Ob.Gyn. News

In a small study, a self-administered vaginal insert containing the antimalarial agent artesunate resolved cervical intraepithelial neoplasia (CIN) 2/3 lesions in two-thirds of patients and cleared human papillomavirus (HPV) genotypes in nearly half of women whose lesions disappeared.

Ying Liu, Shanghai Xinhua News Agency

Among 28 women with biopsy-confirmed CIN 2/3 who used the inserts prior to a planned standard-of-care resection, histologic regression of lesions occurred in 19 patients. In 9 of the 19 women, there was clearance of baseline HPV genotypes.

These results were reported in an abstract that had been slated for presentation at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer. The meeting was canceled because of the COVID-19 pandemic. The study results were also published in Gynecologic Oncology.

An unexpected treatment

“The implications of having a safe, inexpensive, self-administered, shelf-stable, nonsurgical treatment for HPV intraepithelial disease, not only here in the U.S., but also extending to low-resource settings,” are self-evident, said study author Cornelia L. Trimble, MD, of Johns Hopkins University in Baltimore.

“This could change the entire landscape of care,” Dr. Trimble said in an interview. “Who’d have thunk that a freaking Chinese herbal medicine derived from the bark of a tree could have this effect?”

Artesunate is a derivative of artemisinin, an antimalarial isolated from the plant Artemisia annua, which is used in traditional Chinese medicine. According to the Centers for Disease Control and Prevention, intravenous artesunate is the first-line drug for treatment of severe malaria in the United States.

However, artesunate is neither approved by the Food and Drug Administration nor commercially available in the United States. The CDC provides artesunate to U.S. clinicians on an as-needed basis.

In addition to its antimalarial activity, artesunate has been shown to have a cytotoxic effect on squamous cells transformed by HPV in vitro. Dr. Trimble and colleagues are also testing a topical form of the drug for the treatment of vulvar intraepithelial neoplasia.

Patients, dosing, and efficacy

In the current study, Dr. Trimble and colleagues enrolled adult immunocompetent women with CIN 2/3, visible residual lesions, and detectable HPV. The patients were assigned sequentially to one of four treatment groups: one 5-day cycle of 50-mg inserts or one, two, or three 5-day cycles using 200-mg inserts.

The patients were instructed to place the inserts at bedtime using a vaginal applicator, followed by a tampon, and then remove the inserts in the morning.

In a modified intention-to-treat analysis including all women who received at least one dose of artesunate and who had endpoint data available, 19 of 28 (67.9%) had histologic regression of CIN lesions. Of the 19 patients, 9 (47.4%) had clearance of all HPV genotypes that had been present at baseline.

Asked how the investigators could distinguish between the treatment effect of the inserts and spontaneous clearance of lesions seen as part of the natural history of CIN in some patients, Dr. Trimble pointed to two observations suggesting an immunologic effect from treatment.

Specifically, although there was lesion regression to CIN 1 or less in all treatment groups, the patients who had only a single treatment cycle had a longer time to regression than those who received two or three cycles.

Additionally, among the nine patients who had viral clearance, three had clearance at the same study time point where histologic regression was observed. For the other six patients, the virus did not clear until several weeks following lesion regression.

These two observations suggest the therapeutic effect of artesunate is recognized by the immune system, which may stimulate a localized immune-mediated cytotoxic effect, Dr. Trimble said.

Safety and next steps

The safety analysis showed that side effects were generally mild and well tolerated. There were 161 adverse events among 29 women for whom safety data were available. The most frequently reported adverse events were vaginal itching (n = 13), vaginal pain (n = 12), vaginal discharge (n = 8), spotting (n = 6), uterine cramping (n = 6), vaginal dryness (n = 4), pelvic pain (n = 1), perineal pain (n = 1), and dyspareunia (n = 1).

Grade 2 adverse events included vaginal yeast infection (n = 6), bacterial vaginosis (n = 2), vaginal inflammation (n = 2), urinary tract infection (n = 2), and noninfective cystitis (n = 1). There were no grade 3 or 4 adverse events reported, and three women reported no noticeable side effects.

Dr. Trimble and colleagues are continuing to study immune responses in cervical tissues and are examining the composition and functions of the cervicovaginal metagenome, looking at bacterial, viral, and fungal components. The team has joined with collaborators at the University of Texas MD Anderson Cancer Center in Houston to look for immune markers in longitudinally collected, subject-matched cervical swabs.

Frantz Viral Therapeutics supplied the artesunate vaginal inserts and partial financial support for this study. Dr. Trimble disclosed relationships with a range of companies and organizations outside this work.

SOURCE: Trimble C L et al. SGO 2020, Abstract LBA 1.

In a small study, a self-administered vaginal insert containing the antimalarial agent artesunate resolved cervical intraepithelial neoplasia (CIN) 2/3 lesions in two-thirds of patients and cleared human papillomavirus (HPV) genotypes in nearly half of women whose lesions disappeared.

Ying Liu, Shanghai Xinhua News Agency

Among 28 women with biopsy-confirmed CIN 2/3 who used the inserts prior to a planned standard-of-care resection, histologic regression of lesions occurred in 19 patients. In 9 of the 19 women, there was clearance of baseline HPV genotypes.

These results were reported in an abstract that had been slated for presentation at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer. The meeting was canceled because of the COVID-19 pandemic. The study results were also published in Gynecologic Oncology.

An unexpected treatment

“The implications of having a safe, inexpensive, self-administered, shelf-stable, nonsurgical treatment for HPV intraepithelial disease, not only here in the U.S., but also extending to low-resource settings,” are self-evident, said study author Cornelia L. Trimble, MD, of Johns Hopkins University in Baltimore.

“This could change the entire landscape of care,” Dr. Trimble said in an interview. “Who’d have thunk that a freaking Chinese herbal medicine derived from the bark of a tree could have this effect?”

Artesunate is a derivative of artemisinin, an antimalarial isolated from the plant Artemisia annua, which is used in traditional Chinese medicine. According to the Centers for Disease Control and Prevention, intravenous artesunate is the first-line drug for treatment of severe malaria in the United States.

However, artesunate is neither approved by the Food and Drug Administration nor commercially available in the United States. The CDC provides artesunate to U.S. clinicians on an as-needed basis.

In addition to its antimalarial activity, artesunate has been shown to have a cytotoxic effect on squamous cells transformed by HPV in vitro. Dr. Trimble and colleagues are also testing a topical form of the drug for the treatment of vulvar intraepithelial neoplasia.

Patients, dosing, and efficacy

In the current study, Dr. Trimble and colleagues enrolled adult immunocompetent women with CIN 2/3, visible residual lesions, and detectable HPV. The patients were assigned sequentially to one of four treatment groups: one 5-day cycle of 50-mg inserts or one, two, or three 5-day cycles using 200-mg inserts.

The patients were instructed to place the inserts at bedtime using a vaginal applicator, followed by a tampon, and then remove the inserts in the morning.

In a modified intention-to-treat analysis including all women who received at least one dose of artesunate and who had endpoint data available, 19 of 28 (67.9%) had histologic regression of CIN lesions. Of the 19 patients, 9 (47.4%) had clearance of all HPV genotypes that had been present at baseline.

Asked how the investigators could distinguish between the treatment effect of the inserts and spontaneous clearance of lesions seen as part of the natural history of CIN in some patients, Dr. Trimble pointed to two observations suggesting an immunologic effect from treatment.

Specifically, although there was lesion regression to CIN 1 or less in all treatment groups, the patients who had only a single treatment cycle had a longer time to regression than those who received two or three cycles.

Additionally, among the nine patients who had viral clearance, three had clearance at the same study time point where histologic regression was observed. For the other six patients, the virus did not clear until several weeks following lesion regression.

These two observations suggest the therapeutic effect of artesunate is recognized by the immune system, which may stimulate a localized immune-mediated cytotoxic effect, Dr. Trimble said.

Safety and next steps

The safety analysis showed that side effects were generally mild and well tolerated. There were 161 adverse events among 29 women for whom safety data were available. The most frequently reported adverse events were vaginal itching (n = 13), vaginal pain (n = 12), vaginal discharge (n = 8), spotting (n = 6), uterine cramping (n = 6), vaginal dryness (n = 4), pelvic pain (n = 1), perineal pain (n = 1), and dyspareunia (n = 1).

Grade 2 adverse events included vaginal yeast infection (n = 6), bacterial vaginosis (n = 2), vaginal inflammation (n = 2), urinary tract infection (n = 2), and noninfective cystitis (n = 1). There were no grade 3 or 4 adverse events reported, and three women reported no noticeable side effects.

Dr. Trimble and colleagues are continuing to study immune responses in cervical tissues and are examining the composition and functions of the cervicovaginal metagenome, looking at bacterial, viral, and fungal components. The team has joined with collaborators at the University of Texas MD Anderson Cancer Center in Houston to look for immune markers in longitudinally collected, subject-matched cervical swabs.

Frantz Viral Therapeutics supplied the artesunate vaginal inserts and partial financial support for this study. Dr. Trimble disclosed relationships with a range of companies and organizations outside this work.

SOURCE: Trimble C L et al. SGO 2020, Abstract LBA 1.

In a small study, a self-administered vaginal insert containing the antimalarial agent artesunate resolved cervical intraepithelial neoplasia (CIN) 2/3 lesions in two-thirds of patients and cleared human papillomavirus (HPV) genotypes in nearly half of women whose lesions disappeared.

Ying Liu, Shanghai Xinhua News Agency

Among 28 women with biopsy-confirmed CIN 2/3 who used the inserts prior to a planned standard-of-care resection, histologic regression of lesions occurred in 19 patients. In 9 of the 19 women, there was clearance of baseline HPV genotypes.

These results were reported in an abstract that had been slated for presentation at the Society of Gynecologic Oncology’s Annual Meeting on Women’s Cancer. The meeting was canceled because of the COVID-19 pandemic. The study results were also published in Gynecologic Oncology.

An unexpected treatment

“The implications of having a safe, inexpensive, self-administered, shelf-stable, nonsurgical treatment for HPV intraepithelial disease, not only here in the U.S., but also extending to low-resource settings,” are self-evident, said study author Cornelia L. Trimble, MD, of Johns Hopkins University in Baltimore.

“This could change the entire landscape of care,” Dr. Trimble said in an interview. “Who’d have thunk that a freaking Chinese herbal medicine derived from the bark of a tree could have this effect?”

Artesunate is a derivative of artemisinin, an antimalarial isolated from the plant Artemisia annua, which is used in traditional Chinese medicine. According to the Centers for Disease Control and Prevention, intravenous artesunate is the first-line drug for treatment of severe malaria in the United States.

However, artesunate is neither approved by the Food and Drug Administration nor commercially available in the United States. The CDC provides artesunate to U.S. clinicians on an as-needed basis.

In addition to its antimalarial activity, artesunate has been shown to have a cytotoxic effect on squamous cells transformed by HPV in vitro. Dr. Trimble and colleagues are also testing a topical form of the drug for the treatment of vulvar intraepithelial neoplasia.

Patients, dosing, and efficacy

In the current study, Dr. Trimble and colleagues enrolled adult immunocompetent women with CIN 2/3, visible residual lesions, and detectable HPV. The patients were assigned sequentially to one of four treatment groups: one 5-day cycle of 50-mg inserts or one, two, or three 5-day cycles using 200-mg inserts.

The patients were instructed to place the inserts at bedtime using a vaginal applicator, followed by a tampon, and then remove the inserts in the morning.

In a modified intention-to-treat analysis including all women who received at least one dose of artesunate and who had endpoint data available, 19 of 28 (67.9%) had histologic regression of CIN lesions. Of the 19 patients, 9 (47.4%) had clearance of all HPV genotypes that had been present at baseline.

Asked how the investigators could distinguish between the treatment effect of the inserts and spontaneous clearance of lesions seen as part of the natural history of CIN in some patients, Dr. Trimble pointed to two observations suggesting an immunologic effect from treatment.

Specifically, although there was lesion regression to CIN 1 or less in all treatment groups, the patients who had only a single treatment cycle had a longer time to regression than those who received two or three cycles.

Additionally, among the nine patients who had viral clearance, three had clearance at the same study time point where histologic regression was observed. For the other six patients, the virus did not clear until several weeks following lesion regression.

These two observations suggest the therapeutic effect of artesunate is recognized by the immune system, which may stimulate a localized immune-mediated cytotoxic effect, Dr. Trimble said.

Safety and next steps

The safety analysis showed that side effects were generally mild and well tolerated. There were 161 adverse events among 29 women for whom safety data were available. The most frequently reported adverse events were vaginal itching (n = 13), vaginal pain (n = 12), vaginal discharge (n = 8), spotting (n = 6), uterine cramping (n = 6), vaginal dryness (n = 4), pelvic pain (n = 1), perineal pain (n = 1), and dyspareunia (n = 1).

Grade 2 adverse events included vaginal yeast infection (n = 6), bacterial vaginosis (n = 2), vaginal inflammation (n = 2), urinary tract infection (n = 2), and noninfective cystitis (n = 1). There were no grade 3 or 4 adverse events reported, and three women reported no noticeable side effects.

Dr. Trimble and colleagues are continuing to study immune responses in cervical tissues and are examining the composition and functions of the cervicovaginal metagenome, looking at bacterial, viral, and fungal components. The team has joined with collaborators at the University of Texas MD Anderson Cancer Center in Houston to look for immune markers in longitudinally collected, subject-matched cervical swabs.

