrombocytosis, leukocytosis, and disease-related symptoms (eg, aquagenic pruritus, night sweats, fatigue).

Even though the current guidelines recommend maintaining a target Hct of < 45% in patients with high-risk PV, the role of Hct as the main determinant of thrombotic risk in patients with PV is still debated.²¹ In JAK2V617F-positive essential thrombocythemia, Hct levels are usually normal but risk of thrombosis is nevertheless still significant.²² The risk of thrombosis is significantly lower in primary familial and congenital polycythemia and much lower in secondary erythrocytosis such as cyanotic heart disease, long-term native dwellers of high altitude, and those with high-oxygen–affinity hemoglobins.^21,23 In secondary erythrocytosis from hypoxia or upregulated hypoxic pathway such as hypoxia inducible factor-2α (HIF-2α) mutation and Chuvash erythrocytosis, the risk of thrombosis is more associated with the upregulated HIF pathway and its downstream consequences, rather than the elevated Hct level.²⁴

However, most current literature supports the association of increased risk of thrombosis with higher Hct and high WBC count in patients with PV. In addition, the underlying mechanism of thrombogenesis still remains elusive; it is likely a complex process that involves interactions among multiple components, including elevated blood counts arising from clonal hematopoiesis, JAK2V617F allele burden, and platelet and WBC activation and their interaction with endothelial cells and inflammatory cytokines.²⁵

Nevertheless, Hct control and aspirin use are current standard of care for patients with PV to mitigate thrombotic risk, and the results from the 2 analyses by Parasuraman and colleagues, using real-world data from the VHA, support the current practice guidelines to maintain Hct < 45% in these patients. They also provide additional support for considering WBC counts when determining patient risk and treatment plans. Although treatment response criteria from the European LeukemiaNet include achieving normal WBC levels to decrease the risk of thrombosis, current NCCN guidelines do not include WBC counts as a component for establishing patient risk or provide a target WBC count to guide patient management.^11,26,27 Updates to these practice guidelines may be warranted. In addition, further study is needed to understand the mechanism of thrombogenesis in PV and other myeloproliferative disorders in order to develop novel therapeutic targets and improve patient outcomes.

Acknowledgments

Writing assistance was provided by Tania Iqbal, PhD, an employee of ICON (North Wales, PA), and was funded by Incyte Corporation (Wilmington, DE).

Polycythemia vera (PV) is a rare myeloproliferative neoplasm affecting 44 to 57 individuals per 100,000 in the United States.^1,2 It is characterized by somatic mutations in the hematopoietic stem cell, resulting in hyperproliferation of mature myeloid lineage cells.² Sustained erythrocytosis is a hallmark of PV, although many patients also have leukocytosis and thrombocytosis.^2,3 These patients have increased inherent thrombotic risk with arterial events reported to occur at rates of 7 to 21/1000 person-years and venous thrombotic events at 5 to 20/1000 person-years.^4-7 Thrombotic and cardiovascular events are leading causes of morbidity and mortality, resulting in a reduced overall survival of patients with PV compared with the general population.^3,8-10

Blood Cell Counts and Thrombotic Events in PV

Treatment strategies for patients with PV mainly aim to prevent or manage thrombotic and bleeding complications through normalization of blood counts.¹¹ Hematocrit (Hct) control has been reported to be associated with reduced thrombotic risk in patients with PV. This was shown and popularized by the prospective, randomized Cytoreductive Therapy in Polycythemia Vera (CYTO-PV) trial in which participants were randomized 1:1 to maintaining either a low (< 45%) or high (45%-50%) Hct for 5 years to examine the long-term effects of more- or less-intensive cytoreductive therapy.¹² Patients in the low-Hct group were found to have a lower rate of death from cardiovascular events or major thrombosis (1.1/100 person-years in the low-Hct group vs 4.4 in the high-Hct group; hazard ratio [HR], 3.91; 95% confidence interval [CI], 1.45-10.53; P = .007). Likewise, cardiovascular events occurred at a lower rate in patients in the low-Hct group compared with the high-Hct group (4.4% vs 10.9% of patients, respectively; HR, 2.69; 95% CI, 1.19-6.12; P = .02).¹²

Leukocytosis has also been linked to elevated risk for vascular events as shown in several studies, including the real-world European Collaboration on Low-Dose Aspirin in PV (ECLAP) observational study and a post hoc subanalysis of the CYTO-PV study.^13,14 In a multivariate, time-dependent analysis in ECLAP, patients with white blood cell (WBC) counts > 15 × 10⁹/L had a significant increase in the risk of thrombosis compared with those who had lower WBC counts, with higher WBC count more strongly associated with arterial than venous thromboembolism.¹³ In CYTO-PV, a significant correlation between elevated WBC count (≥ 11 × 10⁹/L vs reference level of < 7 × 10⁹/L) and time-dependent risk of major thrombosis was shown (HR, 3.9; 95% CI, 1.24-12.3; P = .02).¹⁴ Likewise, WBC count ≥ 11 × 10⁹/L was found to be a predictor of subsequent venous events in a separate single-center multivariate analysis of patients with PV.⁸

Although CYTO-PV remains one of the largest prospective landmark studies in PV demonstrating the impact of Hct control on thrombosis, it is worthwhile to note that the patients in the high-Hct group who received less frequent myelosuppressive therapy with hydroxyurea than the low-Hct group also had higher WBC counts.^12,15 Work is needed to determine the relative effects of high Hct and high WBC counts on PV independent of each other.

The Veteran Population with PV

Two recently published retrospective analyses from Parasuraman and colleagues used data from the Veterans Health Administration (VHA), the largest integrated health care system in the US, with an aim to replicate findings from CYTO-PV in a real-world population.^16,17 The 2 analyses focused independently on the effects of Hct control and WBC count on the risk of a thrombotic event in patients with PV.

