Ob.Gyn. News

The gout drug colchicine appears to lower the severity of COVID-19, a small new Brazilian study finds, adding to evidence that the familiar medication holds promise as a treatment for hospitalized patients.

Patients who received colchicine in this randomized, double-blinded, placebo-controlled clinical trial presented better evolution in terms of the need for supplemental oxygen and the length of hospitalisation. ... Colchicine was safe and well tolerated,” the study authors wrote in RMD Open. However, deaths were rare in the trial, they added, and it is impossible to “evaluate the capacity of colchicine to avoid admission to ICU and reduce mortality.”

The oral anti-inflammatory colchicine, widely used as treatment in rheumatic disease, was first approved in the United States 60 years ago. Researchers began to explore its potential as a COVID-19 treatment in the early months of the pandemic.

On Jan. 25, an international team of researchers reported in a press release – but not yet a published paper – that the drug seemed to reduce hospitalizations, mechanical ventilation, and deaths in the ColCORONA trial. Earlier, a much-smaller, randomized, open-label, Greek trial linked the drug to reduced time to clinical deterioration and hospital stay.

The Brazilian authors of the new study, led by Maria Isabel Lopes of the University of São Paulo’s Ribeirão Preto Medical School, randomly assigned 75 hospitalized patients with moderate to severe COVID-19 to colchicine or placebo. A total of 72 subjects completed the April-August 2020 trial: 36 received colchicine (typically 0.5 mg three times for 5 days, then 0.5 mg twice daily for 5 days; doses were adjusted in low-weight patients and those with chronic kidney disease). The other 36 received the placebo.

(In the United States, 0.6-mg tablets of generic colchicine cost as little as $1.90 each with free coupons, according to goodrx.com.)

The median age in the groups was similar (55 years); and the placebo group had more women (61% vs. 47% in the colchicine group, P = .34). All 72 patients received the same COVID-19 treatment at the time of the trial: azithromycin, hydroxychloroquine, and unfractionated heparin. Most patients, about two-thirds in both groups, also received methylprednisolone because they needed higher amounts of supplemental oxygen.

Patients in the colchicine group needed supplemental oxygen for less time: Their median time of need was 4.0 days (interquartile range [IQR], 2.0-6.0) vs. 6.5 days (IQR, 4.0-9.0) for the placebo group (P < .001). The median time for hospitalization was also lower at 7.0 days (IQR, 5.0–9.0) for the colchicine group vs. 9.0 (IQR, 7.0–12.0) for the placebo group (log rank test, 10.6; P = .001).

The researchers also reported the percentage of patients who needed supplemental oxygen at day 2 as 67% with colchicine vs. 86% with placebo, and at day 7 as 9% vs. 42% (log rank test, 10.6; P = .001). Two patients in the placebo group died, both from ventilator-associated pneumonia.

As for side effects, new or worsened diarrhea was reported more often in the colchicine group (17% vs. 6% with placebo), but the difference was not statistically significant (P = .26), and diarrhea was controlled via medication.

The researchers reported that limitations include the exclusion criteria and their inability to link colchicine to rates of ICU admissions and death.

The drug appears to help patients with COVID-19, the study authors wrote, by “inhibiting inflammasome, reducing neutrophil migration and activation, or preventing endothelial damage.”

A “well-conceived and well-designed” study

In an interview, NYU Langone Health rheumatologist Michael H. Pillinger, MD – an investigator with the ColCORONA trial – praised the Brazilian study. It “appears well-conceived and well-designed, and was enrolled at a rate that was greater than the sample size that was estimated to be needed based on power analysis,” he said.

The Brazilian study is small, he noted. (In contrast, the ColCORONA trial had 4,488 outpatient participants.) “This study differs from ColCORONA in several ways – the most important being that it is a study of inpatients with moderate to severe COVID (really mostly moderate),” he added. “ColCORONA is looking at a target audience that is much larger – outpatients with mild to moderate COVID with risk factors for hospitalization. Both questions are really important and certainly not mutually exclusive, since our care remains inadequate in both venues. This study also adds value in that several other studies have been conducted in hospital patients with enrollment criteria relatively similar to this one, and all showed benefit, but those were open-label or retrospective, and this is blinded and placebo-controlled.”
 

Using colchicine in patients with COVID-19

Should physicians turn to colchicine in patients with COVID-19? “I would rather that it still be used in the context of research until formal recommendations can be made by bodies like the NIH and CDC,” Dr. Pillinger said. “But certainly, there may be times when physicians feel compelled to treat patients off label.”

He cautioned, however, that colchicine should never be used with some other drugs. Its interaction with the antibiotic clarithromycin can be fatal, he noted. And, he said, the drug must be monitored in general since it can cause rare, severe problems.

“Overall, colchicine probably works on the overabundant inflammatory response to COVID, and it may be that it can be combined with other drugs that affect viral replication or promote immunity – e.g. vaccines,” Dr. Pillinger said. “So far, it seems as if there is no safety problem with combining colchicine with other approaches, but this has not been studied in a rigorous manner.”

Moving forward, he said, the drug’s very low price outside of the United States “could provide resource-poor countries with a way to help keep patients out of precious hospital beds – or help them go home sooner once admitted.” For now, however, “we need a large-scale inpatient study, and one is currently going on in Great Britain. We also need validation of the outpatient ColCORONA study, and studies to look at whether colchicine can work in conjunction with other strategies.”

The study was funded by grants from the São Paulo Research Foundation, Brazilian National Council for Scientific and Technological Development, and CAPES Foundation. No disclosures are reported. Dr. Pillinger reports serving as an investigator for the ColCORONA trial and receiving a unrelated investigator-initiated grant from Hikma, a colchicine manufacturer.

The gout drug colchicine appears to lower the severity of COVID-19, a small new Brazilian study finds, adding to evidence that the familiar medication holds promise as a treatment for hospitalized patients.

Patients who received colchicine in this randomized, double-blinded, placebo-controlled clinical trial presented better evolution in terms of the need for supplemental oxygen and the length of hospitalisation. ... Colchicine was safe and well tolerated,” the study authors wrote in RMD Open. However, deaths were rare in the trial, they added, and it is impossible to “evaluate the capacity of colchicine to avoid admission to ICU and reduce mortality.”

The oral anti-inflammatory colchicine, widely used as treatment in rheumatic disease, was first approved in the United States 60 years ago. Researchers began to explore its potential as a COVID-19 treatment in the early months of the pandemic.

On Jan. 25, an international team of researchers reported in a press release – but not yet a published paper – that the drug seemed to reduce hospitalizations, mechanical ventilation, and deaths in the ColCORONA trial. Earlier, a much-smaller, randomized, open-label, Greek trial linked the drug to reduced time to clinical deterioration and hospital stay.

The Brazilian authors of the new study, led by Maria Isabel Lopes of the University of São Paulo’s Ribeirão Preto Medical School, randomly assigned 75 hospitalized patients with moderate to severe COVID-19 to colchicine or placebo. A total of 72 subjects completed the April-August 2020 trial: 36 received colchicine (typically 0.5 mg three times for 5 days, then 0.5 mg twice daily for 5 days; doses were adjusted in low-weight patients and those with chronic kidney disease). The other 36 received the placebo.

(In the United States, 0.6-mg tablets of generic colchicine cost as little as $1.90 each with free coupons, according to goodrx.com.)

The median age in the groups was similar (55 years); and the placebo group had more women (61% vs. 47% in the colchicine group, P = .34). All 72 patients received the same COVID-19 treatment at the time of the trial: azithromycin, hydroxychloroquine, and unfractionated heparin. Most patients, about two-thirds in both groups, also received methylprednisolone because they needed higher amounts of supplemental oxygen.

Patients in the colchicine group needed supplemental oxygen for less time: Their median time of need was 4.0 days (interquartile range [IQR], 2.0-6.0) vs. 6.5 days (IQR, 4.0-9.0) for the placebo group (P < .001). The median time for hospitalization was also lower at 7.0 days (IQR, 5.0–9.0) for the colchicine group vs. 9.0 (IQR, 7.0–12.0) for the placebo group (log rank test, 10.6; P = .001).

The researchers also reported the percentage of patients who needed supplemental oxygen at day 2 as 67% with colchicine vs. 86% with placebo, and at day 7 as 9% vs. 42% (log rank test, 10.6; P = .001). Two patients in the placebo group died, both from ventilator-associated pneumonia.

As for side effects, new or worsened diarrhea was reported more often in the colchicine group (17% vs. 6% with placebo), but the difference was not statistically significant (P = .26), and diarrhea was controlled via medication.

The researchers reported that limitations include the exclusion criteria and their inability to link colchicine to rates of ICU admissions and death.

The drug appears to help patients with COVID-19, the study authors wrote, by “inhibiting inflammasome, reducing neutrophil migration and activation, or preventing endothelial damage.”

A “well-conceived and well-designed” study

In an interview, NYU Langone Health rheumatologist Michael H. Pillinger, MD – an investigator with the ColCORONA trial – praised the Brazilian study. It “appears well-conceived and well-designed, and was enrolled at a rate that was greater than the sample size that was estimated to be needed based on power analysis,” he said.

The Brazilian study is small, he noted. (In contrast, the ColCORONA trial had 4,488 outpatient participants.) “This study differs from ColCORONA in several ways – the most important being that it is a study of inpatients with moderate to severe COVID (really mostly moderate),” he added. “ColCORONA is looking at a target audience that is much larger – outpatients with mild to moderate COVID with risk factors for hospitalization. Both questions are really important and certainly not mutually exclusive, since our care remains inadequate in both venues. This study also adds value in that several other studies have been conducted in hospital patients with enrollment criteria relatively similar to this one, and all showed benefit, but those were open-label or retrospective, and this is blinded and placebo-controlled.”
 

Using colchicine in patients with COVID-19

Should physicians turn to colchicine in patients with COVID-19? “I would rather that it still be used in the context of research until formal recommendations can be made by bodies like the NIH and CDC,” Dr. Pillinger said. “But certainly, there may be times when physicians feel compelled to treat patients off label.”

He cautioned, however, that colchicine should never be used with some other drugs. Its interaction with the antibiotic clarithromycin can be fatal, he noted. And, he said, the drug must be monitored in general since it can cause rare, severe problems.

“Overall, colchicine probably works on the overabundant inflammatory response to COVID, and it may be that it can be combined with other drugs that affect viral replication or promote immunity – e.g. vaccines,” Dr. Pillinger said. “So far, it seems as if there is no safety problem with combining colchicine with other approaches, but this has not been studied in a rigorous manner.”

Moving forward, he said, the drug’s very low price outside of the United States “could provide resource-poor countries with a way to help keep patients out of precious hospital beds – or help them go home sooner once admitted.” For now, however, “we need a large-scale inpatient study, and one is currently going on in Great Britain. We also need validation of the outpatient ColCORONA study, and studies to look at whether colchicine can work in conjunction with other strategies.”

The study was funded by grants from the São Paulo Research Foundation, Brazilian National Council for Scientific and Technological Development, and CAPES Foundation. No disclosures are reported. Dr. Pillinger reports serving as an investigator for the ColCORONA trial and receiving a unrelated investigator-initiated grant from Hikma, a colchicine manufacturer.

The gout drug colchicine appears to lower the severity of COVID-19, a small new Brazilian study finds, adding to evidence that the familiar medication holds promise as a treatment for hospitalized patients.

Patients who received colchicine in this randomized, double-blinded, placebo-controlled clinical trial presented better evolution in terms of the need for supplemental oxygen and the length of hospitalisation. ... Colchicine was safe and well tolerated,” the study authors wrote in RMD Open. However, deaths were rare in the trial, they added, and it is impossible to “evaluate the capacity of colchicine to avoid admission to ICU and reduce mortality.”

The oral anti-inflammatory colchicine, widely used as treatment in rheumatic disease, was first approved in the United States 60 years ago. Researchers began to explore its potential as a COVID-19 treatment in the early months of the pandemic.

On Jan. 25, an international team of researchers reported in a press release – but not yet a published paper – that the drug seemed to reduce hospitalizations, mechanical ventilation, and deaths in the ColCORONA trial. Earlier, a much-smaller, randomized, open-label, Greek trial linked the drug to reduced time to clinical deterioration and hospital stay.

The Brazilian authors of the new study, led by Maria Isabel Lopes of the University of São Paulo’s Ribeirão Preto Medical School, randomly assigned 75 hospitalized patients with moderate to severe COVID-19 to colchicine or placebo. A total of 72 subjects completed the April-August 2020 trial: 36 received colchicine (typically 0.5 mg three times for 5 days, then 0.5 mg twice daily for 5 days; doses were adjusted in low-weight patients and those with chronic kidney disease). The other 36 received the placebo.

(In the United States, 0.6-mg tablets of generic colchicine cost as little as $1.90 each with free coupons, according to goodrx.com.)

The median age in the groups was similar (55 years); and the placebo group had more women (61% vs. 47% in the colchicine group, P = .34). All 72 patients received the same COVID-19 treatment at the time of the trial: azithromycin, hydroxychloroquine, and unfractionated heparin. Most patients, about two-thirds in both groups, also received methylprednisolone because they needed higher amounts of supplemental oxygen.

Patients in the colchicine group needed supplemental oxygen for less time: Their median time of need was 4.0 days (interquartile range [IQR], 2.0-6.0) vs. 6.5 days (IQR, 4.0-9.0) for the placebo group (P < .001). The median time for hospitalization was also lower at 7.0 days (IQR, 5.0–9.0) for the colchicine group vs. 9.0 (IQR, 7.0–12.0) for the placebo group (log rank test, 10.6; P = .001).

The researchers also reported the percentage of patients who needed supplemental oxygen at day 2 as 67% with colchicine vs. 86% with placebo, and at day 7 as 9% vs. 42% (log rank test, 10.6; P = .001). Two patients in the placebo group died, both from ventilator-associated pneumonia.

As for side effects, new or worsened diarrhea was reported more often in the colchicine group (17% vs. 6% with placebo), but the difference was not statistically significant (P = .26), and diarrhea was controlled via medication.

The researchers reported that limitations include the exclusion criteria and their inability to link colchicine to rates of ICU admissions and death.

The drug appears to help patients with COVID-19, the study authors wrote, by “inhibiting inflammasome, reducing neutrophil migration and activation, or preventing endothelial damage.”