Frantz Viral Therapeutics supplied the artesunate vaginal inserts and partial financial support for this study. Dr. Trimble disclosed relationships with a range of companies and organizations outside this work.

SOURCE: Trimble C L et al. SGO 2020, Abstract LBA 1.

Ramping up health system capacity for the coming surge of U.S. COVID-19 cases requires a commitment to boosting safety, capacity, and communication, according to a physician leader and a health workforce expert.

Polly Pittman, PhD, is hearing a lot of concern among health care workers that it’s difficult to find definitive and accurate information about how best to protect themselves and their families, she said during a webinar by the Alliance for Health Policy titled Health System Capacity: Protecting Frontline Health Workers. “The knowledge base is evolving very quickly,” said Dr. Pittman, Fitzhugh Mullan Professor of Health Workforce Equity at the Milken Institute School of Public Health, George Washington University, Washington.

He noted that Permanente is “working hand in glove with state authorities throughout the country.” Efforts include establishing alternative sites for assessment and testing, as well as opening up closed hospitals and working with the National Guard and the Department of Defense to prepare mobile hospital units that can be deployed in areas with peak infection rates. “Having all of those options available to us is critically important,” he said.

To mitigate potential provider shortages, Dr. Pittman said, “All members of the care team could potentially do more” than their current licenses allow. Expanding the scope of practice for pharmacists, clinical laboratory staff, licensed practical nurses, and medical assistants can help with efficient care delivery.

Other measures include expedited licensing for near-graduates and nonpracticing foreign medical graduates, as well as relicensing for retired health care personnel and those who are not currently working directly with patients, she said.

Getting these things done “requires leadership on behalf of the licensing bodies,” as well as coordination with state regulatory authorities, Dr. Pittman pointed out.

Dr. Parodi called for state and federal governments to implement emergency declarations that suspend some existing health codes to achieve repurposing of staff. Getting these measures in place now will allow facilities “to be able to provide that in-time training now before the surge occurs. ... We are actively developing plans knowing that there’s going to be a need for more critical care.”

The game plan at Permanente, he said, is to repurpose critical care physicians to provide consultations to multiple hospitalists who are providing the bulk of frontline care. At the same time, they plan to repurpose other specialists to backfill the hospitalists, and to repurpose family medicine physicians to supplement staff in emergency departments and other frontline intake areas.

All the organizational measures being taken won’t be in vain if they increase preparedness for the long battle ahead, he said. “We need to double down on the work. ... We need to continue social distancing, and we’ve got to ramp up testing. Until we do that we have to hold the line on basic public health measures.”

Dr. Parodi is employed by Permanente. The panelists reported no disclosures relevant to the presentation, which was sponsored by the Alliance for Health Policy, the Commonwealth Fund, and the National Institute for Health Care Management Foundation.

[email protected]

Ramping up health system capacity for the coming surge of U.S. COVID-19 cases requires a commitment to boosting safety, capacity, and communication, according to a physician leader and a health workforce expert.

Polly Pittman, PhD, is hearing a lot of concern among health care workers that it’s difficult to find definitive and accurate information about how best to protect themselves and their families, she said during a webinar by the Alliance for Health Policy titled Health System Capacity: Protecting Frontline Health Workers. “The knowledge base is evolving very quickly,” said Dr. Pittman, Fitzhugh Mullan Professor of Health Workforce Equity at the Milken Institute School of Public Health, George Washington University, Washington.

He noted that Permanente is “working hand in glove with state authorities throughout the country.” Efforts include establishing alternative sites for assessment and testing, as well as opening up closed hospitals and working with the National Guard and the Department of Defense to prepare mobile hospital units that can be deployed in areas with peak infection rates. “Having all of those options available to us is critically important,” he said.

To mitigate potential provider shortages, Dr. Pittman said, “All members of the care team could potentially do more” than their current licenses allow. Expanding the scope of practice for pharmacists, clinical laboratory staff, licensed practical nurses, and medical assistants can help with efficient care delivery.

Other measures include expedited licensing for near-graduates and nonpracticing foreign medical graduates, as well as relicensing for retired health care personnel and those who are not currently working directly with patients, she said.

Getting these things done “requires leadership on behalf of the licensing bodies,” as well as coordination with state regulatory authorities, Dr. Pittman pointed out.

Dr. Parodi called for state and federal governments to implement emergency declarations that suspend some existing health codes to achieve repurposing of staff. Getting these measures in place now will allow facilities “to be able to provide that in-time training now before the surge occurs. ... We are actively developing plans knowing that there’s going to be a need for more critical care.”

The game plan at Permanente, he said, is to repurpose critical care physicians to provide consultations to multiple hospitalists who are providing the bulk of frontline care. At the same time, they plan to repurpose other specialists to backfill the hospitalists, and to repurpose family medicine physicians to supplement staff in emergency departments and other frontline intake areas.

All the organizational measures being taken won’t be in vain if they increase preparedness for the long battle ahead, he said. “We need to double down on the work. ... We need to continue social distancing, and we’ve got to ramp up testing. Until we do that we have to hold the line on basic public health measures.”

Dr. Parodi is employed by Permanente. The panelists reported no disclosures relevant to the presentation, which was sponsored by the Alliance for Health Policy, the Commonwealth Fund, and the National Institute for Health Care Management Foundation.

[email protected]

Ramping up health system capacity for the coming surge of U.S. COVID-19 cases requires a commitment to boosting safety, capacity, and communication, according to a physician leader and a health workforce expert.

Polly Pittman, PhD, is hearing a lot of concern among health care workers that it’s difficult to find definitive and accurate information about how best to protect themselves and their families, she said during a webinar by the Alliance for Health Policy titled Health System Capacity: Protecting Frontline Health Workers. “The knowledge base is evolving very quickly,” said Dr. Pittman, Fitzhugh Mullan Professor of Health Workforce Equity at the Milken Institute School of Public Health, George Washington University, Washington.

He noted that Permanente is “working hand in glove with state authorities throughout the country.” Efforts include establishing alternative sites for assessment and testing, as well as opening up closed hospitals and working with the National Guard and the Department of Defense to prepare mobile hospital units that can be deployed in areas with peak infection rates. “Having all of those options available to us is critically important,” he said.

To mitigate potential provider shortages, Dr. Pittman said, “All members of the care team could potentially do more” than their current licenses allow. Expanding the scope of practice for pharmacists, clinical laboratory staff, licensed practical nurses, and medical assistants can help with efficient care delivery.

Other measures include expedited licensing for near-graduates and nonpracticing foreign medical graduates, as well as relicensing for retired health care personnel and those who are not currently working directly with patients, she said.

Getting these things done “requires leadership on behalf of the licensing bodies,” as well as coordination with state regulatory authorities, Dr. Pittman pointed out.

Dr. Parodi called for state and federal governments to implement emergency declarations that suspend some existing health codes to achieve repurposing of staff. Getting these measures in place now will allow facilities “to be able to provide that in-time training now before the surge occurs. ... We are actively developing plans knowing that there’s going to be a need for more critical care.”

The game plan at Permanente, he said, is to repurpose critical care physicians to provide consultations to multiple hospitalists who are providing the bulk of frontline care. At the same time, they plan to repurpose other specialists to backfill the hospitalists, and to repurpose family medicine physicians to supplement staff in emergency departments and other frontline intake areas.

All the organizational measures being taken won’t be in vain if they increase preparedness for the long battle ahead, he said. “We need to double down on the work. ... We need to continue social distancing, and we’ve got to ramp up testing. Until we do that we have to hold the line on basic public health measures.”

Dr. Parodi is employed by Permanente. The panelists reported no disclosures relevant to the presentation, which was sponsored by the Alliance for Health Policy, the Commonwealth Fund, and the National Institute for Health Care Management Foundation.

[email protected]

As the proportion of patients infected with COVID-19 continues to rise in the United States, the Food and Drug Administration is facilitating access to COVID-19 convalescent plasma for use in patients with serious or immediately life-threatening COVID-19 infections.

While clinical trials are underway to evaluate the safety and efficacy of administering convalescent plasma to patients with COVID-19, the FDA is granting clinicians permission for use of investigational convalescent plasma under single-patient emergency Investigational New Drug Applications (INDs), since no known cure exists and a vaccine is more than 1 year away from becoming available.

This allows the use of an investigational drug for the treatment of an individual patient by a licensed physician upon FDA authorization. This does not include the use of COVID-19 convalescent plasma for the prevention of infection, according to a statement issued by the agency on March 24.

“It is possible that convalescent plasma that contains antibodies to SARS-CoV-2 (the virus that causes COVID-19) might be effective against the infection,” the FDA statement reads. “Use of convalescent plasma has been studied in outbreaks of other respiratory infections, including the 2009-2010 H1N1 influenza virus pandemic, 2003 SARS-CoV-1 epidemic, and the 2012 MERS-CoV epidemic. Although promising, convalescent plasma has not been shown to be effective in every disease studied.”

“I think the FDA got caught initially a little flat-footed when it came to the development of COVID-19 tests, but they’re quickly catching up,” Peter J. Pitts, who was the FDA’s associate commissioner from 2002 to 2004, said in an interview. “I think that the attitude now is, ‘If it’s safe, let’s create a pathway to see how these things work in the real world.’ I think that’s going to be as true for treatments to lessen the symptoms and shorten the duration of the disease, as well as convalescent plasma as a potential alternative to a yet-to-be-developed vaccine.”

At the University of Washington School of Medicine, Seattle, Terry B. Gernsheimer, MD, and her colleagues are recruiting recovered COVID-19 patients to donate plasma for seriously ill patients affected with the virus. “The thought of using convalescent plasma makes total sense, because it’s immediately available, and it’s something that we can try to give people,” said Dr. Gernsheimer, a hematologist who is professor of medicine at the medical school. “It’s been used in China, and reports should be coming out shortly about their experience with this.”

In a case series that appeared in JAMA on March 27 (doi: 10.1001/jama.2020.4783), Chinese researchers led by Chenguang Shen, PhD, reported findings from five critically ill COVID-19 patients with acute respiratory distress syndrome who received a transfusion with convalescent plasma at Shenzhen Third People’s Hospital 10 and 22 days after hospital admission. The patients ranged in age from 36 to 73 years, three were men, and all were receiving mechanical ventilation at the time of treatment.

Dr. Shen and colleagues reported that viral loads decreased and became negative within 12 days following the transfusion. Three of the patients were discharged from the hospital after a length of stay that ranged from 51 to 55 days, and two remain in stable condition at 37 days after the transfusion. The researchers pointed out that all patients received antiviral agents, including interferon and lopinavir/ritonavir, during and following convalescent plasma treatment, “which also may have contributed to the viral clearance observed.”

Under the FDA policy on emergency IND use, COVID-19 convalescent plasma must only be collected from recovered individuals if they are eligible to donate blood, required testing must be performed, and the donation must be found suitable.

Potential donors “are going to be screened the way all blood donors are screened,” Dr. Gernsheimer said. “It’s not going to be any less safe than any unit of plasma that’s on the shelf that comes from our volunteer donors. There are always transfusion reactions that we have to worry about, [and] there are potentially unknown pathogens that we don’t yet know about that we are not yet testing for. It’s the regular risk we see with any unit of plasma.”

She added that COVID-19 survivors appear to start increasing their titer of the antibody around day 28. “We’ll be looking for recovered individuals who have had a documented infection, and whose symptoms started about 28 days before we collect,” she said.

The FDA advises clinicians to address several considerations for donor eligibility, including prior diagnosis of COVID-19 documented by a laboratory test; complete resolution of symptoms at least 14 days prior to donation; female donors negative for HLA antibodies or male donors, and negative results for COVID-19 either from one or more nasopharyngeal swab specimens or by a molecular diagnostic test from blood. [A partial list of available tests can be accessed on the FDA website.] The agency also advises that donors have defined SARS-CoV-2–neutralizing antibody titers, if testing can be conducted (optimally greater than 1:320).

Patients eligible to receive COVID-19 convalescent plasma must have a severe or immediately life-threatening infection with laboratory-confirmed COVID-19. The agency defines severe disease as dyspnea, respiratory frequency of 30 per minute or greater, blood oxygen saturation of 93% or less, partial pressure of arterial oxygen to fraction of inspired oxygen ratio of less than 300, and/or lung infiltrates of greater than 50% within 24-48 hours. Life-threatening disease is defined as respiratory failure, septic shock, and/or multiple organ dysfunction or failure. Patients must provide informed consent.

The potential risks of receiving COVID-19 convalescent plasma remain unknown, according to Dr. Gernsheimer. “What some people have thought about is, could there be such an inflammatory response with the virus that we would initially see these patients get worse?” she said. “My understanding is that has not occurred in China yet, but we don’t have all those data. But we always worry if we have something that’s going to cause inflammation around an infection, for example, that could initially make it more difficult to breathe if it’s a lung infection. So far, my understanding is that has not been seen.”

For COVID-19 convalescent plasma authorization requests that require a response within 4-8 hours, requesting clinicians may complete form 3296 and submit it by email to [email protected].

For COVID-19 convalescent plasma authorization requests that require a response in less than 4 hours, or if the clinician is unable to complete and submit form 3926 because of extenuating circumstances, verbal authorization can be sought by calling the FDA’s Office of Emergency Operations at 1-866-300-4374.

The FDA is working with the National Institutes of Health, the Centers for Disease Control and Prevention, and other government partners to develop protocols for use by multiple investigators in order to coordinate the collection and use of COVID-19 convalescent plasma.

