Perspectives

As the saying goes, “The more things change, the more they stay the same.” That is particularly true when it comes to the affordability of drugs for our patients even after the launch of so many Humira biosimilars. And we still have the “musical chairs” game of formulary construction — when the music stops, who knows whether your patient’s drug found a chair to sit on. There seems to be only a few chairs available for the many adalimumab biosimilars playing the game.

Nothing has changed since my testimony before the FDA Arthritis Advisory Committee in July 2016 during the approval hearing of the first Humira biosimilar. Below is a quote from that meeting where I was speaking predominantly about the pharmacy side of drugs.

“I’d like to highlight the term ‘access’ because none of us are really naive enough to believe that just approving a biosimilar gives a patient true, hands-on access to the medication, because even if the biosimilar is offered at a 30% discount, I don’t have any patients that can afford it. This means that access is ultimately controlled by third-party payers.”

My prediction, that approving and launching biosimilars with lower prices would not ensure patient access to the drug unless it is paid for by insurance, is now our reality. Today, a drug with an 85% discount on the price of Humira is still unattainable for patients without a “payer.”
 

Competition and Lower Prices

Lawmakers and some in the media cry for more competition to lower prices. This is the main reason that there has been such a push to get biosimilars to the market as quickly as possible. It is abundantly clear that competition to get on the formulary is fierce. Placement of a medication on a formulary can make or break a manufacturer’s ability to get a return on the R&D and make a profit on that medication. For a small biotech manufacturer, it can be the difference between “life and death” of the company.

Does anyone remember when the first interchangeable biosimilar for the reference insulin glargine product Lantus (insulin glargine-yfgn; Semglee) came to market in 2021? Janet Woodcock, MD, then acting FDA commissioner, called it a “momentous day” and further said, “Today’s approval of the first interchangeable biosimilar product furthers FDA’s longstanding commitment to support a competitive marketplace for biological products and ultimately empowers patients by helping to increase access to safe, effective and high-quality medications at potentially lower cost.” There was a high-priced interchangeable biosimilar and an identical unbranded low-priced interchangeable biosimilar, and the only one that could get formulary placement was the high-priced drug.

Patients pay their cost share on the list price of the drug, and because most pharmacy benefit managers’ (PBMs’) formularies cover only the high-priced biosimilar, patients never share in the savings. So much for the “competitive marketplace” creating lower costs for patients. This is just one of hundreds of examples in which lower-priced drugs are excluded from the formulary. It is unfortunate that the bidding process from manufacturers to PBMs to “win” preferred formulary placement is like an art auction, where the highest bidder wins.
 

Biosimilars and Formulary Construction

For those of us who have been looking into PBMs for many years, it is no surprise that PBMs’ formulary construction has become a profit center for them. Now, with so many adalimumab biosimilars having entered the market, it has become the Wild West where only those with the most money to fork over to the PBMs get preferred placement. Unfortunately, many of the choices that make money for the PBM cost employers and patients more.

How did we get here? In the 1980s and 90s, the price of medications began to increase to the point that many were not affordable without insurance. And who better to construct the list of drugs that would be covered by insurance (formulary) than the PBMs who were already adjudicating the claims for these drugs. The Federal Trade Commission (FTC) realized the power inherent in constructing this list of medications known as the formulary. So when the manufacturer Merck acquired the PBM Medco in the mid-1990s, the FTC stepped in. The FTC surmised that making the drugs and deciding which ones will be paid for created a “conflict of interest” with anticompetitive ramifications.

So, in 1998, William J. Baer, director of the FTC’s Bureau of Competition, said, “Our investigation into the PBM industry has revealed that Merck’s acquisition of Medco has reduced competition in the market for pharmaceutical products … We have found that Medco has given favorable treatment to Merck drugs. As a result, in some cases, consumers have been denied access to the drugs of competing manufacturers. In addition, the merger has made it possible for Medco to share with Merck sensitive pricing information it gets from Merck’s competitors, which could foster collusion among drug manufacturers.” Wow!

These anticompetitive behaviors and conflicts of interest resulting from the Medco acquisition led the FTC to propose a consent agreement.

The agreement would require Merck-Medco to maintain an “open formulary” — one that includes drugs selected and approved by an independent Pharmacy and Therapeutics Committee regardless of the manufacturer. Medco would have to accept rebates and other price concessions and reflect these in the ranking of the drugs on the formulary. Merck would have to make known the availability of the open formulary to any drug maker with an agreement with Medco.

Let’s hope the FTC of 2024 remembers the stance of the FTC in the 1990s regarding anticompetitive behavior involved in formulary construction.
 

Conflicts of Interest

But today it is apparent that crafting formularies that pay only for the drugs that make the most money for the PBM is not a conflict of interest. In its policy manual, Cigna directly tells employers and employees that they are collecting and keeping rebates and fees on medical pharmaceuticals, and they are not for the benefit of the employer or the plan.

And now, in August 2023, CVS launched Cordavis, a subsidiary wholly owned by CVS. Cordavis/CVS has partnered with Sandoz, which makes Hyrimoz, an adalimumab biosimilar. There is a high-priced version that is discounted 5% from Humira, a lower-cost unbranded version that is discounted 80% off the list price of Humira, and a co-branded CVS/Sandoz version of Hyrimoz that is lower priced as well.

It isn’t a surprise that CVS’ Standard and Advanced Commercial and Chart formularies are offering only Sandoz adalimumab biosimilar products. While these formularies have excluded Humira, CVS has entered into an agreement with AbbVie to allow Humira on a number of their other formularies. It can be very confusing.

As stated earlier, in the 1990s, the FTC frowned upon manufacturers owning PBMs and allowing them to construct their own formularies. Here we have CVS Health, mothership for the PBM CVS Caremark, owning a company that will be co-producing biosimilars with other manufacturers and then determining which biosimilars are on their formularies. The FTC knew back then that the tendency would be to offer only their own drugs for coverage, thus reducing competition. This is exactly what the CVS-Cordavis-Sandoz partnership has done for their Standard and Advanced Commercial and Chart formularies. It is perhaps anti-competitive but certainly profitable.

Perhaps the FTC should require the same consent agreement that was given to Merck in 1998. CVS Caremark would then have to open their formularies to all competitors of their co-branded, co-produced Sandoz biosimilar.
 

Summary

It is the same old adage, “The more things change, the more they stay the same.” PBMs are still constructing formularies with biosimilars based on their profitability, with huge differences between gross and net cost. Patients still pay their cost share on the list (gross) price. With the CVS-Cordavis-Sandoz partnership, more vertical integration has led to yet another profit river. Self-funded employers are still getting the wool pulled over their eyes by the big three PBMs who threaten to take away rebates if they don’t choose the preferred formularies. The employers don’t realize that sometimes it is less expensive to choose the lower-priced drugs with no rebates, and that holds true for biosimilars as well.

Let’s hope that the FTC investigates the situation of a PBM partnering with a manufacturer and then choosing only that manufacturer’s drugs for many of their formularies.

We need to continue our advocacy for our patients because the medication that has kept them stable for so long may find itself without a chair the next time the music stops.
 

Dr. Feldman is a rheumatologist in private practice with The Rheumatology Group in New Orleans. She is the CSRO’s Vice President of Advocacy and Government Affairs and its immediate Past President, as well as past chair of the Alliance for Safe Biologic Medicines and a past member of the American College of Rheumatology insurance subcommittee. You can reach her at [email protected].

As the saying goes, “The more things change, the more they stay the same.” That is particularly true when it comes to the affordability of drugs for our patients even after the launch of so many Humira biosimilars. And we still have the “musical chairs” game of formulary construction — when the music stops, who knows whether your patient’s drug found a chair to sit on. There seems to be only a few chairs available for the many adalimumab biosimilars playing the game.

Nothing has changed since my testimony before the FDA Arthritis Advisory Committee in July 2016 during the approval hearing of the first Humira biosimilar. Below is a quote from that meeting where I was speaking predominantly about the pharmacy side of drugs.

“I’d like to highlight the term ‘access’ because none of us are really naive enough to believe that just approving a biosimilar gives a patient true, hands-on access to the medication, because even if the biosimilar is offered at a 30% discount, I don’t have any patients that can afford it. This means that access is ultimately controlled by third-party payers.”

My prediction, that approving and launching biosimilars with lower prices would not ensure patient access to the drug unless it is paid for by insurance, is now our reality. Today, a drug with an 85% discount on the price of Humira is still unattainable for patients without a “payer.”
 

Competition and Lower Prices

Lawmakers and some in the media cry for more competition to lower prices. This is the main reason that there has been such a push to get biosimilars to the market as quickly as possible. It is abundantly clear that competition to get on the formulary is fierce. Placement of a medication on a formulary can make or break a manufacturer’s ability to get a return on the R&D and make a profit on that medication. For a small biotech manufacturer, it can be the difference between “life and death” of the company.

Does anyone remember when the first interchangeable biosimilar for the reference insulin glargine product Lantus (insulin glargine-yfgn; Semglee) came to market in 2021? Janet Woodcock, MD, then acting FDA commissioner, called it a “momentous day” and further said, “Today’s approval of the first interchangeable biosimilar product furthers FDA’s longstanding commitment to support a competitive marketplace for biological products and ultimately empowers patients by helping to increase access to safe, effective and high-quality medications at potentially lower cost.” There was a high-priced interchangeable biosimilar and an identical unbranded low-priced interchangeable biosimilar, and the only one that could get formulary placement was the high-priced drug.

Patients pay their cost share on the list price of the drug, and because most pharmacy benefit managers’ (PBMs’) formularies cover only the high-priced biosimilar, patients never share in the savings. So much for the “competitive marketplace” creating lower costs for patients. This is just one of hundreds of examples in which lower-priced drugs are excluded from the formulary. It is unfortunate that the bidding process from manufacturers to PBMs to “win” preferred formulary placement is like an art auction, where the highest bidder wins.
 

Biosimilars and Formulary Construction

For those of us who have been looking into PBMs for many years, it is no surprise that PBMs’ formulary construction has become a profit center for them. Now, with so many adalimumab biosimilars having entered the market, it has become the Wild West where only those with the most money to fork over to the PBMs get preferred placement. Unfortunately, many of the choices that make money for the PBM cost employers and patients more.

How did we get here? In the 1980s and 90s, the price of medications began to increase to the point that many were not affordable without insurance. And who better to construct the list of drugs that would be covered by insurance (formulary) than the PBMs who were already adjudicating the claims for these drugs. The Federal Trade Commission (FTC) realized the power inherent in constructing this list of medications known as the formulary. So when the manufacturer Merck acquired the PBM Medco in the mid-1990s, the FTC stepped in. The FTC surmised that making the drugs and deciding which ones will be paid for created a “conflict of interest” with anticompetitive ramifications.

So, in 1998, William J. Baer, director of the FTC’s Bureau of Competition, said, “Our investigation into the PBM industry has revealed that Merck’s acquisition of Medco has reduced competition in the market for pharmaceutical products … We have found that Medco has given favorable treatment to Merck drugs. As a result, in some cases, consumers have been denied access to the drugs of competing manufacturers. In addition, the merger has made it possible for Medco to share with Merck sensitive pricing information it gets from Merck’s competitors, which could foster collusion among drug manufacturers.” Wow!

These anticompetitive behaviors and conflicts of interest resulting from the Medco acquisition led the FTC to propose a consent agreement.

The agreement would require Merck-Medco to maintain an “open formulary” — one that includes drugs selected and approved by an independent Pharmacy and Therapeutics Committee regardless of the manufacturer. Medco would have to accept rebates and other price concessions and reflect these in the ranking of the drugs on the formulary. Merck would have to make known the availability of the open formulary to any drug maker with an agreement with Medco.

Let’s hope the FTC of 2024 remembers the stance of the FTC in the 1990s regarding anticompetitive behavior involved in formulary construction.
 

Conflicts of Interest

But today it is apparent that crafting formularies that pay only for the drugs that make the most money for the PBM is not a conflict of interest. In its policy manual, Cigna directly tells employers and employees that they are collecting and keeping rebates and fees on medical pharmaceuticals, and they are not for the benefit of the employer or the plan.

And now, in August 2023, CVS launched Cordavis, a subsidiary wholly owned by CVS. Cordavis/CVS has partnered with Sandoz, which makes Hyrimoz, an adalimumab biosimilar. There is a high-priced version that is discounted 5% from Humira, a lower-cost unbranded version that is discounted 80% off the list price of Humira, and a co-branded CVS/Sandoz version of Hyrimoz that is lower priced as well.

It isn’t a surprise that CVS’ Standard and Advanced Commercial and Chart formularies are offering only Sandoz adalimumab biosimilar products. While these formularies have excluded Humira, CVS has entered into an agreement with AbbVie to allow Humira on a number of their other formularies. It can be very confusing.

As stated earlier, in the 1990s, the FTC frowned upon manufacturers owning PBMs and allowing them to construct their own formularies. Here we have CVS Health, mothership for the PBM CVS Caremark, owning a company that will be co-producing biosimilars with other manufacturers and then determining which biosimilars are on their formularies. The FTC knew back then that the tendency would be to offer only their own drugs for coverage, thus reducing competition. This is exactly what the CVS-Cordavis-Sandoz partnership has done for their Standard and Advanced Commercial and Chart formularies. It is perhaps anti-competitive but certainly profitable.

Perhaps the FTC should require the same consent agreement that was given to Merck in 1998. CVS Caremark would then have to open their formularies to all competitors of their co-branded, co-produced Sandoz biosimilar.
 

Summary

It is the same old adage, “The more things change, the more they stay the same.” PBMs are still constructing formularies with biosimilars based on their profitability, with huge differences between gross and net cost. Patients still pay their cost share on the list (gross) price. With the CVS-Cordavis-Sandoz partnership, more vertical integration has led to yet another profit river. Self-funded employers are still getting the wool pulled over their eyes by the big three PBMs who threaten to take away rebates if they don’t choose the preferred formularies. The employers don’t realize that sometimes it is less expensive to choose the lower-priced drugs with no rebates, and that holds true for biosimilars as well.

Let’s hope that the FTC investigates the situation of a PBM partnering with a manufacturer and then choosing only that manufacturer’s drugs for many of their formularies.

We need to continue our advocacy for our patients because the medication that has kept them stable for so long may find itself without a chair the next time the music stops.
 

Dr. Feldman is a rheumatologist in private practice with The Rheumatology Group in New Orleans. She is the CSRO’s Vice President of Advocacy and Government Affairs and its immediate Past President, as well as past chair of the Alliance for Safe Biologic Medicines and a past member of the American College of Rheumatology insurance subcommittee. You can reach her at [email protected].

As the saying goes, “The more things change, the more they stay the same.” That is particularly true when it comes to the affordability of drugs for our patients even after the launch of so many Humira biosimilars. And we still have the “musical chairs” game of formulary construction — when the music stops, who knows whether your patient’s drug found a chair to sit on. There seems to be only a few chairs available for the many adalimumab biosimilars playing the game.

Nothing has changed since my testimony before the FDA Arthritis Advisory Committee in July 2016 during the approval hearing of the first Humira biosimilar. Below is a quote from that meeting where I was speaking predominantly about the pharmacy side of drugs.

“I’d like to highlight the term ‘access’ because none of us are really naive enough to believe that just approving a biosimilar gives a patient true, hands-on access to the medication, because even if the biosimilar is offered at a 30% discount, I don’t have any patients that can afford it. This means that access is ultimately controlled by third-party payers.”

My prediction, that approving and launching biosimilars with lower prices would not ensure patient access to the drug unless it is paid for by insurance, is now our reality. Today, a drug with an 85% discount on the price of Humira is still unattainable for patients without a “payer.”
 

Competition and Lower Prices

Lawmakers and some in the media cry for more competition to lower prices. This is the main reason that there has been such a push to get biosimilars to the market as quickly as possible. It is abundantly clear that competition to get on the formulary is fierce. Placement of a medication on a formulary can make or break a manufacturer’s ability to get a return on the R&D and make a profit on that medication. For a small biotech manufacturer, it can be the difference between “life and death” of the company.

Does anyone remember when the first interchangeable biosimilar for the reference insulin glargine product Lantus (insulin glargine-yfgn; Semglee) came to market in 2021? Janet Woodcock, MD, then acting FDA commissioner, called it a “momentous day” and further said, “Today’s approval of the first interchangeable biosimilar product furthers FDA’s longstanding commitment to support a competitive marketplace for biological products and ultimately empowers patients by helping to increase access to safe, effective and high-quality medications at potentially lower cost.” There was a high-priced interchangeable biosimilar and an identical unbranded low-priced interchangeable biosimilar, and the only one that could get formulary placement was the high-priced drug.

Patients pay their cost share on the list price of the drug, and because most pharmacy benefit managers’ (PBMs’) formularies cover only the high-priced biosimilar, patients never share in the savings. So much for the “competitive marketplace” creating lower costs for patients. This is just one of hundreds of examples in which lower-priced drugs are excluded from the formulary. It is unfortunate that the bidding process from manufacturers to PBMs to “win” preferred formulary placement is like an art auction, where the highest bidder wins.
 

Biosimilars and Formulary Construction

For those of us who have been looking into PBMs for many years, it is no surprise that PBMs’ formulary construction has become a profit center for them. Now, with so many adalimumab biosimilars having entered the market, it has become the Wild West where only those with the most money to fork over to the PBMs get preferred placement. Unfortunately, many of the choices that make money for the PBM cost employers and patients more.

How did we get here? In the 1980s and 90s, the price of medications began to increase to the point that many were not affordable without insurance. And who better to construct the list of drugs that would be covered by insurance (formulary) than the PBMs who were already adjudicating the claims for these drugs. The Federal Trade Commission (FTC) realized the power inherent in constructing this list of medications known as the formulary. So when the manufacturer Merck acquired the PBM Medco in the mid-1990s, the FTC stepped in. The FTC surmised that making the drugs and deciding which ones will be paid for created a “conflict of interest” with anticompetitive ramifications.

So, in 1998, William J. Baer, director of the FTC’s Bureau of Competition, said, “Our investigation into the PBM industry has revealed that Merck’s acquisition of Medco has reduced competition in the market for pharmaceutical products … We have found that Medco has given favorable treatment to Merck drugs. As a result, in some cases, consumers have been denied access to the drugs of competing manufacturers. In addition, the merger has made it possible for Medco to share with Merck sensitive pricing information it gets from Merck’s competitors, which could foster collusion among drug manufacturers.” Wow!

These anticompetitive behaviors and conflicts of interest resulting from the Medco acquisition led the FTC to propose a consent agreement.