A “well-conceived and well-designed” study

In an interview, NYU Langone Health rheumatologist Michael H. Pillinger, MD – an investigator with the ColCORONA trial – praised the Brazilian study. It “appears well-conceived and well-designed, and was enrolled at a rate that was greater than the sample size that was estimated to be needed based on power analysis,” he said.

The Brazilian study is small, he noted. (In contrast, the ColCORONA trial had 4,488 outpatient participants.) “This study differs from ColCORONA in several ways – the most important being that it is a study of inpatients with moderate to severe COVID (really mostly moderate),” he added. “ColCORONA is looking at a target audience that is much larger – outpatients with mild to moderate COVID with risk factors for hospitalization. Both questions are really important and certainly not mutually exclusive, since our care remains inadequate in both venues. This study also adds value in that several other studies have been conducted in hospital patients with enrollment criteria relatively similar to this one, and all showed benefit, but those were open-label or retrospective, and this is blinded and placebo-controlled.”
 

Using colchicine in patients with COVID-19

Should physicians turn to colchicine in patients with COVID-19? “I would rather that it still be used in the context of research until formal recommendations can be made by bodies like the NIH and CDC,” Dr. Pillinger said. “But certainly, there may be times when physicians feel compelled to treat patients off label.”

He cautioned, however, that colchicine should never be used with some other drugs. Its interaction with the antibiotic clarithromycin can be fatal, he noted. And, he said, the drug must be monitored in general since it can cause rare, severe problems.

“Overall, colchicine probably works on the overabundant inflammatory response to COVID, and it may be that it can be combined with other drugs that affect viral replication or promote immunity – e.g. vaccines,” Dr. Pillinger said. “So far, it seems as if there is no safety problem with combining colchicine with other approaches, but this has not been studied in a rigorous manner.”

Moving forward, he said, the drug’s very low price outside of the United States “could provide resource-poor countries with a way to help keep patients out of precious hospital beds – or help them go home sooner once admitted.” For now, however, “we need a large-scale inpatient study, and one is currently going on in Great Britain. We also need validation of the outpatient ColCORONA study, and studies to look at whether colchicine can work in conjunction with other strategies.”

The study was funded by grants from the São Paulo Research Foundation, Brazilian National Council for Scientific and Technological Development, and CAPES Foundation. No disclosures are reported. Dr. Pillinger reports serving as an investigator for the ColCORONA trial and receiving a unrelated investigator-initiated grant from Hikma, a colchicine manufacturer.

The United States has now reported more than 450,000 COVID-19 deaths during the pandemic, adding 3,912 more on Wednesday, according to data from Johns Hopkins University.

Daily COVID-19 deaths still remain high in the United States, though they’ve decreased slightly from the peak of 4,466 deaths on Jan. 12.

The United States also reported more than 121,000 new COVID-19 cases on Wednesday, which is down from a peak of more than 300,000 new cases on Tuesday. In total, more than 26.5 million people in the United States have been diagnosed with COVID-19, making up a quarter of the 104.5 million cases reported worldwide.

The 7-day average for COVID-19 hospitalizations and deaths continues to decline, according to the COVID Tracking Project. The 7-day average for hospitalizations is around 96,500, and the 7-day average for deaths is about 3,000. With the exception of Vermont, all states and territories have reported declines or no changes in their hospitalizations and deaths.

“We have seen the 7-day average for new deaths decrease for over a week. At the same time, states are reporting an average of 3,000 people dying per day,” the COVID Tracking Project wrote in a post on Twitter. “The data is hopeful and devastating.”

More than 2.2 million COVID-19 deaths have been reported worldwide. The United States continues to report the most deaths, followed by Brazil with 227,500, Mexico with 161,200, and India with 154,700 deaths.

The U.S. COVID-19 death toll could reach 496,000-534,000 by the end of February, according to a new forecast by the CDC, which includes models from 36 national groups. Deaths will likely decrease during the next 4 weeks, with about 11,300-22,600 deaths possibly reported during the last week of February.

The 534,000 total would equal about 1 death for every minute of the pandemic, according to CNN, given that the first U.S. death was reported on Feb. 29 last year.

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

The United States has now reported more than 450,000 COVID-19 deaths during the pandemic, adding 3,912 more on Wednesday, according to data from Johns Hopkins University.

Daily COVID-19 deaths still remain high in the United States, though they’ve decreased slightly from the peak of 4,466 deaths on Jan. 12.

The United States also reported more than 121,000 new COVID-19 cases on Wednesday, which is down from a peak of more than 300,000 new cases on Tuesday. In total, more than 26.5 million people in the United States have been diagnosed with COVID-19, making up a quarter of the 104.5 million cases reported worldwide.

The 7-day average for COVID-19 hospitalizations and deaths continues to decline, according to the COVID Tracking Project. The 7-day average for hospitalizations is around 96,500, and the 7-day average for deaths is about 3,000. With the exception of Vermont, all states and territories have reported declines or no changes in their hospitalizations and deaths.

“We have seen the 7-day average for new deaths decrease for over a week. At the same time, states are reporting an average of 3,000 people dying per day,” the COVID Tracking Project wrote in a post on Twitter. “The data is hopeful and devastating.”

More than 2.2 million COVID-19 deaths have been reported worldwide. The United States continues to report the most deaths, followed by Brazil with 227,500, Mexico with 161,200, and India with 154,700 deaths.

The U.S. COVID-19 death toll could reach 496,000-534,000 by the end of February, according to a new forecast by the CDC, which includes models from 36 national groups. Deaths will likely decrease during the next 4 weeks, with about 11,300-22,600 deaths possibly reported during the last week of February.

The 534,000 total would equal about 1 death for every minute of the pandemic, according to CNN, given that the first U.S. death was reported on Feb. 29 last year.

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

The United States has now reported more than 450,000 COVID-19 deaths during the pandemic, adding 3,912 more on Wednesday, according to data from Johns Hopkins University.

Daily COVID-19 deaths still remain high in the United States, though they’ve decreased slightly from the peak of 4,466 deaths on Jan. 12.

The United States also reported more than 121,000 new COVID-19 cases on Wednesday, which is down from a peak of more than 300,000 new cases on Tuesday. In total, more than 26.5 million people in the United States have been diagnosed with COVID-19, making up a quarter of the 104.5 million cases reported worldwide.

The 7-day average for COVID-19 hospitalizations and deaths continues to decline, according to the COVID Tracking Project. The 7-day average for hospitalizations is around 96,500, and the 7-day average for deaths is about 3,000. With the exception of Vermont, all states and territories have reported declines or no changes in their hospitalizations and deaths.

“We have seen the 7-day average for new deaths decrease for over a week. At the same time, states are reporting an average of 3,000 people dying per day,” the COVID Tracking Project wrote in a post on Twitter. “The data is hopeful and devastating.”

More than 2.2 million COVID-19 deaths have been reported worldwide. The United States continues to report the most deaths, followed by Brazil with 227,500, Mexico with 161,200, and India with 154,700 deaths.

The U.S. COVID-19 death toll could reach 496,000-534,000 by the end of February, according to a new forecast by the CDC, which includes models from 36 national groups. Deaths will likely decrease during the next 4 weeks, with about 11,300-22,600 deaths possibly reported during the last week of February.

The 534,000 total would equal about 1 death for every minute of the pandemic, according to CNN, given that the first U.S. death was reported on Feb. 29 last year.

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

Metformin extended gestation by nearly a week in women with preterm preeclampsia and was also linked to a shorter neonatal hospital stay, according to findings from a study presented Jan. 28 at the virtual Society for Maternal-Fetal Medicine 2021 Annual Pregnancy Meeting.

The causes of preeclampsia have continued to elude researchers, but most agree the placenta plays a key role, explained Cathy Cluver, PhD, director of the preeclampsia research unit and an associate professor at Stellenbosch University, Cape Town. Past trials have tested sildenafil, antithrombin, pravastatin, and esomeprazole, but the drugs either did not show promise, had unacceptable side effects, or need further study.

“This trial provides proof of concept that preterm preeclampsia can be treated and that we can slow the progression of preterm preeclampsia,” Dr. Cluver said.

In this trial, the researchers enrolled 180 women with preterm preeclampsia between 26 and 31 weeks of gestation. All the women were taking hypertensives. They were randomly assigned to receive 3 g oral metformin XR or placebo daily. The intention-to-treat analysis included 87 women who received metformin and 84 who received placebo, with baseline characteristics similar in both groups.

Women in the metformin group gave birth a median 16.2 days after randomization, which was 6.7 days longer than the 9.5 days postrandomization delivery of women in the placebo group. The differences, however, narrowly missed statistical significance (P =.056).

But when the researchers took compliance and dose into account, the effect of the metformin increased, showing a dose-dependent effect, and did reach statistical significance. Among the 147 women who continued treatment until delivery, those in the metformin group delivered a median 8.4 days later than those in the placebo group (16.2 vs. 7.4 days; P =.026). Further, when the analysis was further restricted to just the 100 women who continued taking the full dose until delivery, the difference was even greater (16.2 vs. 4.8 days; P =.008). In accordance with the safety profile of metformin, women taking the drug had more diarrhea and a trend toward more nausea than those taking the placebo.

There were no differences between the groups in composite maternal or neonatal outcomes, but the infants were an average 136 g (4.8 ounces) heavier in the metformin group, albeit the difference did not reach statistical significance. The 6-day–shorter neonatal stay at the study site facility for infants of the metformin group also did not reach statistical significance, but there was a significant difference between the groups on overall stay, including transfers to other facilities. Infants in the metformin group averaged 26 days vs. 34 days for infants in the placebo group (P =.007).

“We have shown that metformin XR may be a treatment for preterm preeclampsia. We now plan to do a larger study to hopefully confirm these findings, which will be powered to both prolongation of pregnancy and neonatal outcomes,” Dr. Cluver told this news organization. “We have also shown that one can prolong pregnancy in preterm preeclampsia, and we hope that this will encourage others in our field to continue researching therapeutics for preterm preeclampsia.”

In response to questions from attendees, Dr. Cluver reported that her team did not collect histological data from placentas in this study, and lack of funding is limiting their ability to evaluate longer-term outcomes.

The findings of prolonged gestation were certainly exciting, but they warrant caution before any changes in clinical practice, Michelle Y. Owens, MD, professor and chief of maternal-fetal medicine at the University of Mississippi Medical Center, Jackson, said in an interview.

“While the findings of this study are promising, the sample size was small, the dosing exceeds what we typically use in the U.S., and this was undertaken in Cape Town, South Africa, all of which may render this study less generalizable to our population and others across the globe,” said Dr. Owens, who moderated the oral abstract session.

She also pointed out a possible conflicting effect on birth weight brought on by using metformin to extend gestation.

“If larger studies are undertaken, I believe it is quite possible that, with extended gestation, there will be bigger babies,” she said. “However, metformin also helps control blood glucose and in so doing, may contribute to lower birth weights over time, compared with women not exposed to the drug.”

Dr. Cluver and Dr. Owens have disclosed no relevant financial relationships.

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

*This story was updated on 2/9/2021. 

Metformin extended gestation by nearly a week in women with preterm preeclampsia and was also linked to a shorter neonatal hospital stay, according to findings from a study presented Jan. 28 at the virtual Society for Maternal-Fetal Medicine 2021 Annual Pregnancy Meeting.

The causes of preeclampsia have continued to elude researchers, but most agree the placenta plays a key role, explained Cathy Cluver, PhD, director of the preeclampsia research unit and an associate professor at Stellenbosch University, Cape Town. Past trials have tested sildenafil, antithrombin, pravastatin, and esomeprazole, but the drugs either did not show promise, had unacceptable side effects, or need further study.

“This trial provides proof of concept that preterm preeclampsia can be treated and that we can slow the progression of preterm preeclampsia,” Dr. Cluver said.

In this trial, the researchers enrolled 180 women with preterm preeclampsia between 26 and 31 weeks of gestation. All the women were taking hypertensives. They were randomly assigned to receive 3 g oral metformin XR or placebo daily. The intention-to-treat analysis included 87 women who received metformin and 84 who received placebo, with baseline characteristics similar in both groups.

Women in the metformin group gave birth a median 16.2 days after randomization, which was 6.7 days longer than the 9.5 days postrandomization delivery of women in the placebo group. The differences, however, narrowly missed statistical significance (P =.056).

But when the researchers took compliance and dose into account, the effect of the metformin increased, showing a dose-dependent effect, and did reach statistical significance. Among the 147 women who continued treatment until delivery, those in the metformin group delivered a median 8.4 days later than those in the placebo group (16.2 vs. 7.4 days; P =.026). Further, when the analysis was further restricted to just the 100 women who continued taking the full dose until delivery, the difference was even greater (16.2 vs. 4.8 days; P =.008). In accordance with the safety profile of metformin, women taking the drug had more diarrhea and a trend toward more nausea than those taking the placebo.

There were no differences between the groups in composite maternal or neonatal outcomes, but the infants were an average 136 g (4.8 ounces) heavier in the metformin group, albeit the difference did not reach statistical significance. The 6-day–shorter neonatal stay at the study site facility for infants of the metformin group also did not reach statistical significance, but there was a significant difference between the groups on overall stay, including transfers to other facilities. Infants in the metformin group averaged 26 days vs. 34 days for infants in the placebo group (P =.007).

“We have shown that metformin XR may be a treatment for preterm preeclampsia. We now plan to do a larger study to hopefully confirm these findings, which will be powered to both prolongation of pregnancy and neonatal outcomes,” Dr. Cluver told this news organization. “We have also shown that one can prolong pregnancy in preterm preeclampsia, and we hope that this will encourage others in our field to continue researching therapeutics for preterm preeclampsia.”

In response to questions from attendees, Dr. Cluver reported that her team did not collect histological data from placentas in this study, and lack of funding is limiting their ability to evaluate longer-term outcomes.

The findings of prolonged gestation were certainly exciting, but they warrant caution before any changes in clinical practice, Michelle Y. Owens, MD, professor and chief of maternal-fetal medicine at the University of Mississippi Medical Center, Jackson, said in an interview.

“While the findings of this study are promising, the sample size was small, the dosing exceeds what we typically use in the U.S., and this was undertaken in Cape Town, South Africa, all of which may render this study less generalizable to our population and others across the globe,” said Dr. Owens, who moderated the oral abstract session.

She also pointed out a possible conflicting effect on birth weight brought on by using metformin to extend gestation.

“If larger studies are undertaken, I believe it is quite possible that, with extended gestation, there will be bigger babies,” she said. “However, metformin also helps control blood glucose and in so doing, may contribute to lower birth weights over time, compared with women not exposed to the drug.”

