Dr Gregg Silverman of New York University Langone Medical Center highlights four key studies on lupus nephritis (LN) presented at ASN Kidney Week 2022.  

First, he focuses on a follow-up study of voclosporin after the successful phase 3 trial of the medication. According to the study, persistent proteinuria increases risk for comorbidities in lupus nephritis and rapid reductions in protein are predictive of improved long-term renal health. Voclosporin may be beneficial in limiting the negative long-term effects of proteinuria for patients with LN.  

Next, Dr Silverman discusses a study that investigates the safety and tolerability of a first-in-class selective proteasome inhibitor for the treatment of LN. Use of this type of proteasome may improve autoimmunity for these patients.  

The third abstract he discusses is a study of an investigational agent, VIB 4920, that was first explored over 20 years ago and that may have activity in LN.  

Finally, Dr Silverman examines a phase 2b study that evaluated the efficacy and safety of telitacicept vs placebo in combination with standard therapy in patients with lupus. Early results were encouraging, but more mature results are needed.  

--

Highlights in lupus nephritis (LN) from ASN Kidney Week 2022 focus on results on voclosporin, repurposing of telitacicept, promising agent VIB 4920, and other novel treatments for patients with LN. 

Gregg J. Silverman, MD, has disclosed no relevant financial relationships. 

Dr Gregg Silverman of New York University Langone Medical Center highlights four key studies on lupus nephritis (LN) presented at ASN Kidney Week 2022.  

First, he focuses on a follow-up study of voclosporin after the successful phase 3 trial of the medication. According to the study, persistent proteinuria increases risk for comorbidities in lupus nephritis and rapid reductions in protein are predictive of improved long-term renal health. Voclosporin may be beneficial in limiting the negative long-term effects of proteinuria for patients with LN.  

Next, Dr Silverman discusses a study that investigates the safety and tolerability of a first-in-class selective proteasome inhibitor for the treatment of LN. Use of this type of proteasome may improve autoimmunity for these patients.  

The third abstract he discusses is a study of an investigational agent, VIB 4920, that was first explored over 20 years ago and that may have activity in LN.  

Finally, Dr Silverman examines a phase 2b study that evaluated the efficacy and safety of telitacicept vs placebo in combination with standard therapy in patients with lupus. Early results were encouraging, but more mature results are needed.  

--

Highlights in lupus nephritis (LN) from ASN Kidney Week 2022 focus on results on voclosporin, repurposing of telitacicept, promising agent VIB 4920, and other novel treatments for patients with LN. 

Gregg J. Silverman, MD, has disclosed no relevant financial relationships. 

Dr Gregg Silverman of New York University Langone Medical Center highlights four key studies on lupus nephritis (LN) presented at ASN Kidney Week 2022.  

First, he focuses on a follow-up study of voclosporin after the successful phase 3 trial of the medication. According to the study, persistent proteinuria increases risk for comorbidities in lupus nephritis and rapid reductions in protein are predictive of improved long-term renal health. Voclosporin may be beneficial in limiting the negative long-term effects of proteinuria for patients with LN.  

Next, Dr Silverman discusses a study that investigates the safety and tolerability of a first-in-class selective proteasome inhibitor for the treatment of LN. Use of this type of proteasome may improve autoimmunity for these patients.  

The third abstract he discusses is a study of an investigational agent, VIB 4920, that was first explored over 20 years ago and that may have activity in LN.  

Finally, Dr Silverman examines a phase 2b study that evaluated the efficacy and safety of telitacicept vs placebo in combination with standard therapy in patients with lupus. Early results were encouraging, but more mature results are needed.  

--

Highlights in lupus nephritis (LN) from ASN Kidney Week 2022 focus on results on voclosporin, repurposing of telitacicept, promising agent VIB 4920, and other novel treatments for patients with LN. 

Gregg J. Silverman, MD, has disclosed no relevant financial relationships. 

The calendar year 2022 has been especially good for advancing acne-focused laser and light devices, most recently with the Food and Drug Administration clearance of the Accure Laser System in late November, for the treatment of mild to severe inflammatory acne vulgaris.

This was preceded by the FDA clearance of AviClear, marketed by Cutera, in March, and the commercial launch of TheraClearX, marketed by StrataSkin, in July.

“It’s an exciting time to be working with acne,” Fernanda H. Sakamoto, MD, PhD, a dermatologist at the Wellman Center for Photomedicine at Massachusetts General Hospital, Boston. “We’ll see a lot of people using new devices. I’m looking forward to seeing results in the long term.”

AviClear and the Accure Laser System, marketed by Accure, are both powered by a 1,726-nm laser, but they work differently. AviClear, which was cleared for the treatment of mild, moderate, and severe acne, has a maximum fluence of 30 J/cm² in single-pulse mode and a maximum fluence of 20 J/cm² in double-pulse mode. The treatment handpiece has an integrated scanner for delivering treatment spot(s) in an operator-selected pattern. “It’s a little bit lower powered than the Accure and has a maximum pulse energy of 5 joules and a pulse duration of up to 50 milliseconds,” Dr. Sakamoto said. In the treatment of acne, laser and light treatments target the sebaceous gland.

In pivotal data submitted to the FDA, 104 patients with acne who were enrolled at 7 U.S. sites received 304 treatments with AviClear spaced 2-5 weeks apart. Each treatment took about 30 minutes. Treatment success was defined as having at least 50% fewer inflammatory acne lesions 12 weeks after the final treatment visit, compared with baseline. At the week 4 follow-up visit, there were median and mean reductions of 42% and 37%, respectively, in the inflammatory lesion counts from baseline (P < .001). The researchers found that, at the week 4 follow-up visit, 36% of patients had achieved treatment success, which increased to 78% at the 12-week follow-up visit. Treatment was considered safe and tolerable, according to the manufacturer.

The other newcomer device with a 1,726-nm wavelength is the Accure Laser System, which features a smart laser handpiece for real-time thermal monitoring and precise delivery of laser emissions. The device received CE Mark approval in 2020 for the treatment of moderate acne, and on Nov. 22, 2022, the manufacturer announced that it had been cleared by the FDA for the treatment of mild to severe inflammatory acne vulgaris.

Dr. Sakamoto and her Wellman colleagues have been working with five dermatologists to conduct clinical trials of the device: Emil Tanghetti, MD, and Mitchel Goldman, MD, in California; Roy Geronemus, MD, in New York; Joel Cohen, MD, in Colorado; and Daniel Friedmann, MD, in Texas. As of Oct. 2, 2022, more than 50 patients with mild to severe acne were enrolled in four studies and an additional 30 were enrolled in a pilot facial acne trial, Dr. Sakamoto said. In the trials, patients are followed at 4, 8, 12, and 24 weeks post treatment.

Among patients enrolled in the facial acne trial, researchers have observed a 100% responder rate for patients with more than five acne lesions at 4, 8, 12, and 24 weeks post treatment after four monthly treatment sessions. The average lesion reduction at week 12 was 82% and the mean visual analog scale score immediately after treatment was 2.09 out of 10. Each patient received more than 12,000 trigger pulls of energy from the device overall with no adverse events reported. At 12 months, they observed a 90% inflammatory lesion count reduction from baseline and a rapid response to treatment: a 73% reduction achieved after the first two treatment sessions. Histologic studies revealed selective sebaceous gland destruction with no damage to the epidermis, surrounding dermis, or other skin structures.

Dr. Sakamoto emphasized that to date no direct clinical comparisons have been made between the AviClear and Accure devices. “Are all 1,726-nm lasers made equal? That is a question that we have to keep in our mind,” she said during the meeting, which was sponsored by Harvard Medical School, Massachusetts General Hospital, and the Wellman Center for Photomedicine. “They are using the same wavelength, but they are different types of lasers.”

For example, the Accure Laser treats to temperature, relies on air cooling, and is targeted to dermatologists and plastic surgeons, while the AviClear treats to fluence, relies on contact cooling, and includes med spas and other nonphysician providers as the target users. “Mathematically, the difference between the two devices is that the Accure can achieve deeper penetration in a single pulse, while the AviClear is a little more superficial,” she said. “Whether that is translated clinically is unknown at this point.”

Dr. Sakamoto also discussed the TheraClearX, which is FDA cleared for the treatment of mild, moderate, and severe acne, including comedonal, pustular, and inflammatory acne vulgaris. The device, which is a new version of the Palomar Acleara, uses a vacuum technique with up to 3 psi pressure in conjunction with broadband light with a wavelength spectrum of 500 nm–1,200 nm delivered through a liquid-cooled, handheld delivery system. The predicate device was the Aesthera Isolaz System. The vacuum extracts buildup of sebaceous material. “At the same time, it takes the blood out of the competing chromophore,” she said. “By doing so, it potentially damages the sebaceous glands and reduces the inflammatory lesions.”

Dr. Sakamoto disclosed that she is the founder of and science advisor for Lightwater Bioscience. She is also a science advisor for Accure Acne and has received portions of patent royalties from Massachusetts General Hospital.

The calendar year 2022 has been especially good for advancing acne-focused laser and light devices, most recently with the Food and Drug Administration clearance of the Accure Laser System in late November, for the treatment of mild to severe inflammatory acne vulgaris.

This was preceded by the FDA clearance of AviClear, marketed by Cutera, in March, and the commercial launch of TheraClearX, marketed by StrataSkin, in July.

“It’s an exciting time to be working with acne,” Fernanda H. Sakamoto, MD, PhD, a dermatologist at the Wellman Center for Photomedicine at Massachusetts General Hospital, Boston. “We’ll see a lot of people using new devices. I’m looking forward to seeing results in the long term.”

AviClear and the Accure Laser System, marketed by Accure, are both powered by a 1,726-nm laser, but they work differently. AviClear, which was cleared for the treatment of mild, moderate, and severe acne, has a maximum fluence of 30 J/cm² in single-pulse mode and a maximum fluence of 20 J/cm² in double-pulse mode. The treatment handpiece has an integrated scanner for delivering treatment spot(s) in an operator-selected pattern. “It’s a little bit lower powered than the Accure and has a maximum pulse energy of 5 joules and a pulse duration of up to 50 milliseconds,” Dr. Sakamoto said. In the treatment of acne, laser and light treatments target the sebaceous gland.

In pivotal data submitted to the FDA, 104 patients with acne who were enrolled at 7 U.S. sites received 304 treatments with AviClear spaced 2-5 weeks apart. Each treatment took about 30 minutes. Treatment success was defined as having at least 50% fewer inflammatory acne lesions 12 weeks after the final treatment visit, compared with baseline. At the week 4 follow-up visit, there were median and mean reductions of 42% and 37%, respectively, in the inflammatory lesion counts from baseline (P < .001). The researchers found that, at the week 4 follow-up visit, 36% of patients had achieved treatment success, which increased to 78% at the 12-week follow-up visit. Treatment was considered safe and tolerable, according to the manufacturer.

The other newcomer device with a 1,726-nm wavelength is the Accure Laser System, which features a smart laser handpiece for real-time thermal monitoring and precise delivery of laser emissions. The device received CE Mark approval in 2020 for the treatment of moderate acne, and on Nov. 22, 2022, the manufacturer announced that it had been cleared by the FDA for the treatment of mild to severe inflammatory acne vulgaris.

Dr. Sakamoto and her Wellman colleagues have been working with five dermatologists to conduct clinical trials of the device: Emil Tanghetti, MD, and Mitchel Goldman, MD, in California; Roy Geronemus, MD, in New York; Joel Cohen, MD, in Colorado; and Daniel Friedmann, MD, in Texas. As of Oct. 2, 2022, more than 50 patients with mild to severe acne were enrolled in four studies and an additional 30 were enrolled in a pilot facial acne trial, Dr. Sakamoto said. In the trials, patients are followed at 4, 8, 12, and 24 weeks post treatment.

Among patients enrolled in the facial acne trial, researchers have observed a 100% responder rate for patients with more than five acne lesions at 4, 8, 12, and 24 weeks post treatment after four monthly treatment sessions. The average lesion reduction at week 12 was 82% and the mean visual analog scale score immediately after treatment was 2.09 out of 10. Each patient received more than 12,000 trigger pulls of energy from the device overall with no adverse events reported. At 12 months, they observed a 90% inflammatory lesion count reduction from baseline and a rapid response to treatment: a 73% reduction achieved after the first two treatment sessions. Histologic studies revealed selective sebaceous gland destruction with no damage to the epidermis, surrounding dermis, or other skin structures.

Dr. Sakamoto emphasized that to date no direct clinical comparisons have been made between the AviClear and Accure devices. “Are all 1,726-nm lasers made equal? That is a question that we have to keep in our mind,” she said during the meeting, which was sponsored by Harvard Medical School, Massachusetts General Hospital, and the Wellman Center for Photomedicine. “They are using the same wavelength, but they are different types of lasers.”

For example, the Accure Laser treats to temperature, relies on air cooling, and is targeted to dermatologists and plastic surgeons, while the AviClear treats to fluence, relies on contact cooling, and includes med spas and other nonphysician providers as the target users. “Mathematically, the difference between the two devices is that the Accure can achieve deeper penetration in a single pulse, while the AviClear is a little more superficial,” she said. “Whether that is translated clinically is unknown at this point.”

Dr. Sakamoto also discussed the TheraClearX, which is FDA cleared for the treatment of mild, moderate, and severe acne, including comedonal, pustular, and inflammatory acne vulgaris. The device, which is a new version of the Palomar Acleara, uses a vacuum technique with up to 3 psi pressure in conjunction with broadband light with a wavelength spectrum of 500 nm–1,200 nm delivered through a liquid-cooled, handheld delivery system. The predicate device was the Aesthera Isolaz System. The vacuum extracts buildup of sebaceous material. “At the same time, it takes the blood out of the competing chromophore,” she said. “By doing so, it potentially damages the sebaceous glands and reduces the inflammatory lesions.”

Dr. Sakamoto disclosed that she is the founder of and science advisor for Lightwater Bioscience. She is also a science advisor for Accure Acne and has received portions of patent royalties from Massachusetts General Hospital.