The agreement would require Merck-Medco to maintain an “open formulary” — one that includes drugs selected and approved by an independent Pharmacy and Therapeutics Committee regardless of the manufacturer. Medco would have to accept rebates and other price concessions and reflect these in the ranking of the drugs on the formulary. Merck would have to make known the availability of the open formulary to any drug maker with an agreement with Medco.

Let’s hope the FTC of 2024 remembers the stance of the FTC in the 1990s regarding anticompetitive behavior involved in formulary construction.
 

Conflicts of Interest

But today it is apparent that crafting formularies that pay only for the drugs that make the most money for the PBM is not a conflict of interest. In its policy manual, Cigna directly tells employers and employees that they are collecting and keeping rebates and fees on medical pharmaceuticals, and they are not for the benefit of the employer or the plan.

And now, in August 2023, CVS launched Cordavis, a subsidiary wholly owned by CVS. Cordavis/CVS has partnered with Sandoz, which makes Hyrimoz, an adalimumab biosimilar. There is a high-priced version that is discounted 5% from Humira, a lower-cost unbranded version that is discounted 80% off the list price of Humira, and a co-branded CVS/Sandoz version of Hyrimoz that is lower priced as well.

It isn’t a surprise that CVS’ Standard and Advanced Commercial and Chart formularies are offering only Sandoz adalimumab biosimilar products. While these formularies have excluded Humira, CVS has entered into an agreement with AbbVie to allow Humira on a number of their other formularies. It can be very confusing.

As stated earlier, in the 1990s, the FTC frowned upon manufacturers owning PBMs and allowing them to construct their own formularies. Here we have CVS Health, mothership for the PBM CVS Caremark, owning a company that will be co-producing biosimilars with other manufacturers and then determining which biosimilars are on their formularies. The FTC knew back then that the tendency would be to offer only their own drugs for coverage, thus reducing competition. This is exactly what the CVS-Cordavis-Sandoz partnership has done for their Standard and Advanced Commercial and Chart formularies. It is perhaps anti-competitive but certainly profitable.

Perhaps the FTC should require the same consent agreement that was given to Merck in 1998. CVS Caremark would then have to open their formularies to all competitors of their co-branded, co-produced Sandoz biosimilar.
 

Summary

It is the same old adage, “The more things change, the more they stay the same.” PBMs are still constructing formularies with biosimilars based on their profitability, with huge differences between gross and net cost. Patients still pay their cost share on the list (gross) price. With the CVS-Cordavis-Sandoz partnership, more vertical integration has led to yet another profit river. Self-funded employers are still getting the wool pulled over their eyes by the big three PBMs who threaten to take away rebates if they don’t choose the preferred formularies. The employers don’t realize that sometimes it is less expensive to choose the lower-priced drugs with no rebates, and that holds true for biosimilars as well.

Let’s hope that the FTC investigates the situation of a PBM partnering with a manufacturer and then choosing only that manufacturer’s drugs for many of their formularies.

We need to continue our advocacy for our patients because the medication that has kept them stable for so long may find itself without a chair the next time the music stops.
 

Dr. Feldman is a rheumatologist in private practice with The Rheumatology Group in New Orleans. She is the CSRO’s Vice President of Advocacy and Government Affairs and its immediate Past President, as well as past chair of the Alliance for Safe Biologic Medicines and a past member of the American College of Rheumatology insurance subcommittee. You can reach her at [email protected].

A recent article in Cell & Bioscience suggested that regular coffee consumption can reduce the risk of COVID infections.

The study does make some interesting points about the benefits of coffee’s different polyphenols and antioxidants and their effects on different COVID variants. Most of it is based on lab data, although one section, using serum from coffee versus water drinkers, did find that it was more effective at inhibiting the virions. Caffeinated versus decaffeinated didn’t matter.

I’m not saying coffee doesn’t impair the virus. The data are worth looking at. But the majority of adults in North America, Europe, and pretty much the entire planet drink coffee on a regular basis. A large number of them still caught COVID. Would they have had worse cases if they didn’t drink coffee? Maybe, maybe not.

The problem here is that, as always, preliminary data like this get pushed into mass media, making it sound like “COFFEE CURES COVID!!!” Never mind that that’s not what the article said, but it sure gets clicks and retweets and FaceBook “likes.”

Suddenly fringe groups are claiming the coffee cure was there all along, and hidden from them by the evil government-pharma-medical cartel. Others claim the research is flawed because of this or that. The signal gets drowned out by the noise.

Definitely, food can be a medicine. Look at all the benefits proven of the Mediterranean diet. Coffee may help, especially if we can identify and isolate the specific components that reduce COVID risk. But, as they always say at the end, the study is preliminary and further research is needed.

Once or twice a year, an adult with epilepsy comes in, waving a copy of the ketogenic diet around and upset that I never tried it on them — again proof of the evil government-pharma-medical cartel that I’m in league with. I calm them down and explain the diet in detail. Maybe 50% of them decide to go ahead with it. In 25 years of practice, my record for an otherwise normal adult sticking with it is 5 days.

You don’t have to go too far back to remember Linus Pauling, an absolutely brilliant scientist, but not the best of nutritionists. With two Nobel prizes behind him, he took a stab at medicine in the 1970s, arguing that megadoses of vitamin C worked for the common cold. While it may be good for us, and certainly most people like orange juice, but those claims about the common cold never panned out. In fact, we’re no closer to curing it now than we were then.

Just because something seems promising in early studies doesn’t mean it will pan out. It might, but this doesn’t mean the “truth” is being maliciously hidden by an evil cartel. It just means we have (as always) more to learn.

I’ll still drink my single cup of coffee every weekday morning. I’m a creature of habit, and heaven knows I need the caffeine. If it also boosts my immune system, so much the better.

Besides, we still have that universal antimicrobial called chicken soup.
 

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

A recent article in Cell & Bioscience suggested that regular coffee consumption can reduce the risk of COVID infections.

The study does make some interesting points about the benefits of coffee’s different polyphenols and antioxidants and their effects on different COVID variants. Most of it is based on lab data, although one section, using serum from coffee versus water drinkers, did find that it was more effective at inhibiting the virions. Caffeinated versus decaffeinated didn’t matter.

I’m not saying coffee doesn’t impair the virus. The data are worth looking at. But the majority of adults in North America, Europe, and pretty much the entire planet drink coffee on a regular basis. A large number of them still caught COVID. Would they have had worse cases if they didn’t drink coffee? Maybe, maybe not.

The problem here is that, as always, preliminary data like this get pushed into mass media, making it sound like “COFFEE CURES COVID!!!” Never mind that that’s not what the article said, but it sure gets clicks and retweets and FaceBook “likes.”

Suddenly fringe groups are claiming the coffee cure was there all along, and hidden from them by the evil government-pharma-medical cartel. Others claim the research is flawed because of this or that. The signal gets drowned out by the noise.

Definitely, food can be a medicine. Look at all the benefits proven of the Mediterranean diet. Coffee may help, especially if we can identify and isolate the specific components that reduce COVID risk. But, as they always say at the end, the study is preliminary and further research is needed.

Once or twice a year, an adult with epilepsy comes in, waving a copy of the ketogenic diet around and upset that I never tried it on them — again proof of the evil government-pharma-medical cartel that I’m in league with. I calm them down and explain the diet in detail. Maybe 50% of them decide to go ahead with it. In 25 years of practice, my record for an otherwise normal adult sticking with it is 5 days.

You don’t have to go too far back to remember Linus Pauling, an absolutely brilliant scientist, but not the best of nutritionists. With two Nobel prizes behind him, he took a stab at medicine in the 1970s, arguing that megadoses of vitamin C worked for the common cold. While it may be good for us, and certainly most people like orange juice, but those claims about the common cold never panned out. In fact, we’re no closer to curing it now than we were then.

Just because something seems promising in early studies doesn’t mean it will pan out. It might, but this doesn’t mean the “truth” is being maliciously hidden by an evil cartel. It just means we have (as always) more to learn.

I’ll still drink my single cup of coffee every weekday morning. I’m a creature of habit, and heaven knows I need the caffeine. If it also boosts my immune system, so much the better.

Besides, we still have that universal antimicrobial called chicken soup.
 

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

A recent article in Cell & Bioscience suggested that regular coffee consumption can reduce the risk of COVID infections.

The study does make some interesting points about the benefits of coffee’s different polyphenols and antioxidants and their effects on different COVID variants. Most of it is based on lab data, although one section, using serum from coffee versus water drinkers, did find that it was more effective at inhibiting the virions. Caffeinated versus decaffeinated didn’t matter.

I’m not saying coffee doesn’t impair the virus. The data are worth looking at. But the majority of adults in North America, Europe, and pretty much the entire planet drink coffee on a regular basis. A large number of them still caught COVID. Would they have had worse cases if they didn’t drink coffee? Maybe, maybe not.

The problem here is that, as always, preliminary data like this get pushed into mass media, making it sound like “COFFEE CURES COVID!!!” Never mind that that’s not what the article said, but it sure gets clicks and retweets and FaceBook “likes.”

Suddenly fringe groups are claiming the coffee cure was there all along, and hidden from them by the evil government-pharma-medical cartel. Others claim the research is flawed because of this or that. The signal gets drowned out by the noise.

Definitely, food can be a medicine. Look at all the benefits proven of the Mediterranean diet. Coffee may help, especially if we can identify and isolate the specific components that reduce COVID risk. But, as they always say at the end, the study is preliminary and further research is needed.

Once or twice a year, an adult with epilepsy comes in, waving a copy of the ketogenic diet around and upset that I never tried it on them — again proof of the evil government-pharma-medical cartel that I’m in league with. I calm them down and explain the diet in detail. Maybe 50% of them decide to go ahead with it. In 25 years of practice, my record for an otherwise normal adult sticking with it is 5 days.

You don’t have to go too far back to remember Linus Pauling, an absolutely brilliant scientist, but not the best of nutritionists. With two Nobel prizes behind him, he took a stab at medicine in the 1970s, arguing that megadoses of vitamin C worked for the common cold. While it may be good for us, and certainly most people like orange juice, but those claims about the common cold never panned out. In fact, we’re no closer to curing it now than we were then.

Just because something seems promising in early studies doesn’t mean it will pan out. It might, but this doesn’t mean the “truth” is being maliciously hidden by an evil cartel. It just means we have (as always) more to learn.

I’ll still drink my single cup of coffee every weekday morning. I’m a creature of habit, and heaven knows I need the caffeine. If it also boosts my immune system, so much the better.

Besides, we still have that universal antimicrobial called chicken soup.
 

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

Introduction: The Many Lanes of Research on Magnesium Sulfate

The research that improves human health in the most expedient and most impactful ways is multitiered, with basic or fundamental research, translational research, interventional studies, and retrospective research often occurring simultaneously. There should be no “single lane” of research and one type of research does not preclude the other.

Too often, we fall short in one of these lanes. While we have achieved many moonshots in obstetrics and maternal-fetal medicine, we have tended not to place a high priority on basic research, which can provide a strong understanding of the biology of major diseases and conditions affecting women and their offspring. When conducted with proper commitment and funding, such research can lead to biologically directed therapy.

Within our specialty, research on how we can effectively prevent preterm birth, prematurity, and preeclampsia has taken a long road, with various types of therapies being tried, but none being overwhelmingly effective — with an ongoing need for more basic or fundamental research. Nevertheless, we can benefit and gain great insights from retrospective and interventional studies associated with clinical therapies used to treat premature labor and preeclampsia when these therapies have an unanticipated and important secondary benefit.

This month our Master Class is focused on the neuroprotection of prematurity. Magnesium sulfate is a valuable tool for the treatment of both premature labor and preeclampsia, and more recently, also for neuroprotection of the fetus. Interestingly, this use stemmed from researchers looking retrospectively at outcomes in women who received the compound for other reasons. It took many years for researchers to prove its neuroprotective value through interventional trials, while researchers simultaneously strove to understand on a basic biologic level how magnesium sulfate works to prevent outcomes such as cerebral palsy.

Basic research underway today continues to improve our understanding of its precise mechanisms of action. Combined with other tiers of research — including more interventional studies and more translational research — we can improve its utility for the neuroprotection of prematurity. Alternatively, ongoing research may lead to different, even more effective treatments.

Our guest author is Irina Burd, MD, PhD, Sylvan Freiman, MD Endowed Professor and Chair of the department of obstetrics, gynecology, and reproductive sciences at the University of Maryland School of Medicine.* Dr. Burd is also a physician-scientist. She recounts the important story of magnesium sulfate and what is currently known about its biologic plausibility in neuroprotection — including through her own studies – as well as what may be coming in the future.

E. Albert Reece, MD, PhD, MBA, a maternal-fetal medicine specialist, is dean emeritus of the University of Maryland School of Medicine, former university executive vice president; currently the endowed professor and director of the Center for Advanced Research Training and Innovation (CARTI), and senior scientist in the Center for Birth Defects Research. Dr. Reece reported no relevant disclosures. He is the medical editor of this column. Contact him at [email protected].
 

Magnesium Sulfate for Fetal Neuroprotection in Preterm Birth

Without a doubt, magnesium sulfate (MgSO₄) given before anticipated preterm birth reduces the risk of cerebral palsy. It is a valuable tool for fetal neuroprotection at a time when there are no proven alternatives. Yet without the persistent research that occurred over more than 20 years, it may not have won the endorsement of the American College of Obstetrics and Gynecologists in 2010 and worked its way into routine practice.

Its history is worthy of reflection. It took years of observational trials (not all of which showed neuroprotective effects), six randomized controlled trials (none of which met their primary endpoint), three meta-analyses, and a Cochrane Database Systematic Review to arrive at the conclusion that antenatal magnesium sulfate therapy given to women at risk of preterm birth has definitive neuroprotective benefit.

Origins and Biologic Plausibility

The MgSO₄ story is rooted in the late seventeenth century discovery by physician Nehemiah Grew that the compound was the key component of the then-famous medicinal spring waters in Epsom, England.¹ MgSO₄ was first used for eclampsia in 1906,² and was first reported in the American literature for eclampsia in 1925.³ In 1959, its effect as a tocolytic agent was reported.⁴

More than 30 years later, in 1995, an observational study coauthored by Karin B. Nelson, MD, and Judith K. Grether, PhD of the National Institutes of Health, showed a reduced risk of cerebral palsy in very-low-birth-weight infants (VLBW).⁵ The report marked a turning point in research interest on neuroprotection for anticipated preterm birth.

The precise molecular mechanisms of action of MgSO₄ for neuroprotection are still not well understood. However, research findings from the University of Maryland and other institutions have provided biologic plausibility for its use to prevent cerebral palsy. Our current thinking is that it involves the prevention of periventricular white matter injury and/or the prevention of oxidative stress and a neuronal injury mechanism called excitotoxicity.

Periventricular white matter injury involving injury to preoligodendrocytes before 32 weeks’ gestation is the most prevalent injury seen in cerebral palsy; preoligodendrocytes are precursors of myelinating oligodendrocytes, which constitute a major glial population in the white matter. Our research in a mouse model demonstrated that the intrauterine inflammation frequently associated with preterm birth can lead to neuronal injury as well as white matter damage, and that MgSO₄ may ameliorate both.^6,7

Excitotoxicity results from excessive stimulation of N-methyl-D-aspartate (NMDA) glutamatergic receptors on preoligodendrocytes and a rush of calcium through the voltage-gated channels. This calcium influx leads to the production of nitric oxide, oxidative stress, and subsequent mitochondrial damage and cell death. As a bivalent ion, MgSO₄ sits in the voltage-gated channels of the NMDA receptors and reduces glutamatergic signaling, thus serving as a calcium antagonist and modulating calcium influx (See Figure).

The Long Route of Research

The 1995 Nelson-Grether study compared VLBW (< 1500 g) infants who survived and developed moderate/severe cerebral palsy within 3 years to randomly selected VLBW controls with respect to whether their mothers had received MgSO₄ to prevent seizures in preeclampsia or as a tocolytic agent.⁵ In a population of more than 155,000 children born between 1983 and 1985, in utero exposure to MgSO₄ was reported in 7.1% of 42 VLBW infants with cerebral palsy and 36% of 75 VLBW controls (odds ratio [OR], 0.14; 95% CI, 0.05-0.51). In women without preeclampsia the OR increased to 0.25.

This motivating study had been preceded by several observational studies showing that infants born to women with preeclampsia who received MgSO₄ had significantly lower risks of developing intraventricular hemorrhage (IVH) and germinal matrix hemorrhage (GMH). In one of these studies, published in 1992, Karl C. Kuban, MD, and coauthors reported that “maternal receipt of magnesium sulfate was associated with diminished risk of GMH-IVH even in those babies born to mothers who apparently did not have preeclampsia.”⁹

In the several years following the 1995 Nelson-Grether study, several other case-control/observational studies were reported, with conflicting conclusions, and investigators around the world began designing and conducting needed randomized controlled trials.

The six published randomized controlled trials looking at MgSO₄ and neuroprotection varied in their inclusion and exclusion criteria, their recruitment and enrollment style, the gestational ages for MgSO₄ administration, loading and maintenance doses, how cerebral palsy or neuroprotection was assessed, and other factors (See Table for RCT characteristics and main outcomes).^10-14 One of the trials aimed primarily at evaluating the efficacy of MgSO₄ for preventing preeclampsia.

Moving Forward

The NNTs calculated in these reviews — ranging from 44 to 63 — are convincing, and are comparable with evidence-based medicine data for prevention of other common diseases.¹⁹ For instance, the NNT for a life saved when aspirin is given immediately after a heart attack is 42. Statins given for 5 years in people with known heart disease have an NNT of 83 to save one life, an NNT of 39 to prevent one nonfatal heart attack, and an NNT of 125 to prevent one stroke. For oral anticoagulants used in nonvalvular atrial fibrillation for primary stroke prevention, the NNTs to prevent one stroke, and one death, are 22 and 42, respectively.¹⁹

In its 2010 Committee Opinion on Magnesium Sulfate Before Anticipated Preterm Birth for Neuroprotection (reaffirmed in 2020), the American College of Obstetricians and Gynecologists left it to institutions to develop their own guidelines “regarding inclusion criteria, treatment regimens, concurrent tocolysis, and monitoring in accordance with one of the larger trials.”²⁰

Not surprisingly, most if not all hospitals have chosen a higher dose of MgSO₄ administered up to 31 weeks’ gestation in keeping with the protocols employed in the NICHD-sponsored BEAM trial (See Table).

The hope moving forward is to expand treatment options for neuroprotection in cases of imminent preterm birth. Researchers have been assessing the ability of melatonin to provide neuroprotection in cases of growth restriction and neonatal asphyxia. Melatonin has anti-inflammatory and antioxidant properties and is known to mediate neuronal generation and synaptic plasticity.²¹

N-acetyl-L-cysteine is another potential neuroprotective agent. It acts as an antioxidant, a precursor to glutathione, and a modulator of the glutamate system and has been studied as a neuroprotective agent in cases of maternal chorioamnionitis.²¹ Both melatonin and N-acetyl-L-cysteine are regarded as safe in pregnancy, but much more clinical study is needed to prove their neuroprotective potential when given shortly before birth or earlier.