Dr. Cluver and Dr. Owens have disclosed no relevant financial relationships.

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

*This story was updated on 2/9/2021. 

Metformin extended gestation by nearly a week in women with preterm preeclampsia and was also linked to a shorter neonatal hospital stay, according to findings from a study presented Jan. 28 at the virtual Society for Maternal-Fetal Medicine 2021 Annual Pregnancy Meeting.

The causes of preeclampsia have continued to elude researchers, but most agree the placenta plays a key role, explained Cathy Cluver, PhD, director of the preeclampsia research unit and an associate professor at Stellenbosch University, Cape Town. Past trials have tested sildenafil, antithrombin, pravastatin, and esomeprazole, but the drugs either did not show promise, had unacceptable side effects, or need further study.

“This trial provides proof of concept that preterm preeclampsia can be treated and that we can slow the progression of preterm preeclampsia,” Dr. Cluver said.

In this trial, the researchers enrolled 180 women with preterm preeclampsia between 26 and 31 weeks of gestation. All the women were taking hypertensives. They were randomly assigned to receive 3 g oral metformin XR or placebo daily. The intention-to-treat analysis included 87 women who received metformin and 84 who received placebo, with baseline characteristics similar in both groups.

Women in the metformin group gave birth a median 16.2 days after randomization, which was 6.7 days longer than the 9.5 days postrandomization delivery of women in the placebo group. The differences, however, narrowly missed statistical significance (P =.056).

But when the researchers took compliance and dose into account, the effect of the metformin increased, showing a dose-dependent effect, and did reach statistical significance. Among the 147 women who continued treatment until delivery, those in the metformin group delivered a median 8.4 days later than those in the placebo group (16.2 vs. 7.4 days; P =.026). Further, when the analysis was further restricted to just the 100 women who continued taking the full dose until delivery, the difference was even greater (16.2 vs. 4.8 days; P =.008). In accordance with the safety profile of metformin, women taking the drug had more diarrhea and a trend toward more nausea than those taking the placebo.

There were no differences between the groups in composite maternal or neonatal outcomes, but the infants were an average 136 g (4.8 ounces) heavier in the metformin group, albeit the difference did not reach statistical significance. The 6-day–shorter neonatal stay at the study site facility for infants of the metformin group also did not reach statistical significance, but there was a significant difference between the groups on overall stay, including transfers to other facilities. Infants in the metformin group averaged 26 days vs. 34 days for infants in the placebo group (P =.007).

“We have shown that metformin XR may be a treatment for preterm preeclampsia. We now plan to do a larger study to hopefully confirm these findings, which will be powered to both prolongation of pregnancy and neonatal outcomes,” Dr. Cluver told this news organization. “We have also shown that one can prolong pregnancy in preterm preeclampsia, and we hope that this will encourage others in our field to continue researching therapeutics for preterm preeclampsia.”

In response to questions from attendees, Dr. Cluver reported that her team did not collect histological data from placentas in this study, and lack of funding is limiting their ability to evaluate longer-term outcomes.

The findings of prolonged gestation were certainly exciting, but they warrant caution before any changes in clinical practice, Michelle Y. Owens, MD, professor and chief of maternal-fetal medicine at the University of Mississippi Medical Center, Jackson, said in an interview.

“While the findings of this study are promising, the sample size was small, the dosing exceeds what we typically use in the U.S., and this was undertaken in Cape Town, South Africa, all of which may render this study less generalizable to our population and others across the globe,” said Dr. Owens, who moderated the oral abstract session.

She also pointed out a possible conflicting effect on birth weight brought on by using metformin to extend gestation.

“If larger studies are undertaken, I believe it is quite possible that, with extended gestation, there will be bigger babies,” she said. “However, metformin also helps control blood glucose and in so doing, may contribute to lower birth weights over time, compared with women not exposed to the drug.”

Dr. Cluver and Dr. Owens have disclosed no relevant financial relationships.

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

*This story was updated on 2/9/2021. 

The final numbers won’t look much different, but the 2021 Match results will be unlike any before. As of mid-January, only 16 more institutions were confirmed to be participating in Match Day this year, resulting in about 800 more positions, said Donna Lamb, president and CEO of the National Resident Matching Program (NRMP). The Electronic Residency Application Service reported about 50,000 individual applicant submissions, a slight increase from prior years.

The stats may be similar, but the current residency application cycle may lead to wildly different results after the pandemic forced interviews to be conducted virtually and caused the cancellation of most away clinical rotations. Troy Amen, a fifth-year MD-MBA student at Harvard Medical School, Boston, and copresident of his student class, says the lack of on-campus, in-person experiences means students feel more in the dark than ever. The same is true for institutions. “The programs are also suffering because now they don’t know which students are a good ‘cultural fit’ for them,” he said.

Standing out has always been a concern for prospective residents, but Mr. Amen says fears are even higher this year. “[Institutions are] struggling to vet out 850 applicants, and they have no connection to us.”

Organizations have scrambled to keep the process as fair and informative as possible. “Everyone is trying to do the right thing here,” said Alison J. Whelan, MD, chief academic officer of the Association of American Medical Colleges (AAMC). She says that although the process has significantly changed, the heart of it remains the same. “The bottom line is directors really want to fill their intern class, and schools and students really want to match.”

Since the NRMP was established in 1952, it has never had to contend with a pandemic of this scale. The unprecedented circumstances have led to some much-feared and some unexpected changes, like top candidates “stealing” interview slots, “swag bags” sent to entice residents, beefed-up online profiles, as well as “Zoom fatigue,” a spike in home-field advantage for institutions, and massive anxiety for those students staking their future to a city they may have never seen in person.
 

What was lost and what was gained

“It’s really hard to get a real feel for the program when you’ve not been there in person,” said Christopher Smith, MD, director of the internal medicine residency program at Beth Israel Deaconess Medical Center in Boston. Dr. Smith recalled interviewing for residencies 25 years ago. His wife, a teacher, took time off to travel with him.

“She would ‘interview the town’ while I interviewed the program, and we compared notes at night,” he said. Because of COVID-19-related travel restrictions, just physically seeing the city in which they may live for years wasn’t an option for many. “I have a lot of sympathy for students applying right now,” Dr. Smith said.

For the residency class of 2021, the first shoe really dropped last March, when the AAMC issued guidance strongly recommending that programs pause clinical rotations away from their home schools. As established doctors know well, and as graduating medical students confirmed, these rotations are crucial to understanding a program’s culture and gaining experience that can boost candidacy. “I’m applying to orthopedic surgery, where away rotations are the gold standard for impressing attendees and residents at institutions away from home,” said Mr. Amen.

The pandemic completely cut off that key source of information to determine the right fit. It also meant applicants couldn’t have as diverse a portfolio of recommendation letters, something many worry may be detrimental to their soon-to-be-released Match rankings.

Unlike the loss of away rotations, the forced shift from in-person to virtual interviews had some meaningful benefits. Students no longer incurred expenses for airline flights, hotel rooms, and rental cars. Many organizations and programs have been trying for years to figure out how to lower the financial burden of interviews to make the process more equitable for those at economic or other disadvantage.

“The equity piece of this is huge – decreasing barriers and leveling the field a little bit is a really huge advantage,” said Kate Shaw, MD, residency program director and associate chair of education for the obstetrics and gynecology program at Stanford (Calif.) University. In some ways, this latest change is an extension of a strategy Dr. Shaw and others had already begun implementing.

“Over the last 5 to 10 years, we’ve been working to address the implicit bias in the application process, so we’ve gone to a holistic review of applicants, where we don’t have score cutoffs. We look at the whole person,” she said. “And we did that in an effort to increase diversity and equity.” Dr. Shaw and others hope that the accidental positive changes from COVID restrictions may be intentionally preserved long after the pandemic ends.
 

Home-field advantage vs. swag bags

Many medical students applying to residencies this year say they have given greater weight to their home programs than they might have without the pandemic. “I didn’t get a sense of anyone’s culture other than my home institution,” said Alex Skidmore, a fourth-year medical student at Washington University in St. Louis. “I definitely am ranking Wash-U higher.”

The desire to emphasize the known quality of a student’s home institution isn’t surprising to program directors. Dr. Shaw said she thinks this year’s Match could well end with a higher percentage of students matching either in their home programs or in programs close to loved ones. “The value of being close to family has come up in our conversations, where students are considering the right program for them but also the other life factors,” she said.

To overcome this home-field advantage, many programs have beefed up their websites, including providing video tours of their facilities. They also “upped their social media game” and encouraged residents to create online groups for prospective residents to share information about programs and life outside of work. Some residents even offered video tours of their personal apartments to applicants.

Without in-person access to facilities and staff, a program’s online presence became a deciding factor, applicants said. “If you have a bad website, it’s like having a dirty building to interview applicants in,” Mr. Skidmore said. For many prospective residents, an institution’s Internet presence was a “make or break” factor. “It’s the only thing I saw for many programs, and when we are doing the amount of research we are doing remotely, when I saw a program with a bad website, it made me not like the program as much,” he said.

Some programs, hoping to woo candidates as well as to provide them with more insight into what they and their cities have to offer, sent “swag bags” to candidates. These included things like gift cards for food delivery and offerings from local businesses. Washington University’s pediatrics residency program sent gooey butter cakes – a St. Louis staple – along with other treats from small businesses and copies of magazines that showcased the city’s dining and entertainment scene.

Other programs, even those at the same medical institution, felt quite strongly that those types of packages shouldn’t be sent. “We interviewed almost 500 applicants, so there was no way we could have afforded that,” said Dominique Cosco, MD, director of Washington University’s internal medicine residency program. “Our normal recruitment budget is almost $100,000 in a normal year, and that got cut because of COVID. For us, it was thinking about allocations of resources.”
 

Interview slot theft and zoom fatigue

Remote interviewing also meant that applicants could accept more interviews, something that raised a big concern. Without expenses or travel time, would top-tier candidates take more interviews than normal and thus take limited interview spots from other qualified candidates? Maybe so, says the AAMC’s Dr. Whelan.

“We didn’t have systematic data, but we heard from enough schools and programs ... that students who were maybe not the top-top ranked students in the class but in every way solid were receiving fewer interviews than previous years,” Dr. Whelan said. This is despite guidance that recommended programs add interview slots to serve as a counterbalance.

Some students say they accepted more interview slots in the beginning of the interview season, partly because they could, and partly because some thought of early interviews as “practice” for later interviews. However, as video interviews piled up, some of them described feeling “Zoom fatigue” and said they later canceled interviews with programs they didn’t anticipate joining.
 

More SOAP, less clarity

As for what comes next, the NRMP is preparing for a longer-than-normal Supplemental Offer and Acceptance Program (SOAP) than in years past. SOAP usually offers three rounds of matches after the initial Match Day; Ms. Lamb said things are different this year.

“SOAP will be the same number of days, but we’ve added an additional round on Thursday afternoon,” she said. Will it be unnecessary or not enough? Nobody knows. “How big SOAP actually is going to be is one of the things that we really don’t have a sense of right now and probably aren’t going to have a sense of until the Match.”

Uncertainty is the name of the game. More than any other Match before, programs and applicants won’t know how results from this pandemic year stack up for a few months at the very least. “I really want to see what this looks like on the other side,” Dr. Smith said. “Are applicants happy with the way it looks when they come here? Do they feel like they matched with the right place?”

Whether this unprecedented year will be remembered more for positive changes moving forward, including more flexibility on remote interviews, or for less-informed decisions that result in dissatisfied participants is also unclear.

“I think after the Match is over, we’ll be talking to everyone to get more perspective on what people who are applying now would tell the next class, and how programs can adjust,” said Kathy Diemer, MD, assistant dean for career counseling at Washington University. At the very least, those who are involved in this year after year can start thinking about what the future should look like.

“We’re going to need to do some kind of debriefing after this is over, both program directors and our students as well, so we can determine how to move forward next year and beyond.”

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

The final numbers won’t look much different, but the 2021 Match results will be unlike any before. As of mid-January, only 16 more institutions were confirmed to be participating in Match Day this year, resulting in about 800 more positions, said Donna Lamb, president and CEO of the National Resident Matching Program (NRMP). The Electronic Residency Application Service reported about 50,000 individual applicant submissions, a slight increase from prior years.

The stats may be similar, but the current residency application cycle may lead to wildly different results after the pandemic forced interviews to be conducted virtually and caused the cancellation of most away clinical rotations. Troy Amen, a fifth-year MD-MBA student at Harvard Medical School, Boston, and copresident of his student class, says the lack of on-campus, in-person experiences means students feel more in the dark than ever. The same is true for institutions. “The programs are also suffering because now they don’t know which students are a good ‘cultural fit’ for them,” he said.

Standing out has always been a concern for prospective residents, but Mr. Amen says fears are even higher this year. “[Institutions are] struggling to vet out 850 applicants, and they have no connection to us.”

Organizations have scrambled to keep the process as fair and informative as possible. “Everyone is trying to do the right thing here,” said Alison J. Whelan, MD, chief academic officer of the Association of American Medical Colleges (AAMC). She says that although the process has significantly changed, the heart of it remains the same. “The bottom line is directors really want to fill their intern class, and schools and students really want to match.”

Since the NRMP was established in 1952, it has never had to contend with a pandemic of this scale. The unprecedented circumstances have led to some much-feared and some unexpected changes, like top candidates “stealing” interview slots, “swag bags” sent to entice residents, beefed-up online profiles, as well as “Zoom fatigue,” a spike in home-field advantage for institutions, and massive anxiety for those students staking their future to a city they may have never seen in person.
 

What was lost and what was gained

“It’s really hard to get a real feel for the program when you’ve not been there in person,” said Christopher Smith, MD, director of the internal medicine residency program at Beth Israel Deaconess Medical Center in Boston. Dr. Smith recalled interviewing for residencies 25 years ago. His wife, a teacher, took time off to travel with him.

“She would ‘interview the town’ while I interviewed the program, and we compared notes at night,” he said. Because of COVID-19-related travel restrictions, just physically seeing the city in which they may live for years wasn’t an option for many. “I have a lot of sympathy for students applying right now,” Dr. Smith said.

For the residency class of 2021, the first shoe really dropped last March, when the AAMC issued guidance strongly recommending that programs pause clinical rotations away from their home schools. As established doctors know well, and as graduating medical students confirmed, these rotations are crucial to understanding a program’s culture and gaining experience that can boost candidacy. “I’m applying to orthopedic surgery, where away rotations are the gold standard for impressing attendees and residents at institutions away from home,” said Mr. Amen.

