Clinical Review

In 2009, the Lancet called climate change the biggest global health threat of the 21st century, the effects of which will be experienced in our lifetimes.¹ Significant amounts of data have demonstrated the negative health effects of heat, air pollution, and exposure to toxic substances.^2,3 These effects have been seen in every geographic region of the United States, and in multiple organ systems and specialties, including obstetrics, pediatrics, and even cardiopulmonary and bariatric surgery.^2-5

Although it does not receive the scrutiny of other industries, the global health care industry accounts for almost double the amount of carbon emissions as global aviation, and the United States accounts for 27% of this footprint despite only having 4% of the world’s population.⁶ It therefore serves that our own industry is an excellent target for reducing the carbon emissions that contribute to climate change. Consider the climate impact of hysterectomy, the second-most common surgery that women undergo. In this article, we will use the example of a 50-year-old woman with fibroids who plans to undergo definitive treatment via total laparoscopic hysterectomy (TLH).

Climate impact of US health care

Hospital buildings in the United States are energy intensive, consuming 10% of the energy used in commercial buildings every year, accounting for over $8 billion. Operating rooms (ORs) account for a third of this usage.⁷ Hospitals also use more water than any other type of commercial building, for necessary actions like cooling, sterilization, and laundry.⁸ Further, US hospitals generate 14,000 tons of waste per day, with a third of this coming from the ORs. Sadly, up to 15% is food waste, as we are not very good about selecting and proportioning healthy food for our staff and inpatients.⁶

While health care is utility intensive, the majority of emissions are created through the production, transport, and disposal of goods coming through our supply chain.⁶ Hospitals are significant consumers of single-use objects, the majority of which are petroleum-derived plastics—accounting for an estimated 71% of emissions coming from the health care sector. Supply chain is the second largest expense in health care, but with current shortages, it is estimated to overtake labor costs by this year. The United States is also the largest consumer of pharmaceuticals worldwide, supporting a $20 billion packaging industry,⁹ which creates a significant amount of waste.

Climate impact of the OR

Although ORs only account for a small portion of hospital square footage, they account for a significant amount of health care’s carbon footprint through high waste production and excessive consumption of single-use items. Just one surgical procedure in a hospital is estimated to produce about the same amount of waste as a typical family of 4 would in an entire week.¹⁰ Furthermore, the majority of these single-use items, including sterile packaging, are sorted inappropriately as regulated medical waste (RMW, “biohazardous” or “red bag” waste) (FIGURE 1a). RMW has significant effects on the environment since it must be incinerated or steam autoclaved prior to transport to the landfill, leading to high amounts of air pollution and energy usage.

We all notice the visible impacts of waste in the OR, but other contributors to carbon emissions are invisible. Energy consumption is a huge contributor to the overall carbon footprint of surgery. Heating, ventilation, and air conditioning [HVAC] is responsible for 52% of hospital energy needs but accounts for 99% of OR energy consumption.¹¹ Despite the large energy requirements of the ORs, they are largely unoccupied in the evenings and on weekends, and thermostats are not adjusted accordingly.

Anesthetic gases are another powerful contributor to greenhouse gas emissions from the OR. Anesthetic gases alone contribute about 25% of the overall carbon footprint of the OR, and US health care emits 660,000 tons of carbon equivalents from anesthetic gas use per year.¹² Desflurane is 1,600 times more potent than carbon dioxide (CO₂) in its global warming potential followed by isoflurane and sevoflurane;¹³ this underscores the importance of working with our anesthesia colleagues on the differences between the anesthetic gases they use. Enhanced recovery after surgery recommendations in gynecology already recommend avoiding the use of volatile anesthetic gases in favor of propofol to reduce postoperative nausea and vomiting.¹⁴

In the context of a patient undergoing a TLH, the estimated carbon footprint in the United States is about 560 kg of CO₂ equivalents—roughly the same as driving 1,563 miles in a gas-powered car.

Continue to: Climate impact on our patients...

 

 

Climate impact on our patients

The data in obstetrics and gynecology is clear that climate change is affecting patient outcomes, both globally and in our own country. A systematic review of 32 million births found that air pollution and heat exposure were associated with preterm birth and low birth weight, and these effects were seen in all geographic regions across the United States.¹ A study of 5.9 million births in California found that patients who lived near coal- and oil-power plants had up to a 27% reduction in preterm births when those power plants closed and air pollution decreased.¹⁵ A study in Nature Sustainability on 250,000 pregnancies that ended in missed abortions at 14 weeks or less found the odds ratio of missed abortion increased with the cumulative exposure to air pollution.¹⁶ When air pollution was examined in comparison to other factors, neighborhood air pollution better predicted preterm birth, very preterm birth, and small for gestational age more than race, ethnicity, or any other socio-economic factor.¹⁷ The effects of air pollution have been demonstrated in other fields as well, including increased mortality after cardiac transplantation with exposure to air pollution,⁴ and for patients undergoing bariatric surgery who live near major roadways, decreased weight loss, less improvement in hemoglobin A_1c, and less change in lipids compared with those with less exposure to roadway pollution.⁵

Air pollution and heat are not the only factors that influence health. Endocrine disrupting chemicals (EDCs) and single-use plastic polymers, which are used in significant supply in US health care, have been found in human blood,¹⁸ intestine, and all portions of the placenta.¹⁹ Phthalates, an EDC found in medical use plastics and medications to control delivery, have been associated with increasing fibroid burden in patients undergoing hysterectomy and myomectomy.²⁰ The example case patient with fibroids undergoing TLH may have had her condition worsened by exposure to phthalates.

Specific areas for improvement

There is a huge opportunity for improvement to reduce the total carbon footprint of a TLH.

A lifecycle assessment of hysterectomy in the United States concluded that an 80% reduction in carbon emissions could be achieved by minimizing opened materials, using reusable and reprocessed instruments, reducing off-hour energy use in the OR (HVAC setbacks), and avoiding the use of volatile anesthetic gases.²¹ The sterilization and re-processing of reusable instruments represented the smallest proportion of carbon emissions from a TLH. Data on patient safety supports these interventions, as current practices have more to do with hospital culture and processes than evidence.

Despite a push to use single-use objects by industry and regulatory agencies in the name of patient safety, data demonstrate that single-use objects are in actuality not safer for patients and may be associated with increased surgical site infections (SSIs). A study from a cancer center in California found that when single-use head covers, shoe covers, and facemasks were eliminated due to supply shortages during the pandemic, SSIs went down by half, despite an increase in surgical volume and an increase in the number of contaminated cases.²² The authors reported an increase in hand hygiene throughout the hospital, which likely contributed to the success of reducing SSIs.

Similarly, a systematic review found no evidence to support single-use instruments over reusable or reprocessed instruments when considering instrument function, ease of use, patient safety, SSIs, or long-term patient outcomes.²³ While it may be easy for regulatory agencies to focus on disposing objects as paramount to reducing infections, the Centers for Disease Control and Prevention states that the biggest factors affecting SSIs are appropriate use of prophylactic antibiotics, skin antisepsis, and patient metabolic control.²⁴ Disposing of single-use objects in the name of patient safety will worsen patient health outcomes when considering patient proximity to waste, pollution, and EDCs.

The sterilization process for reusable items is often called out by the medical supply industry as wasteful and energy intensive; however, data refute these claims. A Swedish study researching reusable versus single-use trocars found that a reusable trocar system offers a robust opportunity to reduce both the environmental and financial costs for laparoscopic surgery.²⁵ We can further decrease the environmental impact of reusable instruments by using sets instead of individually packed instruments and packing autoclaves more efficiently. By using rigid sterilization containers, there was an 85% reduction in carbon footprint as compared with the blue wrap system.

Electricity use can be easily reduced across all surgical spaces by performing HVAC setbacks during low occupancy times of day. On nights and weekends, when there are very few surgical cases occurring, one study found that by decreasing the ventilation rate, turning off lights, and performing the minimum temperature control in unused ORs, electricity use was cut in half.¹¹

Waste triage and recycling

Reducing regulated medical waste is another area where hospitals can make a huge impact on carbon emissions and costs with little more than education and process change. Guidelines for regulated medical waste sorting developed out of the HIV epidemic due to the fear of blood products. Although studies show that regulated medical waste is not more infectious than household waste, state departments of public health have kept these guidelines in place for sorting fluid blood and tissue into RMW containers and bags.²⁶ The best hospital performers keep RMW below 10% of the total waste stream, while many ORs send close to 100% of their waste as RMW (FIGURE 1b). ORs can work with nursing and environmental services staff to assess processes and divert waste into recycling and regular waste. Many OR staff are acutely aware of the huge amount of waste produced and want to make a positive impact. Success in this small area often builds momentum to tackle harder sustainability practices throughout the hospital.

Continue to: Removal of EDCs from medical products...

Removal of EDCs from medical products

Single-use medical supplies are not only wasteful but also contain harmful EDCs, such as phthalates, bisphenol A (BPA), parabens, perfluoroalkyl substances, and triclosan. Phthalates, for example, account for 30% to 40% of the weight of medical-use plastics, and parabens are ubiquitously found in ultrasound gel.³ Studies looking at exposure to EDCs within the neonatal intensive care unit reveal substantial BPA, phthalate, and paraben levels within biologic samples from premature infants, thought to be above toxicity limits. While we do not know the full extent to which EDCs can affect neonatal development, there is already mounting evidence that EDCs are associated with endocrine, metabolic, and neurodevelopmental disorders throughout our lifespan.³

30-day climate challenge

Although the example case patient undergoing TLH for fibroids will never need care for her fibroids again, the climate impact of her time in the OR represents the most carbon-intensive care she will ever need. Surgery as practiced in the United States today is unsustainable.

In 2021, the Biden administration issued an executive order requiring all federal facilities, including health care facilities and hospitals, to be carbon neutral by 2035. In order to make meaningful changes industry-wide, we should be petitioning lawmakers for stricter environmental regulations in health care, similar to regulations in the manufacturing and airline industries. We recommend a 30-day climate challenge (FIGURE 2) for bringing awareness to your circles of influence. Physicians have an ethical duty to advocate for change at the local, regional, and national level if we want to see a better future for our patients, their children, and even ourselves. Organizations such as Practice Greenhealth, Health Care without Harm, and Citizens’ Climate Lobby can help amplify our voices to reach the right people to implement sweeping policy changes. ●

In 2009, the Lancet called climate change the biggest global health threat of the 21st century, the effects of which will be experienced in our lifetimes.¹ Significant amounts of data have demonstrated the negative health effects of heat, air pollution, and exposure to toxic substances.^2,3 These effects have been seen in every geographic region of the United States, and in multiple organ systems and specialties, including obstetrics, pediatrics, and even cardiopulmonary and bariatric surgery.^2-5

Although it does not receive the scrutiny of other industries, the global health care industry accounts for almost double the amount of carbon emissions as global aviation, and the United States accounts for 27% of this footprint despite only having 4% of the world’s population.⁶ It therefore serves that our own industry is an excellent target for reducing the carbon emissions that contribute to climate change. Consider the climate impact of hysterectomy, the second-most common surgery that women undergo. In this article, we will use the example of a 50-year-old woman with fibroids who plans to undergo definitive treatment via total laparoscopic hysterectomy (TLH).

Climate impact of US health care

Hospital buildings in the United States are energy intensive, consuming 10% of the energy used in commercial buildings every year, accounting for over $8 billion. Operating rooms (ORs) account for a third of this usage.⁷ Hospitals also use more water than any other type of commercial building, for necessary actions like cooling, sterilization, and laundry.⁸ Further, US hospitals generate 14,000 tons of waste per day, with a third of this coming from the ORs. Sadly, up to 15% is food waste, as we are not very good about selecting and proportioning healthy food for our staff and inpatients.⁶

While health care is utility intensive, the majority of emissions are created through the production, transport, and disposal of goods coming through our supply chain.⁶ Hospitals are significant consumers of single-use objects, the majority of which are petroleum-derived plastics—accounting for an estimated 71% of emissions coming from the health care sector. Supply chain is the second largest expense in health care, but with current shortages, it is estimated to overtake labor costs by this year. The United States is also the largest consumer of pharmaceuticals worldwide, supporting a $20 billion packaging industry,⁹ which creates a significant amount of waste.

Climate impact of the OR

Although ORs only account for a small portion of hospital square footage, they account for a significant amount of health care’s carbon footprint through high waste production and excessive consumption of single-use items. Just one surgical procedure in a hospital is estimated to produce about the same amount of waste as a typical family of 4 would in an entire week.¹⁰ Furthermore, the majority of these single-use items, including sterile packaging, are sorted inappropriately as regulated medical waste (RMW, “biohazardous” or “red bag” waste) (FIGURE 1a). RMW has significant effects on the environment since it must be incinerated or steam autoclaved prior to transport to the landfill, leading to high amounts of air pollution and energy usage.

We all notice the visible impacts of waste in the OR, but other contributors to carbon emissions are invisible. Energy consumption is a huge contributor to the overall carbon footprint of surgery. Heating, ventilation, and air conditioning [HVAC] is responsible for 52% of hospital energy needs but accounts for 99% of OR energy consumption.¹¹ Despite the large energy requirements of the ORs, they are largely unoccupied in the evenings and on weekends, and thermostats are not adjusted accordingly.

Anesthetic gases are another powerful contributor to greenhouse gas emissions from the OR. Anesthetic gases alone contribute about 25% of the overall carbon footprint of the OR, and US health care emits 660,000 tons of carbon equivalents from anesthetic gas use per year.¹² Desflurane is 1,600 times more potent than carbon dioxide (CO₂) in its global warming potential followed by isoflurane and sevoflurane;¹³ this underscores the importance of working with our anesthesia colleagues on the differences between the anesthetic gases they use. Enhanced recovery after surgery recommendations in gynecology already recommend avoiding the use of volatile anesthetic gases in favor of propofol to reduce postoperative nausea and vomiting.¹⁴

In the context of a patient undergoing a TLH, the estimated carbon footprint in the United States is about 560 kg of CO₂ equivalents—roughly the same as driving 1,563 miles in a gas-powered car.

Continue to: Climate impact on our patients...

 

 

Climate impact on our patients

The data in obstetrics and gynecology is clear that climate change is affecting patient outcomes, both globally and in our own country. A systematic review of 32 million births found that air pollution and heat exposure were associated with preterm birth and low birth weight, and these effects were seen in all geographic regions across the United States.¹ A study of 5.9 million births in California found that patients who lived near coal- and oil-power plants had up to a 27% reduction in preterm births when those power plants closed and air pollution decreased.¹⁵ A study in Nature Sustainability on 250,000 pregnancies that ended in missed abortions at 14 weeks or less found the odds ratio of missed abortion increased with the cumulative exposure to air pollution.¹⁶ When air pollution was examined in comparison to other factors, neighborhood air pollution better predicted preterm birth, very preterm birth, and small for gestational age more than race, ethnicity, or any other socio-economic factor.¹⁷ The effects of air pollution have been demonstrated in other fields as well, including increased mortality after cardiac transplantation with exposure to air pollution,⁴ and for patients undergoing bariatric surgery who live near major roadways, decreased weight loss, less improvement in hemoglobin A_1c, and less change in lipids compared with those with less exposure to roadway pollution.⁵

Air pollution and heat are not the only factors that influence health. Endocrine disrupting chemicals (EDCs) and single-use plastic polymers, which are used in significant supply in US health care, have been found in human blood,¹⁸ intestine, and all portions of the placenta.¹⁹ Phthalates, an EDC found in medical use plastics and medications to control delivery, have been associated with increasing fibroid burden in patients undergoing hysterectomy and myomectomy.²⁰ The example case patient with fibroids undergoing TLH may have had her condition worsened by exposure to phthalates.

Specific areas for improvement

There is a huge opportunity for improvement to reduce the total carbon footprint of a TLH.

A lifecycle assessment of hysterectomy in the United States concluded that an 80% reduction in carbon emissions could be achieved by minimizing opened materials, using reusable and reprocessed instruments, reducing off-hour energy use in the OR (HVAC setbacks), and avoiding the use of volatile anesthetic gases.²¹ The sterilization and re-processing of reusable instruments represented the smallest proportion of carbon emissions from a TLH. Data on patient safety supports these interventions, as current practices have more to do with hospital culture and processes than evidence.

Despite a push to use single-use objects by industry and regulatory agencies in the name of patient safety, data demonstrate that single-use objects are in actuality not safer for patients and may be associated with increased surgical site infections (SSIs). A study from a cancer center in California found that when single-use head covers, shoe covers, and facemasks were eliminated due to supply shortages during the pandemic, SSIs went down by half, despite an increase in surgical volume and an increase in the number of contaminated cases.²² The authors reported an increase in hand hygiene throughout the hospital, which likely contributed to the success of reducing SSIs.

Similarly, a systematic review found no evidence to support single-use instruments over reusable or reprocessed instruments when considering instrument function, ease of use, patient safety, SSIs, or long-term patient outcomes.²³ While it may be easy for regulatory agencies to focus on disposing objects as paramount to reducing infections, the Centers for Disease Control and Prevention states that the biggest factors affecting SSIs are appropriate use of prophylactic antibiotics, skin antisepsis, and patient metabolic control.²⁴ Disposing of single-use objects in the name of patient safety will worsen patient health outcomes when considering patient proximity to waste, pollution, and EDCs.

The sterilization process for reusable items is often called out by the medical supply industry as wasteful and energy intensive; however, data refute these claims. A Swedish study researching reusable versus single-use trocars found that a reusable trocar system offers a robust opportunity to reduce both the environmental and financial costs for laparoscopic surgery.²⁵ We can further decrease the environmental impact of reusable instruments by using sets instead of individually packed instruments and packing autoclaves more efficiently. By using rigid sterilization containers, there was an 85% reduction in carbon footprint as compared with the blue wrap system.

Electricity use can be easily reduced across all surgical spaces by performing HVAC setbacks during low occupancy times of day. On nights and weekends, when there are very few surgical cases occurring, one study found that by decreasing the ventilation rate, turning off lights, and performing the minimum temperature control in unused ORs, electricity use was cut in half.¹¹

Waste triage and recycling

Reducing regulated medical waste is another area where hospitals can make a huge impact on carbon emissions and costs with little more than education and process change. Guidelines for regulated medical waste sorting developed out of the HIV epidemic due to the fear of blood products. Although studies show that regulated medical waste is not more infectious than household waste, state departments of public health have kept these guidelines in place for sorting fluid blood and tissue into RMW containers and bags.²⁶ The best hospital performers keep RMW below 10% of the total waste stream, while many ORs send close to 100% of their waste as RMW (FIGURE 1b). ORs can work with nursing and environmental services staff to assess processes and divert waste into recycling and regular waste. Many OR staff are acutely aware of the huge amount of waste produced and want to make a positive impact. Success in this small area often builds momentum to tackle harder sustainability practices throughout the hospital.

Continue to: Removal of EDCs from medical products...

Removal of EDCs from medical products

Single-use medical supplies are not only wasteful but also contain harmful EDCs, such as phthalates, bisphenol A (BPA), parabens, perfluoroalkyl substances, and triclosan. Phthalates, for example, account for 30% to 40% of the weight of medical-use plastics, and parabens are ubiquitously found in ultrasound gel.³ Studies looking at exposure to EDCs within the neonatal intensive care unit reveal substantial BPA, phthalate, and paraben levels within biologic samples from premature infants, thought to be above toxicity limits. While we do not know the full extent to which EDCs can affect neonatal development, there is already mounting evidence that EDCs are associated with endocrine, metabolic, and neurodevelopmental disorders throughout our lifespan.³

30-day climate challenge

Although the example case patient undergoing TLH for fibroids will never need care for her fibroids again, the climate impact of her time in the OR represents the most carbon-intensive care she will ever need. Surgery as practiced in the United States today is unsustainable.

In 2021, the Biden administration issued an executive order requiring all federal facilities, including health care facilities and hospitals, to be carbon neutral by 2035. In order to make meaningful changes industry-wide, we should be petitioning lawmakers for stricter environmental regulations in health care, similar to regulations in the manufacturing and airline industries. We recommend a 30-day climate challenge (FIGURE 2) for bringing awareness to your circles of influence. Physicians have an ethical duty to advocate for change at the local, regional, and national level if we want to see a better future for our patients, their children, and even ourselves. Organizations such as Practice Greenhealth, Health Care without Harm, and Citizens’ Climate Lobby can help amplify our voices to reach the right people to implement sweeping policy changes. ●

In 2009, the Lancet called climate change the biggest global health threat of the 21st century, the effects of which will be experienced in our lifetimes.¹ Significant amounts of data have demonstrated the negative health effects of heat, air pollution, and exposure to toxic substances.^2,3 These effects have been seen in every geographic region of the United States, and in multiple organ systems and specialties, including obstetrics, pediatrics, and even cardiopulmonary and bariatric surgery.^2-5

Although it does not receive the scrutiny of other industries, the global health care industry accounts for almost double the amount of carbon emissions as global aviation, and the United States accounts for 27% of this footprint despite only having 4% of the world’s population.⁶ It therefore serves that our own industry is an excellent target for reducing the carbon emissions that contribute to climate change. Consider the climate impact of hysterectomy, the second-most common surgery that women undergo. In this article, we will use the example of a 50-year-old woman with fibroids who plans to undergo definitive treatment via total laparoscopic hysterectomy (TLH).

Climate impact of US health care

Hospital buildings in the United States are energy intensive, consuming 10% of the energy used in commercial buildings every year, accounting for over $8 billion. Operating rooms (ORs) account for a third of this usage.⁷ Hospitals also use more water than any other type of commercial building, for necessary actions like cooling, sterilization, and laundry.⁸ Further, US hospitals generate 14,000 tons of waste per day, with a third of this coming from the ORs. Sadly, up to 15% is food waste, as we are not very good about selecting and proportioning healthy food for our staff and inpatients.⁶

While health care is utility intensive, the majority of emissions are created through the production, transport, and disposal of goods coming through our supply chain.⁶ Hospitals are significant consumers of single-use objects, the majority of which are petroleum-derived plastics—accounting for an estimated 71% of emissions coming from the health care sector. Supply chain is the second largest expense in health care, but with current shortages, it is estimated to overtake labor costs by this year. The United States is also the largest consumer of pharmaceuticals worldwide, supporting a $20 billion packaging industry,⁹ which creates a significant amount of waste.

Climate impact of the OR

Although ORs only account for a small portion of hospital square footage, they account for a significant amount of health care’s carbon footprint through high waste production and excessive consumption of single-use items. Just one surgical procedure in a hospital is estimated to produce about the same amount of waste as a typical family of 4 would in an entire week.¹⁰ Furthermore, the majority of these single-use items, including sterile packaging, are sorted inappropriately as regulated medical waste (RMW, “biohazardous” or “red bag” waste) (FIGURE 1a). RMW has significant effects on the environment since it must be incinerated or steam autoclaved prior to transport to the landfill, leading to high amounts of air pollution and energy usage.

We all notice the visible impacts of waste in the OR, but other contributors to carbon emissions are invisible. Energy consumption is a huge contributor to the overall carbon footprint of surgery. Heating, ventilation, and air conditioning [HVAC] is responsible for 52% of hospital energy needs but accounts for 99% of OR energy consumption.¹¹ Despite the large energy requirements of the ORs, they are largely unoccupied in the evenings and on weekends, and thermostats are not adjusted accordingly.

Anesthetic gases are another powerful contributor to greenhouse gas emissions from the OR. Anesthetic gases alone contribute about 25% of the overall carbon footprint of the OR, and US health care emits 660,000 tons of carbon equivalents from anesthetic gas use per year.¹² Desflurane is 1,600 times more potent than carbon dioxide (CO₂) in its global warming potential followed by isoflurane and sevoflurane;¹³ this underscores the importance of working with our anesthesia colleagues on the differences between the anesthetic gases they use. Enhanced recovery after surgery recommendations in gynecology already recommend avoiding the use of volatile anesthetic gases in favor of propofol to reduce postoperative nausea and vomiting.¹⁴

In the context of a patient undergoing a TLH, the estimated carbon footprint in the United States is about 560 kg of CO₂ equivalents—roughly the same as driving 1,563 miles in a gas-powered car.

Continue to: Climate impact on our patients...

 

 

Climate impact on our patients

The data in obstetrics and gynecology is clear that climate change is affecting patient outcomes, both globally and in our own country. A systematic review of 32 million births found that air pollution and heat exposure were associated with preterm birth and low birth weight, and these effects were seen in all geographic regions across the United States.¹ A study of 5.9 million births in California found that patients who lived near coal- and oil-power plants had up to a 27% reduction in preterm births when those power plants closed and air pollution decreased.¹⁵ A study in Nature Sustainability on 250,000 pregnancies that ended in missed abortions at 14 weeks or less found the odds ratio of missed abortion increased with the cumulative exposure to air pollution.¹⁶ When air pollution was examined in comparison to other factors, neighborhood air pollution better predicted preterm birth, very preterm birth, and small for gestational age more than race, ethnicity, or any other socio-economic factor.¹⁷ The effects of air pollution have been demonstrated in other fields as well, including increased mortality after cardiac transplantation with exposure to air pollution,⁴ and for patients undergoing bariatric surgery who live near major roadways, decreased weight loss, less improvement in hemoglobin A_1c, and less change in lipids compared with those with less exposure to roadway pollution.⁵

Air pollution and heat are not the only factors that influence health. Endocrine disrupting chemicals (EDCs) and single-use plastic polymers, which are used in significant supply in US health care, have been found in human blood,¹⁸ intestine, and all portions of the placenta.¹⁹ Phthalates, an EDC found in medical use plastics and medications to control delivery, have been associated with increasing fibroid burden in patients undergoing hysterectomy and myomectomy.²⁰ The example case patient with fibroids undergoing TLH may have had her condition worsened by exposure to phthalates.