“It’s crucial that data be captured for every patient so that we really understand what safety and effectiveness looks like on as close to a real-world level as we can, as quickly as we can,” said Mr. Pitts, who is president and cofounder of the Center for Medicine in the Public Interest, and who also does consulting work for the FDA. “I understand that health care professionals are overworked and overburdened right now. I applaud them for their heroic work. But that doesn’t mean that we can shirk off collecting the data. When I was at the FDA, I helped address the SARS epidemic. The agency attitude at that point was, ‘Let’s get things that just might work through the process, as long as the cure isn’t going to be worse than the disease.’ I think that’s the attitude that’s leading the charge today.”

[email protected]

As the proportion of patients infected with COVID-19 continues to rise in the United States, the Food and Drug Administration is facilitating access to COVID-19 convalescent plasma for use in patients with serious or immediately life-threatening COVID-19 infections.

While clinical trials are underway to evaluate the safety and efficacy of administering convalescent plasma to patients with COVID-19, the FDA is granting clinicians permission for use of investigational convalescent plasma under single-patient emergency Investigational New Drug Applications (INDs), since no known cure exists and a vaccine is more than 1 year away from becoming available.

This allows the use of an investigational drug for the treatment of an individual patient by a licensed physician upon FDA authorization. This does not include the use of COVID-19 convalescent plasma for the prevention of infection, according to a statement issued by the agency on March 24.

“It is possible that convalescent plasma that contains antibodies to SARS-CoV-2 (the virus that causes COVID-19) might be effective against the infection,” the FDA statement reads. “Use of convalescent plasma has been studied in outbreaks of other respiratory infections, including the 2009-2010 H1N1 influenza virus pandemic, 2003 SARS-CoV-1 epidemic, and the 2012 MERS-CoV epidemic. Although promising, convalescent plasma has not been shown to be effective in every disease studied.”

“I think the FDA got caught initially a little flat-footed when it came to the development of COVID-19 tests, but they’re quickly catching up,” Peter J. Pitts, who was the FDA’s associate commissioner from 2002 to 2004, said in an interview. “I think that the attitude now is, ‘If it’s safe, let’s create a pathway to see how these things work in the real world.’ I think that’s going to be as true for treatments to lessen the symptoms and shorten the duration of the disease, as well as convalescent plasma as a potential alternative to a yet-to-be-developed vaccine.”

At the University of Washington School of Medicine, Seattle, Terry B. Gernsheimer, MD, and her colleagues are recruiting recovered COVID-19 patients to donate plasma for seriously ill patients affected with the virus. “The thought of using convalescent plasma makes total sense, because it’s immediately available, and it’s something that we can try to give people,” said Dr. Gernsheimer, a hematologist who is professor of medicine at the medical school. “It’s been used in China, and reports should be coming out shortly about their experience with this.”

In a case series that appeared in JAMA on March 27 (doi: 10.1001/jama.2020.4783), Chinese researchers led by Chenguang Shen, PhD, reported findings from five critically ill COVID-19 patients with acute respiratory distress syndrome who received a transfusion with convalescent plasma at Shenzhen Third People’s Hospital 10 and 22 days after hospital admission. The patients ranged in age from 36 to 73 years, three were men, and all were receiving mechanical ventilation at the time of treatment.

Dr. Shen and colleagues reported that viral loads decreased and became negative within 12 days following the transfusion. Three of the patients were discharged from the hospital after a length of stay that ranged from 51 to 55 days, and two remain in stable condition at 37 days after the transfusion. The researchers pointed out that all patients received antiviral agents, including interferon and lopinavir/ritonavir, during and following convalescent plasma treatment, “which also may have contributed to the viral clearance observed.”

Under the FDA policy on emergency IND use, COVID-19 convalescent plasma must only be collected from recovered individuals if they are eligible to donate blood, required testing must be performed, and the donation must be found suitable.

Potential donors “are going to be screened the way all blood donors are screened,” Dr. Gernsheimer said. “It’s not going to be any less safe than any unit of plasma that’s on the shelf that comes from our volunteer donors. There are always transfusion reactions that we have to worry about, [and] there are potentially unknown pathogens that we don’t yet know about that we are not yet testing for. It’s the regular risk we see with any unit of plasma.”

She added that COVID-19 survivors appear to start increasing their titer of the antibody around day 28. “We’ll be looking for recovered individuals who have had a documented infection, and whose symptoms started about 28 days before we collect,” she said.

The FDA advises clinicians to address several considerations for donor eligibility, including prior diagnosis of COVID-19 documented by a laboratory test; complete resolution of symptoms at least 14 days prior to donation; female donors negative for HLA antibodies or male donors, and negative results for COVID-19 either from one or more nasopharyngeal swab specimens or by a molecular diagnostic test from blood. [A partial list of available tests can be accessed on the FDA website.] The agency also advises that donors have defined SARS-CoV-2–neutralizing antibody titers, if testing can be conducted (optimally greater than 1:320).

Patients eligible to receive COVID-19 convalescent plasma must have a severe or immediately life-threatening infection with laboratory-confirmed COVID-19. The agency defines severe disease as dyspnea, respiratory frequency of 30 per minute or greater, blood oxygen saturation of 93% or less, partial pressure of arterial oxygen to fraction of inspired oxygen ratio of less than 300, and/or lung infiltrates of greater than 50% within 24-48 hours. Life-threatening disease is defined as respiratory failure, septic shock, and/or multiple organ dysfunction or failure. Patients must provide informed consent.

The potential risks of receiving COVID-19 convalescent plasma remain unknown, according to Dr. Gernsheimer. “What some people have thought about is, could there be such an inflammatory response with the virus that we would initially see these patients get worse?” she said. “My understanding is that has not occurred in China yet, but we don’t have all those data. But we always worry if we have something that’s going to cause inflammation around an infection, for example, that could initially make it more difficult to breathe if it’s a lung infection. So far, my understanding is that has not been seen.”

For COVID-19 convalescent plasma authorization requests that require a response within 4-8 hours, requesting clinicians may complete form 3296 and submit it by email to [email protected].

For COVID-19 convalescent plasma authorization requests that require a response in less than 4 hours, or if the clinician is unable to complete and submit form 3926 because of extenuating circumstances, verbal authorization can be sought by calling the FDA’s Office of Emergency Operations at 1-866-300-4374.

The FDA is working with the National Institutes of Health, the Centers for Disease Control and Prevention, and other government partners to develop protocols for use by multiple investigators in order to coordinate the collection and use of COVID-19 convalescent plasma.

“It’s crucial that data be captured for every patient so that we really understand what safety and effectiveness looks like on as close to a real-world level as we can, as quickly as we can,” said Mr. Pitts, who is president and cofounder of the Center for Medicine in the Public Interest, and who also does consulting work for the FDA. “I understand that health care professionals are overworked and overburdened right now. I applaud them for their heroic work. But that doesn’t mean that we can shirk off collecting the data. When I was at the FDA, I helped address the SARS epidemic. The agency attitude at that point was, ‘Let’s get things that just might work through the process, as long as the cure isn’t going to be worse than the disease.’ I think that’s the attitude that’s leading the charge today.”

[email protected]

As the proportion of patients infected with COVID-19 continues to rise in the United States, the Food and Drug Administration is facilitating access to COVID-19 convalescent plasma for use in patients with serious or immediately life-threatening COVID-19 infections.

While clinical trials are underway to evaluate the safety and efficacy of administering convalescent plasma to patients with COVID-19, the FDA is granting clinicians permission for use of investigational convalescent plasma under single-patient emergency Investigational New Drug Applications (INDs), since no known cure exists and a vaccine is more than 1 year away from becoming available.

This allows the use of an investigational drug for the treatment of an individual patient by a licensed physician upon FDA authorization. This does not include the use of COVID-19 convalescent plasma for the prevention of infection, according to a statement issued by the agency on March 24.

“It is possible that convalescent plasma that contains antibodies to SARS-CoV-2 (the virus that causes COVID-19) might be effective against the infection,” the FDA statement reads. “Use of convalescent plasma has been studied in outbreaks of other respiratory infections, including the 2009-2010 H1N1 influenza virus pandemic, 2003 SARS-CoV-1 epidemic, and the 2012 MERS-CoV epidemic. Although promising, convalescent plasma has not been shown to be effective in every disease studied.”

“I think the FDA got caught initially a little flat-footed when it came to the development of COVID-19 tests, but they’re quickly catching up,” Peter J. Pitts, who was the FDA’s associate commissioner from 2002 to 2004, said in an interview. “I think that the attitude now is, ‘If it’s safe, let’s create a pathway to see how these things work in the real world.’ I think that’s going to be as true for treatments to lessen the symptoms and shorten the duration of the disease, as well as convalescent plasma as a potential alternative to a yet-to-be-developed vaccine.”

At the University of Washington School of Medicine, Seattle, Terry B. Gernsheimer, MD, and her colleagues are recruiting recovered COVID-19 patients to donate plasma for seriously ill patients affected with the virus. “The thought of using convalescent plasma makes total sense, because it’s immediately available, and it’s something that we can try to give people,” said Dr. Gernsheimer, a hematologist who is professor of medicine at the medical school. “It’s been used in China, and reports should be coming out shortly about their experience with this.”

In a case series that appeared in JAMA on March 27 (doi: 10.1001/jama.2020.4783), Chinese researchers led by Chenguang Shen, PhD, reported findings from five critically ill COVID-19 patients with acute respiratory distress syndrome who received a transfusion with convalescent plasma at Shenzhen Third People’s Hospital 10 and 22 days after hospital admission. The patients ranged in age from 36 to 73 years, three were men, and all were receiving mechanical ventilation at the time of treatment.

Dr. Shen and colleagues reported that viral loads decreased and became negative within 12 days following the transfusion. Three of the patients were discharged from the hospital after a length of stay that ranged from 51 to 55 days, and two remain in stable condition at 37 days after the transfusion. The researchers pointed out that all patients received antiviral agents, including interferon and lopinavir/ritonavir, during and following convalescent plasma treatment, “which also may have contributed to the viral clearance observed.”

Under the FDA policy on emergency IND use, COVID-19 convalescent plasma must only be collected from recovered individuals if they are eligible to donate blood, required testing must be performed, and the donation must be found suitable.

Potential donors “are going to be screened the way all blood donors are screened,” Dr. Gernsheimer said. “It’s not going to be any less safe than any unit of plasma that’s on the shelf that comes from our volunteer donors. There are always transfusion reactions that we have to worry about, [and] there are potentially unknown pathogens that we don’t yet know about that we are not yet testing for. It’s the regular risk we see with any unit of plasma.”

She added that COVID-19 survivors appear to start increasing their titer of the antibody around day 28. “We’ll be looking for recovered individuals who have had a documented infection, and whose symptoms started about 28 days before we collect,” she said.

The FDA advises clinicians to address several considerations for donor eligibility, including prior diagnosis of COVID-19 documented by a laboratory test; complete resolution of symptoms at least 14 days prior to donation; female donors negative for HLA antibodies or male donors, and negative results for COVID-19 either from one or more nasopharyngeal swab specimens or by a molecular diagnostic test from blood. [A partial list of available tests can be accessed on the FDA website.] The agency also advises that donors have defined SARS-CoV-2–neutralizing antibody titers, if testing can be conducted (optimally greater than 1:320).

Patients eligible to receive COVID-19 convalescent plasma must have a severe or immediately life-threatening infection with laboratory-confirmed COVID-19. The agency defines severe disease as dyspnea, respiratory frequency of 30 per minute or greater, blood oxygen saturation of 93% or less, partial pressure of arterial oxygen to fraction of inspired oxygen ratio of less than 300, and/or lung infiltrates of greater than 50% within 24-48 hours. Life-threatening disease is defined as respiratory failure, septic shock, and/or multiple organ dysfunction or failure. Patients must provide informed consent.

The potential risks of receiving COVID-19 convalescent plasma remain unknown, according to Dr. Gernsheimer. “What some people have thought about is, could there be such an inflammatory response with the virus that we would initially see these patients get worse?” she said. “My understanding is that has not occurred in China yet, but we don’t have all those data. But we always worry if we have something that’s going to cause inflammation around an infection, for example, that could initially make it more difficult to breathe if it’s a lung infection. So far, my understanding is that has not been seen.”

For COVID-19 convalescent plasma authorization requests that require a response within 4-8 hours, requesting clinicians may complete form 3296 and submit it by email to [email protected].

For COVID-19 convalescent plasma authorization requests that require a response in less than 4 hours, or if the clinician is unable to complete and submit form 3926 because of extenuating circumstances, verbal authorization can be sought by calling the FDA’s Office of Emergency Operations at 1-866-300-4374.

The FDA is working with the National Institutes of Health, the Centers for Disease Control and Prevention, and other government partners to develop protocols for use by multiple investigators in order to coordinate the collection and use of COVID-19 convalescent plasma.

“It’s crucial that data be captured for every patient so that we really understand what safety and effectiveness looks like on as close to a real-world level as we can, as quickly as we can,” said Mr. Pitts, who is president and cofounder of the Center for Medicine in the Public Interest, and who also does consulting work for the FDA. “I understand that health care professionals are overworked and overburdened right now. I applaud them for their heroic work. But that doesn’t mean that we can shirk off collecting the data. When I was at the FDA, I helped address the SARS epidemic. The agency attitude at that point was, ‘Let’s get things that just might work through the process, as long as the cure isn’t going to be worse than the disease.’ I think that’s the attitude that’s leading the charge today.”

[email protected]

Reports of three neonates with elevated IgM antibody concentrations whose mothers had COVID-19 in two articles raise questions about whether the infants may have been infected with the virus in utero.