The pandemic completely cut off that key source of information to determine the right fit. It also meant applicants couldn’t have as diverse a portfolio of recommendation letters, something many worry may be detrimental to their soon-to-be-released Match rankings.

Unlike the loss of away rotations, the forced shift from in-person to virtual interviews had some meaningful benefits. Students no longer incurred expenses for airline flights, hotel rooms, and rental cars. Many organizations and programs have been trying for years to figure out how to lower the financial burden of interviews to make the process more equitable for those at economic or other disadvantage.

“The equity piece of this is huge – decreasing barriers and leveling the field a little bit is a really huge advantage,” said Kate Shaw, MD, residency program director and associate chair of education for the obstetrics and gynecology program at Stanford (Calif.) University. In some ways, this latest change is an extension of a strategy Dr. Shaw and others had already begun implementing.

“Over the last 5 to 10 years, we’ve been working to address the implicit bias in the application process, so we’ve gone to a holistic review of applicants, where we don’t have score cutoffs. We look at the whole person,” she said. “And we did that in an effort to increase diversity and equity.” Dr. Shaw and others hope that the accidental positive changes from COVID restrictions may be intentionally preserved long after the pandemic ends.
 

Home-field advantage vs. swag bags

Many medical students applying to residencies this year say they have given greater weight to their home programs than they might have without the pandemic. “I didn’t get a sense of anyone’s culture other than my home institution,” said Alex Skidmore, a fourth-year medical student at Washington University in St. Louis. “I definitely am ranking Wash-U higher.”

The desire to emphasize the known quality of a student’s home institution isn’t surprising to program directors. Dr. Shaw said she thinks this year’s Match could well end with a higher percentage of students matching either in their home programs or in programs close to loved ones. “The value of being close to family has come up in our conversations, where students are considering the right program for them but also the other life factors,” she said.

To overcome this home-field advantage, many programs have beefed up their websites, including providing video tours of their facilities. They also “upped their social media game” and encouraged residents to create online groups for prospective residents to share information about programs and life outside of work. Some residents even offered video tours of their personal apartments to applicants.

Without in-person access to facilities and staff, a program’s online presence became a deciding factor, applicants said. “If you have a bad website, it’s like having a dirty building to interview applicants in,” Mr. Skidmore said. For many prospective residents, an institution’s Internet presence was a “make or break” factor. “It’s the only thing I saw for many programs, and when we are doing the amount of research we are doing remotely, when I saw a program with a bad website, it made me not like the program as much,” he said.

Some programs, hoping to woo candidates as well as to provide them with more insight into what they and their cities have to offer, sent “swag bags” to candidates. These included things like gift cards for food delivery and offerings from local businesses. Washington University’s pediatrics residency program sent gooey butter cakes – a St. Louis staple – along with other treats from small businesses and copies of magazines that showcased the city’s dining and entertainment scene.

Other programs, even those at the same medical institution, felt quite strongly that those types of packages shouldn’t be sent. “We interviewed almost 500 applicants, so there was no way we could have afforded that,” said Dominique Cosco, MD, director of Washington University’s internal medicine residency program. “Our normal recruitment budget is almost $100,000 in a normal year, and that got cut because of COVID. For us, it was thinking about allocations of resources.”
 

Interview slot theft and zoom fatigue

Remote interviewing also meant that applicants could accept more interviews, something that raised a big concern. Without expenses or travel time, would top-tier candidates take more interviews than normal and thus take limited interview spots from other qualified candidates? Maybe so, says the AAMC’s Dr. Whelan.

“We didn’t have systematic data, but we heard from enough schools and programs ... that students who were maybe not the top-top ranked students in the class but in every way solid were receiving fewer interviews than previous years,” Dr. Whelan said. This is despite guidance that recommended programs add interview slots to serve as a counterbalance.

Some students say they accepted more interview slots in the beginning of the interview season, partly because they could, and partly because some thought of early interviews as “practice” for later interviews. However, as video interviews piled up, some of them described feeling “Zoom fatigue” and said they later canceled interviews with programs they didn’t anticipate joining.
 

More SOAP, less clarity

As for what comes next, the NRMP is preparing for a longer-than-normal Supplemental Offer and Acceptance Program (SOAP) than in years past. SOAP usually offers three rounds of matches after the initial Match Day; Ms. Lamb said things are different this year.

“SOAP will be the same number of days, but we’ve added an additional round on Thursday afternoon,” she said. Will it be unnecessary or not enough? Nobody knows. “How big SOAP actually is going to be is one of the things that we really don’t have a sense of right now and probably aren’t going to have a sense of until the Match.”

Uncertainty is the name of the game. More than any other Match before, programs and applicants won’t know how results from this pandemic year stack up for a few months at the very least. “I really want to see what this looks like on the other side,” Dr. Smith said. “Are applicants happy with the way it looks when they come here? Do they feel like they matched with the right place?”

Whether this unprecedented year will be remembered more for positive changes moving forward, including more flexibility on remote interviews, or for less-informed decisions that result in dissatisfied participants is also unclear.

“I think after the Match is over, we’ll be talking to everyone to get more perspective on what people who are applying now would tell the next class, and how programs can adjust,” said Kathy Diemer, MD, assistant dean for career counseling at Washington University. At the very least, those who are involved in this year after year can start thinking about what the future should look like.

“We’re going to need to do some kind of debriefing after this is over, both program directors and our students as well, so we can determine how to move forward next year and beyond.”

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

The final numbers won’t look much different, but the 2021 Match results will be unlike any before. As of mid-January, only 16 more institutions were confirmed to be participating in Match Day this year, resulting in about 800 more positions, said Donna Lamb, president and CEO of the National Resident Matching Program (NRMP). The Electronic Residency Application Service reported about 50,000 individual applicant submissions, a slight increase from prior years.

The stats may be similar, but the current residency application cycle may lead to wildly different results after the pandemic forced interviews to be conducted virtually and caused the cancellation of most away clinical rotations. Troy Amen, a fifth-year MD-MBA student at Harvard Medical School, Boston, and copresident of his student class, says the lack of on-campus, in-person experiences means students feel more in the dark than ever. The same is true for institutions. “The programs are also suffering because now they don’t know which students are a good ‘cultural fit’ for them,” he said.

Standing out has always been a concern for prospective residents, but Mr. Amen says fears are even higher this year. “[Institutions are] struggling to vet out 850 applicants, and they have no connection to us.”

Organizations have scrambled to keep the process as fair and informative as possible. “Everyone is trying to do the right thing here,” said Alison J. Whelan, MD, chief academic officer of the Association of American Medical Colleges (AAMC). She says that although the process has significantly changed, the heart of it remains the same. “The bottom line is directors really want to fill their intern class, and schools and students really want to match.”

Since the NRMP was established in 1952, it has never had to contend with a pandemic of this scale. The unprecedented circumstances have led to some much-feared and some unexpected changes, like top candidates “stealing” interview slots, “swag bags” sent to entice residents, beefed-up online profiles, as well as “Zoom fatigue,” a spike in home-field advantage for institutions, and massive anxiety for those students staking their future to a city they may have never seen in person.
 

What was lost and what was gained

“It’s really hard to get a real feel for the program when you’ve not been there in person,” said Christopher Smith, MD, director of the internal medicine residency program at Beth Israel Deaconess Medical Center in Boston. Dr. Smith recalled interviewing for residencies 25 years ago. His wife, a teacher, took time off to travel with him.

“She would ‘interview the town’ while I interviewed the program, and we compared notes at night,” he said. Because of COVID-19-related travel restrictions, just physically seeing the city in which they may live for years wasn’t an option for many. “I have a lot of sympathy for students applying right now,” Dr. Smith said.

For the residency class of 2021, the first shoe really dropped last March, when the AAMC issued guidance strongly recommending that programs pause clinical rotations away from their home schools. As established doctors know well, and as graduating medical students confirmed, these rotations are crucial to understanding a program’s culture and gaining experience that can boost candidacy. “I’m applying to orthopedic surgery, where away rotations are the gold standard for impressing attendees and residents at institutions away from home,” said Mr. Amen.

The pandemic completely cut off that key source of information to determine the right fit. It also meant applicants couldn’t have as diverse a portfolio of recommendation letters, something many worry may be detrimental to their soon-to-be-released Match rankings.

Unlike the loss of away rotations, the forced shift from in-person to virtual interviews had some meaningful benefits. Students no longer incurred expenses for airline flights, hotel rooms, and rental cars. Many organizations and programs have been trying for years to figure out how to lower the financial burden of interviews to make the process more equitable for those at economic or other disadvantage.

“The equity piece of this is huge – decreasing barriers and leveling the field a little bit is a really huge advantage,” said Kate Shaw, MD, residency program director and associate chair of education for the obstetrics and gynecology program at Stanford (Calif.) University. In some ways, this latest change is an extension of a strategy Dr. Shaw and others had already begun implementing.

“Over the last 5 to 10 years, we’ve been working to address the implicit bias in the application process, so we’ve gone to a holistic review of applicants, where we don’t have score cutoffs. We look at the whole person,” she said. “And we did that in an effort to increase diversity and equity.” Dr. Shaw and others hope that the accidental positive changes from COVID restrictions may be intentionally preserved long after the pandemic ends.
 

Home-field advantage vs. swag bags

Many medical students applying to residencies this year say they have given greater weight to their home programs than they might have without the pandemic. “I didn’t get a sense of anyone’s culture other than my home institution,” said Alex Skidmore, a fourth-year medical student at Washington University in St. Louis. “I definitely am ranking Wash-U higher.”

The desire to emphasize the known quality of a student’s home institution isn’t surprising to program directors. Dr. Shaw said she thinks this year’s Match could well end with a higher percentage of students matching either in their home programs or in programs close to loved ones. “The value of being close to family has come up in our conversations, where students are considering the right program for them but also the other life factors,” she said.

To overcome this home-field advantage, many programs have beefed up their websites, including providing video tours of their facilities. They also “upped their social media game” and encouraged residents to create online groups for prospective residents to share information about programs and life outside of work. Some residents even offered video tours of their personal apartments to applicants.

Without in-person access to facilities and staff, a program’s online presence became a deciding factor, applicants said. “If you have a bad website, it’s like having a dirty building to interview applicants in,” Mr. Skidmore said. For many prospective residents, an institution’s Internet presence was a “make or break” factor. “It’s the only thing I saw for many programs, and when we are doing the amount of research we are doing remotely, when I saw a program with a bad website, it made me not like the program as much,” he said.

Some programs, hoping to woo candidates as well as to provide them with more insight into what they and their cities have to offer, sent “swag bags” to candidates. These included things like gift cards for food delivery and offerings from local businesses. Washington University’s pediatrics residency program sent gooey butter cakes – a St. Louis staple – along with other treats from small businesses and copies of magazines that showcased the city’s dining and entertainment scene.

Other programs, even those at the same medical institution, felt quite strongly that those types of packages shouldn’t be sent. “We interviewed almost 500 applicants, so there was no way we could have afforded that,” said Dominique Cosco, MD, director of Washington University’s internal medicine residency program. “Our normal recruitment budget is almost $100,000 in a normal year, and that got cut because of COVID. For us, it was thinking about allocations of resources.”
 

Interview slot theft and zoom fatigue

Remote interviewing also meant that applicants could accept more interviews, something that raised a big concern. Without expenses or travel time, would top-tier candidates take more interviews than normal and thus take limited interview spots from other qualified candidates? Maybe so, says the AAMC’s Dr. Whelan.

“We didn’t have systematic data, but we heard from enough schools and programs ... that students who were maybe not the top-top ranked students in the class but in every way solid were receiving fewer interviews than previous years,” Dr. Whelan said. This is despite guidance that recommended programs add interview slots to serve as a counterbalance.

Some students say they accepted more interview slots in the beginning of the interview season, partly because they could, and partly because some thought of early interviews as “practice” for later interviews. However, as video interviews piled up, some of them described feeling “Zoom fatigue” and said they later canceled interviews with programs they didn’t anticipate joining.
 

More SOAP, less clarity

As for what comes next, the NRMP is preparing for a longer-than-normal Supplemental Offer and Acceptance Program (SOAP) than in years past. SOAP usually offers three rounds of matches after the initial Match Day; Ms. Lamb said things are different this year.

“SOAP will be the same number of days, but we’ve added an additional round on Thursday afternoon,” she said. Will it be unnecessary or not enough? Nobody knows. “How big SOAP actually is going to be is one of the things that we really don’t have a sense of right now and probably aren’t going to have a sense of until the Match.”

Uncertainty is the name of the game. More than any other Match before, programs and applicants won’t know how results from this pandemic year stack up for a few months at the very least. “I really want to see what this looks like on the other side,” Dr. Smith said. “Are applicants happy with the way it looks when they come here? Do they feel like they matched with the right place?”

Whether this unprecedented year will be remembered more for positive changes moving forward, including more flexibility on remote interviews, or for less-informed decisions that result in dissatisfied participants is also unclear.

“I think after the Match is over, we’ll be talking to everyone to get more perspective on what people who are applying now would tell the next class, and how programs can adjust,” said Kathy Diemer, MD, assistant dean for career counseling at Washington University. At the very least, those who are involved in this year after year can start thinking about what the future should look like.

“We’re going to need to do some kind of debriefing after this is over, both program directors and our students as well, so we can determine how to move forward next year and beyond.”

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

Having COVID-19 during pregnancy is linked to a significantly increased risk for gestational hypertension and preeclampsia compared with not having COVID-19 while pregnant, according to findings from a retrospective study presented Jan. 28 at the Society for Maternal-Fetal Medicine 2021 Annual Pregnancy Meeting.

“This was not entirely surprising given that inflammation has been implicated in the pathogenesis of both hypertensive disorders of pregnancy and COVID-19 infection and thus may serve to exacerbate each other,” Nigel Madden, MD, a resident physician in the ob.gyn. department at Columbia University, New York. , told this news organization after she presented the results.

Hypertensive disorders of pregnancy occur in 10%-15% of all pregnancies and are the leading cause of maternal and perinatal morbidity and mortality worldwide, Dr. Madden told attendees of the meeting. Although it’s not clear what causes hypertensive diseases in pregnancy generally, “it is possible that the acute inflammatory state of the COVID infection may incite or exacerbate hypertensive disease of pregnancy,” Dr. Madden said.