Specific areas for improvement

There is a huge opportunity for improvement to reduce the total carbon footprint of a TLH.

A lifecycle assessment of hysterectomy in the United States concluded that an 80% reduction in carbon emissions could be achieved by minimizing opened materials, using reusable and reprocessed instruments, reducing off-hour energy use in the OR (HVAC setbacks), and avoiding the use of volatile anesthetic gases.²¹ The sterilization and re-processing of reusable instruments represented the smallest proportion of carbon emissions from a TLH. Data on patient safety supports these interventions, as current practices have more to do with hospital culture and processes than evidence.

Despite a push to use single-use objects by industry and regulatory agencies in the name of patient safety, data demonstrate that single-use objects are in actuality not safer for patients and may be associated with increased surgical site infections (SSIs). A study from a cancer center in California found that when single-use head covers, shoe covers, and facemasks were eliminated due to supply shortages during the pandemic, SSIs went down by half, despite an increase in surgical volume and an increase in the number of contaminated cases.²² The authors reported an increase in hand hygiene throughout the hospital, which likely contributed to the success of reducing SSIs.

Similarly, a systematic review found no evidence to support single-use instruments over reusable or reprocessed instruments when considering instrument function, ease of use, patient safety, SSIs, or long-term patient outcomes.²³ While it may be easy for regulatory agencies to focus on disposing objects as paramount to reducing infections, the Centers for Disease Control and Prevention states that the biggest factors affecting SSIs are appropriate use of prophylactic antibiotics, skin antisepsis, and patient metabolic control.²⁴ Disposing of single-use objects in the name of patient safety will worsen patient health outcomes when considering patient proximity to waste, pollution, and EDCs.

The sterilization process for reusable items is often called out by the medical supply industry as wasteful and energy intensive; however, data refute these claims. A Swedish study researching reusable versus single-use trocars found that a reusable trocar system offers a robust opportunity to reduce both the environmental and financial costs for laparoscopic surgery.²⁵ We can further decrease the environmental impact of reusable instruments by using sets instead of individually packed instruments and packing autoclaves more efficiently. By using rigid sterilization containers, there was an 85% reduction in carbon footprint as compared with the blue wrap system.

Electricity use can be easily reduced across all surgical spaces by performing HVAC setbacks during low occupancy times of day. On nights and weekends, when there are very few surgical cases occurring, one study found that by decreasing the ventilation rate, turning off lights, and performing the minimum temperature control in unused ORs, electricity use was cut in half.¹¹

Waste triage and recycling

Reducing regulated medical waste is another area where hospitals can make a huge impact on carbon emissions and costs with little more than education and process change. Guidelines for regulated medical waste sorting developed out of the HIV epidemic due to the fear of blood products. Although studies show that regulated medical waste is not more infectious than household waste, state departments of public health have kept these guidelines in place for sorting fluid blood and tissue into RMW containers and bags.²⁶ The best hospital performers keep RMW below 10% of the total waste stream, while many ORs send close to 100% of their waste as RMW (FIGURE 1b). ORs can work with nursing and environmental services staff to assess processes and divert waste into recycling and regular waste. Many OR staff are acutely aware of the huge amount of waste produced and want to make a positive impact. Success in this small area often builds momentum to tackle harder sustainability practices throughout the hospital.

Continue to: Removal of EDCs from medical products...

Removal of EDCs from medical products

Single-use medical supplies are not only wasteful but also contain harmful EDCs, such as phthalates, bisphenol A (BPA), parabens, perfluoroalkyl substances, and triclosan. Phthalates, for example, account for 30% to 40% of the weight of medical-use plastics, and parabens are ubiquitously found in ultrasound gel.³ Studies looking at exposure to EDCs within the neonatal intensive care unit reveal substantial BPA, phthalate, and paraben levels within biologic samples from premature infants, thought to be above toxicity limits. While we do not know the full extent to which EDCs can affect neonatal development, there is already mounting evidence that EDCs are associated with endocrine, metabolic, and neurodevelopmental disorders throughout our lifespan.³

30-day climate challenge

Although the example case patient undergoing TLH for fibroids will never need care for her fibroids again, the climate impact of her time in the OR represents the most carbon-intensive care she will ever need. Surgery as practiced in the United States today is unsustainable.

In 2021, the Biden administration issued an executive order requiring all federal facilities, including health care facilities and hospitals, to be carbon neutral by 2035. In order to make meaningful changes industry-wide, we should be petitioning lawmakers for stricter environmental regulations in health care, similar to regulations in the manufacturing and airline industries. We recommend a 30-day climate challenge (FIGURE 2) for bringing awareness to your circles of influence. Physicians have an ethical duty to advocate for change at the local, regional, and national level if we want to see a better future for our patients, their children, and even ourselves. Organizations such as Practice Greenhealth, Health Care without Harm, and Citizens’ Climate Lobby can help amplify our voices to reach the right people to implement sweeping policy changes. ●

Photo: Shutterstock

CASE Nulliparous young woman desires contraception

An 18-year-old nulliparous patient presents to your office inquiring about contraception before she leaves for college. She not only wants to prevent pregnancy but she also would like a method that can help with her dysmenorrhea. After receiving nondirective counseling about all of the methods available, she selects a levonorgestrel intrauterine device (LNG-IUD). However, she discloses that she is very nervous about placement. She has heard from friends that it can be painful to get an IUD. What are these patient’s risk factors for painful placement? How would you mitigate her experience of pain during the insertion process?
 

IUDs are highly effective and safe methods of preventing unwanted pregnancy. IUDs have become increasingly more common; they were the method of choice for 14% of contraception users in 2016, a rise from 12% in 2014.¹ The Contraceptive CHOICE project demonstrated that IUDs were most likely to be chosen as a reversible method of contraception when unbiased counseling is provided and barriers such as cost are removed. Additionally, rates of continuation were found to be high, thus reducing the number of unwanted pregnancies.² However, pain during IUD insertion as well as the fear and anxiety surrounding the procedure are some of the major limitations to IUD uptake and use. Specifically, fear of pain during IUD insertion is a substantial barrier; this fear is thought to also exacerbate the experience of pain during the insertion process.³

This article aims to identify risk factors for painful IUD placement and to review both nonpharmacologic and pharmacologic methods that may decrease discomfort and anxiety during IUD insertion.

What factors contribute to the experience of pain with IUD placement?

While some women do not report experiencing pain during IUD insertion, approximately 17% describe the pain as severe.⁴ The perception of pain during IUD placement is multifactorial; physiologic, psychological, emotional, cultural, and circumstantial factors all can play a role (TABLE 1). The biologic perception of pain results from the manipulation of the cervix and uterus; noxious stimuli activate both the sympathetic and parasympathetic nervous systems. The sympathetic system at T10-L2 mediates the fundus, the ovarian plexus at the cornua, and the uterosacral ligaments, while the parasympathetic fibers from S2-S4 enter the cervix at 3 o’clock and 9 o’clock and innervate the upper vagina, cervix, and lower uterine segment.^4,5 Nulliparity, history of cesarean delivery, increased size of the IUD inserter, length of the uterine cavity, breastfeeding status, relation to timing of menstruation, and length of time since last vaginal delivery all may be triggers for pain. Other sociocultural influences on a patient’s experience of pain include young age (adolescence), Black race, and history of sexual trauma, as well as existing anxiety and beliefs about expected pain.^3,5,6-8

It also is important to consider all aspects of the procedure that could be painful. Steps during IUD insertion that have been found to invoke average to severe pain include use of tenaculum on the cervix, uterine stabilization, uterine sounding, placement of the insertion tube, and deployment of the actual IUD.^4-7

A secondary analysis of the Contraceptive CHOICE project confirmed that women with higher levels of anticipated pain were more likely to experience increased discomfort during placement.³ Providers tend to underestimate the anxiety and pain experienced by their patients undergoing IUD insertion. In a study about anticipated pain during IUD insertion, clinicians were asked if patients were “pleasant and appropriately engaging” or “anxious.” Only 10% of those patients were noted to be anxious by their provider; however, patients with a positive screen on the PHQ-4 depression and anxiety screen did anticipate more pain than those who did not.⁶ In another study, patients estimated their pain scores at 30 mm higher than their providers on a visual analog scale.⁷ Given these discrepancies, it is imperative to address anxiety and pain anticipation, risk factors for pain, and offerings for pain management during IUD placement to ensure a more holistic experience.

Continue to: What are nonpharmacologic interventions that can reduce anxiety and pain?...

What are nonpharmacologic interventions that can reduce anxiety and pain?

There are few formal studies on nonpharmacologic options for pain reduction at IUD insertion, with varying outcomes.^4,8,10 However, many of them suggest that establishing a trusting clinician-patient relationship, a relaxing and inviting environment, and emotional support during the procedure may help make the procedure more comfortable overall (TABLE 2).^4,5,10

Education and counseling

Patients should be thoroughly informed about the different IUD options, and they should be reassured regarding their contraceptive effectiveness and low risk for insertion difficulties in order to mitigate anxiety about complications and future fertility.¹¹ This counseling session can offer the patient opportunities for relationship building with the provider and for the clinician to assess for anxiety and address concerns about the insertion and removal process. Patients who are adequately informed regarding expectations and procedural steps are more likely to have better pain management.⁵ Another purpose of this counseling session may be to identify any risk factors that may increase pain and tailor nonpharmacologic and pharmacologic options to the individual patient.

Environment

Examination rooms should be comfortable, private, and professional appearing. Patients prefer a more informal, unhurried, and less sterile atmosphere for procedures. Clinicians should strive to engender trust prior to the procedure by sharing information in a straightforward manner, and ensuring that staff of medical assistants, nurses, and clinicians are a “well-oiled machine” to inspire confidence in the competence of the team.⁴ Ultrasonography guidance also may be helpful in reducing pain during IUD placement, but this may not be available in all outpatient settings.⁸

Distraction techniques

Various distraction methods have been employed during gynecologic procedures, and more specifically IUD placement, with some effect. During and after the procedure, heat and ice have been found to be helpful adjuncts for uterine cramping and should be offered as first-line pain management options on the examination table. This can be in the form of reusable heating pads or chemical heat or ice packs.⁴ A small study demonstrated that inhaled lavender may help with lowering anxiety prior to and during the procedure; however, it had limited effects on pain.¹⁰

Clinicians and support staff should engage in conversation with the patient throughout the procedure (ie, “verbacaine”). This can be conducted via a casual chat about unrelated topics or gentle and positive coaching through the procedure with the intent to remove negative imagery associated with elements of the insertion process.⁵ Finally, studies have been conducted using music as a distraction for colposcopy and hysteroscopy, and results have indicated that it is beneficial, reducing both pain and anxiety during these similar types of procedures.⁴ While these options may not fully remove pain and anxiety, many are low investment interventions that many patients will appreciate.

What are pharmacologic interventions that can decrease pain during IUD insertion?

The literature is more robust with studies examining the benefits of pharmacologic methods for reducing pain during IUD insertion; strategies include agents that lessen uterine cramping, numb the cervix, and soften and open the cervical os. Despite the plethora of studies, there is no one standard of care for pain management during IUD insertion (TABLE 3).

Lidocaine injection

Lidocaine is an amine anesthetic that can block the nociceptive response of nerves upon administration; it has the advantages of rapid onset and low risk in appropriate doses. Multiple randomized controlled trials (RCTs) have examined the use of paracervical and intracervical block with lidocaine.^9,12-15 Lopez and colleagues conducted a review in 2015, including 3 studies about injectable lidocaine and demonstrated some effect of injectable lidocaine on reduction in pain at tenaculum placement.⁹

Mody and colleagues conducted a pilot RCT of 50 patients comparing a 10 mL lidocaine 1% paracervical block to no block, which was routine procedure at the time.¹² The authors demonstrated a reduction in pain at the tenaculum site but no decrease in pain with insertion. They also measured pain during the block administration itself and found that the block increased the overall pain of the procedure. In 2018, Mody et al¹³ performed another RCT, but with a higher dose of 20 mL of buffered lidocaine 1% in 64 nulliparous patients. They found that paracervical block improved pain during uterine sounding, IUD insertion, and 5 minutes following insertion, as well as the pain of the overall procedure.

De Nadai and colleagues evaluated if a larger dose of lidocaine (3.6 mL of lidocaine 2%) administered intracervically at the anterior lip was beneficial.¹⁴ They randomly assigned 302 women total: 99 to intracervical block, 101 to intracervical sham block with dry needling at the anterior lip, and 102 to no intervention. Fewer patients reported extreme pain with tenaculum placement and with IUD (levonorgestrel-releasing system) insertion. Given that this option requires less lidocaine overall and fewer injection points, it has the potential to be an easier and more reproducible technique.¹⁴

Finally, Akers and colleagues aimed to evaluate IUD insertion in nulliparous adolescents. They compared a 1% paracervical block of 10 mL with 1 mL at the anterior lip and 4.5 mL at 4 o’clock and 8 o’clock in the cervicovaginal junction versus depression of the wood end of a cotton swab at the same sites. They found that the paracervical block improved pain substantially during all steps of the procedure compared with the sham block in this young population.¹⁶

Nonsteroidal anti-inflammatory drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) show promise in reducing pain during IUD placement, as they inhibit the production of prostaglandins, which can in turn reduce uterine cramping and inflammation during IUD placement.

Lopez and colleagues evaluated the use of NSAIDs in 7 RCTs including oral naproxen, oral ibuprofen, and intramuscular ketorolac.⁹ While it had no effect on pain at the time of placement, naproxen administered at least 90 minutes before the procedure decreased uterine cramping for 2 hours after insertion. Women receiving naproxen also were less likely to describe the insertion as “unpleasant.” Ibuprofen was found to have limited effects during insertion and after the procedure. Intramuscular ketorolac studies were conflicting. Results of one study demonstrated a lower median pain score at 5 minutes but no differences during tenaculum placement or IUD insertion, whereas another demonstrated reduction in pain during and after the procedure.^8,9

Another RCT showed potential benefit of tramadol over the use of naproxen when they were compared; however, tramadol is an opioid, and there are barriers to universal use in the outpatient setting.⁹

Continue to: Topical anesthetics...

 

 

Topical anesthetics

Topical anesthetics offer promise of pain relief without the pain of injection and with the advantage of self-administration for some formulations.

Several RCTs evaluated whether lidocaine gel 2% applied to the cervix or injected via flexible catheter into the cervical os improved pain, but there were no substantial differences in pain perception between topical gel and placebo groups in the insertion of IUDs.⁹

Rapkin and colleagues¹⁵ studied whether self-administered intravaginal lidocaine gel 2% five minutes before insertion was helpful;¹⁵ they found that tenaculum placement was less painful, but IUD placement was not. Conti et al expanded upon the Rapkin study by extending the amount of time of exposure to self-administered intravaginal lidocaine gel 2% to 15 minutes; they found no difference in perception of pain during tenaculum placement, but they did see a substantial difference in discomfort during speculum placement.¹⁷ This finding may be helpful for patients with a history of sexual trauma or anxiety about gynecologic examinations. Based on surveys conducted during their study, they found that patients were willing to wait 15 minutes for this benefit.

In Gemzell-Danielsson and colleagues’ updated review, they identified that different lidocaine formulations, such as a controlled-release lidocaine and a lidocaine-prilocaine compound, resulted in slight reduction in pain scores at multiple points during the IUD insertion process compared with controls.⁸ Two RCTs demonstrated substantial reduction in pain with administration of lidocaine spray 10% during tenaculum placement, sounding, and immediately after IUD placement compared with a placebo group.^18,19 This may be an appealing option for patients who do not want to undergo an injection for local anesthesia.

Nitrous oxide

Nitrous oxide is an odorless colorless gas with anxiolytic, analgesic, and amnestic effects. It has several advantages for outpatient administration including rapid onset, rapid recovery, high safety profile, and no residual incapacitation, enabling a patient to safely leave the office shortly after a procedure.²⁰

Nitrous oxide was studied in an RCT of 74 young (12-20 years of age) nulliparous patients and found to be effective for decreasing pain during IUD insertion and increasing satisfaction with the procedure.²⁰ However, another study of 80 nulliparous patients (aged 13-45 years) did not find any reduction in pain during the insertion procedure.²¹

Prostaglandin analogues

Misoprostol is a synthetic prostaglandin E1 analog that causes cervical softening, uterine contractions, and cervical dilation. Dinoprostone is a synthetic prostaglandin E2 analog that has similar effects on the cervix and uterus. These properties have made it a useful tool in minor gynecologic procedures, such as first trimester uterine aspiration and hysteroscopy. However, both have the disadvantage of causing adverse effects on gastric smooth muscle, leading to nausea, vomiting, diarrhea, and uncomfortable gastric cramping.

Several RCTs have examined the use of misoprostol administration approximately 2 to 4 hours before IUD placement. No studies found any improvement in pain during IUD insertion, but this likely is due to the discomfort caused by the use of misoprostol itself.⁹ A meta-analysis and systematic review of 14 studies found no effect on reducing the pain associated with IUD placement but did find that providers had an easier time with cervical dilation in patients who received it. The meta-analysis also demonstrated that patients receiving vaginal misoprostol were less likely to have gastric side effects.²² In another review of 5 RCTs using 400 µg to 600 µg of misoprostol for cervical preparation, Gemzell-Danielsson et al found reductions in mean pain scores with placement specifically among patients with previous cesarean delivery and/or nulliparous patients.⁸

In an RCT, Ashour and colleagues looked at the use of dinoprostone 3 mg compared with placebo in 160 patients and found that those in the dinoprostone group had less pain during and 15 minutes after the procedure, as well as ease of insertion and overall higher satisfaction with the IUD placement. Dinoprostone traditionally is used for labor induction in the United States and tends to be much more expensive than misoprostol, but it shows the most promise of the prostaglandins in making IUD placement more comfortable.

Conclusion: Integrating evidence and experience

Providers tend to underestimate the pain and anxiety experienced by their patients undergoing IUD insertion. Patients’ concerns about pain and anxiety increase their risk for experiencing pain during IUD insertion. Patient anxieties, and thus, pain may be allayed by offering support and education prior to placement, offering tailored pharmacologic strategies to mitigate pain, and offering supportive and distraction measures during the insertion process. ●

Photo: Shutterstock

CASE Nulliparous young woman desires contraception

An 18-year-old nulliparous patient presents to your office inquiring about contraception before she leaves for college. She not only wants to prevent pregnancy but she also would like a method that can help with her dysmenorrhea. After receiving nondirective counseling about all of the methods available, she selects a levonorgestrel intrauterine device (LNG-IUD). However, she discloses that she is very nervous about placement. She has heard from friends that it can be painful to get an IUD. What are these patient’s risk factors for painful placement? How would you mitigate her experience of pain during the insertion process?
 

IUDs are highly effective and safe methods of preventing unwanted pregnancy. IUDs have become increasingly more common; they were the method of choice for 14% of contraception users in 2016, a rise from 12% in 2014.¹ The Contraceptive CHOICE project demonstrated that IUDs were most likely to be chosen as a reversible method of contraception when unbiased counseling is provided and barriers such as cost are removed. Additionally, rates of continuation were found to be high, thus reducing the number of unwanted pregnancies.² However, pain during IUD insertion as well as the fear and anxiety surrounding the procedure are some of the major limitations to IUD uptake and use. Specifically, fear of pain during IUD insertion is a substantial barrier; this fear is thought to also exacerbate the experience of pain during the insertion process.³

This article aims to identify risk factors for painful IUD placement and to review both nonpharmacologic and pharmacologic methods that may decrease discomfort and anxiety during IUD insertion.

What factors contribute to the experience of pain with IUD placement?

While some women do not report experiencing pain during IUD insertion, approximately 17% describe the pain as severe.⁴ The perception of pain during IUD placement is multifactorial; physiologic, psychological, emotional, cultural, and circumstantial factors all can play a role (TABLE 1). The biologic perception of pain results from the manipulation of the cervix and uterus; noxious stimuli activate both the sympathetic and parasympathetic nervous systems. The sympathetic system at T10-L2 mediates the fundus, the ovarian plexus at the cornua, and the uterosacral ligaments, while the parasympathetic fibers from S2-S4 enter the cervix at 3 o’clock and 9 o’clock and innervate the upper vagina, cervix, and lower uterine segment.^4,5 Nulliparity, history of cesarean delivery, increased size of the IUD inserter, length of the uterine cavity, breastfeeding status, relation to timing of menstruation, and length of time since last vaginal delivery all may be triggers for pain. Other sociocultural influences on a patient’s experience of pain include young age (adolescence), Black race, and history of sexual trauma, as well as existing anxiety and beliefs about expected pain.^3,5,6-8

It also is important to consider all aspects of the procedure that could be painful. Steps during IUD insertion that have been found to invoke average to severe pain include use of tenaculum on the cervix, uterine stabilization, uterine sounding, placement of the insertion tube, and deployment of the actual IUD.^4-7

A secondary analysis of the Contraceptive CHOICE project confirmed that women with higher levels of anticipated pain were more likely to experience increased discomfort during placement.³ Providers tend to underestimate the anxiety and pain experienced by their patients undergoing IUD insertion. In a study about anticipated pain during IUD insertion, clinicians were asked if patients were “pleasant and appropriately engaging” or “anxious.” Only 10% of those patients were noted to be anxious by their provider; however, patients with a positive screen on the PHQ-4 depression and anxiety screen did anticipate more pain than those who did not.⁶ In another study, patients estimated their pain scores at 30 mm higher than their providers on a visual analog scale.⁷ Given these discrepancies, it is imperative to address anxiety and pain anticipation, risk factors for pain, and offerings for pain management during IUD placement to ensure a more holistic experience.

Continue to: What are nonpharmacologic interventions that can reduce anxiety and pain?...

What are nonpharmacologic interventions that can reduce anxiety and pain?

There are few formal studies on nonpharmacologic options for pain reduction at IUD insertion, with varying outcomes.^4,8,10 However, many of them suggest that establishing a trusting clinician-patient relationship, a relaxing and inviting environment, and emotional support during the procedure may help make the procedure more comfortable overall (TABLE 2).^4,5,10

Education and counseling

Patients should be thoroughly informed about the different IUD options, and they should be reassured regarding their contraceptive effectiveness and low risk for insertion difficulties in order to mitigate anxiety about complications and future fertility.¹¹ This counseling session can offer the patient opportunities for relationship building with the provider and for the clinician to assess for anxiety and address concerns about the insertion and removal process. Patients who are adequately informed regarding expectations and procedural steps are more likely to have better pain management.⁵ Another purpose of this counseling session may be to identify any risk factors that may increase pain and tailor nonpharmacologic and pharmacologic options to the individual patient.

Environment

Examination rooms should be comfortable, private, and professional appearing. Patients prefer a more informal, unhurried, and less sterile atmosphere for procedures. Clinicians should strive to engender trust prior to the procedure by sharing information in a straightforward manner, and ensuring that staff of medical assistants, nurses, and clinicians are a “well-oiled machine” to inspire confidence in the competence of the team.⁴ Ultrasonography guidance also may be helpful in reducing pain during IUD placement, but this may not be available in all outpatient settings.⁸

Distraction techniques

Various distraction methods have been employed during gynecologic procedures, and more specifically IUD placement, with some effect. During and after the procedure, heat and ice have been found to be helpful adjuncts for uterine cramping and should be offered as first-line pain management options on the examination table. This can be in the form of reusable heating pads or chemical heat or ice packs.⁴ A small study demonstrated that inhaled lavender may help with lowering anxiety prior to and during the procedure; however, it had limited effects on pain.¹⁰

Clinicians and support staff should engage in conversation with the patient throughout the procedure (ie, “verbacaine”). This can be conducted via a casual chat about unrelated topics or gentle and positive coaching through the procedure with the intent to remove negative imagery associated with elements of the insertion process.⁵ Finally, studies have been conducted using music as a distraction for colposcopy and hysteroscopy, and results have indicated that it is beneficial, reducing both pain and anxiety during these similar types of procedures.⁴ While these options may not fully remove pain and anxiety, many are low investment interventions that many patients will appreciate.

What are pharmacologic interventions that can decrease pain during IUD insertion?

The literature is more robust with studies examining the benefits of pharmacologic methods for reducing pain during IUD insertion; strategies include agents that lessen uterine cramping, numb the cervix, and soften and open the cervical os. Despite the plethora of studies, there is no one standard of care for pain management during IUD insertion (TABLE 3).

Lidocaine injection

Lidocaine is an amine anesthetic that can block the nociceptive response of nerves upon administration; it has the advantages of rapid onset and low risk in appropriate doses. Multiple randomized controlled trials (RCTs) have examined the use of paracervical and intracervical block with lidocaine.^9,12-15 Lopez and colleagues conducted a review in 2015, including 3 studies about injectable lidocaine and demonstrated some effect of injectable lidocaine on reduction in pain at tenaculum placement.⁹

Mody and colleagues conducted a pilot RCT of 50 patients comparing a 10 mL lidocaine 1% paracervical block to no block, which was routine procedure at the time.¹² The authors demonstrated a reduction in pain at the tenaculum site but no decrease in pain with insertion. They also measured pain during the block administration itself and found that the block increased the overall pain of the procedure. In 2018, Mody et al¹³ performed another RCT, but with a higher dose of 20 mL of buffered lidocaine 1% in 64 nulliparous patients. They found that paracervical block improved pain during uterine sounding, IUD insertion, and 5 minutes following insertion, as well as the pain of the overall procedure.