Courtesy CDC

The data, while provocative, “are not conclusive and do not prove in utero transmission” of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), editorialists cautioned.

“The suggestion of in utero transmission rests on IgM detection in these 3 neonates, and IgM is a challenging way to diagnose many congenital infections,” David W. Kimberlin, MD, and Sergio Stagno, MD, of the division of pediatric infectious diseases at University of Alabama at Birmingham, wrote in their editorial. “IgM antibodies are too large to cross the placenta and so detection in a newborn reasonably could be assumed to reflect fetal production following in utero infection. However, most congenital infections are not diagnosed based on IgM detection because IgM assays can be prone to false-positive and false-negative results, along with cross-reactivity and testing challenges.”

None of the three infants had a positive reverse transcriptase–polymerase chain reaction (RT-PCR) test result, “so there is not virologic evidence for congenital infection in these cases to support the serologic suggestion of in utero transmission,” the editorialists noted.
 

Examining the possibility of vertical transmission

A prior case series of nine pregnant women found no transmission of the virus from mother to child, but the question of in utero transmission is not settled, said Lan Dong, MD, of the department of obstetrics and gynecology at Renmin Hospital of Wuhan University in China and colleagues. In their research letter, the investigators described a newborn with elevated IgM antibodies to novel coronavirus 2019 born to a mother with COVID-19. The infant was delivered by cesarean section February 22, 2020, at Renmin Hospital in a negative-pressure isolation room.

“The mother wore an N95 mask and did not hold the infant,” the researchers said. “The neonate had no symptoms and was immediately quarantined in the neonatal intensive care unit. At 2 hours of age, the SARS-CoV-2 IgG level was 140.32 AU/mL and the IgM level was 45.83 AU/mL.” Although the infant may have been infected at delivery, IgM antibodies usually take days to appear, Dr. Dong and colleagues wrote. “The infant’s repeatedly negative RT-PCR test results on nasopharyngeal swabs are difficult to explain, although these tests are not always positive with infection. ... Additional examination of maternal and newborn samples should be done to confirm this preliminary observation.”
 

A review of infants’ serologic characteristics

Hui Zeng, MD, of the department of laboratory medicine at Zhongnan Hospital of Wuhan University in China and colleagues retrospectively reviewed clinical records and laboratory results for six pregnant women with COVID-19, according to a study in JAMA. The women had mild clinical manifestations and were admitted to Zhongnan Hospital between February 16 and March 6. “All had cesarean deliveries in their third trimester in negative pressure isolation rooms,” the investigators said. “All mothers wore masks, and all medical staff wore protective suits and double masks. The infants were isolated from their mothers immediately after delivery.”

Two of the infants had elevated IgG and IgM concentrations. IgM “is not usually transferred from mother to fetus because of its larger macromolecular structure. ... Whether the placentas of women in this study were damaged and abnormal is unknown,” Dr. Zeng and colleagues said. “Alternatively, IgM could have been produced by the infant if the virus crossed the placenta.”

“Although these 2 studies deserve careful evaluation, more definitive evidence is needed” before physicians can “counsel pregnant women that their fetuses are at risk from congenital infection with SARS-CoV-2,” Dr. Kimberlin and Dr. Stagno concluded.

Dr. Dong and associates had no conflicts of interest. Their work was supported by the National Key Research and Development Project and others. Dr. Zeng and colleagues had no relevant financial disclosures. Their study was supported by grants from the National Natural Science Foundation of China and Zhongnan Hospital. Dr. Kimberlin and Dr. Stagno had no conflicts of interest.

[email protected]

SOURCE: Dong L et al. JAMA. 2020 Mar 26. doi: 10.1001/jama.2020.4621; Zeng H et al. JAMA. 2020 Mar 26. doi: 10.1001/jama.2020.4861.

Reports of three neonates with elevated IgM antibody concentrations whose mothers had COVID-19 in two articles raise questions about whether the infants may have been infected with the virus in utero.

Courtesy CDC

The data, while provocative, “are not conclusive and do not prove in utero transmission” of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), editorialists cautioned.

“The suggestion of in utero transmission rests on IgM detection in these 3 neonates, and IgM is a challenging way to diagnose many congenital infections,” David W. Kimberlin, MD, and Sergio Stagno, MD, of the division of pediatric infectious diseases at University of Alabama at Birmingham, wrote in their editorial. “IgM antibodies are too large to cross the placenta and so detection in a newborn reasonably could be assumed to reflect fetal production following in utero infection. However, most congenital infections are not diagnosed based on IgM detection because IgM assays can be prone to false-positive and false-negative results, along with cross-reactivity and testing challenges.”

None of the three infants had a positive reverse transcriptase–polymerase chain reaction (RT-PCR) test result, “so there is not virologic evidence for congenital infection in these cases to support the serologic suggestion of in utero transmission,” the editorialists noted.
 

Examining the possibility of vertical transmission

A prior case series of nine pregnant women found no transmission of the virus from mother to child, but the question of in utero transmission is not settled, said Lan Dong, MD, of the department of obstetrics and gynecology at Renmin Hospital of Wuhan University in China and colleagues. In their research letter, the investigators described a newborn with elevated IgM antibodies to novel coronavirus 2019 born to a mother with COVID-19. The infant was delivered by cesarean section February 22, 2020, at Renmin Hospital in a negative-pressure isolation room.

“The mother wore an N95 mask and did not hold the infant,” the researchers said. “The neonate had no symptoms and was immediately quarantined in the neonatal intensive care unit. At 2 hours of age, the SARS-CoV-2 IgG level was 140.32 AU/mL and the IgM level was 45.83 AU/mL.” Although the infant may have been infected at delivery, IgM antibodies usually take days to appear, Dr. Dong and colleagues wrote. “The infant’s repeatedly negative RT-PCR test results on nasopharyngeal swabs are difficult to explain, although these tests are not always positive with infection. ... Additional examination of maternal and newborn samples should be done to confirm this preliminary observation.”
 

A review of infants’ serologic characteristics

Hui Zeng, MD, of the department of laboratory medicine at Zhongnan Hospital of Wuhan University in China and colleagues retrospectively reviewed clinical records and laboratory results for six pregnant women with COVID-19, according to a study in JAMA. The women had mild clinical manifestations and were admitted to Zhongnan Hospital between February 16 and March 6. “All had cesarean deliveries in their third trimester in negative pressure isolation rooms,” the investigators said. “All mothers wore masks, and all medical staff wore protective suits and double masks. The infants were isolated from their mothers immediately after delivery.”

Two of the infants had elevated IgG and IgM concentrations. IgM “is not usually transferred from mother to fetus because of its larger macromolecular structure. ... Whether the placentas of women in this study were damaged and abnormal is unknown,” Dr. Zeng and colleagues said. “Alternatively, IgM could have been produced by the infant if the virus crossed the placenta.”

“Although these 2 studies deserve careful evaluation, more definitive evidence is needed” before physicians can “counsel pregnant women that their fetuses are at risk from congenital infection with SARS-CoV-2,” Dr. Kimberlin and Dr. Stagno concluded.

Dr. Dong and associates had no conflicts of interest. Their work was supported by the National Key Research and Development Project and others. Dr. Zeng and colleagues had no relevant financial disclosures. Their study was supported by grants from the National Natural Science Foundation of China and Zhongnan Hospital. Dr. Kimberlin and Dr. Stagno had no conflicts of interest.

[email protected]

SOURCE: Dong L et al. JAMA. 2020 Mar 26. doi: 10.1001/jama.2020.4621; Zeng H et al. JAMA. 2020 Mar 26. doi: 10.1001/jama.2020.4861.

Reports of three neonates with elevated IgM antibody concentrations whose mothers had COVID-19 in two articles raise questions about whether the infants may have been infected with the virus in utero.

Courtesy CDC

The data, while provocative, “are not conclusive and do not prove in utero transmission” of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), editorialists cautioned.

“The suggestion of in utero transmission rests on IgM detection in these 3 neonates, and IgM is a challenging way to diagnose many congenital infections,” David W. Kimberlin, MD, and Sergio Stagno, MD, of the division of pediatric infectious diseases at University of Alabama at Birmingham, wrote in their editorial. “IgM antibodies are too large to cross the placenta and so detection in a newborn reasonably could be assumed to reflect fetal production following in utero infection. However, most congenital infections are not diagnosed based on IgM detection because IgM assays can be prone to false-positive and false-negative results, along with cross-reactivity and testing challenges.”

None of the three infants had a positive reverse transcriptase–polymerase chain reaction (RT-PCR) test result, “so there is not virologic evidence for congenital infection in these cases to support the serologic suggestion of in utero transmission,” the editorialists noted.
 

Examining the possibility of vertical transmission

A prior case series of nine pregnant women found no transmission of the virus from mother to child, but the question of in utero transmission is not settled, said Lan Dong, MD, of the department of obstetrics and gynecology at Renmin Hospital of Wuhan University in China and colleagues. In their research letter, the investigators described a newborn with elevated IgM antibodies to novel coronavirus 2019 born to a mother with COVID-19. The infant was delivered by cesarean section February 22, 2020, at Renmin Hospital in a negative-pressure isolation room.

“The mother wore an N95 mask and did not hold the infant,” the researchers said. “The neonate had no symptoms and was immediately quarantined in the neonatal intensive care unit. At 2 hours of age, the SARS-CoV-2 IgG level was 140.32 AU/mL and the IgM level was 45.83 AU/mL.” Although the infant may have been infected at delivery, IgM antibodies usually take days to appear, Dr. Dong and colleagues wrote. “The infant’s repeatedly negative RT-PCR test results on nasopharyngeal swabs are difficult to explain, although these tests are not always positive with infection. ... Additional examination of maternal and newborn samples should be done to confirm this preliminary observation.”
 

A review of infants’ serologic characteristics

Hui Zeng, MD, of the department of laboratory medicine at Zhongnan Hospital of Wuhan University in China and colleagues retrospectively reviewed clinical records and laboratory results for six pregnant women with COVID-19, according to a study in JAMA. The women had mild clinical manifestations and were admitted to Zhongnan Hospital between February 16 and March 6. “All had cesarean deliveries in their third trimester in negative pressure isolation rooms,” the investigators said. “All mothers wore masks, and all medical staff wore protective suits and double masks. The infants were isolated from their mothers immediately after delivery.”

Two of the infants had elevated IgG and IgM concentrations. IgM “is not usually transferred from mother to fetus because of its larger macromolecular structure. ... Whether the placentas of women in this study were damaged and abnormal is unknown,” Dr. Zeng and colleagues said. “Alternatively, IgM could have been produced by the infant if the virus crossed the placenta.”

“Although these 2 studies deserve careful evaluation, more definitive evidence is needed” before physicians can “counsel pregnant women that their fetuses are at risk from congenital infection with SARS-CoV-2,” Dr. Kimberlin and Dr. Stagno concluded.

Dr. Dong and associates had no conflicts of interest. Their work was supported by the National Key Research and Development Project and others. Dr. Zeng and colleagues had no relevant financial disclosures. Their study was supported by grants from the National Natural Science Foundation of China and Zhongnan Hospital. Dr. Kimberlin and Dr. Stagno had no conflicts of interest.

[email protected]

SOURCE: Dong L et al. JAMA. 2020 Mar 26. doi: 10.1001/jama.2020.4621; Zeng H et al. JAMA. 2020 Mar 26. doi: 10.1001/jama.2020.4861.

As most 2020 medical conferences have, one by one, been canceled or rescheduled as virtual meetings in the time of a pandemic, some physicians and other healthcare professionals are wondering if this is the year that will change the scene forever.

Amid the choruses of resignation (“Unfortunately, it’s the right thing to do.”) and optimism (“See you next year!”), there have been plenty of voices describing another broad sentiment – that all was not well with medical meetings even before the coronavirus.

One dominant criticism is that there are too many meetings.

Indeed, there are many, many meetings. During 2005–2015, there were 30,000-plus medical meetings in the United States, according to a report from the Healthcare Convention and Exhibitors Association.

Most of those are of little value, tweeted Dhruv Khullar, MD, an internist at Weill Cornell Medicine, New York City (@DhruvKhullar): “One possible consequence of cancelling so many meetings due to #COVID19 is that we realize we probably don’t need most of them.”

The tweet was liked 1.9K times, which is high for a medical post. Comments were mostly in agreement, with some skepticism.

Michaela West, MD, PhD, a surgeon at North Memorial Health, Minneapolis, Minnesota, responded (@MichaelaWst): “Agree. COVID-19 may forever change our perspective regarding medical professional meetings.”

Nwando Olayiwola, MD, chair of family medicine, Ohio State University, Columbus, strongly agreed (@DrNwando): “This is the tweet I wish I tweeted.”

However, Kelly Swords, MD, MPH, urologist, University of California, San Diego, in a dissenting opinion, stated the obvious (@k_dagger): “Except there is no substitute for human interaction.”
 

Worth the Effort?

The cancellation of medical meetings has given those who regularly attend an opportunity to reassess their value and to question the worth of the effort involved in attending in person.

David Steensma, MD, hematologist-oncologist, Harvard Medical School, Boston, (@DavidSteensma) tweeted that he would like to scale back: “The present crisis is an opportunity to reassess what is actually necessary and rebalance [in terms of meetings].”

Travel to meetings is often unpleasant, said others.