The researchers conducted a retrospective chart review of 1,715 patients who had a singleton pregnancy and who underwent routine nasal polymerase chain reaction testing at admission to one institution’s labor and delivery department between March and June 2020. The researchers excluded patients who had a history of chronic hypertension.

Overall, 10% of the patients tested positive for COVID-19 (n = 167), and 90% tested negative (n = 1,548). There were several differences at baseline between the groups. Those who tested positive tended to be younger, with an average age of 28, compared with an average age of 31 years for the group that tested negative. The group that tested negative also had a higher proportion of mothers aged 35 and older (P < .01). There were also significant differences in the racial makeup of the groups. Half of those in the COVID-positive group reported “other” for their race. The biggest baseline disparity between the groups was with regard to insurance type: 73% of those who tested positive for COVID-19 used Medicaid; only 36% of patients in the COVID-negative group used Medicaid. Those with private insurance were more likely to test negative (43%) than positive (25%) (P < .01).

The researchers defined gestational hypertension as having a systolic blood pressure greater than or equal to 140 mm Hg or a diastolic blood pressure greater than or equal to 90 mm Hg on two occasions at least 4 hours apart. A preeclampsia diagnosis required elevated blood pressure (using the same definition as for hypertension) as well as proteinuria, characterized by a protein/creatine ratio greater than or equal to 0.3 mg/dL or greater than or equal to 300 mg of protein on a 24-hour urine collection. Preeclampsia with severe features required prespecified laboratory abnormalities, pulmonary edema, or symptoms of headache, vision changes, chest pain, shortness of breath, or right upper quadrant pain.

More than twice as many patients with COVID had a hypertensive disorder of pregnancy (18%) as those who tested negative (8%). The patients who were COVID positive were significantly more likely than those who tested negative to have gestational hypertension and preeclampsia without severe features. Rates of preeclampsia with severe features were not significantly different between the groups.

The severity of hypertensive disease did not differ between the groups. Limitations of the study included its retrospective design, the small number of COVID-positive patients, and the fact that it was conducted at a single institution in New York. However, the study population was diverse, and it was conducted during the height of infections at the epicenter of the COVID-19 pandemic.

“This was a study of great clinical significance,” said Kim Boggess, MD, of the University of North Carolina at Chapel Hill, while moderating the session. “I would argue that you guys in New York are the best poised to answer some of the questions that need to be answered as it relates to the effect of coronavirus infection in pregnancy.”

Dr. Boggess asked whether the study examined associations related to the severity of COVID-19. Only 10 of the patients were symptomatic, Dr. Madden said, and only one of those patients developed preeclampsia with severe features.

Michelle Y. Owens, MD, professor and chief of maternal fetal medicine at the University of Mississippi Medical Center, Jackson, who also moderated the session, said in an interview that the findings call for physicians to remain vigilant about evaluating patients who test positive for COVID-19 for hypertensive disease and disorders.

“Additionally, these women should be educated about hypertensive disorders and the common symptoms to facilitate early diagnosis and treatment when indicated,” Dr. Owens said. “I believe this is of particular interest in those women who are not severely affected by COVID, as these changes may occur while they are undergoing quarantine or being monitored remotely. This amplifies the need for remote assessment or home monitoring of maternal blood pressures.”

Dr. Madden, Dr. Boggess, and Dr. Owens have disclosed no relevant financial relationships.

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

Having COVID-19 during pregnancy is linked to a significantly increased risk for gestational hypertension and preeclampsia compared with not having COVID-19 while pregnant, according to findings from a retrospective study presented Jan. 28 at the Society for Maternal-Fetal Medicine 2021 Annual Pregnancy Meeting.

“This was not entirely surprising given that inflammation has been implicated in the pathogenesis of both hypertensive disorders of pregnancy and COVID-19 infection and thus may serve to exacerbate each other,” Nigel Madden, MD, a resident physician in the ob.gyn. department at Columbia University, New York. , told this news organization after she presented the results.

Hypertensive disorders of pregnancy occur in 10%-15% of all pregnancies and are the leading cause of maternal and perinatal morbidity and mortality worldwide, Dr. Madden told attendees of the meeting. Although it’s not clear what causes hypertensive diseases in pregnancy generally, “it is possible that the acute inflammatory state of the COVID infection may incite or exacerbate hypertensive disease of pregnancy,” Dr. Madden said.

The researchers conducted a retrospective chart review of 1,715 patients who had a singleton pregnancy and who underwent routine nasal polymerase chain reaction testing at admission to one institution’s labor and delivery department between March and June 2020. The researchers excluded patients who had a history of chronic hypertension.

Overall, 10% of the patients tested positive for COVID-19 (n = 167), and 90% tested negative (n = 1,548). There were several differences at baseline between the groups. Those who tested positive tended to be younger, with an average age of 28, compared with an average age of 31 years for the group that tested negative. The group that tested negative also had a higher proportion of mothers aged 35 and older (P < .01). There were also significant differences in the racial makeup of the groups. Half of those in the COVID-positive group reported “other” for their race. The biggest baseline disparity between the groups was with regard to insurance type: 73% of those who tested positive for COVID-19 used Medicaid; only 36% of patients in the COVID-negative group used Medicaid. Those with private insurance were more likely to test negative (43%) than positive (25%) (P < .01).

The researchers defined gestational hypertension as having a systolic blood pressure greater than or equal to 140 mm Hg or a diastolic blood pressure greater than or equal to 90 mm Hg on two occasions at least 4 hours apart. A preeclampsia diagnosis required elevated blood pressure (using the same definition as for hypertension) as well as proteinuria, characterized by a protein/creatine ratio greater than or equal to 0.3 mg/dL or greater than or equal to 300 mg of protein on a 24-hour urine collection. Preeclampsia with severe features required prespecified laboratory abnormalities, pulmonary edema, or symptoms of headache, vision changes, chest pain, shortness of breath, or right upper quadrant pain.

More than twice as many patients with COVID had a hypertensive disorder of pregnancy (18%) as those who tested negative (8%). The patients who were COVID positive were significantly more likely than those who tested negative to have gestational hypertension and preeclampsia without severe features. Rates of preeclampsia with severe features were not significantly different between the groups.

The severity of hypertensive disease did not differ between the groups. Limitations of the study included its retrospective design, the small number of COVID-positive patients, and the fact that it was conducted at a single institution in New York. However, the study population was diverse, and it was conducted during the height of infections at the epicenter of the COVID-19 pandemic.

“This was a study of great clinical significance,” said Kim Boggess, MD, of the University of North Carolina at Chapel Hill, while moderating the session. “I would argue that you guys in New York are the best poised to answer some of the questions that need to be answered as it relates to the effect of coronavirus infection in pregnancy.”

Dr. Boggess asked whether the study examined associations related to the severity of COVID-19. Only 10 of the patients were symptomatic, Dr. Madden said, and only one of those patients developed preeclampsia with severe features.

Michelle Y. Owens, MD, professor and chief of maternal fetal medicine at the University of Mississippi Medical Center, Jackson, who also moderated the session, said in an interview that the findings call for physicians to remain vigilant about evaluating patients who test positive for COVID-19 for hypertensive disease and disorders.

“Additionally, these women should be educated about hypertensive disorders and the common symptoms to facilitate early diagnosis and treatment when indicated,” Dr. Owens said. “I believe this is of particular interest in those women who are not severely affected by COVID, as these changes may occur while they are undergoing quarantine or being monitored remotely. This amplifies the need for remote assessment or home monitoring of maternal blood pressures.”

Dr. Madden, Dr. Boggess, and Dr. Owens have disclosed no relevant financial relationships.

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

Having COVID-19 during pregnancy is linked to a significantly increased risk for gestational hypertension and preeclampsia compared with not having COVID-19 while pregnant, according to findings from a retrospective study presented Jan. 28 at the Society for Maternal-Fetal Medicine 2021 Annual Pregnancy Meeting.

“This was not entirely surprising given that inflammation has been implicated in the pathogenesis of both hypertensive disorders of pregnancy and COVID-19 infection and thus may serve to exacerbate each other,” Nigel Madden, MD, a resident physician in the ob.gyn. department at Columbia University, New York. , told this news organization after she presented the results.

Hypertensive disorders of pregnancy occur in 10%-15% of all pregnancies and are the leading cause of maternal and perinatal morbidity and mortality worldwide, Dr. Madden told attendees of the meeting. Although it’s not clear what causes hypertensive diseases in pregnancy generally, “it is possible that the acute inflammatory state of the COVID infection may incite or exacerbate hypertensive disease of pregnancy,” Dr. Madden said.

The researchers conducted a retrospective chart review of 1,715 patients who had a singleton pregnancy and who underwent routine nasal polymerase chain reaction testing at admission to one institution’s labor and delivery department between March and June 2020. The researchers excluded patients who had a history of chronic hypertension.

Overall, 10% of the patients tested positive for COVID-19 (n = 167), and 90% tested negative (n = 1,548). There were several differences at baseline between the groups. Those who tested positive tended to be younger, with an average age of 28, compared with an average age of 31 years for the group that tested negative. The group that tested negative also had a higher proportion of mothers aged 35 and older (P < .01). There were also significant differences in the racial makeup of the groups. Half of those in the COVID-positive group reported “other” for their race. The biggest baseline disparity between the groups was with regard to insurance type: 73% of those who tested positive for COVID-19 used Medicaid; only 36% of patients in the COVID-negative group used Medicaid. Those with private insurance were more likely to test negative (43%) than positive (25%) (P < .01).

The researchers defined gestational hypertension as having a systolic blood pressure greater than or equal to 140 mm Hg or a diastolic blood pressure greater than or equal to 90 mm Hg on two occasions at least 4 hours apart. A preeclampsia diagnosis required elevated blood pressure (using the same definition as for hypertension) as well as proteinuria, characterized by a protein/creatine ratio greater than or equal to 0.3 mg/dL or greater than or equal to 300 mg of protein on a 24-hour urine collection. Preeclampsia with severe features required prespecified laboratory abnormalities, pulmonary edema, or symptoms of headache, vision changes, chest pain, shortness of breath, or right upper quadrant pain.

More than twice as many patients with COVID had a hypertensive disorder of pregnancy (18%) as those who tested negative (8%). The patients who were COVID positive were significantly more likely than those who tested negative to have gestational hypertension and preeclampsia without severe features. Rates of preeclampsia with severe features were not significantly different between the groups.

The severity of hypertensive disease did not differ between the groups. Limitations of the study included its retrospective design, the small number of COVID-positive patients, and the fact that it was conducted at a single institution in New York. However, the study population was diverse, and it was conducted during the height of infections at the epicenter of the COVID-19 pandemic.

“This was a study of great clinical significance,” said Kim Boggess, MD, of the University of North Carolina at Chapel Hill, while moderating the session. “I would argue that you guys in New York are the best poised to answer some of the questions that need to be answered as it relates to the effect of coronavirus infection in pregnancy.”

Dr. Boggess asked whether the study examined associations related to the severity of COVID-19. Only 10 of the patients were symptomatic, Dr. Madden said, and only one of those patients developed preeclampsia with severe features.

Michelle Y. Owens, MD, professor and chief of maternal fetal medicine at the University of Mississippi Medical Center, Jackson, who also moderated the session, said in an interview that the findings call for physicians to remain vigilant about evaluating patients who test positive for COVID-19 for hypertensive disease and disorders.

“Additionally, these women should be educated about hypertensive disorders and the common symptoms to facilitate early diagnosis and treatment when indicated,” Dr. Owens said. “I believe this is of particular interest in those women who are not severely affected by COVID, as these changes may occur while they are undergoing quarantine or being monitored remotely. This amplifies the need for remote assessment or home monitoring of maternal blood pressures.”

Dr. Madden, Dr. Boggess, and Dr. Owens have disclosed no relevant financial relationships.

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

Autopsies on patients who died from COVID-19 are providing important clues on how to treat the disease. In an analysis of 40 hearts from COVID-19 patients who died early in the pandemic, myocyte necrosis was seen in 14 hearts, or 35%.

In the majority of these hearts, pathologists found both small areas of focal necrosis and cardiac thrombi, most of which were microthrombi in myocardial capillaries, arterioles, and small muscular cells.

In an interview, senior author Aloke V. Finn, MD, CVPath Institute, Gaithersburg, Md., stressed the importance of understanding what they saw, but also what they didn’t see.

“What we saw in the majority of patients with myocardial injury were these small areas of infarct and microthrombi in small vessels. What we didn’t see was any evidence of myocarditis and or huge infarcts in, like, the LAD artery,” he said.

“What we’re seeing here is not clinically detectable. ... There is no test that will tell you there are microthrombi and no imaging tests that will show these focal areas of necrosis, but that doesn’t mean it’s not there,” he added.

The finding of myocyte necrosis in about one-third of samples is consistent with another study that showed that 30%-40% of patients hospitalized with COVID-19 have elevated troponins, noted Dr. Finn. The investigators were unable to obtain troponin levels on their patients, which could limit the clinical translation of myocardial necrosis detected at autopsy.

Dr. Finn and colleagues, including first author Dario Pellegrini, MD, from Ospedale Papa Giovanni XXIII in Bergamo, Italy, published their findings online in Circulation on Jan. 22, 2020.

The report is a follow-up to another just published by Dr. Finn’s group in the Journal of the American College of Cardiology, which showed that myocarditis is a very rare finding in COVID-19 autopsies.

Only three of 14 individuals (21.4%) with evidence of myocyte necrosis showed evidence of acute MI, which Dr. Finn and colleagues define as an area of necrosis at least 1 cm² in size. The remaining 11 (78.6%) had only discrete areas of myocyte necrosis (>20 necrotic myocytes with an area of ≥0.05 mm², but <1 cm²).

“This makes sense when we saw what type of thrombus there was in these cases; it wasn’t thrombus in major epicardial vessels but microthombi in small vessels,” said Dr. Finn.

In those with necrosis, cardiac thrombi were present in 11 of 14 (78.6%) cases, with 2 of 14 (14.2%) having epicardial coronary artery thrombi and 0 of 14 (64.3%) having microthrombi in myocardial capillaries, arterioles, and small muscular arteries.

Further supporting the role of COVID-19–related hypercoagulability as the cause of myocardial injury in many patients, the investigators noted that the incidence of severe coronary artery disease (defined as >75% cross sectional narrowing) did not differ significantly between those with and without necrosis.
 

