MDedge ObGyn

A study of the duration of the second stage of labor in more than 2,000 women who delivered twins may provide useful reference ranges for doctors and patients, researchers say.

Although the analysis found statistically significant differences in second-stage labor lengths for twin and singleton deliveries, “ultimately I think the value in this is seeing that it is not much different,” said Nathan Fox, MD, a maternal-fetal medicine specialist who has studied twin pregnancies and delivery of twins.
 

Knowledge gap

While most twin births occur by cesarean delivery, vaginal delivery is a preferred method for diamniotic twins with the first twin in vertex presentation, wrote study author Gabriel Levin, MD, and colleagues. Prior studies, however, have not clearly established the duration of the second stage of labor in twin deliveries – that is, the time from 10-cm dilation until delivery of the first twin, they said.

Knowing “the parameters of the normal second stage of labor” for twin deliveries may help guide clinical practice and possibly avoid unnecessary operative deliveries, the researchers wrote.

To establish normal ranges for the second stage of labor in twin deliveries, Dr. Levin, of the department of obstetrics and gynecology at Hadassah-Hebrew University Medical Center, Jerusalem, and coauthors conducted a retrospective cohort study. They analyzed data from three large academic hospitals in Israel between 2011 and June 2020 and assessed the length of the second stage of labor by obstetric history and clinical characteristics.

The researchers included data from women who delivered the first of diamniotic twins spontaneously or delivered a singleton spontaneously. The researchers excluded twin pregnancies with fetal demise of one or both twins, structural anomaly or chromosomal abnormality, monochorionic complications, and first twin in a nonvertex presentation. They did not consider the delivery mode of the second twin.

The study included 2,009 twin deliveries and 135,217 singleton deliveries. Of the women with twin deliveries, 32.6% were nulliparous (that is, no previous vaginal deliveries), 61.5% were parous (one to four previous vaginal deliveries, and no cesarean deliveries), and 5.9% were grand multiparous (at least five previous deliveries).

Of the women with singleton deliveries, 29% were nulliparous.

For nulliparous women delivering twins, the median length of the second stage was 1 hour 27 minutes (interquartile range, 40-147 minutes), and the 95th percentile was 3 hours 51 minutes.

For parous women delivering twins, the median length of the second stage was 18 minutes (interquartile range, 8-36 minutes), and the 95th percentile was 1 hour 56 minutes.

For grand multiparous women, the median length of the second stage was 10 minutes.

In a multivariable analysis, epidural anesthesia and induction of labor were independently associated with increased length of the second stage of labor.

Second-stage labor longer than the 95th percentile based on parity and epidural status was associated with approximately twice the risk of admission to the neonatal intensive care unit (35.4% vs. 16.4%) and need for phototherapy, the researchers reported.

Compared with singleton deliveries, the second stage was longer in twin deliveries. Among nulliparous patients, the median length of the second stage of labor was 1 hour 18 minutes for singleton deliveries, versus 1 hour 30 minutes for twin deliveries. Among parous patients, the median length of the second stage was 19 minutes for twin deliveries, compared with 10 minutes for singleton deliveries.

The study was conducted in Israel, which may limit its generalizability, the authors noted. In addition, the researchers lacked data about maternal morbidity and had limited data about neonatal morbidity. “The exact time that the woman became 10-cm dilated cannot be known, a problem inherent to all such studies,” and cases where doctors artificially ended labor with operative delivery were not included, the researchers added. “More research is needed to determine at what point, if any, intervention is warranted to shorten the second stage in patients delivering twins,” Dr. Levin and colleagues wrote.

Providing a framework

“We always get more concerned if the labor process is happening in a way that is unusual,” and this study provides data that can provide a framework for that thought process, said Dr. Fox, who was not involved in the study.

The results demonstrate that the second stage of labor for twin deliveries may take a long time and “that is not necessarily a bad thing,” said Dr. Fox, clinical professor of obstetrics and gynecology and maternal and fetal medicine at the Icahn School of Medicine at Mount Sinai in New York.

For women having their first child, the second stage of labor tends to take much longer than it does for women who have had children. “That is well known for singletons, and everyone assumes it is the same for twins,” but this study quantifies the durations for twins, he said. “That is valuable, and it is also helpful for women to know what to expect.”

A study coauthor disclosed financial ties to PregnanTech and Anthem AI, and money paid to their institution from New Sight. Dr. Fox works at Maternal Fetal Medicine Associates and Carnegie Imaging for Women in New York and is the creator and host of the Healthful Woman Podcast. He had no relevant financial disclosures.

jremaly@mdedge.com

A study of the duration of the second stage of labor in more than 2,000 women who delivered twins may provide useful reference ranges for doctors and patients, researchers say.

Although the analysis found statistically significant differences in second-stage labor lengths for twin and singleton deliveries, “ultimately I think the value in this is seeing that it is not much different,” said Nathan Fox, MD, a maternal-fetal medicine specialist who has studied twin pregnancies and delivery of twins.
 

Knowledge gap

While most twin births occur by cesarean delivery, vaginal delivery is a preferred method for diamniotic twins with the first twin in vertex presentation, wrote study author Gabriel Levin, MD, and colleagues. Prior studies, however, have not clearly established the duration of the second stage of labor in twin deliveries – that is, the time from 10-cm dilation until delivery of the first twin, they said.

Knowing “the parameters of the normal second stage of labor” for twin deliveries may help guide clinical practice and possibly avoid unnecessary operative deliveries, the researchers wrote.

To establish normal ranges for the second stage of labor in twin deliveries, Dr. Levin, of the department of obstetrics and gynecology at Hadassah-Hebrew University Medical Center, Jerusalem, and coauthors conducted a retrospective cohort study. They analyzed data from three large academic hospitals in Israel between 2011 and June 2020 and assessed the length of the second stage of labor by obstetric history and clinical characteristics.

The researchers included data from women who delivered the first of diamniotic twins spontaneously or delivered a singleton spontaneously. The researchers excluded twin pregnancies with fetal demise of one or both twins, structural anomaly or chromosomal abnormality, monochorionic complications, and first twin in a nonvertex presentation. They did not consider the delivery mode of the second twin.

The study included 2,009 twin deliveries and 135,217 singleton deliveries. Of the women with twin deliveries, 32.6% were nulliparous (that is, no previous vaginal deliveries), 61.5% were parous (one to four previous vaginal deliveries, and no cesarean deliveries), and 5.9% were grand multiparous (at least five previous deliveries).

Of the women with singleton deliveries, 29% were nulliparous.

For nulliparous women delivering twins, the median length of the second stage was 1 hour 27 minutes (interquartile range, 40-147 minutes), and the 95th percentile was 3 hours 51 minutes.

For parous women delivering twins, the median length of the second stage was 18 minutes (interquartile range, 8-36 minutes), and the 95th percentile was 1 hour 56 minutes.

For grand multiparous women, the median length of the second stage was 10 minutes.

In a multivariable analysis, epidural anesthesia and induction of labor were independently associated with increased length of the second stage of labor.

Second-stage labor longer than the 95th percentile based on parity and epidural status was associated with approximately twice the risk of admission to the neonatal intensive care unit (35.4% vs. 16.4%) and need for phototherapy, the researchers reported.

Compared with singleton deliveries, the second stage was longer in twin deliveries. Among nulliparous patients, the median length of the second stage of labor was 1 hour 18 minutes for singleton deliveries, versus 1 hour 30 minutes for twin deliveries. Among parous patients, the median length of the second stage was 19 minutes for twin deliveries, compared with 10 minutes for singleton deliveries.

The study was conducted in Israel, which may limit its generalizability, the authors noted. In addition, the researchers lacked data about maternal morbidity and had limited data about neonatal morbidity. “The exact time that the woman became 10-cm dilated cannot be known, a problem inherent to all such studies,” and cases where doctors artificially ended labor with operative delivery were not included, the researchers added. “More research is needed to determine at what point, if any, intervention is warranted to shorten the second stage in patients delivering twins,” Dr. Levin and colleagues wrote.

Providing a framework

“We always get more concerned if the labor process is happening in a way that is unusual,” and this study provides data that can provide a framework for that thought process, said Dr. Fox, who was not involved in the study.

The results demonstrate that the second stage of labor for twin deliveries may take a long time and “that is not necessarily a bad thing,” said Dr. Fox, clinical professor of obstetrics and gynecology and maternal and fetal medicine at the Icahn School of Medicine at Mount Sinai in New York.

For women having their first child, the second stage of labor tends to take much longer than it does for women who have had children. “That is well known for singletons, and everyone assumes it is the same for twins,” but this study quantifies the durations for twins, he said. “That is valuable, and it is also helpful for women to know what to expect.”

A study coauthor disclosed financial ties to PregnanTech and Anthem AI, and money paid to their institution from New Sight. Dr. Fox works at Maternal Fetal Medicine Associates and Carnegie Imaging for Women in New York and is the creator and host of the Healthful Woman Podcast. He had no relevant financial disclosures.

jremaly@mdedge.com

A study of the duration of the second stage of labor in more than 2,000 women who delivered twins may provide useful reference ranges for doctors and patients, researchers say.

Although the analysis found statistically significant differences in second-stage labor lengths for twin and singleton deliveries, “ultimately I think the value in this is seeing that it is not much different,” said Nathan Fox, MD, a maternal-fetal medicine specialist who has studied twin pregnancies and delivery of twins.
 

Knowledge gap

While most twin births occur by cesarean delivery, vaginal delivery is a preferred method for diamniotic twins with the first twin in vertex presentation, wrote study author Gabriel Levin, MD, and colleagues. Prior studies, however, have not clearly established the duration of the second stage of labor in twin deliveries – that is, the time from 10-cm dilation until delivery of the first twin, they said.

Knowing “the parameters of the normal second stage of labor” for twin deliveries may help guide clinical practice and possibly avoid unnecessary operative deliveries, the researchers wrote.

To establish normal ranges for the second stage of labor in twin deliveries, Dr. Levin, of the department of obstetrics and gynecology at Hadassah-Hebrew University Medical Center, Jerusalem, and coauthors conducted a retrospective cohort study. They analyzed data from three large academic hospitals in Israel between 2011 and June 2020 and assessed the length of the second stage of labor by obstetric history and clinical characteristics.

The researchers included data from women who delivered the first of diamniotic twins spontaneously or delivered a singleton spontaneously. The researchers excluded twin pregnancies with fetal demise of one or both twins, structural anomaly or chromosomal abnormality, monochorionic complications, and first twin in a nonvertex presentation. They did not consider the delivery mode of the second twin.

The study included 2,009 twin deliveries and 135,217 singleton deliveries. Of the women with twin deliveries, 32.6% were nulliparous (that is, no previous vaginal deliveries), 61.5% were parous (one to four previous vaginal deliveries, and no cesarean deliveries), and 5.9% were grand multiparous (at least five previous deliveries).

Of the women with singleton deliveries, 29% were nulliparous.

For nulliparous women delivering twins, the median length of the second stage was 1 hour 27 minutes (interquartile range, 40-147 minutes), and the 95th percentile was 3 hours 51 minutes.

For parous women delivering twins, the median length of the second stage was 18 minutes (interquartile range, 8-36 minutes), and the 95th percentile was 1 hour 56 minutes.

For grand multiparous women, the median length of the second stage was 10 minutes.

In a multivariable analysis, epidural anesthesia and induction of labor were independently associated with increased length of the second stage of labor.

Second-stage labor longer than the 95th percentile based on parity and epidural status was associated with approximately twice the risk of admission to the neonatal intensive care unit (35.4% vs. 16.4%) and need for phototherapy, the researchers reported.

Compared with singleton deliveries, the second stage was longer in twin deliveries. Among nulliparous patients, the median length of the second stage of labor was 1 hour 18 minutes for singleton deliveries, versus 1 hour 30 minutes for twin deliveries. Among parous patients, the median length of the second stage was 19 minutes for twin deliveries, compared with 10 minutes for singleton deliveries.

The study was conducted in Israel, which may limit its generalizability, the authors noted. In addition, the researchers lacked data about maternal morbidity and had limited data about neonatal morbidity. “The exact time that the woman became 10-cm dilated cannot be known, a problem inherent to all such studies,” and cases where doctors artificially ended labor with operative delivery were not included, the researchers added. “More research is needed to determine at what point, if any, intervention is warranted to shorten the second stage in patients delivering twins,” Dr. Levin and colleagues wrote.

Providing a framework

“We always get more concerned if the labor process is happening in a way that is unusual,” and this study provides data that can provide a framework for that thought process, said Dr. Fox, who was not involved in the study.

The results demonstrate that the second stage of labor for twin deliveries may take a long time and “that is not necessarily a bad thing,” said Dr. Fox, clinical professor of obstetrics and gynecology and maternal and fetal medicine at the Icahn School of Medicine at Mount Sinai in New York.

For women having their first child, the second stage of labor tends to take much longer than it does for women who have had children. “That is well known for singletons, and everyone assumes it is the same for twins,” but this study quantifies the durations for twins, he said. “That is valuable, and it is also helpful for women to know what to expect.”

A study coauthor disclosed financial ties to PregnanTech and Anthem AI, and money paid to their institution from New Sight. Dr. Fox works at Maternal Fetal Medicine Associates and Carnegie Imaging for Women in New York and is the creator and host of the Healthful Woman Podcast. He had no relevant financial disclosures.

jremaly@mdedge.com

In a record year for the Match, ob.gyn. residencies filled 99.8% of their available positions in 2021, according to the National Resident Matching Program.

“Rather than faltering in these uncertain times, program fill rates increased across the board,” the NRMP said in a written statement. Overall, the 2021 Main Residency Match offered (35,194) and filled (33,353) more first-year (PGY-1) slots than ever before, for a fill rate of 94.8%, compared with 94.6% the year before.

The fill rate for obstetrics and gynecology was an even higher 99.8%, with 1,460 positions offered and 1,457 filled – each up 1.2% over 2020. Nearly 90% (1,313) of the available slots were given to U.S. seniors (MDs and DOs), while 6% went to international medical graduates (IMGs). The corresponding PGY-1 numbers for the Match as a whole were 70.4% U.S. and 21.1% international medical graduates, based on NRMP data.

Over the longer term, the number of positions offered in ob.gyn. residencies has increased by 172 (13.4%) since 2017, but that growth lags behind the Match as a whole, which has seen a 22% increase in available slots over the last 5 years, the NRMP said in the report.

“Concerns about the impact of virtual recruitment on applicants’ matching into PGY-1 positions were not realized,” the NRMP noted, as “growth in registration was seen in every applicant group.” Compared with 2020, submissions of rank-order lists of programs were up by 2.8% for U.S. MD seniors, 7.9% for U.S. DO seniors, 2.5% among U.S.-citizen IMGs, and 15.0% for non–U.S.-citizen IMGs.

“The application and recruitment cycle was upended as a result of the pandemic, yet the results of the Match continue to demonstrate strong and consistent outcomes for participants,” said Donna L. Lamb, DHSc, MBA, BSN, president and CEO of the NRMP.

rfranki@mdedge.com

In a record year for the Match, ob.gyn. residencies filled 99.8% of their available positions in 2021, according to the National Resident Matching Program.

“Rather than faltering in these uncertain times, program fill rates increased across the board,” the NRMP said in a written statement. Overall, the 2021 Main Residency Match offered (35,194) and filled (33,353) more first-year (PGY-1) slots than ever before, for a fill rate of 94.8%, compared with 94.6% the year before.

The fill rate for obstetrics and gynecology was an even higher 99.8%, with 1,460 positions offered and 1,457 filled – each up 1.2% over 2020. Nearly 90% (1,313) of the available slots were given to U.S. seniors (MDs and DOs), while 6% went to international medical graduates (IMGs). The corresponding PGY-1 numbers for the Match as a whole were 70.4% U.S. and 21.1% international medical graduates, based on NRMP data.

Over the longer term, the number of positions offered in ob.gyn. residencies has increased by 172 (13.4%) since 2017, but that growth lags behind the Match as a whole, which has seen a 22% increase in available slots over the last 5 years, the NRMP said in the report.

“Concerns about the impact of virtual recruitment on applicants’ matching into PGY-1 positions were not realized,” the NRMP noted, as “growth in registration was seen in every applicant group.” Compared with 2020, submissions of rank-order lists of programs were up by 2.8% for U.S. MD seniors, 7.9% for U.S. DO seniors, 2.5% among U.S.-citizen IMGs, and 15.0% for non–U.S.-citizen IMGs.