Chris Palatucci, life sciences executive recruiter, Coulter Partners, Boston, tweeted (@LifeSciRcruitr): “I will die a happy man if I never get on another plane. Glorified bus travel.” He also believes that once the coronavirus crisis is over, its “silver lining” will be the realization that “40% of all meetings are unnecessary.”

Many professionals have welcomed the announcements that major conferences have been canceled and will be conducted virtually.

The latest change is from the American Society of Clinical Oncology (ASCO), whose annual meeting was to be held in Chicago at the end of May but will now be held online.

Virtual ASCO will be more manageable – and comfy, said Fumiko Ladd Chino, MD, radiation oncologist, Memorial Sloan Kettering Cancer Center, New York City.

She (@fumikochino) explained why in a recent tweet: “1) I will be finally able to see ALL OF THE PRESENTATIONS I wanted to see instead of wandering around feeling overwhelmed. 2) I will be able to FOCUS on the presentations and not searching for a power outlet. 3) PAJAMAS.”

Virtual meetings already beat real meetings, added Adriana Scheliga, MD, hematologist-oncologist, Brazilian National Cancer Institute (@linfopedia): “I’ve been saying this for a while. For me the best ASCO Meetings, for example, are the “virtual meetings!”

However, meetings in place are also very much about professional community and mutual support, reminds Susan E. Sedory, MA, executive director, Society of Interventional Radiology, which canceled its meeting March 6 in a multifaceted process described by Medscape Medical News.
 

Is This the Time to Evaluate Meetings?

Coming up soon is the first major conference to go virtual after being canceled – the American College of Cardiology (ACC), which has been one of the top 20 largest meetings in the United States by attendance.

This meeting, which was to have taken place in Chicago on March 28–30, will now occur online on those days. The ACC says it will stream all “live” sessions on demand and provide access to additional videos, abstracts, and slides for at least 90 days after the meeting. And it will be free to anyone with an Internet connection.

Medical meetings in distant locales may bounce back, as they have grown into a very big business. ASCO is illustrative.

The group’s first scientific annual meeting was held in 1965 in Philadelphia, with about 70 members and invited guests in attendance. Fast forward 50-plus years to 2019: there were 42,500 attendees, a 4.4% increase from 2018. Notably, the top countries in attendance in 2019 were the United States and China.

Not everyone is happy that canceled meetings are being held online in the middle of a pandemic.

“In a COVID-19 world, the brain cannot focus on nonviral topics,” said commentator John Mandrola, MD, Baptist Health, Louisville, Kentucky, in his regular column for Medscape Cardiology/theheart.org.

The virtual ACC meeting should be canceled or delayed – to mirror what is happening in the world, he argues. “In hospitals, we have postponed the elective to make room for the coming surge. Shouldn’t ACC do the same? After the crisis passes, we can have a virtual meeting with a proper discussion of the science,” he writes.

But #MedTwitter, with its collective constructive criticism of medical meetings, is perhaps proof that the brain can function – and arrive at clarity – when under pandemic duress.

“Am I the only one experiencing a certain relief at the cancellation of multiple trips and meetings, and vowing to let this revelation affect my decision making in the future,” tweeted Steven Joffe, MD, MPH, University of Pennsylvania, Philadelphia (@Steve Joffe).

Louise Perkins King, MD, a bioethicist at Harvard Medical School, responded to Joffe. Hoping not to “belittle” the suffering from the COVID-19 pandemic, she (@louise_p_king) addressed her healthcare colleagues: “...there is potential for us all to learn what is essential travel and burden and what is not from this. I hope it leads to lasting change.”

This article first appeared on Medscape.com.

As most 2020 medical conferences have, one by one, been canceled or rescheduled as virtual meetings in the time of a pandemic, some physicians and other healthcare professionals are wondering if this is the year that will change the scene forever.

Amid the choruses of resignation (“Unfortunately, it’s the right thing to do.”) and optimism (“See you next year!”), there have been plenty of voices describing another broad sentiment – that all was not well with medical meetings even before the coronavirus.

One dominant criticism is that there are too many meetings.

Indeed, there are many, many meetings. During 2005–2015, there were 30,000-plus medical meetings in the United States, according to a report from the Healthcare Convention and Exhibitors Association.

Most of those are of little value, tweeted Dhruv Khullar, MD, an internist at Weill Cornell Medicine, New York City (@DhruvKhullar): “One possible consequence of cancelling so many meetings due to #COVID19 is that we realize we probably don’t need most of them.”

The tweet was liked 1.9K times, which is high for a medical post. Comments were mostly in agreement, with some skepticism.

Michaela West, MD, PhD, a surgeon at North Memorial Health, Minneapolis, Minnesota, responded (@MichaelaWst): “Agree. COVID-19 may forever change our perspective regarding medical professional meetings.”

Nwando Olayiwola, MD, chair of family medicine, Ohio State University, Columbus, strongly agreed (@DrNwando): “This is the tweet I wish I tweeted.”

However, Kelly Swords, MD, MPH, urologist, University of California, San Diego, in a dissenting opinion, stated the obvious (@k_dagger): “Except there is no substitute for human interaction.”
 

Worth the Effort?

The cancellation of medical meetings has given those who regularly attend an opportunity to reassess their value and to question the worth of the effort involved in attending in person.

David Steensma, MD, hematologist-oncologist, Harvard Medical School, Boston, (@DavidSteensma) tweeted that he would like to scale back: “The present crisis is an opportunity to reassess what is actually necessary and rebalance [in terms of meetings].”

Travel to meetings is often unpleasant, said others.

Chris Palatucci, life sciences executive recruiter, Coulter Partners, Boston, tweeted (@LifeSciRcruitr): “I will die a happy man if I never get on another plane. Glorified bus travel.” He also believes that once the coronavirus crisis is over, its “silver lining” will be the realization that “40% of all meetings are unnecessary.”

Many professionals have welcomed the announcements that major conferences have been canceled and will be conducted virtually.

The latest change is from the American Society of Clinical Oncology (ASCO), whose annual meeting was to be held in Chicago at the end of May but will now be held online.

Virtual ASCO will be more manageable – and comfy, said Fumiko Ladd Chino, MD, radiation oncologist, Memorial Sloan Kettering Cancer Center, New York City.

She (@fumikochino) explained why in a recent tweet: “1) I will be finally able to see ALL OF THE PRESENTATIONS I wanted to see instead of wandering around feeling overwhelmed. 2) I will be able to FOCUS on the presentations and not searching for a power outlet. 3) PAJAMAS.”

Virtual meetings already beat real meetings, added Adriana Scheliga, MD, hematologist-oncologist, Brazilian National Cancer Institute (@linfopedia): “I’ve been saying this for a while. For me the best ASCO Meetings, for example, are the “virtual meetings!”

However, meetings in place are also very much about professional community and mutual support, reminds Susan E. Sedory, MA, executive director, Society of Interventional Radiology, which canceled its meeting March 6 in a multifaceted process described by Medscape Medical News.
 

Is This the Time to Evaluate Meetings?

Coming up soon is the first major conference to go virtual after being canceled – the American College of Cardiology (ACC), which has been one of the top 20 largest meetings in the United States by attendance.

This meeting, which was to have taken place in Chicago on March 28–30, will now occur online on those days. The ACC says it will stream all “live” sessions on demand and provide access to additional videos, abstracts, and slides for at least 90 days after the meeting. And it will be free to anyone with an Internet connection.

Medical meetings in distant locales may bounce back, as they have grown into a very big business. ASCO is illustrative.

The group’s first scientific annual meeting was held in 1965 in Philadelphia, with about 70 members and invited guests in attendance. Fast forward 50-plus years to 2019: there were 42,500 attendees, a 4.4% increase from 2018. Notably, the top countries in attendance in 2019 were the United States and China.

Not everyone is happy that canceled meetings are being held online in the middle of a pandemic.

“In a COVID-19 world, the brain cannot focus on nonviral topics,” said commentator John Mandrola, MD, Baptist Health, Louisville, Kentucky, in his regular column for Medscape Cardiology/theheart.org.

The virtual ACC meeting should be canceled or delayed – to mirror what is happening in the world, he argues. “In hospitals, we have postponed the elective to make room for the coming surge. Shouldn’t ACC do the same? After the crisis passes, we can have a virtual meeting with a proper discussion of the science,” he writes.

But #MedTwitter, with its collective constructive criticism of medical meetings, is perhaps proof that the brain can function – and arrive at clarity – when under pandemic duress.

“Am I the only one experiencing a certain relief at the cancellation of multiple trips and meetings, and vowing to let this revelation affect my decision making in the future,” tweeted Steven Joffe, MD, MPH, University of Pennsylvania, Philadelphia (@Steve Joffe).

Louise Perkins King, MD, a bioethicist at Harvard Medical School, responded to Joffe. Hoping not to “belittle” the suffering from the COVID-19 pandemic, she (@louise_p_king) addressed her healthcare colleagues: “...there is potential for us all to learn what is essential travel and burden and what is not from this. I hope it leads to lasting change.”

This article first appeared on Medscape.com.

As most 2020 medical conferences have, one by one, been canceled or rescheduled as virtual meetings in the time of a pandemic, some physicians and other healthcare professionals are wondering if this is the year that will change the scene forever.

Amid the choruses of resignation (“Unfortunately, it’s the right thing to do.”) and optimism (“See you next year!”), there have been plenty of voices describing another broad sentiment – that all was not well with medical meetings even before the coronavirus.

One dominant criticism is that there are too many meetings.

Indeed, there are many, many meetings. During 2005–2015, there were 30,000-plus medical meetings in the United States, according to a report from the Healthcare Convention and Exhibitors Association.

Most of those are of little value, tweeted Dhruv Khullar, MD, an internist at Weill Cornell Medicine, New York City (@DhruvKhullar): “One possible consequence of cancelling so many meetings due to #COVID19 is that we realize we probably don’t need most of them.”

The tweet was liked 1.9K times, which is high for a medical post. Comments were mostly in agreement, with some skepticism.

Michaela West, MD, PhD, a surgeon at North Memorial Health, Minneapolis, Minnesota, responded (@MichaelaWst): “Agree. COVID-19 may forever change our perspective regarding medical professional meetings.”

Nwando Olayiwola, MD, chair of family medicine, Ohio State University, Columbus, strongly agreed (@DrNwando): “This is the tweet I wish I tweeted.”

However, Kelly Swords, MD, MPH, urologist, University of California, San Diego, in a dissenting opinion, stated the obvious (@k_dagger): “Except there is no substitute for human interaction.”
 

Worth the Effort?

The cancellation of medical meetings has given those who regularly attend an opportunity to reassess their value and to question the worth of the effort involved in attending in person.

David Steensma, MD, hematologist-oncologist, Harvard Medical School, Boston, (@DavidSteensma) tweeted that he would like to scale back: “The present crisis is an opportunity to reassess what is actually necessary and rebalance [in terms of meetings].”

Travel to meetings is often unpleasant, said others.

Chris Palatucci, life sciences executive recruiter, Coulter Partners, Boston, tweeted (@LifeSciRcruitr): “I will die a happy man if I never get on another plane. Glorified bus travel.” He also believes that once the coronavirus crisis is over, its “silver lining” will be the realization that “40% of all meetings are unnecessary.”

Many professionals have welcomed the announcements that major conferences have been canceled and will be conducted virtually.

The latest change is from the American Society of Clinical Oncology (ASCO), whose annual meeting was to be held in Chicago at the end of May but will now be held online.

Virtual ASCO will be more manageable – and comfy, said Fumiko Ladd Chino, MD, radiation oncologist, Memorial Sloan Kettering Cancer Center, New York City.

She (@fumikochino) explained why in a recent tweet: “1) I will be finally able to see ALL OF THE PRESENTATIONS I wanted to see instead of wandering around feeling overwhelmed. 2) I will be able to FOCUS on the presentations and not searching for a power outlet. 3) PAJAMAS.”

Virtual meetings already beat real meetings, added Adriana Scheliga, MD, hematologist-oncologist, Brazilian National Cancer Institute (@linfopedia): “I’ve been saying this for a while. For me the best ASCO Meetings, for example, are the “virtual meetings!”

However, meetings in place are also very much about professional community and mutual support, reminds Susan E. Sedory, MA, executive director, Society of Interventional Radiology, which canceled its meeting March 6 in a multifaceted process described by Medscape Medical News.
 

Is This the Time to Evaluate Meetings?

Coming up soon is the first major conference to go virtual after being canceled – the American College of Cardiology (ACC), which has been one of the top 20 largest meetings in the United States by attendance.

This meeting, which was to have taken place in Chicago on March 28–30, will now occur online on those days. The ACC says it will stream all “live” sessions on demand and provide access to additional videos, abstracts, and slides for at least 90 days after the meeting. And it will be free to anyone with an Internet connection.

Medical meetings in distant locales may bounce back, as they have grown into a very big business. ASCO is illustrative.

The group’s first scientific annual meeting was held in 1965 in Philadelphia, with about 70 members and invited guests in attendance. Fast forward 50-plus years to 2019: there were 42,500 attendees, a 4.4% increase from 2018. Notably, the top countries in attendance in 2019 were the United States and China.

Not everyone is happy that canceled meetings are being held online in the middle of a pandemic.

“In a COVID-19 world, the brain cannot focus on nonviral topics,” said commentator John Mandrola, MD, Baptist Health, Louisville, Kentucky, in his regular column for Medscape Cardiology/theheart.org.

The virtual ACC meeting should be canceled or delayed – to mirror what is happening in the world, he argues. “In hospitals, we have postponed the elective to make room for the coming surge. Shouldn’t ACC do the same? After the crisis passes, we can have a virtual meeting with a proper discussion of the science,” he writes.