De Nadai and colleagues evaluated if a larger dose of lidocaine (3.6 mL of lidocaine 2%) administered intracervically at the anterior lip was beneficial.¹⁴ They randomly assigned 302 women total: 99 to intracervical block, 101 to intracervical sham block with dry needling at the anterior lip, and 102 to no intervention. Fewer patients reported extreme pain with tenaculum placement and with IUD (levonorgestrel-releasing system) insertion. Given that this option requires less lidocaine overall and fewer injection points, it has the potential to be an easier and more reproducible technique.¹⁴

Finally, Akers and colleagues aimed to evaluate IUD insertion in nulliparous adolescents. They compared a 1% paracervical block of 10 mL with 1 mL at the anterior lip and 4.5 mL at 4 o’clock and 8 o’clock in the cervicovaginal junction versus depression of the wood end of a cotton swab at the same sites. They found that the paracervical block improved pain substantially during all steps of the procedure compared with the sham block in this young population.¹⁶

Nonsteroidal anti-inflammatory drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) show promise in reducing pain during IUD placement, as they inhibit the production of prostaglandins, which can in turn reduce uterine cramping and inflammation during IUD placement.

Lopez and colleagues evaluated the use of NSAIDs in 7 RCTs including oral naproxen, oral ibuprofen, and intramuscular ketorolac.⁹ While it had no effect on pain at the time of placement, naproxen administered at least 90 minutes before the procedure decreased uterine cramping for 2 hours after insertion. Women receiving naproxen also were less likely to describe the insertion as “unpleasant.” Ibuprofen was found to have limited effects during insertion and after the procedure. Intramuscular ketorolac studies were conflicting. Results of one study demonstrated a lower median pain score at 5 minutes but no differences during tenaculum placement or IUD insertion, whereas another demonstrated reduction in pain during and after the procedure.^8,9

Another RCT showed potential benefit of tramadol over the use of naproxen when they were compared; however, tramadol is an opioid, and there are barriers to universal use in the outpatient setting.⁹

Continue to: Topical anesthetics...

 

 

Topical anesthetics

Topical anesthetics offer promise of pain relief without the pain of injection and with the advantage of self-administration for some formulations.

Several RCTs evaluated whether lidocaine gel 2% applied to the cervix or injected via flexible catheter into the cervical os improved pain, but there were no substantial differences in pain perception between topical gel and placebo groups in the insertion of IUDs.⁹

Rapkin and colleagues¹⁵ studied whether self-administered intravaginal lidocaine gel 2% five minutes before insertion was helpful;¹⁵ they found that tenaculum placement was less painful, but IUD placement was not. Conti et al expanded upon the Rapkin study by extending the amount of time of exposure to self-administered intravaginal lidocaine gel 2% to 15 minutes; they found no difference in perception of pain during tenaculum placement, but they did see a substantial difference in discomfort during speculum placement.¹⁷ This finding may be helpful for patients with a history of sexual trauma or anxiety about gynecologic examinations. Based on surveys conducted during their study, they found that patients were willing to wait 15 minutes for this benefit.

In Gemzell-Danielsson and colleagues’ updated review, they identified that different lidocaine formulations, such as a controlled-release lidocaine and a lidocaine-prilocaine compound, resulted in slight reduction in pain scores at multiple points during the IUD insertion process compared with controls.⁸ Two RCTs demonstrated substantial reduction in pain with administration of lidocaine spray 10% during tenaculum placement, sounding, and immediately after IUD placement compared with a placebo group.^18,19 This may be an appealing option for patients who do not want to undergo an injection for local anesthesia.

Nitrous oxide

Nitrous oxide is an odorless colorless gas with anxiolytic, analgesic, and amnestic effects. It has several advantages for outpatient administration including rapid onset, rapid recovery, high safety profile, and no residual incapacitation, enabling a patient to safely leave the office shortly after a procedure.²⁰

Nitrous oxide was studied in an RCT of 74 young (12-20 years of age) nulliparous patients and found to be effective for decreasing pain during IUD insertion and increasing satisfaction with the procedure.²⁰ However, another study of 80 nulliparous patients (aged 13-45 years) did not find any reduction in pain during the insertion procedure.²¹

Prostaglandin analogues

Misoprostol is a synthetic prostaglandin E1 analog that causes cervical softening, uterine contractions, and cervical dilation. Dinoprostone is a synthetic prostaglandin E2 analog that has similar effects on the cervix and uterus. These properties have made it a useful tool in minor gynecologic procedures, such as first trimester uterine aspiration and hysteroscopy. However, both have the disadvantage of causing adverse effects on gastric smooth muscle, leading to nausea, vomiting, diarrhea, and uncomfortable gastric cramping.

Several RCTs have examined the use of misoprostol administration approximately 2 to 4 hours before IUD placement. No studies found any improvement in pain during IUD insertion, but this likely is due to the discomfort caused by the use of misoprostol itself.⁹ A meta-analysis and systematic review of 14 studies found no effect on reducing the pain associated with IUD placement but did find that providers had an easier time with cervical dilation in patients who received it. The meta-analysis also demonstrated that patients receiving vaginal misoprostol were less likely to have gastric side effects.²² In another review of 5 RCTs using 400 µg to 600 µg of misoprostol for cervical preparation, Gemzell-Danielsson et al found reductions in mean pain scores with placement specifically among patients with previous cesarean delivery and/or nulliparous patients.⁸

In an RCT, Ashour and colleagues looked at the use of dinoprostone 3 mg compared with placebo in 160 patients and found that those in the dinoprostone group had less pain during and 15 minutes after the procedure, as well as ease of insertion and overall higher satisfaction with the IUD placement. Dinoprostone traditionally is used for labor induction in the United States and tends to be much more expensive than misoprostol, but it shows the most promise of the prostaglandins in making IUD placement more comfortable.

Conclusion: Integrating evidence and experience

Providers tend to underestimate the pain and anxiety experienced by their patients undergoing IUD insertion. Patients’ concerns about pain and anxiety increase their risk for experiencing pain during IUD insertion. Patient anxieties, and thus, pain may be allayed by offering support and education prior to placement, offering tailored pharmacologic strategies to mitigate pain, and offering supportive and distraction measures during the insertion process. ●

Photo: Shutterstock

CASE Nulliparous young woman desires contraception

An 18-year-old nulliparous patient presents to your office inquiring about contraception before she leaves for college. She not only wants to prevent pregnancy but she also would like a method that can help with her dysmenorrhea. After receiving nondirective counseling about all of the methods available, she selects a levonorgestrel intrauterine device (LNG-IUD). However, she discloses that she is very nervous about placement. She has heard from friends that it can be painful to get an IUD. What are these patient’s risk factors for painful placement? How would you mitigate her experience of pain during the insertion process?
 

IUDs are highly effective and safe methods of preventing unwanted pregnancy. IUDs have become increasingly more common; they were the method of choice for 14% of contraception users in 2016, a rise from 12% in 2014.¹ The Contraceptive CHOICE project demonstrated that IUDs were most likely to be chosen as a reversible method of contraception when unbiased counseling is provided and barriers such as cost are removed. Additionally, rates of continuation were found to be high, thus reducing the number of unwanted pregnancies.² However, pain during IUD insertion as well as the fear and anxiety surrounding the procedure are some of the major limitations to IUD uptake and use. Specifically, fear of pain during IUD insertion is a substantial barrier; this fear is thought to also exacerbate the experience of pain during the insertion process.³

This article aims to identify risk factors for painful IUD placement and to review both nonpharmacologic and pharmacologic methods that may decrease discomfort and anxiety during IUD insertion.

What factors contribute to the experience of pain with IUD placement?

While some women do not report experiencing pain during IUD insertion, approximately 17% describe the pain as severe.⁴ The perception of pain during IUD placement is multifactorial; physiologic, psychological, emotional, cultural, and circumstantial factors all can play a role (TABLE 1). The biologic perception of pain results from the manipulation of the cervix and uterus; noxious stimuli activate both the sympathetic and parasympathetic nervous systems. The sympathetic system at T10-L2 mediates the fundus, the ovarian plexus at the cornua, and the uterosacral ligaments, while the parasympathetic fibers from S2-S4 enter the cervix at 3 o’clock and 9 o’clock and innervate the upper vagina, cervix, and lower uterine segment.^4,5 Nulliparity, history of cesarean delivery, increased size of the IUD inserter, length of the uterine cavity, breastfeeding status, relation to timing of menstruation, and length of time since last vaginal delivery all may be triggers for pain. Other sociocultural influences on a patient’s experience of pain include young age (adolescence), Black race, and history of sexual trauma, as well as existing anxiety and beliefs about expected pain.^3,5,6-8

It also is important to consider all aspects of the procedure that could be painful. Steps during IUD insertion that have been found to invoke average to severe pain include use of tenaculum on the cervix, uterine stabilization, uterine sounding, placement of the insertion tube, and deployment of the actual IUD.^4-7

A secondary analysis of the Contraceptive CHOICE project confirmed that women with higher levels of anticipated pain were more likely to experience increased discomfort during placement.³ Providers tend to underestimate the anxiety and pain experienced by their patients undergoing IUD insertion. In a study about anticipated pain during IUD insertion, clinicians were asked if patients were “pleasant and appropriately engaging” or “anxious.” Only 10% of those patients were noted to be anxious by their provider; however, patients with a positive screen on the PHQ-4 depression and anxiety screen did anticipate more pain than those who did not.⁶ In another study, patients estimated their pain scores at 30 mm higher than their providers on a visual analog scale.⁷ Given these discrepancies, it is imperative to address anxiety and pain anticipation, risk factors for pain, and offerings for pain management during IUD placement to ensure a more holistic experience.

Continue to: What are nonpharmacologic interventions that can reduce anxiety and pain?...

What are nonpharmacologic interventions that can reduce anxiety and pain?

There are few formal studies on nonpharmacologic options for pain reduction at IUD insertion, with varying outcomes.^4,8,10 However, many of them suggest that establishing a trusting clinician-patient relationship, a relaxing and inviting environment, and emotional support during the procedure may help make the procedure more comfortable overall (TABLE 2).^4,5,10

Education and counseling

Patients should be thoroughly informed about the different IUD options, and they should be reassured regarding their contraceptive effectiveness and low risk for insertion difficulties in order to mitigate anxiety about complications and future fertility.¹¹ This counseling session can offer the patient opportunities for relationship building with the provider and for the clinician to assess for anxiety and address concerns about the insertion and removal process. Patients who are adequately informed regarding expectations and procedural steps are more likely to have better pain management.⁵ Another purpose of this counseling session may be to identify any risk factors that may increase pain and tailor nonpharmacologic and pharmacologic options to the individual patient.

Environment

Examination rooms should be comfortable, private, and professional appearing. Patients prefer a more informal, unhurried, and less sterile atmosphere for procedures. Clinicians should strive to engender trust prior to the procedure by sharing information in a straightforward manner, and ensuring that staff of medical assistants, nurses, and clinicians are a “well-oiled machine” to inspire confidence in the competence of the team.⁴ Ultrasonography guidance also may be helpful in reducing pain during IUD placement, but this may not be available in all outpatient settings.⁸

Distraction techniques

Various distraction methods have been employed during gynecologic procedures, and more specifically IUD placement, with some effect. During and after the procedure, heat and ice have been found to be helpful adjuncts for uterine cramping and should be offered as first-line pain management options on the examination table. This can be in the form of reusable heating pads or chemical heat or ice packs.⁴ A small study demonstrated that inhaled lavender may help with lowering anxiety prior to and during the procedure; however, it had limited effects on pain.¹⁰

Clinicians and support staff should engage in conversation with the patient throughout the procedure (ie, “verbacaine”). This can be conducted via a casual chat about unrelated topics or gentle and positive coaching through the procedure with the intent to remove negative imagery associated with elements of the insertion process.⁵ Finally, studies have been conducted using music as a distraction for colposcopy and hysteroscopy, and results have indicated that it is beneficial, reducing both pain and anxiety during these similar types of procedures.⁴ While these options may not fully remove pain and anxiety, many are low investment interventions that many patients will appreciate.

What are pharmacologic interventions that can decrease pain during IUD insertion?

The literature is more robust with studies examining the benefits of pharmacologic methods for reducing pain during IUD insertion; strategies include agents that lessen uterine cramping, numb the cervix, and soften and open the cervical os. Despite the plethora of studies, there is no one standard of care for pain management during IUD insertion (TABLE 3).

Lidocaine injection

Lidocaine is an amine anesthetic that can block the nociceptive response of nerves upon administration; it has the advantages of rapid onset and low risk in appropriate doses. Multiple randomized controlled trials (RCTs) have examined the use of paracervical and intracervical block with lidocaine.^9,12-15 Lopez and colleagues conducted a review in 2015, including 3 studies about injectable lidocaine and demonstrated some effect of injectable lidocaine on reduction in pain at tenaculum placement.⁹

Mody and colleagues conducted a pilot RCT of 50 patients comparing a 10 mL lidocaine 1% paracervical block to no block, which was routine procedure at the time.¹² The authors demonstrated a reduction in pain at the tenaculum site but no decrease in pain with insertion. They also measured pain during the block administration itself and found that the block increased the overall pain of the procedure. In 2018, Mody et al¹³ performed another RCT, but with a higher dose of 20 mL of buffered lidocaine 1% in 64 nulliparous patients. They found that paracervical block improved pain during uterine sounding, IUD insertion, and 5 minutes following insertion, as well as the pain of the overall procedure.

De Nadai and colleagues evaluated if a larger dose of lidocaine (3.6 mL of lidocaine 2%) administered intracervically at the anterior lip was beneficial.¹⁴ They randomly assigned 302 women total: 99 to intracervical block, 101 to intracervical sham block with dry needling at the anterior lip, and 102 to no intervention. Fewer patients reported extreme pain with tenaculum placement and with IUD (levonorgestrel-releasing system) insertion. Given that this option requires less lidocaine overall and fewer injection points, it has the potential to be an easier and more reproducible technique.¹⁴

Finally, Akers and colleagues aimed to evaluate IUD insertion in nulliparous adolescents. They compared a 1% paracervical block of 10 mL with 1 mL at the anterior lip and 4.5 mL at 4 o’clock and 8 o’clock in the cervicovaginal junction versus depression of the wood end of a cotton swab at the same sites. They found that the paracervical block improved pain substantially during all steps of the procedure compared with the sham block in this young population.¹⁶

Nonsteroidal anti-inflammatory drugs

Nonsteroidal anti-inflammatory drugs (NSAIDs) show promise in reducing pain during IUD placement, as they inhibit the production of prostaglandins, which can in turn reduce uterine cramping and inflammation during IUD placement.

Lopez and colleagues evaluated the use of NSAIDs in 7 RCTs including oral naproxen, oral ibuprofen, and intramuscular ketorolac.⁹ While it had no effect on pain at the time of placement, naproxen administered at least 90 minutes before the procedure decreased uterine cramping for 2 hours after insertion. Women receiving naproxen also were less likely to describe the insertion as “unpleasant.” Ibuprofen was found to have limited effects during insertion and after the procedure. Intramuscular ketorolac studies were conflicting. Results of one study demonstrated a lower median pain score at 5 minutes but no differences during tenaculum placement or IUD insertion, whereas another demonstrated reduction in pain during and after the procedure.^8,9

Another RCT showed potential benefit of tramadol over the use of naproxen when they were compared; however, tramadol is an opioid, and there are barriers to universal use in the outpatient setting.⁹

Continue to: Topical anesthetics...

 

 

Topical anesthetics

Topical anesthetics offer promise of pain relief without the pain of injection and with the advantage of self-administration for some formulations.

Several RCTs evaluated whether lidocaine gel 2% applied to the cervix or injected via flexible catheter into the cervical os improved pain, but there were no substantial differences in pain perception between topical gel and placebo groups in the insertion of IUDs.⁹

Rapkin and colleagues¹⁵ studied whether self-administered intravaginal lidocaine gel 2% five minutes before insertion was helpful;¹⁵ they found that tenaculum placement was less painful, but IUD placement was not. Conti et al expanded upon the Rapkin study by extending the amount of time of exposure to self-administered intravaginal lidocaine gel 2% to 15 minutes; they found no difference in perception of pain during tenaculum placement, but they did see a substantial difference in discomfort during speculum placement.¹⁷ This finding may be helpful for patients with a history of sexual trauma or anxiety about gynecologic examinations. Based on surveys conducted during their study, they found that patients were willing to wait 15 minutes for this benefit.

In Gemzell-Danielsson and colleagues’ updated review, they identified that different lidocaine formulations, such as a controlled-release lidocaine and a lidocaine-prilocaine compound, resulted in slight reduction in pain scores at multiple points during the IUD insertion process compared with controls.⁸ Two RCTs demonstrated substantial reduction in pain with administration of lidocaine spray 10% during tenaculum placement, sounding, and immediately after IUD placement compared with a placebo group.^18,19 This may be an appealing option for patients who do not want to undergo an injection for local anesthesia.

Nitrous oxide

Nitrous oxide is an odorless colorless gas with anxiolytic, analgesic, and amnestic effects. It has several advantages for outpatient administration including rapid onset, rapid recovery, high safety profile, and no residual incapacitation, enabling a patient to safely leave the office shortly after a procedure.²⁰

Nitrous oxide was studied in an RCT of 74 young (12-20 years of age) nulliparous patients and found to be effective for decreasing pain during IUD insertion and increasing satisfaction with the procedure.²⁰ However, another study of 80 nulliparous patients (aged 13-45 years) did not find any reduction in pain during the insertion procedure.²¹

Prostaglandin analogues

Misoprostol is a synthetic prostaglandin E1 analog that causes cervical softening, uterine contractions, and cervical dilation. Dinoprostone is a synthetic prostaglandin E2 analog that has similar effects on the cervix and uterus. These properties have made it a useful tool in minor gynecologic procedures, such as first trimester uterine aspiration and hysteroscopy. However, both have the disadvantage of causing adverse effects on gastric smooth muscle, leading to nausea, vomiting, diarrhea, and uncomfortable gastric cramping.

Several RCTs have examined the use of misoprostol administration approximately 2 to 4 hours before IUD placement. No studies found any improvement in pain during IUD insertion, but this likely is due to the discomfort caused by the use of misoprostol itself.⁹ A meta-analysis and systematic review of 14 studies found no effect on reducing the pain associated with IUD placement but did find that providers had an easier time with cervical dilation in patients who received it. The meta-analysis also demonstrated that patients receiving vaginal misoprostol were less likely to have gastric side effects.²² In another review of 5 RCTs using 400 µg to 600 µg of misoprostol for cervical preparation, Gemzell-Danielsson et al found reductions in mean pain scores with placement specifically among patients with previous cesarean delivery and/or nulliparous patients.⁸

In an RCT, Ashour and colleagues looked at the use of dinoprostone 3 mg compared with placebo in 160 patients and found that those in the dinoprostone group had less pain during and 15 minutes after the procedure, as well as ease of insertion and overall higher satisfaction with the IUD placement. Dinoprostone traditionally is used for labor induction in the United States and tends to be much more expensive than misoprostol, but it shows the most promise of the prostaglandins in making IUD placement more comfortable.

Conclusion: Integrating evidence and experience

Providers tend to underestimate the pain and anxiety experienced by their patients undergoing IUD insertion. Patients’ concerns about pain and anxiety increase their risk for experiencing pain during IUD insertion. Patient anxieties, and thus, pain may be allayed by offering support and education prior to placement, offering tailored pharmacologic strategies to mitigate pain, and offering supportive and distraction measures during the insertion process. ●

CASE Patient concerned about hormonal contraception’s impact on lactation

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

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

Breastfeeding prevalence—and challenges

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

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

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

ILLUSTRATION: KIMBERLY MARTENS FOR OBG MANAGEMENT

Physiology of breastfeeding

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

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

Guidance on breastfeeding and hormonal contraception initiation

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

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

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

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

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

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

 

 

How can clinicians integrate evidence into contraception counseling?

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

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

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

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

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

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

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

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

CASE Patient concerned about hormonal contraception’s impact on lactation

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

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

Breastfeeding prevalence—and challenges

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

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

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

ILLUSTRATION: KIMBERLY MARTENS FOR OBG MANAGEMENT

Physiology of breastfeeding

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

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

Guidance on breastfeeding and hormonal contraception initiation

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

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

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

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

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

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

 

 

How can clinicians integrate evidence into contraception counseling?

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

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

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

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

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

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

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

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

CASE Patient concerned about hormonal contraception’s impact on lactation

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

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

Breastfeeding prevalence—and challenges

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

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

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

ILLUSTRATION: KIMBERLY MARTENS FOR OBG MANAGEMENT

Physiology of breastfeeding

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

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

Guidance on breastfeeding and hormonal contraception initiation

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

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

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

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

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

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

 

 

How can clinicians integrate evidence into contraception counseling?

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

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

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

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

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

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

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

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

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

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

Breast cancer risk

Variables that affect risk

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

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

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

Breast cancer risk assessment

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

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

Breast cancer screening: Efficacy and harms

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

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

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

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

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

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

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

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

Continue to: High-risk screening...

 

 

High-risk screening

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

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

Screening in patients with dense breasts

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

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

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

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

Equitable screening

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

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

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

 

 

We have done well, can we do better?

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

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

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

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

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

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

Looking forward

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

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

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

Breast cancer risk

Variables that affect risk

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

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

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

Breast cancer risk assessment

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

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

Breast cancer screening: Efficacy and harms

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

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

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

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

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

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

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

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

Continue to: High-risk screening...

 

 

High-risk screening

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

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

Screening in patients with dense breasts

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

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

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

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

Equitable screening

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

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

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

 

 

We have done well, can we do better?

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

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

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

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

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

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

Looking forward

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

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

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

Breast cancer risk

Variables that affect risk

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

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

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

Breast cancer risk assessment

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

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

Breast cancer screening: Efficacy and harms

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

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

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

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

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

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

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

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

Continue to: High-risk screening...

 

 

High-risk screening

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

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

Screening in patients with dense breasts

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

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

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

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

Equitable screening

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

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

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

 

 

We have done well, can we do better?

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

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

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

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

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

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

Looking forward

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

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

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

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

Know SERMs’ effects on bone health for appropriate prescribing

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

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

A rundown on 4 SERMs and their effects on bone

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

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

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

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

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

 

 

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

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

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

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

The gut microbiome’s relationship with bone health

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

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

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

Composition of the microbiota

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

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

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

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

 

 

Sarcopenia, osteoporosis, and frailty: A fracture risk triple play

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

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

Study details

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

Frailty confers additional risk

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

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

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

 

 

Denosumab effective in reducing falls, strengthening muscle

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

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

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

Denosumab found to increase muscle strength

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

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

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

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

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

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

Know SERMs’ effects on bone health for appropriate prescribing

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

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

A rundown on 4 SERMs and their effects on bone

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

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

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

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

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

 

 

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

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

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

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

The gut microbiome’s relationship with bone health

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

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

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

Composition of the microbiota

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

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

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

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

 

 

Sarcopenia, osteoporosis, and frailty: A fracture risk triple play

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

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

Study details

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

Frailty confers additional risk

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

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

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

 

 

Denosumab effective in reducing falls, strengthening muscle

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

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

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

Denosumab found to increase muscle strength

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

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

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

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

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

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

Know SERMs’ effects on bone health for appropriate prescribing

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

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

A rundown on 4 SERMs and their effects on bone

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

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

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

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

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

 

 

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

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

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

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

The gut microbiome’s relationship with bone health

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

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

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

Composition of the microbiota

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

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

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

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

 

 

Sarcopenia, osteoporosis, and frailty: A fracture risk triple play

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

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

Study details

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

Frailty confers additional risk

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

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

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

 

 

Denosumab effective in reducing falls, strengthening muscle

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

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

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

Denosumab found to increase muscle strength

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

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

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

Allergic contact dermatitis (ACD) is a delayed type IV hypersensitivity reaction that usually manifests with eczematous lesions within hours to days after exposure to a contact allergen. The primary treatment of ACD consists of allergen avoidance, but medications also may be necessary to manage symptoms, particularly in cases where avoidance alone does not lead to resolution of dermatitis. At present, no medical therapies are explicitly approved for use in the management of ACD. Janus kinase (JAK) inhibitors are a class of small molecule inhibitors that are used for the treatment of a range of inflammatory diseases, such as rheumatoid arthritis and psoriatic arthritis. Several oral and topical JAK inhibitors also have recently been approved by the US Food and Drug Administration (FDA) for atopic dermatitis (AD). In this article, we discuss this important class of medications and the role that they may play in the off-label management of refractory ACD.