Dr. Burd is the Sylvan Freiman, MD Endowed Professor and Chair of the department of obstetrics, gynecology, and reproductive sciences at the University of Maryland School of Medicine, Baltimore. She has no conflicts of interest.  
 

References

1. Clio Med. 1984;19(1-2):1-21.

2. Medicinsk Rev. (Bergen) 1906;32:264-272.

3. Am J Obstet Gynecol. 1996;174(4):1390-1391.

4. Am J Obstet Gynecol. 1959;78(1):27-32.

5. Pediatrics. 1995;95(2):263-269.

6. Am J Obstet Gynecol. 2009;201(3):279.e1-279.e8.

7. Am J Obstet Gynecol. 2010;202(3):292.e1-292.e9.

8. Pediatr Res. 2020;87(3):463-471.

9. J Child Neurol. 1992;7(1):70-76.

10. Lancet. 1997;350:1517-1518.

11. JAMA. 2003;290:2669-2676.

12. BJOG. 2007;114(3):310-318.

13. Lancet. 2002;359(9321):1877-1890.

14. N Engl J Med. 2008;359:895-905.

15. Obstet Gynecol. 2009;113(6):1327-1333.

16. Am J Obstet Gynecol. 2009;200(6):595-609.

17. Obstet Gynecol 2009;114:354-364.

18. Cochrane Database Syst Rev. 2009 Jan 21:(1):CD004661.

19. www.thennt.com.

20. Obstet Gynecol. 2010;115:669-671.

21. Front Synaptic Neurosci. 2012;13:680899.

*This story was corrected on June 10, 2024.

Introduction: The Many Lanes of Research on Magnesium Sulfate

The research that improves human health in the most expedient and most impactful ways is multitiered, with basic or fundamental research, translational research, interventional studies, and retrospective research often occurring simultaneously. There should be no “single lane” of research and one type of research does not preclude the other.

Too often, we fall short in one of these lanes. While we have achieved many moonshots in obstetrics and maternal-fetal medicine, we have tended not to place a high priority on basic research, which can provide a strong understanding of the biology of major diseases and conditions affecting women and their offspring. When conducted with proper commitment and funding, such research can lead to biologically directed therapy.

Within our specialty, research on how we can effectively prevent preterm birth, prematurity, and preeclampsia has taken a long road, with various types of therapies being tried, but none being overwhelmingly effective — with an ongoing need for more basic or fundamental research. Nevertheless, we can benefit and gain great insights from retrospective and interventional studies associated with clinical therapies used to treat premature labor and preeclampsia when these therapies have an unanticipated and important secondary benefit.

This month our Master Class is focused on the neuroprotection of prematurity. Magnesium sulfate is a valuable tool for the treatment of both premature labor and preeclampsia, and more recently, also for neuroprotection of the fetus. Interestingly, this use stemmed from researchers looking retrospectively at outcomes in women who received the compound for other reasons. It took many years for researchers to prove its neuroprotective value through interventional trials, while researchers simultaneously strove to understand on a basic biologic level how magnesium sulfate works to prevent outcomes such as cerebral palsy.

Basic research underway today continues to improve our understanding of its precise mechanisms of action. Combined with other tiers of research — including more interventional studies and more translational research — we can improve its utility for the neuroprotection of prematurity. Alternatively, ongoing research may lead to different, even more effective treatments.

Our guest author is Irina Burd, MD, PhD, Sylvan Freiman, MD Endowed Professor and Chair of the department of obstetrics, gynecology, and reproductive sciences at the University of Maryland School of Medicine.* Dr. Burd is also a physician-scientist. She recounts the important story of magnesium sulfate and what is currently known about its biologic plausibility in neuroprotection — including through her own studies – as well as what may be coming in the future.

E. Albert Reece, MD, PhD, MBA, a maternal-fetal medicine specialist, is dean emeritus of the University of Maryland School of Medicine, former university executive vice president; currently the endowed professor and director of the Center for Advanced Research Training and Innovation (CARTI), and senior scientist in the Center for Birth Defects Research. Dr. Reece reported no relevant disclosures. He is the medical editor of this column. Contact him at [email protected].
 

Magnesium Sulfate for Fetal Neuroprotection in Preterm Birth

Without a doubt, magnesium sulfate (MgSO₄) given before anticipated preterm birth reduces the risk of cerebral palsy. It is a valuable tool for fetal neuroprotection at a time when there are no proven alternatives. Yet without the persistent research that occurred over more than 20 years, it may not have won the endorsement of the American College of Obstetrics and Gynecologists in 2010 and worked its way into routine practice.

Its history is worthy of reflection. It took years of observational trials (not all of which showed neuroprotective effects), six randomized controlled trials (none of which met their primary endpoint), three meta-analyses, and a Cochrane Database Systematic Review to arrive at the conclusion that antenatal magnesium sulfate therapy given to women at risk of preterm birth has definitive neuroprotective benefit.

Origins and Biologic Plausibility

The MgSO₄ story is rooted in the late seventeenth century discovery by physician Nehemiah Grew that the compound was the key component of the then-famous medicinal spring waters in Epsom, England.¹ MgSO₄ was first used for eclampsia in 1906,² and was first reported in the American literature for eclampsia in 1925.³ In 1959, its effect as a tocolytic agent was reported.⁴

More than 30 years later, in 1995, an observational study coauthored by Karin B. Nelson, MD, and Judith K. Grether, PhD of the National Institutes of Health, showed a reduced risk of cerebral palsy in very-low-birth-weight infants (VLBW).⁵ The report marked a turning point in research interest on neuroprotection for anticipated preterm birth.

The precise molecular mechanisms of action of MgSO₄ for neuroprotection are still not well understood. However, research findings from the University of Maryland and other institutions have provided biologic plausibility for its use to prevent cerebral palsy. Our current thinking is that it involves the prevention of periventricular white matter injury and/or the prevention of oxidative stress and a neuronal injury mechanism called excitotoxicity.

Periventricular white matter injury involving injury to preoligodendrocytes before 32 weeks’ gestation is the most prevalent injury seen in cerebral palsy; preoligodendrocytes are precursors of myelinating oligodendrocytes, which constitute a major glial population in the white matter. Our research in a mouse model demonstrated that the intrauterine inflammation frequently associated with preterm birth can lead to neuronal injury as well as white matter damage, and that MgSO₄ may ameliorate both.^6,7

Excitotoxicity results from excessive stimulation of N-methyl-D-aspartate (NMDA) glutamatergic receptors on preoligodendrocytes and a rush of calcium through the voltage-gated channels. This calcium influx leads to the production of nitric oxide, oxidative stress, and subsequent mitochondrial damage and cell death. As a bivalent ion, MgSO₄ sits in the voltage-gated channels of the NMDA receptors and reduces glutamatergic signaling, thus serving as a calcium antagonist and modulating calcium influx (See Figure).

The Long Route of Research

The 1995 Nelson-Grether study compared VLBW (< 1500 g) infants who survived and developed moderate/severe cerebral palsy within 3 years to randomly selected VLBW controls with respect to whether their mothers had received MgSO₄ to prevent seizures in preeclampsia or as a tocolytic agent.⁵ In a population of more than 155,000 children born between 1983 and 1985, in utero exposure to MgSO₄ was reported in 7.1% of 42 VLBW infants with cerebral palsy and 36% of 75 VLBW controls (odds ratio [OR], 0.14; 95% CI, 0.05-0.51). In women without preeclampsia the OR increased to 0.25.

This motivating study had been preceded by several observational studies showing that infants born to women with preeclampsia who received MgSO₄ had significantly lower risks of developing intraventricular hemorrhage (IVH) and germinal matrix hemorrhage (GMH). In one of these studies, published in 1992, Karl C. Kuban, MD, and coauthors reported that “maternal receipt of magnesium sulfate was associated with diminished risk of GMH-IVH even in those babies born to mothers who apparently did not have preeclampsia.”⁹

In the several years following the 1995 Nelson-Grether study, several other case-control/observational studies were reported, with conflicting conclusions, and investigators around the world began designing and conducting needed randomized controlled trials.

The six published randomized controlled trials looking at MgSO₄ and neuroprotection varied in their inclusion and exclusion criteria, their recruitment and enrollment style, the gestational ages for MgSO₄ administration, loading and maintenance doses, how cerebral palsy or neuroprotection was assessed, and other factors (See Table for RCT characteristics and main outcomes).^10-14 One of the trials aimed primarily at evaluating the efficacy of MgSO₄ for preventing preeclampsia.

Moving Forward

The NNTs calculated in these reviews — ranging from 44 to 63 — are convincing, and are comparable with evidence-based medicine data for prevention of other common diseases.¹⁹ For instance, the NNT for a life saved when aspirin is given immediately after a heart attack is 42. Statins given for 5 years in people with known heart disease have an NNT of 83 to save one life, an NNT of 39 to prevent one nonfatal heart attack, and an NNT of 125 to prevent one stroke. For oral anticoagulants used in nonvalvular atrial fibrillation for primary stroke prevention, the NNTs to prevent one stroke, and one death, are 22 and 42, respectively.¹⁹

In its 2010 Committee Opinion on Magnesium Sulfate Before Anticipated Preterm Birth for Neuroprotection (reaffirmed in 2020), the American College of Obstetricians and Gynecologists left it to institutions to develop their own guidelines “regarding inclusion criteria, treatment regimens, concurrent tocolysis, and monitoring in accordance with one of the larger trials.”²⁰

Not surprisingly, most if not all hospitals have chosen a higher dose of MgSO₄ administered up to 31 weeks’ gestation in keeping with the protocols employed in the NICHD-sponsored BEAM trial (See Table).

The hope moving forward is to expand treatment options for neuroprotection in cases of imminent preterm birth. Researchers have been assessing the ability of melatonin to provide neuroprotection in cases of growth restriction and neonatal asphyxia. Melatonin has anti-inflammatory and antioxidant properties and is known to mediate neuronal generation and synaptic plasticity.²¹

N-acetyl-L-cysteine is another potential neuroprotective agent. It acts as an antioxidant, a precursor to glutathione, and a modulator of the glutamate system and has been studied as a neuroprotective agent in cases of maternal chorioamnionitis.²¹ Both melatonin and N-acetyl-L-cysteine are regarded as safe in pregnancy, but much more clinical study is needed to prove their neuroprotective potential when given shortly before birth or earlier.

Dr. Burd is the Sylvan Freiman, MD Endowed Professor and Chair of the department of obstetrics, gynecology, and reproductive sciences at the University of Maryland School of Medicine, Baltimore. She has no conflicts of interest.  
 

References

1. Clio Med. 1984;19(1-2):1-21.

2. Medicinsk Rev. (Bergen) 1906;32:264-272.

3. Am J Obstet Gynecol. 1996;174(4):1390-1391.

4. Am J Obstet Gynecol. 1959;78(1):27-32.

5. Pediatrics. 1995;95(2):263-269.

6. Am J Obstet Gynecol. 2009;201(3):279.e1-279.e8.

7. Am J Obstet Gynecol. 2010;202(3):292.e1-292.e9.

8. Pediatr Res. 2020;87(3):463-471.

9. J Child Neurol. 1992;7(1):70-76.

10. Lancet. 1997;350:1517-1518.

11. JAMA. 2003;290:2669-2676.

12. BJOG. 2007;114(3):310-318.

13. Lancet. 2002;359(9321):1877-1890.

14. N Engl J Med. 2008;359:895-905.

15. Obstet Gynecol. 2009;113(6):1327-1333.

16. Am J Obstet Gynecol. 2009;200(6):595-609.

17. Obstet Gynecol 2009;114:354-364.

18. Cochrane Database Syst Rev. 2009 Jan 21:(1):CD004661.

19. www.thennt.com.

20. Obstet Gynecol. 2010;115:669-671.

21. Front Synaptic Neurosci. 2012;13:680899.

*This story was corrected on June 10, 2024.

Introduction: The Many Lanes of Research on Magnesium Sulfate

The research that improves human health in the most expedient and most impactful ways is multitiered, with basic or fundamental research, translational research, interventional studies, and retrospective research often occurring simultaneously. There should be no “single lane” of research and one type of research does not preclude the other.

Too often, we fall short in one of these lanes. While we have achieved many moonshots in obstetrics and maternal-fetal medicine, we have tended not to place a high priority on basic research, which can provide a strong understanding of the biology of major diseases and conditions affecting women and their offspring. When conducted with proper commitment and funding, such research can lead to biologically directed therapy.

Within our specialty, research on how we can effectively prevent preterm birth, prematurity, and preeclampsia has taken a long road, with various types of therapies being tried, but none being overwhelmingly effective — with an ongoing need for more basic or fundamental research. Nevertheless, we can benefit and gain great insights from retrospective and interventional studies associated with clinical therapies used to treat premature labor and preeclampsia when these therapies have an unanticipated and important secondary benefit.

This month our Master Class is focused on the neuroprotection of prematurity. Magnesium sulfate is a valuable tool for the treatment of both premature labor and preeclampsia, and more recently, also for neuroprotection of the fetus. Interestingly, this use stemmed from researchers looking retrospectively at outcomes in women who received the compound for other reasons. It took many years for researchers to prove its neuroprotective value through interventional trials, while researchers simultaneously strove to understand on a basic biologic level how magnesium sulfate works to prevent outcomes such as cerebral palsy.

Basic research underway today continues to improve our understanding of its precise mechanisms of action. Combined with other tiers of research — including more interventional studies and more translational research — we can improve its utility for the neuroprotection of prematurity. Alternatively, ongoing research may lead to different, even more effective treatments.

Our guest author is Irina Burd, MD, PhD, Sylvan Freiman, MD Endowed Professor and Chair of the department of obstetrics, gynecology, and reproductive sciences at the University of Maryland School of Medicine.* Dr. Burd is also a physician-scientist. She recounts the important story of magnesium sulfate and what is currently known about its biologic plausibility in neuroprotection — including through her own studies – as well as what may be coming in the future.

E. Albert Reece, MD, PhD, MBA, a maternal-fetal medicine specialist, is dean emeritus of the University of Maryland School of Medicine, former university executive vice president; currently the endowed professor and director of the Center for Advanced Research Training and Innovation (CARTI), and senior scientist in the Center for Birth Defects Research. Dr. Reece reported no relevant disclosures. He is the medical editor of this column. Contact him at [email protected].
 

Magnesium Sulfate for Fetal Neuroprotection in Preterm Birth

Without a doubt, magnesium sulfate (MgSO₄) given before anticipated preterm birth reduces the risk of cerebral palsy. It is a valuable tool for fetal neuroprotection at a time when there are no proven alternatives. Yet without the persistent research that occurred over more than 20 years, it may not have won the endorsement of the American College of Obstetrics and Gynecologists in 2010 and worked its way into routine practice.

Its history is worthy of reflection. It took years of observational trials (not all of which showed neuroprotective effects), six randomized controlled trials (none of which met their primary endpoint), three meta-analyses, and a Cochrane Database Systematic Review to arrive at the conclusion that antenatal magnesium sulfate therapy given to women at risk of preterm birth has definitive neuroprotective benefit.

Origins and Biologic Plausibility

The MgSO₄ story is rooted in the late seventeenth century discovery by physician Nehemiah Grew that the compound was the key component of the then-famous medicinal spring waters in Epsom, England.¹ MgSO₄ was first used for eclampsia in 1906,² and was first reported in the American literature for eclampsia in 1925.³ In 1959, its effect as a tocolytic agent was reported.⁴

More than 30 years later, in 1995, an observational study coauthored by Karin B. Nelson, MD, and Judith K. Grether, PhD of the National Institutes of Health, showed a reduced risk of cerebral palsy in very-low-birth-weight infants (VLBW).⁵ The report marked a turning point in research interest on neuroprotection for anticipated preterm birth.

The precise molecular mechanisms of action of MgSO₄ for neuroprotection are still not well understood. However, research findings from the University of Maryland and other institutions have provided biologic plausibility for its use to prevent cerebral palsy. Our current thinking is that it involves the prevention of periventricular white matter injury and/or the prevention of oxidative stress and a neuronal injury mechanism called excitotoxicity.

Periventricular white matter injury involving injury to preoligodendrocytes before 32 weeks’ gestation is the most prevalent injury seen in cerebral palsy; preoligodendrocytes are precursors of myelinating oligodendrocytes, which constitute a major glial population in the white matter. Our research in a mouse model demonstrated that the intrauterine inflammation frequently associated with preterm birth can lead to neuronal injury as well as white matter damage, and that MgSO₄ may ameliorate both.^6,7

Excitotoxicity results from excessive stimulation of N-methyl-D-aspartate (NMDA) glutamatergic receptors on preoligodendrocytes and a rush of calcium through the voltage-gated channels. This calcium influx leads to the production of nitric oxide, oxidative stress, and subsequent mitochondrial damage and cell death. As a bivalent ion, MgSO₄ sits in the voltage-gated channels of the NMDA receptors and reduces glutamatergic signaling, thus serving as a calcium antagonist and modulating calcium influx (See Figure).

The Long Route of Research

The 1995 Nelson-Grether study compared VLBW (< 1500 g) infants who survived and developed moderate/severe cerebral palsy within 3 years to randomly selected VLBW controls with respect to whether their mothers had received MgSO₄ to prevent seizures in preeclampsia or as a tocolytic agent.⁵ In a population of more than 155,000 children born between 1983 and 1985, in utero exposure to MgSO₄ was reported in 7.1% of 42 VLBW infants with cerebral palsy and 36% of 75 VLBW controls (odds ratio [OR], 0.14; 95% CI, 0.05-0.51). In women without preeclampsia the OR increased to 0.25.

This motivating study had been preceded by several observational studies showing that infants born to women with preeclampsia who received MgSO₄ had significantly lower risks of developing intraventricular hemorrhage (IVH) and germinal matrix hemorrhage (GMH). In one of these studies, published in 1992, Karl C. Kuban, MD, and coauthors reported that “maternal receipt of magnesium sulfate was associated with diminished risk of GMH-IVH even in those babies born to mothers who apparently did not have preeclampsia.”⁹

In the several years following the 1995 Nelson-Grether study, several other case-control/observational studies were reported, with conflicting conclusions, and investigators around the world began designing and conducting needed randomized controlled trials.

The six published randomized controlled trials looking at MgSO₄ and neuroprotection varied in their inclusion and exclusion criteria, their recruitment and enrollment style, the gestational ages for MgSO₄ administration, loading and maintenance doses, how cerebral palsy or neuroprotection was assessed, and other factors (See Table for RCT characteristics and main outcomes).^10-14 One of the trials aimed primarily at evaluating the efficacy of MgSO₄ for preventing preeclampsia.