But #MedTwitter, with its collective constructive criticism of medical meetings, is perhaps proof that the brain can function – and arrive at clarity – when under pandemic duress.

“Am I the only one experiencing a certain relief at the cancellation of multiple trips and meetings, and vowing to let this revelation affect my decision making in the future,” tweeted Steven Joffe, MD, MPH, University of Pennsylvania, Philadelphia (@Steve Joffe).

Louise Perkins King, MD, a bioethicist at Harvard Medical School, responded to Joffe. Hoping not to “belittle” the suffering from the COVID-19 pandemic, she (@louise_p_king) addressed her healthcare colleagues: “...there is potential for us all to learn what is essential travel and burden and what is not from this. I hope it leads to lasting change.”

This article first appeared on Medscape.com.

In Part I of our discussion we introduced the concept of person-generated health data (PGHD), defined as wellness and/or health-related data created, recorded, or gathered by individuals. The ubiquity and remarkable technological progress of personal computing devices, including wearables, smartphones, and tablets, along with the multitude of sensor modalities embedded within these devices, enables a continuous connection with individuals wanting to share information about their behavior and daily life.

Such rich, longitudinal information is now being used in combination with traditional clinical information to predict, diagnose, and formulate treatment plans for diseases, as well as understand the safety and effectiveness of medical interventions.
 

Identifying a disease early

One novel example of digital technologies being used for early identification of disease was a promising 2019 study by Eli Lilly (in collaboration with Apple and Evidation Health) called the Lilly Exploratory Digital Assessment Study.

In this study, the feasibility of using PGHD for identifying physiological and behavioral signatures of cognitive impairment was examined for the purpose of seeking new methods to detect mild cognitive impairment (MCI) in a timely and cost-effective manner. The study enrolled 31 study participants with cognitive impairment and 82 without cognitive impairment. It used consumer-grade sensor technologies (the iPhone, Apple Watch, iPad, and Beddit sleep monitor) to continuously and unobtrusively collect data. Among the information the researchers collected were interaction with the phone keyboard, accelerometer data from the Apple Watch, volume of messages sent/received, and sleep cycles.¹

Courtesy of Evidation Health, Inc.

A total of 16 terabytes of data were collected over the course of 12 weeks. Data were organized into a behaviorgram (See Figure 1) that gives a holistic picture of a day in a patient’s life. A machine learning model was used to distinguish between behaviorgrams of symptomatic versus healthy controls, identifying typing speed, circadian rhythm shifts, and reliance on helper apps, among other things, as differentiating cognitively impaired from healthy controls. These behaviorgrams may someday serve as “fingerprints” of different diseases, with specific diseases displaying predictable patterns. In the near future, digital measures like the ones investigated in this study are likely to be used to help clinicians predict and diagnose disease, as well as to better understand disease progression and treatment response.
 

Leading to better health outcomes

The potential of PGHD to detect diseases early and lead to better health outcomes is being investigated in the Heartline study, a collaboration between Johnson & Johnson and Apple, which is supported by Evidation.²

This study aims to enroll 150,000 adults age 65 years and over to analyze the impact of Apple Watch–based early detection of irregular heart rhythms consistent with atrial fibrillation (AFib). The researchers’ hypothesis is that jointly detecting atrial fibrillation early and providing cardiovascular health programs to new AFib patients, will lead to patients being treated by a medical provider for AFib that otherwise would not have been detected. This, in turn, would lead to these AFib patients decreasing their risks of stroke and other serious cardiovascular events, including death, the study authors speculated.

Presenting new challenges

While PGHD has the potential to help people, it also presents new challenges. It is highly sensitive and personal – it can be as identifying as DNA.³

Cortesy of Evidation Health

The vast amount of data that PGHD can collect from interaction with consumer wearable devices poses serious privacy risks if done improperly. To address those risks, companies like Evidation have built in protections. Evidation has an app, Achievement, that has enlisted a connected population of more than 3.5 million members who earn rewards for performing health-related actions, as tracked by wearables devices and apps. Through the Achievement app (See Figure 2.), members are provided opportunities to join research studies. As part of these studies, data collected from sensors and apps is used by permission of the member so that it is clear how their data are contributing to specific research questions or use cases.

This is a collaborative model of data collection built upon trust and permission and is substantially different than the collection of data from electronic health records (EHRs) – which is typically aggregated, deidentified, and commercialized, often without the patients’ knowledge or consent. Stringent protections, explicit permission, and transparency are absolutely imperative until privacy frameworks for data outside of HIPAA regulation catches up and protects patients from discrimination and unintended uses of their data.

Large connected cohorts can help advance our understanding of public health. In one study run on Achievement during the 2017-2018 flu season, a survey was sent to the Achievement population every week asking about symptoms of influenza-like illness and requesting permission to access historical data from their wearable around the influenza-like illness event.⁴ With the data, it was possible to analyze patterns of activity, sleep, and resting heart rate change around flu events.  Resting heart rate, in particular, is shown to increase during fever and at the population level. In fact, through the use of PGHD, it is possible to use the fraction of people with resting heart rate above their usual baseline as a proxy to quantify the number of infected people in a region.⁵ This resting heart rate–informed flu surveillance method, if refined to increased accuracy, can work in near real time. This means it may be able detect influenza outbreaks days earlier than current epidemiological methods.

Health data generated by connected populations are in the early stages of development. It is clear that it will yield novel insights into health and disease. Only time will tell if it will be able to help clinicians and patients better predict, diagnose, and formulate treatment plans for disease.

Neil Skolnik, M.D. is a professor of family and community medicine at Sidney Kimmel Medical College, Thomas Jefferson University, and associate director of the Family Medicine Residency Program at Abington Jefferson Health. Luca Foschini PhD, is co-founder & chief data scientist at Evidation Health. Bray Patrick-Lake, MFS, is a patient thought leader and director of strategic partnerships at Evidation Health.

References

1. Chen R et al. Developing measures of cognitive impairment in the real world from consumer-grade multimodal sensor streams. KDD ’19. August 4–8, 2019 Aug 4-8.

2. The Heartline Study. https://www.heartline.com.

3. Foschini L. Privacy of Wearable and Sensors Data (or, the Lack Thereof?). Data Driven Investor, Medium. 2019.

4. Bradshaw B et al. Influenza surveillance using wearable mobile health devices. Online J Public Health Inform. 2019;11(1):e249.

5. Radin JM et al. Harnessing wearable device data to improve state-level real-time surveillance of influenza-like illness in the USA: a population-based study. Lancet Digital Health. 2020. doi: 10.1016/S2589-7500(19)30222-5.

In Part I of our discussion we introduced the concept of person-generated health data (PGHD), defined as wellness and/or health-related data created, recorded, or gathered by individuals. The ubiquity and remarkable technological progress of personal computing devices, including wearables, smartphones, and tablets, along with the multitude of sensor modalities embedded within these devices, enables a continuous connection with individuals wanting to share information about their behavior and daily life.

Such rich, longitudinal information is now being used in combination with traditional clinical information to predict, diagnose, and formulate treatment plans for diseases, as well as understand the safety and effectiveness of medical interventions.
 

Identifying a disease early

One novel example of digital technologies being used for early identification of disease was a promising 2019 study by Eli Lilly (in collaboration with Apple and Evidation Health) called the Lilly Exploratory Digital Assessment Study.

In this study, the feasibility of using PGHD for identifying physiological and behavioral signatures of cognitive impairment was examined for the purpose of seeking new methods to detect mild cognitive impairment (MCI) in a timely and cost-effective manner. The study enrolled 31 study participants with cognitive impairment and 82 without cognitive impairment. It used consumer-grade sensor technologies (the iPhone, Apple Watch, iPad, and Beddit sleep monitor) to continuously and unobtrusively collect data. Among the information the researchers collected were interaction with the phone keyboard, accelerometer data from the Apple Watch, volume of messages sent/received, and sleep cycles.¹

Courtesy of Evidation Health, Inc.

A total of 16 terabytes of data were collected over the course of 12 weeks. Data were organized into a behaviorgram (See Figure 1) that gives a holistic picture of a day in a patient’s life. A machine learning model was used to distinguish between behaviorgrams of symptomatic versus healthy controls, identifying typing speed, circadian rhythm shifts, and reliance on helper apps, among other things, as differentiating cognitively impaired from healthy controls. These behaviorgrams may someday serve as “fingerprints” of different diseases, with specific diseases displaying predictable patterns. In the near future, digital measures like the ones investigated in this study are likely to be used to help clinicians predict and diagnose disease, as well as to better understand disease progression and treatment response.
 

Leading to better health outcomes

The potential of PGHD to detect diseases early and lead to better health outcomes is being investigated in the Heartline study, a collaboration between Johnson & Johnson and Apple, which is supported by Evidation.²

This study aims to enroll 150,000 adults age 65 years and over to analyze the impact of Apple Watch–based early detection of irregular heart rhythms consistent with atrial fibrillation (AFib). The researchers’ hypothesis is that jointly detecting atrial fibrillation early and providing cardiovascular health programs to new AFib patients, will lead to patients being treated by a medical provider for AFib that otherwise would not have been detected. This, in turn, would lead to these AFib patients decreasing their risks of stroke and other serious cardiovascular events, including death, the study authors speculated.

Presenting new challenges

While PGHD has the potential to help people, it also presents new challenges. It is highly sensitive and personal – it can be as identifying as DNA.³

Cortesy of Evidation Health

The vast amount of data that PGHD can collect from interaction with consumer wearable devices poses serious privacy risks if done improperly. To address those risks, companies like Evidation have built in protections. Evidation has an app, Achievement, that has enlisted a connected population of more than 3.5 million members who earn rewards for performing health-related actions, as tracked by wearables devices and apps. Through the Achievement app (See Figure 2.), members are provided opportunities to join research studies. As part of these studies, data collected from sensors and apps is used by permission of the member so that it is clear how their data are contributing to specific research questions or use cases.

This is a collaborative model of data collection built upon trust and permission and is substantially different than the collection of data from electronic health records (EHRs) – which is typically aggregated, deidentified, and commercialized, often without the patients’ knowledge or consent. Stringent protections, explicit permission, and transparency are absolutely imperative until privacy frameworks for data outside of HIPAA regulation catches up and protects patients from discrimination and unintended uses of their data.

Large connected cohorts can help advance our understanding of public health. In one study run on Achievement during the 2017-2018 flu season, a survey was sent to the Achievement population every week asking about symptoms of influenza-like illness and requesting permission to access historical data from their wearable around the influenza-like illness event.⁴ With the data, it was possible to analyze patterns of activity, sleep, and resting heart rate change around flu events.  Resting heart rate, in particular, is shown to increase during fever and at the population level. In fact, through the use of PGHD, it is possible to use the fraction of people with resting heart rate above their usual baseline as a proxy to quantify the number of infected people in a region.⁵ This resting heart rate–informed flu surveillance method, if refined to increased accuracy, can work in near real time. This means it may be able detect influenza outbreaks days earlier than current epidemiological methods.

Health data generated by connected populations are in the early stages of development. It is clear that it will yield novel insights into health and disease. Only time will tell if it will be able to help clinicians and patients better predict, diagnose, and formulate treatment plans for disease.

Neil Skolnik, M.D. is a professor of family and community medicine at Sidney Kimmel Medical College, Thomas Jefferson University, and associate director of the Family Medicine Residency Program at Abington Jefferson Health. Luca Foschini PhD, is co-founder & chief data scientist at Evidation Health. Bray Patrick-Lake, MFS, is a patient thought leader and director of strategic partnerships at Evidation Health.

References

1. Chen R et al. Developing measures of cognitive impairment in the real world from consumer-grade multimodal sensor streams. KDD ’19. August 4–8, 2019 Aug 4-8.

2. The Heartline Study. https://www.heartline.com.

3. Foschini L. Privacy of Wearable and Sensors Data (or, the Lack Thereof?). Data Driven Investor, Medium. 2019.

4. Bradshaw B et al. Influenza surveillance using wearable mobile health devices. Online J Public Health Inform. 2019;11(1):e249.

5. Radin JM et al. Harnessing wearable device data to improve state-level real-time surveillance of influenza-like illness in the USA: a population-based study. Lancet Digital Health. 2020. doi: 10.1016/S2589-7500(19)30222-5.

In Part I of our discussion we introduced the concept of person-generated health data (PGHD), defined as wellness and/or health-related data created, recorded, or gathered by individuals. The ubiquity and remarkable technological progress of personal computing devices, including wearables, smartphones, and tablets, along with the multitude of sensor modalities embedded within these devices, enables a continuous connection with individuals wanting to share information about their behavior and daily life.

Such rich, longitudinal information is now being used in combination with traditional clinical information to predict, diagnose, and formulate treatment plans for diseases, as well as understand the safety and effectiveness of medical interventions.
 

Identifying a disease early

One novel example of digital technologies being used for early identification of disease was a promising 2019 study by Eli Lilly (in collaboration with Apple and Evidation Health) called the Lilly Exploratory Digital Assessment Study.

In this study, the feasibility of using PGHD for identifying physiological and behavioral signatures of cognitive impairment was examined for the purpose of seeking new methods to detect mild cognitive impairment (MCI) in a timely and cost-effective manner. The study enrolled 31 study participants with cognitive impairment and 82 without cognitive impairment. It used consumer-grade sensor technologies (the iPhone, Apple Watch, iPad, and Beddit sleep monitor) to continuously and unobtrusively collect data. Among the information the researchers collected were interaction with the phone keyboard, accelerometer data from the Apple Watch, volume of messages sent/received, and sleep cycles.¹

Courtesy of Evidation Health, Inc.