“The application and recruitment cycle was upended as a result of the pandemic, yet the results of the Match continue to demonstrate strong and consistent outcomes for participants,” said Donna L. Lamb, DHSc, MBA, BSN, president and CEO of the NRMP.

rfranki@mdedge.com

In a record year for the Match, ob.gyn. residencies filled 99.8% of their available positions in 2021, according to the National Resident Matching Program.

“Rather than faltering in these uncertain times, program fill rates increased across the board,” the NRMP said in a written statement. Overall, the 2021 Main Residency Match offered (35,194) and filled (33,353) more first-year (PGY-1) slots than ever before, for a fill rate of 94.8%, compared with 94.6% the year before.

The fill rate for obstetrics and gynecology was an even higher 99.8%, with 1,460 positions offered and 1,457 filled – each up 1.2% over 2020. Nearly 90% (1,313) of the available slots were given to U.S. seniors (MDs and DOs), while 6% went to international medical graduates (IMGs). The corresponding PGY-1 numbers for the Match as a whole were 70.4% U.S. and 21.1% international medical graduates, based on NRMP data.

Over the longer term, the number of positions offered in ob.gyn. residencies has increased by 172 (13.4%) since 2017, but that growth lags behind the Match as a whole, which has seen a 22% increase in available slots over the last 5 years, the NRMP said in the report.

“Concerns about the impact of virtual recruitment on applicants’ matching into PGY-1 positions were not realized,” the NRMP noted, as “growth in registration was seen in every applicant group.” Compared with 2020, submissions of rank-order lists of programs were up by 2.8% for U.S. MD seniors, 7.9% for U.S. DO seniors, 2.5% among U.S.-citizen IMGs, and 15.0% for non–U.S.-citizen IMGs.

“The application and recruitment cycle was upended as a result of the pandemic, yet the results of the Match continue to demonstrate strong and consistent outcomes for participants,” said Donna L. Lamb, DHSc, MBA, BSN, president and CEO of the NRMP.

rfranki@mdedge.com

Metyrapone, an inhibitor of endogenous adrenal corticosteroid synthesis currently used in U.S. practice to test adrenocorticotropic hormone (ACTH) function, was safe and effective for treating endogenous Cushing’s syndrome in a multicenter, open-label, single-arm study of 50 patients, the first prospective test of metyrapone (Metopirone) as a therapeutic agent.

Treatment with metyrapone for 12 weeks normalized mean levels of urinary free cortisol (UFC) in 23 of the 49 patients (47%) in the efficacy analysis, and cut pretreatment mean UFC levels by at least 50% in another 16 patients (33%). Treatment also improved clinical signs of hypercortisolism, associated comorbidities, and quality of life, and was well tolerated, Lynnette K. Nieman, MD, said at the annual meeting of the Endocrine Society.

“This prospective study confirms that metyrapone is effective, has a rapid onset of action, and is a safe medical treatment for endogenous Cushing’s syndrome,” declared Dr. Nieman, chief of the endocrinology consultation service of the National Institutes of Health Clinical Center in Bethesda, Md.

The study included a 24-week extension phase of continued metyrapone treatment in patients whose mean UFC level fell to less than two times the upper limit of normal (ULN), but Dr. Nieman did not report results from this extension.
 

Confirmation of off-label and European experience

“This was the first prospective study of metyrapone, albeit a small study and with only short-term data presented. It confirms what we have known from its off label use in the U.S. and retrospective studies in the U.K. and Europe: Metyrapone normalizes mean UFC in approximately half of patients. Probably with more aggressive up titration efficacy will have been even higher, but of course with the trade-off of adrenal insufficiency,” said Maria Fleseriu, MD, professor and director of the pituitary center at Oregon Health & Science University in Portland, who was not involved with the study.

“Longer-term data from this prospective study is clearly needed to evaluate for possible loss of response, as well as adverse events related to precursors accumulation. We also need data on tumor size with long-term use in patients with Cushing’s disease, “Dr. Fleseriu added in an interview.

“Metyrapone, an 11-hydroxylase inhibitor, is not [Food and Drug Administration–approved for therapy] and thus it will be hard for it to become a first-line medical therapy,” she continued. “Furthermore, multiple times a day administration is not ideal for most patients; however if metyrapone is readily available and cheaper than other drugs, its use might increase over time. Hirsutism in women (though not all women develop this) and hypertension could be issues with long-term use,” she cautioned.

“We have used metyrapone off label for many years. It has a rapid onset of action, and we also have experience using it in combination therapy with ketoconazole, especially in patients with severe Cushing’s, although ketoconazole is not [FDA] approved for Cushing’s syndrome, and all combination therapies are off-label, too,” Dr. Fleseriu noted.

Metyrapone is approved by the European Medicines Agency for treating Cushing’s syndrome based “on observational, retrospective studies published over more than 50 years,” according to Dr. Nieman. The drug has FDA approval only for diagnostic purposes.

The PROMPT (Effects of Metyrapone in Patients With Endogenous Cushing’s Syndrome) study enrolled patients in eight European countries who were newly diagnosed with endogenous Cushing’s syndrome of any etiology. The study excluded patients with an advanced adrenal carcinoma, as well as patients with recurrent or persistent Cushing’s disease following transsphenoidal surgery. Patients also needed three 24-hour measures of UFC that were at least 50% above the ULN (165 nmol/24 hours).

The average age of the patients was 46 years; 69% were women, 90% had Cushing’s disease, and 8% had ectopic ACTH secretion. The average time from initial symptom onset was 4 years. Sixty-one percent had a history of pituitary surgery, 69% were hypertensive, 43% had diabetes or glucose intolerance, and 41% had osteoporosis. The median mean UFC at entry was 570 nmol/24 hours, which is 3.5 times the ULN, and ranged from 291 to 8,476 nmol/24 hours.

Patients began on a metyrapone dosage of 750 mg/day unless their mean UFC exceeded 5 times the ULN, in which case the dosage doubled to 1,500 mg/day. During the 12-week period, clinicians up- or down-titrated the dosage to ideally achieve a UFC less than the ULN while maintaining serum cortisol levels of 7-12 mcg/dL to preclude adrenal insufficiency effects. The median dosage at the end of 12 weeks was 1,500 mg/day, and ranged from 250 to 5,500 mg/day. One of the 50 patients dropped out because of an unrelated acute medical condition, and two patients underwent pituitary surgery despite a response to metyrapone and were included in the efficacy analysis.

After the first week on treatment, patients had a median 49% cut from their baseline UFC level, and after 12 weeks this rose to a median 74% cut from baseline. The study’s primary endpoint was normalization of UFC after 12 weeks, which occurred in 47% of patients, while 22% had a normal level in a late-night salivary cortisol measurement.

Two-thirds of patients had an improvement or resolution of their signs and symptoms, on average quality of life scores improved, median systolic and diastolic blood pressures decreased by 4-5 mm Hg, and average A1c levels were stable, but the mean cholesterol level decreased significantly, and testosterone levels rose significantly in women.

Proper dose titration makes a difference

Adverse events occurred in 26 of the 50 patients (52%) who received any treatment; 1 patient had a serious adverse event, 7 patients required a dosage adjustment because of adverse events, and 6 patients stopped treatment. The most common adverse events were gastrointestinal – nausea in 24% and decreased appetite in 18% – as well as mild symptoms consistent with adrenal insufficiency such as fatigue and headache. Six patients (12%) were identified with reversible adrenal insufficiency, and no patients complained of worsening acne or hirsutism.

“I think the adverse events are a function of [less than optimal] dose titration and variability in UFC levels,” said Dr. Nieman.

This test of metyrapone’s efficacy comes a year after the FDA approved osilodrostat (Isturisa) for treating Cushing’s disease (but not Cushing’s syndrome). Like metyrapone, osilodrostat controls cortisol overproduction by blocking the enzyme 11-beta-hydroxylase and preventing cortisol synthesis, and osilodrostat was the first agent with these properties to receive an FDA label for therapy.

Osilodrostat “is the only adrenal steroidogenesis inhibitor assessed in randomized controlled long-term trials – over 200 patients with Cushing’s disease – and it has been shown to be highly effective at maintaining normal urinary free cortisol in large majority of patients with Cushing’s disease, as well as Cushing’s syndrome in a study in Japan. Adrenal insufficiency was high [with osilodrostat], especially with the high dose in the trial with forced uptitration. In my clinical practice I have noticed less adrenal insufficiency, but I use much slower drug titration,” said Dr. Fleseriu.

“I think these drugs [metyrapone and osilodrostat] are relatively equivalent,” Dr. Nieman said during discussion of her report. “One nonmedical judgment will be cost,” she added. “Everyone is looking forward to what the pricing structure will be for the new drugs.”

Dr. Fleseriu noted that “for most patients, surgery is first-line therapy, and rarely medication is an alternative first option, especially for Cushing’s disease. However, medical therapy is essential in the management of patients with Cushing’s syndrome when curative surgery fails, surgery is not feasible, when a patient is awaiting radiation’s effect, and for recurrent cases of Cushing’s syndrome.”

PROMPT was sponsored by HRA Pharma, the company that markets metyrapone. Dr. Nieman had no disclosures, but several of her associates on the study are HRA employees. Dr. Fleseriu has been a consultant to Novartis, Recordati, Sparrow, and Strongbridge.

mzoler@mdedge.com

Metyrapone, an inhibitor of endogenous adrenal corticosteroid synthesis currently used in U.S. practice to test adrenocorticotropic hormone (ACTH) function, was safe and effective for treating endogenous Cushing’s syndrome in a multicenter, open-label, single-arm study of 50 patients, the first prospective test of metyrapone (Metopirone) as a therapeutic agent.

Treatment with metyrapone for 12 weeks normalized mean levels of urinary free cortisol (UFC) in 23 of the 49 patients (47%) in the efficacy analysis, and cut pretreatment mean UFC levels by at least 50% in another 16 patients (33%). Treatment also improved clinical signs of hypercortisolism, associated comorbidities, and quality of life, and was well tolerated, Lynnette K. Nieman, MD, said at the annual meeting of the Endocrine Society.

“This prospective study confirms that metyrapone is effective, has a rapid onset of action, and is a safe medical treatment for endogenous Cushing’s syndrome,” declared Dr. Nieman, chief of the endocrinology consultation service of the National Institutes of Health Clinical Center in Bethesda, Md.

The study included a 24-week extension phase of continued metyrapone treatment in patients whose mean UFC level fell to less than two times the upper limit of normal (ULN), but Dr. Nieman did not report results from this extension.
 

Confirmation of off-label and European experience

“This was the first prospective study of metyrapone, albeit a small study and with only short-term data presented. It confirms what we have known from its off label use in the U.S. and retrospective studies in the U.K. and Europe: Metyrapone normalizes mean UFC in approximately half of patients. Probably with more aggressive up titration efficacy will have been even higher, but of course with the trade-off of adrenal insufficiency,” said Maria Fleseriu, MD, professor and director of the pituitary center at Oregon Health & Science University in Portland, who was not involved with the study.

“Longer-term data from this prospective study is clearly needed to evaluate for possible loss of response, as well as adverse events related to precursors accumulation. We also need data on tumor size with long-term use in patients with Cushing’s disease, “Dr. Fleseriu added in an interview.

“Metyrapone, an 11-hydroxylase inhibitor, is not [Food and Drug Administration–approved for therapy] and thus it will be hard for it to become a first-line medical therapy,” she continued. “Furthermore, multiple times a day administration is not ideal for most patients; however if metyrapone is readily available and cheaper than other drugs, its use might increase over time. Hirsutism in women (though not all women develop this) and hypertension could be issues with long-term use,” she cautioned.

“We have used metyrapone off label for many years. It has a rapid onset of action, and we also have experience using it in combination therapy with ketoconazole, especially in patients with severe Cushing’s, although ketoconazole is not [FDA] approved for Cushing’s syndrome, and all combination therapies are off-label, too,” Dr. Fleseriu noted.

Metyrapone is approved by the European Medicines Agency for treating Cushing’s syndrome based “on observational, retrospective studies published over more than 50 years,” according to Dr. Nieman. The drug has FDA approval only for diagnostic purposes.

The PROMPT (Effects of Metyrapone in Patients With Endogenous Cushing’s Syndrome) study enrolled patients in eight European countries who were newly diagnosed with endogenous Cushing’s syndrome of any etiology. The study excluded patients with an advanced adrenal carcinoma, as well as patients with recurrent or persistent Cushing’s disease following transsphenoidal surgery. Patients also needed three 24-hour measures of UFC that were at least 50% above the ULN (165 nmol/24 hours).

The average age of the patients was 46 years; 69% were women, 90% had Cushing’s disease, and 8% had ectopic ACTH secretion. The average time from initial symptom onset was 4 years. Sixty-one percent had a history of pituitary surgery, 69% were hypertensive, 43% had diabetes or glucose intolerance, and 41% had osteoporosis. The median mean UFC at entry was 570 nmol/24 hours, which is 3.5 times the ULN, and ranged from 291 to 8,476 nmol/24 hours.

Patients began on a metyrapone dosage of 750 mg/day unless their mean UFC exceeded 5 times the ULN, in which case the dosage doubled to 1,500 mg/day. During the 12-week period, clinicians up- or down-titrated the dosage to ideally achieve a UFC less than the ULN while maintaining serum cortisol levels of 7-12 mcg/dL to preclude adrenal insufficiency effects. The median dosage at the end of 12 weeks was 1,500 mg/day, and ranged from 250 to 5,500 mg/day. One of the 50 patients dropped out because of an unrelated acute medical condition, and two patients underwent pituitary surgery despite a response to metyrapone and were included in the efficacy analysis.

After the first week on treatment, patients had a median 49% cut from their baseline UFC level, and after 12 weeks this rose to a median 74% cut from baseline. The study’s primary endpoint was normalization of UFC after 12 weeks, which occurred in 47% of patients, while 22% had a normal level in a late-night salivary cortisol measurement.

Two-thirds of patients had an improvement or resolution of their signs and symptoms, on average quality of life scores improved, median systolic and diastolic blood pressures decreased by 4-5 mm Hg, and average A1c levels were stable, but the mean cholesterol level decreased significantly, and testosterone levels rose significantly in women.

Proper dose titration makes a difference

Adverse events occurred in 26 of the 50 patients (52%) who received any treatment; 1 patient had a serious adverse event, 7 patients required a dosage adjustment because of adverse events, and 6 patients stopped treatment. The most common adverse events were gastrointestinal – nausea in 24% and decreased appetite in 18% – as well as mild symptoms consistent with adrenal insufficiency such as fatigue and headache. Six patients (12%) were identified with reversible adrenal insufficiency, and no patients complained of worsening acne or hirsutism.

“I think the adverse events are a function of [less than optimal] dose titration and variability in UFC levels,” said Dr. Nieman.

This test of metyrapone’s efficacy comes a year after the FDA approved osilodrostat (Isturisa) for treating Cushing’s disease (but not Cushing’s syndrome). Like metyrapone, osilodrostat controls cortisol overproduction by blocking the enzyme 11-beta-hydroxylase and preventing cortisol synthesis, and osilodrostat was the first agent with these properties to receive an FDA label for therapy.

Osilodrostat “is the only adrenal steroidogenesis inhibitor assessed in randomized controlled long-term trials – over 200 patients with Cushing’s disease – and it has been shown to be highly effective at maintaining normal urinary free cortisol in large majority of patients with Cushing’s disease, as well as Cushing’s syndrome in a study in Japan. Adrenal insufficiency was high [with osilodrostat], especially with the high dose in the trial with forced uptitration. In my clinical practice I have noticed less adrenal insufficiency, but I use much slower drug titration,” said Dr. Fleseriu.

“I think these drugs [metyrapone and osilodrostat] are relatively equivalent,” Dr. Nieman said during discussion of her report. “One nonmedical judgment will be cost,” she added. “Everyone is looking forward to what the pricing structure will be for the new drugs.”

Dr. Fleseriu noted that “for most patients, surgery is first-line therapy, and rarely medication is an alternative first option, especially for Cushing’s disease. However, medical therapy is essential in the management of patients with Cushing’s syndrome when curative surgery fails, surgery is not feasible, when a patient is awaiting radiation’s effect, and for recurrent cases of Cushing’s syndrome.”