COVID-19 vs. non–COVID-19 thrombi

Going one step further, Dr. Finn’s team compared cardiac microthrombi from their COVID-19–positive autopsy cases with intramyocardial thromboemboli from COVID-19 cases. They also compared the samples with aspirated thrombi obtained during primary percutaneous coronary intervention from uninfected and COVID-19–infected patients presenting with ST-segment elevation MI (STEMI).

The autopsy-obtained microthrombi had significantly more fibrin and terminal complement C5b-9 immunostaining than intramyocardial thromboemboli from COVID-19–negative subjects and than aspirated thrombi from either COVID-positive or COVID-negative STEMI patients.

“Basically, what we’re seeing in these thrombi is evidence of an immune-mediated reaction,” said Dr. Finn, explaining that complement C5b-9 is an innate immune system protein that circulates in the blood in response to any kind of activation of the immune system. “It is nonspecific but can also lead to coagulation problems,” he said.
 

Anticoagulation, yes, but dose unclear

These findings clearly support the use of anticoagulation in hospitalized COVID patients, said Jeffrey Weitz, MD, director of the Thrombosis & Atherosclerosis Research Institute, McMaster University, Hamilton, Ont. But the details of how much anticoagulation, what kind, and for whom are still a moving target.

“I think what we can say at this point is that these autopsy findings fit with previous studies that have shown microthrombi in the lungs and thrombi in the legs and gut, and support the notion that these patients should receive prophylactic doses of anticoagulants if they’re sick enough to be hospitalized,” said Dr. Weitz.

“But it’s not as simple as to say that this study shows clots form in the heart of COVID patients and therefore more anticoagulation is going to be better than less anticoagulation,” he said in an interview.

Recent top-line findings from three linked clinical trials – REMAP-CAP, ACTIV-4, and ATTACC – show that full-dose anticoagulation was beneficial in moderately ill patients hospitalized for COVID-19 and reduced the need for mechanical ventilation.

Moderately ill patients are those not in intensive care and who did not require organ support, such as mechanical ventilation, at the time of enrollment.

However, the same group reported findings in December that showed that routine use of full-dose anticoagulation when started in the ICU in critically ill patients was not beneficial and possibly harmful.

Dr. Weitz was only a little bit surprised by this finding of potential harm in the sickest patients. “I figured everybody should get prophylaxis but I wasn’t sure that everybody should get intensified anticoagulant. But my assumption was that if anybody is going to benefit from it, it would be the ICU patients.”

It was notable, said Dr. Weitz, that levels of D-dimer, a fibrin degradation product, were not associated with outcomes. “So, it doesn’t seem to be that patients with evidence of more clotting are more likely to benefit, which might indicate that it’s not the anticoagulant effect of the heparin that’s helping, but maybe the anti-inflammatory effect. At this point, we just don’t know.”

All three studies have paused enrollment of the critically ill subgroup, but are continuing to enroll patients with moderate illness and expect to publish results in the coming months, according to previous coverage from this news organization.

The study was funded by CVPath, a nonprofit institute that receives funding from a number of different industry entities. Dr. Finn and Dr. Weitz reported no relevant conflicts of interest.

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

Autopsies on patients who died from COVID-19 are providing important clues on how to treat the disease. In an analysis of 40 hearts from COVID-19 patients who died early in the pandemic, myocyte necrosis was seen in 14 hearts, or 35%.

In the majority of these hearts, pathologists found both small areas of focal necrosis and cardiac thrombi, most of which were microthrombi in myocardial capillaries, arterioles, and small muscular cells.

In an interview, senior author Aloke V. Finn, MD, CVPath Institute, Gaithersburg, Md., stressed the importance of understanding what they saw, but also what they didn’t see.

“What we saw in the majority of patients with myocardial injury were these small areas of infarct and microthrombi in small vessels. What we didn’t see was any evidence of myocarditis and or huge infarcts in, like, the LAD artery,” he said.

“What we’re seeing here is not clinically detectable. ... There is no test that will tell you there are microthrombi and no imaging tests that will show these focal areas of necrosis, but that doesn’t mean it’s not there,” he added.

The finding of myocyte necrosis in about one-third of samples is consistent with another study that showed that 30%-40% of patients hospitalized with COVID-19 have elevated troponins, noted Dr. Finn. The investigators were unable to obtain troponin levels on their patients, which could limit the clinical translation of myocardial necrosis detected at autopsy.

Dr. Finn and colleagues, including first author Dario Pellegrini, MD, from Ospedale Papa Giovanni XXIII in Bergamo, Italy, published their findings online in Circulation on Jan. 22, 2020.

The report is a follow-up to another just published by Dr. Finn’s group in the Journal of the American College of Cardiology, which showed that myocarditis is a very rare finding in COVID-19 autopsies.

Only three of 14 individuals (21.4%) with evidence of myocyte necrosis showed evidence of acute MI, which Dr. Finn and colleagues define as an area of necrosis at least 1 cm² in size. The remaining 11 (78.6%) had only discrete areas of myocyte necrosis (>20 necrotic myocytes with an area of ≥0.05 mm², but <1 cm²).

“This makes sense when we saw what type of thrombus there was in these cases; it wasn’t thrombus in major epicardial vessels but microthombi in small vessels,” said Dr. Finn.

In those with necrosis, cardiac thrombi were present in 11 of 14 (78.6%) cases, with 2 of 14 (14.2%) having epicardial coronary artery thrombi and 0 of 14 (64.3%) having microthrombi in myocardial capillaries, arterioles, and small muscular arteries.

Further supporting the role of COVID-19–related hypercoagulability as the cause of myocardial injury in many patients, the investigators noted that the incidence of severe coronary artery disease (defined as >75% cross sectional narrowing) did not differ significantly between those with and without necrosis.
 

COVID-19 vs. non–COVID-19 thrombi

Going one step further, Dr. Finn’s team compared cardiac microthrombi from their COVID-19–positive autopsy cases with intramyocardial thromboemboli from COVID-19 cases. They also compared the samples with aspirated thrombi obtained during primary percutaneous coronary intervention from uninfected and COVID-19–infected patients presenting with ST-segment elevation MI (STEMI).

The autopsy-obtained microthrombi had significantly more fibrin and terminal complement C5b-9 immunostaining than intramyocardial thromboemboli from COVID-19–negative subjects and than aspirated thrombi from either COVID-positive or COVID-negative STEMI patients.

“Basically, what we’re seeing in these thrombi is evidence of an immune-mediated reaction,” said Dr. Finn, explaining that complement C5b-9 is an innate immune system protein that circulates in the blood in response to any kind of activation of the immune system. “It is nonspecific but can also lead to coagulation problems,” he said.
 

Anticoagulation, yes, but dose unclear

These findings clearly support the use of anticoagulation in hospitalized COVID patients, said Jeffrey Weitz, MD, director of the Thrombosis & Atherosclerosis Research Institute, McMaster University, Hamilton, Ont. But the details of how much anticoagulation, what kind, and for whom are still a moving target.

“I think what we can say at this point is that these autopsy findings fit with previous studies that have shown microthrombi in the lungs and thrombi in the legs and gut, and support the notion that these patients should receive prophylactic doses of anticoagulants if they’re sick enough to be hospitalized,” said Dr. Weitz.

“But it’s not as simple as to say that this study shows clots form in the heart of COVID patients and therefore more anticoagulation is going to be better than less anticoagulation,” he said in an interview.

Recent top-line findings from three linked clinical trials – REMAP-CAP, ACTIV-4, and ATTACC – show that full-dose anticoagulation was beneficial in moderately ill patients hospitalized for COVID-19 and reduced the need for mechanical ventilation.

Moderately ill patients are those not in intensive care and who did not require organ support, such as mechanical ventilation, at the time of enrollment.

However, the same group reported findings in December that showed that routine use of full-dose anticoagulation when started in the ICU in critically ill patients was not beneficial and possibly harmful.

Dr. Weitz was only a little bit surprised by this finding of potential harm in the sickest patients. “I figured everybody should get prophylaxis but I wasn’t sure that everybody should get intensified anticoagulant. But my assumption was that if anybody is going to benefit from it, it would be the ICU patients.”

It was notable, said Dr. Weitz, that levels of D-dimer, a fibrin degradation product, were not associated with outcomes. “So, it doesn’t seem to be that patients with evidence of more clotting are more likely to benefit, which might indicate that it’s not the anticoagulant effect of the heparin that’s helping, but maybe the anti-inflammatory effect. At this point, we just don’t know.”

All three studies have paused enrollment of the critically ill subgroup, but are continuing to enroll patients with moderate illness and expect to publish results in the coming months, according to previous coverage from this news organization.

The study was funded by CVPath, a nonprofit institute that receives funding from a number of different industry entities. Dr. Finn and Dr. Weitz reported no relevant conflicts of interest.

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

Autopsies on patients who died from COVID-19 are providing important clues on how to treat the disease. In an analysis of 40 hearts from COVID-19 patients who died early in the pandemic, myocyte necrosis was seen in 14 hearts, or 35%.

In the majority of these hearts, pathologists found both small areas of focal necrosis and cardiac thrombi, most of which were microthrombi in myocardial capillaries, arterioles, and small muscular cells.

In an interview, senior author Aloke V. Finn, MD, CVPath Institute, Gaithersburg, Md., stressed the importance of understanding what they saw, but also what they didn’t see.

“What we saw in the majority of patients with myocardial injury were these small areas of infarct and microthrombi in small vessels. What we didn’t see was any evidence of myocarditis and or huge infarcts in, like, the LAD artery,” he said.

“What we’re seeing here is not clinically detectable. ... There is no test that will tell you there are microthrombi and no imaging tests that will show these focal areas of necrosis, but that doesn’t mean it’s not there,” he added.

The finding of myocyte necrosis in about one-third of samples is consistent with another study that showed that 30%-40% of patients hospitalized with COVID-19 have elevated troponins, noted Dr. Finn. The investigators were unable to obtain troponin levels on their patients, which could limit the clinical translation of myocardial necrosis detected at autopsy.

Dr. Finn and colleagues, including first author Dario Pellegrini, MD, from Ospedale Papa Giovanni XXIII in Bergamo, Italy, published their findings online in Circulation on Jan. 22, 2020.

The report is a follow-up to another just published by Dr. Finn’s group in the Journal of the American College of Cardiology, which showed that myocarditis is a very rare finding in COVID-19 autopsies.

Only three of 14 individuals (21.4%) with evidence of myocyte necrosis showed evidence of acute MI, which Dr. Finn and colleagues define as an area of necrosis at least 1 cm² in size. The remaining 11 (78.6%) had only discrete areas of myocyte necrosis (>20 necrotic myocytes with an area of ≥0.05 mm², but <1 cm²).

“This makes sense when we saw what type of thrombus there was in these cases; it wasn’t thrombus in major epicardial vessels but microthombi in small vessels,” said Dr. Finn.

In those with necrosis, cardiac thrombi were present in 11 of 14 (78.6%) cases, with 2 of 14 (14.2%) having epicardial coronary artery thrombi and 0 of 14 (64.3%) having microthrombi in myocardial capillaries, arterioles, and small muscular arteries.

Further supporting the role of COVID-19–related hypercoagulability as the cause of myocardial injury in many patients, the investigators noted that the incidence of severe coronary artery disease (defined as >75% cross sectional narrowing) did not differ significantly between those with and without necrosis.
 

COVID-19 vs. non–COVID-19 thrombi

Going one step further, Dr. Finn’s team compared cardiac microthrombi from their COVID-19–positive autopsy cases with intramyocardial thromboemboli from COVID-19 cases. They also compared the samples with aspirated thrombi obtained during primary percutaneous coronary intervention from uninfected and COVID-19–infected patients presenting with ST-segment elevation MI (STEMI).

The autopsy-obtained microthrombi had significantly more fibrin and terminal complement C5b-9 immunostaining than intramyocardial thromboemboli from COVID-19–negative subjects and than aspirated thrombi from either COVID-positive or COVID-negative STEMI patients.

“Basically, what we’re seeing in these thrombi is evidence of an immune-mediated reaction,” said Dr. Finn, explaining that complement C5b-9 is an innate immune system protein that circulates in the blood in response to any kind of activation of the immune system. “It is nonspecific but can also lead to coagulation problems,” he said.
 

Anticoagulation, yes, but dose unclear

These findings clearly support the use of anticoagulation in hospitalized COVID patients, said Jeffrey Weitz, MD, director of the Thrombosis & Atherosclerosis Research Institute, McMaster University, Hamilton, Ont. But the details of how much anticoagulation, what kind, and for whom are still a moving target.

“I think what we can say at this point is that these autopsy findings fit with previous studies that have shown microthrombi in the lungs and thrombi in the legs and gut, and support the notion that these patients should receive prophylactic doses of anticoagulants if they’re sick enough to be hospitalized,” said Dr. Weitz.

“But it’s not as simple as to say that this study shows clots form in the heart of COVID patients and therefore more anticoagulation is going to be better than less anticoagulation,” he said in an interview.

Recent top-line findings from three linked clinical trials – REMAP-CAP, ACTIV-4, and ATTACC – show that full-dose anticoagulation was beneficial in moderately ill patients hospitalized for COVID-19 and reduced the need for mechanical ventilation.

Moderately ill patients are those not in intensive care and who did not require organ support, such as mechanical ventilation, at the time of enrollment.

However, the same group reported findings in December that showed that routine use of full-dose anticoagulation when started in the ICU in critically ill patients was not beneficial and possibly harmful.

Dr. Weitz was only a little bit surprised by this finding of potential harm in the sickest patients. “I figured everybody should get prophylaxis but I wasn’t sure that everybody should get intensified anticoagulant. But my assumption was that if anybody is going to benefit from it, it would be the ICU patients.”

It was notable, said Dr. Weitz, that levels of D-dimer, a fibrin degradation product, were not associated with outcomes. “So, it doesn’t seem to be that patients with evidence of more clotting are more likely to benefit, which might indicate that it’s not the anticoagulant effect of the heparin that’s helping, but maybe the anti-inflammatory effect. At this point, we just don’t know.”

All three studies have paused enrollment of the critically ill subgroup, but are continuing to enroll patients with moderate illness and expect to publish results in the coming months, according to previous coverage from this news organization.

The study was funded by CVPath, a nonprofit institute that receives funding from a number of different industry entities. Dr. Finn and Dr. Weitz reported no relevant conflicts of interest.