In the first retrospective analysis, 213 patients with PV and no prior thrombosis were placed into groups based on whether Hct levels were consistently either < 45% or ≥ 45% throughout the study period.¹⁷ The mean follow-up time was 2.3 years, during which 44.1% of patients experienced a thrombotic event (Figure 1). Patients with Hct levels < 45% had a lower rate of thrombotic events compared to those with levels ≥ 45% (40.3% vs 54.2%, respectively; HR, 1.61; 95% CI, 1.03-2.51; P = .04). In a sensitivity analysis that included patients with pre-index thrombotic events (N = 342), similar results were noted (55.6% vs 76.9% between the < 45% and ≥ 45% groups, respectively; HR, 1.95; 95% CI, 1.46-2.61; P < .001).

Some limitations to these studies are attributable to their retrospective design, reliance on health records, and the VHA population characteristics, which differ from the general population. For example, in this analysis, patients with PV in the VHA population had significantly increased risk of thrombotic events, even at a lower WBC count threshold (≥ 8.5 × 10⁹/L) compared with those reported in CYTO-PV (≥ 11 × 10⁹/L). Furthermore, approximately one-third of patients had elevated WBC levels, compared with 25.5% in the CYTO-PV study.^14,16 This is most likely due to the unique nature of the VHA patient population, who are predominantly older adult men and generally have a higher comorbidity burden. A notable pre-index comorbidity burden was reported in the VHA population in the Hct analysis, even when compared to patients with PV in the general US population (Charlson Comorbidity Index score, 1.3 vs 0.8).^6,17 Comorbid conditions such as hypertension, diabetes, and tobacco use, which are most common among the VHA population, are independently associated with higher risk of cardiovascular and thrombotic events.^18,19 However, whether these higher levels of comorbidities affected the type of treatments they received was not elucidated, and the effectiveness of treatments to maintain target Hct levels was not addressed in the study.

Current PV Management and Future Implications

The National Comprehensive Cancer Network (NCCN) clinical practice guidelines in oncology in myeloproliferative neoplasms recommend maintaining Hct levels < 45% in patients with PV.¹¹ Patients with high-risk disease (age ≥ 60 years and/or history of thrombosis) are monitored for new thrombosis or bleeding and are managed for their cardiovascular risk factors. In addition, they receive low-dose aspirin (81-100 mg/day), undergo phlebotomy to maintain an Hct < 45%, and are managed with pharmacologic cytoreductive therapy. Cytoreductive therapy primarily consists of hydroxyurea or peginterferon alfa-2a for younger patients. Ruxolitinib, a Janus kinase (JAK1)/JAK2 inhibitor, is now approved by the US Food and Drug Administration as second-line treatment for those with PV that is intolerant or unresponsive to hydroxyurea or peginterferon alfa-2a treatments.^11,20 However, the role of cytoreductive therapy is not clear for patients with low-risk disease (age < 60 years and no history of thrombosis). These patients are managed for their cardiovascular risk factors, undergo phlebotomy to maintain an Hct < 45%, are maintained on low-dose aspirin (81-100 mg/day), and are monitored for indications for cytoreductive therapy, which include any new thrombosis or disease-related major bleeding, frequent or persistent need for phlebotomy with poor tolerance for the procedure, splenomegaly, thrombocytosis, leukocytosis, and disease-related symptoms (eg, aquagenic pruritus, night sweats, fatigue).

Even though the current guidelines recommend maintaining a target Hct of < 45% in patients with high-risk PV, the role of Hct as the main determinant of thrombotic risk in patients with PV is still debated.²¹ In JAK2V617F-positive essential thrombocythemia, Hct levels are usually normal but risk of thrombosis is nevertheless still significant.²² The risk of thrombosis is significantly lower in primary familial and congenital polycythemia and much lower in secondary erythrocytosis such as cyanotic heart disease, long-term native dwellers of high altitude, and those with high-oxygen–affinity hemoglobins.^21,23 In secondary erythrocytosis from hypoxia or upregulated hypoxic pathway such as hypoxia inducible factor-2α (HIF-2α) mutation and Chuvash erythrocytosis, the risk of thrombosis is more associated with the upregulated HIF pathway and its downstream consequences, rather than the elevated Hct level.²⁴

However, most current literature supports the association of increased risk of thrombosis with higher Hct and high WBC count in patients with PV. In addition, the underlying mechanism of thrombogenesis still remains elusive; it is likely a complex process that involves interactions among multiple components, including elevated blood counts arising from clonal hematopoiesis, JAK2V617F allele burden, and platelet and WBC activation and their interaction with endothelial cells and inflammatory cytokines.²⁵

Nevertheless, Hct control and aspirin use are current standard of care for patients with PV to mitigate thrombotic risk, and the results from the 2 analyses by Parasuraman and colleagues, using real-world data from the VHA, support the current practice guidelines to maintain Hct < 45% in these patients. They also provide additional support for considering WBC counts when determining patient risk and treatment plans. Although treatment response criteria from the European LeukemiaNet include achieving normal WBC levels to decrease the risk of thrombosis, current NCCN guidelines do not include WBC counts as a component for establishing patient risk or provide a target WBC count to guide patient management.^11,26,27 Updates to these practice guidelines may be warranted. In addition, further study is needed to understand the mechanism of thrombogenesis in PV and other myeloproliferative disorders in order to develop novel therapeutic targets and improve patient outcomes.

Acknowledgments

Writing assistance was provided by Tania Iqbal, PhD, an employee of ICON (North Wales, PA), and was funded by Incyte Corporation (Wilmington, DE).