PROMPT was sponsored by HRA Pharma, the company that markets metyrapone. Dr. Nieman had no disclosures, but several of her associates on the study are HRA employees. Dr. Fleseriu has been a consultant to Novartis, Recordati, Sparrow, and Strongbridge.

mzoler@mdedge.com

Metyrapone, an inhibitor of endogenous adrenal corticosteroid synthesis currently used in U.S. practice to test adrenocorticotropic hormone (ACTH) function, was safe and effective for treating endogenous Cushing’s syndrome in a multicenter, open-label, single-arm study of 50 patients, the first prospective test of metyrapone (Metopirone) as a therapeutic agent.

Treatment with metyrapone for 12 weeks normalized mean levels of urinary free cortisol (UFC) in 23 of the 49 patients (47%) in the efficacy analysis, and cut pretreatment mean UFC levels by at least 50% in another 16 patients (33%). Treatment also improved clinical signs of hypercortisolism, associated comorbidities, and quality of life, and was well tolerated, Lynnette K. Nieman, MD, said at the annual meeting of the Endocrine Society.

“This prospective study confirms that metyrapone is effective, has a rapid onset of action, and is a safe medical treatment for endogenous Cushing’s syndrome,” declared Dr. Nieman, chief of the endocrinology consultation service of the National Institutes of Health Clinical Center in Bethesda, Md.

The study included a 24-week extension phase of continued metyrapone treatment in patients whose mean UFC level fell to less than two times the upper limit of normal (ULN), but Dr. Nieman did not report results from this extension.
 

Confirmation of off-label and European experience

“This was the first prospective study of metyrapone, albeit a small study and with only short-term data presented. It confirms what we have known from its off label use in the U.S. and retrospective studies in the U.K. and Europe: Metyrapone normalizes mean UFC in approximately half of patients. Probably with more aggressive up titration efficacy will have been even higher, but of course with the trade-off of adrenal insufficiency,” said Maria Fleseriu, MD, professor and director of the pituitary center at Oregon Health & Science University in Portland, who was not involved with the study.

“Longer-term data from this prospective study is clearly needed to evaluate for possible loss of response, as well as adverse events related to precursors accumulation. We also need data on tumor size with long-term use in patients with Cushing’s disease, “Dr. Fleseriu added in an interview.

“Metyrapone, an 11-hydroxylase inhibitor, is not [Food and Drug Administration–approved for therapy] and thus it will be hard for it to become a first-line medical therapy,” she continued. “Furthermore, multiple times a day administration is not ideal for most patients; however if metyrapone is readily available and cheaper than other drugs, its use might increase over time. Hirsutism in women (though not all women develop this) and hypertension could be issues with long-term use,” she cautioned.

“We have used metyrapone off label for many years. It has a rapid onset of action, and we also have experience using it in combination therapy with ketoconazole, especially in patients with severe Cushing’s, although ketoconazole is not [FDA] approved for Cushing’s syndrome, and all combination therapies are off-label, too,” Dr. Fleseriu noted.

Metyrapone is approved by the European Medicines Agency for treating Cushing’s syndrome based “on observational, retrospective studies published over more than 50 years,” according to Dr. Nieman. The drug has FDA approval only for diagnostic purposes.

The PROMPT (Effects of Metyrapone in Patients With Endogenous Cushing’s Syndrome) study enrolled patients in eight European countries who were newly diagnosed with endogenous Cushing’s syndrome of any etiology. The study excluded patients with an advanced adrenal carcinoma, as well as patients with recurrent or persistent Cushing’s disease following transsphenoidal surgery. Patients also needed three 24-hour measures of UFC that were at least 50% above the ULN (165 nmol/24 hours).

The average age of the patients was 46 years; 69% were women, 90% had Cushing’s disease, and 8% had ectopic ACTH secretion. The average time from initial symptom onset was 4 years. Sixty-one percent had a history of pituitary surgery, 69% were hypertensive, 43% had diabetes or glucose intolerance, and 41% had osteoporosis. The median mean UFC at entry was 570 nmol/24 hours, which is 3.5 times the ULN, and ranged from 291 to 8,476 nmol/24 hours.

Patients began on a metyrapone dosage of 750 mg/day unless their mean UFC exceeded 5 times the ULN, in which case the dosage doubled to 1,500 mg/day. During the 12-week period, clinicians up- or down-titrated the dosage to ideally achieve a UFC less than the ULN while maintaining serum cortisol levels of 7-12 mcg/dL to preclude adrenal insufficiency effects. The median dosage at the end of 12 weeks was 1,500 mg/day, and ranged from 250 to 5,500 mg/day. One of the 50 patients dropped out because of an unrelated acute medical condition, and two patients underwent pituitary surgery despite a response to metyrapone and were included in the efficacy analysis.

After the first week on treatment, patients had a median 49% cut from their baseline UFC level, and after 12 weeks this rose to a median 74% cut from baseline. The study’s primary endpoint was normalization of UFC after 12 weeks, which occurred in 47% of patients, while 22% had a normal level in a late-night salivary cortisol measurement.

Two-thirds of patients had an improvement or resolution of their signs and symptoms, on average quality of life scores improved, median systolic and diastolic blood pressures decreased by 4-5 mm Hg, and average A1c levels were stable, but the mean cholesterol level decreased significantly, and testosterone levels rose significantly in women.

Proper dose titration makes a difference

Adverse events occurred in 26 of the 50 patients (52%) who received any treatment; 1 patient had a serious adverse event, 7 patients required a dosage adjustment because of adverse events, and 6 patients stopped treatment. The most common adverse events were gastrointestinal – nausea in 24% and decreased appetite in 18% – as well as mild symptoms consistent with adrenal insufficiency such as fatigue and headache. Six patients (12%) were identified with reversible adrenal insufficiency, and no patients complained of worsening acne or hirsutism.

“I think the adverse events are a function of [less than optimal] dose titration and variability in UFC levels,” said Dr. Nieman.

This test of metyrapone’s efficacy comes a year after the FDA approved osilodrostat (Isturisa) for treating Cushing’s disease (but not Cushing’s syndrome). Like metyrapone, osilodrostat controls cortisol overproduction by blocking the enzyme 11-beta-hydroxylase and preventing cortisol synthesis, and osilodrostat was the first agent with these properties to receive an FDA label for therapy.

Osilodrostat “is the only adrenal steroidogenesis inhibitor assessed in randomized controlled long-term trials – over 200 patients with Cushing’s disease – and it has been shown to be highly effective at maintaining normal urinary free cortisol in large majority of patients with Cushing’s disease, as well as Cushing’s syndrome in a study in Japan. Adrenal insufficiency was high [with osilodrostat], especially with the high dose in the trial with forced uptitration. In my clinical practice I have noticed less adrenal insufficiency, but I use much slower drug titration,” said Dr. Fleseriu.

“I think these drugs [metyrapone and osilodrostat] are relatively equivalent,” Dr. Nieman said during discussion of her report. “One nonmedical judgment will be cost,” she added. “Everyone is looking forward to what the pricing structure will be for the new drugs.”

Dr. Fleseriu noted that “for most patients, surgery is first-line therapy, and rarely medication is an alternative first option, especially for Cushing’s disease. However, medical therapy is essential in the management of patients with Cushing’s syndrome when curative surgery fails, surgery is not feasible, when a patient is awaiting radiation’s effect, and for recurrent cases of Cushing’s syndrome.”

PROMPT was sponsored by HRA Pharma, the company that markets metyrapone. Dr. Nieman had no disclosures, but several of her associates on the study are HRA employees. Dr. Fleseriu has been a consultant to Novartis, Recordati, Sparrow, and Strongbridge.

mzoler@mdedge.com

Cytoreductive surgery should be considered for advanced ovarian cancer even if patients do not respond to chemotherapy, according to researchers.

A retrospective, case-control study showed that optimal cytoreductive surgery is an independent predictor of overall survival, even when controlling for response to chemotherapy.

The findings were presented at the Society of Gynecologic Oncology’s Virtual Annual Meeting on Women’s Cancer (Abstract 10243).

Response to platinum-based chemotherapy is the strongest predictor of overall survival in advanced ovarian cancer, noted Nicholas Cardillo, MD, a gynecologic oncology fellow at the University of Iowa, Iowa City, who presented the findings at the meeting.

In recent years, a poor response to chemotherapy has sometimes been used as justification to forgo cytoreduction, Dr. Cardillo added.

He and his colleagues looked into this issue because evidence to support the practice is lacking. With their study, the researchers found that optimal cytoreduction – removing all disease of 1 cm or more – improved survival regardless of the response to chemotherapy.

“My advice right now is that debulking surgery should still be attempted in all patients with ovarian cancer because, as far as we know right now, optimal cytoreduction will improve survival,” Dr. Cardillo said in an interview. “Basically, this study argues to keep the status quo, which is to perform surgery.”

The status quo might change with future research, Dr. Cardillo acknowledged, “but as of right now, we have no evidence to support not pursuing cytoreduction in these patients.”
 

Study details and results

The researchers analyzed data on 234 patients who responded to platinum-based chemotherapy – meaning they had no evidence of disease for at least 6 months afterward – and 98 patients who did not respond – meaning they progressed during therapy, had stable disease, did not respond completely, or had a progression-free survival duration of less than 6 months. Subjects had stage III or IV high-grade serous ovarian cancer.

About three-quarters of responders and 57% of nonresponders had optimal surgery. Only seven patients in each group had fewer than six cycles of chemotherapy.

The mean age was 59 years in the responder group and 62 years among nonresponders. Stage IV disease, including upper-abdominal and chest involvement, was more common in the nonresponder group.

The median overall survival was 44.8 months in the responder group and 18.1 months among nonresponders (P < .001). The median overall survival was 34.2 months among patients who underwent optimal surgery and 24.8 months among those who did not (P < .001).
 

Predictors of survival

A multivariate analysis showed that response to chemotherapy had the greatest effect on survival, with a hazard ratio of 0.27 (P < .001).

“The second most significant predictor of overall survival was receipt of neoadjuvant chemotherapy [HR, 2.84; P < .001], which is intuitive as that is typically a marker for worse disease burden,” Dr. Cardillo said.

“But most importantly for our question is that optimal surgery is an independent significant factor in overall survival, even when controlling for other significant risk factors, including whether or not a patient responds to chemotherapy. The hazard ratio is 0.73 [P = .023], indicating a 25%-30% improvement in overall survival,” he added.

Based on these results, “surgical debulking should still be considered a component of the treatment algorithm in ovarian cancer patients who have a poor response to chemotherapy, if an optimal surgery is deemed feasible,” Dr. Cardillo concluded.

There was no funding for this study, and the investigators had no relevant disclosures.

aotto@mdedge.com

Cytoreductive surgery should be considered for advanced ovarian cancer even if patients do not respond to chemotherapy, according to researchers.

A retrospective, case-control study showed that optimal cytoreductive surgery is an independent predictor of overall survival, even when controlling for response to chemotherapy.

The findings were presented at the Society of Gynecologic Oncology’s Virtual Annual Meeting on Women’s Cancer (Abstract 10243).

Response to platinum-based chemotherapy is the strongest predictor of overall survival in advanced ovarian cancer, noted Nicholas Cardillo, MD, a gynecologic oncology fellow at the University of Iowa, Iowa City, who presented the findings at the meeting.

In recent years, a poor response to chemotherapy has sometimes been used as justification to forgo cytoreduction, Dr. Cardillo added.

He and his colleagues looked into this issue because evidence to support the practice is lacking. With their study, the researchers found that optimal cytoreduction – removing all disease of 1 cm or more – improved survival regardless of the response to chemotherapy.

“My advice right now is that debulking surgery should still be attempted in all patients with ovarian cancer because, as far as we know right now, optimal cytoreduction will improve survival,” Dr. Cardillo said in an interview. “Basically, this study argues to keep the status quo, which is to perform surgery.”

The status quo might change with future research, Dr. Cardillo acknowledged, “but as of right now, we have no evidence to support not pursuing cytoreduction in these patients.”
 

Study details and results

The researchers analyzed data on 234 patients who responded to platinum-based chemotherapy – meaning they had no evidence of disease for at least 6 months afterward – and 98 patients who did not respond – meaning they progressed during therapy, had stable disease, did not respond completely, or had a progression-free survival duration of less than 6 months. Subjects had stage III or IV high-grade serous ovarian cancer.

About three-quarters of responders and 57% of nonresponders had optimal surgery. Only seven patients in each group had fewer than six cycles of chemotherapy.

The mean age was 59 years in the responder group and 62 years among nonresponders. Stage IV disease, including upper-abdominal and chest involvement, was more common in the nonresponder group.

The median overall survival was 44.8 months in the responder group and 18.1 months among nonresponders (P < .001). The median overall survival was 34.2 months among patients who underwent optimal surgery and 24.8 months among those who did not (P < .001).
 

Predictors of survival

A multivariate analysis showed that response to chemotherapy had the greatest effect on survival, with a hazard ratio of 0.27 (P < .001).

“The second most significant predictor of overall survival was receipt of neoadjuvant chemotherapy [HR, 2.84; P < .001], which is intuitive as that is typically a marker for worse disease burden,” Dr. Cardillo said.

“But most importantly for our question is that optimal surgery is an independent significant factor in overall survival, even when controlling for other significant risk factors, including whether or not a patient responds to chemotherapy. The hazard ratio is 0.73 [P = .023], indicating a 25%-30% improvement in overall survival,” he added.

Based on these results, “surgical debulking should still be considered a component of the treatment algorithm in ovarian cancer patients who have a poor response to chemotherapy, if an optimal surgery is deemed feasible,” Dr. Cardillo concluded.

There was no funding for this study, and the investigators had no relevant disclosures.

aotto@mdedge.com

Cytoreductive surgery should be considered for advanced ovarian cancer even if patients do not respond to chemotherapy, according to researchers.

A retrospective, case-control study showed that optimal cytoreductive surgery is an independent predictor of overall survival, even when controlling for response to chemotherapy.

The findings were presented at the Society of Gynecologic Oncology’s Virtual Annual Meeting on Women’s Cancer (Abstract 10243).

Response to platinum-based chemotherapy is the strongest predictor of overall survival in advanced ovarian cancer, noted Nicholas Cardillo, MD, a gynecologic oncology fellow at the University of Iowa, Iowa City, who presented the findings at the meeting.

In recent years, a poor response to chemotherapy has sometimes been used as justification to forgo cytoreduction, Dr. Cardillo added.

He and his colleagues looked into this issue because evidence to support the practice is lacking. With their study, the researchers found that optimal cytoreduction – removing all disease of 1 cm or more – improved survival regardless of the response to chemotherapy.

“My advice right now is that debulking surgery should still be attempted in all patients with ovarian cancer because, as far as we know right now, optimal cytoreduction will improve survival,” Dr. Cardillo said in an interview. “Basically, this study argues to keep the status quo, which is to perform surgery.”

The status quo might change with future research, Dr. Cardillo acknowledged, “but as of right now, we have no evidence to support not pursuing cytoreduction in these patients.”
 

Study details and results

The researchers analyzed data on 234 patients who responded to platinum-based chemotherapy – meaning they had no evidence of disease for at least 6 months afterward – and 98 patients who did not respond – meaning they progressed during therapy, had stable disease, did not respond completely, or had a progression-free survival duration of less than 6 months. Subjects had stage III or IV high-grade serous ovarian cancer.

About three-quarters of responders and 57% of nonresponders had optimal surgery. Only seven patients in each group had fewer than six cycles of chemotherapy.

The mean age was 59 years in the responder group and 62 years among nonresponders. Stage IV disease, including upper-abdominal and chest involvement, was more common in the nonresponder group.

The median overall survival was 44.8 months in the responder group and 18.1 months among nonresponders (P < .001). The median overall survival was 34.2 months among patients who underwent optimal surgery and 24.8 months among those who did not (P < .001).
 

Predictors of survival

A multivariate analysis showed that response to chemotherapy had the greatest effect on survival, with a hazard ratio of 0.27 (P < .001).

“The second most significant predictor of overall survival was receipt of neoadjuvant chemotherapy [HR, 2.84; P < .001], which is intuitive as that is typically a marker for worse disease burden,” Dr. Cardillo said.

“But most importantly for our question is that optimal surgery is an independent significant factor in overall survival, even when controlling for other significant risk factors, including whether or not a patient responds to chemotherapy. The hazard ratio is 0.73 [P = .023], indicating a 25%-30% improvement in overall survival,” he added.

Based on these results, “surgical debulking should still be considered a component of the treatment algorithm in ovarian cancer patients who have a poor response to chemotherapy, if an optimal surgery is deemed feasible,” Dr. Cardillo concluded.