JAK/STAT Signaling Pathway

The JAK/signal transducer and activator of transcription (STAT) pathway plays a crucial role in many biologic processes. Notably, JAK/STAT signaling is involved in the development and regulation of the immune system.¹ The cascade begins when a particular transmembrane receptor binds a ligand, such as an interferon or interleukin.² Upon ligand binding, the receptor dimerizes or oligomerizes, bringing the relevant JAK proteins into close approximation to each other.³ This allows the JAK proteins to autophosphorylate or transphosphorylate.^2-4 Phosphorylation activates the JAK proteins and increases their kinase activity.³ In humans, there are 4 JAK proteins: JAK1, JAK2, JAK3, and tyrosine kinase 2.⁴ When activated, the JAK proteins phosphorylate specific tyrosine residues on the receptor, which creates a docking site for STAT proteins. After binding, the STAT proteins then are phosphorylated, leading to their dimerization and translocation to the nucleus.^2,3 Once in the nucleus, the STAT proteins act as transcription factors for target genes.³

JAK Inhibitors

Janus kinase inhibitors are immunomodulatory medications that work through inhibition of 1 or more of the JAK proteins in the JAK/STAT pathway. Through this mechanism, JAK inhibitors can impede the activity of proinflammatory cytokines and T cells.⁴ A brief overview of the commercially available JAK inhibitors in Europe, Japan, and the United States is provided in the Table.^5-29

Of the approved JAK inhibitors, more than 40% are indicated for AD. The first JAK inhibitor to be approved in the topical form was delgocitinib in 2020 in Japan.⁵ In a phase 3 trial, delgocitinib demonstrated significant reductions in modified Eczema Area and Severity Index (EASI) score (P<.001) as well as Peak Pruritus Numerical Rating Scale (P<.001) when compared with vehicle.³⁰ Topical ruxolitinib soon followed when its approval for AD was announced by the FDA in 2021.³¹ Results from 2 phase 3 trials found that significantly more patients achieved investigator global assessment (IGA) treatment success (P<.0001) and a significant reduction in itch as measured by the Peak Pruritus Numerical Rating Scale (P<.001) with topical ruxolitinib vs vehicle.³²

The first oral JAK inhibitor to attain approval for AD was baricitinib in Europe and Japan, but it is not currently approved for this indication in the United States by the FDA.^11,12,33 Consistent findings across phase 3 trials revealed that baricitinib was more effective at achieving IGA treatment success and improved EASI scores compared with placebo.³³

Upadacitinib, another oral JAK inhibitor, was subsequently approved for AD in Europe and Japan in 2021 and in the United States in early 2022.^5,9,26,27 Two replicate phase 3 trials demonstrated significant improvement in EASI score, itch, and quality of life with upadacitinib compared with placebo (P<.0001).³⁴ Abrocitinib was granted FDA approval for AD in the same time period, with phase 3 trials exhibiting greater responses in IGA and EASI scores vs placebo.³⁵

Potential for Use in ACD

Given the successful use of JAK inhibitors in the management of AD, there is optimism that these medications also may have potential application in ACD. Recent literature suggests that the 2 conditions may be more closely related mechanistically than previously understood. As a result, AD and ACD often are managed with the same therapeutic agents.³⁶

Although the exact etiology of ACD is still being elucidated, activation of T cells and cytokines plays an important role.³⁷ Notably, more than 40 cytokines exert their effects through the JAK/STAT signaling pathway, including IL-2, IL-6, IL-17, IL-22, and IFN-γ.^37,38 A study on nickel contact allergy revealed that JAK/STAT activation may regulate the balance between IL-12 and IL-23 and increase type 1 T-helper (T_H1) polarization.³⁹ Skin inflammation and chronic pruritus, which are major components of ACD, also are thought to be mediated in part by JAK signaling.^34,40

Animal studies have suggested that JAK inhibitors may show benefit in the management of ACD. Rats with oxazolone-induced ACD were found to have less swelling and epidermal thickening in the area of induced dermatitis after treatment with oral tofacitinib, comparable to the effects of cyclosporine. Tofacitinib was presumed to exert its effects through cytokine suppression, particularly that of IFN-γ, IL-22, and tumor necrosis factor α.⁴¹ In a separate study on mice with toluene-2,4-diisocyanate–induced ACD, both tofacitinib and another JAK inhibitor, oclacitinib, demonstrated inhibition of cytokine production, migration, and maturation of bone marrow–derived dendritic cells. Both topical and oral formulations of these 2 JAK inhibitors also were found to decrease scratching behavior; only the topicals improved ear thickness (used as a marker of skin inflammation), suggesting potential benefits to local application.⁴² In a murine model, oral delgocitinib also attenuated contact hypersensitivity via inhibition of antigen-specific T-cell proliferation and cytokine production.³⁷ Finally, in a randomized clinical trial conducted on dogs with allergic dermatitis (of which 10% were presumed to be from contact allergy), oral oclacitinib significantly reduced pruritus and clinical severity scores vs placebo (P<.0001).⁴³

There also are early clinical studies and case reports highlighting the effective use of JAK inhibitors in the management of ACD in humans. A 37-year-old man with occupational airborne ACD to Compositae saw full clearance of his dermatitis with daily oral abrocitinib after topical corticosteroids and dupilumab failed.⁴⁴ Another patient, a 57-year-old woman, had near-complete resolution of chronic Parthenium-induced airborne ACD after starting twice-daily oral tofacitinib. Allergen avoidance, as well as multiple medications, including topical and oral corticosteroids, topical calcineurin inhibitors, and azathioprine, previously failed in this patient.⁴⁵ Finally, a phase 2 study on patients with irritant and nonirritant chronic hand eczema found that significantly more patients achieved treatment success (as measured by the physician global assessment) with topical delgocitinib vs vehicle (P=.009).⁴⁶ Chronic hand eczema may be due to a variety of causes, including AD, irritant contact dermatitis, and ACD. Thus, these studies begin to highlight the potential role for JAK inhibitors in the management of refractory ACD.

Side Effects of JAK Inhibitors

The safety profile of JAK inhibitors must be taken into consideration. In general, topical JAK inhibitors are safe and well tolerated, with the majority of adverse events (AEs) seen in clinical trials considered mild or unrelated to the medication.^30,32 Nasopharyngitis, local skin infection, and acne were reported; a systematic review found no increased risk of AEs with topical JAK inhibitors compared with placebo.^30,32,47 Application-site reactions, a common concern among the existing topical calcineurin and phosphodiesterase 4 inhibitors, were rare (approximately 2% of patients).⁴⁷ The most frequent AEs seen in clinical trials of oral JAK inhibitors included acne, nasopharyngitis/upper respiratory tract infections, nausea, and headache.^33-35 Herpes simplex virus infection and worsening of AD also were seen. Although elevations in creatine phosphokinase levels were reported, patients often were asymptomatic and elevations were related to exercise or resolved without treatment interruption.^33-35

As a class, JAK inhibitors carry a boxed warning for serious infections, malignancy, major adverse cardiovascular events, thrombosis, and mortality. The FDA placed this label on JAK inhibitors because of the results of a randomized controlled trial of oral tofacitinib vs tumor necrosis factor α inhibitors in RA.^48,49 Notably, participants in the trial had to be 50 years or older and have at least 1 additional cardiovascular risk factor. Postmarket safety data are still being collected for patients with AD and other dermatologic conditions, but the findings of safety analyses have been reassuring to date.^50,51 Regular follow-up and routine laboratory monitoring are recommended for any patient started on an oral JAK inhibitor, which often includes monitoring of the complete blood cell count, comprehensive metabolic panel, and lipids, as well as baseline screening for tuberculosis and hepatitis.^52,53 For topical JAK inhibitors, no specific laboratory monitoring is recommended.

Finally, it must be considered that the challenges of off-label prescribing combined with high costs may limit access to JAK inhibitors for use in ACD.

Final Interpretation

Early investigations, including studies on animals and humans, suggest that JAK inhibitors are a promising option in the management of treatment-refractory ACD. Patients and providers should be aware of both the benefits and known side effects of JAK inhibitors prior to treatment initiation.

Allergic contact dermatitis (ACD) is a delayed type IV hypersensitivity reaction that usually manifests with eczematous lesions within hours to days after exposure to a contact allergen. The primary treatment of ACD consists of allergen avoidance, but medications also may be necessary to manage symptoms, particularly in cases where avoidance alone does not lead to resolution of dermatitis. At present, no medical therapies are explicitly approved for use in the management of ACD. Janus kinase (JAK) inhibitors are a class of small molecule inhibitors that are used for the treatment of a range of inflammatory diseases, such as rheumatoid arthritis and psoriatic arthritis. Several oral and topical JAK inhibitors also have recently been approved by the US Food and Drug Administration (FDA) for atopic dermatitis (AD). In this article, we discuss this important class of medications and the role that they may play in the off-label management of refractory ACD.

JAK/STAT Signaling Pathway

The JAK/signal transducer and activator of transcription (STAT) pathway plays a crucial role in many biologic processes. Notably, JAK/STAT signaling is involved in the development and regulation of the immune system.¹ The cascade begins when a particular transmembrane receptor binds a ligand, such as an interferon or interleukin.² Upon ligand binding, the receptor dimerizes or oligomerizes, bringing the relevant JAK proteins into close approximation to each other.³ This allows the JAK proteins to autophosphorylate or transphosphorylate.^2-4 Phosphorylation activates the JAK proteins and increases their kinase activity.³ In humans, there are 4 JAK proteins: JAK1, JAK2, JAK3, and tyrosine kinase 2.⁴ When activated, the JAK proteins phosphorylate specific tyrosine residues on the receptor, which creates a docking site for STAT proteins. After binding, the STAT proteins then are phosphorylated, leading to their dimerization and translocation to the nucleus.^2,3 Once in the nucleus, the STAT proteins act as transcription factors for target genes.³

JAK Inhibitors

Janus kinase inhibitors are immunomodulatory medications that work through inhibition of 1 or more of the JAK proteins in the JAK/STAT pathway. Through this mechanism, JAK inhibitors can impede the activity of proinflammatory cytokines and T cells.⁴ A brief overview of the commercially available JAK inhibitors in Europe, Japan, and the United States is provided in the Table.^5-29

Of the approved JAK inhibitors, more than 40% are indicated for AD. The first JAK inhibitor to be approved in the topical form was delgocitinib in 2020 in Japan.⁵ In a phase 3 trial, delgocitinib demonstrated significant reductions in modified Eczema Area and Severity Index (EASI) score (P<.001) as well as Peak Pruritus Numerical Rating Scale (P<.001) when compared with vehicle.³⁰ Topical ruxolitinib soon followed when its approval for AD was announced by the FDA in 2021.³¹ Results from 2 phase 3 trials found that significantly more patients achieved investigator global assessment (IGA) treatment success (P<.0001) and a significant reduction in itch as measured by the Peak Pruritus Numerical Rating Scale (P<.001) with topical ruxolitinib vs vehicle.³²

The first oral JAK inhibitor to attain approval for AD was baricitinib in Europe and Japan, but it is not currently approved for this indication in the United States by the FDA.^11,12,33 Consistent findings across phase 3 trials revealed that baricitinib was more effective at achieving IGA treatment success and improved EASI scores compared with placebo.³³

Upadacitinib, another oral JAK inhibitor, was subsequently approved for AD in Europe and Japan in 2021 and in the United States in early 2022.^5,9,26,27 Two replicate phase 3 trials demonstrated significant improvement in EASI score, itch, and quality of life with upadacitinib compared with placebo (P<.0001).³⁴ Abrocitinib was granted FDA approval for AD in the same time period, with phase 3 trials exhibiting greater responses in IGA and EASI scores vs placebo.³⁵

Potential for Use in ACD

Given the successful use of JAK inhibitors in the management of AD, there is optimism that these medications also may have potential application in ACD. Recent literature suggests that the 2 conditions may be more closely related mechanistically than previously understood. As a result, AD and ACD often are managed with the same therapeutic agents.³⁶

Although the exact etiology of ACD is still being elucidated, activation of T cells and cytokines plays an important role.³⁷ Notably, more than 40 cytokines exert their effects through the JAK/STAT signaling pathway, including IL-2, IL-6, IL-17, IL-22, and IFN-γ.^37,38 A study on nickel contact allergy revealed that JAK/STAT activation may regulate the balance between IL-12 and IL-23 and increase type 1 T-helper (T_H1) polarization.³⁹ Skin inflammation and chronic pruritus, which are major components of ACD, also are thought to be mediated in part by JAK signaling.^34,40

Animal studies have suggested that JAK inhibitors may show benefit in the management of ACD. Rats with oxazolone-induced ACD were found to have less swelling and epidermal thickening in the area of induced dermatitis after treatment with oral tofacitinib, comparable to the effects of cyclosporine. Tofacitinib was presumed to exert its effects through cytokine suppression, particularly that of IFN-γ, IL-22, and tumor necrosis factor α.⁴¹ In a separate study on mice with toluene-2,4-diisocyanate–induced ACD, both tofacitinib and another JAK inhibitor, oclacitinib, demonstrated inhibition of cytokine production, migration, and maturation of bone marrow–derived dendritic cells. Both topical and oral formulations of these 2 JAK inhibitors also were found to decrease scratching behavior; only the topicals improved ear thickness (used as a marker of skin inflammation), suggesting potential benefits to local application.⁴² In a murine model, oral delgocitinib also attenuated contact hypersensitivity via inhibition of antigen-specific T-cell proliferation and cytokine production.³⁷ Finally, in a randomized clinical trial conducted on dogs with allergic dermatitis (of which 10% were presumed to be from contact allergy), oral oclacitinib significantly reduced pruritus and clinical severity scores vs placebo (P<.0001).⁴³

There also are early clinical studies and case reports highlighting the effective use of JAK inhibitors in the management of ACD in humans. A 37-year-old man with occupational airborne ACD to Compositae saw full clearance of his dermatitis with daily oral abrocitinib after topical corticosteroids and dupilumab failed.⁴⁴ Another patient, a 57-year-old woman, had near-complete resolution of chronic Parthenium-induced airborne ACD after starting twice-daily oral tofacitinib. Allergen avoidance, as well as multiple medications, including topical and oral corticosteroids, topical calcineurin inhibitors, and azathioprine, previously failed in this patient.⁴⁵ Finally, a phase 2 study on patients with irritant and nonirritant chronic hand eczema found that significantly more patients achieved treatment success (as measured by the physician global assessment) with topical delgocitinib vs vehicle (P=.009).⁴⁶ Chronic hand eczema may be due to a variety of causes, including AD, irritant contact dermatitis, and ACD. Thus, these studies begin to highlight the potential role for JAK inhibitors in the management of refractory ACD.

Side Effects of JAK Inhibitors

The safety profile of JAK inhibitors must be taken into consideration. In general, topical JAK inhibitors are safe and well tolerated, with the majority of adverse events (AEs) seen in clinical trials considered mild or unrelated to the medication.^30,32 Nasopharyngitis, local skin infection, and acne were reported; a systematic review found no increased risk of AEs with topical JAK inhibitors compared with placebo.^30,32,47 Application-site reactions, a common concern among the existing topical calcineurin and phosphodiesterase 4 inhibitors, were rare (approximately 2% of patients).⁴⁷ The most frequent AEs seen in clinical trials of oral JAK inhibitors included acne, nasopharyngitis/upper respiratory tract infections, nausea, and headache.^33-35 Herpes simplex virus infection and worsening of AD also were seen. Although elevations in creatine phosphokinase levels were reported, patients often were asymptomatic and elevations were related to exercise or resolved without treatment interruption.^33-35

As a class, JAK inhibitors carry a boxed warning for serious infections, malignancy, major adverse cardiovascular events, thrombosis, and mortality. The FDA placed this label on JAK inhibitors because of the results of a randomized controlled trial of oral tofacitinib vs tumor necrosis factor α inhibitors in RA.^48,49 Notably, participants in the trial had to be 50 years or older and have at least 1 additional cardiovascular risk factor. Postmarket safety data are still being collected for patients with AD and other dermatologic conditions, but the findings of safety analyses have been reassuring to date.^50,51 Regular follow-up and routine laboratory monitoring are recommended for any patient started on an oral JAK inhibitor, which often includes monitoring of the complete blood cell count, comprehensive metabolic panel, and lipids, as well as baseline screening for tuberculosis and hepatitis.^52,53 For topical JAK inhibitors, no specific laboratory monitoring is recommended.

Finally, it must be considered that the challenges of off-label prescribing combined with high costs may limit access to JAK inhibitors for use in ACD.

Final Interpretation

Early investigations, including studies on animals and humans, suggest that JAK inhibitors are a promising option in the management of treatment-refractory ACD. Patients and providers should be aware of both the benefits and known side effects of JAK inhibitors prior to treatment initiation.

Allergic contact dermatitis (ACD) is a delayed type IV hypersensitivity reaction that usually manifests with eczematous lesions within hours to days after exposure to a contact allergen. The primary treatment of ACD consists of allergen avoidance, but medications also may be necessary to manage symptoms, particularly in cases where avoidance alone does not lead to resolution of dermatitis. At present, no medical therapies are explicitly approved for use in the management of ACD. Janus kinase (JAK) inhibitors are a class of small molecule inhibitors that are used for the treatment of a range of inflammatory diseases, such as rheumatoid arthritis and psoriatic arthritis. Several oral and topical JAK inhibitors also have recently been approved by the US Food and Drug Administration (FDA) for atopic dermatitis (AD). In this article, we discuss this important class of medications and the role that they may play in the off-label management of refractory ACD.

JAK/STAT Signaling Pathway

The JAK/signal transducer and activator of transcription (STAT) pathway plays a crucial role in many biologic processes. Notably, JAK/STAT signaling is involved in the development and regulation of the immune system.¹ The cascade begins when a particular transmembrane receptor binds a ligand, such as an interferon or interleukin.² Upon ligand binding, the receptor dimerizes or oligomerizes, bringing the relevant JAK proteins into close approximation to each other.³ This allows the JAK proteins to autophosphorylate or transphosphorylate.^2-4 Phosphorylation activates the JAK proteins and increases their kinase activity.³ In humans, there are 4 JAK proteins: JAK1, JAK2, JAK3, and tyrosine kinase 2.⁴ When activated, the JAK proteins phosphorylate specific tyrosine residues on the receptor, which creates a docking site for STAT proteins. After binding, the STAT proteins then are phosphorylated, leading to their dimerization and translocation to the nucleus.^2,3 Once in the nucleus, the STAT proteins act as transcription factors for target genes.³

JAK Inhibitors

Janus kinase inhibitors are immunomodulatory medications that work through inhibition of 1 or more of the JAK proteins in the JAK/STAT pathway. Through this mechanism, JAK inhibitors can impede the activity of proinflammatory cytokines and T cells.⁴ A brief overview of the commercially available JAK inhibitors in Europe, Japan, and the United States is provided in the Table.^5-29

Of the approved JAK inhibitors, more than 40% are indicated for AD. The first JAK inhibitor to be approved in the topical form was delgocitinib in 2020 in Japan.⁵ In a phase 3 trial, delgocitinib demonstrated significant reductions in modified Eczema Area and Severity Index (EASI) score (P<.001) as well as Peak Pruritus Numerical Rating Scale (P<.001) when compared with vehicle.³⁰ Topical ruxolitinib soon followed when its approval for AD was announced by the FDA in 2021.³¹ Results from 2 phase 3 trials found that significantly more patients achieved investigator global assessment (IGA) treatment success (P<.0001) and a significant reduction in itch as measured by the Peak Pruritus Numerical Rating Scale (P<.001) with topical ruxolitinib vs vehicle.³²

The first oral JAK inhibitor to attain approval for AD was baricitinib in Europe and Japan, but it is not currently approved for this indication in the United States by the FDA.^11,12,33 Consistent findings across phase 3 trials revealed that baricitinib was more effective at achieving IGA treatment success and improved EASI scores compared with placebo.³³

Upadacitinib, another oral JAK inhibitor, was subsequently approved for AD in Europe and Japan in 2021 and in the United States in early 2022.^5,9,26,27 Two replicate phase 3 trials demonstrated significant improvement in EASI score, itch, and quality of life with upadacitinib compared with placebo (P<.0001).³⁴ Abrocitinib was granted FDA approval for AD in the same time period, with phase 3 trials exhibiting greater responses in IGA and EASI scores vs placebo.³⁵

Potential for Use in ACD

Given the successful use of JAK inhibitors in the management of AD, there is optimism that these medications also may have potential application in ACD. Recent literature suggests that the 2 conditions may be more closely related mechanistically than previously understood. As a result, AD and ACD often are managed with the same therapeutic agents.³⁶

Although the exact etiology of ACD is still being elucidated, activation of T cells and cytokines plays an important role.³⁷ Notably, more than 40 cytokines exert their effects through the JAK/STAT signaling pathway, including IL-2, IL-6, IL-17, IL-22, and IFN-γ.^37,38 A study on nickel contact allergy revealed that JAK/STAT activation may regulate the balance between IL-12 and IL-23 and increase type 1 T-helper (T_H1) polarization.³⁹ Skin inflammation and chronic pruritus, which are major components of ACD, also are thought to be mediated in part by JAK signaling.^34,40

Animal studies have suggested that JAK inhibitors may show benefit in the management of ACD. Rats with oxazolone-induced ACD were found to have less swelling and epidermal thickening in the area of induced dermatitis after treatment with oral tofacitinib, comparable to the effects of cyclosporine. Tofacitinib was presumed to exert its effects through cytokine suppression, particularly that of IFN-γ, IL-22, and tumor necrosis factor α.⁴¹ In a separate study on mice with toluene-2,4-diisocyanate–induced ACD, both tofacitinib and another JAK inhibitor, oclacitinib, demonstrated inhibition of cytokine production, migration, and maturation of bone marrow–derived dendritic cells. Both topical and oral formulations of these 2 JAK inhibitors also were found to decrease scratching behavior; only the topicals improved ear thickness (used as a marker of skin inflammation), suggesting potential benefits to local application.⁴² In a murine model, oral delgocitinib also attenuated contact hypersensitivity via inhibition of antigen-specific T-cell proliferation and cytokine production.³⁷ Finally, in a randomized clinical trial conducted on dogs with allergic dermatitis (of which 10% were presumed to be from contact allergy), oral oclacitinib significantly reduced pruritus and clinical severity scores vs placebo (P<.0001).⁴³

There also are early clinical studies and case reports highlighting the effective use of JAK inhibitors in the management of ACD in humans. A 37-year-old man with occupational airborne ACD to Compositae saw full clearance of his dermatitis with daily oral abrocitinib after topical corticosteroids and dupilumab failed.⁴⁴ Another patient, a 57-year-old woman, had near-complete resolution of chronic Parthenium-induced airborne ACD after starting twice-daily oral tofacitinib. Allergen avoidance, as well as multiple medications, including topical and oral corticosteroids, topical calcineurin inhibitors, and azathioprine, previously failed in this patient.⁴⁵ Finally, a phase 2 study on patients with irritant and nonirritant chronic hand eczema found that significantly more patients achieved treatment success (as measured by the physician global assessment) with topical delgocitinib vs vehicle (P=.009).⁴⁶ Chronic hand eczema may be due to a variety of causes, including AD, irritant contact dermatitis, and ACD. Thus, these studies begin to highlight the potential role for JAK inhibitors in the management of refractory ACD.

Side Effects of JAK Inhibitors

The safety profile of JAK inhibitors must be taken into consideration. In general, topical JAK inhibitors are safe and well tolerated, with the majority of adverse events (AEs) seen in clinical trials considered mild or unrelated to the medication.^30,32 Nasopharyngitis, local skin infection, and acne were reported; a systematic review found no increased risk of AEs with topical JAK inhibitors compared with placebo.^30,32,47 Application-site reactions, a common concern among the existing topical calcineurin and phosphodiesterase 4 inhibitors, were rare (approximately 2% of patients).⁴⁷ The most frequent AEs seen in clinical trials of oral JAK inhibitors included acne, nasopharyngitis/upper respiratory tract infections, nausea, and headache.^33-35 Herpes simplex virus infection and worsening of AD also were seen. Although elevations in creatine phosphokinase levels were reported, patients often were asymptomatic and elevations were related to exercise or resolved without treatment interruption.^33-35

As a class, JAK inhibitors carry a boxed warning for serious infections, malignancy, major adverse cardiovascular events, thrombosis, and mortality. The FDA placed this label on JAK inhibitors because of the results of a randomized controlled trial of oral tofacitinib vs tumor necrosis factor α inhibitors in RA.^48,49 Notably, participants in the trial had to be 50 years or older and have at least 1 additional cardiovascular risk factor. Postmarket safety data are still being collected for patients with AD and other dermatologic conditions, but the findings of safety analyses have been reassuring to date.^50,51 Regular follow-up and routine laboratory monitoring are recommended for any patient started on an oral JAK inhibitor, which often includes monitoring of the complete blood cell count, comprehensive metabolic panel, and lipids, as well as baseline screening for tuberculosis and hepatitis.^52,53 For topical JAK inhibitors, no specific laboratory monitoring is recommended.

Finally, it must be considered that the challenges of off-label prescribing combined with high costs may limit access to JAK inhibitors for use in ACD.

Final Interpretation

Early investigations, including studies on animals and humans, suggest that JAK inhibitors are a promising option in the management of treatment-refractory ACD. Patients and providers should be aware of both the benefits and known side effects of JAK inhibitors prior to treatment initiation.

The landscape of psoriasis treatments has undergone rapid change within the last decade, and the dizzying speed of drug development has not slowed, with 4 notable entries into the psoriasis treatment armamentarium within the last year: tapinarof, roflumilast, deucravacitinib, and spesolimab. Several others are in late-stage development, and these therapies represent new mechanisms, pathways, and delivery systems that will meaningfully broaden the spectrum of treatment choices for our patients. However, it can be quite difficult to keep track of all of the medication options. This review aims to present the mechanisms and data on both newly available therapeutics for psoriasis and products in the pipeline that may have a major impact on our treatment paradigm for psoriasis in the near future.

Topical Treatments

Tapinarof—Tapinarof is a topical aryl hydrocarbon receptor (AhR)–modulating agent derived from a secondary metabolite produced by a bacterial symbiont of entomopathogenic nematodes.¹ Tapinarof binds and activates AhR, inducing a signaling cascade that suppresses the expression of helper T cells T_H17 and T_H22, upregulates skin barrier protein expression, and reduces epidermal oxidative stress.² This is a familiar mechanism, as AhR agonism is one of the pathways modulated by coal tar. Tapinarof’s overall effects on immune function, skin barrier integrity, and antioxidant activity show great promise for the treatment of plaque psoriasis.