Moving Forward

The NNTs calculated in these reviews — ranging from 44 to 63 — are convincing, and are comparable with evidence-based medicine data for prevention of other common diseases.¹⁹ For instance, the NNT for a life saved when aspirin is given immediately after a heart attack is 42. Statins given for 5 years in people with known heart disease have an NNT of 83 to save one life, an NNT of 39 to prevent one nonfatal heart attack, and an NNT of 125 to prevent one stroke. For oral anticoagulants used in nonvalvular atrial fibrillation for primary stroke prevention, the NNTs to prevent one stroke, and one death, are 22 and 42, respectively.¹⁹

In its 2010 Committee Opinion on Magnesium Sulfate Before Anticipated Preterm Birth for Neuroprotection (reaffirmed in 2020), the American College of Obstetricians and Gynecologists left it to institutions to develop their own guidelines “regarding inclusion criteria, treatment regimens, concurrent tocolysis, and monitoring in accordance with one of the larger trials.”²⁰

Not surprisingly, most if not all hospitals have chosen a higher dose of MgSO₄ administered up to 31 weeks’ gestation in keeping with the protocols employed in the NICHD-sponsored BEAM trial (See Table).

The hope moving forward is to expand treatment options for neuroprotection in cases of imminent preterm birth. Researchers have been assessing the ability of melatonin to provide neuroprotection in cases of growth restriction and neonatal asphyxia. Melatonin has anti-inflammatory and antioxidant properties and is known to mediate neuronal generation and synaptic plasticity.²¹

N-acetyl-L-cysteine is another potential neuroprotective agent. It acts as an antioxidant, a precursor to glutathione, and a modulator of the glutamate system and has been studied as a neuroprotective agent in cases of maternal chorioamnionitis.²¹ Both melatonin and N-acetyl-L-cysteine are regarded as safe in pregnancy, but much more clinical study is needed to prove their neuroprotective potential when given shortly before birth or earlier.

Dr. Burd is the Sylvan Freiman, MD Endowed Professor and Chair of the department of obstetrics, gynecology, and reproductive sciences at the University of Maryland School of Medicine, Baltimore. She has no conflicts of interest.  
 

References

1. Clio Med. 1984;19(1-2):1-21.

2. Medicinsk Rev. (Bergen) 1906;32:264-272.

3. Am J Obstet Gynecol. 1996;174(4):1390-1391.

4. Am J Obstet Gynecol. 1959;78(1):27-32.

5. Pediatrics. 1995;95(2):263-269.

6. Am J Obstet Gynecol. 2009;201(3):279.e1-279.e8.

7. Am J Obstet Gynecol. 2010;202(3):292.e1-292.e9.

8. Pediatr Res. 2020;87(3):463-471.

9. J Child Neurol. 1992;7(1):70-76.

10. Lancet. 1997;350:1517-1518.

11. JAMA. 2003;290:2669-2676.

12. BJOG. 2007;114(3):310-318.

13. Lancet. 2002;359(9321):1877-1890.

14. N Engl J Med. 2008;359:895-905.

15. Obstet Gynecol. 2009;113(6):1327-1333.

16. Am J Obstet Gynecol. 2009;200(6):595-609.

17. Obstet Gynecol 2009;114:354-364.

18. Cochrane Database Syst Rev. 2009 Jan 21:(1):CD004661.

19. www.thennt.com.

20. Obstet Gynecol. 2010;115:669-671.

21. Front Synaptic Neurosci. 2012;13:680899.

*This story was corrected on June 10, 2024.

Making eye contact is important in human interactions. It shows attention and comprehension. It also helps us read the nuances of another’s facial expressions when interacting.

Although the idea of video phone calls isn’t new — I remember it from my childhood in “house of the future” TV shows — it certainly didn’t take off until the advent of high-speed Internet, computers, and phones with cameras. Then Facetime, Skype, Zoom, Teams, and others.

Of course, it all still took a back seat to actually seeing people and having meetings in person. Until the pandemic made that the least attractive option. Then the adoption of such things went into hyperdrive and has stayed there ever since.

And ya know, I don’t have too many complaints. Between clinical trials and legal cases, both of which involve A LOT of meetings, it’s made my life easier. I no longer have to leave the office, allow time to drive somewhere and back, fight traffic, burn gas, and find parking. I move from a patient to the meeting and back to a patient from the cozy confines of my office, all without my tea getting cold.

But you can’t really make eye contact on Zoom. Instinctively, we generally look directly at the eyes of the person we’re speaking to, but in the virtual world we really don’t do that. On their end you’re on a screen, your gaze fixed somewhere below the level of your camera.

Try talking directly to the camera on Zoom — or any video platform. It doesn’t work. You feel like Dave addressing HAL’s red light in 2001. Inevitably your eyes are drawn back to the other person’s face, which is what you’re programmed to do. If they’re speaking you look at them, even though the sound is really coming from your speakers.

Interestingly, though, it seems something is lost in there. A recent perspective noted that Zoom meetings seemed to stifle creativity and produced fewer ideas than in person.

An interesting study compared neural response signals of people seeing a presentation on Zoom versus the same talk in person. When looking at a “real” speaker, there was synchronized neural activity, a higher level of engagement, and increased activation of the dorsal-parietal cortex.

Without actual eye contact it’s harder to read subtle facial expressions. Hand gestures and other body language may be out of the camera frame, or absent altogether. The nuances of voice pitch, timbre, and tone may not be the same over the speaker.

Our brains have spent several million of years developing facial recognition and reading, knowing friend from foe, and understanding what’s meant not just in what sounds are used but how they’re conveyed.

I’m not saying we should stop using Zoom altogether — it makes meetings more convenient for most people, including myself. But we also need to keep in mind that what it doesn’t convey is as important as what it does, and that virtual is never a perfect substitute for reality.
 

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

Making eye contact is important in human interactions. It shows attention and comprehension. It also helps us read the nuances of another’s facial expressions when interacting.

Although the idea of video phone calls isn’t new — I remember it from my childhood in “house of the future” TV shows — it certainly didn’t take off until the advent of high-speed Internet, computers, and phones with cameras. Then Facetime, Skype, Zoom, Teams, and others.

Of course, it all still took a back seat to actually seeing people and having meetings in person. Until the pandemic made that the least attractive option. Then the adoption of such things went into hyperdrive and has stayed there ever since.

And ya know, I don’t have too many complaints. Between clinical trials and legal cases, both of which involve A LOT of meetings, it’s made my life easier. I no longer have to leave the office, allow time to drive somewhere and back, fight traffic, burn gas, and find parking. I move from a patient to the meeting and back to a patient from the cozy confines of my office, all without my tea getting cold.

But you can’t really make eye contact on Zoom. Instinctively, we generally look directly at the eyes of the person we’re speaking to, but in the virtual world we really don’t do that. On their end you’re on a screen, your gaze fixed somewhere below the level of your camera.

Try talking directly to the camera on Zoom — or any video platform. It doesn’t work. You feel like Dave addressing HAL’s red light in 2001. Inevitably your eyes are drawn back to the other person’s face, which is what you’re programmed to do. If they’re speaking you look at them, even though the sound is really coming from your speakers.

Interestingly, though, it seems something is lost in there. A recent perspective noted that Zoom meetings seemed to stifle creativity and produced fewer ideas than in person.

An interesting study compared neural response signals of people seeing a presentation on Zoom versus the same talk in person. When looking at a “real” speaker, there was synchronized neural activity, a higher level of engagement, and increased activation of the dorsal-parietal cortex.

Without actual eye contact it’s harder to read subtle facial expressions. Hand gestures and other body language may be out of the camera frame, or absent altogether. The nuances of voice pitch, timbre, and tone may not be the same over the speaker.

Our brains have spent several million of years developing facial recognition and reading, knowing friend from foe, and understanding what’s meant not just in what sounds are used but how they’re conveyed.

I’m not saying we should stop using Zoom altogether — it makes meetings more convenient for most people, including myself. But we also need to keep in mind that what it doesn’t convey is as important as what it does, and that virtual is never a perfect substitute for reality.
 

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

Making eye contact is important in human interactions. It shows attention and comprehension. It also helps us read the nuances of another’s facial expressions when interacting.

Although the idea of video phone calls isn’t new — I remember it from my childhood in “house of the future” TV shows — it certainly didn’t take off until the advent of high-speed Internet, computers, and phones with cameras. Then Facetime, Skype, Zoom, Teams, and others.

Of course, it all still took a back seat to actually seeing people and having meetings in person. Until the pandemic made that the least attractive option. Then the adoption of such things went into hyperdrive and has stayed there ever since.

And ya know, I don’t have too many complaints. Between clinical trials and legal cases, both of which involve A LOT of meetings, it’s made my life easier. I no longer have to leave the office, allow time to drive somewhere and back, fight traffic, burn gas, and find parking. I move from a patient to the meeting and back to a patient from the cozy confines of my office, all without my tea getting cold.

But you can’t really make eye contact on Zoom. Instinctively, we generally look directly at the eyes of the person we’re speaking to, but in the virtual world we really don’t do that. On their end you’re on a screen, your gaze fixed somewhere below the level of your camera.

Try talking directly to the camera on Zoom — or any video platform. It doesn’t work. You feel like Dave addressing HAL’s red light in 2001. Inevitably your eyes are drawn back to the other person’s face, which is what you’re programmed to do. If they’re speaking you look at them, even though the sound is really coming from your speakers.

Interestingly, though, it seems something is lost in there. A recent perspective noted that Zoom meetings seemed to stifle creativity and produced fewer ideas than in person.

An interesting study compared neural response signals of people seeing a presentation on Zoom versus the same talk in person. When looking at a “real” speaker, there was synchronized neural activity, a higher level of engagement, and increased activation of the dorsal-parietal cortex.

Without actual eye contact it’s harder to read subtle facial expressions. Hand gestures and other body language may be out of the camera frame, or absent altogether. The nuances of voice pitch, timbre, and tone may not be the same over the speaker.

Our brains have spent several million of years developing facial recognition and reading, knowing friend from foe, and understanding what’s meant not just in what sounds are used but how they’re conveyed.

I’m not saying we should stop using Zoom altogether — it makes meetings more convenient for most people, including myself. But we also need to keep in mind that what it doesn’t convey is as important as what it does, and that virtual is never a perfect substitute for reality.
 

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

This transcript has been edited for clarity.

The first time I saw a patient in the hospital was in 2004, twenty years ago, when I was a third-year med student. I mean, look at that guy. The things I could tell him.

Since that time, I have spent countless hours in the hospital as a resident, a renal fellow, and finally as an attending. And I’m sure many of you in the medical community feel the same thing I do, which is that patients are much more complicated now than they used to be. I’ll listen to an intern present a new case on rounds and she’ll have an assessment and plan that encompasses a dozen individual medical problems. Sometimes I have to literally be like, “Wait, why is this patient here again?”

But until now, I had no data to convince myself that this feeling was real — that hospitalized patients are getting more and more complicated, or that they only seem more complicated because I’m getting older. Maybe I was better able to keep track of things when I was an intern rather than now as an attending, spending just a couple months of the year in the hospital. I mean, after all, if patients were getting more complicated, surely hospitals would know this and allocate more resources to patient care, right?

Right?

It’s not an illusion. At least not according to this paper, Population-Based Trends in Complexity of Hospital Inpatients, appearing in JAMA Internal Medicine, which examines about 15 years of inpatient hospital admissions in British Columbia.

I like Canada for this study for two reasons: First, their electronic health record system is province-wide, so they don’t have issues of getting data from hospital A vs hospital B. All the data are there — in this case, more than 3 million nonelective hospital admissions from British Columbia. Second, there is universal healthcare. We don’t have to worry about insurance companies changing, or the start of a new program like the Affordable Care Act. It’s just a cleaner set-up.

Of course, complexity is hard to define, and the authors here decide to look at a variety of metrics I think we can agree are tied into complexity. These include things like patient age, comorbidities, medications, frequency of hospitalization, and so on. They also looked at outcomes associated with hospitalization: Did the patient require the ICU? Did they survive? Were they readmitted?

And the tale of the tape is as clear as that British Columbian air: Over the past 15 years, your average hospitalized patient is about 3 years older, is twice as likely to have kidney disease, 70% more likely to have diabetes, is on more medications (particularly anticoagulants), and is much more likely to be admitted through the emergency room. They’ve also spent more time in the hospital in the past year.

Given the increased complexity, you might expect that the outcomes for these patients are worse than years ago, but the data do not bear that out. In fact, inpatient mortality is lower now than it was 15 years ago, although 30-day postdischarge mortality is higher. Put those together and it turns out that death rates are pretty stable: 9% of people admitted for nonelective reasons to the hospital will die within 30 days. It’s just that nowadays, we tend to discharge them before that happens.

Why are our patients getting more complex? Some of it is demographics; the population is aging, after all. Some of it relates to the increasing burden of comorbidities like diabetes and kidney disease, which are associated with the obesity epidemic. But in some ways, we’re a victim of our own success. We have the ability to keep people alive today who would not have survived 15 years ago. We have better treatments for metastatic cancer, less-invasive therapies for heart disease, better protocolized ICU care.

Given all that, does it make any sense that many of our hospitals are at skeleton-crew staffing levels? That hospitalists report taking care of more patients than they ever have before?

There’s been so much talk about burnout in the health professions lately. Maybe something people need to start acknowledging — particularly those who haven’t practiced on the front lines for a decade or two — is that the job is, quite simply, harder now. As patients become more complex, we need more resources, human and otherwise, to care for them.

F. Perry Wilson, MD, MSCE, is an associate professor of medicine and public health and director of Yale’s Clinical and Translational Research Accelerator. His science communication work can be found in the Huffington Post, on NPR, and here on Medscape. He tweets @fperrywilson and his book, How Medicine Works and When It Doesn’t, is available now. He has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

The first time I saw a patient in the hospital was in 2004, twenty years ago, when I was a third-year med student. I mean, look at that guy. The things I could tell him.

Since that time, I have spent countless hours in the hospital as a resident, a renal fellow, and finally as an attending. And I’m sure many of you in the medical community feel the same thing I do, which is that patients are much more complicated now than they used to be. I’ll listen to an intern present a new case on rounds and she’ll have an assessment and plan that encompasses a dozen individual medical problems. Sometimes I have to literally be like, “Wait, why is this patient here again?”

But until now, I had no data to convince myself that this feeling was real — that hospitalized patients are getting more and more complicated, or that they only seem more complicated because I’m getting older. Maybe I was better able to keep track of things when I was an intern rather than now as an attending, spending just a couple months of the year in the hospital. I mean, after all, if patients were getting more complicated, surely hospitals would know this and allocate more resources to patient care, right?

Right?

It’s not an illusion. At least not according to this paper, Population-Based Trends in Complexity of Hospital Inpatients, appearing in JAMA Internal Medicine, which examines about 15 years of inpatient hospital admissions in British Columbia.

I like Canada for this study for two reasons: First, their electronic health record system is province-wide, so they don’t have issues of getting data from hospital A vs hospital B. All the data are there — in this case, more than 3 million nonelective hospital admissions from British Columbia. Second, there is universal healthcare. We don’t have to worry about insurance companies changing, or the start of a new program like the Affordable Care Act. It’s just a cleaner set-up.

Of course, complexity is hard to define, and the authors here decide to look at a variety of metrics I think we can agree are tied into complexity. These include things like patient age, comorbidities, medications, frequency of hospitalization, and so on. They also looked at outcomes associated with hospitalization: Did the patient require the ICU? Did they survive? Were they readmitted?

And the tale of the tape is as clear as that British Columbian air: Over the past 15 years, your average hospitalized patient is about 3 years older, is twice as likely to have kidney disease, 70% more likely to have diabetes, is on more medications (particularly anticoagulants), and is much more likely to be admitted through the emergency room. They’ve also spent more time in the hospital in the past year.

Given the increased complexity, you might expect that the outcomes for these patients are worse than years ago, but the data do not bear that out. In fact, inpatient mortality is lower now than it was 15 years ago, although 30-day postdischarge mortality is higher. Put those together and it turns out that death rates are pretty stable: 9% of people admitted for nonelective reasons to the hospital will die within 30 days. It’s just that nowadays, we tend to discharge them before that happens.

Why are our patients getting more complex? Some of it is demographics; the population is aging, after all. Some of it relates to the increasing burden of comorbidities like diabetes and kidney disease, which are associated with the obesity epidemic. But in some ways, we’re a victim of our own success. We have the ability to keep people alive today who would not have survived 15 years ago. We have better treatments for metastatic cancer, less-invasive therapies for heart disease, better protocolized ICU care.

Given all that, does it make any sense that many of our hospitals are at skeleton-crew staffing levels? That hospitalists report taking care of more patients than they ever have before?

There’s been so much talk about burnout in the health professions lately. Maybe something people need to start acknowledging — particularly those who haven’t practiced on the front lines for a decade or two — is that the job is, quite simply, harder now. As patients become more complex, we need more resources, human and otherwise, to care for them.

F. Perry Wilson, MD, MSCE, is an associate professor of medicine and public health and director of Yale’s Clinical and Translational Research Accelerator. His science communication work can be found in the Huffington Post, on NPR, and here on Medscape. He tweets @fperrywilson and his book, How Medicine Works and When It Doesn’t, is available now. He has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

The first time I saw a patient in the hospital was in 2004, twenty years ago, when I was a third-year med student. I mean, look at that guy. The things I could tell him.

Since that time, I have spent countless hours in the hospital as a resident, a renal fellow, and finally as an attending. And I’m sure many of you in the medical community feel the same thing I do, which is that patients are much more complicated now than they used to be. I’ll listen to an intern present a new case on rounds and she’ll have an assessment and plan that encompasses a dozen individual medical problems. Sometimes I have to literally be like, “Wait, why is this patient here again?”

But until now, I had no data to convince myself that this feeling was real — that hospitalized patients are getting more and more complicated, or that they only seem more complicated because I’m getting older. Maybe I was better able to keep track of things when I was an intern rather than now as an attending, spending just a couple months of the year in the hospital. I mean, after all, if patients were getting more complicated, surely hospitals would know this and allocate more resources to patient care, right?

Right?

It’s not an illusion. At least not according to this paper, Population-Based Trends in Complexity of Hospital Inpatients, appearing in JAMA Internal Medicine, which examines about 15 years of inpatient hospital admissions in British Columbia.

I like Canada for this study for two reasons: First, their electronic health record system is province-wide, so they don’t have issues of getting data from hospital A vs hospital B. All the data are there — in this case, more than 3 million nonelective hospital admissions from British Columbia. Second, there is universal healthcare. We don’t have to worry about insurance companies changing, or the start of a new program like the Affordable Care Act. It’s just a cleaner set-up.