There was no funding for this study, and the investigators had no relevant disclosures.

aotto@mdedge.com

High-intensity interval training (HIIT) was better than moderate-intensity continuous training (MICT) for improving several measures of cardiometabolic health in women with polycystic ovary syndrome (PCOS) in a prospective, randomized, single-center study with 27 women.

yacobchuk/Getty Images

After 12 weeks on a supervised exercise regimen, the women with PCOS who followed the HIIT program had significantly better improvements in aerobic capacity, insulin sensitivity, and level of sex hormone–binding globulin, Rhiannon K. Patten, MSc, said at the annual meeting of the Endocrine Society.

“HIIT can offer superior improvements in health outcomes, and should be considered as an effective tool to reduce cardiometabolic risk in women with PCOS,” concluded Ms. Patten, a researcher in the Institute for Health and Sport at Victoria University in Melbourne in her presentation (Abstract OR10-1).

“The changes we see [after 12 weeks on the HIIT regimen] seem to occur despite no change in body mass index, so rather than focus on weight loss we encourage participants to focus on the health improvements that seem to be greater with HIIT. We actively encourage the HIIT protocol right now,” she said.

Both regimens use a stationary cycle ergometer. In the HIIT protocol patients twice weekly pedal through 12 1-minute intervals at a heart rate of 90%-100% maximum, interspersed with 1 minute rest intervals. On a third day per week, patients pedal to a heart rate of 90%-95% maximum for 6-8 intervals maintained for 2 minutes and interspersed with rest intervals of 2 minutes. The MICT regimen used as a comparator has participants pedal to 60%-70% of their maximum heart rate continuously for 50 minutes 3 days weekly.



HIIT saves time

“These findings are relevant to clinical practice, because they demonstrate that HIIT is effective in women with PCOS. Reducing the time devoted to exercise to achieve fitness goals is attractive to patients. The reduced time to achieve training benefits with HIIT should improve patient compliance,” commented Andrea Dunaif, MD, professor and chief of the division of endocrinology, diabetes, and bone disease of the Mount Sinai Health System in New York, who was not involved with the study.

The overall weekly exercise time on the MICT regimen, 150 minutes, halves down to 75 minutes a week in the HIIT program. Guideline recommendations released in 2018 by the International PCOS Network recommended these as acceptable alternative exercise strategies. Ms. Patten and her associates sought to determine whether one strategy surpassed the other, the first time this has been examined in women with PCOS, she said.

They randomized 27 sedentary women 18-45 years old with a body mass index (BMI) above 25 kg/m² and diagnosed with PCOS by the Rotterdam criteria to a 12-week supervised exercise program on either the HIIT or MICT protocol. Their average BMI at entry was 36-37 kg/m². The study excluded women who smoked, were pregnant, had an illness or injury that would prevent exercise, or were on an oral contraceptive or insulin-sensitizing medication.

At the end of 12 weeks, neither group had a significant change in average weight or BMI, and waist circumference dropped by an average of just over 2 cm in both treatment groups. Lean mass increased by a mean 1 kg in the HIIT group, a significant change, compared with a nonsignificant 0.3 kg average increase in the MICT group.
 

Increased aerobic capacity ‘partially explains’ improved insulin sensitivity

Aerobic capacity, measured as peak oxygen consumption (VO₂peak), increased by an average 5.7 mL/kg per min among the HIIT patients, significantly more than the mean 3.2 mL/kg per min increase among those in the MICT program.

The insulin sensitivity index rose by a significant, relative 35% among the HIIT patients, but barely budged in the MICT group. Fasting glucose fell significantly and the glucose infusion rate increased significantly among the women who performed HIIT, but again showed little change among those doing MICT.

Analysis showed a significant link between the increase in VO₂peak and the increase in insulin sensitivity among the women engaged in HIIT, Ms. Patten reported. The improvement in the insulin sensitivity index was “partially explained” by the increase in VO₂peak, she said.

Assessment of hormone levels showed a significant increase in sex hormone–binding globulin in the HIIT patients while those in the MICT group showed a small decline in this level. The free androgen index fell by a relative 39% on average in the HIIT group, a significant drop, but decreased by a much smaller and not significant amount among the women who did MICT. The women who performed HIIT also showed a significant drop in their free testosterone level, a change not seen with MICT.

Women who performed the HIIT protocol also had a significant improvement in their menstrual cyclicity, and significant improvements in depression, stress, and anxiety, Ms Patten reported. She next plans to do longer follow-up on study participants, out to 6 and 12 months after the end of the exercise protocol.

“Overall, the findings suggest that HIIT is superior to MICT for improving fitness and insulin sensitivity in the short term. Results from a number of studies in individuals without PCOS suggest that HIIT is superior to MICT for improving fitness short term,” commented Dr. Dunaif. “This study makes an important contribution by directly investigating the impact of training intensity in women with PCOS. Larger studies will be needed before the superiority of HIIT is established for women with PCOS, and study durations of at least several months will be needed to assess the impact on reproductive outcomes such as ovulation,” she said in an interview. She also called for assessing the effects of HIIT in more diverse populations of women with PCOS.

Ms. Patten had no disclosures. Dr. Dunaif has been a consultant to Equator Therapeutics, Fractyl Laboratories, and Globe Life Sciences.

mzoler@mdedge.com
 

High-intensity interval training (HIIT) was better than moderate-intensity continuous training (MICT) for improving several measures of cardiometabolic health in women with polycystic ovary syndrome (PCOS) in a prospective, randomized, single-center study with 27 women.

yacobchuk/Getty Images

After 12 weeks on a supervised exercise regimen, the women with PCOS who followed the HIIT program had significantly better improvements in aerobic capacity, insulin sensitivity, and level of sex hormone–binding globulin, Rhiannon K. Patten, MSc, said at the annual meeting of the Endocrine Society.

“HIIT can offer superior improvements in health outcomes, and should be considered as an effective tool to reduce cardiometabolic risk in women with PCOS,” concluded Ms. Patten, a researcher in the Institute for Health and Sport at Victoria University in Melbourne in her presentation (Abstract OR10-1).

“The changes we see [after 12 weeks on the HIIT regimen] seem to occur despite no change in body mass index, so rather than focus on weight loss we encourage participants to focus on the health improvements that seem to be greater with HIIT. We actively encourage the HIIT protocol right now,” she said.

Both regimens use a stationary cycle ergometer. In the HIIT protocol patients twice weekly pedal through 12 1-minute intervals at a heart rate of 90%-100% maximum, interspersed with 1 minute rest intervals. On a third day per week, patients pedal to a heart rate of 90%-95% maximum for 6-8 intervals maintained for 2 minutes and interspersed with rest intervals of 2 minutes. The MICT regimen used as a comparator has participants pedal to 60%-70% of their maximum heart rate continuously for 50 minutes 3 days weekly.



HIIT saves time

“These findings are relevant to clinical practice, because they demonstrate that HIIT is effective in women with PCOS. Reducing the time devoted to exercise to achieve fitness goals is attractive to patients. The reduced time to achieve training benefits with HIIT should improve patient compliance,” commented Andrea Dunaif, MD, professor and chief of the division of endocrinology, diabetes, and bone disease of the Mount Sinai Health System in New York, who was not involved with the study.

The overall weekly exercise time on the MICT regimen, 150 minutes, halves down to 75 minutes a week in the HIIT program. Guideline recommendations released in 2018 by the International PCOS Network recommended these as acceptable alternative exercise strategies. Ms. Patten and her associates sought to determine whether one strategy surpassed the other, the first time this has been examined in women with PCOS, she said.

They randomized 27 sedentary women 18-45 years old with a body mass index (BMI) above 25 kg/m² and diagnosed with PCOS by the Rotterdam criteria to a 12-week supervised exercise program on either the HIIT or MICT protocol. Their average BMI at entry was 36-37 kg/m². The study excluded women who smoked, were pregnant, had an illness or injury that would prevent exercise, or were on an oral contraceptive or insulin-sensitizing medication.

At the end of 12 weeks, neither group had a significant change in average weight or BMI, and waist circumference dropped by an average of just over 2 cm in both treatment groups. Lean mass increased by a mean 1 kg in the HIIT group, a significant change, compared with a nonsignificant 0.3 kg average increase in the MICT group.
 

Increased aerobic capacity ‘partially explains’ improved insulin sensitivity

Aerobic capacity, measured as peak oxygen consumption (VO₂peak), increased by an average 5.7 mL/kg per min among the HIIT patients, significantly more than the mean 3.2 mL/kg per min increase among those in the MICT program.

The insulin sensitivity index rose by a significant, relative 35% among the HIIT patients, but barely budged in the MICT group. Fasting glucose fell significantly and the glucose infusion rate increased significantly among the women who performed HIIT, but again showed little change among those doing MICT.

Analysis showed a significant link between the increase in VO₂peak and the increase in insulin sensitivity among the women engaged in HIIT, Ms. Patten reported. The improvement in the insulin sensitivity index was “partially explained” by the increase in VO₂peak, she said.

Assessment of hormone levels showed a significant increase in sex hormone–binding globulin in the HIIT patients while those in the MICT group showed a small decline in this level. The free androgen index fell by a relative 39% on average in the HIIT group, a significant drop, but decreased by a much smaller and not significant amount among the women who did MICT. The women who performed HIIT also showed a significant drop in their free testosterone level, a change not seen with MICT.

Women who performed the HIIT protocol also had a significant improvement in their menstrual cyclicity, and significant improvements in depression, stress, and anxiety, Ms Patten reported. She next plans to do longer follow-up on study participants, out to 6 and 12 months after the end of the exercise protocol.

“Overall, the findings suggest that HIIT is superior to MICT for improving fitness and insulin sensitivity in the short term. Results from a number of studies in individuals without PCOS suggest that HIIT is superior to MICT for improving fitness short term,” commented Dr. Dunaif. “This study makes an important contribution by directly investigating the impact of training intensity in women with PCOS. Larger studies will be needed before the superiority of HIIT is established for women with PCOS, and study durations of at least several months will be needed to assess the impact on reproductive outcomes such as ovulation,” she said in an interview. She also called for assessing the effects of HIIT in more diverse populations of women with PCOS.

Ms. Patten had no disclosures. Dr. Dunaif has been a consultant to Equator Therapeutics, Fractyl Laboratories, and Globe Life Sciences.

mzoler@mdedge.com
 

High-intensity interval training (HIIT) was better than moderate-intensity continuous training (MICT) for improving several measures of cardiometabolic health in women with polycystic ovary syndrome (PCOS) in a prospective, randomized, single-center study with 27 women.

yacobchuk/Getty Images

After 12 weeks on a supervised exercise regimen, the women with PCOS who followed the HIIT program had significantly better improvements in aerobic capacity, insulin sensitivity, and level of sex hormone–binding globulin, Rhiannon K. Patten, MSc, said at the annual meeting of the Endocrine Society.

“HIIT can offer superior improvements in health outcomes, and should be considered as an effective tool to reduce cardiometabolic risk in women with PCOS,” concluded Ms. Patten, a researcher in the Institute for Health and Sport at Victoria University in Melbourne in her presentation (Abstract OR10-1).

“The changes we see [after 12 weeks on the HIIT regimen] seem to occur despite no change in body mass index, so rather than focus on weight loss we encourage participants to focus on the health improvements that seem to be greater with HIIT. We actively encourage the HIIT protocol right now,” she said.

Both regimens use a stationary cycle ergometer. In the HIIT protocol patients twice weekly pedal through 12 1-minute intervals at a heart rate of 90%-100% maximum, interspersed with 1 minute rest intervals. On a third day per week, patients pedal to a heart rate of 90%-95% maximum for 6-8 intervals maintained for 2 minutes and interspersed with rest intervals of 2 minutes. The MICT regimen used as a comparator has participants pedal to 60%-70% of their maximum heart rate continuously for 50 minutes 3 days weekly.



HIIT saves time

“These findings are relevant to clinical practice, because they demonstrate that HIIT is effective in women with PCOS. Reducing the time devoted to exercise to achieve fitness goals is attractive to patients. The reduced time to achieve training benefits with HIIT should improve patient compliance,” commented Andrea Dunaif, MD, professor and chief of the division of endocrinology, diabetes, and bone disease of the Mount Sinai Health System in New York, who was not involved with the study.

The overall weekly exercise time on the MICT regimen, 150 minutes, halves down to 75 minutes a week in the HIIT program. Guideline recommendations released in 2018 by the International PCOS Network recommended these as acceptable alternative exercise strategies. Ms. Patten and her associates sought to determine whether one strategy surpassed the other, the first time this has been examined in women with PCOS, she said.

They randomized 27 sedentary women 18-45 years old with a body mass index (BMI) above 25 kg/m² and diagnosed with PCOS by the Rotterdam criteria to a 12-week supervised exercise program on either the HIIT or MICT protocol. Their average BMI at entry was 36-37 kg/m². The study excluded women who smoked, were pregnant, had an illness or injury that would prevent exercise, or were on an oral contraceptive or insulin-sensitizing medication.

At the end of 12 weeks, neither group had a significant change in average weight or BMI, and waist circumference dropped by an average of just over 2 cm in both treatment groups. Lean mass increased by a mean 1 kg in the HIIT group, a significant change, compared with a nonsignificant 0.3 kg average increase in the MICT group.
 

Increased aerobic capacity ‘partially explains’ improved insulin sensitivity

Aerobic capacity, measured as peak oxygen consumption (VO₂peak), increased by an average 5.7 mL/kg per min among the HIIT patients, significantly more than the mean 3.2 mL/kg per min increase among those in the MICT program.

The insulin sensitivity index rose by a significant, relative 35% among the HIIT patients, but barely budged in the MICT group. Fasting glucose fell significantly and the glucose infusion rate increased significantly among the women who performed HIIT, but again showed little change among those doing MICT.

Analysis showed a significant link between the increase in VO₂peak and the increase in insulin sensitivity among the women engaged in HIIT, Ms. Patten reported. The improvement in the insulin sensitivity index was “partially explained” by the increase in VO₂peak, she said.

Assessment of hormone levels showed a significant increase in sex hormone–binding globulin in the HIIT patients while those in the MICT group showed a small decline in this level. The free androgen index fell by a relative 39% on average in the HIIT group, a significant drop, but decreased by a much smaller and not significant amount among the women who did MICT. The women who performed HIIT also showed a significant drop in their free testosterone level, a change not seen with MICT.

Women who performed the HIIT protocol also had a significant improvement in their menstrual cyclicity, and significant improvements in depression, stress, and anxiety, Ms Patten reported. She next plans to do longer follow-up on study participants, out to 6 and 12 months after the end of the exercise protocol.

“Overall, the findings suggest that HIIT is superior to MICT for improving fitness and insulin sensitivity in the short term. Results from a number of studies in individuals without PCOS suggest that HIIT is superior to MICT for improving fitness short term,” commented Dr. Dunaif. “This study makes an important contribution by directly investigating the impact of training intensity in women with PCOS. Larger studies will be needed before the superiority of HIIT is established for women with PCOS, and study durations of at least several months will be needed to assess the impact on reproductive outcomes such as ovulation,” she said in an interview. She also called for assessing the effects of HIIT in more diverse populations of women with PCOS.

Ms. Patten had no disclosures. Dr. Dunaif has been a consultant to Equator Therapeutics, Fractyl Laboratories, and Globe Life Sciences.

mzoler@mdedge.com
 

New research underscores the importance of folic acid supplementation for pregnant women with epilepsy who are taking antiepileptic drugs (AEDs).

Dietary folate alone, even in the United States, where food is fortified with folic acid, is “not sufficient” to improve cognitive outcomes for children of women who take AEDs during pregnancy, the researchers report.

“We found that dietary folate was not related to outcomes,” study investigator Kimford Meador, MD, professor of neurology and neurologic sciences, Stanford (Calif.) University, told this news organization.

“Only when the mother was taking extra folate did we see an improvement in child outcomes,” he added.

The findings were published online Feb. 23 in Epilepsy and Behavior.
 

Cognitive boost

“Daily folate is recommended to women in the general populations to reduce congenital malformations,” Dr. Meador said. In addition, periconceptional use of folate has been shown in previous research to improve neurodevelopmental outcomes for children of mothers with epilepsy who are taking AEDs.

Whether folate-fortified food alone, without supplements, has any effect on cognitive outcomes in this population of children has not been examined previously.

To investigate, the researchers assessed 117 children from the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study, a prospective, observational study of women with epilepsy who were taking one of four AEDs: carbamazepine, lamotrigine, phenytoin, or valproate.

Results showed that dietary folate from fortified food alone, without supplements, had no significant impact on IQ at age 6 years among children with prenatal exposure to AEDs.