A total of 16 terabytes of data were collected over the course of 12 weeks. Data were organized into a behaviorgram (See Figure 1) that gives a holistic picture of a day in a patient’s life. A machine learning model was used to distinguish between behaviorgrams of symptomatic versus healthy controls, identifying typing speed, circadian rhythm shifts, and reliance on helper apps, among other things, as differentiating cognitively impaired from healthy controls. These behaviorgrams may someday serve as “fingerprints” of different diseases, with specific diseases displaying predictable patterns. In the near future, digital measures like the ones investigated in this study are likely to be used to help clinicians predict and diagnose disease, as well as to better understand disease progression and treatment response.
 

Leading to better health outcomes

The potential of PGHD to detect diseases early and lead to better health outcomes is being investigated in the Heartline study, a collaboration between Johnson & Johnson and Apple, which is supported by Evidation.²

This study aims to enroll 150,000 adults age 65 years and over to analyze the impact of Apple Watch–based early detection of irregular heart rhythms consistent with atrial fibrillation (AFib). The researchers’ hypothesis is that jointly detecting atrial fibrillation early and providing cardiovascular health programs to new AFib patients, will lead to patients being treated by a medical provider for AFib that otherwise would not have been detected. This, in turn, would lead to these AFib patients decreasing their risks of stroke and other serious cardiovascular events, including death, the study authors speculated.

Presenting new challenges

While PGHD has the potential to help people, it also presents new challenges. It is highly sensitive and personal – it can be as identifying as DNA.³

Cortesy of Evidation Health

The vast amount of data that PGHD can collect from interaction with consumer wearable devices poses serious privacy risks if done improperly. To address those risks, companies like Evidation have built in protections. Evidation has an app, Achievement, that has enlisted a connected population of more than 3.5 million members who earn rewards for performing health-related actions, as tracked by wearables devices and apps. Through the Achievement app (See Figure 2.), members are provided opportunities to join research studies. As part of these studies, data collected from sensors and apps is used by permission of the member so that it is clear how their data are contributing to specific research questions or use cases.

This is a collaborative model of data collection built upon trust and permission and is substantially different than the collection of data from electronic health records (EHRs) – which is typically aggregated, deidentified, and commercialized, often without the patients’ knowledge or consent. Stringent protections, explicit permission, and transparency are absolutely imperative until privacy frameworks for data outside of HIPAA regulation catches up and protects patients from discrimination and unintended uses of their data.

Large connected cohorts can help advance our understanding of public health. In one study run on Achievement during the 2017-2018 flu season, a survey was sent to the Achievement population every week asking about symptoms of influenza-like illness and requesting permission to access historical data from their wearable around the influenza-like illness event.⁴ With the data, it was possible to analyze patterns of activity, sleep, and resting heart rate change around flu events.  Resting heart rate, in particular, is shown to increase during fever and at the population level. In fact, through the use of PGHD, it is possible to use the fraction of people with resting heart rate above their usual baseline as a proxy to quantify the number of infected people in a region.⁵ This resting heart rate–informed flu surveillance method, if refined to increased accuracy, can work in near real time. This means it may be able detect influenza outbreaks days earlier than current epidemiological methods.

Health data generated by connected populations are in the early stages of development. It is clear that it will yield novel insights into health and disease. Only time will tell if it will be able to help clinicians and patients better predict, diagnose, and formulate treatment plans for disease.

Neil Skolnik, M.D. is a professor of family and community medicine at Sidney Kimmel Medical College, Thomas Jefferson University, and associate director of the Family Medicine Residency Program at Abington Jefferson Health. Luca Foschini PhD, is co-founder & chief data scientist at Evidation Health. Bray Patrick-Lake, MFS, is a patient thought leader and director of strategic partnerships at Evidation Health.

References

1. Chen R et al. Developing measures of cognitive impairment in the real world from consumer-grade multimodal sensor streams. KDD ’19. August 4–8, 2019 Aug 4-8.

2. The Heartline Study. https://www.heartline.com.

3. Foschini L. Privacy of Wearable and Sensors Data (or, the Lack Thereof?). Data Driven Investor, Medium. 2019.

4. Bradshaw B et al. Influenza surveillance using wearable mobile health devices. Online J Public Health Inform. 2019;11(1):e249.

5. Radin JM et al. Harnessing wearable device data to improve state-level real-time surveillance of influenza-like illness in the USA: a population-based study. Lancet Digital Health. 2020. doi: 10.1016/S2589-7500(19)30222-5.

In 2019, the Food and Drug Administration approved 42 drugs, 6 of which will not be discussed here because of space limitations: recarbrio, a three-drug combination, containing imipenem, cilastatin, and relebactam; polatuzumab (Polivy) combined with bendamustine and a rituximab product; pretomanid combined with bedaquiline and linezolid; romosozumab (Evenity) for postmenopausal women; and alpelisib (Piqray) for postmenopausal women. In addition, darolutamide (Nubeqa) will not be included because it is indicated for the treatment of patients with prostate cancer. The remaining 36 agents are listed alphabetically below with the trade names in parentheses.

PhotoDisk

The molecular weights (if available), rounded to the nearest whole number, are shown in parentheses. As with nearly all drugs, avoiding these agents in pregnancy is the best choice.

Air polymer-type a intrauterine foam (ExEm Foam), an ultrasound contrast agent, is indicated for sonohysterosalpingography to assess fallopian tube patency in women with known or suspected infertility. Animal studies have not been conducted, and the agent is contraindicated in pregnancy.

Afamelanotide implant (Scenesse) (1,647) is a melanocortin 1 receptor agonist that is indicated to increase pain-free light exposure in adult patients with a history of phototoxic reactions from erythropoietic protoporphyria. The drug caused no embryofetal toxicity in two species of rats. The molecular weight suggests that it will not cross the placenta, at least early in pregnancy.

Alpelisib (Piqray) (441) is a kinase inhibitor that is combined with fulvestrant for the treatment of advanced breast cancer in women and men. The molecular weight suggests that it can cross the human placenta. It is contraindicated in pregnancy because it can cause embryofetal toxicity.

Bremelanotide (Vyleesi) (1,025) is indicated for the treatment of premenopausal women with hypoactive sexual disorder. The drug caused fetal harm in dogs and mice. If a pregnant woman is exposed to the drug, health care providers are encouraged to call the VYLEESI Pregnancy Exposure Registry at 877-411-2510.

Brolucizumab (Beovu) (26,000) is a human vascular endothelial growth factor that is indicated for the treatment of neovascular age-related macular degeneration. In animals, it caused malformations, embryofetal resorption, and decreased fetal weight. Other adverse effects were follicular development, corpus luteum function, and fertility.

Caplacizumab (Cablivi) (28,000) is indicated for the treatment of adult patients with acquired thrombotic thrombocytopenia purpura, in combination with plasma exchange and immunosuppressive therapy. If used in pregnancy, there is a risk of hemorrhage in the mother and fetus. In guinea pigs given intramuscular doses of the drug, there was no evidence of adverse developmental outcomes.

Cefiderocol (Fetroja) (3,044) is an IV cephalosporin antibiotic indicated for the treatment of urinary tract infections, including pyelonephritis. The manufacturer states that it should be used in patients 18 years of age or older who have limited or no alternative treatment options. Consistent with other cephalosporins, no developmental adverse effects were observed in rats and mice.

Cenobamate (Xcopri) (268) is indicated for the treatment of partial-onset seizures in adults. In pregnant animals given the drug, there was increased embryo-fetal mortality, decreased fetal and offspring body weight, and neurobehavioral and reproductive impairment in offspring. If a pregnant woman receives this drug, encourage her to enroll in the North American Antiepileptic Drug Pregnancy Registry by calling the toll-free number 1-888-233-2334.

Crizanlizumab (Adakveo) (146,000) is indicated to reduce the frequency of vaso-occlusive crises in patients with sickle cell disease. In monkeys given doses slightly higher than those given to humans, there was increased fetal loss (abortions/stillbirths).

Entrectinib (Rozlytrek) (561) is a kinase inhibitor indicated for the treatment of cancer. The drug was teratogenic in rats. It is contraindicated in pregnancy because it can cause embryo-fetal toxicity.

Erdafitinib (Balversa) (447), a kinase inhibitor, is indicated for the treatment of locally advanced or metastatic urothelial carcinoma. In rats given doses during organogenesis with maternal exposures less than human exposures, the drug was teratogenic and caused embryofetal death. The manufacturer states that women of reproductive potential should use effective contraception during treatment and for 1 month after the last dose. The same advice was provided for male patients with female partners of reproductive potential. It is contraindicated in pregnancy because it can cause embryofetal toxicity.

Fedratinib (Inrebic) (616), a kinase inhibitor, is indicated for patients with intermediate-2 or high-risk primary or secondary myelofibrosis. The drug was teratogenic in rats when doses that were about 0.1 times the human exposure based on AUC (area under the curve) at the recommended daily dose during organogenesis. It is contraindicated in pregnancy because it can cause embryofetal toxicity.

Fluorodopa f18 (214) is a radioactive diagnostic agent. It is indicated for use in positron emission tomography to visualize dopaminergic nerve terminals in the striatum for evaluation of adult patients with suspected parkinsonian syndromes. The potential for adverse pregnant outcomes is based on the radiation dose and the gestational timing of exposure.

Givosiran sodium (Givlaari) (17,2460) is an aminolevulinate synthase 1-directed small interfering RNA given subcutaneously. It is indicated for the treatment of adults with acute hepatic porphyria. Doses less than 10 times the human dose in rats and rabbits produced maternal toxicity. In rats there was increased postimplantation loss, and in rats there was skeletal variation (incomplete ossification of pubes).

Golodirsen (Vyondys 53) (8,647) is indicated for the treatment of Duchenne muscular dystrophy given intravenously. There are no human or animal data available to assess the use of this drug during pregnancy.

Istradefylline (Nourianz) (384) is an adenosine receptor antagonist given orally. It is indicated as adjunctive treatment to levodopa/carbidopa in patients with Parkinson’s disease experiencing “off” episodes. In pregnant rats and rabbits, the drug was related to teratogenicity, embryo-fetal and offspring mortality, and growth deficits at clinically relevant exposures.

Lasmiditan (Reyvow) (436), a serotonin receptor agonist, is indicated for acute treatment of migraine with or without aura. In animals, the drug caused increased incidences of fetal defects, increased embryo-fetal and offspring mortality, and decreased fetal body weight at maternal exposures less than (rabbits) or greater than (rat) those observed clinically.

Lefamulin (Xenleta) (568) is an antibacterial agent available for oral and IV administration. They are indicated for the treatment of community-acquired bacterial pneumonia. The drug was teratogenic in rats at systemic exposures lower than those in humans, an increased incidence of post-implantation fetal loss and stillbirths, and decreased fetal body weights and ossification. There was also an apparent delay in sexual maturation in rats.

Luspatercept (Reblozyl) (76,000) is given subcutaneously for the treatment of anemia in patients with beta thalassemia who require regular red blood cell transfusions. In rats and rabbits, the drug cause increased embryo-fetal mortality, alteration to growth, and structural defects at exposures (based on AUC) that were about 13 times (rats) and 18 times (rabbits) the maximum recommended human dose.

Pexidartinib (Turalio) (454) is an oral kinase inhibitor that is indicated for the treatment of symptomatic tenosynovial giant cell tumor associated with severe morbidity or functional limitations and not amenable with surgery. In rats and rabbits, the drug caused malformations, increased post-implantation loss, and abortion at exposures nearly equal to the human exposure. It is contraindicated in pregnancy because it can cause embryo-fetal toxicity.

Pitolisant HCl (Wakix) (296) is an histamine-3 receptor antagonist/inverse agonist indicated for the treatment of excessive daytime sleepiness in patients with narcolepsy. The drug has caused maternal and embryofetal toxicity in rats and rabbits at doses greater than and equal to 13 times and greater than 4 times the maximum human dose, respectively. The manufacturer has a pregnancy exposure registry that patients can contact at 1-800-833-7460.

Prabotulinum toxin A (Jeuveau) (900,000) is an acetylcholine release inhibitor and a neuromuscular blocking agent indicated for the temporary improvement in the appearance of moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity. The drug caused no adverse embryo-fetal in rats with doses up to 12 times the human dose.

Risankizumab-rzaa (Skyrizi) (molecular weight unknown), an interleukin-23 antagonist, is used for the treatment of moderate-to-severe plaque psoriasis. In pregnant monkeys, doses that were 20 times the maximum human dose increased fetal/infant loss.

Selinexor (Xpovio) (443) is an oral nuclear export inhibitor given in combination with dexamethasone for the treatment of relapsed or refractory myeloma. At doses lower than those used clinically, the drug caused structural abnormalities and alterations to growth in fetal rats.

Siponimod (Mayzent) (1,149) is an oral sphingosine 1-phosphate receptor modulator. It is indicated for the treatment of relapsing forms of multiple sclerosis. At low doses, the drug caused embryotoxicity and fetotoxicity in rats and rabbits including embryofetal deaths and abortions. The drug was teratogenic in both species.

Solriamfetol (Sunosi) (231) is an oral dopamine and norepinephrine reuptake inhibitor that is indicated to improve wakefulness in adult patients with excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnea. The drug caused maternal and fetal toxicities in rats and rabbits and was teratogenic. The manufacturer has a pregnancy exposure registry to monitor pregnancy outcomes. Health care providers or patients can enroll in the program by calling 1-877-283-6220 or contacting the company.