The calendar year 2022 has been especially good for advancing acne-focused laser and light devices, most recently with the Food and Drug Administration clearance of the Accure Laser System in late November, for the treatment of mild to severe inflammatory acne vulgaris.

This was preceded by the FDA clearance of AviClear, marketed by Cutera, in March, and the commercial launch of TheraClearX, marketed by StrataSkin, in July.

“It’s an exciting time to be working with acne,” Fernanda H. Sakamoto, MD, PhD, a dermatologist at the Wellman Center for Photomedicine at Massachusetts General Hospital, Boston. “We’ll see a lot of people using new devices. I’m looking forward to seeing results in the long term.”

AviClear and the Accure Laser System, marketed by Accure, are both powered by a 1,726-nm laser, but they work differently. AviClear, which was cleared for the treatment of mild, moderate, and severe acne, has a maximum fluence of 30 J/cm² in single-pulse mode and a maximum fluence of 20 J/cm² in double-pulse mode. The treatment handpiece has an integrated scanner for delivering treatment spot(s) in an operator-selected pattern. “It’s a little bit lower powered than the Accure and has a maximum pulse energy of 5 joules and a pulse duration of up to 50 milliseconds,” Dr. Sakamoto said. In the treatment of acne, laser and light treatments target the sebaceous gland.

In pivotal data submitted to the FDA, 104 patients with acne who were enrolled at 7 U.S. sites received 304 treatments with AviClear spaced 2-5 weeks apart. Each treatment took about 30 minutes. Treatment success was defined as having at least 50% fewer inflammatory acne lesions 12 weeks after the final treatment visit, compared with baseline. At the week 4 follow-up visit, there were median and mean reductions of 42% and 37%, respectively, in the inflammatory lesion counts from baseline (P < .001). The researchers found that, at the week 4 follow-up visit, 36% of patients had achieved treatment success, which increased to 78% at the 12-week follow-up visit. Treatment was considered safe and tolerable, according to the manufacturer.

The other newcomer device with a 1,726-nm wavelength is the Accure Laser System, which features a smart laser handpiece for real-time thermal monitoring and precise delivery of laser emissions. The device received CE Mark approval in 2020 for the treatment of moderate acne, and on Nov. 22, 2022, the manufacturer announced that it had been cleared by the FDA for the treatment of mild to severe inflammatory acne vulgaris.

Dr. Sakamoto and her Wellman colleagues have been working with five dermatologists to conduct clinical trials of the device: Emil Tanghetti, MD, and Mitchel Goldman, MD, in California; Roy Geronemus, MD, in New York; Joel Cohen, MD, in Colorado; and Daniel Friedmann, MD, in Texas. As of Oct. 2, 2022, more than 50 patients with mild to severe acne were enrolled in four studies and an additional 30 were enrolled in a pilot facial acne trial, Dr. Sakamoto said. In the trials, patients are followed at 4, 8, 12, and 24 weeks post treatment.

Among patients enrolled in the facial acne trial, researchers have observed a 100% responder rate for patients with more than five acne lesions at 4, 8, 12, and 24 weeks post treatment after four monthly treatment sessions. The average lesion reduction at week 12 was 82% and the mean visual analog scale score immediately after treatment was 2.09 out of 10. Each patient received more than 12,000 trigger pulls of energy from the device overall with no adverse events reported. At 12 months, they observed a 90% inflammatory lesion count reduction from baseline and a rapid response to treatment: a 73% reduction achieved after the first two treatment sessions. Histologic studies revealed selective sebaceous gland destruction with no damage to the epidermis, surrounding dermis, or other skin structures.

Dr. Sakamoto emphasized that to date no direct clinical comparisons have been made between the AviClear and Accure devices. “Are all 1,726-nm lasers made equal? That is a question that we have to keep in our mind,” she said during the meeting, which was sponsored by Harvard Medical School, Massachusetts General Hospital, and the Wellman Center for Photomedicine. “They are using the same wavelength, but they are different types of lasers.”

For example, the Accure Laser treats to temperature, relies on air cooling, and is targeted to dermatologists and plastic surgeons, while the AviClear treats to fluence, relies on contact cooling, and includes med spas and other nonphysician providers as the target users. “Mathematically, the difference between the two devices is that the Accure can achieve deeper penetration in a single pulse, while the AviClear is a little more superficial,” she said. “Whether that is translated clinically is unknown at this point.”

Dr. Sakamoto also discussed the TheraClearX, which is FDA cleared for the treatment of mild, moderate, and severe acne, including comedonal, pustular, and inflammatory acne vulgaris. The device, which is a new version of the Palomar Acleara, uses a vacuum technique with up to 3 psi pressure in conjunction with broadband light with a wavelength spectrum of 500 nm–1,200 nm delivered through a liquid-cooled, handheld delivery system. The predicate device was the Aesthera Isolaz System. The vacuum extracts buildup of sebaceous material. “At the same time, it takes the blood out of the competing chromophore,” she said. “By doing so, it potentially damages the sebaceous glands and reduces the inflammatory lesions.”

Dr. Sakamoto disclosed that she is the founder of and science advisor for Lightwater Bioscience. She is also a science advisor for Accure Acne and has received portions of patent royalties from Massachusetts General Hospital.

The patient safety record of U.S. hospitals improved over the past decade, according to the 10th annual report from nonprofit the Leapfrog Group, a national nonprofit organization focused on health care safety and quality.

For five outcome measures, the safety improvements saved an estimated 16,000 lives during the 10-year period, the report said. These included two “never” events that both declined by approximately 25%: incidents of falls and trauma and incidents of objects unintentionally left in a body after surgery.

There were also decreases in three health care–associated infections, including methicillin-resistant Staphylococcus aureus (MRSA), which decreased by 22%; central line–associated bloodstream infection (CLABSI), which fell by 43%; and Clostridioides difficile infection (C. Diff), which declined by 8%.

The patient safety record of U.S. hospitals improved over the past decade, according to the report.

“Never in history have we seen across-the-board improvement in patient safety until this last decade, coinciding with the history of the [Leapfrog] Hospital Safety Grade,” said Leah Binder, president and CEO of the Leapfrog Group, in a news release. “We salute hospitals for this milestone and encourage them to accelerate their hard work saving patient lives.”

During the past decade, the report noted, hospitals have widely adopted technology and staffing strategies that can protect patients from preventable harm and death. Leapfrog cited a nearly sevenfold increase in the adoption of computerized provider order entry, which can reduce medication errors by more than 40%. 

However, federal health officials separately have reported that the pandemic may have eroded some of those gains.

The Leapfrog report also cited a recent study, published in JAMA, that found that the rates of preventable adverse events in hospitalized patients – including adverse drug events, hospital-acquired infections, postprocedure events, and hospital-acquired pressure ulcers and falls – significantly declined between 2010 and 2019.

That study pointed to specific decreases in the rates of adverse events for patients admitted for myocardial infarction, heart failure, pneumonia, and major surgical procedures. There were also significant drops in adverse events for all other conditions, the study found.

Quality improvement efforts targeting those four conditions might have partly accounted for the lower rates of adverse events in patients with the conditions, the study observed. But “similar interventions did not occur for most of the conditions represented in the ‘all other conditions’ group,” it said.

In a 2019 report by the U.S. Agency for Healthcare Research and Quality (AHRQ), the agency noted that from 2000 to 2017, there had been gains in nearly two-thirds of patient-safety measures in acute, post-acute, and ambulatory care. Hospital safety improved on nine metrics and was unchanged on three. For example, from 2014 to 2017, the number of some hospital-acquired conditions, including adverse drug events and C. Diff infections, dropped about 20%.

However, in an article this past February, officials of the Centers for Medicare & Medicaid Services (CMS) said they had observed deterioration on multiple patient-safety metrics since the start of the pandemic. For example, central line infections, which had dropped by 31% in the five years before the COVID-19 outbreak, jumped 28% in the second quarter of 2020, compared with the prior-year period.

Commenting on these developments, the CMS authors said “the fact that the pandemic degraded patient safety so quickly and severely suggests that our health care system lacks a sufficiently resilient safety culture and infrastructure.”

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

The patient safety record of U.S. hospitals improved over the past decade, according to the 10th annual report from nonprofit the Leapfrog Group, a national nonprofit organization focused on health care safety and quality.

For five outcome measures, the safety improvements saved an estimated 16,000 lives during the 10-year period, the report said. These included two “never” events that both declined by approximately 25%: incidents of falls and trauma and incidents of objects unintentionally left in a body after surgery.

There were also decreases in three health care–associated infections, including methicillin-resistant Staphylococcus aureus (MRSA), which decreased by 22%; central line–associated bloodstream infection (CLABSI), which fell by 43%; and Clostridioides difficile infection (C. Diff), which declined by 8%.

The patient safety record of U.S. hospitals improved over the past decade, according to the report.

“Never in history have we seen across-the-board improvement in patient safety until this last decade, coinciding with the history of the [Leapfrog] Hospital Safety Grade,” said Leah Binder, president and CEO of the Leapfrog Group, in a news release. “We salute hospitals for this milestone and encourage them to accelerate their hard work saving patient lives.”

During the past decade, the report noted, hospitals have widely adopted technology and staffing strategies that can protect patients from preventable harm and death. Leapfrog cited a nearly sevenfold increase in the adoption of computerized provider order entry, which can reduce medication errors by more than 40%. 

However, federal health officials separately have reported that the pandemic may have eroded some of those gains.

The Leapfrog report also cited a recent study, published in JAMA, that found that the rates of preventable adverse events in hospitalized patients – including adverse drug events, hospital-acquired infections, postprocedure events, and hospital-acquired pressure ulcers and falls – significantly declined between 2010 and 2019.

That study pointed to specific decreases in the rates of adverse events for patients admitted for myocardial infarction, heart failure, pneumonia, and major surgical procedures. There were also significant drops in adverse events for all other conditions, the study found.

Quality improvement efforts targeting those four conditions might have partly accounted for the lower rates of adverse events in patients with the conditions, the study observed. But “similar interventions did not occur for most of the conditions represented in the ‘all other conditions’ group,” it said.

In a 2019 report by the U.S. Agency for Healthcare Research and Quality (AHRQ), the agency noted that from 2000 to 2017, there had been gains in nearly two-thirds of patient-safety measures in acute, post-acute, and ambulatory care. Hospital safety improved on nine metrics and was unchanged on three. For example, from 2014 to 2017, the number of some hospital-acquired conditions, including adverse drug events and C. Diff infections, dropped about 20%.

However, in an article this past February, officials of the Centers for Medicare & Medicaid Services (CMS) said they had observed deterioration on multiple patient-safety metrics since the start of the pandemic. For example, central line infections, which had dropped by 31% in the five years before the COVID-19 outbreak, jumped 28% in the second quarter of 2020, compared with the prior-year period.

Commenting on these developments, the CMS authors said “the fact that the pandemic degraded patient safety so quickly and severely suggests that our health care system lacks a sufficiently resilient safety culture and infrastructure.”

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

The patient safety record of U.S. hospitals improved over the past decade, according to the 10th annual report from nonprofit the Leapfrog Group, a national nonprofit organization focused on health care safety and quality.

For five outcome measures, the safety improvements saved an estimated 16,000 lives during the 10-year period, the report said. These included two “never” events that both declined by approximately 25%: incidents of falls and trauma and incidents of objects unintentionally left in a body after surgery.

There were also decreases in three health care–associated infections, including methicillin-resistant Staphylococcus aureus (MRSA), which decreased by 22%; central line–associated bloodstream infection (CLABSI), which fell by 43%; and Clostridioides difficile infection (C. Diff), which declined by 8%.

The patient safety record of U.S. hospitals improved over the past decade, according to the report.

“Never in history have we seen across-the-board improvement in patient safety until this last decade, coinciding with the history of the [Leapfrog] Hospital Safety Grade,” said Leah Binder, president and CEO of the Leapfrog Group, in a news release. “We salute hospitals for this milestone and encourage them to accelerate their hard work saving patient lives.”

During the past decade, the report noted, hospitals have widely adopted technology and staffing strategies that can protect patients from preventable harm and death. Leapfrog cited a nearly sevenfold increase in the adoption of computerized provider order entry, which can reduce medication errors by more than 40%. 

However, federal health officials separately have reported that the pandemic may have eroded some of those gains.

The Leapfrog report also cited a recent study, published in JAMA, that found that the rates of preventable adverse events in hospitalized patients – including adverse drug events, hospital-acquired infections, postprocedure events, and hospital-acquired pressure ulcers and falls – significantly declined between 2010 and 2019.

That study pointed to specific decreases in the rates of adverse events for patients admitted for myocardial infarction, heart failure, pneumonia, and major surgical procedures. There were also significant drops in adverse events for all other conditions, the study found.

Quality improvement efforts targeting those four conditions might have partly accounted for the lower rates of adverse events in patients with the conditions, the study observed. But “similar interventions did not occur for most of the conditions represented in the ‘all other conditions’ group,” it said.

In a 2019 report by the U.S. Agency for Healthcare Research and Quality (AHRQ), the agency noted that from 2000 to 2017, there had been gains in nearly two-thirds of patient-safety measures in acute, post-acute, and ambulatory care. Hospital safety improved on nine metrics and was unchanged on three. For example, from 2014 to 2017, the number of some hospital-acquired conditions, including adverse drug events and C. Diff infections, dropped about 20%.

However, in an article this past February, officials of the Centers for Medicare & Medicaid Services (CMS) said they had observed deterioration on multiple patient-safety metrics since the start of the pandemic. For example, central line infections, which had dropped by 31% in the five years before the COVID-19 outbreak, jumped 28% in the second quarter of 2020, compared with the prior-year period.

Commenting on these developments, the CMS authors said “the fact that the pandemic degraded patient safety so quickly and severely suggests that our health care system lacks a sufficiently resilient safety culture and infrastructure.”