Of course, complexity is hard to define, and the authors here decide to look at a variety of metrics I think we can agree are tied into complexity. These include things like patient age, comorbidities, medications, frequency of hospitalization, and so on. They also looked at outcomes associated with hospitalization: Did the patient require the ICU? Did they survive? Were they readmitted?

And the tale of the tape is as clear as that British Columbian air: Over the past 15 years, your average hospitalized patient is about 3 years older, is twice as likely to have kidney disease, 70% more likely to have diabetes, is on more medications (particularly anticoagulants), and is much more likely to be admitted through the emergency room. They’ve also spent more time in the hospital in the past year.

Given the increased complexity, you might expect that the outcomes for these patients are worse than years ago, but the data do not bear that out. In fact, inpatient mortality is lower now than it was 15 years ago, although 30-day postdischarge mortality is higher. Put those together and it turns out that death rates are pretty stable: 9% of people admitted for nonelective reasons to the hospital will die within 30 days. It’s just that nowadays, we tend to discharge them before that happens.

Why are our patients getting more complex? Some of it is demographics; the population is aging, after all. Some of it relates to the increasing burden of comorbidities like diabetes and kidney disease, which are associated with the obesity epidemic. But in some ways, we’re a victim of our own success. We have the ability to keep people alive today who would not have survived 15 years ago. We have better treatments for metastatic cancer, less-invasive therapies for heart disease, better protocolized ICU care.

Given all that, does it make any sense that many of our hospitals are at skeleton-crew staffing levels? That hospitalists report taking care of more patients than they ever have before?

There’s been so much talk about burnout in the health professions lately. Maybe something people need to start acknowledging — particularly those who haven’t practiced on the front lines for a decade or two — is that the job is, quite simply, harder now. As patients become more complex, we need more resources, human and otherwise, to care for them.

F. Perry Wilson, MD, MSCE, is an associate professor of medicine and public health and director of Yale’s Clinical and Translational Research Accelerator. His science communication work can be found in the Huffington Post, on NPR, and here on Medscape. He tweets @fperrywilson and his book, How Medicine Works and When It Doesn’t, is available now. He has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

This month, I want to tackle the difficult subject of violence toward healthcare workers. There’s a reason this is top of mind for me in my practice, but I want to start by acknowledging that this has been a much larger issue for our profession and one that has been growing for a number of years now.

The US Bureau of Labor Statistics estimates that medical professionals are fivefold more likely than members of other industries to suffer workplace violence. They also estimate that that rate doubled between 2011 and 2018. I think that range is important because it proves this was a problem, and a crescendoing problem, even before COVID.

Another thing I think is relevant is to look at where in the healthcare system are these attacks most likely. In the emergency room, ER staff have seen hostility toward them rise by at least 25% over the past several years. Some of the seeds of mistrust that were sown between the general public and the scientific and medical communities around the pandemic. I think there’s some explanation there for why that might be a particular crucible.

Perhaps most disturbingly of all, 60% of the victims of healthcare workplace violence are bedside nurses. There is something about the intensity of the inpatient setting that makes nerves particularly frayed and unfortunately makes patients and family members more likely to lash out. I think it’s actually the heightened sense of mortality.

I’m not excusing any of these behaviors, but maybe it’s akin to road rage. On the road, behind the wheel, tiny gestures can actually be, on some level, perceived as threats to our survival. Another driver swerving into your lane activates a fight-or-flight response, you feel threatened, and you might respond in the moment very rashly. I wonder if we’re not seeing that, quite unfairly, play out against bedside staff in our hospitals.

Here’s the thing. Those of us who practice in the outpatient setting — 95% of my work, for instance, happens in clinic — are not immune to this either. There are some very harrowing recent examples of physicians being killed, typically at gunpoint, often by patients, sometimes by aggrieved family members, in their offices. An orthopedist in Tennessee, a back surgeon in Tulsa, along with three of their colleagues. In the latter case, the assailant specifically blamed the surgeon for their pain.

This is where I think things get even more scary. We have to be the bearers of bad news in our profession. This has long been the task of the oncologist, in particular, to convey things that people don’t want to hear.

I think what brought this to my mind in terms of my reading was an incredible article in The ASCO Post and also in the Journal of Clinical Oncology by Dr. Noelle LoConte, who’s a medical oncologist in Wisconsin. The article is called, “I Want to Kill You,” and it recounts her telling a previously stage III colon cancer patient, with whom she thought she had good rapport, that the disease had recurred. The patient’s immediate reaction in the heat of that moment was to say, Dr LoConte, I want to kill you. I want to blow your face off.

Already, there’s clearly tension when we are telling people what they don’t want to hear. I think the final piece of the puzzle goes back to the intrusion of the business of healthcare on the practice of medicine. This is what I witnessed very recently. One of the things that’s interesting to think about is how what we do is now framed as customer service. I know there’s deriding of this model, but if perception is reality, we have a system where patients are set up to view themselves as consumers.

Let’s say, for instance, you’re in the unfortunate circumstance of being diagnosed with cancer and your insurer gives you the option to go to multiple oncologists. If you’re online browsing for oncologists, how do you differentiate me from some of my colleagues? The answer on these rating websites often has to do with domains that are about the overall experience — not just the patient-doctor interaction but also things like wait time, friendliness of staff, and promptness of care delivery.

That, I think, is the final piece of the puzzle, because what I really risk when I sit down with a patient and lay out a treatment plan is overpromising and underdelivering. I am long used to citing median overall survival for expectation of outcome. Of course, every patient wants to be an exceptional responder. Most patients want to be on the latter half of median survival. No one wants to be on the disappointingly shorter half.

My point is that I’ve long been able to mitigate that uncertainty for patients. What is getting harder and harder to explain away is the delay incurred between someone’s diagnosis, my meeting them and laying out a treatment plan, and their actual initiation of that therapy.

This finally brings me to my recent personal encounter. I have long taken care of a patient, much like Dr LoConte’s, with an extremely calm demeanor. I thought we had a great therapeutic alliance. I had to tell the patient that the disease had recurred, and then I laid out a treatment plan. It took weeks and then months for the insurer to approve this plan despite my providing my note in a timely fashion with a mountain of evidence behind the regimen that I’d selected.

This is where I think insurers — when they deny, deflect, and delay — are not taking adequate responsibility for the impact that has on the therapeutic alliance between a patient and their doctor. These people are trusting us with their lives. As an oncologist, I’ve already told them something they didn’t want to hear, and now I’m compounding that with the uncertainty of when we can actually begin treatment.

This gentleman — who, again, is normally extremely kind and affable — showed up at my office and was incredibly hostile toward me and my staff because of the delay that he was encountering. We literally couldn’t tell him when his insurer was going to approve his treatment, which would have been financially disastrous if he had tried to pay for it himself out of pocket. He needed his insurer’s approval before we could start, but we didn’t know when he could start. That uncertainty and not knowing was gnawing away at him until he was at the end of his rope.

What I’m here to say is that this has been a difficult couple of years in healthcare. I’m well aware that our ER staff are on the front lines, as are our bedside and inpatient teams. Even in the outpatient setting, I think we’re seeing this crucible and we’re seeing the pressure just grow, and grow, and grow. It’s like fracking. The more you increase the pressure, the more eventually you’re going to find out where the cracks are.

These patients are the ultimate stakeholders. It’s their lives on the line, and we should be concerned, but perhaps ultimately not surprised, that they’re lashing out to be heard. Given no other resort, they are taking out their frustration and their aggression on us. It›s not fair, but I am newly aware of it because, in a patient with whom I thought we had a superb rapport, I saw that vanish. As soon as he thought that his life was at risk, his fight-or-flight response kicked in. I was not dealing with the same man I knew. I was dealing with someone who was desperate and who just wanted to know when he could get the treatment.

I think this has taken the likelihood of workplace hostility to a whole other level for those of us in healthcare.

For any patients listening, I beg of you, please don’t shoot the messenger. We are here to serve you the best we can, but there are many external factors at play. We are doing our best to mitigate those for you so we can deliver the care that we promised in as timely a fashion as we can.

I hope everyone out there can stay safe. Thank you.
 

Dr. Lewis is director of gastrointestinal oncology at Intermountain Healthcare in Salt Lake City, Utah. He has an interest in neuroendocrine tumors, hereditary cancer syndromes, and patient-physician communication. He has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

This month, I want to tackle the difficult subject of violence toward healthcare workers. There’s a reason this is top of mind for me in my practice, but I want to start by acknowledging that this has been a much larger issue for our profession and one that has been growing for a number of years now.

The US Bureau of Labor Statistics estimates that medical professionals are fivefold more likely than members of other industries to suffer workplace violence. They also estimate that that rate doubled between 2011 and 2018. I think that range is important because it proves this was a problem, and a crescendoing problem, even before COVID.

Another thing I think is relevant is to look at where in the healthcare system are these attacks most likely. In the emergency room, ER staff have seen hostility toward them rise by at least 25% over the past several years. Some of the seeds of mistrust that were sown between the general public and the scientific and medical communities around the pandemic. I think there’s some explanation there for why that might be a particular crucible.

Perhaps most disturbingly of all, 60% of the victims of healthcare workplace violence are bedside nurses. There is something about the intensity of the inpatient setting that makes nerves particularly frayed and unfortunately makes patients and family members more likely to lash out. I think it’s actually the heightened sense of mortality.

I’m not excusing any of these behaviors, but maybe it’s akin to road rage. On the road, behind the wheel, tiny gestures can actually be, on some level, perceived as threats to our survival. Another driver swerving into your lane activates a fight-or-flight response, you feel threatened, and you might respond in the moment very rashly. I wonder if we’re not seeing that, quite unfairly, play out against bedside staff in our hospitals.

Here’s the thing. Those of us who practice in the outpatient setting — 95% of my work, for instance, happens in clinic — are not immune to this either. There are some very harrowing recent examples of physicians being killed, typically at gunpoint, often by patients, sometimes by aggrieved family members, in their offices. An orthopedist in Tennessee, a back surgeon in Tulsa, along with three of their colleagues. In the latter case, the assailant specifically blamed the surgeon for their pain.

This is where I think things get even more scary. We have to be the bearers of bad news in our profession. This has long been the task of the oncologist, in particular, to convey things that people don’t want to hear.

I think what brought this to my mind in terms of my reading was an incredible article in The ASCO Post and also in the Journal of Clinical Oncology by Dr. Noelle LoConte, who’s a medical oncologist in Wisconsin. The article is called, “I Want to Kill You,” and it recounts her telling a previously stage III colon cancer patient, with whom she thought she had good rapport, that the disease had recurred. The patient’s immediate reaction in the heat of that moment was to say, Dr LoConte, I want to kill you. I want to blow your face off.

Already, there’s clearly tension when we are telling people what they don’t want to hear. I think the final piece of the puzzle goes back to the intrusion of the business of healthcare on the practice of medicine. This is what I witnessed very recently. One of the things that’s interesting to think about is how what we do is now framed as customer service. I know there’s deriding of this model, but if perception is reality, we have a system where patients are set up to view themselves as consumers.

Let’s say, for instance, you’re in the unfortunate circumstance of being diagnosed with cancer and your insurer gives you the option to go to multiple oncologists. If you’re online browsing for oncologists, how do you differentiate me from some of my colleagues? The answer on these rating websites often has to do with domains that are about the overall experience — not just the patient-doctor interaction but also things like wait time, friendliness of staff, and promptness of care delivery.

That, I think, is the final piece of the puzzle, because what I really risk when I sit down with a patient and lay out a treatment plan is overpromising and underdelivering. I am long used to citing median overall survival for expectation of outcome. Of course, every patient wants to be an exceptional responder. Most patients want to be on the latter half of median survival. No one wants to be on the disappointingly shorter half.

My point is that I’ve long been able to mitigate that uncertainty for patients. What is getting harder and harder to explain away is the delay incurred between someone’s diagnosis, my meeting them and laying out a treatment plan, and their actual initiation of that therapy.

This finally brings me to my recent personal encounter. I have long taken care of a patient, much like Dr LoConte’s, with an extremely calm demeanor. I thought we had a great therapeutic alliance. I had to tell the patient that the disease had recurred, and then I laid out a treatment plan. It took weeks and then months for the insurer to approve this plan despite my providing my note in a timely fashion with a mountain of evidence behind the regimen that I’d selected.

This is where I think insurers — when they deny, deflect, and delay — are not taking adequate responsibility for the impact that has on the therapeutic alliance between a patient and their doctor. These people are trusting us with their lives. As an oncologist, I’ve already told them something they didn’t want to hear, and now I’m compounding that with the uncertainty of when we can actually begin treatment.

This gentleman — who, again, is normally extremely kind and affable — showed up at my office and was incredibly hostile toward me and my staff because of the delay that he was encountering. We literally couldn’t tell him when his insurer was going to approve his treatment, which would have been financially disastrous if he had tried to pay for it himself out of pocket. He needed his insurer’s approval before we could start, but we didn’t know when he could start. That uncertainty and not knowing was gnawing away at him until he was at the end of his rope.

What I’m here to say is that this has been a difficult couple of years in healthcare. I’m well aware that our ER staff are on the front lines, as are our bedside and inpatient teams. Even in the outpatient setting, I think we’re seeing this crucible and we’re seeing the pressure just grow, and grow, and grow. It’s like fracking. The more you increase the pressure, the more eventually you’re going to find out where the cracks are.

These patients are the ultimate stakeholders. It’s their lives on the line, and we should be concerned, but perhaps ultimately not surprised, that they’re lashing out to be heard. Given no other resort, they are taking out their frustration and their aggression on us. It›s not fair, but I am newly aware of it because, in a patient with whom I thought we had a superb rapport, I saw that vanish. As soon as he thought that his life was at risk, his fight-or-flight response kicked in. I was not dealing with the same man I knew. I was dealing with someone who was desperate and who just wanted to know when he could get the treatment.

I think this has taken the likelihood of workplace hostility to a whole other level for those of us in healthcare.

For any patients listening, I beg of you, please don’t shoot the messenger. We are here to serve you the best we can, but there are many external factors at play. We are doing our best to mitigate those for you so we can deliver the care that we promised in as timely a fashion as we can.

I hope everyone out there can stay safe. Thank you.
 

Dr. Lewis is director of gastrointestinal oncology at Intermountain Healthcare in Salt Lake City, Utah. He has an interest in neuroendocrine tumors, hereditary cancer syndromes, and patient-physician communication. He has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

This transcript has been edited for clarity.

This month, I want to tackle the difficult subject of violence toward healthcare workers. There’s a reason this is top of mind for me in my practice, but I want to start by acknowledging that this has been a much larger issue for our profession and one that has been growing for a number of years now.

The US Bureau of Labor Statistics estimates that medical professionals are fivefold more likely than members of other industries to suffer workplace violence. They also estimate that that rate doubled between 2011 and 2018. I think that range is important because it proves this was a problem, and a crescendoing problem, even before COVID.

Another thing I think is relevant is to look at where in the healthcare system are these attacks most likely. In the emergency room, ER staff have seen hostility toward them rise by at least 25% over the past several years. Some of the seeds of mistrust that were sown between the general public and the scientific and medical communities around the pandemic. I think there’s some explanation there for why that might be a particular crucible.

Perhaps most disturbingly of all, 60% of the victims of healthcare workplace violence are bedside nurses. There is something about the intensity of the inpatient setting that makes nerves particularly frayed and unfortunately makes patients and family members more likely to lash out. I think it’s actually the heightened sense of mortality.

I’m not excusing any of these behaviors, but maybe it’s akin to road rage. On the road, behind the wheel, tiny gestures can actually be, on some level, perceived as threats to our survival. Another driver swerving into your lane activates a fight-or-flight response, you feel threatened, and you might respond in the moment very rashly. I wonder if we’re not seeing that, quite unfairly, play out against bedside staff in our hospitals.

Here’s the thing. Those of us who practice in the outpatient setting — 95% of my work, for instance, happens in clinic — are not immune to this either. There are some very harrowing recent examples of physicians being killed, typically at gunpoint, often by patients, sometimes by aggrieved family members, in their offices. An orthopedist in Tennessee, a back surgeon in Tulsa, along with three of their colleagues. In the latter case, the assailant specifically blamed the surgeon for their pain.

This is where I think things get even more scary. We have to be the bearers of bad news in our profession. This has long been the task of the oncologist, in particular, to convey things that people don’t want to hear.

I think what brought this to my mind in terms of my reading was an incredible article in The ASCO Post and also in the Journal of Clinical Oncology by Dr. Noelle LoConte, who’s a medical oncologist in Wisconsin. The article is called, “I Want to Kill You,” and it recounts her telling a previously stage III colon cancer patient, with whom she thought she had good rapport, that the disease had recurred. The patient’s immediate reaction in the heat of that moment was to say, Dr LoConte, I want to kill you. I want to blow your face off.

Already, there’s clearly tension when we are telling people what they don’t want to hear. I think the final piece of the puzzle goes back to the intrusion of the business of healthcare on the practice of medicine. This is what I witnessed very recently. One of the things that’s interesting to think about is how what we do is now framed as customer service. I know there’s deriding of this model, but if perception is reality, we have a system where patients are set up to view themselves as consumers.

Let’s say, for instance, you’re in the unfortunate circumstance of being diagnosed with cancer and your insurer gives you the option to go to multiple oncologists. If you’re online browsing for oncologists, how do you differentiate me from some of my colleagues? The answer on these rating websites often has to do with domains that are about the overall experience — not just the patient-doctor interaction but also things like wait time, friendliness of staff, and promptness of care delivery.

That, I think, is the final piece of the puzzle, because what I really risk when I sit down with a patient and lay out a treatment plan is overpromising and underdelivering. I am long used to citing median overall survival for expectation of outcome. Of course, every patient wants to be an exceptional responder. Most patients want to be on the latter half of median survival. No one wants to be on the disappointingly shorter half.

My point is that I’ve long been able to mitigate that uncertainty for patients. What is getting harder and harder to explain away is the delay incurred between someone’s diagnosis, my meeting them and laying out a treatment plan, and their actual initiation of that therapy.

This finally brings me to my recent personal encounter. I have long taken care of a patient, much like Dr LoConte’s, with an extremely calm demeanor. I thought we had a great therapeutic alliance. I had to tell the patient that the disease had recurred, and then I laid out a treatment plan. It took weeks and then months for the insurer to approve this plan despite my providing my note in a timely fashion with a mountain of evidence behind the regimen that I’d selected.