In contrast, use of periconceptual folate supplements was significantly associated with a 10-point higher IQ at age 6 in the adjusted analyses (95% confidence interval, 5.2-15.0; P < .001).

These six other nutrients from food and supplements had no significant association with IQ at age 6 years: vitamins C, D, and E, omega-3, gamma tocopherol, and vitamin B12.
 

Optimal dose unclear

The findings indicate that folates, including natural folate and folic acid, in food do not have positive cognitive effects for children of women with epilepsy who take AEDs, the researchers write.

Dr. Meador noted that the optimal dose of folic acid supplementation to provide a cognitive benefit remains unclear.

The U.S. Centers for Disease Control recommends 0.4 mg/d for the general population of women of childbearing age. In Europe, the recommendation is 1 mg/d.

“Higher doses are recommended if there is a personal or family history of spina bifida in prior pregnancies, but there is some concern that very high doses of folate may be detrimental,” Dr. Meador said.

For women with epilepsy, he would recommend “at least 1 mg/d and not more than 4 mg/d.”
 

Proves a point?

Commenting on the study for this news organization, Derek Chong, MD, vice chair of neurology and director of epilepsy at Lenox Hill Hospital, New York, said the finding that folate fortification of food alone is not adequate for women with epilepsy is “not groundbreaking” but does prove something previously thought.

“Folic acid is important for all women, but it does seem like folic acid may be even more important in the epilepsy population,” said Dr. Chong, who was not involved with the research.

He cautioned that the current analysis included only four medications, three of which are not used very often anymore.

“Lamotrigine is probably the most commonly used one now. It’s unfortunate that this study did not include Keppra [levetiracetam], which probably is the number one medication that we use now,” Dr. Chong said.

The research was supported by the National Institutes of Health. Dr. Meador and Dr. Chong have reported no relevant financial relationships.

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

New research underscores the importance of folic acid supplementation for pregnant women with epilepsy who are taking antiepileptic drugs (AEDs).

Dietary folate alone, even in the United States, where food is fortified with folic acid, is “not sufficient” to improve cognitive outcomes for children of women who take AEDs during pregnancy, the researchers report.

“We found that dietary folate was not related to outcomes,” study investigator Kimford Meador, MD, professor of neurology and neurologic sciences, Stanford (Calif.) University, told this news organization.

“Only when the mother was taking extra folate did we see an improvement in child outcomes,” he added.

The findings were published online Feb. 23 in Epilepsy and Behavior.
 

Cognitive boost

“Daily folate is recommended to women in the general populations to reduce congenital malformations,” Dr. Meador said. In addition, periconceptional use of folate has been shown in previous research to improve neurodevelopmental outcomes for children of mothers with epilepsy who are taking AEDs.

Whether folate-fortified food alone, without supplements, has any effect on cognitive outcomes in this population of children has not been examined previously.

To investigate, the researchers assessed 117 children from the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study, a prospective, observational study of women with epilepsy who were taking one of four AEDs: carbamazepine, lamotrigine, phenytoin, or valproate.

Results showed that dietary folate from fortified food alone, without supplements, had no significant impact on IQ at age 6 years among children with prenatal exposure to AEDs.

In contrast, use of periconceptual folate supplements was significantly associated with a 10-point higher IQ at age 6 in the adjusted analyses (95% confidence interval, 5.2-15.0; P < .001).

These six other nutrients from food and supplements had no significant association with IQ at age 6 years: vitamins C, D, and E, omega-3, gamma tocopherol, and vitamin B12.
 

Optimal dose unclear

The findings indicate that folates, including natural folate and folic acid, in food do not have positive cognitive effects for children of women with epilepsy who take AEDs, the researchers write.

Dr. Meador noted that the optimal dose of folic acid supplementation to provide a cognitive benefit remains unclear.

The U.S. Centers for Disease Control recommends 0.4 mg/d for the general population of women of childbearing age. In Europe, the recommendation is 1 mg/d.

“Higher doses are recommended if there is a personal or family history of spina bifida in prior pregnancies, but there is some concern that very high doses of folate may be detrimental,” Dr. Meador said.

For women with epilepsy, he would recommend “at least 1 mg/d and not more than 4 mg/d.”
 

Proves a point?

Commenting on the study for this news organization, Derek Chong, MD, vice chair of neurology and director of epilepsy at Lenox Hill Hospital, New York, said the finding that folate fortification of food alone is not adequate for women with epilepsy is “not groundbreaking” but does prove something previously thought.

“Folic acid is important for all women, but it does seem like folic acid may be even more important in the epilepsy population,” said Dr. Chong, who was not involved with the research.

He cautioned that the current analysis included only four medications, three of which are not used very often anymore.

“Lamotrigine is probably the most commonly used one now. It’s unfortunate that this study did not include Keppra [levetiracetam], which probably is the number one medication that we use now,” Dr. Chong said.

The research was supported by the National Institutes of Health. Dr. Meador and Dr. Chong have reported no relevant financial relationships.

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

New research underscores the importance of folic acid supplementation for pregnant women with epilepsy who are taking antiepileptic drugs (AEDs).

Dietary folate alone, even in the United States, where food is fortified with folic acid, is “not sufficient” to improve cognitive outcomes for children of women who take AEDs during pregnancy, the researchers report.

“We found that dietary folate was not related to outcomes,” study investigator Kimford Meador, MD, professor of neurology and neurologic sciences, Stanford (Calif.) University, told this news organization.

“Only when the mother was taking extra folate did we see an improvement in child outcomes,” he added.

The findings were published online Feb. 23 in Epilepsy and Behavior.
 

Cognitive boost

“Daily folate is recommended to women in the general populations to reduce congenital malformations,” Dr. Meador said. In addition, periconceptional use of folate has been shown in previous research to improve neurodevelopmental outcomes for children of mothers with epilepsy who are taking AEDs.

Whether folate-fortified food alone, without supplements, has any effect on cognitive outcomes in this population of children has not been examined previously.

To investigate, the researchers assessed 117 children from the Neurodevelopmental Effects of Antiepileptic Drugs (NEAD) study, a prospective, observational study of women with epilepsy who were taking one of four AEDs: carbamazepine, lamotrigine, phenytoin, or valproate.

Results showed that dietary folate from fortified food alone, without supplements, had no significant impact on IQ at age 6 years among children with prenatal exposure to AEDs.

In contrast, use of periconceptual folate supplements was significantly associated with a 10-point higher IQ at age 6 in the adjusted analyses (95% confidence interval, 5.2-15.0; P < .001).

These six other nutrients from food and supplements had no significant association with IQ at age 6 years: vitamins C, D, and E, omega-3, gamma tocopherol, and vitamin B12.
 

Optimal dose unclear

The findings indicate that folates, including natural folate and folic acid, in food do not have positive cognitive effects for children of women with epilepsy who take AEDs, the researchers write.

Dr. Meador noted that the optimal dose of folic acid supplementation to provide a cognitive benefit remains unclear.

The U.S. Centers for Disease Control recommends 0.4 mg/d for the general population of women of childbearing age. In Europe, the recommendation is 1 mg/d.

“Higher doses are recommended if there is a personal or family history of spina bifida in prior pregnancies, but there is some concern that very high doses of folate may be detrimental,” Dr. Meador said.

For women with epilepsy, he would recommend “at least 1 mg/d and not more than 4 mg/d.”
 

Proves a point?

Commenting on the study for this news organization, Derek Chong, MD, vice chair of neurology and director of epilepsy at Lenox Hill Hospital, New York, said the finding that folate fortification of food alone is not adequate for women with epilepsy is “not groundbreaking” but does prove something previously thought.

“Folic acid is important for all women, but it does seem like folic acid may be even more important in the epilepsy population,” said Dr. Chong, who was not involved with the research.

He cautioned that the current analysis included only four medications, three of which are not used very often anymore.

“Lamotrigine is probably the most commonly used one now. It’s unfortunate that this study did not include Keppra [levetiracetam], which probably is the number one medication that we use now,” Dr. Chong said.

The research was supported by the National Institutes of Health. Dr. Meador and Dr. Chong have reported no relevant financial relationships.

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

Delta-9-Tetrahydrocannabinol (THC), the main psychoactive component of cannabis, remains detectable in breast milk even after weeks of abstinence, new data show. The estimated half-life of THC in breast milk is 17 days, according to the study results, with a projected time to elimination of more than 6 weeks. The clinical importance of the remaining THC is up for debate, according to some experts.

“To limit THC effects on fetal brain development and promote safe breastfeeding, it is critical to emphasize marijuana abstention both early in pregnancy and post partum,” Erica M. Wymore, MD, MPH, an assistant professor of pediatrics and neonatology at the University of Colorado at Denver, Aurora, and colleagues wrote. The group published their results online March 8, 2021, in JAMA Pediatrics.

And while the study was a pharmacokinetic analysis rather than a safety investigation, Dr. Wymore said in an interview that the detectable levels of THC suggest any use is of concern and no safety thresholds have been established. “We wish we had more data on the potential effects on the neurocognitive development of children, but for now we must discourage any use in prepregnancy, pregnancy, and breastfeeding, as our national guidelines recommend.”

Therefore, the findings support current guidelines discouraging any cannabis use in mothers-to-be and breast-feeding mothers issued by national organizations, including those from the American Academy of Pediatrics, the American College of Obstetricians and Gynecologists, and the Academy of Breastfeeding Medicine.

Furthermore, the difficulties many mothers face in abstaining from marijuana, a commonly used drug in pregnancy, and the persistence of THC in maternal milk led the authors to question the feasibility of having women who use marijuana simply discard their breast milk until THC is cleared.

“We report challenges in abstention and prolonged excretion of THC in breast milk greater than 6 weeks among women with prenatal marijuana use,” they wrote. “These findings make the recommendations for mothers to discard breast milk until THC is undetectable unrealistic for mothers committed to breastfeeding.”

However, not all experts are equally concerned about low THC concentrations in breast milk. Neonatal pharmacologist Thomas R. Hale, PhD, a professor of pediatrics at Texas Tech University, Lubbock, said a previous study by his group showed that THC levels in maternal milk peaked within 60 minutes of a moderate dose of inhaled marijuana and fell to quite low levels over the next 4 hours. The highest concentration in maternal milk occurred shortly after the peak in plasma.

“So you can see that, just because a mom is drug screen positive, the clinical dose transferred to the infant is probably exceedingly low,” he said in an interview.

Dr. Hale also stressed that judgments about drugs in this context should weigh the risk of the drug against the risk of not breastfeeding. “All of us caution women not to use cannabis when pregnant or breastfeeding,” Dr. Hale said. “But when the decision has to be made as to whether a mom breastfeeds or not if she is drug screen positive, a lot of other factors must be analyzed to make such a decision.”
 

Study cohort

For the study, Dr. Wymore and colleagues screened 394 women who gave birth between Nov. 1, 2016, and June 30, 2019. Of those, 25 women, with a median age of 26 years, were eligible and enrolled. Inclusion criteria included known prenatal marijuana use, intention to breastfeed, and self-reported abstinence. Prenatal use primarily involved inhaling cannabis more than twice a week.

Of the 25 enrolled mothers, 12 who self-reported marijuana abstinence were in fact found to be abstinent according to the results of plasma analysis. Those who continued to use the substance were younger than the overall sample, with a median age of 21, and were less likely to have attended college (23%) than abstainers (58%).

The researchers prospectively collected data on self-reported marijuana usage and paired maternal plasma and breast milk samples several times a week. All participants had detectable THC in breast milk throughout the study. Initial median THC concentrations were 3.2 ng/mL (interquartile range, 1.2-6.8) within the first week after delivery. These increased to 5.5 ng/mL (IQR, 4.4-16.0) at 2 weeks and declined to 1.9 ng/mL (IQR, 1.1-4.3) at 6 weeks. In terms of ratio, the milk:plasma partition coefficient for THC was approximately 6:1 (IQR, 3.8:1-8.1:1).

Dr. Hale noted that, although THC was detectable in milk, the levels were exceedingly low. “This is where the risk assessment comes in. There’s a lot of hysteria in the cannabis field right now, and we’re going to need time and a lot more studies to really be able to predict any untoward complications.”

Dr. Wymore, however, countered that THC levels were low only in those who abstained and that her concerns relate not just to postpartum breast milk levels but the health effects on children of mothers’ cannabis use over the course of prepregnancy, pregnancy, and lactation. “[Dr. Hale’s] message makes it difficult for clinicians to counsel mothers since it goes against national guidelines,” she said. “We need to be consistent.”

But Dr. Wymore and other experts acknowledge the dilemma faced in that breast milk clearly offers substantial benefits for infant and child health. “The risks of an infant’s exposure to marijuana versus the benefit of breast milk must be considered,” said Amy B. Hair, MD, assistant professor of pediatrics and neonatal medicine at Baylor College of Medicine, Houston, who was not involved in the Colorado study. “And it’s unrealistic, as the study suggests, for mothers to discard breast milk for 6 weeks.”

Nevertheless, calling the findings of THC persistence after abstinence “troublesome,” Dr. Hair said the legalization of marijuana in some states gives the public the impression it’s safe to use marijuana even during pregnancy and lactation. “Research studies, however, are concerning for potential detrimental effects on brain growth and development in infants whose mothers use marijuana during pregnancy and breastfeeding,” she added.

Dr. Wymore stressed that more U.S. cannabis dispensaries must engage in rigorous point-of-sale counseling to women on the potential harms during pregnancy. This is the case in Canada, she noted, where recreational and medicinal cannabis has been legal since 2018 and more than 90% of outlets (vs. two thirds of their U.S. counterparts) advise women not to use cannabis during pregnancy or lactation, even for nausea.

“This is where many women are getting their information on cannabis,” she said. “We learned the hard way with alcohol and we don’t want to make the same mistake with marijuana.”

The study was funded by the Colorado Department of Public Health and Environment, the Children’s Hospital Colorado Research Institute, the Colorado Fetal Care Center, the Colorado Perinatal Clinical and Translational Research Center, and the Children’s Colorado Research Institute. Two study coauthors disclosed relationships with the private sector outside the submitted work. Dr. Hale and Dr. Hair have disclosed no competing interests with regard to their comments.

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

Delta-9-Tetrahydrocannabinol (THC), the main psychoactive component of cannabis, remains detectable in breast milk even after weeks of abstinence, new data show. The estimated half-life of THC in breast milk is 17 days, according to the study results, with a projected time to elimination of more than 6 weeks. The clinical importance of the remaining THC is up for debate, according to some experts.

“To limit THC effects on fetal brain development and promote safe breastfeeding, it is critical to emphasize marijuana abstention both early in pregnancy and post partum,” Erica M. Wymore, MD, MPH, an assistant professor of pediatrics and neonatology at the University of Colorado at Denver, Aurora, and colleagues wrote. The group published their results online March 8, 2021, in JAMA Pediatrics.

And while the study was a pharmacokinetic analysis rather than a safety investigation, Dr. Wymore said in an interview that the detectable levels of THC suggest any use is of concern and no safety thresholds have been established. “We wish we had more data on the potential effects on the neurocognitive development of children, but for now we must discourage any use in prepregnancy, pregnancy, and breastfeeding, as our national guidelines recommend.”

Therefore, the findings support current guidelines discouraging any cannabis use in mothers-to-be and breast-feeding mothers issued by national organizations, including those from the American Academy of Pediatrics, the American College of Obstetricians and Gynecologists, and the Academy of Breastfeeding Medicine.

Furthermore, the difficulties many mothers face in abstaining from marijuana, a commonly used drug in pregnancy, and the persistence of THC in maternal milk led the authors to question the feasibility of having women who use marijuana simply discard their breast milk until THC is cleared.

“We report challenges in abstention and prolonged excretion of THC in breast milk greater than 6 weeks among women with prenatal marijuana use,” they wrote. “These findings make the recommendations for mothers to discard breast milk until THC is undetectable unrealistic for mothers committed to breastfeeding.”

However, not all experts are equally concerned about low THC concentrations in breast milk. Neonatal pharmacologist Thomas R. Hale, PhD, a professor of pediatrics at Texas Tech University, Lubbock, said a previous study by his group showed that THC levels in maternal milk peaked within 60 minutes of a moderate dose of inhaled marijuana and fell to quite low levels over the next 4 hours. The highest concentration in maternal milk occurred shortly after the peak in plasma.

“So you can see that, just because a mom is drug screen positive, the clinical dose transferred to the infant is probably exceedingly low,” he said in an interview.