Two phase 3 trials (N=1025) evaluated the efficacy and safety of once-daily tapinarof cream 1% for plaque psoriasis.³ A physician global assessment (PGA) score of 0/1 occurred in 35.4% to 40.2% of patients in the tapinarof group and in 6.0% of patients in the vehicle group. At week 12, 36.1% to 47.6% of patients treated with daily applications of tapinarof cream achieved a 75% reduction in their baseline psoriasis area and severity index (PASI 75) score compared with 6.9% to 10.2% in the vehicle group.³ In a long-term extension study, a substantial remittive effect of at least 4 months off tapinarof therapy was observed in patients who achieved complete clearance (PGA=0).⁴ Use of tapinarof cream was associated with folliculitis in up to 23.5% of patients.^3,4

Roflumilast—Phosphodiesterase 4 (PDE-4) is an intracellular enzyme involved in the regulation of cell proliferation, differentiation, and immune responses.⁵ The inhibition of PDE-4 decreases the expression of proinflammatory cytokines implicated in the pathogenesis of plaque psoriasis, such as tumor necrosis factor α, IFN-γ, and IL-2, IL-12, and IL-23.⁶ Phosphodiesterase 4–targeted therapies have been thoroughly explored to treat various inflammatory conditions, including atopic dermatitis and plaque psoriasis. The oral PDE-4 inhibitor apremilast was shown to achieve PASI 75 in approximately 30% of 562 patients, accompanied by severe gastrointestinal adverse events (AEs) including diarrhea and nausea associated with treatment.⁷ Local irritation from the topical PDE-4 inhibitor crisaborole for atopic dermatitis and psoriasis (where it only completed phase 2 trials) limits its widespread use. The lack of tolerable and effective treatment alternatives for psoriasis prompted the investigation of new PDE-4–targeted therapies.

Topical roflumilast is a selective, highly potent PDE-4 inhibitor with greater affinity for PDE-4 compared to crisaborole and apremilast.⁸ Two phase 3 trials (N=881) evaluated the efficacy and safety profile of roflumilast cream for plaque psoriasis, with a particular interest in its use for intertriginous areas.⁹ At week 8, 37.5% to 42.4% of roflumilast-treated patients achieved investigator global assessment (IGA) success compared with 6.1% to 6.9% of vehicle-treated patients. Intertriginous IGA success was observed in 68.1% to 71.2% of patients treated with roflumilast cream compared with 13.8% to 18.5% of vehicle-treated patients. At 8-week follow-up, 39.0% to 41.6% of roflumilast-treated patients achieved PASI 75 vs 5.3% to 7.6% of patients in the vehicle group. Few stinging, burning, or application-site reactions were reported with roflumilast, along with rare instances of gastrointestinal AEs (<4%).⁹

Oral Therapy

Deucravacitinib—Tyrosine kinase 2 (TYK2) mediates the intracellular signaling of the T_H17 and T_H1 inflammatory cytokines IL-12/IL-23 and type I interferons, respectively, the former of which are critical in the development of psoriasis via the Janus kinase (JAK) signal transducer and activator of transcription pathway.¹⁰ Deucravacitinib is an oral selective TYK2 allosteric inhibitor that binds to the regulatory domain of the enzyme rather than the active catalytic domain, where other TYK2 and JAK1, JAK2, and JAK3 inhibitors bind.¹¹ This unique inhibitory mechanism accounts for the high functional selectivity of deucravacitinib for TYK2 vs the closely related JAK1, JAK2, and JAK3 kinases, thus avoiding the pitfall of prior JAK inhibitors that were associated with major AEs, including an increased risk for serious infections, malignancies, and thrombosis.¹² The selective suppression of the inflammatory TYK2 pathway has the potential to shift future therapeutic targets to a narrower range of receptors that may contribute to favorable benefit-risk profiles.

Two phase 3 trials (N=1686) compared the efficacy and safety of deucravacitinib vs placebo and apremilast in adults with moderate to severe plaque psoriasis.^13,14 At week 16, 53.0% to 58.4% of deucravacitinib-treated patients achieved PASI 75 compared with 35.1% to 39.8% of apremilast-treated patients. At 16-week follow-up, static PGA response was observed in 49.5% to 53.6% of patients in the deucravacitinib group and 32.1% to 33.9% of the apremilast group. The most frequent AEs associated with deucravacitinib therapy were nasopharyngitis and upper respiratory tract infection, whereas headache, diarrhea, and nausea were more common with apremilast. Treatment with deucravacitinib caused no meaningful changes in laboratory parameters, which are known to change with JAK1, JAK2, and JAK3 inhibitors.^13,14 A long-term extension study demonstrated that deucravacitinib had persistent efficacy and consistent safety for up to 2 years.¹⁵

 

 

Other TYK2 Inhibitors in the Pipeline

Novel oral allosteric TYK2 inhibitors—VTX958 and NDI-034858—and the competitive TYK2 inhibitor PF-06826647 are being developed. Theoretically, these new allosteric inhibitors possess unique structural properties to provide greater TYK2 suppression while bypassing JAK1, JAK2, and JAK3 pathways that may contribute to improved efficacy and safety profiles compared with other TYK2 inhibitors such as deucravacitinib. The results of a phase 1b trial (ClinicalTrials.gov Identifier NCT04999839) showed a dose-dependent reduction of disease severity associated with NDI-034858 treatment for patients with moderate to severe plaque psoriasis, albeit in only 26 patients. At week 4, PASI 50 was achieved in 13%, 57%, and 40% of patients in the 5-, 10-, and 30-mg groups, respectively, compared with 0% in the placebo group.¹⁶ In a phase 2 trial of 179 patients, 46.5% and 33.0% of patients treated with 400 and 200 mg of PF-06826647, respectively, achieved PASI 90 at week 16. Conversely, dose-dependent laboratory abnormalities were observed with PF-06826647, including anemia, neutropenia, and increases in creatine phosphokinase.¹⁷ At high concentrations, PF-06826647 may disrupt JAK signaling pathways involved in hematopoiesis and renal functions owing to its mode of action as a competitive inhibitor. Overall, these agents are much farther from market, and long-term studies with larger diverse patient cohorts are required to adequately assess the efficacy and safety data of these novel oral TYK2 inhibitors for patients with psoriasis.

EDP1815—EDP1815 is an oral preparation of a single strain of Prevotella histicola being developed for the treatment of inflammatory diseases, including psoriasis. EDP1815 interacts with host intestinal immune cells through the small intestinal axis (SINTAX) to suppress systemic inflammation across the T_H1, T_H2, and T_H17 pathways. Therapy triggers broad immunomodulatory effects without causing systemic absorption, colonic colonization, or modification of the gut microbiome.¹⁸ In a phase 2 study (NCT04603027), the primary end point analysis, mean percentage change in PASI between treatment and placebo, demonstrated that at week 16, EDP1815 was superior to placebo with 80% to 90% probability across each cohort. At week 16, 25% to 32% of patients across the 3 cohorts treated with EDP1815 achieved PASI 50 compared with 12% of patients receiving placebo. Gastrointestinal AEs were comparable between treatment and placebo groups. These results suggest that SINTAX-targeted therapies may provide efficacious and safe immunomodulatory effects for patients with mild to moderate psoriasis, who often have limited treatment options. Although improvements may be mild, SINTAX-targeted therapies can be seen as a particularly attractive adjunctive treatment for patients with severe psoriasis taking other medications or as part of a treatment approach for a patient with milder psoriasis.

Biologics

Bimekizumab—Bimekizumab is a monoclonal IgG1 antibody that selectively inhibits IL-17A and IL-17F. Although IL-17A is a more potent cytokine, IL-17F may be more highly expressed in psoriatic lesional skin and independently contribute to the activation of proinflammatory signaling pathways implicated in the pathophysiology of psoriasis.¹⁹ Evidence suggests that dual inhibition of IL-17A and IL-17F may provide more complete suppression of inflammation and improved clinical responses than IL-17A inhibition alone.²⁰

Prior bimekizumab phase 3 clinical studies have shown both rapid and durable clinical improvements in skin clearance compared with placebo.²¹ Three phase 3 trials—BE VIVID (N=567),²² BE SURE (N=478),²³ and BE RADIANT (N=743)²⁴—assessed the efficacy and safety of bimekizumab vs the IL-12/IL-23 inhibitor ustekinumab, the tumor necrosis factor inhibitor adalimumab, and the selective IL-17A inhibitor secukinumab, respectively. At week 4, significantly more patients treated with bimekizumab (71%–77%) achieved PASI 75 than patients treated with ustekinumab (15%; P<.0001), adalimumab (31.4%; P<.001), or secukinumab (47.3%; P<.001).^22-24 After 16 weeks of treatment, PASI 90 was achieved by 85% to 86.2%, 50%, and 47.2% of patients treated with bimekizumab, ustekinumab, and adalimumab, respectively.^22,23 At week 16, PASI 100 was observed in 59% to 61.7%, 21%, 23.9%, and 48.9% of patients treated with bimekizumab, ustekinumab, adalimumab, and secukinumab, respectively. An IGA response (score of 0/1) at week 16 was achieved by 84% to 85.5%, 53%, 57.2%, and 78.6% of patients receiving bimekizumab, ustekinumab, adalimumab, and secukinumab, respectively.^22-24

The most common AEs in bimekizumab-treated patients were nasopharyngitis, oral candidiasis, and upper respiratory tract infection.^22-24 The dual inhibition of IL-17A and IL-17F suppresses host defenses against Candida at the oral mucosa, increasing the incidence of bimekizumab-associated oral candidiasis.²⁵ Despite the increased risk of Candida infections, these data suggest that inhibition of both IL-17A and IL-17F with bimekizumab may provide faster and greater clinical benefit for patients with moderate to severe plaque psoriasis than inhibition of IL-17A alone and other biologic therapies, as the PASI 100 clearance rates across the multiple comparator trials and the placebo-controlled pivotal trial are consistently the highest among any biologic for the treatment of psoriasis.

Spesolimab—The IL-36 pathway and IL-36 receptor genes have been linked to the pathogenesis of generalized pustular psoriasis.²⁶ In a phase 2 trial, 19 of 35 patients (54%) receiving an intravenous dose of spesolimab, an IL-36 receptor inhibitor, had a generalized pustular psoriasis PGA pustulation subscore of 0 (no visible pustules) at the end of week 1 vs 6% of patients in the placebo group.²⁷ A generalized pustular psoriasis PGA total score of 0 or 1 was observed in 43% (15/35) of spesolimab-treated patients compared with 11% (2/18) of patients in the placebo group. The most common AEs in patients treated with spesolimab were minor infections.²⁷ Two open-label phase 3 trials—NCT05200247 and NCT05239039—are underway to determine the long-term efficacy and safety of spesolimab in patients with generalized pustular psoriasis.

Conclusion

Although we have seen a renaissance in psoriasis therapies with the advent of biologics in the last 20 years, recent evidence shows that more innovation is underway. Just in the last year, 2 new mechanisms for treating psoriasis topically without steroids have come to fruition, and there have not been truly novel mechanisms for treating psoriasis topically since approvals for tazarotene and calcipotriene in the 1990s. An entirely new class—TYK2 inhibitors—was developed and landed in psoriasis first, greatly improving the efficacy measures attained with oral medications in general. Finally, an orphan diagnosis got its due with an ambitiously designed study looking at a previously unheard-of 1-week end point, but it comes for one of the few true dermatologic emergencies we encounter, generalized pustular psoriasis. We are fortunate to have so many meaningful new treatments available to us, and it is invigorating to see that even more efficacious biologics and treatments are coming, along with novel concepts such as a treatment affecting the microbiome. Now, we just need to make sure that our patients have the access they deserve to the wide array of available treatments.

The landscape of psoriasis treatments has undergone rapid change within the last decade, and the dizzying speed of drug development has not slowed, with 4 notable entries into the psoriasis treatment armamentarium within the last year: tapinarof, roflumilast, deucravacitinib, and spesolimab. Several others are in late-stage development, and these therapies represent new mechanisms, pathways, and delivery systems that will meaningfully broaden the spectrum of treatment choices for our patients. However, it can be quite difficult to keep track of all of the medication options. This review aims to present the mechanisms and data on both newly available therapeutics for psoriasis and products in the pipeline that may have a major impact on our treatment paradigm for psoriasis in the near future.

Topical Treatments

Tapinarof—Tapinarof is a topical aryl hydrocarbon receptor (AhR)–modulating agent derived from a secondary metabolite produced by a bacterial symbiont of entomopathogenic nematodes.¹ Tapinarof binds and activates AhR, inducing a signaling cascade that suppresses the expression of helper T cells T_H17 and T_H22, upregulates skin barrier protein expression, and reduces epidermal oxidative stress.² This is a familiar mechanism, as AhR agonism is one of the pathways modulated by coal tar. Tapinarof’s overall effects on immune function, skin barrier integrity, and antioxidant activity show great promise for the treatment of plaque psoriasis.

Two phase 3 trials (N=1025) evaluated the efficacy and safety of once-daily tapinarof cream 1% for plaque psoriasis.³ A physician global assessment (PGA) score of 0/1 occurred in 35.4% to 40.2% of patients in the tapinarof group and in 6.0% of patients in the vehicle group. At week 12, 36.1% to 47.6% of patients treated with daily applications of tapinarof cream achieved a 75% reduction in their baseline psoriasis area and severity index (PASI 75) score compared with 6.9% to 10.2% in the vehicle group.³ In a long-term extension study, a substantial remittive effect of at least 4 months off tapinarof therapy was observed in patients who achieved complete clearance (PGA=0).⁴ Use of tapinarof cream was associated with folliculitis in up to 23.5% of patients.^3,4

Roflumilast—Phosphodiesterase 4 (PDE-4) is an intracellular enzyme involved in the regulation of cell proliferation, differentiation, and immune responses.⁵ The inhibition of PDE-4 decreases the expression of proinflammatory cytokines implicated in the pathogenesis of plaque psoriasis, such as tumor necrosis factor α, IFN-γ, and IL-2, IL-12, and IL-23.⁶ Phosphodiesterase 4–targeted therapies have been thoroughly explored to treat various inflammatory conditions, including atopic dermatitis and plaque psoriasis. The oral PDE-4 inhibitor apremilast was shown to achieve PASI 75 in approximately 30% of 562 patients, accompanied by severe gastrointestinal adverse events (AEs) including diarrhea and nausea associated with treatment.⁷ Local irritation from the topical PDE-4 inhibitor crisaborole for atopic dermatitis and psoriasis (where it only completed phase 2 trials) limits its widespread use. The lack of tolerable and effective treatment alternatives for psoriasis prompted the investigation of new PDE-4–targeted therapies.

Topical roflumilast is a selective, highly potent PDE-4 inhibitor with greater affinity for PDE-4 compared to crisaborole and apremilast.⁸ Two phase 3 trials (N=881) evaluated the efficacy and safety profile of roflumilast cream for plaque psoriasis, with a particular interest in its use for intertriginous areas.⁹ At week 8, 37.5% to 42.4% of roflumilast-treated patients achieved investigator global assessment (IGA) success compared with 6.1% to 6.9% of vehicle-treated patients. Intertriginous IGA success was observed in 68.1% to 71.2% of patients treated with roflumilast cream compared with 13.8% to 18.5% of vehicle-treated patients. At 8-week follow-up, 39.0% to 41.6% of roflumilast-treated patients achieved PASI 75 vs 5.3% to 7.6% of patients in the vehicle group. Few stinging, burning, or application-site reactions were reported with roflumilast, along with rare instances of gastrointestinal AEs (<4%).⁹

Oral Therapy

Deucravacitinib—Tyrosine kinase 2 (TYK2) mediates the intracellular signaling of the T_H17 and T_H1 inflammatory cytokines IL-12/IL-23 and type I interferons, respectively, the former of which are critical in the development of psoriasis via the Janus kinase (JAK) signal transducer and activator of transcription pathway.¹⁰ Deucravacitinib is an oral selective TYK2 allosteric inhibitor that binds to the regulatory domain of the enzyme rather than the active catalytic domain, where other TYK2 and JAK1, JAK2, and JAK3 inhibitors bind.¹¹ This unique inhibitory mechanism accounts for the high functional selectivity of deucravacitinib for TYK2 vs the closely related JAK1, JAK2, and JAK3 kinases, thus avoiding the pitfall of prior JAK inhibitors that were associated with major AEs, including an increased risk for serious infections, malignancies, and thrombosis.¹² The selective suppression of the inflammatory TYK2 pathway has the potential to shift future therapeutic targets to a narrower range of receptors that may contribute to favorable benefit-risk profiles.

Two phase 3 trials (N=1686) compared the efficacy and safety of deucravacitinib vs placebo and apremilast in adults with moderate to severe plaque psoriasis.^13,14 At week 16, 53.0% to 58.4% of deucravacitinib-treated patients achieved PASI 75 compared with 35.1% to 39.8% of apremilast-treated patients. At 16-week follow-up, static PGA response was observed in 49.5% to 53.6% of patients in the deucravacitinib group and 32.1% to 33.9% of the apremilast group. The most frequent AEs associated with deucravacitinib therapy were nasopharyngitis and upper respiratory tract infection, whereas headache, diarrhea, and nausea were more common with apremilast. Treatment with deucravacitinib caused no meaningful changes in laboratory parameters, which are known to change with JAK1, JAK2, and JAK3 inhibitors.^13,14 A long-term extension study demonstrated that deucravacitinib had persistent efficacy and consistent safety for up to 2 years.¹⁵

 

 

Other TYK2 Inhibitors in the Pipeline

Novel oral allosteric TYK2 inhibitors—VTX958 and NDI-034858—and the competitive TYK2 inhibitor PF-06826647 are being developed. Theoretically, these new allosteric inhibitors possess unique structural properties to provide greater TYK2 suppression while bypassing JAK1, JAK2, and JAK3 pathways that may contribute to improved efficacy and safety profiles compared with other TYK2 inhibitors such as deucravacitinib. The results of a phase 1b trial (ClinicalTrials.gov Identifier NCT04999839) showed a dose-dependent reduction of disease severity associated with NDI-034858 treatment for patients with moderate to severe plaque psoriasis, albeit in only 26 patients. At week 4, PASI 50 was achieved in 13%, 57%, and 40% of patients in the 5-, 10-, and 30-mg groups, respectively, compared with 0% in the placebo group.¹⁶ In a phase 2 trial of 179 patients, 46.5% and 33.0% of patients treated with 400 and 200 mg of PF-06826647, respectively, achieved PASI 90 at week 16. Conversely, dose-dependent laboratory abnormalities were observed with PF-06826647, including anemia, neutropenia, and increases in creatine phosphokinase.¹⁷ At high concentrations, PF-06826647 may disrupt JAK signaling pathways involved in hematopoiesis and renal functions owing to its mode of action as a competitive inhibitor. Overall, these agents are much farther from market, and long-term studies with larger diverse patient cohorts are required to adequately assess the efficacy and safety data of these novel oral TYK2 inhibitors for patients with psoriasis.

EDP1815—EDP1815 is an oral preparation of a single strain of Prevotella histicola being developed for the treatment of inflammatory diseases, including psoriasis. EDP1815 interacts with host intestinal immune cells through the small intestinal axis (SINTAX) to suppress systemic inflammation across the T_H1, T_H2, and T_H17 pathways. Therapy triggers broad immunomodulatory effects without causing systemic absorption, colonic colonization, or modification of the gut microbiome.¹⁸ In a phase 2 study (NCT04603027), the primary end point analysis, mean percentage change in PASI between treatment and placebo, demonstrated that at week 16, EDP1815 was superior to placebo with 80% to 90% probability across each cohort. At week 16, 25% to 32% of patients across the 3 cohorts treated with EDP1815 achieved PASI 50 compared with 12% of patients receiving placebo. Gastrointestinal AEs were comparable between treatment and placebo groups. These results suggest that SINTAX-targeted therapies may provide efficacious and safe immunomodulatory effects for patients with mild to moderate psoriasis, who often have limited treatment options. Although improvements may be mild, SINTAX-targeted therapies can be seen as a particularly attractive adjunctive treatment for patients with severe psoriasis taking other medications or as part of a treatment approach for a patient with milder psoriasis.

Biologics

Bimekizumab—Bimekizumab is a monoclonal IgG1 antibody that selectively inhibits IL-17A and IL-17F. Although IL-17A is a more potent cytokine, IL-17F may be more highly expressed in psoriatic lesional skin and independently contribute to the activation of proinflammatory signaling pathways implicated in the pathophysiology of psoriasis.¹⁹ Evidence suggests that dual inhibition of IL-17A and IL-17F may provide more complete suppression of inflammation and improved clinical responses than IL-17A inhibition alone.²⁰

Prior bimekizumab phase 3 clinical studies have shown both rapid and durable clinical improvements in skin clearance compared with placebo.²¹ Three phase 3 trials—BE VIVID (N=567),²² BE SURE (N=478),²³ and BE RADIANT (N=743)²⁴—assessed the efficacy and safety of bimekizumab vs the IL-12/IL-23 inhibitor ustekinumab, the tumor necrosis factor inhibitor adalimumab, and the selective IL-17A inhibitor secukinumab, respectively. At week 4, significantly more patients treated with bimekizumab (71%–77%) achieved PASI 75 than patients treated with ustekinumab (15%; P<.0001), adalimumab (31.4%; P<.001), or secukinumab (47.3%; P<.001).^22-24 After 16 weeks of treatment, PASI 90 was achieved by 85% to 86.2%, 50%, and 47.2% of patients treated with bimekizumab, ustekinumab, and adalimumab, respectively.^22,23 At week 16, PASI 100 was observed in 59% to 61.7%, 21%, 23.9%, and 48.9% of patients treated with bimekizumab, ustekinumab, adalimumab, and secukinumab, respectively. An IGA response (score of 0/1) at week 16 was achieved by 84% to 85.5%, 53%, 57.2%, and 78.6% of patients receiving bimekizumab, ustekinumab, adalimumab, and secukinumab, respectively.^22-24

The most common AEs in bimekizumab-treated patients were nasopharyngitis, oral candidiasis, and upper respiratory tract infection.^22-24 The dual inhibition of IL-17A and IL-17F suppresses host defenses against Candida at the oral mucosa, increasing the incidence of bimekizumab-associated oral candidiasis.²⁵ Despite the increased risk of Candida infections, these data suggest that inhibition of both IL-17A and IL-17F with bimekizumab may provide faster and greater clinical benefit for patients with moderate to severe plaque psoriasis than inhibition of IL-17A alone and other biologic therapies, as the PASI 100 clearance rates across the multiple comparator trials and the placebo-controlled pivotal trial are consistently the highest among any biologic for the treatment of psoriasis.

Spesolimab—The IL-36 pathway and IL-36 receptor genes have been linked to the pathogenesis of generalized pustular psoriasis.²⁶ In a phase 2 trial, 19 of 35 patients (54%) receiving an intravenous dose of spesolimab, an IL-36 receptor inhibitor, had a generalized pustular psoriasis PGA pustulation subscore of 0 (no visible pustules) at the end of week 1 vs 6% of patients in the placebo group.²⁷ A generalized pustular psoriasis PGA total score of 0 or 1 was observed in 43% (15/35) of spesolimab-treated patients compared with 11% (2/18) of patients in the placebo group. The most common AEs in patients treated with spesolimab were minor infections.²⁷ Two open-label phase 3 trials—NCT05200247 and NCT05239039—are underway to determine the long-term efficacy and safety of spesolimab in patients with generalized pustular psoriasis.

Conclusion

Although we have seen a renaissance in psoriasis therapies with the advent of biologics in the last 20 years, recent evidence shows that more innovation is underway. Just in the last year, 2 new mechanisms for treating psoriasis topically without steroids have come to fruition, and there have not been truly novel mechanisms for treating psoriasis topically since approvals for tazarotene and calcipotriene in the 1990s. An entirely new class—TYK2 inhibitors—was developed and landed in psoriasis first, greatly improving the efficacy measures attained with oral medications in general. Finally, an orphan diagnosis got its due with an ambitiously designed study looking at a previously unheard-of 1-week end point, but it comes for one of the few true dermatologic emergencies we encounter, generalized pustular psoriasis. We are fortunate to have so many meaningful new treatments available to us, and it is invigorating to see that even more efficacious biologics and treatments are coming, along with novel concepts such as a treatment affecting the microbiome. Now, we just need to make sure that our patients have the access they deserve to the wide array of available treatments.

The landscape of psoriasis treatments has undergone rapid change within the last decade, and the dizzying speed of drug development has not slowed, with 4 notable entries into the psoriasis treatment armamentarium within the last year: tapinarof, roflumilast, deucravacitinib, and spesolimab. Several others are in late-stage development, and these therapies represent new mechanisms, pathways, and delivery systems that will meaningfully broaden the spectrum of treatment choices for our patients. However, it can be quite difficult to keep track of all of the medication options. This review aims to present the mechanisms and data on both newly available therapeutics for psoriasis and products in the pipeline that may have a major impact on our treatment paradigm for psoriasis in the near future.

Topical Treatments

Tapinarof—Tapinarof is a topical aryl hydrocarbon receptor (AhR)–modulating agent derived from a secondary metabolite produced by a bacterial symbiont of entomopathogenic nematodes.¹ Tapinarof binds and activates AhR, inducing a signaling cascade that suppresses the expression of helper T cells T_H17 and T_H22, upregulates skin barrier protein expression, and reduces epidermal oxidative stress.² This is a familiar mechanism, as AhR agonism is one of the pathways modulated by coal tar. Tapinarof’s overall effects on immune function, skin barrier integrity, and antioxidant activity show great promise for the treatment of plaque psoriasis.

Two phase 3 trials (N=1025) evaluated the efficacy and safety of once-daily tapinarof cream 1% for plaque psoriasis.³ A physician global assessment (PGA) score of 0/1 occurred in 35.4% to 40.2% of patients in the tapinarof group and in 6.0% of patients in the vehicle group. At week 12, 36.1% to 47.6% of patients treated with daily applications of tapinarof cream achieved a 75% reduction in their baseline psoriasis area and severity index (PASI 75) score compared with 6.9% to 10.2% in the vehicle group.³ In a long-term extension study, a substantial remittive effect of at least 4 months off tapinarof therapy was observed in patients who achieved complete clearance (PGA=0).⁴ Use of tapinarof cream was associated with folliculitis in up to 23.5% of patients.^3,4

Roflumilast—Phosphodiesterase 4 (PDE-4) is an intracellular enzyme involved in the regulation of cell proliferation, differentiation, and immune responses.⁵ The inhibition of PDE-4 decreases the expression of proinflammatory cytokines implicated in the pathogenesis of plaque psoriasis, such as tumor necrosis factor α, IFN-γ, and IL-2, IL-12, and IL-23.⁶ Phosphodiesterase 4–targeted therapies have been thoroughly explored to treat various inflammatory conditions, including atopic dermatitis and plaque psoriasis. The oral PDE-4 inhibitor apremilast was shown to achieve PASI 75 in approximately 30% of 562 patients, accompanied by severe gastrointestinal adverse events (AEs) including diarrhea and nausea associated with treatment.⁷ Local irritation from the topical PDE-4 inhibitor crisaborole for atopic dermatitis and psoriasis (where it only completed phase 2 trials) limits its widespread use. The lack of tolerable and effective treatment alternatives for psoriasis prompted the investigation of new PDE-4–targeted therapies.

Topical roflumilast is a selective, highly potent PDE-4 inhibitor with greater affinity for PDE-4 compared to crisaborole and apremilast.⁸ Two phase 3 trials (N=881) evaluated the efficacy and safety profile of roflumilast cream for plaque psoriasis, with a particular interest in its use for intertriginous areas.⁹ At week 8, 37.5% to 42.4% of roflumilast-treated patients achieved investigator global assessment (IGA) success compared with 6.1% to 6.9% of vehicle-treated patients. Intertriginous IGA success was observed in 68.1% to 71.2% of patients treated with roflumilast cream compared with 13.8% to 18.5% of vehicle-treated patients. At 8-week follow-up, 39.0% to 41.6% of roflumilast-treated patients achieved PASI 75 vs 5.3% to 7.6% of patients in the vehicle group. Few stinging, burning, or application-site reactions were reported with roflumilast, along with rare instances of gastrointestinal AEs (<4%).⁹

Oral Therapy

Deucravacitinib—Tyrosine kinase 2 (TYK2) mediates the intracellular signaling of the T_H17 and T_H1 inflammatory cytokines IL-12/IL-23 and type I interferons, respectively, the former of which are critical in the development of psoriasis via the Janus kinase (JAK) signal transducer and activator of transcription pathway.¹⁰ Deucravacitinib is an oral selective TYK2 allosteric inhibitor that binds to the regulatory domain of the enzyme rather than the active catalytic domain, where other TYK2 and JAK1, JAK2, and JAK3 inhibitors bind.¹¹ This unique inhibitory mechanism accounts for the high functional selectivity of deucravacitinib for TYK2 vs the closely related JAK1, JAK2, and JAK3 kinases, thus avoiding the pitfall of prior JAK inhibitors that were associated with major AEs, including an increased risk for serious infections, malignancies, and thrombosis.¹² The selective suppression of the inflammatory TYK2 pathway has the potential to shift future therapeutic targets to a narrower range of receptors that may contribute to favorable benefit-risk profiles.

Two phase 3 trials (N=1686) compared the efficacy and safety of deucravacitinib vs placebo and apremilast in adults with moderate to severe plaque psoriasis.^13,14 At week 16, 53.0% to 58.4% of deucravacitinib-treated patients achieved PASI 75 compared with 35.1% to 39.8% of apremilast-treated patients. At 16-week follow-up, static PGA response was observed in 49.5% to 53.6% of patients in the deucravacitinib group and 32.1% to 33.9% of the apremilast group. The most frequent AEs associated with deucravacitinib therapy were nasopharyngitis and upper respiratory tract infection, whereas headache, diarrhea, and nausea were more common with apremilast. Treatment with deucravacitinib caused no meaningful changes in laboratory parameters, which are known to change with JAK1, JAK2, and JAK3 inhibitors.^13,14 A long-term extension study demonstrated that deucravacitinib had persistent efficacy and consistent safety for up to 2 years.¹⁵

 

 

Other TYK2 Inhibitors in the Pipeline

Novel oral allosteric TYK2 inhibitors—VTX958 and NDI-034858—and the competitive TYK2 inhibitor PF-06826647 are being developed. Theoretically, these new allosteric inhibitors possess unique structural properties to provide greater TYK2 suppression while bypassing JAK1, JAK2, and JAK3 pathways that may contribute to improved efficacy and safety profiles compared with other TYK2 inhibitors such as deucravacitinib. The results of a phase 1b trial (ClinicalTrials.gov Identifier NCT04999839) showed a dose-dependent reduction of disease severity associated with NDI-034858 treatment for patients with moderate to severe plaque psoriasis, albeit in only 26 patients. At week 4, PASI 50 was achieved in 13%, 57%, and 40% of patients in the 5-, 10-, and 30-mg groups, respectively, compared with 0% in the placebo group.¹⁶ In a phase 2 trial of 179 patients, 46.5% and 33.0% of patients treated with 400 and 200 mg of PF-06826647, respectively, achieved PASI 90 at week 16. Conversely, dose-dependent laboratory abnormalities were observed with PF-06826647, including anemia, neutropenia, and increases in creatine phosphokinase.¹⁷ At high concentrations, PF-06826647 may disrupt JAK signaling pathways involved in hematopoiesis and renal functions owing to its mode of action as a competitive inhibitor. Overall, these agents are much farther from market, and long-term studies with larger diverse patient cohorts are required to adequately assess the efficacy and safety data of these novel oral TYK2 inhibitors for patients with psoriasis.

EDP1815—EDP1815 is an oral preparation of a single strain of Prevotella histicola being developed for the treatment of inflammatory diseases, including psoriasis. EDP1815 interacts with host intestinal immune cells through the small intestinal axis (SINTAX) to suppress systemic inflammation across the T_H1, T_H2, and T_H17 pathways. Therapy triggers broad immunomodulatory effects without causing systemic absorption, colonic colonization, or modification of the gut microbiome.¹⁸ In a phase 2 study (NCT04603027), the primary end point analysis, mean percentage change in PASI between treatment and placebo, demonstrated that at week 16, EDP1815 was superior to placebo with 80% to 90% probability across each cohort. At week 16, 25% to 32% of patients across the 3 cohorts treated with EDP1815 achieved PASI 50 compared with 12% of patients receiving placebo. Gastrointestinal AEs were comparable between treatment and placebo groups. These results suggest that SINTAX-targeted therapies may provide efficacious and safe immunomodulatory effects for patients with mild to moderate psoriasis, who often have limited treatment options. Although improvements may be mild, SINTAX-targeted therapies can be seen as a particularly attractive adjunctive treatment for patients with severe psoriasis taking other medications or as part of a treatment approach for a patient with milder psoriasis.

Biologics

Bimekizumab—Bimekizumab is a monoclonal IgG1 antibody that selectively inhibits IL-17A and IL-17F. Although IL-17A is a more potent cytokine, IL-17F may be more highly expressed in psoriatic lesional skin and independently contribute to the activation of proinflammatory signaling pathways implicated in the pathophysiology of psoriasis.¹⁹ Evidence suggests that dual inhibition of IL-17A and IL-17F may provide more complete suppression of inflammation and improved clinical responses than IL-17A inhibition alone.²⁰

Prior bimekizumab phase 3 clinical studies have shown both rapid and durable clinical improvements in skin clearance compared with placebo.²¹ Three phase 3 trials—BE VIVID (N=567),²² BE SURE (N=478),²³ and BE RADIANT (N=743)²⁴—assessed the efficacy and safety of bimekizumab vs the IL-12/IL-23 inhibitor ustekinumab, the tumor necrosis factor inhibitor adalimumab, and the selective IL-17A inhibitor secukinumab, respectively. At week 4, significantly more patients treated with bimekizumab (71%–77%) achieved PASI 75 than patients treated with ustekinumab (15%; P<.0001), adalimumab (31.4%; P<.001), or secukinumab (47.3%; P<.001).^22-24 After 16 weeks of treatment, PASI 90 was achieved by 85% to 86.2%, 50%, and 47.2% of patients treated with bimekizumab, ustekinumab, and adalimumab, respectively.^22,23 At week 16, PASI 100 was observed in 59% to 61.7%, 21%, 23.9%, and 48.9% of patients treated with bimekizumab, ustekinumab, adalimumab, and secukinumab, respectively. An IGA response (score of 0/1) at week 16 was achieved by 84% to 85.5%, 53%, 57.2%, and 78.6% of patients receiving bimekizumab, ustekinumab, adalimumab, and secukinumab, respectively.^22-24

The most common AEs in bimekizumab-treated patients were nasopharyngitis, oral candidiasis, and upper respiratory tract infection.^22-24 The dual inhibition of IL-17A and IL-17F suppresses host defenses against Candida at the oral mucosa, increasing the incidence of bimekizumab-associated oral candidiasis.²⁵ Despite the increased risk of Candida infections, these data suggest that inhibition of both IL-17A and IL-17F with bimekizumab may provide faster and greater clinical benefit for patients with moderate to severe plaque psoriasis than inhibition of IL-17A alone and other biologic therapies, as the PASI 100 clearance rates across the multiple comparator trials and the placebo-controlled pivotal trial are consistently the highest among any biologic for the treatment of psoriasis.

Spesolimab—The IL-36 pathway and IL-36 receptor genes have been linked to the pathogenesis of generalized pustular psoriasis.²⁶ In a phase 2 trial, 19 of 35 patients (54%) receiving an intravenous dose of spesolimab, an IL-36 receptor inhibitor, had a generalized pustular psoriasis PGA pustulation subscore of 0 (no visible pustules) at the end of week 1 vs 6% of patients in the placebo group.²⁷ A generalized pustular psoriasis PGA total score of 0 or 1 was observed in 43% (15/35) of spesolimab-treated patients compared with 11% (2/18) of patients in the placebo group. The most common AEs in patients treated with spesolimab were minor infections.²⁷ Two open-label phase 3 trials—NCT05200247 and NCT05239039—are underway to determine the long-term efficacy and safety of spesolimab in patients with generalized pustular psoriasis.

Conclusion

Although we have seen a renaissance in psoriasis therapies with the advent of biologics in the last 20 years, recent evidence shows that more innovation is underway. Just in the last year, 2 new mechanisms for treating psoriasis topically without steroids have come to fruition, and there have not been truly novel mechanisms for treating psoriasis topically since approvals for tazarotene and calcipotriene in the 1990s. An entirely new class—TYK2 inhibitors—was developed and landed in psoriasis first, greatly improving the efficacy measures attained with oral medications in general. Finally, an orphan diagnosis got its due with an ambitiously designed study looking at a previously unheard-of 1-week end point, but it comes for one of the few true dermatologic emergencies we encounter, generalized pustular psoriasis. We are fortunate to have so many meaningful new treatments available to us, and it is invigorating to see that even more efficacious biologics and treatments are coming, along with novel concepts such as a treatment affecting the microbiome. Now, we just need to make sure that our patients have the access they deserve to the wide array of available treatments.

Abstract

Diagnostic errors in hospitalized patients are a leading cause of preventable morbidity and mortality. Significant challenges in defining and measuring diagnostic errors and underlying process failure points have led to considerable variability in reported rates of diagnostic errors and adverse outcomes. In this article, we explore the diagnostic process and its discrete components, emphasizing the centrality of the patient in decision-making as well as the continuous nature of the process. We review the incidence of diagnostic errors in hospitalized patients and different methodological approaches that have been used to arrive at these estimates. We discuss different but interdependent provider- and system-related process-failure points that lead to diagnostic errors. We examine specific challenges related to measurement of diagnostic errors and describe traditional and novel approaches that are being used to obtain the most precise estimates. Finally, we examine various patient-, provider-, and organizational-level interventions that have been proposed to improve diagnostic safety in hospitalized patients.

Keywords: diagnostic error, hospital medicine, patient safety.

Diagnosis is defined as a “pre-existing set of categories agreed upon by the medical profession to designate a specific condition.”¹ The diagnostic process involves obtaining a clinical history, performing a physical examination, conducting diagnostic testing, and consulting with other clinical providers to gather data that are relevant to understanding the underlying disease processes. This exercise involves generating hypotheses and updating prior probabilities as more information and evidence become available. Throughout this process of information gathering, integration, and interpretation, there is an ongoing assessment of whether sufficient and necessary knowledge has been obtained to make an accurate diagnosis and provide appropriate treatment.²

Diagnostic error is defined as a missed opportunity to make a timely diagnosis as part of this iterative process, including the failure of communicating the diagnosis to the patient in a timely manner.³ It can be categorized as a missed, delayed, or incorrect diagnosis based on available evidence at the time. Establishing the correct diagnosis has important implications. A timely and precise diagnosis ensures the patient the highest probability of having a positive health outcome that reflects an appropriate understanding of underlying disease processes and is consistent with their overall goals of care.³ When diagnostic errors occur, they can cause patient harm. Adverse events due to medical errors, including diagnostic errors, are estimated to be the third leading cause of death in the United States.⁴ Most people will experience at least 1 diagnostic error in their lifetime. In the 2015 National Academy of Medicine report Improving Diagnosis in Healthcare, diagnostic errors were identified as a major hazard as well as an opportunity to improve patient outcomes.²

Diagnostic errors during hospitalizations are especially concerning, as they are more likely to be implicated in a wider spectrum of harm, including permanent disability and death. This has become even more relevant for hospital medicine physicians and other clinical providers as they encounter increasing cognitive and administrative workloads, rising dissatisfaction and burnout, and unique obstacles such as night-time scheduling.⁵

Incidence of Diagnostic Errors in Hospitalized Patients

Several methodological approaches have been used to estimate the incidence of diagnostic errors in hospitalized patients. These include retrospective reviews of a sample of all hospital admissions, evaluations of selected adverse outcomes including autopsy studies, patient and provider surveys, and malpractice claims. Laboratory testing audits and secondary reviews in other diagnostic subspecialities (eg, radiology, pathology, and microbiology) are also essential to improving diagnostic performance in these specialized fields, which in turn affects overall hospital diagnostic error rates.^6-8 These diverse approaches provide unique insights regarding our ability to assess the degree to which potential harms, ranging from temporary impairment to permanent disability, to death, are attributable to different failure points in the diagnostic process.

Large retrospective chart reviews of random hospital admissions remain the most accurate way to determine the overall incidence of diagnostic errors in hospitalized patients.⁹ The Harvard Medical Practice Study, published in 1991, laid the groundwork for measuring the incidence of adverse events in hospitalized patients and assessing their relation to medical error, negligence, and disability. Reviewing 30,121 randomly selected records from 51 randomly selected acute care hospitals in New York State, the study found that adverse events occurred in 3.7% of hospitalizations, diagnostic errors accounted for 13.8% of these events, and these errors were likely attributable to negligence in 74.7% of cases. The study not only outlined individual-level process failures, but also focused attention on some of the systemic causes, setting the agenda for quality improvement research in hospital-based care for years to come.^10-12 A recent systematic review and meta-analysis of 22 hospital admission studies found a pooled rate of 0.7% (95% CI, 0.5%-1.1%) for harmful diagnostic errors.⁹ It found significant variations in the rates of adverse events, diagnostic errors, and range of diagnoses that were missed. This was primarily because of variabilities in pre-test probabilities in detecting diagnostic errors in these specific cohorts, as well as due to heterogeneity in study definitions and methodologies, especially regarding how they defined and measured “diagnostic error.” The analysis, however, did not account for diagnostic errors that were not related to patient harm (missed opportunities); therefore, it likely significantly underestimated the true incidence of diagnostic errors in these study populations. Table 1 summarizes some of key studies that have examined the incidence of harmful diagnostic errors in hospitalized patients.^9-21

The chief limitation of reviewing random hospital admissions is that, since overall rates of diagnostic errors are still relatively low, a large number of case reviews are required to identify a sufficient sample of adverse outcomes to gain a meaningful understanding of the underlying process failure points and develop tools for remediation. Patient and provider surveys or data from malpractice claims can be high-yield starting points for research on process errors.^22,23 Reviews of enriched cohorts of adverse outcomes, such as rapid-response events, intensive care unit (ICU) transfers, deaths, and hospital readmissions, can be an efficient way to identify process failures that lead to greatest harm. Depending on the research approach and the types of underlying patient populations sampled, rates of diagnostic errors in these high-risk groups have been estimated to be approximately 5% to 20%, or even higher.^6,24-31 For example, a retrospective study of 391 cases of unplanned 7-day readmissions found that 5.6% of cases contained at least 1 diagnostic error during the index admission.³² In a study conducted at 6 Belgian acute-care hospitals, 56% of patients requiring an unplanned transfer to a higher level of care were determined to have had an adverse event, and of these adverse events, 12.4% of cases were associated with errors in diagnosis.²⁹ A systematic review of 16 hospital-based studies estimated that 3.1% of all inpatient deaths were likely preventable, which corresponded to 22,165 deaths annually in the United States.³⁰ Another such review of 31 autopsy studies reported that 28% of autopsied ICU patients had at least 1 misdiagnosis; of these diagnostic errors, 8% were classified as potentially lethal, and 15% were considered major but not lethal.³¹ Significant drawbacks of such enriched cohort studies, however, are their poor generalizability and inability to detect failure points that do not lead to patient harm (near-miss events).³³

Causes of Diagnostic Errors in Hospitalized Patients

All aspects of the diagnostic process are susceptible to errors. These errors stem from a variety of faulty processes, including failure of the patient to engage with the health care system (eg, due to lack of insurance or transportation, or delay in seeking care); failure in information gathering (eg, missed history or exam findings, ordering wrong tests, laboratory errors); failure in information interpretation (eg, exam finding or test result misinterpretation); inaccurate hypothesis generation (eg, due to suboptimal prioritization or weighing of supporting evidence); and failure in communication (eg, with other team members or with the patient).^2,34 Reasons for diagnostic process failures vary widely across different health care settings. While clinician assessment errors (eg, failure to consider or alternatively overweigh competing diagnoses) and errors in testing and the monitoring phase (eg, failure to order or follow up diagnostic tests) can lead to a majority of diagnostic errors in some patient populations, in other settings, social (eg, poor health literacy, punitive cultural practices) and economic factors (eg, lack of access to appropriate diagnostic tests or to specialty expertise) play a more prominent role.^34,35

The Figure describes the relationship between components of the diagnostic process and subsequent outcomes, including diagnostic process failures, diagnostic errors, and absence or presence of patient harm.^2,36,37 It reemphasizes the centrality of the patient in decision-making and the continuous nature of the process. The Figure also illustrates that only a minority of process failures result in diagnostic errors, and a smaller proportion of diagnostic errors actually lead to patient harm. Conversely, it also shows that diagnostic errors can happen without any obvious process-failure points, and, similarly, patient harm can take place in the absence of any evident diagnostic errors.^36-38 Finally, it highlights the need to incorporate feedback from process failures, diagnostic errors, and favorable and unfavorable patient outcomes in order to inform future quality improvement efforts and research.

A significant proportion of diagnostic errors are due to system-related vulnerabilities, such as limitations in availability, adoption or quality of work force training, health informatics resources, and diagnostic capabilities. Lack of institutional culture that promotes safety and transparency also predisposes to diagnostic errors.^39,40 The other major domain of process failures is related to cognitive errors in clinician decision-making. Anchoring, confirmation bias, availability bias, and base-rate neglect are some of the common cognitive biases that, along with personality traits (aversion to risk or ambiguity, overconfidence) and affective biases (influence of emotion on decision-making), often determine the degree of utilization of resources and the possibility of suboptimal diagnostic performance.^41,42 Further, implicit biases related to age, race, gender, and sexual orientation contribute to disparities in access to health care and outcomes.⁴³ In a large number of cases of preventable adverse outcomes, however, there are multiple interdependent individual and system-related failure points that lead to diagnostic error and patient harm.^6,32

Challenges in Defining and Measuring Diagnostic Errors

In order to develop effective, evidence-based interventions to reduce diagnostic errors in hospitalized patients, it is essential to be able to first operationally define, and then accurately measure, diagnostic errors and the process failures that contribute to these errors in a standardized way that is reproducible across different settings.^6,44 There are a number of obstacles in this endeavor.

A fundamental problem is that establishing a diagnosis is not a single act but a process. Patterns of symptoms and clinical presentations often differ for the same disease. Information required to make a diagnosis is usually gathered in stages, where the clinician obtains additional data, while considering many possibilities, of which 1 may be ultimately correct. Diagnoses evolve over time and in different care settings. “The most likely diagnosis” is not always the same as “the final correct diagnosis.” Moreover, the diagnostic process is influenced by patients’ individual clinical courses and preferences over time. This makes determination of missed, delayed, or incorrect diagnoses challenging.^45,46

For hospitalized patients, generally the goal is to first rule out more serious and acute conditions (eg, pulmonary embolism or stroke), even if their probability is rather low. Conversely, a diagnosis that appears less consequential if delayed (eg, chronic anemia of unclear etiology) might not be pursued on an urgent basis, and is often left to outpatient providers to examine, but still may manifest in downstream harm (eg, delayed diagnosis of gastrointestinal malignancy or recurrent admissions for heart failure due to missed iron-deficiency anemia). Therefore, coming up with disease diagnosis likelihoods in hindsight may turn out to be highly subjective and not always accurate. This can be particularly difficult when clinician and other team deliberations are not recorded in their entirety.⁴⁷

Another hurdle in the practice of diagnostic medicine is to preserve the balance between underdiagnosing versus pursuing overly aggressive diagnostic approaches. Conducting laboratory, imaging, or other diagnostic studies without a clear shared understanding of how they would affect clinical decision-making (eg, use of prostate-specific antigen to detect prostate cancer) not only leads to increased costs but can also delay appropriate care. Worse, subsequent unnecessary diagnostic tests and treatments can sometimes lead to serious harm.^48,49

Finally, retrospective reviews by clinicians are subject to multiple potential limitations that include failure to create well-defined research questions, poorly developed inclusion and exclusion criteria, and issues related to inter- and intra-rater reliability.⁵⁰ These methodological deficiencies can occur despite following "best practice" guidelines during the study planning, execution, and analysis phases. They further add to the challenge of defining and measuring diagnostic errors.⁴⁷

Strategies to Improve Measurement of Diagnostic Errors

Development of new methodologies to reliably measure diagnostic errors is an area of active research. The advancement of uniform and universally agreed-upon frameworks to define and identify process failure points and diagnostic errors would help reduce measurement error and support development and testing of interventions that could be generalizable across different health care settings. To more accurately define and measure diagnostic errors, several novel approaches have been proposed (Table 2).

The Safer Dx framework is an all-round tool developed to advance the discipline of measuring diagnostic errors. For an episode of care under review, the instrument scores various items to determine the likelihood of a diagnostic error. These items evaluate multiple dimensions affecting diagnostic performance and measurements across 3 broad domains: structure (provider and organizational characteristics—from everyone involved with patient care, to computing infrastructure, to policies and regulations), process (elements of the patient-provider encounter, diagnostic test performance and follow-up, and subspecialty- and referral-specific factors), and outcome (establishing accurate and timely diagnosis as opposed to missed, delayed, or incorrect diagnosis). This instrument has been revised and can be further modified by a variety of stakeholders, including clinicians, health care organizations, and policymakers, to identify potential diagnostic errors in a standardized way for patient safety and quality improvement research.^51,52

Use of standardized tools, such as the Diagnosis Error Evaluation and Research (DEER) taxonomy, can help to identify and classify specific failure points across different diagnostic process dimensions.³⁷ These failure points can be classified into: issues related to patient presentation or access to health care; failure to obtain or misinterpretation of history or physical exam findings; errors in use of diagnostics tests due to technical or clinician-related factors; failures in appropriate weighing of evidence and hypothesis generation; errors associated with referral or consultation process; and failure to monitor the patient or obtain timely follow-up.³⁴ The DEER taxonomy can also be modified based on specific research questions and study populations. Further, it can be recategorized to correspond to Safer Dx framework diagnostic process dimensions to provide insights into reasons for specific process failures and to develop new interventions to mitigate errors and patient harm.⁶

Since a majority of diagnostic errors do not lead to actual harm, use of “triggers” or clues (eg, procedure-related complications, patient falls, transfers to a higher level of care, readmissions within 30 days) can be a more efficient method to identify diagnostic errors and adverse events that do cause harm. The Global Trigger Tool, developed by the Institute for Healthcare Improvement, uses this strategy. This tool has been shown to identify a significantly higher number of serious adverse events than comparable methods.⁵³ This facilitates selection and development of strategies at the institutional level that are most likely to improve patient outcomes.²⁴

Encouraging and facilitating voluntary or prompted reporting from patients and clinicians can also play an important role in capturing diagnostic errors. Patients and clinicians are not only the key stakeholders but are also uniquely placed within the diagnostic process to detect and report potential errors.^25,54 Patient-safety-event reporting systems, such as RL6, play a vital role in reporting near-misses and adverse events. These systems provide a mechanism for team members at all levels within the hospital to contribute toward reporting patient adverse events, including those arising from diagnostic errors.⁵⁵ The Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey is the first standardized, nationally reported patient survey designed to measure patients’ perceptions of their hospital experience. The US Centers for Medicare and Medicaid Services (CMS) publishes HCAHPS results on its website 4 times a year, which serves as an important incentive for hospitals to improve patient safety and quality of health care delivery.⁵⁶

Another novel approach links multiple symptoms to a range of target diseases using the Symptom-Disease Pair Analysis of Diagnostic Error (SPADE) framework. Using “big data” technologies, this technique can help discover otherwise hidden symptom-disease links and improve overall diagnostic performance. This approach is proposed for both case-control (look-back) and cohort (look-forward) studies assessing diagnostic errors and misdiagnosis-related harms. For example, starting with a known diagnosis with high potential for harm (eg, stroke), the “look-back” approach can be used to identify high-risk symptoms (eg, dizziness, vertigo). In the “look-forward” approach, a single symptom or exposure risk factor known to be frequently misdiagnosed (eg, dizziness) can be analyzed to identify potential adverse disease outcomes (eg, stroke, migraine).⁵⁷

Many large ongoing studies looking at diagnostic errors among hospitalized patients, such as Utility of Predictive Systems to identify Inpatient Diagnostic Errors (UPSIDE),⁵⁸ Patient Safety Learning Lab (PSLL),⁵⁹ and Achieving Diagnostic Excellence through Prevention and Teamwork (ADEPT),⁶⁰ are using structured chart review methodologies incorporating many of the above strategies in combination. Cases triggered by certain events (eg, ICU transfer, death, rapid response event, new or worsening acute kidney injury) are reviewed using validated tools, including Safer Dx framework and DEER taxonomy, to provide the most precise estimates of the burden of diagnostic errors in hospitalized patients. These estimates may be much higher than previously predicted using traditional chart review approaches.^6,24 For example, a recently published study of 2809 random admissions in 11 Massachusetts hospitals identified 978 adverse events but only 10 diagnostic errors (diagnostic error rate, 0.4%).¹⁹ This was likely because the trigger method used in the study did not specifically examine the diagnostic process as critically as done by the Safer Dx framework and DEER taxonomy tools, thereby underestimating the total number of diagnostic errors. Further, these ongoing studies (eg, UPSIDE, ADEPT) aim to employ new and upcoming advanced machine-learning methods to create models that can improve overall diagnostic performance. This would pave the way to test and build novel, efficient, and scalable interventions to reduce diagnostic errors and improve patient outcomes.

Strategies to Improve Diagnostic Safety in Hospitalized Patients

Disease-specific biomedical research, as well as advances in laboratory, imaging, and other technologies, play a critical role in improving diagnostic accuracy. However, these technical approaches do not address many of the broader clinician- and system-level failure points and opportunities for improvement. Various patient-, provider-, and organizational-level interventions that could make diagnostic processes more resilient and reduce the risk of error and patient harm have been proposed.⁶¹

Among these strategies are approaches to empower patients and their families. Fostering therapeutic relationships between patients and members of the care team is essential to reducing diagnostic errors.⁶² Facilitating timely access to health records, ensuring transparency in decision making, and tailoring communication strategies to patients’ cultural and educational backgrounds can reduce harm.⁶³ Similarly, at the system level, enhancing communication among different providers by use of tools such as structured handoffs can prevent communication breakdowns and facilitate positive outcomes.⁶⁴

Interventions targeted at individual health care providers, such as educational programs to improve content-specific knowledge, can enhance diagnostic performance. Regular feedback, strategies to enhance equity, and fostering an environment where all providers are actively encouraged to think critically and participate in the diagnostic process (training programs to use “diagnostic time-outs” and making it a “team sport”) can improve clinical reasoning.^65,66 Use of standardized patients can help identify individual-level cognitive failure points and facilitate creation of new interventions to improve clinical decision-making processes.⁶⁷

Novel health information technologies can further augment these efforts. These include effective documentation by maintaining dynamic and accurate patient histories, problem lists, and medication lists^68-70; use of electronic health record–based algorithms to identify potential diagnostic delays for serious conditions^71,72; use of telemedicine technologies to improve accessibility and coordination⁷³; application of mobile health and wearable technologies to facilitate data-gathering and care delivery^74,75; and use of computerized decision-support tools, including applications to interpret electrocardiograms, imaging studies, and other diagnostic tests.⁷⁶

Use of precision medicine, powered by new artificial intelligence (AI) tools, is becoming more widespread. Algorithms powered by AI can augment and sometimes even outperform clinician decision-making in areas such as oncology, radiology, and primary care.⁷⁷ Creation of large biobanks like the All of Us research program can be used to study thousands of environmental and genetic risk factors and health conditions simultaneously, and help identify specific treatments that work best for people of different backgrounds.⁷⁸ Active research in these areas holds great promise in terms of how and when we diagnose diseases and make appropriate preventative and treatment decisions. Significant scientific, ethical, and regulatory challenges will need to be overcome before these technologies can address some of the most complex problems in health care.⁷⁹

Finally, diagnostic performance is affected by the external environment, including the functioning of the medical liability system. Diagnostic errors that lead to patient harm are a leading cause of malpractice claims.⁸⁰ Developing a legal environment, in collaboration with patient advocacy groups and health care organizations, that promotes and facilitates timely disclosure of diagnostic errors could decrease the incentive to hide errors, advance care processes, and improve outcomes.^81,82

Conclusion

The burden of diagnostic errors in hospitalized patients is unacceptably high and remains an underemphasized cause of preventable morbidity and mortality. Diagnostic errors often result from a breakdown in multiple interdependent processes that involve patient-, provider-, and system-level factors. Significant challenges remain in defining and identifying diagnostic errors as well as underlying process-failure points. The most effective interventions to reduce diagnostic errors will require greater patient participation in the diagnostic process and a mix of evidence-based interventions that promote individual-provider excellence as well as system-level changes. Further research and collaboration among various stakeholders should help improve diagnostic safety for hospitalized patients.

Corresponding author: Abhishek Goyal, MD, MPH; [email protected]

Disclosures: Dr. Dalal disclosed receiving income ≥ $250 from MayaMD.

Abstract

Diagnostic errors in hospitalized patients are a leading cause of preventable morbidity and mortality. Significant challenges in defining and measuring diagnostic errors and underlying process failure points have led to considerable variability in reported rates of diagnostic errors and adverse outcomes. In this article, we explore the diagnostic process and its discrete components, emphasizing the centrality of the patient in decision-making as well as the continuous nature of the process. We review the incidence of diagnostic errors in hospitalized patients and different methodological approaches that have been used to arrive at these estimates. We discuss different but interdependent provider- and system-related process-failure points that lead to diagnostic errors. We examine specific challenges related to measurement of diagnostic errors and describe traditional and novel approaches that are being used to obtain the most precise estimates. Finally, we examine various patient-, provider-, and organizational-level interventions that have been proposed to improve diagnostic safety in hospitalized patients.

Keywords: diagnostic error, hospital medicine, patient safety.

Diagnosis is defined as a “pre-existing set of categories agreed upon by the medical profession to designate a specific condition.”¹ The diagnostic process involves obtaining a clinical history, performing a physical examination, conducting diagnostic testing, and consulting with other clinical providers to gather data that are relevant to understanding the underlying disease processes. This exercise involves generating hypotheses and updating prior probabilities as more information and evidence become available. Throughout this process of information gathering, integration, and interpretation, there is an ongoing assessment of whether sufficient and necessary knowledge has been obtained to make an accurate diagnosis and provide appropriate treatment.²

Diagnostic error is defined as a missed opportunity to make a timely diagnosis as part of this iterative process, including the failure of communicating the diagnosis to the patient in a timely manner.³ It can be categorized as a missed, delayed, or incorrect diagnosis based on available evidence at the time. Establishing the correct diagnosis has important implications. A timely and precise diagnosis ensures the patient the highest probability of having a positive health outcome that reflects an appropriate understanding of underlying disease processes and is consistent with their overall goals of care.³ When diagnostic errors occur, they can cause patient harm. Adverse events due to medical errors, including diagnostic errors, are estimated to be the third leading cause of death in the United States.⁴ Most people will experience at least 1 diagnostic error in their lifetime. In the 2015 National Academy of Medicine report Improving Diagnosis in Healthcare, diagnostic errors were identified as a major hazard as well as an opportunity to improve patient outcomes.²

Diagnostic errors during hospitalizations are especially concerning, as they are more likely to be implicated in a wider spectrum of harm, including permanent disability and death. This has become even more relevant for hospital medicine physicians and other clinical providers as they encounter increasing cognitive and administrative workloads, rising dissatisfaction and burnout, and unique obstacles such as night-time scheduling.⁵

Incidence of Diagnostic Errors in Hospitalized Patients

Several methodological approaches have been used to estimate the incidence of diagnostic errors in hospitalized patients. These include retrospective reviews of a sample of all hospital admissions, evaluations of selected adverse outcomes including autopsy studies, patient and provider surveys, and malpractice claims. Laboratory testing audits and secondary reviews in other diagnostic subspecialities (eg, radiology, pathology, and microbiology) are also essential to improving diagnostic performance in these specialized fields, which in turn affects overall hospital diagnostic error rates.^6-8 These diverse approaches provide unique insights regarding our ability to assess the degree to which potential harms, ranging from temporary impairment to permanent disability, to death, are attributable to different failure points in the diagnostic process.

Large retrospective chart reviews of random hospital admissions remain the most accurate way to determine the overall incidence of diagnostic errors in hospitalized patients.⁹ The Harvard Medical Practice Study, published in 1991, laid the groundwork for measuring the incidence of adverse events in hospitalized patients and assessing their relation to medical error, negligence, and disability. Reviewing 30,121 randomly selected records from 51 randomly selected acute care hospitals in New York State, the study found that adverse events occurred in 3.7% of hospitalizations, diagnostic errors accounted for 13.8% of these events, and these errors were likely attributable to negligence in 74.7% of cases. The study not only outlined individual-level process failures, but also focused attention on some of the systemic causes, setting the agenda for quality improvement research in hospital-based care for years to come.^10-12 A recent systematic review and meta-analysis of 22 hospital admission studies found a pooled rate of 0.7% (95% CI, 0.5%-1.1%) for harmful diagnostic errors.⁹ It found significant variations in the rates of adverse events, diagnostic errors, and range of diagnoses that were missed. This was primarily because of variabilities in pre-test probabilities in detecting diagnostic errors in these specific cohorts, as well as due to heterogeneity in study definitions and methodologies, especially regarding how they defined and measured “diagnostic error.” The analysis, however, did not account for diagnostic errors that were not related to patient harm (missed opportunities); therefore, it likely significantly underestimated the true incidence of diagnostic errors in these study populations. Table 1 summarizes some of key studies that have examined the incidence of harmful diagnostic errors in hospitalized patients.^9-21

The chief limitation of reviewing random hospital admissions is that, since overall rates of diagnostic errors are still relatively low, a large number of case reviews are required to identify a sufficient sample of adverse outcomes to gain a meaningful understanding of the underlying process failure points and develop tools for remediation. Patient and provider surveys or data from malpractice claims can be high-yield starting points for research on process errors.^22,23 Reviews of enriched cohorts of adverse outcomes, such as rapid-response events, intensive care unit (ICU) transfers, deaths, and hospital readmissions, can be an efficient way to identify process failures that lead to greatest harm. Depending on the research approach and the types of underlying patient populations sampled, rates of diagnostic errors in these high-risk groups have been estimated to be approximately 5% to 20%, or even higher.^6,24-31 For example, a retrospective study of 391 cases of unplanned 7-day readmissions found that 5.6% of cases contained at least 1 diagnostic error during the index admission.³² In a study conducted at 6 Belgian acute-care hospitals, 56% of patients requiring an unplanned transfer to a higher level of care were determined to have had an adverse event, and of these adverse events, 12.4% of cases were associated with errors in diagnosis.²⁹ A systematic review of 16 hospital-based studies estimated that 3.1% of all inpatient deaths were likely preventable, which corresponded to 22,165 deaths annually in the United States.³⁰ Another such review of 31 autopsy studies reported that 28% of autopsied ICU patients had at least 1 misdiagnosis; of these diagnostic errors, 8% were classified as potentially lethal, and 15% were considered major but not lethal.³¹ Significant drawbacks of such enriched cohort studies, however, are their poor generalizability and inability to detect failure points that do not lead to patient harm (near-miss events).³³

Causes of Diagnostic Errors in Hospitalized Patients

All aspects of the diagnostic process are susceptible to errors. These errors stem from a variety of faulty processes, including failure of the patient to engage with the health care system (eg, due to lack of insurance or transportation, or delay in seeking care); failure in information gathering (eg, missed history or exam findings, ordering wrong tests, laboratory errors); failure in information interpretation (eg, exam finding or test result misinterpretation); inaccurate hypothesis generation (eg, due to suboptimal prioritization or weighing of supporting evidence); and failure in communication (eg, with other team members or with the patient).^2,34 Reasons for diagnostic process failures vary widely across different health care settings. While clinician assessment errors (eg, failure to consider or alternatively overweigh competing diagnoses) and errors in testing and the monitoring phase (eg, failure to order or follow up diagnostic tests) can lead to a majority of diagnostic errors in some patient populations, in other settings, social (eg, poor health literacy, punitive cultural practices) and economic factors (eg, lack of access to appropriate diagnostic tests or to specialty expertise) play a more prominent role.^34,35

The Figure describes the relationship between components of the diagnostic process and subsequent outcomes, including diagnostic process failures, diagnostic errors, and absence or presence of patient harm.^2,36,37 It reemphasizes the centrality of the patient in decision-making and the continuous nature of the process. The Figure also illustrates that only a minority of process failures result in diagnostic errors, and a smaller proportion of diagnostic errors actually lead to patient harm. Conversely, it also shows that diagnostic errors can happen without any obvious process-failure points, and, similarly, patient harm can take place in the absence of any evident diagnostic errors.^36-38 Finally, it highlights the need to incorporate feedback from process failures, diagnostic errors, and favorable and unfavorable patient outcomes in order to inform future quality improvement efforts and research.

A significant proportion of diagnostic errors are due to system-related vulnerabilities, such as limitations in availability, adoption or quality of work force training, health informatics resources, and diagnostic capabilities. Lack of institutional culture that promotes safety and transparency also predisposes to diagnostic errors.^39,40 The other major domain of process failures is related to cognitive errors in clinician decision-making. Anchoring, confirmation bias, availability bias, and base-rate neglect are some of the common cognitive biases that, along with personality traits (aversion to risk or ambiguity, overconfidence) and affective biases (influence of emotion on decision-making), often determine the degree of utilization of resources and the possibility of suboptimal diagnostic performance.^41,42 Further, implicit biases related to age, race, gender, and sexual orientation contribute to disparities in access to health care and outcomes.⁴³ In a large number of cases of preventable adverse outcomes, however, there are multiple interdependent individual and system-related failure points that lead to diagnostic error and patient harm.^6,32

Challenges in Defining and Measuring Diagnostic Errors

In order to develop effective, evidence-based interventions to reduce diagnostic errors in hospitalized patients, it is essential to be able to first operationally define, and then accurately measure, diagnostic errors and the process failures that contribute to these errors in a standardized way that is reproducible across different settings.^6,44 There are a number of obstacles in this endeavor.

A fundamental problem is that establishing a diagnosis is not a single act but a process. Patterns of symptoms and clinical presentations often differ for the same disease. Information required to make a diagnosis is usually gathered in stages, where the clinician obtains additional data, while considering many possibilities, of which 1 may be ultimately correct. Diagnoses evolve over time and in different care settings. “The most likely diagnosis” is not always the same as “the final correct diagnosis.” Moreover, the diagnostic process is influenced by patients’ individual clinical courses and preferences over time. This makes determination of missed, delayed, or incorrect diagnoses challenging.^45,46

For hospitalized patients, generally the goal is to first rule out more serious and acute conditions (eg, pulmonary embolism or stroke), even if their probability is rather low. Conversely, a diagnosis that appears less consequential if delayed (eg, chronic anemia of unclear etiology) might not be pursued on an urgent basis, and is often left to outpatient providers to examine, but still may manifest in downstream harm (eg, delayed diagnosis of gastrointestinal malignancy or recurrent admissions for heart failure due to missed iron-deficiency anemia). Therefore, coming up with disease diagnosis likelihoods in hindsight may turn out to be highly subjective and not always accurate. This can be particularly difficult when clinician and other team deliberations are not recorded in their entirety.⁴⁷

Another hurdle in the practice of diagnostic medicine is to preserve the balance between underdiagnosing versus pursuing overly aggressive diagnostic approaches. Conducting laboratory, imaging, or other diagnostic studies without a clear shared understanding of how they would affect clinical decision-making (eg, use of prostate-specific antigen to detect prostate cancer) not only leads to increased costs but can also delay appropriate care. Worse, subsequent unnecessary diagnostic tests and treatments can sometimes lead to serious harm.^48,49

Finally, retrospective reviews by clinicians are subject to multiple potential limitations that include failure to create well-defined research questions, poorly developed inclusion and exclusion criteria, and issues related to inter- and intra-rater reliability.⁵⁰ These methodological deficiencies can occur despite following "best practice" guidelines during the study planning, execution, and analysis phases. They further add to the challenge of defining and measuring diagnostic errors.⁴⁷

Strategies to Improve Measurement of Diagnostic Errors

Development of new methodologies to reliably measure diagnostic errors is an area of active research. The advancement of uniform and universally agreed-upon frameworks to define and identify process failure points and diagnostic errors would help reduce measurement error and support development and testing of interventions that could be generalizable across different health care settings. To more accurately define and measure diagnostic errors, several novel approaches have been proposed (Table 2).

The Safer Dx framework is an all-round tool developed to advance the discipline of measuring diagnostic errors. For an episode of care under review, the instrument scores various items to determine the likelihood of a diagnostic error. These items evaluate multiple dimensions affecting diagnostic performance and measurements across 3 broad domains: structure (provider and organizational characteristics—from everyone involved with patient care, to computing infrastructure, to policies and regulations), process (elements of the patient-provider encounter, diagnostic test performance and follow-up, and subspecialty- and referral-specific factors), and outcome (establishing accurate and timely diagnosis as opposed to missed, delayed, or incorrect diagnosis). This instrument has been revised and can be further modified by a variety of stakeholders, including clinicians, health care organizations, and policymakers, to identify potential diagnostic errors in a standardized way for patient safety and quality improvement research.^51,52

Use of standardized tools, such as the Diagnosis Error Evaluation and Research (DEER) taxonomy, can help to identify and classify specific failure points across different diagnostic process dimensions.³⁷ These failure points can be classified into: issues related to patient presentation or access to health care; failure to obtain or misinterpretation of history or physical exam findings; errors in use of diagnostics tests due to technical or clinician-related factors; failures in appropriate weighing of evidence and hypothesis generation; errors associated with referral or consultation process; and failure to monitor the patient or obtain timely follow-up.³⁴ The DEER taxonomy can also be modified based on specific research questions and study populations. Further, it can be recategorized to correspond to Safer Dx framework diagnostic process dimensions to provide insights into reasons for specific process failures and to develop new interventions to mitigate errors and patient harm.⁶

Since a majority of diagnostic errors do not lead to actual harm, use of “triggers” or clues (eg, procedure-related complications, patient falls, transfers to a higher level of care, readmissions within 30 days) can be a more efficient method to identify diagnostic errors and adverse events that do cause harm. The Global Trigger Tool, developed by the Institute for Healthcare Improvement, uses this strategy. This tool has been shown to identify a significantly higher number of serious adverse events than comparable methods.⁵³ This facilitates selection and development of strategies at the institutional level that are most likely to improve patient outcomes.²⁴

Encouraging and facilitating voluntary or prompted reporting from patients and clinicians can also play an important role in capturing diagnostic errors. Patients and clinicians are not only the key stakeholders but are also uniquely placed within the diagnostic process to detect and report potential errors.^25,54 Patient-safety-event reporting systems, such as RL6, play a vital role in reporting near-misses and adverse events. These systems provide a mechanism for team members at all levels within the hospital to contribute toward reporting patient adverse events, including those arising from diagnostic errors.⁵⁵ The Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey is the first standardized, nationally reported patient survey designed to measure patients’ perceptions of their hospital experience. The US Centers for Medicare and Medicaid Services (CMS) publishes HCAHPS results on its website 4 times a year, which serves as an important incentive for hospitals to improve patient safety and quality of health care delivery.⁵⁶

Another novel approach links multiple symptoms to a range of target diseases using the Symptom-Disease Pair Analysis of Diagnostic Error (SPADE) framework. Using “big data” technologies, this technique can help discover otherwise hidden symptom-disease links and improve overall diagnostic performance. This approach is proposed for both case-control (look-back) and cohort (look-forward) studies assessing diagnostic errors and misdiagnosis-related harms. For example, starting with a known diagnosis with high potential for harm (eg, stroke), the “look-back” approach can be used to identify high-risk symptoms (eg, dizziness, vertigo). In the “look-forward” approach, a single symptom or exposure risk factor known to be frequently misdiagnosed (eg, dizziness) can be analyzed to identify potential adverse disease outcomes (eg, stroke, migraine).⁵⁷

Many large ongoing studies looking at diagnostic errors among hospitalized patients, such as Utility of Predictive Systems to identify Inpatient Diagnostic Errors (UPSIDE),⁵⁸ Patient Safety Learning Lab (PSLL),⁵⁹ and Achieving Diagnostic Excellence through Prevention and Teamwork (ADEPT),⁶⁰ are using structured chart review methodologies incorporating many of the above strategies in combination. Cases triggered by certain events (eg, ICU transfer, death, rapid response event, new or worsening acute kidney injury) are reviewed using validated tools, including Safer Dx framework and DEER taxonomy, to provide the most precise estimates of the burden of diagnostic errors in hospitalized patients. These estimates may be much higher than previously predicted using traditional chart review approaches.^6,24 For example, a recently published study of 2809 random admissions in 11 Massachusetts hospitals identified 978 adverse events but only 10 diagnostic errors (diagnostic error rate, 0.4%).¹⁹ This was likely because the trigger method used in the study did not specifically examine the diagnostic process as critically as done by the Safer Dx framework and DEER taxonomy tools, thereby underestimating the total number of diagnostic errors. Further, these ongoing studies (eg, UPSIDE, ADEPT) aim to employ new and upcoming advanced machine-learning methods to create models that can improve overall diagnostic performance. This would pave the way to test and build novel, efficient, and scalable interventions to reduce diagnostic errors and improve patient outcomes.

Strategies to Improve Diagnostic Safety in Hospitalized Patients

Disease-specific biomedical research, as well as advances in laboratory, imaging, and other technologies, play a critical role in improving diagnostic accuracy. However, these technical approaches do not address many of the broader clinician- and system-level failure points and opportunities for improvement. Various patient-, provider-, and organizational-level interventions that could make diagnostic processes more resilient and reduce the risk of error and patient harm have been proposed.⁶¹

Among these strategies are approaches to empower patients and their families. Fostering therapeutic relationships between patients and members of the care team is essential to reducing diagnostic errors.⁶² Facilitating timely access to health records, ensuring transparency in decision making, and tailoring communication strategies to patients’ cultural and educational backgrounds can reduce harm.⁶³ Similarly, at the system level, enhancing communication among different providers by use of tools such as structured handoffs can prevent communication breakdowns and facilitate positive outcomes.⁶⁴

Interventions targeted at individual health care providers, such as educational programs to improve content-specific knowledge, can enhance diagnostic performance. Regular feedback, strategies to enhance equity, and fostering an environment where all providers are actively encouraged to think critically and participate in the diagnostic process (training programs to use “diagnostic time-outs” and making it a “team sport”) can improve clinical reasoning.^65,66 Use of standardized patients can help identify individual-level cognitive failure points and facilitate creation of new interventions to improve clinical decision-making processes.⁶⁷

Novel health information technologies can further augment these efforts. These include effective documentation by maintaining dynamic and accurate patient histories, problem lists, and medication lists^68-70; use of electronic health record–based algorithms to identify potential diagnostic delays for serious conditions^71,72; use of telemedicine technologies to improve accessibility and coordination⁷³; application of mobile health and wearable technologies to facilitate data-gathering and care delivery^74,75; and use of computerized decision-support tools, including applications to interpret electrocardiograms, imaging studies, and other diagnostic tests.⁷⁶

Use of precision medicine, powered by new artificial intelligence (AI) tools, is becoming more widespread. Algorithms powered by AI can augment and sometimes even outperform clinician decision-making in areas such as oncology, radiology, and primary care.⁷⁷ Creation of large biobanks like the All of Us research program can be used to study thousands of environmental and genetic risk factors and health conditions simultaneously, and help identify specific treatments that work best for people of different backgrounds.⁷⁸ Active research in these areas holds great promise in terms of how and when we diagnose diseases and make appropriate preventative and treatment decisions. Significant scientific, ethical, and regulatory challenges will need to be overcome before these technologies can address some of the most complex problems in health care.⁷⁹

Finally, diagnostic performance is affected by the external environment, including the functioning of the medical liability system. Diagnostic errors that lead to patient harm are a leading cause of malpractice claims.⁸⁰ Developing a legal environment, in collaboration with patient advocacy groups and health care organizations, that promotes and facilitates timely disclosure of diagnostic errors could decrease the incentive to hide errors, advance care processes, and improve outcomes.^81,82

Conclusion

The burden of diagnostic errors in hospitalized patients is unacceptably high and remains an underemphasized cause of preventable morbidity and mortality. Diagnostic errors often result from a breakdown in multiple interdependent processes that involve patient-, provider-, and system-level factors. Significant challenges remain in defining and identifying diagnostic errors as well as underlying process-failure points. The most effective interventions to reduce diagnostic errors will require greater patient participation in the diagnostic process and a mix of evidence-based interventions that promote individual-provider excellence as well as system-level changes. Further research and collaboration among various stakeholders should help improve diagnostic safety for hospitalized patients.