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

Oral contraceptive use is associated with a decreased risk of ovarian and endometrial cancer 3 decades after discontinuation, according to an analysis of data from more than 250,000 women.

At the same time, oral contraceptive use is associated with a short-term increased risk of breast cancer after discontinuation, although the lifetime risk of breast cancer is not significantly different, the researchers found.

The absolute risk of breast cancer after discontinuation is “extremely small” and should be a limited factor when deciding whether to start oral contraceptive pills (OCPs), a doctor said.

The study was conducted by Torgny Karlsson, PhD, a researcher in the department of immunology, genetics, and pathology at Uppsala (Sweden) University, and colleagues and published online in Cancer Research.


 

Reinforcing and extending knowledge

“These findings are generally consistent with what is known, but extend that knowledge, most notably by the longer-term follow-up for the cohort,” commented Nancy L. Keating, MD, MPH, professor of health care policy and medicine at Harvard Medical School and a physician at Brigham and Women’s Hospital, both in Boston. “Other studies have also shown that OCPs lower risk of ovarian and endometrial cancer. This study suggests that this protective benefit extends up to 30-35 years after discontinuing OCPs.”

The results “reinforce the message to patients of the protective effect of OCPs on risk of ovarian and endometrial cancer,” Dr. Keating said. “Women concerned about these cancers can be reassured that this protective effect appears to persist for decades after discontinuing use.”

Prior studies have indicated that oral contraceptives may be associated with an increased risk of breast cancer.

In terms of breast cancer risk, the study “again extends follow-up and shows that risk of breast cancer was higher for current and ever users through age 50,” although the lifetime risk was not elevated, Dr. Keating said.

“The counseling regarding the effect on breast cancer is more complex,” she said. “I tell women about the very small increased risk of breast cancer during and immediately after use. Because cancer is very rare among women at the ages when OCPs are typically prescribed, the absolute risk increase is extremely small. This paper adds reassurance that this small increase in risk does not persist.”

For certain patients, the association may be more relevant.

“For most women, this risk is so small that it should be a limited factor in their decision to start OCPs,” Dr. Keating said. “However, for women with a substantially higher risk of breast cancer, or a family history of breast cancer at a young age, the small increased risk of breast cancer during and immediately after OCP use is more relevant, and counseling should include carefully weighing the benefits and harms of OCPs with other forms of contraception (and no contraception).”

Although the protective effects of oral contraceptives on ovarian and endometrial cancer were well known, the study describes long-term outcomes that can further inform patient counseling, said Samuel S. Badalian, MD, PhD, chief of the department of obstetrics and gynecology at Bassett Medical Center in Cooperstown, N.Y., and clinical professor of obstetrics and gynecology at the State University of New York, Syracuse.

“Women with individual or family risk factors of ovarian or endometrial cancers will need to know about the protective effects of oral contraceptives and long-term benefits related with their use (30-35 years after discontinuation),” Dr. Badalian said. “Women with family history of breast cancer need to know that lifetime risk of breast cancer might not differ between ever and never users, even if there is an increased short-term risk.”
 

Data from the U.K. Biobank

To examine the time-dependent effects between long-term oral contraceptive use and cancer risk, the researchers examined data from 256,661 women from the U.K. Biobank who were born between 1939 and 1970. The researchers identified cancer diagnoses using information from national registers and self-reported data until March 2019.

Of the women included in the study, 82% had used or still were using oral contraceptives, whereas 18% had never used oral contraceptives. Overall, ever users were younger, more frequently smokers, and had a lower body mass index, compared with never users. Most women started using oral contraceptives between 1969 and 1978. Last use of oral contraceptives occurred on average 10.7 years after starting.

The researchers adjusted for covariates and used logistic regression analyses to measure the cumulative risk of cancer. They used Cox regression analysis to examine instantaneous risk, measured using hazard ratios.

In all, there were 17,739 cases of breast cancer (6.9%), 1,966 cases of ovarian cancer (0.76%), and 2,462 cases of endometrial cancer (0.96%).

Among ever users, the likelihood of ovarian cancer (OR, 0.72) and endometrial cancer (OR, 0.68) was lower, compared with never users. “However, we did not see a significant association between oral contraceptive use and breast cancer” for the study period as a whole, the researchers reported. When the researchers limited follow-up to age 50 years, however, the odds ratio for breast cancer was increased (OR, 1.09).

“Surprisingly, we only found a small increased risk of breast cancer among oral contraceptive users, and the increased risk disappeared within a few years after discontinuation,” Åsa Johansson, PhD, a researcher in the department of immunology, genetics, and pathology at Uppsala University and one of the study authors, said in a news release. “Our results suggest that the lifetime risk of breast cancer might not differ between ever and never users, even if there is an increased short-term risk.”

Oral contraceptives today typically use lower doses of estrogen and other types of progesterone, compared with formulas commonly used when participants in the study started taking them, so the results may not directly apply to patients currently taking oral contraceptives, the researchers noted.

The study was supported by the Swedish Research Council, the Swedish Cancer Society, and the Kjell and Märta Beijers, the Marcus Borgström, the Åke Wiberg, and the A and M Rudbergs foundations. The authors, Dr. Keating, and Dr. Badalian had no conflicts of interest.
 

[email protected]

Oral contraceptive use is associated with a decreased risk of ovarian and endometrial cancer 3 decades after discontinuation, according to an analysis of data from more than 250,000 women.

At the same time, oral contraceptive use is associated with a short-term increased risk of breast cancer after discontinuation, although the lifetime risk of breast cancer is not significantly different, the researchers found.

The absolute risk of breast cancer after discontinuation is “extremely small” and should be a limited factor when deciding whether to start oral contraceptive pills (OCPs), a doctor said.

The study was conducted by Torgny Karlsson, PhD, a researcher in the department of immunology, genetics, and pathology at Uppsala (Sweden) University, and colleagues and published online in Cancer Research.


 

Reinforcing and extending knowledge

“These findings are generally consistent with what is known, but extend that knowledge, most notably by the longer-term follow-up for the cohort,” commented Nancy L. Keating, MD, MPH, professor of health care policy and medicine at Harvard Medical School and a physician at Brigham and Women’s Hospital, both in Boston. “Other studies have also shown that OCPs lower risk of ovarian and endometrial cancer. This study suggests that this protective benefit extends up to 30-35 years after discontinuing OCPs.”

The results “reinforce the message to patients of the protective effect of OCPs on risk of ovarian and endometrial cancer,” Dr. Keating said. “Women concerned about these cancers can be reassured that this protective effect appears to persist for decades after discontinuing use.”

Prior studies have indicated that oral contraceptives may be associated with an increased risk of breast cancer.

In terms of breast cancer risk, the study “again extends follow-up and shows that risk of breast cancer was higher for current and ever users through age 50,” although the lifetime risk was not elevated, Dr. Keating said.

“The counseling regarding the effect on breast cancer is more complex,” she said. “I tell women about the very small increased risk of breast cancer during and immediately after use. Because cancer is very rare among women at the ages when OCPs are typically prescribed, the absolute risk increase is extremely small. This paper adds reassurance that this small increase in risk does not persist.”

For certain patients, the association may be more relevant.

“For most women, this risk is so small that it should be a limited factor in their decision to start OCPs,” Dr. Keating said. “However, for women with a substantially higher risk of breast cancer, or a family history of breast cancer at a young age, the small increased risk of breast cancer during and immediately after OCP use is more relevant, and counseling should include carefully weighing the benefits and harms of OCPs with other forms of contraception (and no contraception).”

Although the protective effects of oral contraceptives on ovarian and endometrial cancer were well known, the study describes long-term outcomes that can further inform patient counseling, said Samuel S. Badalian, MD, PhD, chief of the department of obstetrics and gynecology at Bassett Medical Center in Cooperstown, N.Y., and clinical professor of obstetrics and gynecology at the State University of New York, Syracuse.

“Women with individual or family risk factors of ovarian or endometrial cancers will need to know about the protective effects of oral contraceptives and long-term benefits related with their use (30-35 years after discontinuation),” Dr. Badalian said. “Women with family history of breast cancer need to know that lifetime risk of breast cancer might not differ between ever and never users, even if there is an increased short-term risk.”
 

Data from the U.K. Biobank

To examine the time-dependent effects between long-term oral contraceptive use and cancer risk, the researchers examined data from 256,661 women from the U.K. Biobank who were born between 1939 and 1970. The researchers identified cancer diagnoses using information from national registers and self-reported data until March 2019.

Of the women included in the study, 82% had used or still were using oral contraceptives, whereas 18% had never used oral contraceptives. Overall, ever users were younger, more frequently smokers, and had a lower body mass index, compared with never users. Most women started using oral contraceptives between 1969 and 1978. Last use of oral contraceptives occurred on average 10.7 years after starting.

The researchers adjusted for covariates and used logistic regression analyses to measure the cumulative risk of cancer. They used Cox regression analysis to examine instantaneous risk, measured using hazard ratios.

In all, there were 17,739 cases of breast cancer (6.9%), 1,966 cases of ovarian cancer (0.76%), and 2,462 cases of endometrial cancer (0.96%).

Among ever users, the likelihood of ovarian cancer (OR, 0.72) and endometrial cancer (OR, 0.68) was lower, compared with never users. “However, we did not see a significant association between oral contraceptive use and breast cancer” for the study period as a whole, the researchers reported. When the researchers limited follow-up to age 50 years, however, the odds ratio for breast cancer was increased (OR, 1.09).

“Surprisingly, we only found a small increased risk of breast cancer among oral contraceptive users, and the increased risk disappeared within a few years after discontinuation,” Åsa Johansson, PhD, a researcher in the department of immunology, genetics, and pathology at Uppsala University and one of the study authors, said in a news release. “Our results suggest that the lifetime risk of breast cancer might not differ between ever and never users, even if there is an increased short-term risk.”

Oral contraceptives today typically use lower doses of estrogen and other types of progesterone, compared with formulas commonly used when participants in the study started taking them, so the results may not directly apply to patients currently taking oral contraceptives, the researchers noted.

The study was supported by the Swedish Research Council, the Swedish Cancer Society, and the Kjell and Märta Beijers, the Marcus Borgström, the Åke Wiberg, and the A and M Rudbergs foundations. The authors, Dr. Keating, and Dr. Badalian had no conflicts of interest.
 

[email protected]

Oral contraceptive use is associated with a decreased risk of ovarian and endometrial cancer 3 decades after discontinuation, according to an analysis of data from more than 250,000 women.

At the same time, oral contraceptive use is associated with a short-term increased risk of breast cancer after discontinuation, although the lifetime risk of breast cancer is not significantly different, the researchers found.

The absolute risk of breast cancer after discontinuation is “extremely small” and should be a limited factor when deciding whether to start oral contraceptive pills (OCPs), a doctor said.

The study was conducted by Torgny Karlsson, PhD, a researcher in the department of immunology, genetics, and pathology at Uppsala (Sweden) University, and colleagues and published online in Cancer Research.


 

Reinforcing and extending knowledge

“These findings are generally consistent with what is known, but extend that knowledge, most notably by the longer-term follow-up for the cohort,” commented Nancy L. Keating, MD, MPH, professor of health care policy and medicine at Harvard Medical School and a physician at Brigham and Women’s Hospital, both in Boston. “Other studies have also shown that OCPs lower risk of ovarian and endometrial cancer. This study suggests that this protective benefit extends up to 30-35 years after discontinuing OCPs.”

The results “reinforce the message to patients of the protective effect of OCPs on risk of ovarian and endometrial cancer,” Dr. Keating said. “Women concerned about these cancers can be reassured that this protective effect appears to persist for decades after discontinuing use.”

Prior studies have indicated that oral contraceptives may be associated with an increased risk of breast cancer.

In terms of breast cancer risk, the study “again extends follow-up and shows that risk of breast cancer was higher for current and ever users through age 50,” although the lifetime risk was not elevated, Dr. Keating said.

“The counseling regarding the effect on breast cancer is more complex,” she said. “I tell women about the very small increased risk of breast cancer during and immediately after use. Because cancer is very rare among women at the ages when OCPs are typically prescribed, the absolute risk increase is extremely small. This paper adds reassurance that this small increase in risk does not persist.”

For certain patients, the association may be more relevant.

“For most women, this risk is so small that it should be a limited factor in their decision to start OCPs,” Dr. Keating said. “However, for women with a substantially higher risk of breast cancer, or a family history of breast cancer at a young age, the small increased risk of breast cancer during and immediately after OCP use is more relevant, and counseling should include carefully weighing the benefits and harms of OCPs with other forms of contraception (and no contraception).”

Although the protective effects of oral contraceptives on ovarian and endometrial cancer were well known, the study describes long-term outcomes that can further inform patient counseling, said Samuel S. Badalian, MD, PhD, chief of the department of obstetrics and gynecology at Bassett Medical Center in Cooperstown, N.Y., and clinical professor of obstetrics and gynecology at the State University of New York, Syracuse.

“Women with individual or family risk factors of ovarian or endometrial cancers will need to know about the protective effects of oral contraceptives and long-term benefits related with their use (30-35 years after discontinuation),” Dr. Badalian said. “Women with family history of breast cancer need to know that lifetime risk of breast cancer might not differ between ever and never users, even if there is an increased short-term risk.”
 

Data from the U.K. Biobank

To examine the time-dependent effects between long-term oral contraceptive use and cancer risk, the researchers examined data from 256,661 women from the U.K. Biobank who were born between 1939 and 1970. The researchers identified cancer diagnoses using information from national registers and self-reported data until March 2019.

Of the women included in the study, 82% had used or still were using oral contraceptives, whereas 18% had never used oral contraceptives. Overall, ever users were younger, more frequently smokers, and had a lower body mass index, compared with never users. Most women started using oral contraceptives between 1969 and 1978. Last use of oral contraceptives occurred on average 10.7 years after starting.

The researchers adjusted for covariates and used logistic regression analyses to measure the cumulative risk of cancer. They used Cox regression analysis to examine instantaneous risk, measured using hazard ratios.

In all, there were 17,739 cases of breast cancer (6.9%), 1,966 cases of ovarian cancer (0.76%), and 2,462 cases of endometrial cancer (0.96%).

Among ever users, the likelihood of ovarian cancer (OR, 0.72) and endometrial cancer (OR, 0.68) was lower, compared with never users. “However, we did not see a significant association between oral contraceptive use and breast cancer” for the study period as a whole, the researchers reported. When the researchers limited follow-up to age 50 years, however, the odds ratio for breast cancer was increased (OR, 1.09).