This is where I think insurers — when they deny, deflect, and delay — are not taking adequate responsibility for the impact that has on the therapeutic alliance between a patient and their doctor. These people are trusting us with their lives. As an oncologist, I’ve already told them something they didn’t want to hear, and now I’m compounding that with the uncertainty of when we can actually begin treatment.

This gentleman — who, again, is normally extremely kind and affable — showed up at my office and was incredibly hostile toward me and my staff because of the delay that he was encountering. We literally couldn’t tell him when his insurer was going to approve his treatment, which would have been financially disastrous if he had tried to pay for it himself out of pocket. He needed his insurer’s approval before we could start, but we didn’t know when he could start. That uncertainty and not knowing was gnawing away at him until he was at the end of his rope.

What I’m here to say is that this has been a difficult couple of years in healthcare. I’m well aware that our ER staff are on the front lines, as are our bedside and inpatient teams. Even in the outpatient setting, I think we’re seeing this crucible and we’re seeing the pressure just grow, and grow, and grow. It’s like fracking. The more you increase the pressure, the more eventually you’re going to find out where the cracks are.

These patients are the ultimate stakeholders. It’s their lives on the line, and we should be concerned, but perhaps ultimately not surprised, that they’re lashing out to be heard. Given no other resort, they are taking out their frustration and their aggression on us. It›s not fair, but I am newly aware of it because, in a patient with whom I thought we had a superb rapport, I saw that vanish. As soon as he thought that his life was at risk, his fight-or-flight response kicked in. I was not dealing with the same man I knew. I was dealing with someone who was desperate and who just wanted to know when he could get the treatment.

I think this has taken the likelihood of workplace hostility to a whole other level for those of us in healthcare.

For any patients listening, I beg of you, please don’t shoot the messenger. We are here to serve you the best we can, but there are many external factors at play. We are doing our best to mitigate those for you so we can deliver the care that we promised in as timely a fashion as we can.

I hope everyone out there can stay safe. Thank you.
 

Dr. Lewis is director of gastrointestinal oncology at Intermountain Healthcare in Salt Lake City, Utah. He has an interest in neuroendocrine tumors, hereditary cancer syndromes, and patient-physician communication. He has disclosed no relevant financial relationships.

A version of this article appeared on Medscape.com.

The past year has been a challenging time for many, both at the local level and globally, with divisive undercurrents across many communities. Many times, the end of the year is an opportunity for reflection. As I reflect on the state of perinatal psychiatry in the new year, I see several evolving issues that I’d like to share in this first column of 2024.

In 2023, the American College of Obstetricians and Gynecologists published new recommendations meant to enhance the well-being of pregnant and postpartum women and families. A main message from discussion papers borne out of these recommendations was that as a field, we should be doing more than identifying perinatal illness. We should be screening women at risk for postpartum psychiatric illness and see that those suffering from posttraumatic stress disorder (PTSD) have access to care and “wrap-around services” from clinicians with varying expertise.

Screening is a primary way we identify patients at risk for psychiatric illness and also those who are suffering at the time of a screen. One problem I see in the near future is our disparate collection and management of data. When we look closely across health care systems, it’s not clear how screening data are captured, let alone managed. What is being done in one hospital system may be very different from what is being done elsewhere. Some clinicians are adopting digital platforms to identify those with postpartum depression, while others are practicing as they always have, either through a paper screening process or with queries as part of a clinical encounter.

Given this amalgam of methods for collecting and storing information, there does not appear to be a systematic way clinicians and researchers are recording whether women are meeting criteria for significant depressive symptoms or frank postpartum psychiatric illness. It is clear a more cohesive method for collection and management is needed to optimize the likelihood that next steps can be taken to get patients the care they need.

However, screening is only one part of the story. Certainly, in our own center, one of our greatest interests, both clinically and on the research side, is what happens after screening. Through our center’s initiation of the Screening and Treatment Enhancement for Postpartum Depression (STEPS for PPD) project funded by the Marriott Foundation, we are evaluating the outcomes of women who are screened at 6 weeks postpartum with significant depressive symptoms, and who are then given an opportunity to engage with a perinatal social worker who can assist with direct psychotherapy, arranging for referrals, and navigating care for a new mother.

What we are learning as we enroll women through the initial stages of STEPS for PPD is that screening and identifying women who likely suffer from PPD simply is not enough. In fact, once identified with a depression screening tool, women who are suffering from postpartum depression can be very challenging to engage clinically. What I am learning decades after starting to work with perinatal patients is that even with a screening system and effective tools for treatment of PPD, optimizing engagement with these depressed women seems a critical and understudied step on the road to optimizing positive clinical outcomes.

A recent study published in the Journal of Women’s Health explored gaps in care for perinatal depression and found that patients without a history of psychiatric illness prior to pregnancy were less likely to be screened for depression and 80% less likely to receive care if they developed depression compared with women with a previous history of psychiatric illness (J Womens Health (Larchmt). 2023 Oct;32[10]:1111-9).

That history may help women navigate to care, while women for whom psychiatric illness is a new experience may be less likely to engage, be referred for care, and receive appropriate treatment. The study indicates that, as a field, we must strive to ensure universal screening for depression in perinatal populations.

While we have always been particularly interested in populations of patients at highest risk for PPD, helping women at risk for PPD in the general population without a history of psychiatric illness is a large public health issue and will be an even larger undertaking. As women’s mental health is gaining more appropriate focus, both at the local level and even in the recent White House Initiative on Women’s Health Research, the focus has been on screening and developing new treatments.

We are not lacking in pharmacologic agents nor nonpharmacologic options as treatments for women experiencing PPD. Newer alternative treatments are being explored, such as transcranial magnetic stimulation (TMS) and even psychedelics as a potential therapy for PPD. But perhaps what we’ve learned in 2023 and as we move into a new year, is that the problem of tackling PPD is not only about having the right tools, but is about helping women navigate to the care that they need.

The COVID-19 pandemic brought with it an explosion of telehealth options that have enhanced the odds women can find support during such a challenging time; as society has returned to some semblance of normal, nearly all support groups for postpartum women have remained online.

When we set up Virtual Rounds at the Center for Women’s Mental Health at the beginning of the pandemic, I was struck by the community of colleagues at various stages of their careers dedicated to mitigating the suffering associated with perinatal psychiatric illness. As I’ve often said, it takes a village to care for these patients. We need help from colleagues with varying expertise — from lactation consultants, psychiatrists, psychologists, obstetricians, nurse practitioners, support group leaders, and a host of others — who can help reach these women.

At the end of the day, helping depressed women find resources is a challenge that we have not met in this country. We should be excited that we have so many treatment options to offer patients — whether it be a new first-in-class medication, TMS, or digital apps to ensure patients are receiving effective treatment. But there should also be a focus on reaching women who still need treatment, particularly in underserved communities where resources are sparse or nonexistent. Identifying the path to reaching these women where they are and getting them well should be a top priority in 2024.
 

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital (MGH) in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. STEPS for PPD is funded by the Marriott Foundation. Full disclosure information for Dr. Cohen is available at womensmentalhealth.org. Email Dr. Cohen at [email protected].

The past year has been a challenging time for many, both at the local level and globally, with divisive undercurrents across many communities. Many times, the end of the year is an opportunity for reflection. As I reflect on the state of perinatal psychiatry in the new year, I see several evolving issues that I’d like to share in this first column of 2024.

In 2023, the American College of Obstetricians and Gynecologists published new recommendations meant to enhance the well-being of pregnant and postpartum women and families. A main message from discussion papers borne out of these recommendations was that as a field, we should be doing more than identifying perinatal illness. We should be screening women at risk for postpartum psychiatric illness and see that those suffering from posttraumatic stress disorder (PTSD) have access to care and “wrap-around services” from clinicians with varying expertise.

Screening is a primary way we identify patients at risk for psychiatric illness and also those who are suffering at the time of a screen. One problem I see in the near future is our disparate collection and management of data. When we look closely across health care systems, it’s not clear how screening data are captured, let alone managed. What is being done in one hospital system may be very different from what is being done elsewhere. Some clinicians are adopting digital platforms to identify those with postpartum depression, while others are practicing as they always have, either through a paper screening process or with queries as part of a clinical encounter.

Given this amalgam of methods for collecting and storing information, there does not appear to be a systematic way clinicians and researchers are recording whether women are meeting criteria for significant depressive symptoms or frank postpartum psychiatric illness. It is clear a more cohesive method for collection and management is needed to optimize the likelihood that next steps can be taken to get patients the care they need.

However, screening is only one part of the story. Certainly, in our own center, one of our greatest interests, both clinically and on the research side, is what happens after screening. Through our center’s initiation of the Screening and Treatment Enhancement for Postpartum Depression (STEPS for PPD) project funded by the Marriott Foundation, we are evaluating the outcomes of women who are screened at 6 weeks postpartum with significant depressive symptoms, and who are then given an opportunity to engage with a perinatal social worker who can assist with direct psychotherapy, arranging for referrals, and navigating care for a new mother.

What we are learning as we enroll women through the initial stages of STEPS for PPD is that screening and identifying women who likely suffer from PPD simply is not enough. In fact, once identified with a depression screening tool, women who are suffering from postpartum depression can be very challenging to engage clinically. What I am learning decades after starting to work with perinatal patients is that even with a screening system and effective tools for treatment of PPD, optimizing engagement with these depressed women seems a critical and understudied step on the road to optimizing positive clinical outcomes.

A recent study published in the Journal of Women’s Health explored gaps in care for perinatal depression and found that patients without a history of psychiatric illness prior to pregnancy were less likely to be screened for depression and 80% less likely to receive care if they developed depression compared with women with a previous history of psychiatric illness (J Womens Health (Larchmt). 2023 Oct;32[10]:1111-9).

That history may help women navigate to care, while women for whom psychiatric illness is a new experience may be less likely to engage, be referred for care, and receive appropriate treatment. The study indicates that, as a field, we must strive to ensure universal screening for depression in perinatal populations.

While we have always been particularly interested in populations of patients at highest risk for PPD, helping women at risk for PPD in the general population without a history of psychiatric illness is a large public health issue and will be an even larger undertaking. As women’s mental health is gaining more appropriate focus, both at the local level and even in the recent White House Initiative on Women’s Health Research, the focus has been on screening and developing new treatments.

We are not lacking in pharmacologic agents nor nonpharmacologic options as treatments for women experiencing PPD. Newer alternative treatments are being explored, such as transcranial magnetic stimulation (TMS) and even psychedelics as a potential therapy for PPD. But perhaps what we’ve learned in 2023 and as we move into a new year, is that the problem of tackling PPD is not only about having the right tools, but is about helping women navigate to the care that they need.

The COVID-19 pandemic brought with it an explosion of telehealth options that have enhanced the odds women can find support during such a challenging time; as society has returned to some semblance of normal, nearly all support groups for postpartum women have remained online.

When we set up Virtual Rounds at the Center for Women’s Mental Health at the beginning of the pandemic, I was struck by the community of colleagues at various stages of their careers dedicated to mitigating the suffering associated with perinatal psychiatric illness. As I’ve often said, it takes a village to care for these patients. We need help from colleagues with varying expertise — from lactation consultants, psychiatrists, psychologists, obstetricians, nurse practitioners, support group leaders, and a host of others — who can help reach these women.

At the end of the day, helping depressed women find resources is a challenge that we have not met in this country. We should be excited that we have so many treatment options to offer patients — whether it be a new first-in-class medication, TMS, or digital apps to ensure patients are receiving effective treatment. But there should also be a focus on reaching women who still need treatment, particularly in underserved communities where resources are sparse or nonexistent. Identifying the path to reaching these women where they are and getting them well should be a top priority in 2024.
 

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital (MGH) in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. STEPS for PPD is funded by the Marriott Foundation. Full disclosure information for Dr. Cohen is available at womensmentalhealth.org. Email Dr. Cohen at [email protected].

The past year has been a challenging time for many, both at the local level and globally, with divisive undercurrents across many communities. Many times, the end of the year is an opportunity for reflection. As I reflect on the state of perinatal psychiatry in the new year, I see several evolving issues that I’d like to share in this first column of 2024.

In 2023, the American College of Obstetricians and Gynecologists published new recommendations meant to enhance the well-being of pregnant and postpartum women and families. A main message from discussion papers borne out of these recommendations was that as a field, we should be doing more than identifying perinatal illness. We should be screening women at risk for postpartum psychiatric illness and see that those suffering from posttraumatic stress disorder (PTSD) have access to care and “wrap-around services” from clinicians with varying expertise.

Screening is a primary way we identify patients at risk for psychiatric illness and also those who are suffering at the time of a screen. One problem I see in the near future is our disparate collection and management of data. When we look closely across health care systems, it’s not clear how screening data are captured, let alone managed. What is being done in one hospital system may be very different from what is being done elsewhere. Some clinicians are adopting digital platforms to identify those with postpartum depression, while others are practicing as they always have, either through a paper screening process or with queries as part of a clinical encounter.

Given this amalgam of methods for collecting and storing information, there does not appear to be a systematic way clinicians and researchers are recording whether women are meeting criteria for significant depressive symptoms or frank postpartum psychiatric illness. It is clear a more cohesive method for collection and management is needed to optimize the likelihood that next steps can be taken to get patients the care they need.

However, screening is only one part of the story. Certainly, in our own center, one of our greatest interests, both clinically and on the research side, is what happens after screening. Through our center’s initiation of the Screening and Treatment Enhancement for Postpartum Depression (STEPS for PPD) project funded by the Marriott Foundation, we are evaluating the outcomes of women who are screened at 6 weeks postpartum with significant depressive symptoms, and who are then given an opportunity to engage with a perinatal social worker who can assist with direct psychotherapy, arranging for referrals, and navigating care for a new mother.

What we are learning as we enroll women through the initial stages of STEPS for PPD is that screening and identifying women who likely suffer from PPD simply is not enough. In fact, once identified with a depression screening tool, women who are suffering from postpartum depression can be very challenging to engage clinically. What I am learning decades after starting to work with perinatal patients is that even with a screening system and effective tools for treatment of PPD, optimizing engagement with these depressed women seems a critical and understudied step on the road to optimizing positive clinical outcomes.

A recent study published in the Journal of Women’s Health explored gaps in care for perinatal depression and found that patients without a history of psychiatric illness prior to pregnancy were less likely to be screened for depression and 80% less likely to receive care if they developed depression compared with women with a previous history of psychiatric illness (J Womens Health (Larchmt). 2023 Oct;32[10]:1111-9).

That history may help women navigate to care, while women for whom psychiatric illness is a new experience may be less likely to engage, be referred for care, and receive appropriate treatment. The study indicates that, as a field, we must strive to ensure universal screening for depression in perinatal populations.

While we have always been particularly interested in populations of patients at highest risk for PPD, helping women at risk for PPD in the general population without a history of psychiatric illness is a large public health issue and will be an even larger undertaking. As women’s mental health is gaining more appropriate focus, both at the local level and even in the recent White House Initiative on Women’s Health Research, the focus has been on screening and developing new treatments.

We are not lacking in pharmacologic agents nor nonpharmacologic options as treatments for women experiencing PPD. Newer alternative treatments are being explored, such as transcranial magnetic stimulation (TMS) and even psychedelics as a potential therapy for PPD. But perhaps what we’ve learned in 2023 and as we move into a new year, is that the problem of tackling PPD is not only about having the right tools, but is about helping women navigate to the care that they need.

The COVID-19 pandemic brought with it an explosion of telehealth options that have enhanced the odds women can find support during such a challenging time; as society has returned to some semblance of normal, nearly all support groups for postpartum women have remained online.

When we set up Virtual Rounds at the Center for Women’s Mental Health at the beginning of the pandemic, I was struck by the community of colleagues at various stages of their careers dedicated to mitigating the suffering associated with perinatal psychiatric illness. As I’ve often said, it takes a village to care for these patients. We need help from colleagues with varying expertise — from lactation consultants, psychiatrists, psychologists, obstetricians, nurse practitioners, support group leaders, and a host of others — who can help reach these women.

At the end of the day, helping depressed women find resources is a challenge that we have not met in this country. We should be excited that we have so many treatment options to offer patients — whether it be a new first-in-class medication, TMS, or digital apps to ensure patients are receiving effective treatment. But there should also be a focus on reaching women who still need treatment, particularly in underserved communities where resources are sparse or nonexistent. Identifying the path to reaching these women where they are and getting them well should be a top priority in 2024.
 

Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital (MGH) in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He has been a consultant to manufacturers of psychiatric medications. STEPS for PPD is funded by the Marriott Foundation. Full disclosure information for Dr. Cohen is available at womensmentalhealth.org. Email Dr. Cohen at [email protected].

Matthew F. Watto, MD: Welcome back to The Curbsiders. I’m Dr. Matthew Watto, here with America’s primary care physician, Dr. Paul Nelson Williams. Paul, are you ready to talk about some adrenal insufficiency? We had a great conversation with Dr. Atil Kargi, and I’d like you to start us off.

Paul N. Williams, MD: How about thinking about it? It’s a good place to start.

That’s one of the ways this episode changed my approach a little bit. I never really thought about the fact that many patients present for evaluation of adrenal insufficiency from gastroenterology clinics. It’s such a protean sort of nonspecific presentation. But if you have someone with chronic malaise and poor appetite and maybe unexplained weight loss, and your GI workup is not really leading you anywhere, it’s probably worth thinking about adrenal insufficiency. Even though primary adrenal insufficiency is pretty rare — we’re talking cases per millions — secondary adrenal insufficiency is actually fairly common. It’s probably worth thinking about and testing for more often than I have in the past. So for me, it’s having a lower threshold to start looking for it.

Dr. Watto: When it’s adrenal crisis, you probably think about it, but then it’s too late. Ideally, you would think about it before that happens. But the symptoms can be quite vague. The mineralocorticoid symptoms, like salt cravings, dizziness, near syncope, muscle cramps, might make me think of it because they sound more like something endocrine is going on. But if it’s just a little weight loss, a little fatigue, or a little nausea, that’s everybody.

Dr. Williams: Right. If a patient came to me saying, “I’m craving salt,” that might hasten the workup a little bit, but that’s not the typical presentation.

Dr. Watto: If you are going to check a cortisol level, you should really check it in the morning, between 7 AM and 9 AM. If you check it too early, it might not have peaked yet, so you might get a level that looks low. But if you had checked an hour or 2 later, it might have been above a threshold, and then you would know you could rule out the diagnosis. The cutoffs depend on your source:  < 3-5 µg/dL that early in the morning is pretty much diagnostic of adrenal insufficiency. If it’s > 15 µg/dL, that’s a pretty robust cortisol and the patient probably doesn’t have adrenal insufficiency. But if the level is between 5 µg/dL and 15 µg/dL, you’re in a gray zone, and that’s where you might think about doing a stimulation (stim) test.

Dr. Kargi gave us a quick and dirty version of the stim test. Paul, have you had a chance to try this yet?