Dr. Hale also stressed that judgments about drugs in this context should weigh the risk of the drug against the risk of not breastfeeding. “All of us caution women not to use cannabis when pregnant or breastfeeding,” Dr. Hale said. “But when the decision has to be made as to whether a mom breastfeeds or not if she is drug screen positive, a lot of other factors must be analyzed to make such a decision.”
 

Study cohort

For the study, Dr. Wymore and colleagues screened 394 women who gave birth between Nov. 1, 2016, and June 30, 2019. Of those, 25 women, with a median age of 26 years, were eligible and enrolled. Inclusion criteria included known prenatal marijuana use, intention to breastfeed, and self-reported abstinence. Prenatal use primarily involved inhaling cannabis more than twice a week.

Of the 25 enrolled mothers, 12 who self-reported marijuana abstinence were in fact found to be abstinent according to the results of plasma analysis. Those who continued to use the substance were younger than the overall sample, with a median age of 21, and were less likely to have attended college (23%) than abstainers (58%).

The researchers prospectively collected data on self-reported marijuana usage and paired maternal plasma and breast milk samples several times a week. All participants had detectable THC in breast milk throughout the study. Initial median THC concentrations were 3.2 ng/mL (interquartile range, 1.2-6.8) within the first week after delivery. These increased to 5.5 ng/mL (IQR, 4.4-16.0) at 2 weeks and declined to 1.9 ng/mL (IQR, 1.1-4.3) at 6 weeks. In terms of ratio, the milk:plasma partition coefficient for THC was approximately 6:1 (IQR, 3.8:1-8.1:1).

Dr. Hale noted that, although THC was detectable in milk, the levels were exceedingly low. “This is where the risk assessment comes in. There’s a lot of hysteria in the cannabis field right now, and we’re going to need time and a lot more studies to really be able to predict any untoward complications.”

Dr. Wymore, however, countered that THC levels were low only in those who abstained and that her concerns relate not just to postpartum breast milk levels but the health effects on children of mothers’ cannabis use over the course of prepregnancy, pregnancy, and lactation. “[Dr. Hale’s] message makes it difficult for clinicians to counsel mothers since it goes against national guidelines,” she said. “We need to be consistent.”

But Dr. Wymore and other experts acknowledge the dilemma faced in that breast milk clearly offers substantial benefits for infant and child health. “The risks of an infant’s exposure to marijuana versus the benefit of breast milk must be considered,” said Amy B. Hair, MD, assistant professor of pediatrics and neonatal medicine at Baylor College of Medicine, Houston, who was not involved in the Colorado study. “And it’s unrealistic, as the study suggests, for mothers to discard breast milk for 6 weeks.”

Nevertheless, calling the findings of THC persistence after abstinence “troublesome,” Dr. Hair said the legalization of marijuana in some states gives the public the impression it’s safe to use marijuana even during pregnancy and lactation. “Research studies, however, are concerning for potential detrimental effects on brain growth and development in infants whose mothers use marijuana during pregnancy and breastfeeding,” she added.

Dr. Wymore stressed that more U.S. cannabis dispensaries must engage in rigorous point-of-sale counseling to women on the potential harms during pregnancy. This is the case in Canada, she noted, where recreational and medicinal cannabis has been legal since 2018 and more than 90% of outlets (vs. two thirds of their U.S. counterparts) advise women not to use cannabis during pregnancy or lactation, even for nausea.

“This is where many women are getting their information on cannabis,” she said. “We learned the hard way with alcohol and we don’t want to make the same mistake with marijuana.”

The study was funded by the Colorado Department of Public Health and Environment, the Children’s Hospital Colorado Research Institute, the Colorado Fetal Care Center, the Colorado Perinatal Clinical and Translational Research Center, and the Children’s Colorado Research Institute. Two study coauthors disclosed relationships with the private sector outside the submitted work. Dr. Hale and Dr. Hair have disclosed no competing interests with regard to their comments.

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

Delta-9-Tetrahydrocannabinol (THC), the main psychoactive component of cannabis, remains detectable in breast milk even after weeks of abstinence, new data show. The estimated half-life of THC in breast milk is 17 days, according to the study results, with a projected time to elimination of more than 6 weeks. The clinical importance of the remaining THC is up for debate, according to some experts.

“To limit THC effects on fetal brain development and promote safe breastfeeding, it is critical to emphasize marijuana abstention both early in pregnancy and post partum,” Erica M. Wymore, MD, MPH, an assistant professor of pediatrics and neonatology at the University of Colorado at Denver, Aurora, and colleagues wrote. The group published their results online March 8, 2021, in JAMA Pediatrics.

And while the study was a pharmacokinetic analysis rather than a safety investigation, Dr. Wymore said in an interview that the detectable levels of THC suggest any use is of concern and no safety thresholds have been established. “We wish we had more data on the potential effects on the neurocognitive development of children, but for now we must discourage any use in prepregnancy, pregnancy, and breastfeeding, as our national guidelines recommend.”

Therefore, the findings support current guidelines discouraging any cannabis use in mothers-to-be and breast-feeding mothers issued by national organizations, including those from the American Academy of Pediatrics, the American College of Obstetricians and Gynecologists, and the Academy of Breastfeeding Medicine.

Furthermore, the difficulties many mothers face in abstaining from marijuana, a commonly used drug in pregnancy, and the persistence of THC in maternal milk led the authors to question the feasibility of having women who use marijuana simply discard their breast milk until THC is cleared.

“We report challenges in abstention and prolonged excretion of THC in breast milk greater than 6 weeks among women with prenatal marijuana use,” they wrote. “These findings make the recommendations for mothers to discard breast milk until THC is undetectable unrealistic for mothers committed to breastfeeding.”

However, not all experts are equally concerned about low THC concentrations in breast milk. Neonatal pharmacologist Thomas R. Hale, PhD, a professor of pediatrics at Texas Tech University, Lubbock, said a previous study by his group showed that THC levels in maternal milk peaked within 60 minutes of a moderate dose of inhaled marijuana and fell to quite low levels over the next 4 hours. The highest concentration in maternal milk occurred shortly after the peak in plasma.

“So you can see that, just because a mom is drug screen positive, the clinical dose transferred to the infant is probably exceedingly low,” he said in an interview.

Dr. Hale also stressed that judgments about drugs in this context should weigh the risk of the drug against the risk of not breastfeeding. “All of us caution women not to use cannabis when pregnant or breastfeeding,” Dr. Hale said. “But when the decision has to be made as to whether a mom breastfeeds or not if she is drug screen positive, a lot of other factors must be analyzed to make such a decision.”
 

Study cohort

For the study, Dr. Wymore and colleagues screened 394 women who gave birth between Nov. 1, 2016, and June 30, 2019. Of those, 25 women, with a median age of 26 years, were eligible and enrolled. Inclusion criteria included known prenatal marijuana use, intention to breastfeed, and self-reported abstinence. Prenatal use primarily involved inhaling cannabis more than twice a week.

Of the 25 enrolled mothers, 12 who self-reported marijuana abstinence were in fact found to be abstinent according to the results of plasma analysis. Those who continued to use the substance were younger than the overall sample, with a median age of 21, and were less likely to have attended college (23%) than abstainers (58%).

The researchers prospectively collected data on self-reported marijuana usage and paired maternal plasma and breast milk samples several times a week. All participants had detectable THC in breast milk throughout the study. Initial median THC concentrations were 3.2 ng/mL (interquartile range, 1.2-6.8) within the first week after delivery. These increased to 5.5 ng/mL (IQR, 4.4-16.0) at 2 weeks and declined to 1.9 ng/mL (IQR, 1.1-4.3) at 6 weeks. In terms of ratio, the milk:plasma partition coefficient for THC was approximately 6:1 (IQR, 3.8:1-8.1:1).

Dr. Hale noted that, although THC was detectable in milk, the levels were exceedingly low. “This is where the risk assessment comes in. There’s a lot of hysteria in the cannabis field right now, and we’re going to need time and a lot more studies to really be able to predict any untoward complications.”

Dr. Wymore, however, countered that THC levels were low only in those who abstained and that her concerns relate not just to postpartum breast milk levels but the health effects on children of mothers’ cannabis use over the course of prepregnancy, pregnancy, and lactation. “[Dr. Hale’s] message makes it difficult for clinicians to counsel mothers since it goes against national guidelines,” she said. “We need to be consistent.”

But Dr. Wymore and other experts acknowledge the dilemma faced in that breast milk clearly offers substantial benefits for infant and child health. “The risks of an infant’s exposure to marijuana versus the benefit of breast milk must be considered,” said Amy B. Hair, MD, assistant professor of pediatrics and neonatal medicine at Baylor College of Medicine, Houston, who was not involved in the Colorado study. “And it’s unrealistic, as the study suggests, for mothers to discard breast milk for 6 weeks.”

Nevertheless, calling the findings of THC persistence after abstinence “troublesome,” Dr. Hair said the legalization of marijuana in some states gives the public the impression it’s safe to use marijuana even during pregnancy and lactation. “Research studies, however, are concerning for potential detrimental effects on brain growth and development in infants whose mothers use marijuana during pregnancy and breastfeeding,” she added.

Dr. Wymore stressed that more U.S. cannabis dispensaries must engage in rigorous point-of-sale counseling to women on the potential harms during pregnancy. This is the case in Canada, she noted, where recreational and medicinal cannabis has been legal since 2018 and more than 90% of outlets (vs. two thirds of their U.S. counterparts) advise women not to use cannabis during pregnancy or lactation, even for nausea.

“This is where many women are getting their information on cannabis,” she said. “We learned the hard way with alcohol and we don’t want to make the same mistake with marijuana.”

The study was funded by the Colorado Department of Public Health and Environment, the Children’s Hospital Colorado Research Institute, the Colorado Fetal Care Center, the Colorado Perinatal Clinical and Translational Research Center, and the Children’s Colorado Research Institute. Two study coauthors disclosed relationships with the private sector outside the submitted work. Dr. Hale and Dr. Hair have disclosed no competing interests with regard to their comments.

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

Women with polycystic ovary syndrome (PCOS) face an almost 30% increased risk for COVID-19 compared with unaffected women, even after adjusting for cardiometabolic and other related factors, suggests an analysis of United Kingdom primary care data.

“Our research has highlighted that women with PCOS are an often overlooked and potentially high-risk population for contracting COVID-19,” said joint senior author Wiebke Arlt, MD, PhD, director of the Institute of Metabolism and Systems Research at the University of Birmingham (England), in a press release.

“Before the onset of the COVID-19 pandemic, women with PCOS consistently report fragmented care, delayed diagnosis and a perception of poor clinician understanding of their condition,” added co-author Michael W. O’Reilly, MD, PhD, University of Medicine and Health Sciences, Dublin.

“Women suffering from this condition may fear, with some degree of justification, that an enhanced risk of COVID-19 infection will further compromise timely access to health care and serve to increase the sense of disenfranchisement currently experienced by many patients,” he added.

Consequently, “these findings need to be considered when designing public health policy and advice as our understanding of COVID-19 evolves,” noted first author Anuradhaa Subramanian, PhD Student, Institute of Applied Health Research, University of Birmingham.

The research was published by the European Journal of Endocrinology on March 9.
 

Women with PCOS: A distinct subgroup?

PCOS, which is thought to affect up to 16% of women, is associated with a significantly increased risk for type 2 diabetes, non-alcoholic fatty liver disease, and cardiovascular disease, all which have been linked to more severe COVID-19.

The condition is more prevalent in Black and South Asian women, who also appear to have an increased risk for severe COVID-19 vs. their White counterparts.

However, women and younger people in general have a lower overall risk for severe COVID-19 and mortality compared with older people and men.

Women with PCOS may therefore “represent a distinct subgroup of women at higher than average [on the basis of their sex and age] risk of adverse COVID-19–related outcomes,” the researchers note.

To investigate further, they collated data from The Health Improvement Network primary care database, which includes information from 365 active general practices in the U.K. for the period Jan. 31, 2020, to July 22, 2020.

They identified women with PCOS or a coded diagnosis of polycystic ovaries (PCO), and then for each woman randomly selected four unaffected controls matched for age and general practice location.

They included 21,292 women with PCOS/PCO and 78,310 controls, who had a mean age at study entry of 39.3 years and 39.5 years, respectively. The mean age at diagnosis of PCOS was 27 years, and the mean duration of the condition was 12.4 years.

The crude incidence of COVID-19 was 18.1 per 1000 person-years among women with PCOS vs. 11.9 per 1000 person-years in those without.

Cox regression analysis adjusted for age indicated that women with PCOS faced a significantly increased risk for COVID-19 than those without, at a hazard ratio of 1.51 (P < .001).

Further adjustment for body mass index (BMI) and age reduced the hazard ratio to 1.36 (P = .001).

In the fully adjusted model, which also took into account impaired glucose regulation, androgen excess, anovulation, hypertension, and other PCOS-related factors, the hazard ratio remained significant, at 1.28 (P = .015).
 

For shielding, balance benefits with impact on mental health

Joint senior author Krishnarajah Nirantharakumar, MD, PhD, also of the University of Birmingham, commented that, despite the increased risks, shielding strategies for COVID-19 need to take into account the impact of PCOS on women’s mental health.

“The risk of mental health problems, including low self-esteem, anxiety, and depression, is significantly higher in women with PCOS,” he said, “and advice on strict adherence to social distancing needs to be tempered by the associated risk of exacerbating these underlying problems.”

Arlt also pointed out that the study only looked at the incidence of COVID-19 infection, rather than outcomes.

“Our study does not provide information on the risk of a severe course of the COVID-19 infection or on the risk of COVID-19–related long-term complications [in women with PCOS], and further research is required,” she concluded.

The study was funded by Health Data Research UK and supported by the Wellcome Trust, the Health Research Board, and the National Institute for Health Research Birmingham Biomedical Research Centre based at the University of Birmingham and University Hospitals Birmingham NHS Foundation Trust. The study authors have disclosed no relevant financial relationships.

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

Women with polycystic ovary syndrome (PCOS) face an almost 30% increased risk for COVID-19 compared with unaffected women, even after adjusting for cardiometabolic and other related factors, suggests an analysis of United Kingdom primary care data.

“Our research has highlighted that women with PCOS are an often overlooked and potentially high-risk population for contracting COVID-19,” said joint senior author Wiebke Arlt, MD, PhD, director of the Institute of Metabolism and Systems Research at the University of Birmingham (England), in a press release.

“Before the onset of the COVID-19 pandemic, women with PCOS consistently report fragmented care, delayed diagnosis and a perception of poor clinician understanding of their condition,” added co-author Michael W. O’Reilly, MD, PhD, University of Medicine and Health Sciences, Dublin.

“Women suffering from this condition may fear, with some degree of justification, that an enhanced risk of COVID-19 infection will further compromise timely access to health care and serve to increase the sense of disenfranchisement currently experienced by many patients,” he added.

Consequently, “these findings need to be considered when designing public health policy and advice as our understanding of COVID-19 evolves,” noted first author Anuradhaa Subramanian, PhD Student, Institute of Applied Health Research, University of Birmingham.

The research was published by the European Journal of Endocrinology on March 9.
 

Women with PCOS: A distinct subgroup?

PCOS, which is thought to affect up to 16% of women, is associated with a significantly increased risk for type 2 diabetes, non-alcoholic fatty liver disease, and cardiovascular disease, all which have been linked to more severe COVID-19.

The condition is more prevalent in Black and South Asian women, who also appear to have an increased risk for severe COVID-19 vs. their White counterparts.

However, women and younger people in general have a lower overall risk for severe COVID-19 and mortality compared with older people and men.

Women with PCOS may therefore “represent a distinct subgroup of women at higher than average [on the basis of their sex and age] risk of adverse COVID-19–related outcomes,” the researchers note.

To investigate further, they collated data from The Health Improvement Network primary care database, which includes information from 365 active general practices in the U.K. for the period Jan. 31, 2020, to July 22, 2020.

They identified women with PCOS or a coded diagnosis of polycystic ovaries (PCO), and then for each woman randomly selected four unaffected controls matched for age and general practice location.

They included 21,292 women with PCOS/PCO and 78,310 controls, who had a mean age at study entry of 39.3 years and 39.5 years, respectively. The mean age at diagnosis of PCOS was 27 years, and the mean duration of the condition was 12.4 years.

The crude incidence of COVID-19 was 18.1 per 1000 person-years among women with PCOS vs. 11.9 per 1000 person-years in those without.

Cox regression analysis adjusted for age indicated that women with PCOS faced a significantly increased risk for COVID-19 than those without, at a hazard ratio of 1.51 (P < .001).