Corresponding author: Abhishek Goyal, MD, MPH; [email protected]

Disclosures: Dr. Dalal disclosed receiving income ≥ $250 from MayaMD.

Abstract

Diagnostic errors in hospitalized patients are a leading cause of preventable morbidity and mortality. Significant challenges in defining and measuring diagnostic errors and underlying process failure points have led to considerable variability in reported rates of diagnostic errors and adverse outcomes. In this article, we explore the diagnostic process and its discrete components, emphasizing the centrality of the patient in decision-making as well as the continuous nature of the process. We review the incidence of diagnostic errors in hospitalized patients and different methodological approaches that have been used to arrive at these estimates. We discuss different but interdependent provider- and system-related process-failure points that lead to diagnostic errors. We examine specific challenges related to measurement of diagnostic errors and describe traditional and novel approaches that are being used to obtain the most precise estimates. Finally, we examine various patient-, provider-, and organizational-level interventions that have been proposed to improve diagnostic safety in hospitalized patients.

Keywords: diagnostic error, hospital medicine, patient safety.

Diagnosis is defined as a “pre-existing set of categories agreed upon by the medical profession to designate a specific condition.”¹ The diagnostic process involves obtaining a clinical history, performing a physical examination, conducting diagnostic testing, and consulting with other clinical providers to gather data that are relevant to understanding the underlying disease processes. This exercise involves generating hypotheses and updating prior probabilities as more information and evidence become available. Throughout this process of information gathering, integration, and interpretation, there is an ongoing assessment of whether sufficient and necessary knowledge has been obtained to make an accurate diagnosis and provide appropriate treatment.²

Diagnostic error is defined as a missed opportunity to make a timely diagnosis as part of this iterative process, including the failure of communicating the diagnosis to the patient in a timely manner.³ It can be categorized as a missed, delayed, or incorrect diagnosis based on available evidence at the time. Establishing the correct diagnosis has important implications. A timely and precise diagnosis ensures the patient the highest probability of having a positive health outcome that reflects an appropriate understanding of underlying disease processes and is consistent with their overall goals of care.³ When diagnostic errors occur, they can cause patient harm. Adverse events due to medical errors, including diagnostic errors, are estimated to be the third leading cause of death in the United States.⁴ Most people will experience at least 1 diagnostic error in their lifetime. In the 2015 National Academy of Medicine report Improving Diagnosis in Healthcare, diagnostic errors were identified as a major hazard as well as an opportunity to improve patient outcomes.²

Diagnostic errors during hospitalizations are especially concerning, as they are more likely to be implicated in a wider spectrum of harm, including permanent disability and death. This has become even more relevant for hospital medicine physicians and other clinical providers as they encounter increasing cognitive and administrative workloads, rising dissatisfaction and burnout, and unique obstacles such as night-time scheduling.⁵

Incidence of Diagnostic Errors in Hospitalized Patients

Several methodological approaches have been used to estimate the incidence of diagnostic errors in hospitalized patients. These include retrospective reviews of a sample of all hospital admissions, evaluations of selected adverse outcomes including autopsy studies, patient and provider surveys, and malpractice claims. Laboratory testing audits and secondary reviews in other diagnostic subspecialities (eg, radiology, pathology, and microbiology) are also essential to improving diagnostic performance in these specialized fields, which in turn affects overall hospital diagnostic error rates.^6-8 These diverse approaches provide unique insights regarding our ability to assess the degree to which potential harms, ranging from temporary impairment to permanent disability, to death, are attributable to different failure points in the diagnostic process.

Large retrospective chart reviews of random hospital admissions remain the most accurate way to determine the overall incidence of diagnostic errors in hospitalized patients.⁹ The Harvard Medical Practice Study, published in 1991, laid the groundwork for measuring the incidence of adverse events in hospitalized patients and assessing their relation to medical error, negligence, and disability. Reviewing 30,121 randomly selected records from 51 randomly selected acute care hospitals in New York State, the study found that adverse events occurred in 3.7% of hospitalizations, diagnostic errors accounted for 13.8% of these events, and these errors were likely attributable to negligence in 74.7% of cases. The study not only outlined individual-level process failures, but also focused attention on some of the systemic causes, setting the agenda for quality improvement research in hospital-based care for years to come.^10-12 A recent systematic review and meta-analysis of 22 hospital admission studies found a pooled rate of 0.7% (95% CI, 0.5%-1.1%) for harmful diagnostic errors.⁹ It found significant variations in the rates of adverse events, diagnostic errors, and range of diagnoses that were missed. This was primarily because of variabilities in pre-test probabilities in detecting diagnostic errors in these specific cohorts, as well as due to heterogeneity in study definitions and methodologies, especially regarding how they defined and measured “diagnostic error.” The analysis, however, did not account for diagnostic errors that were not related to patient harm (missed opportunities); therefore, it likely significantly underestimated the true incidence of diagnostic errors in these study populations. Table 1 summarizes some of key studies that have examined the incidence of harmful diagnostic errors in hospitalized patients.^9-21

The chief limitation of reviewing random hospital admissions is that, since overall rates of diagnostic errors are still relatively low, a large number of case reviews are required to identify a sufficient sample of adverse outcomes to gain a meaningful understanding of the underlying process failure points and develop tools for remediation. Patient and provider surveys or data from malpractice claims can be high-yield starting points for research on process errors.^22,23 Reviews of enriched cohorts of adverse outcomes, such as rapid-response events, intensive care unit (ICU) transfers, deaths, and hospital readmissions, can be an efficient way to identify process failures that lead to greatest harm. Depending on the research approach and the types of underlying patient populations sampled, rates of diagnostic errors in these high-risk groups have been estimated to be approximately 5% to 20%, or even higher.^6,24-31 For example, a retrospective study of 391 cases of unplanned 7-day readmissions found that 5.6% of cases contained at least 1 diagnostic error during the index admission.³² In a study conducted at 6 Belgian acute-care hospitals, 56% of patients requiring an unplanned transfer to a higher level of care were determined to have had an adverse event, and of these adverse events, 12.4% of cases were associated with errors in diagnosis.²⁹ A systematic review of 16 hospital-based studies estimated that 3.1% of all inpatient deaths were likely preventable, which corresponded to 22,165 deaths annually in the United States.³⁰ Another such review of 31 autopsy studies reported that 28% of autopsied ICU patients had at least 1 misdiagnosis; of these diagnostic errors, 8% were classified as potentially lethal, and 15% were considered major but not lethal.³¹ Significant drawbacks of such enriched cohort studies, however, are their poor generalizability and inability to detect failure points that do not lead to patient harm (near-miss events).³³

Causes of Diagnostic Errors in Hospitalized Patients

All aspects of the diagnostic process are susceptible to errors. These errors stem from a variety of faulty processes, including failure of the patient to engage with the health care system (eg, due to lack of insurance or transportation, or delay in seeking care); failure in information gathering (eg, missed history or exam findings, ordering wrong tests, laboratory errors); failure in information interpretation (eg, exam finding or test result misinterpretation); inaccurate hypothesis generation (eg, due to suboptimal prioritization or weighing of supporting evidence); and failure in communication (eg, with other team members or with the patient).^2,34 Reasons for diagnostic process failures vary widely across different health care settings. While clinician assessment errors (eg, failure to consider or alternatively overweigh competing diagnoses) and errors in testing and the monitoring phase (eg, failure to order or follow up diagnostic tests) can lead to a majority of diagnostic errors in some patient populations, in other settings, social (eg, poor health literacy, punitive cultural practices) and economic factors (eg, lack of access to appropriate diagnostic tests or to specialty expertise) play a more prominent role.^34,35

The Figure describes the relationship between components of the diagnostic process and subsequent outcomes, including diagnostic process failures, diagnostic errors, and absence or presence of patient harm.^2,36,37 It reemphasizes the centrality of the patient in decision-making and the continuous nature of the process. The Figure also illustrates that only a minority of process failures result in diagnostic errors, and a smaller proportion of diagnostic errors actually lead to patient harm. Conversely, it also shows that diagnostic errors can happen without any obvious process-failure points, and, similarly, patient harm can take place in the absence of any evident diagnostic errors.^36-38 Finally, it highlights the need to incorporate feedback from process failures, diagnostic errors, and favorable and unfavorable patient outcomes in order to inform future quality improvement efforts and research.

A significant proportion of diagnostic errors are due to system-related vulnerabilities, such as limitations in availability, adoption or quality of work force training, health informatics resources, and diagnostic capabilities. Lack of institutional culture that promotes safety and transparency also predisposes to diagnostic errors.^39,40 The other major domain of process failures is related to cognitive errors in clinician decision-making. Anchoring, confirmation bias, availability bias, and base-rate neglect are some of the common cognitive biases that, along with personality traits (aversion to risk or ambiguity, overconfidence) and affective biases (influence of emotion on decision-making), often determine the degree of utilization of resources and the possibility of suboptimal diagnostic performance.^41,42 Further, implicit biases related to age, race, gender, and sexual orientation contribute to disparities in access to health care and outcomes.⁴³ In a large number of cases of preventable adverse outcomes, however, there are multiple interdependent individual and system-related failure points that lead to diagnostic error and patient harm.^6,32

Challenges in Defining and Measuring Diagnostic Errors

In order to develop effective, evidence-based interventions to reduce diagnostic errors in hospitalized patients, it is essential to be able to first operationally define, and then accurately measure, diagnostic errors and the process failures that contribute to these errors in a standardized way that is reproducible across different settings.^6,44 There are a number of obstacles in this endeavor.

A fundamental problem is that establishing a diagnosis is not a single act but a process. Patterns of symptoms and clinical presentations often differ for the same disease. Information required to make a diagnosis is usually gathered in stages, where the clinician obtains additional data, while considering many possibilities, of which 1 may be ultimately correct. Diagnoses evolve over time and in different care settings. “The most likely diagnosis” is not always the same as “the final correct diagnosis.” Moreover, the diagnostic process is influenced by patients’ individual clinical courses and preferences over time. This makes determination of missed, delayed, or incorrect diagnoses challenging.^45,46

For hospitalized patients, generally the goal is to first rule out more serious and acute conditions (eg, pulmonary embolism or stroke), even if their probability is rather low. Conversely, a diagnosis that appears less consequential if delayed (eg, chronic anemia of unclear etiology) might not be pursued on an urgent basis, and is often left to outpatient providers to examine, but still may manifest in downstream harm (eg, delayed diagnosis of gastrointestinal malignancy or recurrent admissions for heart failure due to missed iron-deficiency anemia). Therefore, coming up with disease diagnosis likelihoods in hindsight may turn out to be highly subjective and not always accurate. This can be particularly difficult when clinician and other team deliberations are not recorded in their entirety.⁴⁷

Another hurdle in the practice of diagnostic medicine is to preserve the balance between underdiagnosing versus pursuing overly aggressive diagnostic approaches. Conducting laboratory, imaging, or other diagnostic studies without a clear shared understanding of how they would affect clinical decision-making (eg, use of prostate-specific antigen to detect prostate cancer) not only leads to increased costs but can also delay appropriate care. Worse, subsequent unnecessary diagnostic tests and treatments can sometimes lead to serious harm.^48,49

Finally, retrospective reviews by clinicians are subject to multiple potential limitations that include failure to create well-defined research questions, poorly developed inclusion and exclusion criteria, and issues related to inter- and intra-rater reliability.⁵⁰ These methodological deficiencies can occur despite following "best practice" guidelines during the study planning, execution, and analysis phases. They further add to the challenge of defining and measuring diagnostic errors.⁴⁷

Strategies to Improve Measurement of Diagnostic Errors

Development of new methodologies to reliably measure diagnostic errors is an area of active research. The advancement of uniform and universally agreed-upon frameworks to define and identify process failure points and diagnostic errors would help reduce measurement error and support development and testing of interventions that could be generalizable across different health care settings. To more accurately define and measure diagnostic errors, several novel approaches have been proposed (Table 2).

The Safer Dx framework is an all-round tool developed to advance the discipline of measuring diagnostic errors. For an episode of care under review, the instrument scores various items to determine the likelihood of a diagnostic error. These items evaluate multiple dimensions affecting diagnostic performance and measurements across 3 broad domains: structure (provider and organizational characteristics—from everyone involved with patient care, to computing infrastructure, to policies and regulations), process (elements of the patient-provider encounter, diagnostic test performance and follow-up, and subspecialty- and referral-specific factors), and outcome (establishing accurate and timely diagnosis as opposed to missed, delayed, or incorrect diagnosis). This instrument has been revised and can be further modified by a variety of stakeholders, including clinicians, health care organizations, and policymakers, to identify potential diagnostic errors in a standardized way for patient safety and quality improvement research.^51,52

Use of standardized tools, such as the Diagnosis Error Evaluation and Research (DEER) taxonomy, can help to identify and classify specific failure points across different diagnostic process dimensions.³⁷ These failure points can be classified into: issues related to patient presentation or access to health care; failure to obtain or misinterpretation of history or physical exam findings; errors in use of diagnostics tests due to technical or clinician-related factors; failures in appropriate weighing of evidence and hypothesis generation; errors associated with referral or consultation process; and failure to monitor the patient or obtain timely follow-up.³⁴ The DEER taxonomy can also be modified based on specific research questions and study populations. Further, it can be recategorized to correspond to Safer Dx framework diagnostic process dimensions to provide insights into reasons for specific process failures and to develop new interventions to mitigate errors and patient harm.⁶

Since a majority of diagnostic errors do not lead to actual harm, use of “triggers” or clues (eg, procedure-related complications, patient falls, transfers to a higher level of care, readmissions within 30 days) can be a more efficient method to identify diagnostic errors and adverse events that do cause harm. The Global Trigger Tool, developed by the Institute for Healthcare Improvement, uses this strategy. This tool has been shown to identify a significantly higher number of serious adverse events than comparable methods.⁵³ This facilitates selection and development of strategies at the institutional level that are most likely to improve patient outcomes.²⁴

Encouraging and facilitating voluntary or prompted reporting from patients and clinicians can also play an important role in capturing diagnostic errors. Patients and clinicians are not only the key stakeholders but are also uniquely placed within the diagnostic process to detect and report potential errors.^25,54 Patient-safety-event reporting systems, such as RL6, play a vital role in reporting near-misses and adverse events. These systems provide a mechanism for team members at all levels within the hospital to contribute toward reporting patient adverse events, including those arising from diagnostic errors.⁵⁵ The Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey is the first standardized, nationally reported patient survey designed to measure patients’ perceptions of their hospital experience. The US Centers for Medicare and Medicaid Services (CMS) publishes HCAHPS results on its website 4 times a year, which serves as an important incentive for hospitals to improve patient safety and quality of health care delivery.⁵⁶

Another novel approach links multiple symptoms to a range of target diseases using the Symptom-Disease Pair Analysis of Diagnostic Error (SPADE) framework. Using “big data” technologies, this technique can help discover otherwise hidden symptom-disease links and improve overall diagnostic performance. This approach is proposed for both case-control (look-back) and cohort (look-forward) studies assessing diagnostic errors and misdiagnosis-related harms. For example, starting with a known diagnosis with high potential for harm (eg, stroke), the “look-back” approach can be used to identify high-risk symptoms (eg, dizziness, vertigo). In the “look-forward” approach, a single symptom or exposure risk factor known to be frequently misdiagnosed (eg, dizziness) can be analyzed to identify potential adverse disease outcomes (eg, stroke, migraine).⁵⁷

Many large ongoing studies looking at diagnostic errors among hospitalized patients, such as Utility of Predictive Systems to identify Inpatient Diagnostic Errors (UPSIDE),⁵⁸ Patient Safety Learning Lab (PSLL),⁵⁹ and Achieving Diagnostic Excellence through Prevention and Teamwork (ADEPT),⁶⁰ are using structured chart review methodologies incorporating many of the above strategies in combination. Cases triggered by certain events (eg, ICU transfer, death, rapid response event, new or worsening acute kidney injury) are reviewed using validated tools, including Safer Dx framework and DEER taxonomy, to provide the most precise estimates of the burden of diagnostic errors in hospitalized patients. These estimates may be much higher than previously predicted using traditional chart review approaches.^6,24 For example, a recently published study of 2809 random admissions in 11 Massachusetts hospitals identified 978 adverse events but only 10 diagnostic errors (diagnostic error rate, 0.4%).¹⁹ This was likely because the trigger method used in the study did not specifically examine the diagnostic process as critically as done by the Safer Dx framework and DEER taxonomy tools, thereby underestimating the total number of diagnostic errors. Further, these ongoing studies (eg, UPSIDE, ADEPT) aim to employ new and upcoming advanced machine-learning methods to create models that can improve overall diagnostic performance. This would pave the way to test and build novel, efficient, and scalable interventions to reduce diagnostic errors and improve patient outcomes.

Strategies to Improve Diagnostic Safety in Hospitalized Patients

Disease-specific biomedical research, as well as advances in laboratory, imaging, and other technologies, play a critical role in improving diagnostic accuracy. However, these technical approaches do not address many of the broader clinician- and system-level failure points and opportunities for improvement. Various patient-, provider-, and organizational-level interventions that could make diagnostic processes more resilient and reduce the risk of error and patient harm have been proposed.⁶¹

Among these strategies are approaches to empower patients and their families. Fostering therapeutic relationships between patients and members of the care team is essential to reducing diagnostic errors.⁶² Facilitating timely access to health records, ensuring transparency in decision making, and tailoring communication strategies to patients’ cultural and educational backgrounds can reduce harm.⁶³ Similarly, at the system level, enhancing communication among different providers by use of tools such as structured handoffs can prevent communication breakdowns and facilitate positive outcomes.⁶⁴

Interventions targeted at individual health care providers, such as educational programs to improve content-specific knowledge, can enhance diagnostic performance. Regular feedback, strategies to enhance equity, and fostering an environment where all providers are actively encouraged to think critically and participate in the diagnostic process (training programs to use “diagnostic time-outs” and making it a “team sport”) can improve clinical reasoning.^65,66 Use of standardized patients can help identify individual-level cognitive failure points and facilitate creation of new interventions to improve clinical decision-making processes.⁶⁷

Novel health information technologies can further augment these efforts. These include effective documentation by maintaining dynamic and accurate patient histories, problem lists, and medication lists^68-70; use of electronic health record–based algorithms to identify potential diagnostic delays for serious conditions^71,72; use of telemedicine technologies to improve accessibility and coordination⁷³; application of mobile health and wearable technologies to facilitate data-gathering and care delivery^74,75; and use of computerized decision-support tools, including applications to interpret electrocardiograms, imaging studies, and other diagnostic tests.⁷⁶

Use of precision medicine, powered by new artificial intelligence (AI) tools, is becoming more widespread. Algorithms powered by AI can augment and sometimes even outperform clinician decision-making in areas such as oncology, radiology, and primary care.⁷⁷ Creation of large biobanks like the All of Us research program can be used to study thousands of environmental and genetic risk factors and health conditions simultaneously, and help identify specific treatments that work best for people of different backgrounds.⁷⁸ Active research in these areas holds great promise in terms of how and when we diagnose diseases and make appropriate preventative and treatment decisions. Significant scientific, ethical, and regulatory challenges will need to be overcome before these technologies can address some of the most complex problems in health care.⁷⁹

Finally, diagnostic performance is affected by the external environment, including the functioning of the medical liability system. Diagnostic errors that lead to patient harm are a leading cause of malpractice claims.⁸⁰ Developing a legal environment, in collaboration with patient advocacy groups and health care organizations, that promotes and facilitates timely disclosure of diagnostic errors could decrease the incentive to hide errors, advance care processes, and improve outcomes.^81,82

Conclusion

The burden of diagnostic errors in hospitalized patients is unacceptably high and remains an underemphasized cause of preventable morbidity and mortality. Diagnostic errors often result from a breakdown in multiple interdependent processes that involve patient-, provider-, and system-level factors. Significant challenges remain in defining and identifying diagnostic errors as well as underlying process-failure points. The most effective interventions to reduce diagnostic errors will require greater patient participation in the diagnostic process and a mix of evidence-based interventions that promote individual-provider excellence as well as system-level changes. Further research and collaboration among various stakeholders should help improve diagnostic safety for hospitalized patients.

Corresponding author: Abhishek Goyal, MD, MPH; [email protected]

Disclosures: Dr. Dalal disclosed receiving income ≥ $250 from MayaMD.

Photo: Shutterstock

Six months after the Supreme Court decision that overturned the constitutional right to abortion, trainees across the United States are asking a critical question in the current resident recruitment season: How will the restrictions on abortion access affect my training as an obstetrician-gynecologist, and will they impact my ability to be the kind of provider I want to be in the future?

Among the myriad of downstream effects to patient care, the Dobbs decision will indisputably impact the scope of residency training for those that provide reproductive health services. Almost half of ObGyn residents train in states that have abortion restrictions in place.¹ New educational milestones for abortion training, which are a requirement by the Accreditation Council for Graduate Medical Education (ACGME), were proposed quickly after Dobbs, guiding programs to offer opportunities for training in nonrestricted areas or the “combination of didactic activities, including simulation” to meet the training requirement in abortion care.²

Like many providers, residents already are grappling with precarious and risky circumstances, balancing patient safety and patient-driven care amidst pre-existing and newly enforced abortion restrictions. Whether managing a patient with an undesired pregnancy, severe medical comorbidities, unexpected pregnancy complications such as preterm premature rupture of membranes, or bleeding, or substantial fetal anomalies, ObGyn residents cannot gain the experience of providing the full scope of reproductive health care without the ability to offer all possible management options. While some enacted abortion restrictions have exceptions for the health of or life-saving measures for the mother, there is no standard guidance for timing of interventions, leaving providers confused and in fear of legal retribution. At a time when trainees should be learning to provide patient-centered, evidence-based care, they are instead paralyzed by the legal or professional consequences they may face for offering their best medical judgements.

Furthermore, the lack of exposure to dilation and evacuation procedures for residents in restricted practice areas will undoubtably decrease their confidence in managing acute complications, which is one of the critical facets of residency training. In a surgical field where repetition is crucial for technical competence, highlighted by ACGME minimum case requirements, the decreased volume of abortion procedures is a disadvantage for trainees and a disservice for patients. While anti-choice promoters may argue that involvement in surgical management of early pregnancy loss should suffice for ObGyn training in family planning, this piecemeal approach will leave gaps in technical skills.

The fear of legal ramifications, moral injury, and inadequate surgical training may lead to the siphoning of talented trainees to areas in the country with fewer restrictions.³ Dobbs already has demonstrated how limiting abortion access will deepen inequities in reproductive health care service delivery. Approximately 55% of ObGyn trainees and nearly two-thirds of maternal-fetal medicine graduates join the workforce in the state where they received their training.⁴ Medical students will seek opportunities for high-quality ObGyn training in areas that will help them to be well-prepared, competent physicians—and more often than not, stay in the area or region that they trained in. This will lead to provider shortages in areas where access to reproductive health care and subspecialist providers already is limited, further exacerbating existing health disparities.

During this recruitment season, trainees and residency programs alike will need to reckon with how the ramifications of Dobbs will alter both the immediate and long-term training in comprehensive reproductive health care for the ObGyn workforce. ObGyn trainees have taken a stand in response to the Dobbs decision, and nearly 750 current residents signed onto the statement below as a commitment to high-quality training and patient-centered care. Clinical experience in performing abortions is essential to the provision of comprehensive evidence-based reproductive health care, and access to these procedures is as important for physicians-in-training as it is for patients.

Actions to take to ensure high-quality abortion training in ObGyn residencies include the following:

• Connect with and stay involved with organizations such as the American College of Obstetricians and Gynecologists (ACOG), Physicians for Reproductive Health (PRH), and Medical Students for Choice (MSFC) for initiatives, toolkits, and resources for training at your institutions.
• Seek specific abortion training opportunities through the Leadership Training Academy (offered through PRH) or the Abortion Training Institute (offered through MSFC).
• Ensure that your residency program meets the ACGME criteria of providing opportunities for clinical experiences for abortion care and work with program leadership at a program, state, or regional level to enforce these competencies.
• Reach out to your local American Civil Liberties Union or other local reproductive legal rights organizations if you want to be involved with advocacy around abortion access and training but have concerns about legal protections.
• Have a voice at the table for empowering training opportunities by seeking leadership positions through ACOG, ACGME, Council on Resident Education in Obstetrics and Gynecology and the Association of Professors of Gynecology and Obstetrics, American Medical Association, Student National Medical Association, and subspecialty organizations.
• Vote in every election and promote voting registration and access to your patients, colleagues, and communities. ●

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