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

CASE Concern for surgical management after repeat miscarriage

A 34-year-old woman (G3P0030) with a history of recurrent pregnancy loss was recently diagnosed with a 7-week missed abortion. After her second miscarriage, she had an evaluation for recurrent pregnancy loss which was unremarkable. Both prior miscarriages were managed with dilation & curettage (D&C), but cytogenetic testing of the tissue did not yield a result in either case. The karyotype from the first pregnancy resulted as 46, XX but was confirmed to be due to maternal cell contamination, and the karyotype from the second pregnancy resulted in cell culture failure. The patient is interested in surgical management for her current missed abortion to help with tissue collection for cytogenetic testing, she but is concerned about her risk of intrauterine adhesions with repeated uterine instrumentation given 2 prior D&Cs, one of which was complicated by retained products of conception.

How do you approach the surgical management of this patient with recurrent pregnancy loss?

Approximately 1 in every 8 recognized pregnancies results in miscarriage. The risk of loss is lowest in women with no history of miscarriage (11%), and increases by about 10% for each additional miscarriage, reaching 42% in women with 3 or more previous losses. The population prevalence of women who have had 1 miscarriage is 11%, 2 miscarriages is 2%, and 3 or more is <1%.¹ While 90% of miscarriages occur in the first trimester, their etiology can be quite varied.² A woman’s age is the most strongly associated risk factor, with both very young (<20 years) and older age (>35 years) groups at highest risk. This association is largely attributed to an age-related increase in embryonic chromosomal aneuploidies, of which trisomies, particularly trisomy 16, are the most common.³ Maternal anatomic anomalies such as leiomyomas, intrauterine adhesions, Müllerian anomalies, and adenomyosis have been linked to an increased risk of miscarriage in addition to several lifestyle and environmental factor exposures.¹

Regardless of the etiology, women with recurrent miscarriage are exposed to the potential for iatrogenic harm from the management of their pregnancy loss, including intrauterine adhesions and retained products, which may negatively impact future reproductive attempts. The management of patients with recurrent miscarriages demands special attention to reduce the risk of iatrogenic harm, maximize diagnostic evaluation of the products of conception, and improve future reproductive outcomes.

Management strategies

First trimester pregnancy loss may be managed expectantly, medically, or surgically. Approximately 76% of women who opt for expectant management will successfully pass pregnancy tissue, but for 1 out of every 6 women it may take longer than 14 days.⁴ For patients who prefer to expedite this process, medication abortion is a highly effective and safe option. According to Schreiber and colleagues, a combination of mifepristone and misoprostol together resulted in expulsion in approximately 91% of 148 patients, although 9% still required surgical intervention for incomplete passage of tissue.⁵ Both expectant management and medical management strategies are associated with the potential for retained products of conception requiring subsequent instrumentation as well as tissue that is often unsuitable or contaminated for cytogenetic analysis.

The most definitive treatment option is surgical management via manual or electric vacuum aspiration or curettage, with efficacy approaching 99.6% in some series.⁶ While highly effective, even ultrasound-guided evacuation carries with it procedure-related risks that are of particular consequence for patients of reproductive age, including adhesion formation and retained products of conception.

In 1997, Goldenberg and colleagues reported on the use of hysteroscopy for the management of retained products of conception as a strategy to minimize trauma to the uterus and maximize excision of retained tissue, both of which reduce potential for adhesion formation.⁷ Based on these data, several groups have extended the use of hysteroscopic resection for retained tissue to upfront evacuation following pregnancy loss, in lieu of D&C.^8,9 This approach allows for the direct visualization of the focal removal of the implanted pregnancy tissue, which can:

• decrease the risk of intrauterine adhesion formation
• decrease the risk of retained products of conception
• allow for directed tissue sampling to improve the accuracy of cytogenetic testing
• allow for detection of embryo anatomic anomalies that often go undetected on traditional cytogenetic analysis.

For the remainder of this article, we will discuss the advantages of hysteroscopic management of a missed abortion in greater detail.

Continue to: Hysteroscopic management...

Hysteroscopic management

Like aspiration or curettage, hysteroscopic management may be offered once the diagnosis of fetal demise is confirmed on ultrasonography. The procedure may be accomplished in the office setting or in the operative room with either morcellation or resectoscopic instruments. Morcellation allows for improved visibility during the procedure given the ability of continuous suction to manage tissue fragments in the surgical field, while resectoscopic instruments offer the added benefit of electrosurgery should bleeding that is unresponsive to increased distention pressure be encountered. Use of the cold loop of the resectoscope to accomplish evacuation is advocated to avoid the thermal damage to the endometrium with electrosurgery. Regardless of the chosen instrument, there are several potential benefits for a hysteroscopic approach over the traditional ultrasound-guided or blind D&C.

Reducing risk of iatrogenic harm

Intrauterine adhesions form secondary to trauma to the endometrial basalis layer, where a population of adult progenitor stem cells continuously work to regenerate the overlying functionalis layer. Once damaged, adhesions may form and range from thin, filmy adhesions to dense, cavity obliterating bands of scar tissue (FIGURE). The degree of severity and location of the adhesions account for the variable presentation that range from menstrual abnormalities to infertility and recurrent pregnancy loss. While several classification systems exist for scoring severity of adhesions, the American Fertility Society (now American Society for Reproductive Medicine) Classification system from 1988 is still commonly utilized (TABLE 1).

ILLUSTRATIONS: MARCIA HARTSOCK FOR OBG MANAGEMENT

Intrauterine adhesions from D&C after pregnancy loss are not uncommon. A 2014 meta-analysis of 10 prospective studies including 912 women reported a pooled prevalence for intrauterine adhesions of 19.1% (95% confidence interval [CI], 12.8–27.5) on hysteroscopic evaluation within 12 months following curettage.¹⁰ Once formed, these adhesions are associated with long-term impairment in reproductive outcomes, regardless of if they were treated or not. In a long-term follow-up study of women with and without adhesions after recurrent D&C for miscarriage, women with treated adhesions reported lower live birth rates, longer time to pregnancy, higher rates of preterm birth and higher rates of peripartum complications compared with those without adhesions.¹¹

Compared with curettage, hysteroscopy affords the surgeon complete visualization of the uterine cavity and tissue to be resected. This, in turn, minimizes trauma to the surrounding uterine cavity, minimizes the potential for post-procedural adhesion formation and their associated sequelae, and maximizes complete resection of tissue. Those treated with D&C appear to be significantly more likely to have adhesions than those treated via a hysteroscopic approach (30% vs 13%).¹²

Retained products of conception. Classically, a “gritty” sensation of the endometrium following evacuation of the uterus with a sharp curette has been used to indicate complete removal of tissue. The evolution from a nonvisualized procedure to ultrasound-guided vacuum aspiration of 1st trimester pregnancy tissue has been associated with a decreased risk of procedural complications and retained products of conception.¹³ However, even with intraoperative imaging, the risk of retained products of conception remains because it can be difficult to distinguish a small blood clot from retained pregnancy tissue on ultrasonography.

Retained pregnancy tissue can result in abnormal or heavy bleeding, require additional medical or surgical intervention, and is associated with endometrial inflammation and infection. Approximately 1 in every 4 women undergoing hysteroscopic resection of retained products are found to have evidence of endometritis in the resected tissue.¹⁴ This number is even higher in women with a diagnosis of recurrent pregnancy loss (62%).¹⁵

These complications from retained products of conception can be avoided with the hysteroscopic approach due to the direct visualization of the tissue removal. This benefit may be particularly beneficial in patients with known abnormal uterine cavities, such as those with Müllerian anomalies, uterine leiomyomas, preexisting adhesions, and history of placenta accreta spectrum disorder.

Continue to: Maximizing diagnostic yield...

Maximizing diagnostic yield

Many patients prefer surgical management of a missed abortion not for the procedural advantages, but to assist with tissue collection for cytogenetic testing of the pregnancy tissue. Given that embryonic chromosomal aneuploidy is implicated in 70% of miscarriages prior to 20 weeks’ gestation, genetic evaluation of the products of conception is commonly performed to identify a potential cause for the miscarriage.¹⁶ G-band karyotype is the most commonly performed genetic evaluation. Karyotype requires culturing of pregnancy tissue for 7-14 days to produce metaphase cells that are then chemically treated to arrest them at their maximally contracted stage. Cytogenetic evaluation is often curtailed when nonviable cells from products of conception fail to culture due to either time elapsed from diagnosis to demise or damage from tissue handling. Careful, directly observed tissue handling via a hysteroscopic approach may alleviate culture failure secondary to tissue damage.

Another concern with cultures of products of conception is the potential for maternal cell contamination. Early studies from the 1970s noted a significant skew toward 46, XX karyotype results in miscarried tissue as compared with 46, XY results. It was not until microsatellite analysis technology was available that it was determined that the result was due to analysis of maternal cells instead of products of conception.¹⁷ A 2014 study by Levy and colleagues and another by Lathi and colleagues that utilized single-nucleotide polymorphism (SNP) microarray found that maternal cell contamination affected 22% of all miscarriage samples analyzed and over half of karyotypes with a 46, XX result.^18,19

Traditional “blind” suction and curettage may inadvertently collect maternal endometrial tissue and contaminate the culture of fetal cells, limiting the validity of karyotype for products of conception.²⁰ The hysteroscopic approach may provide a higher diagnostic yield for karyotype analysis of fetal tissue by the nature of targeted tissue sampling under direct visualization, minimizing maternal cell contamination. One retrospective study by Cholkeri-Singh and colleagues evaluated rates of fetal chromosome detection without maternal contamination in a total of 264 patients undergoing either suction curettage or hysteroscopic resection. They found that fetal chromosomal detection without contamination was significantly higher in the hysteroscopy group compared with the suction curettage group (88.5 vs 64.8%, P< .001).²¹ Additionally, biopsies of tissue under direct visualization may enable the diagnosis of a true placental mosaicism and the study of the individual karyotype of each embryo in dizygotic twin missed abortions.

Finally, a hysteroscopic approach may afford the opportunity to also perform morphologic evaluation of the intact early fetus furthering the diagnostic utility of the procedure. With hysteroscopy, the gestational sac is identified and carefully entered, allowing for complete visualization of the early fetus and assessment of anatomic malformations that may provide insight into the pregnancy loss (ie, embryoscopy). In one series of 272 patients with missed abortions, while nearly 75% of conceptuses had abnormal karyotypes, 18% were found to have gross morphologic defects with a normal karyotype.²²

Bottom line

When faced with a patient with an early pregnancy loss, physicians should consider the decreased iatrogenic risks and improved diagnostic yield when deciding between D&C versus hysteroscopy for surgical management. There are certain patients with pre-existing risk factors that may stand to benefit the most (TABLE 2). Much like the opening case, those at risk for intrauterine adhesions, retained products of conception, or in whom a successful and accurate cytogenetic analysis is essential are the most likely to benefit from a hysteroscopic approach. The hysteroscopic approach also affords concurrent diagnosis and treatment of intrauterine pathology, such as leiomyomas and uterine septum, which are encountered approximately 12.5% of the time after one miscarriage and 29.4% of the time in patients with a history of more than one miscarriage.¹⁰ In the appropriately counseled patient and clinical setting, clinicians could also perform definitive surgical management during the same hysteroscopy. Finally, evaluation of the morphology of the demised fetus may provide additional information for patient counseling in those with euploid pregnancy losses.

CASE Resolved

Ultimately, our patient underwent complete hysteroscopic resection of the pregnancy tissue, which confirmed both a morphologically abnormal fetus and a 45, X karyotype of the products of conception. ●

CASE Concern for surgical management after repeat miscarriage

A 34-year-old woman (G3P0030) with a history of recurrent pregnancy loss was recently diagnosed with a 7-week missed abortion. After her second miscarriage, she had an evaluation for recurrent pregnancy loss which was unremarkable. Both prior miscarriages were managed with dilation & curettage (D&C), but cytogenetic testing of the tissue did not yield a result in either case. The karyotype from the first pregnancy resulted as 46, XX but was confirmed to be due to maternal cell contamination, and the karyotype from the second pregnancy resulted in cell culture failure. The patient is interested in surgical management for her current missed abortion to help with tissue collection for cytogenetic testing, she but is concerned about her risk of intrauterine adhesions with repeated uterine instrumentation given 2 prior D&Cs, one of which was complicated by retained products of conception.

How do you approach the surgical management of this patient with recurrent pregnancy loss?

Approximately 1 in every 8 recognized pregnancies results in miscarriage. The risk of loss is lowest in women with no history of miscarriage (11%), and increases by about 10% for each additional miscarriage, reaching 42% in women with 3 or more previous losses. The population prevalence of women who have had 1 miscarriage is 11%, 2 miscarriages is 2%, and 3 or more is <1%.¹ While 90% of miscarriages occur in the first trimester, their etiology can be quite varied.² A woman’s age is the most strongly associated risk factor, with both very young (<20 years) and older age (>35 years) groups at highest risk. This association is largely attributed to an age-related increase in embryonic chromosomal aneuploidies, of which trisomies, particularly trisomy 16, are the most common.³ Maternal anatomic anomalies such as leiomyomas, intrauterine adhesions, Müllerian anomalies, and adenomyosis have been linked to an increased risk of miscarriage in addition to several lifestyle and environmental factor exposures.¹

Regardless of the etiology, women with recurrent miscarriage are exposed to the potential for iatrogenic harm from the management of their pregnancy loss, including intrauterine adhesions and retained products, which may negatively impact future reproductive attempts. The management of patients with recurrent miscarriages demands special attention to reduce the risk of iatrogenic harm, maximize diagnostic evaluation of the products of conception, and improve future reproductive outcomes.

Management strategies

First trimester pregnancy loss may be managed expectantly, medically, or surgically. Approximately 76% of women who opt for expectant management will successfully pass pregnancy tissue, but for 1 out of every 6 women it may take longer than 14 days.⁴ For patients who prefer to expedite this process, medication abortion is a highly effective and safe option. According to Schreiber and colleagues, a combination of mifepristone and misoprostol together resulted in expulsion in approximately 91% of 148 patients, although 9% still required surgical intervention for incomplete passage of tissue.⁵ Both expectant management and medical management strategies are associated with the potential for retained products of conception requiring subsequent instrumentation as well as tissue that is often unsuitable or contaminated for cytogenetic analysis.