Further adjustment for body mass index (BMI) and age reduced the hazard ratio to 1.36 (P = .001).

In the fully adjusted model, which also took into account impaired glucose regulation, androgen excess, anovulation, hypertension, and other PCOS-related factors, the hazard ratio remained significant, at 1.28 (P = .015).
 

For shielding, balance benefits with impact on mental health

Joint senior author Krishnarajah Nirantharakumar, MD, PhD, also of the University of Birmingham, commented that, despite the increased risks, shielding strategies for COVID-19 need to take into account the impact of PCOS on women’s mental health.

“The risk of mental health problems, including low self-esteem, anxiety, and depression, is significantly higher in women with PCOS,” he said, “and advice on strict adherence to social distancing needs to be tempered by the associated risk of exacerbating these underlying problems.”

Arlt also pointed out that the study only looked at the incidence of COVID-19 infection, rather than outcomes.

“Our study does not provide information on the risk of a severe course of the COVID-19 infection or on the risk of COVID-19–related long-term complications [in women with PCOS], and further research is required,” she concluded.

The study was funded by Health Data Research UK and supported by the Wellcome Trust, the Health Research Board, and the National Institute for Health Research Birmingham Biomedical Research Centre based at the University of Birmingham and University Hospitals Birmingham NHS Foundation Trust. The study authors have disclosed no relevant financial relationships.

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

Women with polycystic ovary syndrome (PCOS) face an almost 30% increased risk for COVID-19 compared with unaffected women, even after adjusting for cardiometabolic and other related factors, suggests an analysis of United Kingdom primary care data.

“Our research has highlighted that women with PCOS are an often overlooked and potentially high-risk population for contracting COVID-19,” said joint senior author Wiebke Arlt, MD, PhD, director of the Institute of Metabolism and Systems Research at the University of Birmingham (England), in a press release.

“Before the onset of the COVID-19 pandemic, women with PCOS consistently report fragmented care, delayed diagnosis and a perception of poor clinician understanding of their condition,” added co-author Michael W. O’Reilly, MD, PhD, University of Medicine and Health Sciences, Dublin.

“Women suffering from this condition may fear, with some degree of justification, that an enhanced risk of COVID-19 infection will further compromise timely access to health care and serve to increase the sense of disenfranchisement currently experienced by many patients,” he added.

Consequently, “these findings need to be considered when designing public health policy and advice as our understanding of COVID-19 evolves,” noted first author Anuradhaa Subramanian, PhD Student, Institute of Applied Health Research, University of Birmingham.

The research was published by the European Journal of Endocrinology on March 9.
 

Women with PCOS: A distinct subgroup?

PCOS, which is thought to affect up to 16% of women, is associated with a significantly increased risk for type 2 diabetes, non-alcoholic fatty liver disease, and cardiovascular disease, all which have been linked to more severe COVID-19.

The condition is more prevalent in Black and South Asian women, who also appear to have an increased risk for severe COVID-19 vs. their White counterparts.

However, women and younger people in general have a lower overall risk for severe COVID-19 and mortality compared with older people and men.

Women with PCOS may therefore “represent a distinct subgroup of women at higher than average [on the basis of their sex and age] risk of adverse COVID-19–related outcomes,” the researchers note.

To investigate further, they collated data from The Health Improvement Network primary care database, which includes information from 365 active general practices in the U.K. for the period Jan. 31, 2020, to July 22, 2020.

They identified women with PCOS or a coded diagnosis of polycystic ovaries (PCO), and then for each woman randomly selected four unaffected controls matched for age and general practice location.

They included 21,292 women with PCOS/PCO and 78,310 controls, who had a mean age at study entry of 39.3 years and 39.5 years, respectively. The mean age at diagnosis of PCOS was 27 years, and the mean duration of the condition was 12.4 years.

The crude incidence of COVID-19 was 18.1 per 1000 person-years among women with PCOS vs. 11.9 per 1000 person-years in those without.

Cox regression analysis adjusted for age indicated that women with PCOS faced a significantly increased risk for COVID-19 than those without, at a hazard ratio of 1.51 (P < .001).

Further adjustment for body mass index (BMI) and age reduced the hazard ratio to 1.36 (P = .001).

In the fully adjusted model, which also took into account impaired glucose regulation, androgen excess, anovulation, hypertension, and other PCOS-related factors, the hazard ratio remained significant, at 1.28 (P = .015).
 

For shielding, balance benefits with impact on mental health

Joint senior author Krishnarajah Nirantharakumar, MD, PhD, also of the University of Birmingham, commented that, despite the increased risks, shielding strategies for COVID-19 need to take into account the impact of PCOS on women’s mental health.

“The risk of mental health problems, including low self-esteem, anxiety, and depression, is significantly higher in women with PCOS,” he said, “and advice on strict adherence to social distancing needs to be tempered by the associated risk of exacerbating these underlying problems.”

Arlt also pointed out that the study only looked at the incidence of COVID-19 infection, rather than outcomes.

“Our study does not provide information on the risk of a severe course of the COVID-19 infection or on the risk of COVID-19–related long-term complications [in women with PCOS], and further research is required,” she concluded.

The study was funded by Health Data Research UK and supported by the Wellcome Trust, the Health Research Board, and the National Institute for Health Research Birmingham Biomedical Research Centre based at the University of Birmingham and University Hospitals Birmingham NHS Foundation Trust. The study authors have disclosed no relevant financial relationships.

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

Women with gynecologic cancers can safely continue anticancer therapy, despite the threat of COVID-19, according to researchers.

The team found no significant association between recent anticancer therapy and COVID-19 hospitalization or mortality among patients with gynecologic cancers and COVID-19.

Some gynecologic cancer patients have expressed concerns that chemotherapy would weaken their immune system and increase their risk of more severe illness if they developed COVID-19, according to Olivia Lara, MD, a gynecologic oncology fellow at New York University.

Furthermore, some prior studies had shown an increased risk of health complications from COVID-19 among cancer patients. However, patients with gynecologic cancer were underrepresented in those studies.

With all this in mind, Dr. Lara and colleagues conducted a study of 193 patients with gynecologic cancers and COVID-19 who were treated at eight hospital systems in the New York City area from March 2020 through May 2020.

Dr. Lara presented the results at the Society of Gynecologic Oncology’s Virtual Annual Meeting on Women’s Cancer (Abstract 10663).
 

Study results

Of the 193 patients analyzed, 106 (54.9%) required hospitalization for COVID-19, including 13 (12.3%) who required mechanical ventilation and 39 (36.8%) who required ICU admission. There were 34 patients (17.6%) who died of COVID-19-related complications, including all who required mechanical ventilation.

Multivariable analyses showed that recent cytotoxic chemotherapy, which was used in 13 of the 34 patients who died (38.2%), and recent immunotherapy, which was used in 4 of the 34 patients (11.8%), were not predictive of COVID-19 hospitalization or mortality.

Only current or former smoking was associated with COVID-19-related death (odds ratio, 2.75).

An earlier analysis of data from 121 patients in this cohort showed an association between immunotherapy and COVID-19-related death, but this was no longer statistically significant in the updated analysis.

Factors significantly associated with hospitalization in the updated cohort were age 65 years or older (OR, 2.12), Black race (OR, 2.53), performance status of 2 or greater (OR, 3.67), and the presence of three or more comorbidities (OR, 2.00), the most common of which were hypertension, diabetes, and chronic kidney disease.
 

More research needed

The current findings show that recent chemotherapy or immunotherapy for gynecologic cancer do not raise the risk of death due to COVID-19, Dr. Lara said, adding that “[w]e can reassure women with gynecologic cancer that they can continue anticancer therapy.”

The finding of a nearly threefold increased risk of hospitalization among Black patients in this study underscores the need for “better understanding of the risks of COVID-19 in vulnerable populations,” Dr. Lara noted.

“Going forward, the impact of the COVID-19 pandemic on cancer care delivery and cancer screening must be evaluated,” she said. “Data collection is ongoing, with additional analyses and studies planned to investigate the impact COVID-19 has had on gynecologic cancer care through the SGO registry.”

The current findings are strengthened by the collaborative multicenter study design and use of multivariable analyses, said invited discussant and study coauthor Bhavana Pothuri, MD, of New York University.

However, it is unclear whether the results are generalizable to other parts of the country or world, and whether the outcomes have changed since the initial surge of COVID-19 cases.

Dr. Lara said the fatality rate in this cohort is similar to that of age-matched women with COVID-19 who did not have cancer, and she acknowledged that fatality rates may be lower now than they were early in the pandemic when the study was conducted.

This study was supported, in part, by a Cancer Center Support Grant from the National Institutes of Health/National Cancer Institute. Dr. Lara reported having no disclosures. Dr. Pothuri disclosed relationships with Tesaro/GlaxoSmithKline, AstraZeneca, Merck, Genentech/Roche, Celsion, Clovis Oncology, Toray, Mersana, Elevar, and Eisai. She is also a member of GOG Partners leadership.

sworcester@mdedge.com

Women with gynecologic cancers can safely continue anticancer therapy, despite the threat of COVID-19, according to researchers.

The team found no significant association between recent anticancer therapy and COVID-19 hospitalization or mortality among patients with gynecologic cancers and COVID-19.

Some gynecologic cancer patients have expressed concerns that chemotherapy would weaken their immune system and increase their risk of more severe illness if they developed COVID-19, according to Olivia Lara, MD, a gynecologic oncology fellow at New York University.

Furthermore, some prior studies had shown an increased risk of health complications from COVID-19 among cancer patients. However, patients with gynecologic cancer were underrepresented in those studies.

With all this in mind, Dr. Lara and colleagues conducted a study of 193 patients with gynecologic cancers and COVID-19 who were treated at eight hospital systems in the New York City area from March 2020 through May 2020.

Dr. Lara presented the results at the Society of Gynecologic Oncology’s Virtual Annual Meeting on Women’s Cancer (Abstract 10663).
 

Study results

Of the 193 patients analyzed, 106 (54.9%) required hospitalization for COVID-19, including 13 (12.3%) who required mechanical ventilation and 39 (36.8%) who required ICU admission. There were 34 patients (17.6%) who died of COVID-19-related complications, including all who required mechanical ventilation.

Multivariable analyses showed that recent cytotoxic chemotherapy, which was used in 13 of the 34 patients who died (38.2%), and recent immunotherapy, which was used in 4 of the 34 patients (11.8%), were not predictive of COVID-19 hospitalization or mortality.

Only current or former smoking was associated with COVID-19-related death (odds ratio, 2.75).

An earlier analysis of data from 121 patients in this cohort showed an association between immunotherapy and COVID-19-related death, but this was no longer statistically significant in the updated analysis.

Factors significantly associated with hospitalization in the updated cohort were age 65 years or older (OR, 2.12), Black race (OR, 2.53), performance status of 2 or greater (OR, 3.67), and the presence of three or more comorbidities (OR, 2.00), the most common of which were hypertension, diabetes, and chronic kidney disease.
 

More research needed

The current findings show that recent chemotherapy or immunotherapy for gynecologic cancer do not raise the risk of death due to COVID-19, Dr. Lara said, adding that “[w]e can reassure women with gynecologic cancer that they can continue anticancer therapy.”

The finding of a nearly threefold increased risk of hospitalization among Black patients in this study underscores the need for “better understanding of the risks of COVID-19 in vulnerable populations,” Dr. Lara noted.

“Going forward, the impact of the COVID-19 pandemic on cancer care delivery and cancer screening must be evaluated,” she said. “Data collection is ongoing, with additional analyses and studies planned to investigate the impact COVID-19 has had on gynecologic cancer care through the SGO registry.”

The current findings are strengthened by the collaborative multicenter study design and use of multivariable analyses, said invited discussant and study coauthor Bhavana Pothuri, MD, of New York University.

However, it is unclear whether the results are generalizable to other parts of the country or world, and whether the outcomes have changed since the initial surge of COVID-19 cases.

Dr. Lara said the fatality rate in this cohort is similar to that of age-matched women with COVID-19 who did not have cancer, and she acknowledged that fatality rates may be lower now than they were early in the pandemic when the study was conducted.

This study was supported, in part, by a Cancer Center Support Grant from the National Institutes of Health/National Cancer Institute. Dr. Lara reported having no disclosures. Dr. Pothuri disclosed relationships with Tesaro/GlaxoSmithKline, AstraZeneca, Merck, Genentech/Roche, Celsion, Clovis Oncology, Toray, Mersana, Elevar, and Eisai. She is also a member of GOG Partners leadership.

sworcester@mdedge.com

Women with gynecologic cancers can safely continue anticancer therapy, despite the threat of COVID-19, according to researchers.

The team found no significant association between recent anticancer therapy and COVID-19 hospitalization or mortality among patients with gynecologic cancers and COVID-19.

Some gynecologic cancer patients have expressed concerns that chemotherapy would weaken their immune system and increase their risk of more severe illness if they developed COVID-19, according to Olivia Lara, MD, a gynecologic oncology fellow at New York University.

Furthermore, some prior studies had shown an increased risk of health complications from COVID-19 among cancer patients. However, patients with gynecologic cancer were underrepresented in those studies.

With all this in mind, Dr. Lara and colleagues conducted a study of 193 patients with gynecologic cancers and COVID-19 who were treated at eight hospital systems in the New York City area from March 2020 through May 2020.

Dr. Lara presented the results at the Society of Gynecologic Oncology’s Virtual Annual Meeting on Women’s Cancer (Abstract 10663).
 

Study results

Of the 193 patients analyzed, 106 (54.9%) required hospitalization for COVID-19, including 13 (12.3%) who required mechanical ventilation and 39 (36.8%) who required ICU admission. There were 34 patients (17.6%) who died of COVID-19-related complications, including all who required mechanical ventilation.

Multivariable analyses showed that recent cytotoxic chemotherapy, which was used in 13 of the 34 patients who died (38.2%), and recent immunotherapy, which was used in 4 of the 34 patients (11.8%), were not predictive of COVID-19 hospitalization or mortality.

Only current or former smoking was associated with COVID-19-related death (odds ratio, 2.75).

An earlier analysis of data from 121 patients in this cohort showed an association between immunotherapy and COVID-19-related death, but this was no longer statistically significant in the updated analysis.

Factors significantly associated with hospitalization in the updated cohort were age 65 years or older (OR, 2.12), Black race (OR, 2.53), performance status of 2 or greater (OR, 3.67), and the presence of three or more comorbidities (OR, 2.00), the most common of which were hypertension, diabetes, and chronic kidney disease.
 

More research needed

The current findings show that recent chemotherapy or immunotherapy for gynecologic cancer do not raise the risk of death due to COVID-19, Dr. Lara said, adding that “[w]e can reassure women with gynecologic cancer that they can continue anticancer therapy.”

The finding of a nearly threefold increased risk of hospitalization among Black patients in this study underscores the need for “better understanding of the risks of COVID-19 in vulnerable populations,” Dr. Lara noted.

“Going forward, the impact of the COVID-19 pandemic on cancer care delivery and cancer screening must be evaluated,” she said. “Data collection is ongoing, with additional analyses and studies planned to investigate the impact COVID-19 has had on gynecologic cancer care through the SGO registry.”

The current findings are strengthened by the collaborative multicenter study design and use of multivariable analyses, said invited discussant and study coauthor Bhavana Pothuri, MD, of New York University.

However, it is unclear whether the results are generalizable to other parts of the country or world, and whether the outcomes have changed since the initial surge of COVID-19 cases.

Dr. Lara said the fatality rate in this cohort is similar to that of age-matched women with COVID-19 who did not have cancer, and she acknowledged that fatality rates may be lower now than they were early in the pandemic when the study was conducted.

This study was supported, in part, by a Cancer Center Support Grant from the National Institutes of Health/National Cancer Institute. Dr. Lara reported having no disclosures. Dr. Pothuri disclosed relationships with Tesaro/GlaxoSmithKline, AstraZeneca, Merck, Genentech/Roche, Celsion, Clovis Oncology, Toray, Mersana, Elevar, and Eisai. She is also a member of GOG Partners leadership.

sworcester@mdedge.com

Federal regulators on March 23 said they were “concerned” that drug maker AstraZeneca included “outdated information” in its announcement the previous day that the company’s COVID-19 vaccine was effective.

The federal Data and Safety Monitoring Board shared those concerns with the company as well as with the National Institute of Allergy and Infectious Diseases, and the U.S. Biomedical Advanced Research and Development Authority, according to a statement from NIAID issued early March 23.