Dr. Williams: I have not. Have you? I’m sure you’ve been just waiting for the chance.

Dr. Watto: I would love to do this. I don›t know whether I›m set up to do it in the office right now. But this is an aspirational goal for my practice, and I›m sure some physicians are set up in their office already to do it. You can give either intramuscular or subcutaneous cosyntropin 250 µg. You don›t even have to get a baseline cortisol level right before the injection. Let›s say the patient›s previous cortisol level was between 5 µg/dL and 15 µg/dL, so you weren›t sure about the diagnosis. You bring them back to the office one day, give them a shot of cosyntropin, and then 30-60 minutes later, have a random cortisol drawn. If it›s > 19 µg/dL, you›ve ruled out adrenal insufficiency. If it›s anything else, send them to an endocrinologist to sort it out. You might be able to make the diagnosis yourself doing that.

Any treatment pearls to leave the audience with?

Dr. Williams: I hope endocrinologists don›t take issue with this. I say this with respect and admiration, but it feels kind of vibe-based to me. Without a lab value to guide treatment, you are dependent on the patient telling you how they feel much of the time. You have to let their symptoms guide you. It is probably worth noting that because hydrocortisone has a relatively short half-life, within hours, in fact, you typically have to do twice-daily dosing, sometimes even three times daily dosing to get patients to where they feel okay. It sounds like there›s a fair amount of trial and error and some adjustments that you have to make depending on what›s going on with the patient at any given time. You land somewhere between a dose of 15-30 mg per day, but there will be some variability, even within an individual patient, depending on what›s going on with them from a physiologic standpoint.

Dr. Watto: They are going to take one dose in the morning and then a second dose in the afternoon, but they don’t want them to take it too late in the evening because it could cause insomnia, and you want to try to mimic physiologic levels as much as you can. Two thirds of the daily dose is given early in the morning and then another third of the daily dose later in the day if you are prescribing two times daily dosing.

And Dr. Kargi had a low threshold for doubling the dose. If the patient has a cold, double the dose for 2 or 3 days. With a high fever, triple the dose for a few days. If they are going for surgery, they are probably going to be getting some intravenous hydrocortisone while they’re in the hospital.

We really turned over like every stone we could possibly think of on this podcast. There were so many great pearls that we don’t have time to go through them all here. But we talked about steroid tapers and a lot more. You can check it out here.

Dr. Watto has disclosed no relevant financial relationships.

Dr. Williams has disclosed the following relevant financial relationships:Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: The CurbsidersReceived income in an amount equal to or greater than $250 from: The Curbsiders.

A version of this article appeared on Medscape.com.

Matthew F. Watto, MD: Welcome back to The Curbsiders. I’m Dr. Matthew Watto, here with America’s primary care physician, Dr. Paul Nelson Williams. Paul, are you ready to talk about some adrenal insufficiency? We had a great conversation with Dr. Atil Kargi, and I’d like you to start us off.

Paul N. Williams, MD: How about thinking about it? It’s a good place to start.

That’s one of the ways this episode changed my approach a little bit. I never really thought about the fact that many patients present for evaluation of adrenal insufficiency from gastroenterology clinics. It’s such a protean sort of nonspecific presentation. But if you have someone with chronic malaise and poor appetite and maybe unexplained weight loss, and your GI workup is not really leading you anywhere, it’s probably worth thinking about adrenal insufficiency. Even though primary adrenal insufficiency is pretty rare — we’re talking cases per millions — secondary adrenal insufficiency is actually fairly common. It’s probably worth thinking about and testing for more often than I have in the past. So for me, it’s having a lower threshold to start looking for it.

Dr. Watto: When it’s adrenal crisis, you probably think about it, but then it’s too late. Ideally, you would think about it before that happens. But the symptoms can be quite vague. The mineralocorticoid symptoms, like salt cravings, dizziness, near syncope, muscle cramps, might make me think of it because they sound more like something endocrine is going on. But if it’s just a little weight loss, a little fatigue, or a little nausea, that’s everybody.

Dr. Williams: Right. If a patient came to me saying, “I’m craving salt,” that might hasten the workup a little bit, but that’s not the typical presentation.

Dr. Watto: If you are going to check a cortisol level, you should really check it in the morning, between 7 AM and 9 AM. If you check it too early, it might not have peaked yet, so you might get a level that looks low. But if you had checked an hour or 2 later, it might have been above a threshold, and then you would know you could rule out the diagnosis. The cutoffs depend on your source:  < 3-5 µg/dL that early in the morning is pretty much diagnostic of adrenal insufficiency. If it’s > 15 µg/dL, that’s a pretty robust cortisol and the patient probably doesn’t have adrenal insufficiency. But if the level is between 5 µg/dL and 15 µg/dL, you’re in a gray zone, and that’s where you might think about doing a stimulation (stim) test.

Dr. Kargi gave us a quick and dirty version of the stim test. Paul, have you had a chance to try this yet?

Dr. Williams: I have not. Have you? I’m sure you’ve been just waiting for the chance.

Dr. Watto: I would love to do this. I don›t know whether I›m set up to do it in the office right now. But this is an aspirational goal for my practice, and I›m sure some physicians are set up in their office already to do it. You can give either intramuscular or subcutaneous cosyntropin 250 µg. You don›t even have to get a baseline cortisol level right before the injection. Let›s say the patient›s previous cortisol level was between 5 µg/dL and 15 µg/dL, so you weren›t sure about the diagnosis. You bring them back to the office one day, give them a shot of cosyntropin, and then 30-60 minutes later, have a random cortisol drawn. If it›s > 19 µg/dL, you›ve ruled out adrenal insufficiency. If it›s anything else, send them to an endocrinologist to sort it out. You might be able to make the diagnosis yourself doing that.

Any treatment pearls to leave the audience with?

Dr. Williams: I hope endocrinologists don›t take issue with this. I say this with respect and admiration, but it feels kind of vibe-based to me. Without a lab value to guide treatment, you are dependent on the patient telling you how they feel much of the time. You have to let their symptoms guide you. It is probably worth noting that because hydrocortisone has a relatively short half-life, within hours, in fact, you typically have to do twice-daily dosing, sometimes even three times daily dosing to get patients to where they feel okay. It sounds like there›s a fair amount of trial and error and some adjustments that you have to make depending on what›s going on with the patient at any given time. You land somewhere between a dose of 15-30 mg per day, but there will be some variability, even within an individual patient, depending on what›s going on with them from a physiologic standpoint.

Dr. Watto: They are going to take one dose in the morning and then a second dose in the afternoon, but they don’t want them to take it too late in the evening because it could cause insomnia, and you want to try to mimic physiologic levels as much as you can. Two thirds of the daily dose is given early in the morning and then another third of the daily dose later in the day if you are prescribing two times daily dosing.

And Dr. Kargi had a low threshold for doubling the dose. If the patient has a cold, double the dose for 2 or 3 days. With a high fever, triple the dose for a few days. If they are going for surgery, they are probably going to be getting some intravenous hydrocortisone while they’re in the hospital.

We really turned over like every stone we could possibly think of on this podcast. There were so many great pearls that we don’t have time to go through them all here. But we talked about steroid tapers and a lot more. You can check it out here.

Dr. Watto has disclosed no relevant financial relationships.

Dr. Williams has disclosed the following relevant financial relationships:Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: The CurbsidersReceived income in an amount equal to or greater than $250 from: The Curbsiders.

A version of this article appeared on Medscape.com.

Matthew F. Watto, MD: Welcome back to The Curbsiders. I’m Dr. Matthew Watto, here with America’s primary care physician, Dr. Paul Nelson Williams. Paul, are you ready to talk about some adrenal insufficiency? We had a great conversation with Dr. Atil Kargi, and I’d like you to start us off.

Paul N. Williams, MD: How about thinking about it? It’s a good place to start.

That’s one of the ways this episode changed my approach a little bit. I never really thought about the fact that many patients present for evaluation of adrenal insufficiency from gastroenterology clinics. It’s such a protean sort of nonspecific presentation. But if you have someone with chronic malaise and poor appetite and maybe unexplained weight loss, and your GI workup is not really leading you anywhere, it’s probably worth thinking about adrenal insufficiency. Even though primary adrenal insufficiency is pretty rare — we’re talking cases per millions — secondary adrenal insufficiency is actually fairly common. It’s probably worth thinking about and testing for more often than I have in the past. So for me, it’s having a lower threshold to start looking for it.

Dr. Watto: When it’s adrenal crisis, you probably think about it, but then it’s too late. Ideally, you would think about it before that happens. But the symptoms can be quite vague. The mineralocorticoid symptoms, like salt cravings, dizziness, near syncope, muscle cramps, might make me think of it because they sound more like something endocrine is going on. But if it’s just a little weight loss, a little fatigue, or a little nausea, that’s everybody.

Dr. Williams: Right. If a patient came to me saying, “I’m craving salt,” that might hasten the workup a little bit, but that’s not the typical presentation.

Dr. Watto: If you are going to check a cortisol level, you should really check it in the morning, between 7 AM and 9 AM. If you check it too early, it might not have peaked yet, so you might get a level that looks low. But if you had checked an hour or 2 later, it might have been above a threshold, and then you would know you could rule out the diagnosis. The cutoffs depend on your source:  < 3-5 µg/dL that early in the morning is pretty much diagnostic of adrenal insufficiency. If it’s > 15 µg/dL, that’s a pretty robust cortisol and the patient probably doesn’t have adrenal insufficiency. But if the level is between 5 µg/dL and 15 µg/dL, you’re in a gray zone, and that’s where you might think about doing a stimulation (stim) test.

Dr. Kargi gave us a quick and dirty version of the stim test. Paul, have you had a chance to try this yet?

Dr. Williams: I have not. Have you? I’m sure you’ve been just waiting for the chance.

Dr. Watto: I would love to do this. I don›t know whether I›m set up to do it in the office right now. But this is an aspirational goal for my practice, and I›m sure some physicians are set up in their office already to do it. You can give either intramuscular or subcutaneous cosyntropin 250 µg. You don›t even have to get a baseline cortisol level right before the injection. Let›s say the patient›s previous cortisol level was between 5 µg/dL and 15 µg/dL, so you weren›t sure about the diagnosis. You bring them back to the office one day, give them a shot of cosyntropin, and then 30-60 minutes later, have a random cortisol drawn. If it›s > 19 µg/dL, you›ve ruled out adrenal insufficiency. If it›s anything else, send them to an endocrinologist to sort it out. You might be able to make the diagnosis yourself doing that.

Any treatment pearls to leave the audience with?

Dr. Williams: I hope endocrinologists don›t take issue with this. I say this with respect and admiration, but it feels kind of vibe-based to me. Without a lab value to guide treatment, you are dependent on the patient telling you how they feel much of the time. You have to let their symptoms guide you. It is probably worth noting that because hydrocortisone has a relatively short half-life, within hours, in fact, you typically have to do twice-daily dosing, sometimes even three times daily dosing to get patients to where they feel okay. It sounds like there›s a fair amount of trial and error and some adjustments that you have to make depending on what›s going on with the patient at any given time. You land somewhere between a dose of 15-30 mg per day, but there will be some variability, even within an individual patient, depending on what›s going on with them from a physiologic standpoint.

Dr. Watto: They are going to take one dose in the morning and then a second dose in the afternoon, but they don’t want them to take it too late in the evening because it could cause insomnia, and you want to try to mimic physiologic levels as much as you can. Two thirds of the daily dose is given early in the morning and then another third of the daily dose later in the day if you are prescribing two times daily dosing.

And Dr. Kargi had a low threshold for doubling the dose. If the patient has a cold, double the dose for 2 or 3 days. With a high fever, triple the dose for a few days. If they are going for surgery, they are probably going to be getting some intravenous hydrocortisone while they’re in the hospital.

We really turned over like every stone we could possibly think of on this podcast. There were so many great pearls that we don’t have time to go through them all here. But we talked about steroid tapers and a lot more. You can check it out here.

Dr. Watto has disclosed no relevant financial relationships.

Dr. Williams has disclosed the following relevant financial relationships:Serve(d) as a director, officer, partner, employee, advisor, consultant, or trustee for: The CurbsidersReceived income in an amount equal to or greater than $250 from: The Curbsiders.

A version of this article appeared on Medscape.com.

Often known as a “silent killer,” ascending thoracic aortic aneurysms (ATAAs) may grow asymptomatically until they rupture, at which point, mortality is over 90%.

But ATAAs may also carry a potential flip side: Apparent protection against the development of atherosclerotic plaque and by extension, for those who have one, a significantly reduced risk for coronary artery disease and myocardial infarction (MI).

“We noticed in the operating room that many patients we worked on who had an ATAA had pristine arteries, like a teenager’s,” said John Elefteriades, MD, William W.L. Glenn Professor of Cardiothoracic Surgery and former chief of cardiothoracic surgery at Yale University and Yale New Haven Hospital, New Haven, Connecticut. “The same was true of the femoral artery, which we use to hook up to the heart-lung machine.”

Elefteriades and colleagues have been investigating the implications of this association for more than two decades. Many of their studies are highlighted in a recent review of the evidence supporting the protective relationship between ATAAs and the development of atherosclerosis and the possible mechanisms driving the relationship.

“We see four different layers of protection,” said Sandip Mukherjee, MD, medical director of the Aortic Institute at Yale New Haven Hospital and a senior editor of the journal AORTA. Mukherjee collaborated with Elefteriades on many of the studies.

The first layer of protection is lower intima-media thickness, specifically, 0.131 mm lower than in individuals without an ATAA. “It may not seem like very much, but one point can actually translate into a 13%-15% decline in the rate of myocardial infarction or stroke,” Dr. Mukherjee said.

The second layer is lower levels of low-density lipoprotein (LDL) cholesterol. Lower LDL cholesterol levels (75 mg/dL) were associated with increased odds of ATAAs (odds ratio [OR], 1.21), whereas elevated levels (150 mg/dL and 200 mg/dL) were associated with decreased odds of ATAAs (OR, 0.62 and 0.29, respectively).

Lower calcification scores for the coronary arteries are the third layer of protection (6.73 vs 9.36 in one study).

The fourth protective layer is a significantly reduced prevalence of coronary artery disease. A study of individuals with ATAA compared to controls found 61 of those with ATAA had coronary artery disease vs 140 of controls, and 11 vs 83 had experienced an MI. Of note, patients with ATAAs were protected despite having higher body mass indices than controls.

Other MI risk factors such as age increased the risk even among those with an ATAA but, again, much less so than among controls; a multivariable binary logistic regression of data in the team’s review showed that patients with ATAAs were 298, 250, and 232 times less likely to have an MI than if they had a family history of MI, dyslipidemia, or hypertension, respectively.

Why the Protection?

The ligamentum arteriosum separates the ascending from the descending (thoracoabdominal) aorta. ATAAs, located above the ligamentum, tend to be pro-aneurysmal but anti-atherosclerotic. In the descending aorta, below the ligamentum, atherosclerotic aneurysms develop.

The differences between the two sections of the aorta originate in the germ layer in the embryo, Dr. Elefteriades said. “The fundamental difference in tissue of origin translates into marked differences in the character of aneurysms in the different aortic segments.”

What specifically underlies the reduced cardiovascular risk? “We don’t really know, but we think that there may be two possible etiologies,” Dr. Mukherjee said. One hypothesis involves transforming growth factor–beta (TGF-beta), which is overexpressed in patients with ATAA and seems to increase their vulnerability to aneurysms while also conferring protection from coronary disease risk.

Some studies have shown differences in cellular responses to TGF-beta between the thoracic and abdominal aorta, including collagen production and contractility. Others have shown that some patients who have had an MI have polymorphisms that decrease their levels of TGF-beta.

Furthermore, TGF-beta plays a key role in the development of the intimal layer, which could underpin the lack of intimal thickening in patients with ATAA.

But overall, studies have been mixed and challenging to interpret, Dr. Elefteriades and Dr. Mukherjee agreed. TGF-beta has multiple remodeling roles in the body, and it is difficult at this point to isolate its exact role in aortic disease.

Another hypothesis involves matrix metalloproteinases (MMPs), which are dysregulated in patients with ATAA and may confer some protection, Mukherjee said. Several studies have shown higher plasma levels of certain MMPs in patients with ATAAs. MMPs also were found to be elevated in the thoracic aortic walls of patients with ATAA who had an aortic dissection, as well as in the aortic smooth muscle cells in the intima and media.

In addition, some studies have shown increased levels of MMP-2 in the aortas of patients with ATAAs compared with patients with coronary artery disease.

Adding to the mix of possibilities, “We recently found a gene that’s dysregulated in our aneurysm patients that is very intimately related to atherosclerosis,” Dr. Elefteriades said. “But the work is too preliminary to say anything more at this point.”

“It would be fabulous to prove what it is causing this protection,” Dr. Mukherjee added. “But the truth is we don’t know. These are hypotheses.”

“The most important message from our work is that most clinicians need to dissociate an ATAA from the concept of atherosclerosis,” Dr. Elefteriades said. “The ascending aorta is not an atherosclerotic phenomenon.”

How to Manage Patients With ATAA

What does the distinct character of ATAAs mean for patient management? “Finding a drug to treat ATAAs — to prevent growth, rupture, or dissection — has been like a search for the Holy Grail,” Dr. Elefteriades said. “Statins are not necessary, as this is a non-atherosclerotic process. Although sporadic studies have reported beneficial effects from beta-blockers or angiotensin II receptor blockers (ARBs), this has often been based on ‘soft’ evidence, requiring a combination of outcome measures to achieve significance.”

That said, he noted, “The mainstay, common sense treatment is to keep blood pressure controlled. This is usually achieved by a beta-blocker and an ARB, even if the benefit is not via a direct biologic effect on the aneurysmal degenerative process, but via simple hemodynamics — discouraging rupture by keeping pressure in the aorta low.”

Dr. Mukherjee suggested that these patients should be referred to a specialty aneurysm center where their genes will be evaluated, and then the aneurysm will be followed very closely.

“If the aneurysm is larger than 4.5 cm, we screen the patient every single year, and if they have chest pain, we treat them the same way as we treat other aneurysms,” he said. “As a rule of thumb, if the aneurysm reaches 5 cm, it should come out, although the size at which this should happen may differ between 4.5 cm and 5.5 cm, depending on the patient’s body size.”

As for lifestyle management, Dr. Elefteriades said, “Protection from atherosclerosis and MI won’t go away after the aneurysm is removed. We think it’s in the body’s chemistry. But even though it’s very hard for those patients to have a heart attack, we don’t recommend they eat roast beef every night — although I do think they’d be protected from such lifestyle aberrations.”