The most definitive treatment option is surgical management via manual or electric vacuum aspiration or curettage, with efficacy approaching 99.6% in some series.⁶ While highly effective, even ultrasound-guided evacuation carries with it procedure-related risks that are of particular consequence for patients of reproductive age, including adhesion formation and retained products of conception.

In 1997, Goldenberg and colleagues reported on the use of hysteroscopy for the management of retained products of conception as a strategy to minimize trauma to the uterus and maximize excision of retained tissue, both of which reduce potential for adhesion formation.⁷ Based on these data, several groups have extended the use of hysteroscopic resection for retained tissue to upfront evacuation following pregnancy loss, in lieu of D&C.^8,9 This approach allows for the direct visualization of the focal removal of the implanted pregnancy tissue, which can:

• decrease the risk of intrauterine adhesion formation
• decrease the risk of retained products of conception
• allow for directed tissue sampling to improve the accuracy of cytogenetic testing
• allow for detection of embryo anatomic anomalies that often go undetected on traditional cytogenetic analysis.

For the remainder of this article, we will discuss the advantages of hysteroscopic management of a missed abortion in greater detail.

Continue to: Hysteroscopic management...

Hysteroscopic management

Like aspiration or curettage, hysteroscopic management may be offered once the diagnosis of fetal demise is confirmed on ultrasonography. The procedure may be accomplished in the office setting or in the operative room with either morcellation or resectoscopic instruments. Morcellation allows for improved visibility during the procedure given the ability of continuous suction to manage tissue fragments in the surgical field, while resectoscopic instruments offer the added benefit of electrosurgery should bleeding that is unresponsive to increased distention pressure be encountered. Use of the cold loop of the resectoscope to accomplish evacuation is advocated to avoid the thermal damage to the endometrium with electrosurgery. Regardless of the chosen instrument, there are several potential benefits for a hysteroscopic approach over the traditional ultrasound-guided or blind D&C.

Reducing risk of iatrogenic harm

Intrauterine adhesions form secondary to trauma to the endometrial basalis layer, where a population of adult progenitor stem cells continuously work to regenerate the overlying functionalis layer. Once damaged, adhesions may form and range from thin, filmy adhesions to dense, cavity obliterating bands of scar tissue (FIGURE). The degree of severity and location of the adhesions account for the variable presentation that range from menstrual abnormalities to infertility and recurrent pregnancy loss. While several classification systems exist for scoring severity of adhesions, the American Fertility Society (now American Society for Reproductive Medicine) Classification system from 1988 is still commonly utilized (TABLE 1).

ILLUSTRATIONS: MARCIA HARTSOCK FOR OBG MANAGEMENT

Intrauterine adhesions from D&C after pregnancy loss are not uncommon. A 2014 meta-analysis of 10 prospective studies including 912 women reported a pooled prevalence for intrauterine adhesions of 19.1% (95% confidence interval [CI], 12.8–27.5) on hysteroscopic evaluation within 12 months following curettage.¹⁰ Once formed, these adhesions are associated with long-term impairment in reproductive outcomes, regardless of if they were treated or not. In a long-term follow-up study of women with and without adhesions after recurrent D&C for miscarriage, women with treated adhesions reported lower live birth rates, longer time to pregnancy, higher rates of preterm birth and higher rates of peripartum complications compared with those without adhesions.¹¹

Compared with curettage, hysteroscopy affords the surgeon complete visualization of the uterine cavity and tissue to be resected. This, in turn, minimizes trauma to the surrounding uterine cavity, minimizes the potential for post-procedural adhesion formation and their associated sequelae, and maximizes complete resection of tissue. Those treated with D&C appear to be significantly more likely to have adhesions than those treated via a hysteroscopic approach (30% vs 13%).¹²

Retained products of conception. Classically, a “gritty” sensation of the endometrium following evacuation of the uterus with a sharp curette has been used to indicate complete removal of tissue. The evolution from a nonvisualized procedure to ultrasound-guided vacuum aspiration of 1st trimester pregnancy tissue has been associated with a decreased risk of procedural complications and retained products of conception.¹³ However, even with intraoperative imaging, the risk of retained products of conception remains because it can be difficult to distinguish a small blood clot from retained pregnancy tissue on ultrasonography.

Retained pregnancy tissue can result in abnormal or heavy bleeding, require additional medical or surgical intervention, and is associated with endometrial inflammation and infection. Approximately 1 in every 4 women undergoing hysteroscopic resection of retained products are found to have evidence of endometritis in the resected tissue.¹⁴ This number is even higher in women with a diagnosis of recurrent pregnancy loss (62%).¹⁵

These complications from retained products of conception can be avoided with the hysteroscopic approach due to the direct visualization of the tissue removal. This benefit may be particularly beneficial in patients with known abnormal uterine cavities, such as those with Müllerian anomalies, uterine leiomyomas, preexisting adhesions, and history of placenta accreta spectrum disorder.

Continue to: Maximizing diagnostic yield...

Maximizing diagnostic yield

Many patients prefer surgical management of a missed abortion not for the procedural advantages, but to assist with tissue collection for cytogenetic testing of the pregnancy tissue. Given that embryonic chromosomal aneuploidy is implicated in 70% of miscarriages prior to 20 weeks’ gestation, genetic evaluation of the products of conception is commonly performed to identify a potential cause for the miscarriage.¹⁶ G-band karyotype is the most commonly performed genetic evaluation. Karyotype requires culturing of pregnancy tissue for 7-14 days to produce metaphase cells that are then chemically treated to arrest them at their maximally contracted stage. Cytogenetic evaluation is often curtailed when nonviable cells from products of conception fail to culture due to either time elapsed from diagnosis to demise or damage from tissue handling. Careful, directly observed tissue handling via a hysteroscopic approach may alleviate culture failure secondary to tissue damage.

Another concern with cultures of products of conception is the potential for maternal cell contamination. Early studies from the 1970s noted a significant skew toward 46, XX karyotype results in miscarried tissue as compared with 46, XY results. It was not until microsatellite analysis technology was available that it was determined that the result was due to analysis of maternal cells instead of products of conception.¹⁷ A 2014 study by Levy and colleagues and another by Lathi and colleagues that utilized single-nucleotide polymorphism (SNP) microarray found that maternal cell contamination affected 22% of all miscarriage samples analyzed and over half of karyotypes with a 46, XX result.^18,19

Traditional “blind” suction and curettage may inadvertently collect maternal endometrial tissue and contaminate the culture of fetal cells, limiting the validity of karyotype for products of conception.²⁰ The hysteroscopic approach may provide a higher diagnostic yield for karyotype analysis of fetal tissue by the nature of targeted tissue sampling under direct visualization, minimizing maternal cell contamination. One retrospective study by Cholkeri-Singh and colleagues evaluated rates of fetal chromosome detection without maternal contamination in a total of 264 patients undergoing either suction curettage or hysteroscopic resection. They found that fetal chromosomal detection without contamination was significantly higher in the hysteroscopy group compared with the suction curettage group (88.5 vs 64.8%, P< .001).²¹ Additionally, biopsies of tissue under direct visualization may enable the diagnosis of a true placental mosaicism and the study of the individual karyotype of each embryo in dizygotic twin missed abortions.

Finally, a hysteroscopic approach may afford the opportunity to also perform morphologic evaluation of the intact early fetus furthering the diagnostic utility of the procedure. With hysteroscopy, the gestational sac is identified and carefully entered, allowing for complete visualization of the early fetus and assessment of anatomic malformations that may provide insight into the pregnancy loss (ie, embryoscopy). In one series of 272 patients with missed abortions, while nearly 75% of conceptuses had abnormal karyotypes, 18% were found to have gross morphologic defects with a normal karyotype.²²

Bottom line

When faced with a patient with an early pregnancy loss, physicians should consider the decreased iatrogenic risks and improved diagnostic yield when deciding between D&C versus hysteroscopy for surgical management. There are certain patients with pre-existing risk factors that may stand to benefit the most (TABLE 2). Much like the opening case, those at risk for intrauterine adhesions, retained products of conception, or in whom a successful and accurate cytogenetic analysis is essential are the most likely to benefit from a hysteroscopic approach. The hysteroscopic approach also affords concurrent diagnosis and treatment of intrauterine pathology, such as leiomyomas and uterine septum, which are encountered approximately 12.5% of the time after one miscarriage and 29.4% of the time in patients with a history of more than one miscarriage.¹⁰ In the appropriately counseled patient and clinical setting, clinicians could also perform definitive surgical management during the same hysteroscopy. Finally, evaluation of the morphology of the demised fetus may provide additional information for patient counseling in those with euploid pregnancy losses.

CASE Resolved

Ultimately, our patient underwent complete hysteroscopic resection of the pregnancy tissue, which confirmed both a morphologically abnormal fetus and a 45, X karyotype of the products of conception. ●

CASE Concern for surgical management after repeat miscarriage

A 34-year-old woman (G3P0030) with a history of recurrent pregnancy loss was recently diagnosed with a 7-week missed abortion. After her second miscarriage, she had an evaluation for recurrent pregnancy loss which was unremarkable. Both prior miscarriages were managed with dilation & curettage (D&C), but cytogenetic testing of the tissue did not yield a result in either case. The karyotype from the first pregnancy resulted as 46, XX but was confirmed to be due to maternal cell contamination, and the karyotype from the second pregnancy resulted in cell culture failure. The patient is interested in surgical management for her current missed abortion to help with tissue collection for cytogenetic testing, she but is concerned about her risk of intrauterine adhesions with repeated uterine instrumentation given 2 prior D&Cs, one of which was complicated by retained products of conception.

How do you approach the surgical management of this patient with recurrent pregnancy loss?

Approximately 1 in every 8 recognized pregnancies results in miscarriage. The risk of loss is lowest in women with no history of miscarriage (11%), and increases by about 10% for each additional miscarriage, reaching 42% in women with 3 or more previous losses. The population prevalence of women who have had 1 miscarriage is 11%, 2 miscarriages is 2%, and 3 or more is <1%.¹ While 90% of miscarriages occur in the first trimester, their etiology can be quite varied.² A woman’s age is the most strongly associated risk factor, with both very young (<20 years) and older age (>35 years) groups at highest risk. This association is largely attributed to an age-related increase in embryonic chromosomal aneuploidies, of which trisomies, particularly trisomy 16, are the most common.³ Maternal anatomic anomalies such as leiomyomas, intrauterine adhesions, Müllerian anomalies, and adenomyosis have been linked to an increased risk of miscarriage in addition to several lifestyle and environmental factor exposures.¹

Regardless of the etiology, women with recurrent miscarriage are exposed to the potential for iatrogenic harm from the management of their pregnancy loss, including intrauterine adhesions and retained products, which may negatively impact future reproductive attempts. The management of patients with recurrent miscarriages demands special attention to reduce the risk of iatrogenic harm, maximize diagnostic evaluation of the products of conception, and improve future reproductive outcomes.

Management strategies

First trimester pregnancy loss may be managed expectantly, medically, or surgically. Approximately 76% of women who opt for expectant management will successfully pass pregnancy tissue, but for 1 out of every 6 women it may take longer than 14 days.⁴ For patients who prefer to expedite this process, medication abortion is a highly effective and safe option. According to Schreiber and colleagues, a combination of mifepristone and misoprostol together resulted in expulsion in approximately 91% of 148 patients, although 9% still required surgical intervention for incomplete passage of tissue.⁵ Both expectant management and medical management strategies are associated with the potential for retained products of conception requiring subsequent instrumentation as well as tissue that is often unsuitable or contaminated for cytogenetic analysis.

The most definitive treatment option is surgical management via manual or electric vacuum aspiration or curettage, with efficacy approaching 99.6% in some series.⁶ While highly effective, even ultrasound-guided evacuation carries with it procedure-related risks that are of particular consequence for patients of reproductive age, including adhesion formation and retained products of conception.

In 1997, Goldenberg and colleagues reported on the use of hysteroscopy for the management of retained products of conception as a strategy to minimize trauma to the uterus and maximize excision of retained tissue, both of which reduce potential for adhesion formation.⁷ Based on these data, several groups have extended the use of hysteroscopic resection for retained tissue to upfront evacuation following pregnancy loss, in lieu of D&C.^8,9 This approach allows for the direct visualization of the focal removal of the implanted pregnancy tissue, which can:

• decrease the risk of intrauterine adhesion formation
• decrease the risk of retained products of conception
• allow for directed tissue sampling to improve the accuracy of cytogenetic testing
• allow for detection of embryo anatomic anomalies that often go undetected on traditional cytogenetic analysis.

For the remainder of this article, we will discuss the advantages of hysteroscopic management of a missed abortion in greater detail.

Continue to: Hysteroscopic management...

Hysteroscopic management

Like aspiration or curettage, hysteroscopic management may be offered once the diagnosis of fetal demise is confirmed on ultrasonography. The procedure may be accomplished in the office setting or in the operative room with either morcellation or resectoscopic instruments. Morcellation allows for improved visibility during the procedure given the ability of continuous suction to manage tissue fragments in the surgical field, while resectoscopic instruments offer the added benefit of electrosurgery should bleeding that is unresponsive to increased distention pressure be encountered. Use of the cold loop of the resectoscope to accomplish evacuation is advocated to avoid the thermal damage to the endometrium with electrosurgery. Regardless of the chosen instrument, there are several potential benefits for a hysteroscopic approach over the traditional ultrasound-guided or blind D&C.

Reducing risk of iatrogenic harm

Intrauterine adhesions form secondary to trauma to the endometrial basalis layer, where a population of adult progenitor stem cells continuously work to regenerate the overlying functionalis layer. Once damaged, adhesions may form and range from thin, filmy adhesions to dense, cavity obliterating bands of scar tissue (FIGURE). The degree of severity and location of the adhesions account for the variable presentation that range from menstrual abnormalities to infertility and recurrent pregnancy loss. While several classification systems exist for scoring severity of adhesions, the American Fertility Society (now American Society for Reproductive Medicine) Classification system from 1988 is still commonly utilized (TABLE 1).

ILLUSTRATIONS: MARCIA HARTSOCK FOR OBG MANAGEMENT

Intrauterine adhesions from D&C after pregnancy loss are not uncommon. A 2014 meta-analysis of 10 prospective studies including 912 women reported a pooled prevalence for intrauterine adhesions of 19.1% (95% confidence interval [CI], 12.8–27.5) on hysteroscopic evaluation within 12 months following curettage.¹⁰ Once formed, these adhesions are associated with long-term impairment in reproductive outcomes, regardless of if they were treated or not. In a long-term follow-up study of women with and without adhesions after recurrent D&C for miscarriage, women with treated adhesions reported lower live birth rates, longer time to pregnancy, higher rates of preterm birth and higher rates of peripartum complications compared with those without adhesions.¹¹

Compared with curettage, hysteroscopy affords the surgeon complete visualization of the uterine cavity and tissue to be resected. This, in turn, minimizes trauma to the surrounding uterine cavity, minimizes the potential for post-procedural adhesion formation and their associated sequelae, and maximizes complete resection of tissue. Those treated with D&C appear to be significantly more likely to have adhesions than those treated via a hysteroscopic approach (30% vs 13%).¹²

Retained products of conception. Classically, a “gritty” sensation of the endometrium following evacuation of the uterus with a sharp curette has been used to indicate complete removal of tissue. The evolution from a nonvisualized procedure to ultrasound-guided vacuum aspiration of 1st trimester pregnancy tissue has been associated with a decreased risk of procedural complications and retained products of conception.¹³ However, even with intraoperative imaging, the risk of retained products of conception remains because it can be difficult to distinguish a small blood clot from retained pregnancy tissue on ultrasonography.

Retained pregnancy tissue can result in abnormal or heavy bleeding, require additional medical or surgical intervention, and is associated with endometrial inflammation and infection. Approximately 1 in every 4 women undergoing hysteroscopic resection of retained products are found to have evidence of endometritis in the resected tissue.¹⁴ This number is even higher in women with a diagnosis of recurrent pregnancy loss (62%).¹⁵

These complications from retained products of conception can be avoided with the hysteroscopic approach due to the direct visualization of the tissue removal. This benefit may be particularly beneficial in patients with known abnormal uterine cavities, such as those with Müllerian anomalies, uterine leiomyomas, preexisting adhesions, and history of placenta accreta spectrum disorder.

Continue to: Maximizing diagnostic yield...

Maximizing diagnostic yield

Many patients prefer surgical management of a missed abortion not for the procedural advantages, but to assist with tissue collection for cytogenetic testing of the pregnancy tissue. Given that embryonic chromosomal aneuploidy is implicated in 70% of miscarriages prior to 20 weeks’ gestation, genetic evaluation of the products of conception is commonly performed to identify a potential cause for the miscarriage.¹⁶ G-band karyotype is the most commonly performed genetic evaluation. Karyotype requires culturing of pregnancy tissue for 7-14 days to produce metaphase cells that are then chemically treated to arrest them at their maximally contracted stage. Cytogenetic evaluation is often curtailed when nonviable cells from products of conception fail to culture due to either time elapsed from diagnosis to demise or damage from tissue handling. Careful, directly observed tissue handling via a hysteroscopic approach may alleviate culture failure secondary to tissue damage.

Another concern with cultures of products of conception is the potential for maternal cell contamination. Early studies from the 1970s noted a significant skew toward 46, XX karyotype results in miscarried tissue as compared with 46, XY results. It was not until microsatellite analysis technology was available that it was determined that the result was due to analysis of maternal cells instead of products of conception.¹⁷ A 2014 study by Levy and colleagues and another by Lathi and colleagues that utilized single-nucleotide polymorphism (SNP) microarray found that maternal cell contamination affected 22% of all miscarriage samples analyzed and over half of karyotypes with a 46, XX result.^18,19

Traditional “blind” suction and curettage may inadvertently collect maternal endometrial tissue and contaminate the culture of fetal cells, limiting the validity of karyotype for products of conception.²⁰ The hysteroscopic approach may provide a higher diagnostic yield for karyotype analysis of fetal tissue by the nature of targeted tissue sampling under direct visualization, minimizing maternal cell contamination. One retrospective study by Cholkeri-Singh and colleagues evaluated rates of fetal chromosome detection without maternal contamination in a total of 264 patients undergoing either suction curettage or hysteroscopic resection. They found that fetal chromosomal detection without contamination was significantly higher in the hysteroscopy group compared with the suction curettage group (88.5 vs 64.8%, P< .001).²¹ Additionally, biopsies of tissue under direct visualization may enable the diagnosis of a true placental mosaicism and the study of the individual karyotype of each embryo in dizygotic twin missed abortions.

Finally, a hysteroscopic approach may afford the opportunity to also perform morphologic evaluation of the intact early fetus furthering the diagnostic utility of the procedure. With hysteroscopy, the gestational sac is identified and carefully entered, allowing for complete visualization of the early fetus and assessment of anatomic malformations that may provide insight into the pregnancy loss (ie, embryoscopy). In one series of 272 patients with missed abortions, while nearly 75% of conceptuses had abnormal karyotypes, 18% were found to have gross morphologic defects with a normal karyotype.²²

Bottom line

When faced with a patient with an early pregnancy loss, physicians should consider the decreased iatrogenic risks and improved diagnostic yield when deciding between D&C versus hysteroscopy for surgical management. There are certain patients with pre-existing risk factors that may stand to benefit the most (TABLE 2). Much like the opening case, those at risk for intrauterine adhesions, retained products of conception, or in whom a successful and accurate cytogenetic analysis is essential are the most likely to benefit from a hysteroscopic approach. The hysteroscopic approach also affords concurrent diagnosis and treatment of intrauterine pathology, such as leiomyomas and uterine septum, which are encountered approximately 12.5% of the time after one miscarriage and 29.4% of the time in patients with a history of more than one miscarriage.¹⁰ In the appropriately counseled patient and clinical setting, clinicians could also perform definitive surgical management during the same hysteroscopy. Finally, evaluation of the morphology of the demised fetus may provide additional information for patient counseling in those with euploid pregnancy losses.

CASE Resolved

Ultimately, our patient underwent complete hysteroscopic resection of the pregnancy tissue, which confirmed both a morphologically abnormal fetus and a 45, X karyotype of the products of conception. ●

The U.S. Food and Drug Administration has approved etranacogene dezaparvovec (Hemgenix), the first gene therapy option for adults with hemophilia B who currently use factor IX prophylaxis therapy, have current or historical life-threatening hemorrhage, or have repeated, serious spontaneous bleeding episodes.*

“Gene therapy for hemophilia has been on the horizon for more than 2 decades. Despite advancements in the treatment of hemophilia, the prevention and treatment of bleeding episodes can adversely impact individuals’ quality of life,” said Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research. “Today’s approval provides a new treatment option for patients with hemophilia B and represents important progress in the development of innovative therapies for those experiencing a high burden of disease associated with this form of hemophilia.”

Hemophilia B is caused by a deficiency in clotting factor IX attributable to a faulty gene. The newly approved IV infusion delivers a functional gene to liver cells via an adeno-associated virus that instructs them to make the clotting factor. The genetic instructions remain in the cell but aren’t incorporated into the patient’s own DNA, according to a press release from maker CSL Behring.

The gene therapy will cost $3.5 million, making it the most expensive treatment to date -- more than Bluebird's recently approved gene therapies. A recent analysis from the Institute for Clinical and Economic Review said charging $2.93-$2.96 million would be justified because etranacogene dezaparvovec would offset the need for ongoing factor IX replacement, which can top $20 million over a lifetime.

Approval was based on the single-arm, open-label HOPE-B trial in 54 men who relied on factor IX replacement therapy; most patients with hemophilia B are male.

Over the 18 months after infusion, their adjusted annualized bleeding rate fell 64% compared with baseline (P = .0002), and factor IX–treated bleeds fell 77% (P < .0001); 98% of subjects treated with a full dose of etranacogene dezaparvovec discontinued factor IX prophylaxis.

Durability of the effect remains a concern, but data have been reassuring, with subjects having a mean factor IX activity of 39 IU/dL at 6 months – 39% of normal – and 36.9 IU/dL at 18 months, about 37% of normal. There’s been no sign so far of patients developing inhibitors against the infusion.

Adverse events were common but largely mild and included headache and influenza-like illness, both in 13% of subjects. Nine patients needed steroids for liver enzyme elevations.

The trial was temporarily halted due to a case of liver cancer, but it was ultimately deemed not to be related to treatment, based on molecular tumor characterization and vector integration analysis. A death in the trial was also not considered treatment related.

Other gene therapies are in the pipeline for hemophilia, including valoctocogene roxaparvovec (Roctavian, BioMarin) for hemophilia A. FDA’s approval decision is expected in March 2023.

This article was updated 11/23/22.

Correction, 11/23/22: The brand name Hemgenix was misstated in an earlier version of this article.

The U.S. Food and Drug Administration has approved etranacogene dezaparvovec (Hemgenix), the first gene therapy option for adults with hemophilia B who currently use factor IX prophylaxis therapy, have current or historical life-threatening hemorrhage, or have repeated, serious spontaneous bleeding episodes.*

“Gene therapy for hemophilia has been on the horizon for more than 2 decades. Despite advancements in the treatment of hemophilia, the prevention and treatment of bleeding episodes can adversely impact individuals’ quality of life,” said Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research. “Today’s approval provides a new treatment option for patients with hemophilia B and represents important progress in the development of innovative therapies for those experiencing a high burden of disease associated with this form of hemophilia.”

Hemophilia B is caused by a deficiency in clotting factor IX attributable to a faulty gene. The newly approved IV infusion delivers a functional gene to liver cells via an adeno-associated virus that instructs them to make the clotting factor. The genetic instructions remain in the cell but aren’t incorporated into the patient’s own DNA, according to a press release from maker CSL Behring.

The gene therapy will cost $3.5 million, making it the most expensive treatment to date -- more than Bluebird's recently approved gene therapies. A recent analysis from the Institute for Clinical and Economic Review said charging $2.93-$2.96 million would be justified because etranacogene dezaparvovec would offset the need for ongoing factor IX replacement, which can top $20 million over a lifetime.

Approval was based on the single-arm, open-label HOPE-B trial in 54 men who relied on factor IX replacement therapy; most patients with hemophilia B are male.

Over the 18 months after infusion, their adjusted annualized bleeding rate fell 64% compared with baseline (P = .0002), and factor IX–treated bleeds fell 77% (P < .0001); 98% of subjects treated with a full dose of etranacogene dezaparvovec discontinued factor IX prophylaxis.

Durability of the effect remains a concern, but data have been reassuring, with subjects having a mean factor IX activity of 39 IU/dL at 6 months – 39% of normal – and 36.9 IU/dL at 18 months, about 37% of normal. There’s been no sign so far of patients developing inhibitors against the infusion.

Adverse events were common but largely mild and included headache and influenza-like illness, both in 13% of subjects. Nine patients needed steroids for liver enzyme elevations.

The trial was temporarily halted due to a case of liver cancer, but it was ultimately deemed not to be related to treatment, based on molecular tumor characterization and vector integration analysis. A death in the trial was also not considered treatment related.

Other gene therapies are in the pipeline for hemophilia, including valoctocogene roxaparvovec (Roctavian, BioMarin) for hemophilia A. FDA’s approval decision is expected in March 2023.

This article was updated 11/23/22.

Correction, 11/23/22: The brand name Hemgenix was misstated in an earlier version of this article.

The U.S. Food and Drug Administration has approved etranacogene dezaparvovec (Hemgenix), the first gene therapy option for adults with hemophilia B who currently use factor IX prophylaxis therapy, have current or historical life-threatening hemorrhage, or have repeated, serious spontaneous bleeding episodes.*

“Gene therapy for hemophilia has been on the horizon for more than 2 decades. Despite advancements in the treatment of hemophilia, the prevention and treatment of bleeding episodes can adversely impact individuals’ quality of life,” said Peter Marks, MD, PhD, director of the FDA’s Center for Biologics Evaluation and Research. “Today’s approval provides a new treatment option for patients with hemophilia B and represents important progress in the development of innovative therapies for those experiencing a high burden of disease associated with this form of hemophilia.”

Hemophilia B is caused by a deficiency in clotting factor IX attributable to a faulty gene. The newly approved IV infusion delivers a functional gene to liver cells via an adeno-associated virus that instructs them to make the clotting factor. The genetic instructions remain in the cell but aren’t incorporated into the patient’s own DNA, according to a press release from maker CSL Behring.

The gene therapy will cost $3.5 million, making it the most expensive treatment to date -- more than Bluebird's recently approved gene therapies. A recent analysis from the Institute for Clinical and Economic Review said charging $2.93-$2.96 million would be justified because etranacogene dezaparvovec would offset the need for ongoing factor IX replacement, which can top $20 million over a lifetime.

Approval was based on the single-arm, open-label HOPE-B trial in 54 men who relied on factor IX replacement therapy; most patients with hemophilia B are male.

Over the 18 months after infusion, their adjusted annualized bleeding rate fell 64% compared with baseline (P = .0002), and factor IX–treated bleeds fell 77% (P < .0001); 98% of subjects treated with a full dose of etranacogene dezaparvovec discontinued factor IX prophylaxis.

Durability of the effect remains a concern, but data have been reassuring, with subjects having a mean factor IX activity of 39 IU/dL at 6 months – 39% of normal – and 36.9 IU/dL at 18 months, about 37% of normal. There’s been no sign so far of patients developing inhibitors against the infusion.

Adverse events were common but largely mild and included headache and influenza-like illness, both in 13% of subjects. Nine patients needed steroids for liver enzyme elevations.

The trial was temporarily halted due to a case of liver cancer, but it was ultimately deemed not to be related to treatment, based on molecular tumor characterization and vector integration analysis. A death in the trial was also not considered treatment related.

Other gene therapies are in the pipeline for hemophilia, including valoctocogene roxaparvovec (Roctavian, BioMarin) for hemophilia A. FDA’s approval decision is expected in March 2023.

This article was updated 11/23/22.

Correction, 11/23/22: The brand name Hemgenix was misstated in an earlier version of this article.

High-density lipoprotein cholesterol may not be as effective a biomarker of cardiovascular disease risk as once thought, particularly in Black adults, according to results from a large biracial cohort study that also raised questions about the validity of high HDL cholesterol as a potentially protective factor in White and Black adults alike.

“I think this opens the door to suggest that every biomarker we use might have a race-specific association with disease outcome,” Nathalie Pamir, PhD, an associate professor at Oregon Health & Science University in Portland, said in an interview. “So, something as basic as HDL cholesterol – we’ve known about it since 1970 – has a race signature.”

Dr. Pamir and colleagues reported their findings from the REGARDS (Reasons for Geographic and Racial Differences in Stroke) cohort study that recruited 30,239 Black and White individuals aged 45 years and older from the contiguous United States from 2003 to 2007.

The study found that LDL cholesterol “modestly” predicted coronary heart disease (CHD) risk in Black and White adults. However, low HDL cholesterol, while associated with an increased risk in White patients (hazard ratio, 1.22; 95% confidence interval, 1.05-1.43), did not have a similar association in Blacks (HR, 0.94; 95% CI: 0.78-1.14). And high HDL cholesterol wasn’t found to be predictive in either group (HR, 0.96; 95% CI, 0.79-1.16 for White participants: HR, 0.91; 95% CI, 0.74-1.12 for Black participants).

Among 23,901 study participants who were CHD-risk free over a 10-year follow-up, 664 and 951 CHD events occurred in Black and White participants, respectively. The study cohort was 57.8% White and 58.4% women, with a mean age of 65 years.

The study noted that LDL cholesterol and triglycerides conferred similar risks for CHD in both White and Black participants.

Acknowledging that this study focused on Blacks, Dr. Pamir added that “we need to know about Asian Americans; we need to know about Hispanic Americans.”
 

Change of approach to lipid management called for

Dr. Pamir noted that the current understanding about HDL cholesterol and CHD risk comes from the Framingham heart study in the 1970s, whose population was 100% White.

Care algorithms derived from the Framingham study as well as the Multi-Ethnic Study of Atherosclerosis incorporate that association between HDL cholesterol and CHD risk, she noted, but these findings from REGARDS should change how cardiologists approach lipid management in Black and White patients.

“The conversation would go something like: High HDL cholesterol levels put you in a higher risk [bracket] but HDL cholesterol levels are not something we treat; we have no drugs for that,” Dr. Pamir said.

“The conversation would continue along the lines that: ‘You need to do more exercise, you need to change your diet, incorporate healthy fats, walnuts, and omega 3s.’

“But what might the conversation be for Black patients? ‘We don’t see the association that we see for White patients. Do adopt the good habits to exercise and dietary changes, but don’t get too worried about it.’ ”

The study report raises “caution” about using the Framingham, MESA, and other algorithms for evaluating CHD risk. Dr. Pamir explained what that means. “We might be underestimating risk, because what our study showed was that, when we looked at clinically high HDL cholesterol, about 60 mg/dL, it has no benefit for White and Black patients.”

She added, “So that pat on the back we get for patients that have high HDL-C levels? Maybe that pat on the back shouldn’t be there.”

In an invited commentary, Keith C. Ferdinand, MD, of Tulane University in New Orleans, wrote that using HDL cholesterol in risk calculations could inaccurately assess atherosclerotic cardiovascular risk in Black adults “and become a barrier to optimal care.”

In an interview, he said the REGARDS findings call for consideration of other biomarkers for evaluating CHD risk and point to the importance of socioeconomic factors in health outcomes.

“Physicians and other clinicians need to recognize the powerful impact of the social determinants of health and to also recognize the limits of HDL itself as either protective if it’s high or a definitive predictor of risk if it’s low, and focus on some more modern approaches, including coronary artery calcium scoring.”

He also said risk evaluation should include lipoprotein(a), which, he noted in the editorial, the European Atherosclerosis Society recommends measuring. “One of the reasons it’s underutilized is that we really don’t have a specific treatment for it,” he said of Lp(a) in the United States.

In his editorial comment, Dr. Ferdinand called for future research aimed at eliminating health disparities. “Regardless of the development of better tools for the assessment of risk, newer drugs to treat CVD, the use of coronary artery calcium, if we don’t apply evidence-based medicine equally across the population based on race, ethnicity, sex, gender, socioeconomic status, or geography, then the disparities are going to persist,” he said.

The National Institute of Neurological Disorders and Stroke and the National Institute on Aging provided funding for the study. Dr. Pamir has no relevant relationships to disclose. Dr. Ferdinand disclosed relationships with Boehringer Ingelheim, Novartis, Janssen, and Lilly.

High-density lipoprotein cholesterol may not be as effective a biomarker of cardiovascular disease risk as once thought, particularly in Black adults, according to results from a large biracial cohort study that also raised questions about the validity of high HDL cholesterol as a potentially protective factor in White and Black adults alike.

“I think this opens the door to suggest that every biomarker we use might have a race-specific association with disease outcome,” Nathalie Pamir, PhD, an associate professor at Oregon Health & Science University in Portland, said in an interview. “So, something as basic as HDL cholesterol – we’ve known about it since 1970 – has a race signature.”

Dr. Pamir and colleagues reported their findings from the REGARDS (Reasons for Geographic and Racial Differences in Stroke) cohort study that recruited 30,239 Black and White individuals aged 45 years and older from the contiguous United States from 2003 to 2007.

The study found that LDL cholesterol “modestly” predicted coronary heart disease (CHD) risk in Black and White adults. However, low HDL cholesterol, while associated with an increased risk in White patients (hazard ratio, 1.22; 95% confidence interval, 1.05-1.43), did not have a similar association in Blacks (HR, 0.94; 95% CI: 0.78-1.14). And high HDL cholesterol wasn’t found to be predictive in either group (HR, 0.96; 95% CI, 0.79-1.16 for White participants: HR, 0.91; 95% CI, 0.74-1.12 for Black participants).

Among 23,901 study participants who were CHD-risk free over a 10-year follow-up, 664 and 951 CHD events occurred in Black and White participants, respectively. The study cohort was 57.8% White and 58.4% women, with a mean age of 65 years.

The study noted that LDL cholesterol and triglycerides conferred similar risks for CHD in both White and Black participants.

Acknowledging that this study focused on Blacks, Dr. Pamir added that “we need to know about Asian Americans; we need to know about Hispanic Americans.”
 

Change of approach to lipid management called for

Dr. Pamir noted that the current understanding about HDL cholesterol and CHD risk comes from the Framingham heart study in the 1970s, whose population was 100% White.

Care algorithms derived from the Framingham study as well as the Multi-Ethnic Study of Atherosclerosis incorporate that association between HDL cholesterol and CHD risk, she noted, but these findings from REGARDS should change how cardiologists approach lipid management in Black and White patients.

“The conversation would go something like: High HDL cholesterol levels put you in a higher risk [bracket] but HDL cholesterol levels are not something we treat; we have no drugs for that,” Dr. Pamir said.

“The conversation would continue along the lines that: ‘You need to do more exercise, you need to change your diet, incorporate healthy fats, walnuts, and omega 3s.’

“But what might the conversation be for Black patients? ‘We don’t see the association that we see for White patients. Do adopt the good habits to exercise and dietary changes, but don’t get too worried about it.’ ”

The study report raises “caution” about using the Framingham, MESA, and other algorithms for evaluating CHD risk. Dr. Pamir explained what that means. “We might be underestimating risk, because what our study showed was that, when we looked at clinically high HDL cholesterol, about 60 mg/dL, it has no benefit for White and Black patients.”

She added, “So that pat on the back we get for patients that have high HDL-C levels? Maybe that pat on the back shouldn’t be there.”

In an invited commentary, Keith C. Ferdinand, MD, of Tulane University in New Orleans, wrote that using HDL cholesterol in risk calculations could inaccurately assess atherosclerotic cardiovascular risk in Black adults “and become a barrier to optimal care.”

In an interview, he said the REGARDS findings call for consideration of other biomarkers for evaluating CHD risk and point to the importance of socioeconomic factors in health outcomes.

“Physicians and other clinicians need to recognize the powerful impact of the social determinants of health and to also recognize the limits of HDL itself as either protective if it’s high or a definitive predictor of risk if it’s low, and focus on some more modern approaches, including coronary artery calcium scoring.”

He also said risk evaluation should include lipoprotein(a), which, he noted in the editorial, the European Atherosclerosis Society recommends measuring. “One of the reasons it’s underutilized is that we really don’t have a specific treatment for it,” he said of Lp(a) in the United States.

In his editorial comment, Dr. Ferdinand called for future research aimed at eliminating health disparities. “Regardless of the development of better tools for the assessment of risk, newer drugs to treat CVD, the use of coronary artery calcium, if we don’t apply evidence-based medicine equally across the population based on race, ethnicity, sex, gender, socioeconomic status, or geography, then the disparities are going to persist,” he said.

The National Institute of Neurological Disorders and Stroke and the National Institute on Aging provided funding for the study. Dr. Pamir has no relevant relationships to disclose. Dr. Ferdinand disclosed relationships with Boehringer Ingelheim, Novartis, Janssen, and Lilly.

High-density lipoprotein cholesterol may not be as effective a biomarker of cardiovascular disease risk as once thought, particularly in Black adults, according to results from a large biracial cohort study that also raised questions about the validity of high HDL cholesterol as a potentially protective factor in White and Black adults alike.

“I think this opens the door to suggest that every biomarker we use might have a race-specific association with disease outcome,” Nathalie Pamir, PhD, an associate professor at Oregon Health & Science University in Portland, said in an interview. “So, something as basic as HDL cholesterol – we’ve known about it since 1970 – has a race signature.”

Dr. Pamir and colleagues reported their findings from the REGARDS (Reasons for Geographic and Racial Differences in Stroke) cohort study that recruited 30,239 Black and White individuals aged 45 years and older from the contiguous United States from 2003 to 2007.

The study found that LDL cholesterol “modestly” predicted coronary heart disease (CHD) risk in Black and White adults. However, low HDL cholesterol, while associated with an increased risk in White patients (hazard ratio, 1.22; 95% confidence interval, 1.05-1.43), did not have a similar association in Blacks (HR, 0.94; 95% CI: 0.78-1.14). And high HDL cholesterol wasn’t found to be predictive in either group (HR, 0.96; 95% CI, 0.79-1.16 for White participants: HR, 0.91; 95% CI, 0.74-1.12 for Black participants).

Among 23,901 study participants who were CHD-risk free over a 10-year follow-up, 664 and 951 CHD events occurred in Black and White participants, respectively. The study cohort was 57.8% White and 58.4% women, with a mean age of 65 years.

The study noted that LDL cholesterol and triglycerides conferred similar risks for CHD in both White and Black participants.

Acknowledging that this study focused on Blacks, Dr. Pamir added that “we need to know about Asian Americans; we need to know about Hispanic Americans.”
 

Change of approach to lipid management called for

Dr. Pamir noted that the current understanding about HDL cholesterol and CHD risk comes from the Framingham heart study in the 1970s, whose population was 100% White.

Care algorithms derived from the Framingham study as well as the Multi-Ethnic Study of Atherosclerosis incorporate that association between HDL cholesterol and CHD risk, she noted, but these findings from REGARDS should change how cardiologists approach lipid management in Black and White patients.

“The conversation would go something like: High HDL cholesterol levels put you in a higher risk [bracket] but HDL cholesterol levels are not something we treat; we have no drugs for that,” Dr. Pamir said.

“The conversation would continue along the lines that: ‘You need to do more exercise, you need to change your diet, incorporate healthy fats, walnuts, and omega 3s.’

“But what might the conversation be for Black patients? ‘We don’t see the association that we see for White patients. Do adopt the good habits to exercise and dietary changes, but don’t get too worried about it.’ ”

The study report raises “caution” about using the Framingham, MESA, and other algorithms for evaluating CHD risk. Dr. Pamir explained what that means. “We might be underestimating risk, because what our study showed was that, when we looked at clinically high HDL cholesterol, about 60 mg/dL, it has no benefit for White and Black patients.”

She added, “So that pat on the back we get for patients that have high HDL-C levels? Maybe that pat on the back shouldn’t be there.”

In an invited commentary, Keith C. Ferdinand, MD, of Tulane University in New Orleans, wrote that using HDL cholesterol in risk calculations could inaccurately assess atherosclerotic cardiovascular risk in Black adults “and become a barrier to optimal care.”

In an interview, he said the REGARDS findings call for consideration of other biomarkers for evaluating CHD risk and point to the importance of socioeconomic factors in health outcomes.

“Physicians and other clinicians need to recognize the powerful impact of the social determinants of health and to also recognize the limits of HDL itself as either protective if it’s high or a definitive predictor of risk if it’s low, and focus on some more modern approaches, including coronary artery calcium scoring.”

He also said risk evaluation should include lipoprotein(a), which, he noted in the editorial, the European Atherosclerosis Society recommends measuring. “One of the reasons it’s underutilized is that we really don’t have a specific treatment for it,” he said of Lp(a) in the United States.

In his editorial comment, Dr. Ferdinand called for future research aimed at eliminating health disparities. “Regardless of the development of better tools for the assessment of risk, newer drugs to treat CVD, the use of coronary artery calcium, if we don’t apply evidence-based medicine equally across the population based on race, ethnicity, sex, gender, socioeconomic status, or geography, then the disparities are going to persist,” he said.

The National Institute of Neurological Disorders and Stroke and the National Institute on Aging provided funding for the study. Dr. Pamir has no relevant relationships to disclose. Dr. Ferdinand disclosed relationships with Boehringer Ingelheim, Novartis, Janssen, and Lilly.

A drug used in the treatment of relapsed/refractory multiple myeloma (RRMM) is in the process of being pulled off the U.S. market by its manufacturer.

The drug is belantamab mafodotin-blmf (Blenrep), an antibody drug conjugate that targets B-cell maturation antigen (BCMA).

The manufacturer, GSK, announced that it has started the process of withdrawing this drug from the market at the request of the U.S. Food and Drug Administration (FDA).

This request follows disappointing results from a large confirmatory trial, known as DREAMM-3, in which the drug failed to meet the primary endpoint of showing an improvement in progression-free survival (PFS).

The company was obliged to carry out this confirmatory trial after the FDA granted an accelerated approval for the drug in August 2020.

The accelerated approval was based on response data, and it was dependent on later trials’ confirming a clinical benefit. In this case, those trials did not confirm a clinical benefit.

“We respect the Agency’s approach to the accelerated approval regulations and associated process,” commented the GSK Chief Medical Officer Sabine Luik.

The company will continue to “work with the U.S. FDA on a path forward for this important treatment option for patients with multiple myeloma.”

Further clinical trials in the DREAMM program are still underway. Results from the DREAMM-7 and DREAMM-8 trials are expected in early 2023.

The company had high hopes for the drug when it was launched. At that time, belanatamab mafodotin-blmf was the only drug on the market that targeted BCMA, and so it was the first drug in its class.

However, it is no longer unique. In the 2 years that it has been available, several other products that target BCMA have been launched for use in the treatment of multiple myeloma. These include the two chimeric antigen receptor T-cell products, idecabtagene vicleucel (Abecma) and ciltacabtagene autoleucel (Carvykti), as well as the bispecific antibody teclistamab (Tecvayli).
 

For relapsed/refractory disease

Belantamab mafodotin-blmf was approved for use in patients with RRMM who had already undergone treatment with one of the three major classes of drugs, namely, an immunomodulatory agent, a proteasome inhibitor, and a CD-38 monoclonal antibody.

Patients who are currently taking the drug and would like to continue doing so will have the option to enroll in a compassionate use program to retain their access to treatment, the company said.

“GSK continues to believe, based on the totality of data available from the DREAMM (DRiving Excellence in Approaches to Multiple Myeloma) development program, that the benefit-risk profile of belantamab mafodotin remains favorable in this hard-to-treat RRMM patient population. Patients responding to belantamab mafodotin experienced durable clinical benefit, and safety remains consistent with the known safety profile,” the company said.
 

Details of DREAMM-3 results

DREAMM-3 was a phase 3 trial that compared single-agent belantamab mafodotin to pomalidomide (Pomalyst) in combination with low-dose dexamethasone (PomDex) for patients with RRMM.

The results for the primary endpoint of PFS did not reach statistical significance: median PFS was 11.2 vs. 7 months with PomDex (hazard ratio, 1.03; 95% confidence interval, 0.72-1.47).

At the time of the primary analysis, the overall survival (OS) data had only achieved 37.5% overall maturity. The median OS was 21.2 vs. 21.1 months with PomDex (HR, 1.14; 95% CI, 0.77-1.68).

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

A drug used in the treatment of relapsed/refractory multiple myeloma (RRMM) is in the process of being pulled off the U.S. market by its manufacturer.

The drug is belantamab mafodotin-blmf (Blenrep), an antibody drug conjugate that targets B-cell maturation antigen (BCMA).

The manufacturer, GSK, announced that it has started the process of withdrawing this drug from the market at the request of the U.S. Food and Drug Administration (FDA).

This request follows disappointing results from a large confirmatory trial, known as DREAMM-3, in which the drug failed to meet the primary endpoint of showing an improvement in progression-free survival (PFS).

The company was obliged to carry out this confirmatory trial after the FDA granted an accelerated approval for the drug in August 2020.

The accelerated approval was based on response data, and it was dependent on later trials’ confirming a clinical benefit. In this case, those trials did not confirm a clinical benefit.

“We respect the Agency’s approach to the accelerated approval regulations and associated process,” commented the GSK Chief Medical Officer Sabine Luik.

The company will continue to “work with the U.S. FDA on a path forward for this important treatment option for patients with multiple myeloma.”

Further clinical trials in the DREAMM program are still underway. Results from the DREAMM-7 and DREAMM-8 trials are expected in early 2023.

The company had high hopes for the drug when it was launched. At that time, belanatamab mafodotin-blmf was the only drug on the market that targeted BCMA, and so it was the first drug in its class.

However, it is no longer unique. In the 2 years that it has been available, several other products that target BCMA have been launched for use in the treatment of multiple myeloma. These include the two chimeric antigen receptor T-cell products, idecabtagene vicleucel (Abecma) and ciltacabtagene autoleucel (Carvykti), as well as the bispecific antibody teclistamab (Tecvayli).
 

For relapsed/refractory disease

Belantamab mafodotin-blmf was approved for use in patients with RRMM who had already undergone treatment with one of the three major classes of drugs, namely, an immunomodulatory agent, a proteasome inhibitor, and a CD-38 monoclonal antibody.

Patients who are currently taking the drug and would like to continue doing so will have the option to enroll in a compassionate use program to retain their access to treatment, the company said.

“GSK continues to believe, based on the totality of data available from the DREAMM (DRiving Excellence in Approaches to Multiple Myeloma) development program, that the benefit-risk profile of belantamab mafodotin remains favorable in this hard-to-treat RRMM patient population. Patients responding to belantamab mafodotin experienced durable clinical benefit, and safety remains consistent with the known safety profile,” the company said.
 

Details of DREAMM-3 results

DREAMM-3 was a phase 3 trial that compared single-agent belantamab mafodotin to pomalidomide (Pomalyst) in combination with low-dose dexamethasone (PomDex) for patients with RRMM.

The results for the primary endpoint of PFS did not reach statistical significance: median PFS was 11.2 vs. 7 months with PomDex (hazard ratio, 1.03; 95% confidence interval, 0.72-1.47).

At the time of the primary analysis, the overall survival (OS) data had only achieved 37.5% overall maturity. The median OS was 21.2 vs. 21.1 months with PomDex (HR, 1.14; 95% CI, 0.77-1.68).

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

A drug used in the treatment of relapsed/refractory multiple myeloma (RRMM) is in the process of being pulled off the U.S. market by its manufacturer.

The drug is belantamab mafodotin-blmf (Blenrep), an antibody drug conjugate that targets B-cell maturation antigen (BCMA).

The manufacturer, GSK, announced that it has started the process of withdrawing this drug from the market at the request of the U.S. Food and Drug Administration (FDA).

This request follows disappointing results from a large confirmatory trial, known as DREAMM-3, in which the drug failed to meet the primary endpoint of showing an improvement in progression-free survival (PFS).

The company was obliged to carry out this confirmatory trial after the FDA granted an accelerated approval for the drug in August 2020.

The accelerated approval was based on response data, and it was dependent on later trials’ confirming a clinical benefit. In this case, those trials did not confirm a clinical benefit.

“We respect the Agency’s approach to the accelerated approval regulations and associated process,” commented the GSK Chief Medical Officer Sabine Luik.

The company will continue to “work with the U.S. FDA on a path forward for this important treatment option for patients with multiple myeloma.”

Further clinical trials in the DREAMM program are still underway. Results from the DREAMM-7 and DREAMM-8 trials are expected in early 2023.

The company had high hopes for the drug when it was launched. At that time, belanatamab mafodotin-blmf was the only drug on the market that targeted BCMA, and so it was the first drug in its class.

However, it is no longer unique. In the 2 years that it has been available, several other products that target BCMA have been launched for use in the treatment of multiple myeloma. These include the two chimeric antigen receptor T-cell products, idecabtagene vicleucel (Abecma) and ciltacabtagene autoleucel (Carvykti), as well as the bispecific antibody teclistamab (Tecvayli).
 

For relapsed/refractory disease

Belantamab mafodotin-blmf was approved for use in patients with RRMM who had already undergone treatment with one of the three major classes of drugs, namely, an immunomodulatory agent, a proteasome inhibitor, and a CD-38 monoclonal antibody.

Patients who are currently taking the drug and would like to continue doing so will have the option to enroll in a compassionate use program to retain their access to treatment, the company said.

“GSK continues to believe, based on the totality of data available from the DREAMM (DRiving Excellence in Approaches to Multiple Myeloma) development program, that the benefit-risk profile of belantamab mafodotin remains favorable in this hard-to-treat RRMM patient population. Patients responding to belantamab mafodotin experienced durable clinical benefit, and safety remains consistent with the known safety profile,” the company said.
 

Details of DREAMM-3 results

DREAMM-3 was a phase 3 trial that compared single-agent belantamab mafodotin to pomalidomide (Pomalyst) in combination with low-dose dexamethasone (PomDex) for patients with RRMM.

The results for the primary endpoint of PFS did not reach statistical significance: median PFS was 11.2 vs. 7 months with PomDex (hazard ratio, 1.03; 95% confidence interval, 0.72-1.47).

At the time of the primary analysis, the overall survival (OS) data had only achieved 37.5% overall maturity. The median OS was 21.2 vs. 21.1 months with PomDex (HR, 1.14; 95% CI, 0.77-1.68).

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

Updated clinical guidelines for the early diagnosis and management of cerebral palsy have been issued by the American Academy of Pediatrics.

Coauthored with the American Academy for Cerebral Palsy and Developmental Medicine, the report builds on new evidence for improved care and outcomes since the 2006 consensus guidelines.

Cerebral palsy, the most common neuromotor disorder of childhood, is often accompanied by cognitive impairments, epilepsy, sensory impairments, behavioral problems, communication difficulties, breathing and sleep problems, gastrointestinal and nutritional problems, and bone and orthopedic problems.

In the United States, the estimated prevalence of cerebral palsy ranges from 1.5 to 4 per 1,000 live births.

“Early identification and initiation of evidence-based motor therapies can improve outcomes by taking advantage of the neuroplasticity in the infant brain,” said the guideline authors in an executive summary.

The guideline, published in Pediatrics, is directed to primary care physicians with pediatrics, family practice, or internal medicine training. “It’s a much more comprehensive overview of the important role that primary care providers play in the lifetime care of people with cerebral palsy,” explained Garey Noritz, MD, chair of the 2021-2022 Executive Committee of the Council on Children with Disabilities. Dr. Noritz, a professor of pediatrics at Ohio State University and division chief of the complex health care program at Nationwide Children’s Hospital, both in Columbus, said: “The combined efforts of the primary care physician and specialty providers are needed to achieve the best outcomes.”

The AAP recommends that primary care pediatricians, neonatologists, and other specialists caring for hospitalized newborns recognize those at high risk of cerebral palsy, diagnose them as early as possible, and promptly refer them for therapy. Primary care physicians are advised to identify motor delays early by formalizing standardized developmental surveillance and screening at 9, 18, and 30 months, and to implement family-centered care across multiple specialists.

“If a motor disorder is suspected, primary care physicians should simultaneously begin a medical evaluation, refer to a specialist for definitive diagnosis, and to therapists for treatment,” Dr. Noritz emphasized.

“The earlier any possible movement disorder is recognized and intervention begins, the better a child can develop a gait pattern and work toward living an independent life, said Manish N. Shah, MD, associate professor of pediatric neurosurgery at the University of Texas, Houston, who was not involved in developing the guidelines.

For children in whom physical therapy and medication have not reduced leg spasticity, a minimally invasive spinal procedure can help release contracted tendons and encourage independent walking. The optimal age for selective dorsal rhizotomy is about 4 years, said Dr. Shah, who is director of the Texas Comprehensive Spasticity Center at Children’s Memorial Hermann Hospital in Houston. “You can turn these children into walkers. As adults, they can get jobs, have their own families. It’s life-changing.”

Importantly, the guidelines address the health care disparities leading to a higher prevalence of cerebral palsy in Black children and in those from families with lower socioeconomic status. “Efforts to combat racism and eliminate barriers to culturally sensitive prenatal, perinatal, and later pediatric care may help to improve outcomes for all children with cerebral palsy,” the authors said.

“Every child with cerebral palsy needs an individual plan, but only 30% or 40% are getting interventions,” said Dr. Shah. The updated guidelines could help payers rethink the 15-20 visits a year that are often approved, compared with the 2-3 visits per week that are needed for speech, physical, and occupational therapy, he pointed out.

“Financial issues often compromise the interdisciplinary and coordinated care associated with favorable outcomes in children with cerebral palsy,” said Heidi Feldman, MD, PhD, a developmental and behavioral pediatric specialist at Stanford (Calif.) Medicine Children’s Health’s Johnson Center for Pregnancy and Newborn Services. “With a new guideline, there may be greater willingness to fund these essential services.”

In the meantime, the AAP recommends that pediatricians advise families about available medical, social, and educational services, such as early intervention services, the Title V Maternal and Child Health block grant program, and special education services through the public school system.

Children with cerebral palsy need the same standardized primary care as any child, including the full schedule of recommended vaccinations and vision and hearing testing. They also need to be monitored and treated for the many problems that commonly co-occur, including chronic pain.

When secondary complications arise, the frequency of visits should increase.

Pneumonia, the leading cause of death in children and adolescents with cerebral palsy, can be prevented or minimized through immunization against respiratory diseases and screening for signs and symptoms of aspiration and sleep-disordered breathing.

The AAP also recommends that symptoms or functional declines undergo full investigation into other potential causes.

Since the sedentary lifestyle associated with cerebral palsy is now known to be related to the higher rates of cardiovascular complications in this patient population, the AAP recommends more attention be paid to physical activity and a healthy diet early in life. Pediatricians are advised to help families locate suitable opportunities for adaptive sports and recreation.

Almost 50% of children and adolescents with cerebral palsy have intellectual disability, 60%-80% have difficulty speaking, and about 25% are nonverbal. To address this, pediatricians should maximize the use of augmentative and alternative communication devices and involve experts in speech and language pathology, according to the guidelines.

“Many individuals with cerebral palsy and severe motor limitations have active, creative minds, and may need assistive technology, such as electronic talking devices, to demonstrate that mental life,” said Dr. Feldman. “Primary care clinicians should advocate for assistive technology.”

For challenging behavior, especially in the patient with limited verbal skills, potential nonbehavioral culprits such as constipation, esophageal reflux disease, and musculoskeletal or dental pain must be ruled out.

In the lead-up to adolescence, youth with cerebral palsy must be prepared for puberty, menstruation, and healthy, safe sexual relationships, much like their nonaffected peers. Since a disproportionate number of children with cerebral palsy experience neglect and physical, sexual, and emotional abuse, however, family stressors should be identified and caregivers referred for support services.

For the transition from pediatric to adult health care, the AAP recommends that structured planning begin between 12 and 14 years of age. Before transfer, the pediatrician should prepare a comprehensive medical summary with the input of the patient, parent/guardian, and pediatric subspecialists.

Without a proper handoff, “there is an increased risk of morbidity, medical complications, unnecessary emergency department visits, hospitalizations, and procedures,” the authors warned.

Transitions are likely to run more smoothly when youth are given the opportunity to understand their medical condition and be involved in decisions about their health. With this in mind, the AAP recommends that pediatricians actively discourage overprotective parents from getting in the way of their child developing “maximal independence.”

No potential conflicts of interest were disclosed by the authors, Dr. Shah, or Dr. Feldman.

*This story was updated on Nov. 28, 2022.
 

Updated clinical guidelines for the early diagnosis and management of cerebral palsy have been issued by the American Academy of Pediatrics.

Coauthored with the American Academy for Cerebral Palsy and Developmental Medicine, the report builds on new evidence for improved care and outcomes since the 2006 consensus guidelines.

Cerebral palsy, the most common neuromotor disorder of childhood, is often accompanied by cognitive impairments, epilepsy, sensory impairments, behavioral problems, communication difficulties, breathing and sleep problems, gastrointestinal and nutritional problems, and bone and orthopedic problems.

In the United States, the estimated prevalence of cerebral palsy ranges from 1.5 to 4 per 1,000 live births.

“Early identification and initiation of evidence-based motor therapies can improve outcomes by taking advantage of the neuroplasticity in the infant brain,” said the guideline authors in an executive summary.

The guideline, published in Pediatrics, is directed to primary care physicians with pediatrics, family practice, or internal medicine training. “It’s a much more comprehensive overview of the important role that primary care providers play in the lifetime care of people with cerebral palsy,” explained Garey Noritz, MD, chair of the 2021-2022 Executive Committee of the Council on Children with Disabilities. Dr. Noritz, a professor of pediatrics at Ohio State University and division chief of the complex health care program at Nationwide Children’s Hospital, both in Columbus, said: “The combined efforts of the primary care physician and specialty providers are needed to achieve the best outcomes.”

The AAP recommends that primary care pediatricians, neonatologists, and other specialists caring for hospitalized newborns recognize those at high risk of cerebral palsy, diagnose them as early as possible, and promptly refer them for therapy. Primary care physicians are advised to identify motor delays early by formalizing standardized developmental surveillance and screening at 9, 18, and 30 months, and to implement family-centered care across multiple specialists.

“If a motor disorder is suspected, primary care physicians should simultaneously begin a medical evaluation, refer to a specialist for definitive diagnosis, and to therapists for treatment,” Dr. Noritz emphasized.

“The earlier any possible movement disorder is recognized and intervention begins, the better a child can develop a gait pattern and work toward living an independent life, said Manish N. Shah, MD, associate professor of pediatric neurosurgery at the University of Texas, Houston, who was not involved in developing the guidelines.

For children in whom physical therapy and medication have not reduced leg spasticity, a minimally invasive spinal procedure can help release contracted tendons and encourage independent walking. The optimal age for selective dorsal rhizotomy is about 4 years, said Dr. Shah, who is director of the Texas Comprehensive Spasticity Center at Children’s Memorial Hermann Hospital in Houston. “You can turn these children into walkers. As adults, they can get jobs, have their own families. It’s life-changing.”

Importantly, the guidelines address the health care disparities leading to a higher prevalence of cerebral palsy in Black children and in those from families with lower socioeconomic status. “Efforts to combat racism and eliminate barriers to culturally sensitive prenatal, perinatal, and later pediatric care may help to improve outcomes for all children with cerebral palsy,” the authors said.

“Every child with cerebral palsy needs an individual plan, but only 30% or 40% are getting interventions,” said Dr. Shah. The updated guidelines could help payers rethink the 15-20 visits a year that are often approved, compared with the 2-3 visits per week that are needed for speech, physical, and occupational therapy, he pointed out.

“Financial issues often compromise the interdisciplinary and coordinated care associated with favorable outcomes in children with cerebral palsy,” said Heidi Feldman, MD, PhD, a developmental and behavioral pediatric specialist at Stanford (Calif.) Medicine Children’s Health’s Johnson Center for Pregnancy and Newborn Services. “With a new guideline, there may be greater willingness to fund these essential services.”

In the meantime, the AAP recommends that pediatricians advise families about available medical, social, and educational services, such as early intervention services, the Title V Maternal and Child Health block grant program, and special education services through the public school system.

Children with cerebral palsy need the same standardized primary care as any child, including the full schedule of recommended vaccinations and vision and hearing testing. They also need to be monitored and treated for the many problems that commonly co-occur, including chronic pain.

When secondary complications arise, the frequency of visits should increase.

Pneumonia, the leading cause of death in children and adolescents with cerebral palsy, can be prevented or minimized through immunization against respiratory diseases and screening for signs and symptoms of aspiration and sleep-disordered breathing.

The AAP also recommends that symptoms or functional declines undergo full investigation into other potential causes.

Since the sedentary lifestyle associated with cerebral palsy is now known to be related to the higher rates of cardiovascular complications in this patient population, the AAP recommends more attention be paid to physical activity and a healthy diet early in life. Pediatricians are advised to help families locate suitable opportunities for adaptive sports and recreation.

Almost 50% of children and adolescents with cerebral palsy have intellectual disability, 60%-80% have difficulty speaking, and about 25% are nonverbal. To address this, pediatricians should maximize the use of augmentative and alternative communication devices and involve experts in speech and language pathology, according to the guidelines.

“Many individuals with cerebral palsy and severe motor limitations have active, creative minds, and may need assistive technology, such as electronic talking devices, to demonstrate that mental life,” said Dr. Feldman. “Primary care clinicians should advocate for assistive technology.”

For challenging behavior, especially in the patient with limited verbal skills, potential nonbehavioral culprits such as constipation, esophageal reflux disease, and musculoskeletal or dental pain must be ruled out.

In the lead-up to adolescence, youth with cerebral palsy must be prepared for puberty, menstruation, and healthy, safe sexual relationships, much like their nonaffected peers. Since a disproportionate number of children with cerebral palsy experience neglect and physical, sexual, and emotional abuse, however, family stressors should be identified and caregivers referred for support services.

For the transition from pediatric to adult health care, the AAP recommends that structured planning begin between 12 and 14 years of age. Before transfer, the pediatrician should prepare a comprehensive medical summary with the input of the patient, parent/guardian, and pediatric subspecialists.

Without a proper handoff, “there is an increased risk of morbidity, medical complications, unnecessary emergency department visits, hospitalizations, and procedures,” the authors warned.

Transitions are likely to run more smoothly when youth are given the opportunity to understand their medical condition and be involved in decisions about their health. With this in mind, the AAP recommends that pediatricians actively discourage overprotective parents from getting in the way of their child developing “maximal independence.”

No potential conflicts of interest were disclosed by the authors, Dr. Shah, or Dr. Feldman.

*This story was updated on Nov. 28, 2022.
 

Updated clinical guidelines for the early diagnosis and management of cerebral palsy have been issued by the American Academy of Pediatrics.

Coauthored with the American Academy for Cerebral Palsy and Developmental Medicine, the report builds on new evidence for improved care and outcomes since the 2006 consensus guidelines.

Cerebral palsy, the most common neuromotor disorder of childhood, is often accompanied by cognitive impairments, epilepsy, sensory impairments, behavioral problems, communication difficulties, breathing and sleep problems, gastrointestinal and nutritional problems, and bone and orthopedic problems.

In the United States, the estimated prevalence of cerebral palsy ranges from 1.5 to 4 per 1,000 live births.

“Early identification and initiation of evidence-based motor therapies can improve outcomes by taking advantage of the neuroplasticity in the infant brain,” said the guideline authors in an executive summary.

The guideline, published in Pediatrics, is directed to primary care physicians with pediatrics, family practice, or internal medicine training. “It’s a much more comprehensive overview of the important role that primary care providers play in the lifetime care of people with cerebral palsy,” explained Garey Noritz, MD, chair of the 2021-2022 Executive Committee of the Council on Children with Disabilities. Dr. Noritz, a professor of pediatrics at Ohio State University and division chief of the complex health care program at Nationwide Children’s Hospital, both in Columbus, said: “The combined efforts of the primary care physician and specialty providers are needed to achieve the best outcomes.”

The AAP recommends that primary care pediatricians, neonatologists, and other specialists caring for hospitalized newborns recognize those at high risk of cerebral palsy, diagnose them as early as possible, and promptly refer them for therapy. Primary care physicians are advised to identify motor delays early by formalizing standardized developmental surveillance and screening at 9, 18, and 30 months, and to implement family-centered care across multiple specialists.

“If a motor disorder is suspected, primary care physicians should simultaneously begin a medical evaluation, refer to a specialist for definitive diagnosis, and to therapists for treatment,” Dr. Noritz emphasized.

“The earlier any possible movement disorder is recognized and intervention begins, the better a child can develop a gait pattern and work toward living an independent life, said Manish N. Shah, MD, associate professor of pediatric neurosurgery at the University of Texas, Houston, who was not involved in developing the guidelines.

For children in whom physical therapy and medication have not reduced leg spasticity, a minimally invasive spinal procedure can help release contracted tendons and encourage independent walking. The optimal age for selective dorsal rhizotomy is about 4 years, said Dr. Shah, who is director of the Texas Comprehensive Spasticity Center at Children’s Memorial Hermann Hospital in Houston. “You can turn these children into walkers. As adults, they can get jobs, have their own families. It’s life-changing.”

Importantly, the guidelines address the health care disparities leading to a higher prevalence of cerebral palsy in Black children and in those from families with lower socioeconomic status. “Efforts to combat racism and eliminate barriers to culturally sensitive prenatal, perinatal, and later pediatric care may help to improve outcomes for all children with cerebral palsy,” the authors said.

“Every child with cerebral palsy needs an individual plan, but only 30% or 40% are getting interventions,” said Dr. Shah. The updated guidelines could help payers rethink the 15-20 visits a year that are often approved, compared with the 2-3 visits per week that are needed for speech, physical, and occupational therapy, he pointed out.

“Financial issues often compromise the interdisciplinary and coordinated care associated with favorable outcomes in children with cerebral palsy,” said Heidi Feldman, MD, PhD, a developmental and behavioral pediatric specialist at Stanford (Calif.) Medicine Children’s Health’s Johnson Center for Pregnancy and Newborn Services. “With a new guideline, there may be greater willingness to fund these essential services.”

In the meantime, the AAP recommends that pediatricians advise families about available medical, social, and educational services, such as early intervention services, the Title V Maternal and Child Health block grant program, and special education services through the public school system.

Children with cerebral palsy need the same standardized primary care as any child, including the full schedule of recommended vaccinations and vision and hearing testing. They also need to be monitored and treated for the many problems that commonly co-occur, including chronic pain.

When secondary complications arise, the frequency of visits should increase.

Pneumonia, the leading cause of death in children and adolescents with cerebral palsy, can be prevented or minimized through immunization against respiratory diseases and screening for signs and symptoms of aspiration and sleep-disordered breathing.

The AAP also recommends that symptoms or functional declines undergo full investigation into other potential causes.

Since the sedentary lifestyle associated with cerebral palsy is now known to be related to the higher rates of cardiovascular complications in this patient population, the AAP recommends more attention be paid to physical activity and a healthy diet early in life. Pediatricians are advised to help families locate suitable opportunities for adaptive sports and recreation.

Almost 50% of children and adolescents with cerebral palsy have intellectual disability, 60%-80% have difficulty speaking, and about 25% are nonverbal. To address this, pediatricians should maximize the use of augmentative and alternative communication devices and involve experts in speech and language pathology, according to the guidelines.

“Many individuals with cerebral palsy and severe motor limitations have active, creative minds, and may need assistive technology, such as electronic talking devices, to demonstrate that mental life,” said Dr. Feldman. “Primary care clinicians should advocate for assistive technology.”

For challenging behavior, especially in the patient with limited verbal skills, potential nonbehavioral culprits such as constipation, esophageal reflux disease, and musculoskeletal or dental pain must be ruled out.

In the lead-up to adolescence, youth with cerebral palsy must be prepared for puberty, menstruation, and healthy, safe sexual relationships, much like their nonaffected peers. Since a disproportionate number of children with cerebral palsy experience neglect and physical, sexual, and emotional abuse, however, family stressors should be identified and caregivers referred for support services.

For the transition from pediatric to adult health care, the AAP recommends that structured planning begin between 12 and 14 years of age. Before transfer, the pediatrician should prepare a comprehensive medical summary with the input of the patient, parent/guardian, and pediatric subspecialists.

Without a proper handoff, “there is an increased risk of morbidity, medical complications, unnecessary emergency department visits, hospitalizations, and procedures,” the authors warned.

Transitions are likely to run more smoothly when youth are given the opportunity to understand their medical condition and be involved in decisions about their health. With this in mind, the AAP recommends that pediatricians actively discourage overprotective parents from getting in the way of their child developing “maximal independence.”

No potential conflicts of interest were disclosed by the authors, Dr. Shah, or Dr. Feldman.

*This story was updated on Nov. 28, 2022.