“We urge the company to work with the DSMB to review the efficacy data and ensure the most accurate, up-to-date efficacy data be made public as quickly as possible,” the agency said.

The NIAID statement does not say what data may have been outdated or how it may have changed the results. The company said March 22 it plans to see U.S. authorization for the vaccine in April.

The statement from NIAID comes a day after AstraZeneca said the interim results of their phase III U.S. study found it was 79% effective against symptomatic COVID-19, 80% effective in people 65 years and older, and 100% effective against severe or critical disease and hospitalization.

Company officials and clinical trial investigators on March 22 also addressed the recent concerns about blood clots, how well the vaccine will perform against variants, and provided a timeline for seeking regulatory approval.

“There are many countries in Europe and throughout the world that have already authorized this. The fact that a United States-run study has confirmed the efficacy and safety of this vaccine, I think is an important contribution to global health in general,” Anthony Fauci, MD, chief medical advisor to President Joe Biden, said during a White House press briefing March 22.

Andy Slavitt, White House senior advisor for the COVID-19 Response Team, had a more tempered reaction.

“It’s important to remind everyone we cannot and will not get ahead of the FDA,” he said. “While we would certainly call today’s news encouraging, it’s the kind of thing we like to see, we have a rigorous process that will come once an EUA is submitted and that will give us more information.”

With 30 million doses at the ready, the company plans to file for FDA emergency use authorization “within weeks,” Menelas Pangalos, executive vice president of biopharmaceuticals research and development at AstraZeneca, said during a media briefing March 22.
 

Risk of thrombosis addressed

Regarding highly publicized reports of problems with blood clots from the AstraZeneca vaccine, the World Health Organization found the vaccine creates no greater risks, as did the European Medicines Agency

“We’ve had absolute confidence in the efficacy of the vaccine. Seeing this data now I hope gives others increased confidence that this is a very safe and effective vaccine,” Mr. Pangalos said.

“We’re glad this is being investigated really thoroughly,” Magda Sobieszczyk, MD, an infectious disease specialist at Columbia University In New York City, said. “It’s incredibly reassuring that the regulatory agencies have looked at the data thoroughly and there is no enhanced signal above what is seen in the population.”

“There were no concerning signals noted in the U.S. data,” she added.

Regarding the risk of blood clots, “These data are therefore timely in further addressing any safety concerns that could undermine vaccine uptake.” Andrew Garrett, PhD, executive vice president of scientific operations at ICON Clinical Research, agreed.

The vaccine was well-tolerated, the company reported, with no serious adverse events. Temporary pain and tenderness at the injection site, mild-to-moderate headaches, fatigue, chills, fever, muscle aches. and malaise were among the reported reactions.

The phase III interim results show 141 cases of symptomatic COVID-19 in the study of 32,449 adults. “We don’t have the whole breakdown yet . . . these are the high-level results we just got this week,” Mr. Pangalos said. Further information on rates of mild to moderate COVID-19 illness between groups is not yet available, for example.

The company explained that participants were randomly assigned to vaccine or placebo, with twice as many receiving the actual vaccine.

The trial is ongoing, so the FDA will receive information on more than the 141 COVID-19 symptomatic cases when the company submits a full primary analysis to the agency, Mr. Pangalos said.

In the phase III study, patients received two doses 4 weeks apart.

Beyond the U.S. study, the company has additional information, including real-world data from the United Kingdom, that it intends to submit to the FDA. Part of this evidence suggests increased efficacy when a second dose is administered at 3 months
 

‘Robust’ findings

“This is a large study, so these results can be expected to be robust. They could be expected to be even more so if there were more cases to compare between the groups, but 141 is still a substantial number of cases,” said Peter English, MD, of Horsham, United Kingdom, who is immediate past chair of the British Medical Association Public Health Medicine Committee.

Experts welcomed the 80% efficacy in people 65 and older in particular. “Importantly, the trial provides further support for efficacy in the elderly where previous clinical trial data, other than immunologic data, had been lacking,” Dr. Garrett said.

“It is clear this vaccine has very good efficacy. Remember that 60% was, prior to any trials being started, regarded as a good target,” said Stephen Evans, professor of pharmacoepidemiology at the London School of Hygiene & Tropical Medicine. “This efficacy does not show a notable decline at older ages. This was expected and the speculation that it was ineffective or quasi-ineffective at older ages was totally unjustified.

“This is good news for the global community and one hopes that any political statements around this good news are avoided,” he added.
 

Efficacy against variants?

Regarding virus variants, Mr. Pangalos noted the study was conducted when several variants of concern were in circulation.

“What I can say is given this study was conducted much later in terms of timing, it’s very encouraging that we’ve got such high efficacy numbers when undoubtedly there are variants of concern in circulation in this study,” Mr. Pangalos said.

“It also highlights why we believe that against severe disease, our vaccine will be effective against all variants of concern,” he added.

Once the company submits its EUA to the FDA, the company is ready to immediately distribute 30 million doses of the vaccine and expects to ship 50 million total within the first month, Ruud Dobber, PhD, AstraZeneca executive vice president and president of the AZ Biopharmaceuticals Business Unit, said during the briefing.

The vaccine can be stored at 2 to 8 degrees Celsius for at least 6 months. Like other COVID-19 vaccines already authorized for emergency use, the duration of protection with the AstraZeneca product remains unknown.

This article was updated March 23, 2021.

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

Federal regulators on March 23 said they were “concerned” that drug maker AstraZeneca included “outdated information” in its announcement the previous day that the company’s COVID-19 vaccine was effective.

The federal Data and Safety Monitoring Board shared those concerns with the company as well as with the National Institute of Allergy and Infectious Diseases, and the U.S. Biomedical Advanced Research and Development Authority, according to a statement from NIAID issued early March 23.

“We urge the company to work with the DSMB to review the efficacy data and ensure the most accurate, up-to-date efficacy data be made public as quickly as possible,” the agency said.

The NIAID statement does not say what data may have been outdated or how it may have changed the results. The company said March 22 it plans to see U.S. authorization for the vaccine in April.

The statement from NIAID comes a day after AstraZeneca said the interim results of their phase III U.S. study found it was 79% effective against symptomatic COVID-19, 80% effective in people 65 years and older, and 100% effective against severe or critical disease and hospitalization.

Company officials and clinical trial investigators on March 22 also addressed the recent concerns about blood clots, how well the vaccine will perform against variants, and provided a timeline for seeking regulatory approval.

“There are many countries in Europe and throughout the world that have already authorized this. The fact that a United States-run study has confirmed the efficacy and safety of this vaccine, I think is an important contribution to global health in general,” Anthony Fauci, MD, chief medical advisor to President Joe Biden, said during a White House press briefing March 22.

Andy Slavitt, White House senior advisor for the COVID-19 Response Team, had a more tempered reaction.

“It’s important to remind everyone we cannot and will not get ahead of the FDA,” he said. “While we would certainly call today’s news encouraging, it’s the kind of thing we like to see, we have a rigorous process that will come once an EUA is submitted and that will give us more information.”

With 30 million doses at the ready, the company plans to file for FDA emergency use authorization “within weeks,” Menelas Pangalos, executive vice president of biopharmaceuticals research and development at AstraZeneca, said during a media briefing March 22.
 

Risk of thrombosis addressed

Regarding highly publicized reports of problems with blood clots from the AstraZeneca vaccine, the World Health Organization found the vaccine creates no greater risks, as did the European Medicines Agency

“We’ve had absolute confidence in the efficacy of the vaccine. Seeing this data now I hope gives others increased confidence that this is a very safe and effective vaccine,” Mr. Pangalos said.

“We’re glad this is being investigated really thoroughly,” Magda Sobieszczyk, MD, an infectious disease specialist at Columbia University In New York City, said. “It’s incredibly reassuring that the regulatory agencies have looked at the data thoroughly and there is no enhanced signal above what is seen in the population.”

“There were no concerning signals noted in the U.S. data,” she added.

Regarding the risk of blood clots, “These data are therefore timely in further addressing any safety concerns that could undermine vaccine uptake.” Andrew Garrett, PhD, executive vice president of scientific operations at ICON Clinical Research, agreed.

The vaccine was well-tolerated, the company reported, with no serious adverse events. Temporary pain and tenderness at the injection site, mild-to-moderate headaches, fatigue, chills, fever, muscle aches. and malaise were among the reported reactions.

The phase III interim results show 141 cases of symptomatic COVID-19 in the study of 32,449 adults. “We don’t have the whole breakdown yet . . . these are the high-level results we just got this week,” Mr. Pangalos said. Further information on rates of mild to moderate COVID-19 illness between groups is not yet available, for example.

The company explained that participants were randomly assigned to vaccine or placebo, with twice as many receiving the actual vaccine.

The trial is ongoing, so the FDA will receive information on more than the 141 COVID-19 symptomatic cases when the company submits a full primary analysis to the agency, Mr. Pangalos said.

In the phase III study, patients received two doses 4 weeks apart.

Beyond the U.S. study, the company has additional information, including real-world data from the United Kingdom, that it intends to submit to the FDA. Part of this evidence suggests increased efficacy when a second dose is administered at 3 months
 

‘Robust’ findings

“This is a large study, so these results can be expected to be robust. They could be expected to be even more so if there were more cases to compare between the groups, but 141 is still a substantial number of cases,” said Peter English, MD, of Horsham, United Kingdom, who is immediate past chair of the British Medical Association Public Health Medicine Committee.

Experts welcomed the 80% efficacy in people 65 and older in particular. “Importantly, the trial provides further support for efficacy in the elderly where previous clinical trial data, other than immunologic data, had been lacking,” Dr. Garrett said.

“It is clear this vaccine has very good efficacy. Remember that 60% was, prior to any trials being started, regarded as a good target,” said Stephen Evans, professor of pharmacoepidemiology at the London School of Hygiene & Tropical Medicine. “This efficacy does not show a notable decline at older ages. This was expected and the speculation that it was ineffective or quasi-ineffective at older ages was totally unjustified.

“This is good news for the global community and one hopes that any political statements around this good news are avoided,” he added.
 

Efficacy against variants?

Regarding virus variants, Mr. Pangalos noted the study was conducted when several variants of concern were in circulation.

“What I can say is given this study was conducted much later in terms of timing, it’s very encouraging that we’ve got such high efficacy numbers when undoubtedly there are variants of concern in circulation in this study,” Mr. Pangalos said.

“It also highlights why we believe that against severe disease, our vaccine will be effective against all variants of concern,” he added.

Once the company submits its EUA to the FDA, the company is ready to immediately distribute 30 million doses of the vaccine and expects to ship 50 million total within the first month, Ruud Dobber, PhD, AstraZeneca executive vice president and president of the AZ Biopharmaceuticals Business Unit, said during the briefing.

The vaccine can be stored at 2 to 8 degrees Celsius for at least 6 months. Like other COVID-19 vaccines already authorized for emergency use, the duration of protection with the AstraZeneca product remains unknown.

This article was updated March 23, 2021.

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

Federal regulators on March 23 said they were “concerned” that drug maker AstraZeneca included “outdated information” in its announcement the previous day that the company’s COVID-19 vaccine was effective.

The federal Data and Safety Monitoring Board shared those concerns with the company as well as with the National Institute of Allergy and Infectious Diseases, and the U.S. Biomedical Advanced Research and Development Authority, according to a statement from NIAID issued early March 23.

“We urge the company to work with the DSMB to review the efficacy data and ensure the most accurate, up-to-date efficacy data be made public as quickly as possible,” the agency said.

The NIAID statement does not say what data may have been outdated or how it may have changed the results. The company said March 22 it plans to see U.S. authorization for the vaccine in April.

The statement from NIAID comes a day after AstraZeneca said the interim results of their phase III U.S. study found it was 79% effective against symptomatic COVID-19, 80% effective in people 65 years and older, and 100% effective against severe or critical disease and hospitalization.

Company officials and clinical trial investigators on March 22 also addressed the recent concerns about blood clots, how well the vaccine will perform against variants, and provided a timeline for seeking regulatory approval.

“There are many countries in Europe and throughout the world that have already authorized this. The fact that a United States-run study has confirmed the efficacy and safety of this vaccine, I think is an important contribution to global health in general,” Anthony Fauci, MD, chief medical advisor to President Joe Biden, said during a White House press briefing March 22.

Andy Slavitt, White House senior advisor for the COVID-19 Response Team, had a more tempered reaction.

“It’s important to remind everyone we cannot and will not get ahead of the FDA,” he said. “While we would certainly call today’s news encouraging, it’s the kind of thing we like to see, we have a rigorous process that will come once an EUA is submitted and that will give us more information.”

With 30 million doses at the ready, the company plans to file for FDA emergency use authorization “within weeks,” Menelas Pangalos, executive vice president of biopharmaceuticals research and development at AstraZeneca, said during a media briefing March 22.
 

Risk of thrombosis addressed

Regarding highly publicized reports of problems with blood clots from the AstraZeneca vaccine, the World Health Organization found the vaccine creates no greater risks, as did the European Medicines Agency

“We’ve had absolute confidence in the efficacy of the vaccine. Seeing this data now I hope gives others increased confidence that this is a very safe and effective vaccine,” Mr. Pangalos said.

“We’re glad this is being investigated really thoroughly,” Magda Sobieszczyk, MD, an infectious disease specialist at Columbia University In New York City, said. “It’s incredibly reassuring that the regulatory agencies have looked at the data thoroughly and there is no enhanced signal above what is seen in the population.”

“There were no concerning signals noted in the U.S. data,” she added.

Regarding the risk of blood clots, “These data are therefore timely in further addressing any safety concerns that could undermine vaccine uptake.” Andrew Garrett, PhD, executive vice president of scientific operations at ICON Clinical Research, agreed.

The vaccine was well-tolerated, the company reported, with no serious adverse events. Temporary pain and tenderness at the injection site, mild-to-moderate headaches, fatigue, chills, fever, muscle aches. and malaise were among the reported reactions.

The phase III interim results show 141 cases of symptomatic COVID-19 in the study of 32,449 adults. “We don’t have the whole breakdown yet . . . these are the high-level results we just got this week,” Mr. Pangalos said. Further information on rates of mild to moderate COVID-19 illness between groups is not yet available, for example.

The company explained that participants were randomly assigned to vaccine or placebo, with twice as many receiving the actual vaccine.

The trial is ongoing, so the FDA will receive information on more than the 141 COVID-19 symptomatic cases when the company submits a full primary analysis to the agency, Mr. Pangalos said.

In the phase III study, patients received two doses 4 weeks apart.

Beyond the U.S. study, the company has additional information, including real-world data from the United Kingdom, that it intends to submit to the FDA. Part of this evidence suggests increased efficacy when a second dose is administered at 3 months
 

‘Robust’ findings

“This is a large study, so these results can be expected to be robust. They could be expected to be even more so if there were more cases to compare between the groups, but 141 is still a substantial number of cases,” said Peter English, MD, of Horsham, United Kingdom, who is immediate past chair of the British Medical Association Public Health Medicine Committee.

Experts welcomed the 80% efficacy in people 65 and older in particular. “Importantly, the trial provides further support for efficacy in the elderly where previous clinical trial data, other than immunologic data, had been lacking,” Dr. Garrett said.

“It is clear this vaccine has very good efficacy. Remember that 60% was, prior to any trials being started, regarded as a good target,” said Stephen Evans, professor of pharmacoepidemiology at the London School of Hygiene & Tropical Medicine. “This efficacy does not show a notable decline at older ages. This was expected and the speculation that it was ineffective or quasi-ineffective at older ages was totally unjustified.

“This is good news for the global community and one hopes that any political statements around this good news are avoided,” he added.
 

Efficacy against variants?

Regarding virus variants, Mr. Pangalos noted the study was conducted when several variants of concern were in circulation.

“What I can say is given this study was conducted much later in terms of timing, it’s very encouraging that we’ve got such high efficacy numbers when undoubtedly there are variants of concern in circulation in this study,” Mr. Pangalos said.

“It also highlights why we believe that against severe disease, our vaccine will be effective against all variants of concern,” he added.

Once the company submits its EUA to the FDA, the company is ready to immediately distribute 30 million doses of the vaccine and expects to ship 50 million total within the first month, Ruud Dobber, PhD, AstraZeneca executive vice president and president of the AZ Biopharmaceuticals Business Unit, said during the briefing.

The vaccine can be stored at 2 to 8 degrees Celsius for at least 6 months. Like other COVID-19 vaccines already authorized for emergency use, the duration of protection with the AstraZeneca product remains unknown.

This article was updated March 23, 2021.

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