For now, he added, “Our team is on a hunt to find a drug to treat ascending disease directly and effectively. We have ongoing laboratory experiments with two drugs undergoing investigation at some level. We hope to embark soon on clinical trials.”

‘A Milestone’

James Hamilton Black III, MD, vice chair of the writing committee for the 2022 American College of Cardiology/American Heart Association Aortic Disease Guideline and chief of Division of Vascular Surgery and Endovascular Therapy at Johns Hopkins Medicine, Baltimore, commented on the review and the concept of ATAA’s atherosclerotic protection.

“The association of ascending aortic aneurysms with a lower risk for MI is an interesting one, but it’s probably influenced, at least in part, by the patient population.” That population is at least partially curated since people are coming to an academic center. In addition, Dr. Black noted, “the patients with ATAAs are younger, and so age may be a confounding factor in the analyses. We wouldn’t expect them to have the same burden of atherosclerosis” as older patients.

Nevertheless, he said, “the findings speak to an emerging body of literature suggesting that although the aorta is a single organ, there are certainly different areas, and these would respond quite differently to environmental or genetic or heritable stressors. This isn’t surprising, and there probably are a lot of factors involved.”

Overall, he said, the findings underscore “the precision medicine approaches we need to take with patients with aortic diseases.”

In a commentary on the team’s review article, published in 2022, John G.T. Augoustides, MD, professor of anesthesiology and critical care at the Perelman School of Medicine in Philadelphia, Pennsylvania, suggested that ATAA’s “silver lining” could advance the understanding of thoracic aortic aneurysm (TAA) management, be integrated with the expanding horizons in hereditary thoracic aortic disease, and might be explored in the context of bicuspid aortic valve disease.

Highlighting the “relative absence” of atherosclerosis in ascending aortic aneurysms and its importance is a “milestone in our understanding,” he concluded. “It is likely that future advances in TAAs will be significantly influenced by this observation.”

Dr. Elefteriades, Dr. Mukherjee, and Dr. Black have no relevant conflicts of interest.

A version of this article appeared on Medscape.com.

Often known as a “silent killer,” ascending thoracic aortic aneurysms (ATAAs) may grow asymptomatically until they rupture, at which point, mortality is over 90%.

But ATAAs may also carry a potential flip side: Apparent protection against the development of atherosclerotic plaque and by extension, for those who have one, a significantly reduced risk for coronary artery disease and myocardial infarction (MI).

“We noticed in the operating room that many patients we worked on who had an ATAA had pristine arteries, like a teenager’s,” said John Elefteriades, MD, William W.L. Glenn Professor of Cardiothoracic Surgery and former chief of cardiothoracic surgery at Yale University and Yale New Haven Hospital, New Haven, Connecticut. “The same was true of the femoral artery, which we use to hook up to the heart-lung machine.”

Elefteriades and colleagues have been investigating the implications of this association for more than two decades. Many of their studies are highlighted in a recent review of the evidence supporting the protective relationship between ATAAs and the development of atherosclerosis and the possible mechanisms driving the relationship.

“We see four different layers of protection,” said Sandip Mukherjee, MD, medical director of the Aortic Institute at Yale New Haven Hospital and a senior editor of the journal AORTA. Mukherjee collaborated with Elefteriades on many of the studies.

The first layer of protection is lower intima-media thickness, specifically, 0.131 mm lower than in individuals without an ATAA. “It may not seem like very much, but one point can actually translate into a 13%-15% decline in the rate of myocardial infarction or stroke,” Dr. Mukherjee said.

The second layer is lower levels of low-density lipoprotein (LDL) cholesterol. Lower LDL cholesterol levels (75 mg/dL) were associated with increased odds of ATAAs (odds ratio [OR], 1.21), whereas elevated levels (150 mg/dL and 200 mg/dL) were associated with decreased odds of ATAAs (OR, 0.62 and 0.29, respectively).

Lower calcification scores for the coronary arteries are the third layer of protection (6.73 vs 9.36 in one study).

The fourth protective layer is a significantly reduced prevalence of coronary artery disease. A study of individuals with ATAA compared to controls found 61 of those with ATAA had coronary artery disease vs 140 of controls, and 11 vs 83 had experienced an MI. Of note, patients with ATAAs were protected despite having higher body mass indices than controls.

Other MI risk factors such as age increased the risk even among those with an ATAA but, again, much less so than among controls; a multivariable binary logistic regression of data in the team’s review showed that patients with ATAAs were 298, 250, and 232 times less likely to have an MI than if they had a family history of MI, dyslipidemia, or hypertension, respectively.

Why the Protection?

The ligamentum arteriosum separates the ascending from the descending (thoracoabdominal) aorta. ATAAs, located above the ligamentum, tend to be pro-aneurysmal but anti-atherosclerotic. In the descending aorta, below the ligamentum, atherosclerotic aneurysms develop.

The differences between the two sections of the aorta originate in the germ layer in the embryo, Dr. Elefteriades said. “The fundamental difference in tissue of origin translates into marked differences in the character of aneurysms in the different aortic segments.”

What specifically underlies the reduced cardiovascular risk? “We don’t really know, but we think that there may be two possible etiologies,” Dr. Mukherjee said. One hypothesis involves transforming growth factor–beta (TGF-beta), which is overexpressed in patients with ATAA and seems to increase their vulnerability to aneurysms while also conferring protection from coronary disease risk.

Some studies have shown differences in cellular responses to TGF-beta between the thoracic and abdominal aorta, including collagen production and contractility. Others have shown that some patients who have had an MI have polymorphisms that decrease their levels of TGF-beta.

Furthermore, TGF-beta plays a key role in the development of the intimal layer, which could underpin the lack of intimal thickening in patients with ATAA.

But overall, studies have been mixed and challenging to interpret, Dr. Elefteriades and Dr. Mukherjee agreed. TGF-beta has multiple remodeling roles in the body, and it is difficult at this point to isolate its exact role in aortic disease.

Another hypothesis involves matrix metalloproteinases (MMPs), which are dysregulated in patients with ATAA and may confer some protection, Mukherjee said. Several studies have shown higher plasma levels of certain MMPs in patients with ATAAs. MMPs also were found to be elevated in the thoracic aortic walls of patients with ATAA who had an aortic dissection, as well as in the aortic smooth muscle cells in the intima and media.

In addition, some studies have shown increased levels of MMP-2 in the aortas of patients with ATAAs compared with patients with coronary artery disease.

Adding to the mix of possibilities, “We recently found a gene that’s dysregulated in our aneurysm patients that is very intimately related to atherosclerosis,” Dr. Elefteriades said. “But the work is too preliminary to say anything more at this point.”

“It would be fabulous to prove what it is causing this protection,” Dr. Mukherjee added. “But the truth is we don’t know. These are hypotheses.”

“The most important message from our work is that most clinicians need to dissociate an ATAA from the concept of atherosclerosis,” Dr. Elefteriades said. “The ascending aorta is not an atherosclerotic phenomenon.”

How to Manage Patients With ATAA

What does the distinct character of ATAAs mean for patient management? “Finding a drug to treat ATAAs — to prevent growth, rupture, or dissection — has been like a search for the Holy Grail,” Dr. Elefteriades said. “Statins are not necessary, as this is a non-atherosclerotic process. Although sporadic studies have reported beneficial effects from beta-blockers or angiotensin II receptor blockers (ARBs), this has often been based on ‘soft’ evidence, requiring a combination of outcome measures to achieve significance.”

That said, he noted, “The mainstay, common sense treatment is to keep blood pressure controlled. This is usually achieved by a beta-blocker and an ARB, even if the benefit is not via a direct biologic effect on the aneurysmal degenerative process, but via simple hemodynamics — discouraging rupture by keeping pressure in the aorta low.”

Dr. Mukherjee suggested that these patients should be referred to a specialty aneurysm center where their genes will be evaluated, and then the aneurysm will be followed very closely.

“If the aneurysm is larger than 4.5 cm, we screen the patient every single year, and if they have chest pain, we treat them the same way as we treat other aneurysms,” he said. “As a rule of thumb, if the aneurysm reaches 5 cm, it should come out, although the size at which this should happen may differ between 4.5 cm and 5.5 cm, depending on the patient’s body size.”

As for lifestyle management, Dr. Elefteriades said, “Protection from atherosclerosis and MI won’t go away after the aneurysm is removed. We think it’s in the body’s chemistry. But even though it’s very hard for those patients to have a heart attack, we don’t recommend they eat roast beef every night — although I do think they’d be protected from such lifestyle aberrations.”

For now, he added, “Our team is on a hunt to find a drug to treat ascending disease directly and effectively. We have ongoing laboratory experiments with two drugs undergoing investigation at some level. We hope to embark soon on clinical trials.”

‘A Milestone’

James Hamilton Black III, MD, vice chair of the writing committee for the 2022 American College of Cardiology/American Heart Association Aortic Disease Guideline and chief of Division of Vascular Surgery and Endovascular Therapy at Johns Hopkins Medicine, Baltimore, commented on the review and the concept of ATAA’s atherosclerotic protection.

“The association of ascending aortic aneurysms with a lower risk for MI is an interesting one, but it’s probably influenced, at least in part, by the patient population.” That population is at least partially curated since people are coming to an academic center. In addition, Dr. Black noted, “the patients with ATAAs are younger, and so age may be a confounding factor in the analyses. We wouldn’t expect them to have the same burden of atherosclerosis” as older patients.

Nevertheless, he said, “the findings speak to an emerging body of literature suggesting that although the aorta is a single organ, there are certainly different areas, and these would respond quite differently to environmental or genetic or heritable stressors. This isn’t surprising, and there probably are a lot of factors involved.”

Overall, he said, the findings underscore “the precision medicine approaches we need to take with patients with aortic diseases.”

In a commentary on the team’s review article, published in 2022, John G.T. Augoustides, MD, professor of anesthesiology and critical care at the Perelman School of Medicine in Philadelphia, Pennsylvania, suggested that ATAA’s “silver lining” could advance the understanding of thoracic aortic aneurysm (TAA) management, be integrated with the expanding horizons in hereditary thoracic aortic disease, and might be explored in the context of bicuspid aortic valve disease.

Highlighting the “relative absence” of atherosclerosis in ascending aortic aneurysms and its importance is a “milestone in our understanding,” he concluded. “It is likely that future advances in TAAs will be significantly influenced by this observation.”

Dr. Elefteriades, Dr. Mukherjee, and Dr. Black have no relevant conflicts of interest.

A version of this article appeared on Medscape.com.

Often known as a “silent killer,” ascending thoracic aortic aneurysms (ATAAs) may grow asymptomatically until they rupture, at which point, mortality is over 90%.

But ATAAs may also carry a potential flip side: Apparent protection against the development of atherosclerotic plaque and by extension, for those who have one, a significantly reduced risk for coronary artery disease and myocardial infarction (MI).

“We noticed in the operating room that many patients we worked on who had an ATAA had pristine arteries, like a teenager’s,” said John Elefteriades, MD, William W.L. Glenn Professor of Cardiothoracic Surgery and former chief of cardiothoracic surgery at Yale University and Yale New Haven Hospital, New Haven, Connecticut. “The same was true of the femoral artery, which we use to hook up to the heart-lung machine.”

Elefteriades and colleagues have been investigating the implications of this association for more than two decades. Many of their studies are highlighted in a recent review of the evidence supporting the protective relationship between ATAAs and the development of atherosclerosis and the possible mechanisms driving the relationship.

“We see four different layers of protection,” said Sandip Mukherjee, MD, medical director of the Aortic Institute at Yale New Haven Hospital and a senior editor of the journal AORTA. Mukherjee collaborated with Elefteriades on many of the studies.

The first layer of protection is lower intima-media thickness, specifically, 0.131 mm lower than in individuals without an ATAA. “It may not seem like very much, but one point can actually translate into a 13%-15% decline in the rate of myocardial infarction or stroke,” Dr. Mukherjee said.

The second layer is lower levels of low-density lipoprotein (LDL) cholesterol. Lower LDL cholesterol levels (75 mg/dL) were associated with increased odds of ATAAs (odds ratio [OR], 1.21), whereas elevated levels (150 mg/dL and 200 mg/dL) were associated with decreased odds of ATAAs (OR, 0.62 and 0.29, respectively).

Lower calcification scores for the coronary arteries are the third layer of protection (6.73 vs 9.36 in one study).

The fourth protective layer is a significantly reduced prevalence of coronary artery disease. A study of individuals with ATAA compared to controls found 61 of those with ATAA had coronary artery disease vs 140 of controls, and 11 vs 83 had experienced an MI. Of note, patients with ATAAs were protected despite having higher body mass indices than controls.

Other MI risk factors such as age increased the risk even among those with an ATAA but, again, much less so than among controls; a multivariable binary logistic regression of data in the team’s review showed that patients with ATAAs were 298, 250, and 232 times less likely to have an MI than if they had a family history of MI, dyslipidemia, or hypertension, respectively.

Why the Protection?

The ligamentum arteriosum separates the ascending from the descending (thoracoabdominal) aorta. ATAAs, located above the ligamentum, tend to be pro-aneurysmal but anti-atherosclerotic. In the descending aorta, below the ligamentum, atherosclerotic aneurysms develop.

The differences between the two sections of the aorta originate in the germ layer in the embryo, Dr. Elefteriades said. “The fundamental difference in tissue of origin translates into marked differences in the character of aneurysms in the different aortic segments.”

What specifically underlies the reduced cardiovascular risk? “We don’t really know, but we think that there may be two possible etiologies,” Dr. Mukherjee said. One hypothesis involves transforming growth factor–beta (TGF-beta), which is overexpressed in patients with ATAA and seems to increase their vulnerability to aneurysms while also conferring protection from coronary disease risk.

Some studies have shown differences in cellular responses to TGF-beta between the thoracic and abdominal aorta, including collagen production and contractility. Others have shown that some patients who have had an MI have polymorphisms that decrease their levels of TGF-beta.

Furthermore, TGF-beta plays a key role in the development of the intimal layer, which could underpin the lack of intimal thickening in patients with ATAA.

But overall, studies have been mixed and challenging to interpret, Dr. Elefteriades and Dr. Mukherjee agreed. TGF-beta has multiple remodeling roles in the body, and it is difficult at this point to isolate its exact role in aortic disease.

Another hypothesis involves matrix metalloproteinases (MMPs), which are dysregulated in patients with ATAA and may confer some protection, Mukherjee said. Several studies have shown higher plasma levels of certain MMPs in patients with ATAAs. MMPs also were found to be elevated in the thoracic aortic walls of patients with ATAA who had an aortic dissection, as well as in the aortic smooth muscle cells in the intima and media.

In addition, some studies have shown increased levels of MMP-2 in the aortas of patients with ATAAs compared with patients with coronary artery disease.

Adding to the mix of possibilities, “We recently found a gene that’s dysregulated in our aneurysm patients that is very intimately related to atherosclerosis,” Dr. Elefteriades said. “But the work is too preliminary to say anything more at this point.”

“It would be fabulous to prove what it is causing this protection,” Dr. Mukherjee added. “But the truth is we don’t know. These are hypotheses.”

“The most important message from our work is that most clinicians need to dissociate an ATAA from the concept of atherosclerosis,” Dr. Elefteriades said. “The ascending aorta is not an atherosclerotic phenomenon.”

How to Manage Patients With ATAA

What does the distinct character of ATAAs mean for patient management? “Finding a drug to treat ATAAs — to prevent growth, rupture, or dissection — has been like a search for the Holy Grail,” Dr. Elefteriades said. “Statins are not necessary, as this is a non-atherosclerotic process. Although sporadic studies have reported beneficial effects from beta-blockers or angiotensin II receptor blockers (ARBs), this has often been based on ‘soft’ evidence, requiring a combination of outcome measures to achieve significance.”

That said, he noted, “The mainstay, common sense treatment is to keep blood pressure controlled. This is usually achieved by a beta-blocker and an ARB, even if the benefit is not via a direct biologic effect on the aneurysmal degenerative process, but via simple hemodynamics — discouraging rupture by keeping pressure in the aorta low.”

Dr. Mukherjee suggested that these patients should be referred to a specialty aneurysm center where their genes will be evaluated, and then the aneurysm will be followed very closely.

“If the aneurysm is larger than 4.5 cm, we screen the patient every single year, and if they have chest pain, we treat them the same way as we treat other aneurysms,” he said. “As a rule of thumb, if the aneurysm reaches 5 cm, it should come out, although the size at which this should happen may differ between 4.5 cm and 5.5 cm, depending on the patient’s body size.”

As for lifestyle management, Dr. Elefteriades said, “Protection from atherosclerosis and MI won’t go away after the aneurysm is removed. We think it’s in the body’s chemistry. But even though it’s very hard for those patients to have a heart attack, we don’t recommend they eat roast beef every night — although I do think they’d be protected from such lifestyle aberrations.”

For now, he added, “Our team is on a hunt to find a drug to treat ascending disease directly and effectively. We have ongoing laboratory experiments with two drugs undergoing investigation at some level. We hope to embark soon on clinical trials.”

‘A Milestone’

James Hamilton Black III, MD, vice chair of the writing committee for the 2022 American College of Cardiology/American Heart Association Aortic Disease Guideline and chief of Division of Vascular Surgery and Endovascular Therapy at Johns Hopkins Medicine, Baltimore, commented on the review and the concept of ATAA’s atherosclerotic protection.

“The association of ascending aortic aneurysms with a lower risk for MI is an interesting one, but it’s probably influenced, at least in part, by the patient population.” That population is at least partially curated since people are coming to an academic center. In addition, Dr. Black noted, “the patients with ATAAs are younger, and so age may be a confounding factor in the analyses. We wouldn’t expect them to have the same burden of atherosclerosis” as older patients.

Nevertheless, he said, “the findings speak to an emerging body of literature suggesting that although the aorta is a single organ, there are certainly different areas, and these would respond quite differently to environmental or genetic or heritable stressors. This isn’t surprising, and there probably are a lot of factors involved.”

Overall, he said, the findings underscore “the precision medicine approaches we need to take with patients with aortic diseases.”

In a commentary on the team’s review article, published in 2022, John G.T. Augoustides, MD, professor of anesthesiology and critical care at the Perelman School of Medicine in Philadelphia, Pennsylvania, suggested that ATAA’s “silver lining” could advance the understanding of thoracic aortic aneurysm (TAA) management, be integrated with the expanding horizons in hereditary thoracic aortic disease, and might be explored in the context of bicuspid aortic valve disease.

Highlighting the “relative absence” of atherosclerosis in ascending aortic aneurysms and its importance is a “milestone in our understanding,” he concluded. “It is likely that future advances in TAAs will be significantly influenced by this observation.”

Dr. Elefteriades, Dr. Mukherjee, and Dr. Black have no relevant conflicts of interest.

A version of this article appeared on Medscape.com.