“Surprisingly, we only found a small increased risk of breast cancer among oral contraceptive users, and the increased risk disappeared within a few years after discontinuation,” Åsa Johansson, PhD, a researcher in the department of immunology, genetics, and pathology at Uppsala University and one of the study authors, said in a news release. “Our results suggest that the lifetime risk of breast cancer might not differ between ever and never users, even if there is an increased short-term risk.”

Oral contraceptives today typically use lower doses of estrogen and other types of progesterone, compared with formulas commonly used when participants in the study started taking them, so the results may not directly apply to patients currently taking oral contraceptives, the researchers noted.

The study was supported by the Swedish Research Council, the Swedish Cancer Society, and the Kjell and Märta Beijers, the Marcus Borgström, the Åke Wiberg, and the A and M Rudbergs foundations. The authors, Dr. Keating, and Dr. Badalian had no conflicts of interest.
 

[email protected]

The use of low-dose aspirin among older people shows no effect in reducing the incidence of certain cancer types. However, the treatment – particularly with frequency of at least three times a week – is associated with reductions in mortality in bladder cancer and breast cancer, new observational research shows.

“The results presented here add to the accumulating evidence that aspirin may improve survival for some cancers,” the authors write in their cohort study that uses data from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. The new research was published online Jan. 15 in JAMA Network Open. 

“Although prior research has been most heavily concentrated in gastrointestinal cancers, our analysis extends the advantages associated with aspirin use to other cancers, such as bladder and breast cancers,” they explained.

In commenting on the study, John J. McNeil, MBBS, PhD, head of the department of epidemiology and preventive medicine at Monash University in Melbourne, said the findings, though intriguing, are not necessarily conclusive.

“The data was derived from a very large and well-conducted study,” Dr. McNeil, who has led other research on aspirin use and the elderly, said in an interview.

“But these conclusions were drawn from the observational component of the study and therefore potentially confounded by other characteristics that differentiate aspirin users from nonusers.”
 

Aspirin/cancer research in older people lacking

With well-known reports of decreased risks of heart disease, stroke, cancer – particularly gastrointestinal cancers – and all-cause mortality, as many as 25%-50% of adults in the U.S. report taking aspirin daily or every other day.

However, evidence of the benefits relating to cancer, specifically in older people, has been inconsistent, with one recent notable study, the randomized, double-blind ASPREE trial, showing no effect of aspirin on cancer incidence, but a higher mortality rate in elderly patients randomly assigned to aspirin for primary prevention.

To further investigate the effects in older patients, first author Holli A. Loomans-Kropp, PhD, and colleagues with the National Cancer Institute evaluated data on patients who were either 65 years or older at baseline or who had reached aged 65 during follow-up in the PLCO Cancer Screening Trial, which had enrollment from 1993 to 2001.

The authors identified 139,896 individuals with a mean age at baseline of 66.4 years; about half were women and 88.5% were non-Hispanic White.

Follow-up took place until the time of death, December 2014 for those who consented to follow-up, or December 2009 for those who refused consent to follow-up. The authors reported that there were 32,580 incident cancers, including 5.4% bladder, 14% breast, 1% esophageal, 1.2% gastric, 2.7% pancreatic, and 2.2% uterine cancers.

The study showed no association between aspirin use and the incidence of any of the cancer types included in the study among those over age 65.

However, further multivariate analysis of survival showed that, with follow-up adjusted to until the time of death, Dec. 31, 2015, or earlier refusal to consent, the use of aspirin at least three times per week was associated with reduced mortality in those with bladder (hazard ratio, 0.67) and breast (HR, 0.75) cancers, whereas no significant associations were observed with esophageal, gastric, pancreatic, or uterine cancer.

A similar association of any aspirin use (less than three times per week) with bladder (HR, 0.75) and breast (HR, 0.79) cancer survival was observed, the authors noted.

“These results may indicate that, for some cancer types, any aspirin use may be advantageous; however, greater benefit may be observed with increased frequency of use,” the authors wrote.
 

Mechanism speculation focuses on COX-2 pathway

Theories of the mechanisms behind a potential benefit of aspirin for those with bladder cancer include that urothelial cancer has increased RNA and protein expression of cyclooxygenase-2 (COX-2) and urinary prostaglandin E2, “suggesting up-regulation of the COX-2 pathway during cancer progression,” the authors wrote.  

In breast cancer, a similar elevated expression of COX-2 has been shown to predict disease outcomes, including progression and decreased survival.

“This may be partly due to the mechanistic interplay between angiogenesis, cell proliferation, apoptosis, and inflammatory processes,” the authors noted.

The study isn’t the first to show a benefit specifically with bladder cancer; other studies include recent research (J Urol. 2018 Nov;200[5]:1014-21) showing that daily aspirin use among patients with bladder cancer was associated with increased 5-year survival following radical cystectomy, the authors noted.

Dr. McNeil noted that the new findings from the U.S. researchers, particularly regarding bladder cancer, are of interest. “The reduction in mortality from breast cancer is modest, but the reduction in mortality from bladder cancer was more impressive,” he said.

“However, given the fact that this finding is observational data and was a sole finding among multiple comparisons, it must be seen as suggestive rather than proven.”

Regarding possible mechanisms, Dr. McNeil added that, like the bulk of the prior research, many questions remain.

“There have been many suggestions about ways that aspirin might work at a molecular and cellular level, but no firm consensus has been reached.”

The study authors and Dr. McNeil disclosed no relevant financial relationships.

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

The use of low-dose aspirin among older people shows no effect in reducing the incidence of certain cancer types. However, the treatment – particularly with frequency of at least three times a week – is associated with reductions in mortality in bladder cancer and breast cancer, new observational research shows.

“The results presented here add to the accumulating evidence that aspirin may improve survival for some cancers,” the authors write in their cohort study that uses data from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. The new research was published online Jan. 15 in JAMA Network Open. 

“Although prior research has been most heavily concentrated in gastrointestinal cancers, our analysis extends the advantages associated with aspirin use to other cancers, such as bladder and breast cancers,” they explained.

In commenting on the study, John J. McNeil, MBBS, PhD, head of the department of epidemiology and preventive medicine at Monash University in Melbourne, said the findings, though intriguing, are not necessarily conclusive.

“The data was derived from a very large and well-conducted study,” Dr. McNeil, who has led other research on aspirin use and the elderly, said in an interview.

“But these conclusions were drawn from the observational component of the study and therefore potentially confounded by other characteristics that differentiate aspirin users from nonusers.”
 

Aspirin/cancer research in older people lacking

With well-known reports of decreased risks of heart disease, stroke, cancer – particularly gastrointestinal cancers – and all-cause mortality, as many as 25%-50% of adults in the U.S. report taking aspirin daily or every other day.

However, evidence of the benefits relating to cancer, specifically in older people, has been inconsistent, with one recent notable study, the randomized, double-blind ASPREE trial, showing no effect of aspirin on cancer incidence, but a higher mortality rate in elderly patients randomly assigned to aspirin for primary prevention.

To further investigate the effects in older patients, first author Holli A. Loomans-Kropp, PhD, and colleagues with the National Cancer Institute evaluated data on patients who were either 65 years or older at baseline or who had reached aged 65 during follow-up in the PLCO Cancer Screening Trial, which had enrollment from 1993 to 2001.

The authors identified 139,896 individuals with a mean age at baseline of 66.4 years; about half were women and 88.5% were non-Hispanic White.

Follow-up took place until the time of death, December 2014 for those who consented to follow-up, or December 2009 for those who refused consent to follow-up. The authors reported that there were 32,580 incident cancers, including 5.4% bladder, 14% breast, 1% esophageal, 1.2% gastric, 2.7% pancreatic, and 2.2% uterine cancers.

The study showed no association between aspirin use and the incidence of any of the cancer types included in the study among those over age 65.

However, further multivariate analysis of survival showed that, with follow-up adjusted to until the time of death, Dec. 31, 2015, or earlier refusal to consent, the use of aspirin at least three times per week was associated with reduced mortality in those with bladder (hazard ratio, 0.67) and breast (HR, 0.75) cancers, whereas no significant associations were observed with esophageal, gastric, pancreatic, or uterine cancer.

A similar association of any aspirin use (less than three times per week) with bladder (HR, 0.75) and breast (HR, 0.79) cancer survival was observed, the authors noted.

“These results may indicate that, for some cancer types, any aspirin use may be advantageous; however, greater benefit may be observed with increased frequency of use,” the authors wrote.
 

Mechanism speculation focuses on COX-2 pathway

Theories of the mechanisms behind a potential benefit of aspirin for those with bladder cancer include that urothelial cancer has increased RNA and protein expression of cyclooxygenase-2 (COX-2) and urinary prostaglandin E2, “suggesting up-regulation of the COX-2 pathway during cancer progression,” the authors wrote.  

In breast cancer, a similar elevated expression of COX-2 has been shown to predict disease outcomes, including progression and decreased survival.

“This may be partly due to the mechanistic interplay between angiogenesis, cell proliferation, apoptosis, and inflammatory processes,” the authors noted.

The study isn’t the first to show a benefit specifically with bladder cancer; other studies include recent research (J Urol. 2018 Nov;200[5]:1014-21) showing that daily aspirin use among patients with bladder cancer was associated with increased 5-year survival following radical cystectomy, the authors noted.

Dr. McNeil noted that the new findings from the U.S. researchers, particularly regarding bladder cancer, are of interest. “The reduction in mortality from breast cancer is modest, but the reduction in mortality from bladder cancer was more impressive,” he said.

“However, given the fact that this finding is observational data and was a sole finding among multiple comparisons, it must be seen as suggestive rather than proven.”

Regarding possible mechanisms, Dr. McNeil added that, like the bulk of the prior research, many questions remain.

“There have been many suggestions about ways that aspirin might work at a molecular and cellular level, but no firm consensus has been reached.”

The study authors and Dr. McNeil disclosed no relevant financial relationships.

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

The use of low-dose aspirin among older people shows no effect in reducing the incidence of certain cancer types. However, the treatment – particularly with frequency of at least three times a week – is associated with reductions in mortality in bladder cancer and breast cancer, new observational research shows.

“The results presented here add to the accumulating evidence that aspirin may improve survival for some cancers,” the authors write in their cohort study that uses data from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. The new research was published online Jan. 15 in JAMA Network Open. 

“Although prior research has been most heavily concentrated in gastrointestinal cancers, our analysis extends the advantages associated with aspirin use to other cancers, such as bladder and breast cancers,” they explained.

In commenting on the study, John J. McNeil, MBBS, PhD, head of the department of epidemiology and preventive medicine at Monash University in Melbourne, said the findings, though intriguing, are not necessarily conclusive.

“The data was derived from a very large and well-conducted study,” Dr. McNeil, who has led other research on aspirin use and the elderly, said in an interview.

“But these conclusions were drawn from the observational component of the study and therefore potentially confounded by other characteristics that differentiate aspirin users from nonusers.”
 

Aspirin/cancer research in older people lacking

With well-known reports of decreased risks of heart disease, stroke, cancer – particularly gastrointestinal cancers – and all-cause mortality, as many as 25%-50% of adults in the U.S. report taking aspirin daily or every other day.

However, evidence of the benefits relating to cancer, specifically in older people, has been inconsistent, with one recent notable study, the randomized, double-blind ASPREE trial, showing no effect of aspirin on cancer incidence, but a higher mortality rate in elderly patients randomly assigned to aspirin for primary prevention.

To further investigate the effects in older patients, first author Holli A. Loomans-Kropp, PhD, and colleagues with the National Cancer Institute evaluated data on patients who were either 65 years or older at baseline or who had reached aged 65 during follow-up in the PLCO Cancer Screening Trial, which had enrollment from 1993 to 2001.

The authors identified 139,896 individuals with a mean age at baseline of 66.4 years; about half were women and 88.5% were non-Hispanic White.

Follow-up took place until the time of death, December 2014 for those who consented to follow-up, or December 2009 for those who refused consent to follow-up. The authors reported that there were 32,580 incident cancers, including 5.4% bladder, 14% breast, 1% esophageal, 1.2% gastric, 2.7% pancreatic, and 2.2% uterine cancers.

The study showed no association between aspirin use and the incidence of any of the cancer types included in the study among those over age 65.

However, further multivariate analysis of survival showed that, with follow-up adjusted to until the time of death, Dec. 31, 2015, or earlier refusal to consent, the use of aspirin at least three times per week was associated with reduced mortality in those with bladder (hazard ratio, 0.67) and breast (HR, 0.75) cancers, whereas no significant associations were observed with esophageal, gastric, pancreatic, or uterine cancer.

A similar association of any aspirin use (less than three times per week) with bladder (HR, 0.75) and breast (HR, 0.79) cancer survival was observed, the authors noted.

“These results may indicate that, for some cancer types, any aspirin use may be advantageous; however, greater benefit may be observed with increased frequency of use,” the authors wrote.
 

Mechanism speculation focuses on COX-2 pathway

Theories of the mechanisms behind a potential benefit of aspirin for those with bladder cancer include that urothelial cancer has increased RNA and protein expression of cyclooxygenase-2 (COX-2) and urinary prostaglandin E2, “suggesting up-regulation of the COX-2 pathway during cancer progression,” the authors wrote.  

In breast cancer, a similar elevated expression of COX-2 has been shown to predict disease outcomes, including progression and decreased survival.

“This may be partly due to the mechanistic interplay between angiogenesis, cell proliferation, apoptosis, and inflammatory processes,” the authors noted.

The study isn’t the first to show a benefit specifically with bladder cancer; other studies include recent research (J Urol. 2018 Nov;200[5]:1014-21) showing that daily aspirin use among patients with bladder cancer was associated with increased 5-year survival following radical cystectomy, the authors noted.

Dr. McNeil noted that the new findings from the U.S. researchers, particularly regarding bladder cancer, are of interest. “The reduction in mortality from breast cancer is modest, but the reduction in mortality from bladder cancer was more impressive,” he said.

“However, given the fact that this finding is observational data and was a sole finding among multiple comparisons, it must be seen as suggestive rather than proven.”

Regarding possible mechanisms, Dr. McNeil added that, like the bulk of the prior research, many questions remain.

“There have been many suggestions about ways that aspirin might work at a molecular and cellular level, but no firm consensus has been reached.”

The study authors and Dr. McNeil disclosed no relevant financial relationships.

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