Tafamidis meglumine (Vyndaqel) (503) and tafamidis (Vyndamax) (308) are indicated for the treatment of the cardiomyopathy of wild type or hereditary transthyretin-mediated amyloidosis to reduce cardiovascular mortality and cardiovascular-related hospitalization. In rabbits and rats, use of the drugs during pregnancy caused birth defects, embryo-fetal mortality, and fetal body weight reduction. Limited available data with Vyndaqel use in human pregnancy at a dose of 20 mg/day have not identified any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes (see package insert).

Tenapanor (Ibsrela) (1,218) is indicated for the treatment of irritable bowel syndrome with constipation. The drug is minimally absorbed systemically, with plasma concentrations below the limit of quantification. No adverse maternal or fetal outcomes in rats or rabbits were observed. As reported by the manufacturer, in a small number of pregnant women, no drug-induced adverse maternal or fetal outcomes were identified.

Triclabendazole (Egaten) (360), an oral anthelmintic, is indicated for the treatment of fascioliasis. The drug was not teratogenic in mice and rabbits.

Trifarotene (Aklief) (460) cream is a retinoid that is indicated for the topical treatment of acne vulgaris. Animal data was related to oral retinoids and it not applicable to this agent. The manufacturer reported that available data from the use of the cream in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.

Upadacitinib (Rinvoq) (389) is an oral Janus inhibitor. It is indicated for the treatment of moderate to severe active rheumatoid arthritis in patients who have had an inadequate response or intolerance to methotrexate. The drug caused increases in fetal malformations when given to rats and rabbits during organogenesis.

Voxelotor (Oxbryta) (337) is an oral hemoglobin S polymerization inhibitor indicated for the treatment of sickle cell disease. In rats and rabbits, there was no evidence of adverse developmental outcomes.

Zanubrutinib (Brukinsa) (472), an oral kinase inhibitor, is indicated for the treatment of mantle cell lymphoma. The drug caused embryofetal toxicity in pregnant rats, including malformations. It is contraindicated in pregnancy because it can cause embryo-fetal toxicity.

Breastfeeding

Brexanolone (Zulresso) (319) is indicated for the treatment of postpartum depression. It is given as a continuous IV infusion over 60 hours. The drug, at exposures close to those seen in humans, did not cause structural defects in rabbits and rats, but did cause fetal toxicity. Because patients are at risk of excessive sedation or sudden loss of consciousness when receiving the drug, it is only available through a restricted program called the ZULRESSO REMS. Health care providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 844-405-6185. To obtain a list of health care facilities enrolled in the program call 844-472-4379.

Nearly all of the above drugs will cross into a woman’s colostrum during the first 48 hours post partum. These amounts should be very small, but not breastfeeding is the best choice.
 

Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. Mr. Briggs said he had no relevant financial disclosures. Email him at [email protected].

In 2019, the Food and Drug Administration approved 42 drugs, 6 of which will not be discussed here because of space limitations: recarbrio, a three-drug combination, containing imipenem, cilastatin, and relebactam; polatuzumab (Polivy) combined with bendamustine and a rituximab product; pretomanid combined with bedaquiline and linezolid; romosozumab (Evenity) for postmenopausal women; and alpelisib (Piqray) for postmenopausal women. In addition, darolutamide (Nubeqa) will not be included because it is indicated for the treatment of patients with prostate cancer. The remaining 36 agents are listed alphabetically below with the trade names in parentheses.

PhotoDisk

The molecular weights (if available), rounded to the nearest whole number, are shown in parentheses. As with nearly all drugs, avoiding these agents in pregnancy is the best choice.

Air polymer-type a intrauterine foam (ExEm Foam), an ultrasound contrast agent, is indicated for sonohysterosalpingography to assess fallopian tube patency in women with known or suspected infertility. Animal studies have not been conducted, and the agent is contraindicated in pregnancy.

Afamelanotide implant (Scenesse) (1,647) is a melanocortin 1 receptor agonist that is indicated to increase pain-free light exposure in adult patients with a history of phototoxic reactions from erythropoietic protoporphyria. The drug caused no embryofetal toxicity in two species of rats. The molecular weight suggests that it will not cross the placenta, at least early in pregnancy.

Alpelisib (Piqray) (441) is a kinase inhibitor that is combined with fulvestrant for the treatment of advanced breast cancer in women and men. The molecular weight suggests that it can cross the human placenta. It is contraindicated in pregnancy because it can cause embryofetal toxicity.

Bremelanotide (Vyleesi) (1,025) is indicated for the treatment of premenopausal women with hypoactive sexual disorder. The drug caused fetal harm in dogs and mice. If a pregnant woman is exposed to the drug, health care providers are encouraged to call the VYLEESI Pregnancy Exposure Registry at 877-411-2510.

Brolucizumab (Beovu) (26,000) is a human vascular endothelial growth factor that is indicated for the treatment of neovascular age-related macular degeneration. In animals, it caused malformations, embryofetal resorption, and decreased fetal weight. Other adverse effects were follicular development, corpus luteum function, and fertility.

Caplacizumab (Cablivi) (28,000) is indicated for the treatment of adult patients with acquired thrombotic thrombocytopenia purpura, in combination with plasma exchange and immunosuppressive therapy. If used in pregnancy, there is a risk of hemorrhage in the mother and fetus. In guinea pigs given intramuscular doses of the drug, there was no evidence of adverse developmental outcomes.

Cefiderocol (Fetroja) (3,044) is an IV cephalosporin antibiotic indicated for the treatment of urinary tract infections, including pyelonephritis. The manufacturer states that it should be used in patients 18 years of age or older who have limited or no alternative treatment options. Consistent with other cephalosporins, no developmental adverse effects were observed in rats and mice.

Cenobamate (Xcopri) (268) is indicated for the treatment of partial-onset seizures in adults. In pregnant animals given the drug, there was increased embryo-fetal mortality, decreased fetal and offspring body weight, and neurobehavioral and reproductive impairment in offspring. If a pregnant woman receives this drug, encourage her to enroll in the North American Antiepileptic Drug Pregnancy Registry by calling the toll-free number 1-888-233-2334.

Crizanlizumab (Adakveo) (146,000) is indicated to reduce the frequency of vaso-occlusive crises in patients with sickle cell disease. In monkeys given doses slightly higher than those given to humans, there was increased fetal loss (abortions/stillbirths).

Entrectinib (Rozlytrek) (561) is a kinase inhibitor indicated for the treatment of cancer. The drug was teratogenic in rats. It is contraindicated in pregnancy because it can cause embryo-fetal toxicity.

Erdafitinib (Balversa) (447), a kinase inhibitor, is indicated for the treatment of locally advanced or metastatic urothelial carcinoma. In rats given doses during organogenesis with maternal exposures less than human exposures, the drug was teratogenic and caused embryofetal death. The manufacturer states that women of reproductive potential should use effective contraception during treatment and for 1 month after the last dose. The same advice was provided for male patients with female partners of reproductive potential. It is contraindicated in pregnancy because it can cause embryofetal toxicity.

Fedratinib (Inrebic) (616), a kinase inhibitor, is indicated for patients with intermediate-2 or high-risk primary or secondary myelofibrosis. The drug was teratogenic in rats when doses that were about 0.1 times the human exposure based on AUC (area under the curve) at the recommended daily dose during organogenesis. It is contraindicated in pregnancy because it can cause embryofetal toxicity.

Fluorodopa f18 (214) is a radioactive diagnostic agent. It is indicated for use in positron emission tomography to visualize dopaminergic nerve terminals in the striatum for evaluation of adult patients with suspected parkinsonian syndromes. The potential for adverse pregnant outcomes is based on the radiation dose and the gestational timing of exposure.

Givosiran sodium (Givlaari) (17,2460) is an aminolevulinate synthase 1-directed small interfering RNA given subcutaneously. It is indicated for the treatment of adults with acute hepatic porphyria. Doses less than 10 times the human dose in rats and rabbits produced maternal toxicity. In rats there was increased postimplantation loss, and in rats there was skeletal variation (incomplete ossification of pubes).

Golodirsen (Vyondys 53) (8,647) is indicated for the treatment of Duchenne muscular dystrophy given intravenously. There are no human or animal data available to assess the use of this drug during pregnancy.

Istradefylline (Nourianz) (384) is an adenosine receptor antagonist given orally. It is indicated as adjunctive treatment to levodopa/carbidopa in patients with Parkinson’s disease experiencing “off” episodes. In pregnant rats and rabbits, the drug was related to teratogenicity, embryo-fetal and offspring mortality, and growth deficits at clinically relevant exposures.

Lasmiditan (Reyvow) (436), a serotonin receptor agonist, is indicated for acute treatment of migraine with or without aura. In animals, the drug caused increased incidences of fetal defects, increased embryo-fetal and offspring mortality, and decreased fetal body weight at maternal exposures less than (rabbits) or greater than (rat) those observed clinically.

Lefamulin (Xenleta) (568) is an antibacterial agent available for oral and IV administration. They are indicated for the treatment of community-acquired bacterial pneumonia. The drug was teratogenic in rats at systemic exposures lower than those in humans, an increased incidence of post-implantation fetal loss and stillbirths, and decreased fetal body weights and ossification. There was also an apparent delay in sexual maturation in rats.

Luspatercept (Reblozyl) (76,000) is given subcutaneously for the treatment of anemia in patients with beta thalassemia who require regular red blood cell transfusions. In rats and rabbits, the drug cause increased embryo-fetal mortality, alteration to growth, and structural defects at exposures (based on AUC) that were about 13 times (rats) and 18 times (rabbits) the maximum recommended human dose.

Pexidartinib (Turalio) (454) is an oral kinase inhibitor that is indicated for the treatment of symptomatic tenosynovial giant cell tumor associated with severe morbidity or functional limitations and not amenable with surgery. In rats and rabbits, the drug caused malformations, increased post-implantation loss, and abortion at exposures nearly equal to the human exposure. It is contraindicated in pregnancy because it can cause embryo-fetal toxicity.

Pitolisant HCl (Wakix) (296) is an histamine-3 receptor antagonist/inverse agonist indicated for the treatment of excessive daytime sleepiness in patients with narcolepsy. The drug has caused maternal and embryofetal toxicity in rats and rabbits at doses greater than and equal to 13 times and greater than 4 times the maximum human dose, respectively. The manufacturer has a pregnancy exposure registry that patients can contact at 1-800-833-7460.

Prabotulinum toxin A (Jeuveau) (900,000) is an acetylcholine release inhibitor and a neuromuscular blocking agent indicated for the temporary improvement in the appearance of moderate to severe glabellar lines associated with corrugator and/or procerus muscle activity. The drug caused no adverse embryo-fetal in rats with doses up to 12 times the human dose.

Risankizumab-rzaa (Skyrizi) (molecular weight unknown), an interleukin-23 antagonist, is used for the treatment of moderate-to-severe plaque psoriasis. In pregnant monkeys, doses that were 20 times the maximum human dose increased fetal/infant loss.

Selinexor (Xpovio) (443) is an oral nuclear export inhibitor given in combination with dexamethasone for the treatment of relapsed or refractory myeloma. At doses lower than those used clinically, the drug caused structural abnormalities and alterations to growth in fetal rats.

Siponimod (Mayzent) (1,149) is an oral sphingosine 1-phosphate receptor modulator. It is indicated for the treatment of relapsing forms of multiple sclerosis. At low doses, the drug caused embryotoxicity and fetotoxicity in rats and rabbits including embryofetal deaths and abortions. The drug was teratogenic in both species.

Solriamfetol (Sunosi) (231) is an oral dopamine and norepinephrine reuptake inhibitor that is indicated to improve wakefulness in adult patients with excessive daytime sleepiness associated with narcolepsy or obstructive sleep apnea. The drug caused maternal and fetal toxicities in rats and rabbits and was teratogenic. The manufacturer has a pregnancy exposure registry to monitor pregnancy outcomes. Health care providers or patients can enroll in the program by calling 1-877-283-6220 or contacting the company.

Tafamidis meglumine (Vyndaqel) (503) and tafamidis (Vyndamax) (308) are indicated for the treatment of the cardiomyopathy of wild type or hereditary transthyretin-mediated amyloidosis to reduce cardiovascular mortality and cardiovascular-related hospitalization. In rabbits and rats, use of the drugs during pregnancy caused birth defects, embryo-fetal mortality, and fetal body weight reduction. Limited available data with Vyndaqel use in human pregnancy at a dose of 20 mg/day have not identified any drug-associated risks for major birth defects, miscarriage, or adverse maternal or fetal outcomes (see package insert).

Tenapanor (Ibsrela) (1,218) is indicated for the treatment of irritable bowel syndrome with constipation. The drug is minimally absorbed systemically, with plasma concentrations below the limit of quantification. No adverse maternal or fetal outcomes in rats or rabbits were observed. As reported by the manufacturer, in a small number of pregnant women, no drug-induced adverse maternal or fetal outcomes were identified.

Triclabendazole (Egaten) (360), an oral anthelmintic, is indicated for the treatment of fascioliasis. The drug was not teratogenic in mice and rabbits.

Trifarotene (Aklief) (460) cream is a retinoid that is indicated for the topical treatment of acne vulgaris. Animal data was related to oral retinoids and it not applicable to this agent. The manufacturer reported that available data from the use of the cream in pregnant women have not identified a drug-associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes.