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Aspirin cuts risk of ovarian and liver cancer
Regular long-term aspirin use may lower the risk of hepatocellular carcinoma (HCC) and ovarian cancer, adding to the growing evidence that aspirin may play a role as a chemopreventive agent, according to two new studies published in JAMA Oncology.
In the first study, led by Tracey G. Simon, MD, of Massachusetts General Hospital, Boston, the authors evaluated the associations between aspirin dose and duration of use and the risk of developing HCC. They conducted a population-based study, with a pooled analysis of two large prospective U.S. cohort studies: the Nurses’ Health Study and the Health Professionals Follow-up Study. The cohort included a total of 133,371 health care professionals who reported long-term data on aspirin use, frequency, dosage, and duration of use.
For the 87,507 female participants, reporting began in 1980, and for the 45,864 men, reporting began in 1986. The mean age for women was 62 years and was 64 years for men at the midpoint of follow-up (1996). Compared with nonaspirin users, those who used aspirin regularly tended to be older, former smokers, and regularly used statins and multivitamins. During the follow-up period, which was more than 26 years, there were 108 incident cases of HCC (65 women, 43 men; 47 with noncirrhotic HCC).
The investigators found that regular aspirin use was associated with a significantly lower HCC risk versus nonregular use (multivariable hazard ratio, 0.51; 95% confidence interval, 0.34-0.77), and estimates were similar for both sexes. Adjustments for regular NSAID use (for example, at least two tablets per week) did not change the data, and results were similar after further adjustment for coffee consumption and adherence to a healthy diet. The benefit also appeared to be dose related, as compared with nonuse, the multivariable-adjusted HR for HCC was 0.87 (95% CI, 0.51-1.48) for up to 1.5 tablets of standard-dose aspirin per week and 0.51 (95% CI, 0.30-0.86) for 1.5-5 tablets per week. The most benefit was for at least five tablets per week (HR, 0.49; 95% CI, 0.28-0.96; P = .006).
“Our findings add to the growing literature suggesting that the chemopreventive effects of aspirin may extend beyond colorectal cancer,” they wrote.
In the second study, Mollie E. Barnard, ScD, of the Harvard School of Public Health, Boston, and her colleagues looked at whether regular aspirin or NSAID use, as well as the patterns of use, were associated with a lower risk of ovarian cancer.
The data used were obtained from 93,664 women in the Nurses’ Health Study (NHS), who were followed up from 1980 to 2014, and 111,834 people in the Nurses’ Health Study II (NHSII), who were followed up from 1989 to 2015. For each type of agent, including aspirin, low-dose aspirin, nonaspirin NSAIDs, and acetaminophen, they evaluated the timing, duration, frequency, and number of tablets that were used. The mean age of participants in the NHS at baseline was 45.9 years and 34.2 years in the NHSII.
There were 1,054 incident cases of epithelial ovarian cancer identified during the study period. The authors did not detect any significant associations between aspirin and ovarian cancer risk when current users and nonusers were compared, regardless of dose (HR, 0.99; 95% CI, 0.83-1.19). But when low-dose (less than or equal to 100 mg) and standard-dose (325 mg) aspirin were analyzed separately, an inverse association for low-dose aspirin (HR, 0.77; 95% CI, 0.61-0.96) was observed. However, there was no association for standard-dose aspirin (HR, 1.17; 95% CI, 0.92-1.49).
In contrast, use of nonaspirin NSAIDs was positively associated with a higher risk of ovarian cancer when compared with nonuse (HR, 1.19; 95% CI, 1.00-1.41), and there were significant positive trends for duration of use (P = .02) and cumulative average tablets per week (P = .03). No clear associations were identified for acetaminophen use.
“Our results also suggest an increased risk of ovarian cancer among long-term, high-quantity users of nonaspirin analgesics, although this finding may reflect unmeasured confounding,” wrote Dr. Barnard and her coauthors. “Further exploration is warranted to evaluate the mechanisms by which heavy use of aspirin, nonaspirin NSAIDs, and acetaminophen may contribute to the development of ovarian cancer and to replicate our findings.”
The ovarian cancer study was supported by awards from the National Institutes of Health. Dr. Barnard was supported by awards from the National Cancer Institute, and her coauthors had no disclosures to report. The HCC study was funded by an infrastructure grant from the Nurses’ Health Study, an infrastructure grant from the Health Professionals Follow-up Study, and NIH grants to several of the authors. Dr. Chan has previously served as a consultant for Bayer on work unrelated to this article. No other disclosures were reported.
SOURCES: Barnard ME et al. JAMA Oncol. 2018 Oct 4. doi: 10.1001/jamaoncol.2018.4149; Simon TG et al. JAMA Oncol. 2018 Oct 4. doi: 10.1001/jamaoncol.2018.4154.
In an accompanying editorial published in JAMA Oncology, Victoria L. Seewaldt, MD, of the City of Hope Comprehensive Cancer Center in Duarte, Calif., asked if we “have arrived,” as these two studies are a critical step in realizing the potential of aspirin for cancer chemoprevention beyond colorectal cancer.
Aspirin use is very common in the United States, with almost half of adults aged between 45 and 75 years taking it regularly. Many regular users also believe that aspirin has potential to protect against cancer, and in a 2015 study – which was conducted prior to any formal cancer prevention guidelines – 18% of those taking aspirin on a regular basis reported doing so to prevent cancer.
Based on the strength of the association between aspirin use and colorectal cancer risk reduction, the U.S. Preventive Services Task Force recommended in 2015 that, among individuals aged between 50 and 69 years who have specific cardiovascular risk profiles, colorectal cancer prevention be included as part of the rationale for regular aspirin prophylaxis, Dr. Seewaldt noted. Aspirin became the first drug to be included in USPSTF recommendations for cancer chemoprevention in a “population not characterized as having a high risk of developing cancer.”
But it now appears aspirin may be able to go beyond colorectal cancer for chemoprevention. Ovarian cancer and hepatocellular carcinoma are in need of new prevention strategies and these findings provide important information that can help guide chemoprevention with aspirin.
These two studies “have the power to start to change clinical practice,” Dr. Seewaldt wrote, but more research is needed to better understand the underlying mechanism behind the appropriate dose and duration of use. Importantly, the authors of both studies cautioned that the potential benefits of aspirin must be weighed against the risk of bleeding, which is particularly important in patients with chronic liver disease.
“To reach the full promise of aspirin’s ability to prevent cancer, there needs to be better understanding of dose, duration, and mechanism,” she emphasized.
Dr. Seewaldt reported receiving grants from the National Institutes of Health/National Cancer Institute and is supported by the Prevent Cancer Foundation.
In an accompanying editorial published in JAMA Oncology, Victoria L. Seewaldt, MD, of the City of Hope Comprehensive Cancer Center in Duarte, Calif., asked if we “have arrived,” as these two studies are a critical step in realizing the potential of aspirin for cancer chemoprevention beyond colorectal cancer.
Aspirin use is very common in the United States, with almost half of adults aged between 45 and 75 years taking it regularly. Many regular users also believe that aspirin has potential to protect against cancer, and in a 2015 study – which was conducted prior to any formal cancer prevention guidelines – 18% of those taking aspirin on a regular basis reported doing so to prevent cancer.
Based on the strength of the association between aspirin use and colorectal cancer risk reduction, the U.S. Preventive Services Task Force recommended in 2015 that, among individuals aged between 50 and 69 years who have specific cardiovascular risk profiles, colorectal cancer prevention be included as part of the rationale for regular aspirin prophylaxis, Dr. Seewaldt noted. Aspirin became the first drug to be included in USPSTF recommendations for cancer chemoprevention in a “population not characterized as having a high risk of developing cancer.”
But it now appears aspirin may be able to go beyond colorectal cancer for chemoprevention. Ovarian cancer and hepatocellular carcinoma are in need of new prevention strategies and these findings provide important information that can help guide chemoprevention with aspirin.
These two studies “have the power to start to change clinical practice,” Dr. Seewaldt wrote, but more research is needed to better understand the underlying mechanism behind the appropriate dose and duration of use. Importantly, the authors of both studies cautioned that the potential benefits of aspirin must be weighed against the risk of bleeding, which is particularly important in patients with chronic liver disease.
“To reach the full promise of aspirin’s ability to prevent cancer, there needs to be better understanding of dose, duration, and mechanism,” she emphasized.
Dr. Seewaldt reported receiving grants from the National Institutes of Health/National Cancer Institute and is supported by the Prevent Cancer Foundation.
In an accompanying editorial published in JAMA Oncology, Victoria L. Seewaldt, MD, of the City of Hope Comprehensive Cancer Center in Duarte, Calif., asked if we “have arrived,” as these two studies are a critical step in realizing the potential of aspirin for cancer chemoprevention beyond colorectal cancer.
Aspirin use is very common in the United States, with almost half of adults aged between 45 and 75 years taking it regularly. Many regular users also believe that aspirin has potential to protect against cancer, and in a 2015 study – which was conducted prior to any formal cancer prevention guidelines – 18% of those taking aspirin on a regular basis reported doing so to prevent cancer.
Based on the strength of the association between aspirin use and colorectal cancer risk reduction, the U.S. Preventive Services Task Force recommended in 2015 that, among individuals aged between 50 and 69 years who have specific cardiovascular risk profiles, colorectal cancer prevention be included as part of the rationale for regular aspirin prophylaxis, Dr. Seewaldt noted. Aspirin became the first drug to be included in USPSTF recommendations for cancer chemoprevention in a “population not characterized as having a high risk of developing cancer.”
But it now appears aspirin may be able to go beyond colorectal cancer for chemoprevention. Ovarian cancer and hepatocellular carcinoma are in need of new prevention strategies and these findings provide important information that can help guide chemoprevention with aspirin.
These two studies “have the power to start to change clinical practice,” Dr. Seewaldt wrote, but more research is needed to better understand the underlying mechanism behind the appropriate dose and duration of use. Importantly, the authors of both studies cautioned that the potential benefits of aspirin must be weighed against the risk of bleeding, which is particularly important in patients with chronic liver disease.
“To reach the full promise of aspirin’s ability to prevent cancer, there needs to be better understanding of dose, duration, and mechanism,” she emphasized.
Dr. Seewaldt reported receiving grants from the National Institutes of Health/National Cancer Institute and is supported by the Prevent Cancer Foundation.
Regular long-term aspirin use may lower the risk of hepatocellular carcinoma (HCC) and ovarian cancer, adding to the growing evidence that aspirin may play a role as a chemopreventive agent, according to two new studies published in JAMA Oncology.
In the first study, led by Tracey G. Simon, MD, of Massachusetts General Hospital, Boston, the authors evaluated the associations between aspirin dose and duration of use and the risk of developing HCC. They conducted a population-based study, with a pooled analysis of two large prospective U.S. cohort studies: the Nurses’ Health Study and the Health Professionals Follow-up Study. The cohort included a total of 133,371 health care professionals who reported long-term data on aspirin use, frequency, dosage, and duration of use.
For the 87,507 female participants, reporting began in 1980, and for the 45,864 men, reporting began in 1986. The mean age for women was 62 years and was 64 years for men at the midpoint of follow-up (1996). Compared with nonaspirin users, those who used aspirin regularly tended to be older, former smokers, and regularly used statins and multivitamins. During the follow-up period, which was more than 26 years, there were 108 incident cases of HCC (65 women, 43 men; 47 with noncirrhotic HCC).
The investigators found that regular aspirin use was associated with a significantly lower HCC risk versus nonregular use (multivariable hazard ratio, 0.51; 95% confidence interval, 0.34-0.77), and estimates were similar for both sexes. Adjustments for regular NSAID use (for example, at least two tablets per week) did not change the data, and results were similar after further adjustment for coffee consumption and adherence to a healthy diet. The benefit also appeared to be dose related, as compared with nonuse, the multivariable-adjusted HR for HCC was 0.87 (95% CI, 0.51-1.48) for up to 1.5 tablets of standard-dose aspirin per week and 0.51 (95% CI, 0.30-0.86) for 1.5-5 tablets per week. The most benefit was for at least five tablets per week (HR, 0.49; 95% CI, 0.28-0.96; P = .006).
“Our findings add to the growing literature suggesting that the chemopreventive effects of aspirin may extend beyond colorectal cancer,” they wrote.
In the second study, Mollie E. Barnard, ScD, of the Harvard School of Public Health, Boston, and her colleagues looked at whether regular aspirin or NSAID use, as well as the patterns of use, were associated with a lower risk of ovarian cancer.
The data used were obtained from 93,664 women in the Nurses’ Health Study (NHS), who were followed up from 1980 to 2014, and 111,834 people in the Nurses’ Health Study II (NHSII), who were followed up from 1989 to 2015. For each type of agent, including aspirin, low-dose aspirin, nonaspirin NSAIDs, and acetaminophen, they evaluated the timing, duration, frequency, and number of tablets that were used. The mean age of participants in the NHS at baseline was 45.9 years and 34.2 years in the NHSII.
There were 1,054 incident cases of epithelial ovarian cancer identified during the study period. The authors did not detect any significant associations between aspirin and ovarian cancer risk when current users and nonusers were compared, regardless of dose (HR, 0.99; 95% CI, 0.83-1.19). But when low-dose (less than or equal to 100 mg) and standard-dose (325 mg) aspirin were analyzed separately, an inverse association for low-dose aspirin (HR, 0.77; 95% CI, 0.61-0.96) was observed. However, there was no association for standard-dose aspirin (HR, 1.17; 95% CI, 0.92-1.49).
In contrast, use of nonaspirin NSAIDs was positively associated with a higher risk of ovarian cancer when compared with nonuse (HR, 1.19; 95% CI, 1.00-1.41), and there were significant positive trends for duration of use (P = .02) and cumulative average tablets per week (P = .03). No clear associations were identified for acetaminophen use.
“Our results also suggest an increased risk of ovarian cancer among long-term, high-quantity users of nonaspirin analgesics, although this finding may reflect unmeasured confounding,” wrote Dr. Barnard and her coauthors. “Further exploration is warranted to evaluate the mechanisms by which heavy use of aspirin, nonaspirin NSAIDs, and acetaminophen may contribute to the development of ovarian cancer and to replicate our findings.”
The ovarian cancer study was supported by awards from the National Institutes of Health. Dr. Barnard was supported by awards from the National Cancer Institute, and her coauthors had no disclosures to report. The HCC study was funded by an infrastructure grant from the Nurses’ Health Study, an infrastructure grant from the Health Professionals Follow-up Study, and NIH grants to several of the authors. Dr. Chan has previously served as a consultant for Bayer on work unrelated to this article. No other disclosures were reported.
SOURCES: Barnard ME et al. JAMA Oncol. 2018 Oct 4. doi: 10.1001/jamaoncol.2018.4149; Simon TG et al. JAMA Oncol. 2018 Oct 4. doi: 10.1001/jamaoncol.2018.4154.
Regular long-term aspirin use may lower the risk of hepatocellular carcinoma (HCC) and ovarian cancer, adding to the growing evidence that aspirin may play a role as a chemopreventive agent, according to two new studies published in JAMA Oncology.
In the first study, led by Tracey G. Simon, MD, of Massachusetts General Hospital, Boston, the authors evaluated the associations between aspirin dose and duration of use and the risk of developing HCC. They conducted a population-based study, with a pooled analysis of two large prospective U.S. cohort studies: the Nurses’ Health Study and the Health Professionals Follow-up Study. The cohort included a total of 133,371 health care professionals who reported long-term data on aspirin use, frequency, dosage, and duration of use.
For the 87,507 female participants, reporting began in 1980, and for the 45,864 men, reporting began in 1986. The mean age for women was 62 years and was 64 years for men at the midpoint of follow-up (1996). Compared with nonaspirin users, those who used aspirin regularly tended to be older, former smokers, and regularly used statins and multivitamins. During the follow-up period, which was more than 26 years, there were 108 incident cases of HCC (65 women, 43 men; 47 with noncirrhotic HCC).
The investigators found that regular aspirin use was associated with a significantly lower HCC risk versus nonregular use (multivariable hazard ratio, 0.51; 95% confidence interval, 0.34-0.77), and estimates were similar for both sexes. Adjustments for regular NSAID use (for example, at least two tablets per week) did not change the data, and results were similar after further adjustment for coffee consumption and adherence to a healthy diet. The benefit also appeared to be dose related, as compared with nonuse, the multivariable-adjusted HR for HCC was 0.87 (95% CI, 0.51-1.48) for up to 1.5 tablets of standard-dose aspirin per week and 0.51 (95% CI, 0.30-0.86) for 1.5-5 tablets per week. The most benefit was for at least five tablets per week (HR, 0.49; 95% CI, 0.28-0.96; P = .006).
“Our findings add to the growing literature suggesting that the chemopreventive effects of aspirin may extend beyond colorectal cancer,” they wrote.
In the second study, Mollie E. Barnard, ScD, of the Harvard School of Public Health, Boston, and her colleagues looked at whether regular aspirin or NSAID use, as well as the patterns of use, were associated with a lower risk of ovarian cancer.
The data used were obtained from 93,664 women in the Nurses’ Health Study (NHS), who were followed up from 1980 to 2014, and 111,834 people in the Nurses’ Health Study II (NHSII), who were followed up from 1989 to 2015. For each type of agent, including aspirin, low-dose aspirin, nonaspirin NSAIDs, and acetaminophen, they evaluated the timing, duration, frequency, and number of tablets that were used. The mean age of participants in the NHS at baseline was 45.9 years and 34.2 years in the NHSII.
There were 1,054 incident cases of epithelial ovarian cancer identified during the study period. The authors did not detect any significant associations between aspirin and ovarian cancer risk when current users and nonusers were compared, regardless of dose (HR, 0.99; 95% CI, 0.83-1.19). But when low-dose (less than or equal to 100 mg) and standard-dose (325 mg) aspirin were analyzed separately, an inverse association for low-dose aspirin (HR, 0.77; 95% CI, 0.61-0.96) was observed. However, there was no association for standard-dose aspirin (HR, 1.17; 95% CI, 0.92-1.49).
In contrast, use of nonaspirin NSAIDs was positively associated with a higher risk of ovarian cancer when compared with nonuse (HR, 1.19; 95% CI, 1.00-1.41), and there were significant positive trends for duration of use (P = .02) and cumulative average tablets per week (P = .03). No clear associations were identified for acetaminophen use.
“Our results also suggest an increased risk of ovarian cancer among long-term, high-quantity users of nonaspirin analgesics, although this finding may reflect unmeasured confounding,” wrote Dr. Barnard and her coauthors. “Further exploration is warranted to evaluate the mechanisms by which heavy use of aspirin, nonaspirin NSAIDs, and acetaminophen may contribute to the development of ovarian cancer and to replicate our findings.”
The ovarian cancer study was supported by awards from the National Institutes of Health. Dr. Barnard was supported by awards from the National Cancer Institute, and her coauthors had no disclosures to report. The HCC study was funded by an infrastructure grant from the Nurses’ Health Study, an infrastructure grant from the Health Professionals Follow-up Study, and NIH grants to several of the authors. Dr. Chan has previously served as a consultant for Bayer on work unrelated to this article. No other disclosures were reported.
SOURCES: Barnard ME et al. JAMA Oncol. 2018 Oct 4. doi: 10.1001/jamaoncol.2018.4149; Simon TG et al. JAMA Oncol. 2018 Oct 4. doi: 10.1001/jamaoncol.2018.4154.
FROM JAMA ONCOLOGY
Key clinical point: Regular aspirin use was associated with a decreased risk of ovarian cancer and hepatocellular carcinoma.
Major finding: Low-dose aspirin was associated with a 23% lower risk of ovarian cancer and a 49% reduced risk of developing hepatocellular carcinoma.
Study details: The hepatocellular carcinoma study was a population-based study of two nationwide, prospective cohorts of 87,507 men and 45,864 women; the ovarian cancer study was a cohort study using data from two prospective cohorts, with 93,664 people in one and 111,834 in the other.
Disclosures: The ovarian cancer study was supported by awards from the National Institutes of Health. Dr. Barnard was supported by awards from the National Cancer Institute, and her coauthors had no disclosures to report. The hepatocellular carcinoma study was funded by an infrastructure grant from the Nurses’ Health Study, an infrastructure grant from the Health Professionals Follow-up Study, and NIH grants to several of the authors. Dr. Chan has previously served as a consultant for Bayer on work unrelated to this article. No other disclosures were reported.
Sources: Barnard ME et al. JAMA Oncol. 2018 Oct 4. doi: 10.1001/jamaoncol.2018.4149; Simon TG et al. JAMA Oncol. 2018 Oct 4. doi: 10.1001/jamaoncol.2018.4154.
Higher rate of loss seen in unplanned pregnancies for women with epilepsy
when compared against women with epilepsy who planned their pregnancy, according to recent results from a retrospective study published in JAMA Neurology.
“This analysis adds the finding that unplanned pregnancy may increase the risk of [spontaneous fetal loss] in women with epilepsy and identifies pregnancy planning, maternal age, and interpregnancy interval as significant modifiable variables,” Andrew G. Herzog, MD, of the Harvard Neuroendocrine Unit at Beth Israel Deaconess Medical Center in Wellesley, Mass., and colleagues wrote in their study.
The researchers examined results from a web-based survey completed by 1,144 women in the Epilepsy Birth Control Registry (EBCR) between 2010 and 2014 with data on contraception use, pregnancy history, and antiepileptic drug (AED) treatment. Patients were aged 18-47 years (mean 28.5 years) with 8.7% of the cohort consisting of minority women and 39.8% having household incomes of $25,000 or less.
Pregnancy history data included number of pregnancies, number of planned or unplanned pregnancies, AED type used during pregnancies, pregnancy outcomes such as live birth, induced abortion, and spontaneous fetal loss (SFL), while AED data included categorizing patients into no therapy, monotherapy, and polytherapy groups. AED use was further subdivided into no AED, enzyme-inducing AED, non–enzyme-inducing AED, enzyme-inhibiting AED, glucuronidated AED, and mixed category groups.
Of 794 pregnancies, 530 pregnancies (66.8%) were unplanned and 264 (33.2%) were planned, with 473 live births (59.6%), 141 induced abortions (17.8%), and 180 SFL (22.7%). Among patients who did not have an induced abortion, SFL risk was higher if the pregnancy was unplanned (137 patients, 35.0%), compared with those who planned (43 patients, 16.4%) their pregnancy (risk ratio = 2.14; 95% confidence interval, 1.59-2.90; P less than .001). According to a regression analysis, SFL risk was higher for patients where “planning was entered alone” in unplanned pregnancies (odds ratio = 2.75; 95% CI, 1.87-4.05; P less than .001) as well as when adjusted for AED category, maternal age, and interpregnancy interval (OR = 3.57; 95% CI, 1.54-8.78; P = .003).
There was an association between maternal age (OR = 0.957; 95% CI, 0.928-0.986; P = .02) and risk of SFL, with lower risk seen in the 18- to 27-year-old group (118 patients, 29.5%; RR = 0.57; 95% CI, 0.39-0.84; P less than .004) and 28- to 37-year-old group (44 patients, 20.8%; RR = 0.40; 95% CI, 0.26-0.62; P less than .001), compared with the under-18 group (15 patients, 51.7%). There was also a higher risk of SFL with regard to interpregnancy interval (OR = 2.878; 95% CI, 1.8094-4.5801; P = .008), with a greater risk seen if the interpregnancy interval was under 1 year (56 patients, 45.9%), compared with 1 year (56 patients, 22.8%) or higher (RR = 2.02; 95% CI, 1.49-2.72; P less than .001).
“In view of the finding of increased risk for SFL in unplanned pregnancies in women with epilepsy, and because a history of SFL in women with epilepsy may increase the risk that subsequent live-born offspring will develop epilepsy, the finding warrants prospective investigation with medical record verification of pregnancy outcomes,” Dr. Herzog and his colleagues wrote.
The Epilepsy Foundation and Lundbeck funded the study. Dr. Herzog reports support by grants, and two coauthors received salary support from grants, from the two organizations.
SOURCE: Herzog AG et al. JAMA Neurol. 2018 Oct 15. doi: 10.1001/jamaneurol.2018.3089.
when compared against women with epilepsy who planned their pregnancy, according to recent results from a retrospective study published in JAMA Neurology.
“This analysis adds the finding that unplanned pregnancy may increase the risk of [spontaneous fetal loss] in women with epilepsy and identifies pregnancy planning, maternal age, and interpregnancy interval as significant modifiable variables,” Andrew G. Herzog, MD, of the Harvard Neuroendocrine Unit at Beth Israel Deaconess Medical Center in Wellesley, Mass., and colleagues wrote in their study.
The researchers examined results from a web-based survey completed by 1,144 women in the Epilepsy Birth Control Registry (EBCR) between 2010 and 2014 with data on contraception use, pregnancy history, and antiepileptic drug (AED) treatment. Patients were aged 18-47 years (mean 28.5 years) with 8.7% of the cohort consisting of minority women and 39.8% having household incomes of $25,000 or less.
Pregnancy history data included number of pregnancies, number of planned or unplanned pregnancies, AED type used during pregnancies, pregnancy outcomes such as live birth, induced abortion, and spontaneous fetal loss (SFL), while AED data included categorizing patients into no therapy, monotherapy, and polytherapy groups. AED use was further subdivided into no AED, enzyme-inducing AED, non–enzyme-inducing AED, enzyme-inhibiting AED, glucuronidated AED, and mixed category groups.
Of 794 pregnancies, 530 pregnancies (66.8%) were unplanned and 264 (33.2%) were planned, with 473 live births (59.6%), 141 induced abortions (17.8%), and 180 SFL (22.7%). Among patients who did not have an induced abortion, SFL risk was higher if the pregnancy was unplanned (137 patients, 35.0%), compared with those who planned (43 patients, 16.4%) their pregnancy (risk ratio = 2.14; 95% confidence interval, 1.59-2.90; P less than .001). According to a regression analysis, SFL risk was higher for patients where “planning was entered alone” in unplanned pregnancies (odds ratio = 2.75; 95% CI, 1.87-4.05; P less than .001) as well as when adjusted for AED category, maternal age, and interpregnancy interval (OR = 3.57; 95% CI, 1.54-8.78; P = .003).
There was an association between maternal age (OR = 0.957; 95% CI, 0.928-0.986; P = .02) and risk of SFL, with lower risk seen in the 18- to 27-year-old group (118 patients, 29.5%; RR = 0.57; 95% CI, 0.39-0.84; P less than .004) and 28- to 37-year-old group (44 patients, 20.8%; RR = 0.40; 95% CI, 0.26-0.62; P less than .001), compared with the under-18 group (15 patients, 51.7%). There was also a higher risk of SFL with regard to interpregnancy interval (OR = 2.878; 95% CI, 1.8094-4.5801; P = .008), with a greater risk seen if the interpregnancy interval was under 1 year (56 patients, 45.9%), compared with 1 year (56 patients, 22.8%) or higher (RR = 2.02; 95% CI, 1.49-2.72; P less than .001).
“In view of the finding of increased risk for SFL in unplanned pregnancies in women with epilepsy, and because a history of SFL in women with epilepsy may increase the risk that subsequent live-born offspring will develop epilepsy, the finding warrants prospective investigation with medical record verification of pregnancy outcomes,” Dr. Herzog and his colleagues wrote.
The Epilepsy Foundation and Lundbeck funded the study. Dr. Herzog reports support by grants, and two coauthors received salary support from grants, from the two organizations.
SOURCE: Herzog AG et al. JAMA Neurol. 2018 Oct 15. doi: 10.1001/jamaneurol.2018.3089.
when compared against women with epilepsy who planned their pregnancy, according to recent results from a retrospective study published in JAMA Neurology.
“This analysis adds the finding that unplanned pregnancy may increase the risk of [spontaneous fetal loss] in women with epilepsy and identifies pregnancy planning, maternal age, and interpregnancy interval as significant modifiable variables,” Andrew G. Herzog, MD, of the Harvard Neuroendocrine Unit at Beth Israel Deaconess Medical Center in Wellesley, Mass., and colleagues wrote in their study.
The researchers examined results from a web-based survey completed by 1,144 women in the Epilepsy Birth Control Registry (EBCR) between 2010 and 2014 with data on contraception use, pregnancy history, and antiepileptic drug (AED) treatment. Patients were aged 18-47 years (mean 28.5 years) with 8.7% of the cohort consisting of minority women and 39.8% having household incomes of $25,000 or less.
Pregnancy history data included number of pregnancies, number of planned or unplanned pregnancies, AED type used during pregnancies, pregnancy outcomes such as live birth, induced abortion, and spontaneous fetal loss (SFL), while AED data included categorizing patients into no therapy, monotherapy, and polytherapy groups. AED use was further subdivided into no AED, enzyme-inducing AED, non–enzyme-inducing AED, enzyme-inhibiting AED, glucuronidated AED, and mixed category groups.
Of 794 pregnancies, 530 pregnancies (66.8%) were unplanned and 264 (33.2%) were planned, with 473 live births (59.6%), 141 induced abortions (17.8%), and 180 SFL (22.7%). Among patients who did not have an induced abortion, SFL risk was higher if the pregnancy was unplanned (137 patients, 35.0%), compared with those who planned (43 patients, 16.4%) their pregnancy (risk ratio = 2.14; 95% confidence interval, 1.59-2.90; P less than .001). According to a regression analysis, SFL risk was higher for patients where “planning was entered alone” in unplanned pregnancies (odds ratio = 2.75; 95% CI, 1.87-4.05; P less than .001) as well as when adjusted for AED category, maternal age, and interpregnancy interval (OR = 3.57; 95% CI, 1.54-8.78; P = .003).
There was an association between maternal age (OR = 0.957; 95% CI, 0.928-0.986; P = .02) and risk of SFL, with lower risk seen in the 18- to 27-year-old group (118 patients, 29.5%; RR = 0.57; 95% CI, 0.39-0.84; P less than .004) and 28- to 37-year-old group (44 patients, 20.8%; RR = 0.40; 95% CI, 0.26-0.62; P less than .001), compared with the under-18 group (15 patients, 51.7%). There was also a higher risk of SFL with regard to interpregnancy interval (OR = 2.878; 95% CI, 1.8094-4.5801; P = .008), with a greater risk seen if the interpregnancy interval was under 1 year (56 patients, 45.9%), compared with 1 year (56 patients, 22.8%) or higher (RR = 2.02; 95% CI, 1.49-2.72; P less than .001).
“In view of the finding of increased risk for SFL in unplanned pregnancies in women with epilepsy, and because a history of SFL in women with epilepsy may increase the risk that subsequent live-born offspring will develop epilepsy, the finding warrants prospective investigation with medical record verification of pregnancy outcomes,” Dr. Herzog and his colleagues wrote.
The Epilepsy Foundation and Lundbeck funded the study. Dr. Herzog reports support by grants, and two coauthors received salary support from grants, from the two organizations.
SOURCE: Herzog AG et al. JAMA Neurol. 2018 Oct 15. doi: 10.1001/jamaneurol.2018.3089.
FROM JAMA NEUROLOGY
Key clinical point: Women with epilepsy who experience unplanned pregnancies have a higher rate of spontaneous fetal loss, compared with those with epilepsy who plan their pregnancies.
Major finding: Thirty-five percent of women with unplanned pregnancies experienced spontaneous fetal loss, compared with 16.4% of women in the planned pregnancy group.
Study details: A retrospective analysis of results from a web-based survey of 1,144 women from the Epilepsy Birth Control Registry.
Disclosures: The Epilepsy Foundation and Lundbeck funded the study. Dr. Herzog reports support by grants, and two coauthors received salary support from grants, from the two organizations.
Source: Herzog AG et al. JAMA Neurol. 2018 Oct 15. doi: 10.1001/jamaneurol.2018.3089.
Brexanolone injection quickly improves postpartum depression
BARCELONA – Brexanolone injection provided rapid and durable improvement in postpartum depression in an integrated analysis of three pivotal randomized trials collectively known as the Hummingbird trials, Christine Clemson, PhD, reported at the annual congress of the European College of Neuropsychopharmacology.
This was accomplished with a favorable safety experience. The most common treatment-emergent adverse events – dizziness and sleepiness – were roughly twice as common as with placebo in the 247-patient Hummingbird safety analysis.
On Dec. 19, 2018, the agency is expected to respond to SAGE Therapeutics’s application for marketing approval of intravenous brexanolone given as a continuous 60-hour infusion at 90 mcg/kg per hour, according to Dr. Clemson, senior medical director at Cambridge, Mass.–based SAGE Therapeutics, which is developing the therapy.
Brexanolone is a proprietary IV formulation of allopregnanolone, a metabolite of progesterone. The drug’s mechanism of action involves modulation of the neurotransmitter gamma-aminobutyric acid (GABA). The drug binds to both synaptic and extra-synaptic GABA A receptors, thereby increasing receptor functionality.
The decision to target GABA as a novel therapeutic strategy in PPD was based upon translational studies demonstrating that GABA is the chief neuroinhibitory mechanism in the brain, and its actions are mediated mainly by GABA A receptors. Brexanolone’s efficacy is consistent with a theory that the pathogenesis of PPD involves triggers such as inflammation, hormonal fluctuations, or chronic stress, which in some women cause GABA hypofunction, both at the receptors and in terms of tissue GABA levels. This, in turn, leads to an overactive HPA axis and dysregulated neural networks, with resultant PPD, Dr. Clemson explained.
The three Hummingbird clinical trials were double blind, randomized, and placebo controlled. Two were restricted to women with severe PPD. The third and largest focused on moderately affected patients as defined by a baseline Hamilton Depression Scale for Depression (HAM-D) score of 20-25.
The efficacy analysis included 207 patients who received brexanolone at 90 mcg/kg per hour or placebo for 60 hours in an inpatient setting and were followed for 30 days. The primary endpoint was the change in HAM-D total score from baseline to 60 hours. The mean 17-point reduction in the active treatment arm was significantly better than the 12.8-point decrease with placebo. The between-group difference was significant within the first 24 hours and remained so at all time points out to the study’s end at day 30. There was no individual item on the HAM-D in which the drug performed worse than placebo, and there were many in which brexanolone performed significantly better, including depressed mood, anxiety, insomnia, and feelings of guilt.
In terms of the rigorous secondary endpoint of HAM-D remission as defined by a total score of 7 or less, the brexanolone injection significantly outperformed placebo at every time point except for day 30.
There was a 2% rate of serious adverse events in both study arms. These included suicidal ideation, an intentional overdose attempt post discharge, altered state of consciousness, and syncope.
A vastly more convenient once-daily oral formulation of brexanolone is now in phase 3 clinical trials for PPD and major depressive disorder, and in phase 2 for insomnia and bipolar depression.
Elsewhere at the ECNP congress, other investigators from Sage Therapeutics presented for the first time the outcomes of an 89-patient, randomized, double-blind, multicenter, placebo-controlled, phase 2 clinical trial of SAGE-217 for treatment of major depressive disorder.
Participants received a nightly 30-mg dose of the drug or placebo for 2 weeks, with a primary study endpoint being the change in HAM-D total score from baseline to day 15. Patients on the oral GABA A receptor positive modulator averaged a 17.4-point improvement, significantly better than the 10.3-point spread in placebo-treated controls. A statistically significant between-group difference was noted on days 2 through 28. HAM-D remission at day 15 was documented in 64% of the oral brexanolone group, compared with 26% of controls.
Those improvements in depression were accompanied by significant gains in numerous domains of health-related quality of life as assessed via the 36-Item Short Form Health Survey. Indeed, day 15 health-related quality of life scores in the oral brexanolone group approached normative values for the general population.
The studies were funded by SAGE Therapeutics.
BARCELONA – Brexanolone injection provided rapid and durable improvement in postpartum depression in an integrated analysis of three pivotal randomized trials collectively known as the Hummingbird trials, Christine Clemson, PhD, reported at the annual congress of the European College of Neuropsychopharmacology.
This was accomplished with a favorable safety experience. The most common treatment-emergent adverse events – dizziness and sleepiness – were roughly twice as common as with placebo in the 247-patient Hummingbird safety analysis.
On Dec. 19, 2018, the agency is expected to respond to SAGE Therapeutics’s application for marketing approval of intravenous brexanolone given as a continuous 60-hour infusion at 90 mcg/kg per hour, according to Dr. Clemson, senior medical director at Cambridge, Mass.–based SAGE Therapeutics, which is developing the therapy.
Brexanolone is a proprietary IV formulation of allopregnanolone, a metabolite of progesterone. The drug’s mechanism of action involves modulation of the neurotransmitter gamma-aminobutyric acid (GABA). The drug binds to both synaptic and extra-synaptic GABA A receptors, thereby increasing receptor functionality.
The decision to target GABA as a novel therapeutic strategy in PPD was based upon translational studies demonstrating that GABA is the chief neuroinhibitory mechanism in the brain, and its actions are mediated mainly by GABA A receptors. Brexanolone’s efficacy is consistent with a theory that the pathogenesis of PPD involves triggers such as inflammation, hormonal fluctuations, or chronic stress, which in some women cause GABA hypofunction, both at the receptors and in terms of tissue GABA levels. This, in turn, leads to an overactive HPA axis and dysregulated neural networks, with resultant PPD, Dr. Clemson explained.
The three Hummingbird clinical trials were double blind, randomized, and placebo controlled. Two were restricted to women with severe PPD. The third and largest focused on moderately affected patients as defined by a baseline Hamilton Depression Scale for Depression (HAM-D) score of 20-25.
The efficacy analysis included 207 patients who received brexanolone at 90 mcg/kg per hour or placebo for 60 hours in an inpatient setting and were followed for 30 days. The primary endpoint was the change in HAM-D total score from baseline to 60 hours. The mean 17-point reduction in the active treatment arm was significantly better than the 12.8-point decrease with placebo. The between-group difference was significant within the first 24 hours and remained so at all time points out to the study’s end at day 30. There was no individual item on the HAM-D in which the drug performed worse than placebo, and there were many in which brexanolone performed significantly better, including depressed mood, anxiety, insomnia, and feelings of guilt.
In terms of the rigorous secondary endpoint of HAM-D remission as defined by a total score of 7 or less, the brexanolone injection significantly outperformed placebo at every time point except for day 30.
There was a 2% rate of serious adverse events in both study arms. These included suicidal ideation, an intentional overdose attempt post discharge, altered state of consciousness, and syncope.
A vastly more convenient once-daily oral formulation of brexanolone is now in phase 3 clinical trials for PPD and major depressive disorder, and in phase 2 for insomnia and bipolar depression.
Elsewhere at the ECNP congress, other investigators from Sage Therapeutics presented for the first time the outcomes of an 89-patient, randomized, double-blind, multicenter, placebo-controlled, phase 2 clinical trial of SAGE-217 for treatment of major depressive disorder.
Participants received a nightly 30-mg dose of the drug or placebo for 2 weeks, with a primary study endpoint being the change in HAM-D total score from baseline to day 15. Patients on the oral GABA A receptor positive modulator averaged a 17.4-point improvement, significantly better than the 10.3-point spread in placebo-treated controls. A statistically significant between-group difference was noted on days 2 through 28. HAM-D remission at day 15 was documented in 64% of the oral brexanolone group, compared with 26% of controls.
Those improvements in depression were accompanied by significant gains in numerous domains of health-related quality of life as assessed via the 36-Item Short Form Health Survey. Indeed, day 15 health-related quality of life scores in the oral brexanolone group approached normative values for the general population.
The studies were funded by SAGE Therapeutics.
BARCELONA – Brexanolone injection provided rapid and durable improvement in postpartum depression in an integrated analysis of three pivotal randomized trials collectively known as the Hummingbird trials, Christine Clemson, PhD, reported at the annual congress of the European College of Neuropsychopharmacology.
This was accomplished with a favorable safety experience. The most common treatment-emergent adverse events – dizziness and sleepiness – were roughly twice as common as with placebo in the 247-patient Hummingbird safety analysis.
On Dec. 19, 2018, the agency is expected to respond to SAGE Therapeutics’s application for marketing approval of intravenous brexanolone given as a continuous 60-hour infusion at 90 mcg/kg per hour, according to Dr. Clemson, senior medical director at Cambridge, Mass.–based SAGE Therapeutics, which is developing the therapy.
Brexanolone is a proprietary IV formulation of allopregnanolone, a metabolite of progesterone. The drug’s mechanism of action involves modulation of the neurotransmitter gamma-aminobutyric acid (GABA). The drug binds to both synaptic and extra-synaptic GABA A receptors, thereby increasing receptor functionality.
The decision to target GABA as a novel therapeutic strategy in PPD was based upon translational studies demonstrating that GABA is the chief neuroinhibitory mechanism in the brain, and its actions are mediated mainly by GABA A receptors. Brexanolone’s efficacy is consistent with a theory that the pathogenesis of PPD involves triggers such as inflammation, hormonal fluctuations, or chronic stress, which in some women cause GABA hypofunction, both at the receptors and in terms of tissue GABA levels. This, in turn, leads to an overactive HPA axis and dysregulated neural networks, with resultant PPD, Dr. Clemson explained.
The three Hummingbird clinical trials were double blind, randomized, and placebo controlled. Two were restricted to women with severe PPD. The third and largest focused on moderately affected patients as defined by a baseline Hamilton Depression Scale for Depression (HAM-D) score of 20-25.
The efficacy analysis included 207 patients who received brexanolone at 90 mcg/kg per hour or placebo for 60 hours in an inpatient setting and were followed for 30 days. The primary endpoint was the change in HAM-D total score from baseline to 60 hours. The mean 17-point reduction in the active treatment arm was significantly better than the 12.8-point decrease with placebo. The between-group difference was significant within the first 24 hours and remained so at all time points out to the study’s end at day 30. There was no individual item on the HAM-D in which the drug performed worse than placebo, and there were many in which brexanolone performed significantly better, including depressed mood, anxiety, insomnia, and feelings of guilt.
In terms of the rigorous secondary endpoint of HAM-D remission as defined by a total score of 7 or less, the brexanolone injection significantly outperformed placebo at every time point except for day 30.
There was a 2% rate of serious adverse events in both study arms. These included suicidal ideation, an intentional overdose attempt post discharge, altered state of consciousness, and syncope.
A vastly more convenient once-daily oral formulation of brexanolone is now in phase 3 clinical trials for PPD and major depressive disorder, and in phase 2 for insomnia and bipolar depression.
Elsewhere at the ECNP congress, other investigators from Sage Therapeutics presented for the first time the outcomes of an 89-patient, randomized, double-blind, multicenter, placebo-controlled, phase 2 clinical trial of SAGE-217 for treatment of major depressive disorder.
Participants received a nightly 30-mg dose of the drug or placebo for 2 weeks, with a primary study endpoint being the change in HAM-D total score from baseline to day 15. Patients on the oral GABA A receptor positive modulator averaged a 17.4-point improvement, significantly better than the 10.3-point spread in placebo-treated controls. A statistically significant between-group difference was noted on days 2 through 28. HAM-D remission at day 15 was documented in 64% of the oral brexanolone group, compared with 26% of controls.
Those improvements in depression were accompanied by significant gains in numerous domains of health-related quality of life as assessed via the 36-Item Short Form Health Survey. Indeed, day 15 health-related quality of life scores in the oral brexanolone group approached normative values for the general population.
The studies were funded by SAGE Therapeutics.
REPORTING FROM THE ECNP CONGRESS
Key clinical point: A novel investigational GABA modulator is turning heads for treatment of postpartum depression.
Major finding: At 60 hours, mean HAM-D total scores had dropped by 17 points with brexanolone, versus 12.8 with placebo.
Study details: A prespecified integrated safety and efficacy analysis incorporating three pivotal clinical trials.
Disclosures: The studies were funded by SAGE Therapeutics and presented by a company executive.
Consider different etiologies in patients with vaginal pruritus
CHICAGO – Diagnosing the cause of vaginal itching, which can have a significant negative impact on a woman’s quality of life, can be particularly difficult for multiple reasons, according to Rachel Kornik, MD, of the departments of dermatology and obstetrics and gynecology at the University of Wisconsin, Madison.
“The anatomy is really challenging in this area, and there’s a broad differential. Often there’s more than one thing happening,” Dr. Kornik said during a session on diagnosing and managing genital pruritus in women at the American Academy of Dermatology summer meeting. Like hair loss, vaginal pruritus is also very emotionally distressing.
“Patients are very anxious when they have all this itching,” she said. “It has an impact on personal relationships. Some patients find it difficult to talk about because it’s a taboo subject, so we have to make them comfortable.”
Dr. Kornik showed a chart of the inflammatory, neoplastic, infections, infestations, environmental, neuropathic, and hormonal. But she focused her presentation primarily on the most common causes: contact dermatitis, lichen sclerosus, and lichen simplex chronicus.
Contact dermatitis
The most common factors that contribute to contact dermatitis are friction, hygiene practices, unique body exposures (such as body fluids and menstrual and personal care products), and occlusion/maceration, which facilitates penetration of external agents. Estrogen deficiency may also play a role.
Taking a thorough history from the patient is key to finding out possible causes. Dr. Kornik provided a list of common irritants to consider.
- Hygiene-related irritants, such as frequent washing and the use of soaps, wash cloths, loofahs, wipes, bath oil, bubbles, and water.
- Laundry products, such as fabric softeners or dryer sheets.
- Menstrual products, such as panty liners, pads, and scents or additives for retaining moisture.
- Over-the-counter itch products, such as those containing benzocaine.
- Medications, such as alcohol-based creams and gels, trichloroacetic acid, fluorouracil (Efudex), imiquimod, and topical antifungals.
- Heat-related irritants, such as use of hair dryers and heating pads.
- Body fluids, including urine, feces, menstrual blood, sweat, semen, and excessive discharge.
It’s also important to consider whether there is an allergic cause. “Contact dermatitis and allergic dermatitis can look very similar both clinically and histologically, and patients can even have them both at the same time,” Dr. Kornik said. “So really, patch testing is essential sometimes to identify a true allergic contact dermatitis.”
She cited a study that identified the top five most common allergens as fragrance mixes, balsam of Peru, benzocaine, terconazole, and quaternium-15 (a formaldehyde-releasing preservative) (Dermatitis. 2013 Mar-Apr;24(2):64-72).
“If somebody’s coming into your office and they have vulvar itching for any reason, the No. 1 thing is making sure that they eliminate and not use any products with fragrances,” Dr. Kornik said. “It’s also important to note that over time, industries’ use of preservatives does change, the concentrations change, and so we may see more emerging allergens or different ones over time.”
The causative allergens are rarely consumed orally, but they may be ectopic, such as shampoo or nail polish.
“What I’ve learned over the years in treating patients with vulvar itching is that they don’t always think to tell you about everything they are applying,” Dr. Kornik said. “You have to ask specific questions. Are you using any wipes or using any lubricants? What is the type and brand of menstrual pad you’re using?”
Patients might also think they can eliminate the cause of irritation by changing products, but “there are cross reactants in many preservatives and fragrances in many products, so they might not eliminate exposure, and intermittent exposures can lead to chronic dermatitis,” she pointed out.
One example is wipes: Some women may use them only periodically, such as after a yoga class, and not think of this as a possibility or realize that wipes could perpetuate chronic dermatitis.
Research has also found that it’s very common for patients with allergic contact dermatitis to have a concomitant vulvar diagnosis. In one study, more than half of patients had another condition, the most common of which was lichen sclerosus. Others included simplex chronicus, atopic dermatitis, condyloma acuminatum, psoriasis, and Paget disease.
Therefore, if patients are not responding as expected, it’s important to consider that the condition is multifactorial “and consider allergic contact dermatitis in addition to whatever other underlying dermatosis they have,” Dr. Kornik said.
Lichen sclerosus
Prevalence of the scarring disorder lichen sclerosus ranges from 1.7% to 3% in the research literature and pathogenesis is likely multifactorial.
“It’s a very frustrating condition for patients and for physicians because we don’t know exactly what causes it, but it definitely has a predilection for the vulva area, and it affects women of all ages,” she said. “I also think it’s more common than we think.”
Loss of normal anatomical structures are a key feature, so physicians need to know their anatomy well to look for what’s not there. Lichen sclerosus involves modified mucous membranes and the perianal area, and it may spread to the crural folds and upper thighs. Symptoms can include periclitoral edema, white patches, pale skin, textural changes (such as wrinkling, waxiness, or hyperkeratosis), fissures, melanosis, and sometimes ulcerations or erosions from scratching.
There is no standardized treatment for lichen sclerosus. Research suggests using a high potency topical steroid treatment daily until skin texture normalizes, which can take anywhere from 6 weeks to 5 months, depending on severity, Dr. Kornik said. Few data are available for management if topical steroids do not work, she added.*
If dealing with recalcitrant disease, she recommends first checking the patients’ compliance and then considering alternative diagnoses or secondary conditions. Do patch testing, rule out contact dermatitis, and rebiopsy if needed. Other options are to add tacrolimus ointment, offer intralesional triamcinolone, consider a systemic agent (acitretin, methotrexate, or possibly hydroxychloroquine), or try laser or photodynamic therapy. She emphasizes the importance of demonstrating to the patient where to apply ointment, since they may not be applying to the right areas.*
Lichen simplex chronicus
Lichen simplex chronicus is a clinical description of the result of chronic rubbing and scratching. It might be triggered by something that has now resolved or be linked to other itching conditions, but clinicians need to consider the possibility of neuropathic itch as well.
Features of lichen simplex chronicus can include bilateral or unilateral involvement of the labia majora, erythematous plaques with lichenification, hyper- or hypopigmentation, or angulated excoriations and hypertrophy of labia caused by thickened skin, though the signs may be subtle, she said.
Treatment requires management of the skin problem itself – the underlying cause of the itch – as well as the behavioral component. Topical steroids are first line, plus an antihistamine at night as needed to stop the scratching. If those are insufficient, the next treatments to consider are intralesional triamcinolone (Kenalog), tacrolimus ointment, topical or oral doxepin, mirtazapine, or even selective serotonin reuptake inhibitors.
Women using topical steroids should also be aware of the possible side effects, including atrophy, infections, and allergic contact dermatitis if the steroid itself or the cream it’s in is an allergen. If stinging or burning occurs, switch to a steroid without propylene glycol, she added.
If no changes occur in the skin, clinicians may have to consider the existence of neuropathic pruritus diagnosis, an injury or dysfunction along the afferent itch pathway. Burning is more common with this neuropathy, but itching can occur too.
Other issues include symptoms that worsen with sitting and pain that worsens throughout the day. Causes can include childbirth, surgery, pelvic trauma, infection, and chemoradiation, and diagnosis requires imaging to rule out other possible causes. Treatment involves pelvic floor physical therapy, pudendal nerve block, or gabapentin.
Dr. Kornik wrapped up with a reminder that vulvar itch is often multifactorial, so clinicians need to chip away at the potential causes – sometimes with cultures, scrapes, and biopsies as needed.
She reported no financial disclosures.
Correction, 10/26/18: Dr. Kornik's treatment recommendations for lichen sclerosus were misstated.
CHICAGO – Diagnosing the cause of vaginal itching, which can have a significant negative impact on a woman’s quality of life, can be particularly difficult for multiple reasons, according to Rachel Kornik, MD, of the departments of dermatology and obstetrics and gynecology at the University of Wisconsin, Madison.
“The anatomy is really challenging in this area, and there’s a broad differential. Often there’s more than one thing happening,” Dr. Kornik said during a session on diagnosing and managing genital pruritus in women at the American Academy of Dermatology summer meeting. Like hair loss, vaginal pruritus is also very emotionally distressing.
“Patients are very anxious when they have all this itching,” she said. “It has an impact on personal relationships. Some patients find it difficult to talk about because it’s a taboo subject, so we have to make them comfortable.”
Dr. Kornik showed a chart of the inflammatory, neoplastic, infections, infestations, environmental, neuropathic, and hormonal. But she focused her presentation primarily on the most common causes: contact dermatitis, lichen sclerosus, and lichen simplex chronicus.
Contact dermatitis
The most common factors that contribute to contact dermatitis are friction, hygiene practices, unique body exposures (such as body fluids and menstrual and personal care products), and occlusion/maceration, which facilitates penetration of external agents. Estrogen deficiency may also play a role.
Taking a thorough history from the patient is key to finding out possible causes. Dr. Kornik provided a list of common irritants to consider.
- Hygiene-related irritants, such as frequent washing and the use of soaps, wash cloths, loofahs, wipes, bath oil, bubbles, and water.
- Laundry products, such as fabric softeners or dryer sheets.
- Menstrual products, such as panty liners, pads, and scents or additives for retaining moisture.
- Over-the-counter itch products, such as those containing benzocaine.
- Medications, such as alcohol-based creams and gels, trichloroacetic acid, fluorouracil (Efudex), imiquimod, and topical antifungals.
- Heat-related irritants, such as use of hair dryers and heating pads.
- Body fluids, including urine, feces, menstrual blood, sweat, semen, and excessive discharge.
It’s also important to consider whether there is an allergic cause. “Contact dermatitis and allergic dermatitis can look very similar both clinically and histologically, and patients can even have them both at the same time,” Dr. Kornik said. “So really, patch testing is essential sometimes to identify a true allergic contact dermatitis.”
She cited a study that identified the top five most common allergens as fragrance mixes, balsam of Peru, benzocaine, terconazole, and quaternium-15 (a formaldehyde-releasing preservative) (Dermatitis. 2013 Mar-Apr;24(2):64-72).
“If somebody’s coming into your office and they have vulvar itching for any reason, the No. 1 thing is making sure that they eliminate and not use any products with fragrances,” Dr. Kornik said. “It’s also important to note that over time, industries’ use of preservatives does change, the concentrations change, and so we may see more emerging allergens or different ones over time.”
The causative allergens are rarely consumed orally, but they may be ectopic, such as shampoo or nail polish.
“What I’ve learned over the years in treating patients with vulvar itching is that they don’t always think to tell you about everything they are applying,” Dr. Kornik said. “You have to ask specific questions. Are you using any wipes or using any lubricants? What is the type and brand of menstrual pad you’re using?”
Patients might also think they can eliminate the cause of irritation by changing products, but “there are cross reactants in many preservatives and fragrances in many products, so they might not eliminate exposure, and intermittent exposures can lead to chronic dermatitis,” she pointed out.
One example is wipes: Some women may use them only periodically, such as after a yoga class, and not think of this as a possibility or realize that wipes could perpetuate chronic dermatitis.
Research has also found that it’s very common for patients with allergic contact dermatitis to have a concomitant vulvar diagnosis. In one study, more than half of patients had another condition, the most common of which was lichen sclerosus. Others included simplex chronicus, atopic dermatitis, condyloma acuminatum, psoriasis, and Paget disease.
Therefore, if patients are not responding as expected, it’s important to consider that the condition is multifactorial “and consider allergic contact dermatitis in addition to whatever other underlying dermatosis they have,” Dr. Kornik said.
Lichen sclerosus
Prevalence of the scarring disorder lichen sclerosus ranges from 1.7% to 3% in the research literature and pathogenesis is likely multifactorial.
“It’s a very frustrating condition for patients and for physicians because we don’t know exactly what causes it, but it definitely has a predilection for the vulva area, and it affects women of all ages,” she said. “I also think it’s more common than we think.”
Loss of normal anatomical structures are a key feature, so physicians need to know their anatomy well to look for what’s not there. Lichen sclerosus involves modified mucous membranes and the perianal area, and it may spread to the crural folds and upper thighs. Symptoms can include periclitoral edema, white patches, pale skin, textural changes (such as wrinkling, waxiness, or hyperkeratosis), fissures, melanosis, and sometimes ulcerations or erosions from scratching.
There is no standardized treatment for lichen sclerosus. Research suggests using a high potency topical steroid treatment daily until skin texture normalizes, which can take anywhere from 6 weeks to 5 months, depending on severity, Dr. Kornik said. Few data are available for management if topical steroids do not work, she added.*
If dealing with recalcitrant disease, she recommends first checking the patients’ compliance and then considering alternative diagnoses or secondary conditions. Do patch testing, rule out contact dermatitis, and rebiopsy if needed. Other options are to add tacrolimus ointment, offer intralesional triamcinolone, consider a systemic agent (acitretin, methotrexate, or possibly hydroxychloroquine), or try laser or photodynamic therapy. She emphasizes the importance of demonstrating to the patient where to apply ointment, since they may not be applying to the right areas.*
Lichen simplex chronicus
Lichen simplex chronicus is a clinical description of the result of chronic rubbing and scratching. It might be triggered by something that has now resolved or be linked to other itching conditions, but clinicians need to consider the possibility of neuropathic itch as well.
Features of lichen simplex chronicus can include bilateral or unilateral involvement of the labia majora, erythematous plaques with lichenification, hyper- or hypopigmentation, or angulated excoriations and hypertrophy of labia caused by thickened skin, though the signs may be subtle, she said.
Treatment requires management of the skin problem itself – the underlying cause of the itch – as well as the behavioral component. Topical steroids are first line, plus an antihistamine at night as needed to stop the scratching. If those are insufficient, the next treatments to consider are intralesional triamcinolone (Kenalog), tacrolimus ointment, topical or oral doxepin, mirtazapine, or even selective serotonin reuptake inhibitors.
Women using topical steroids should also be aware of the possible side effects, including atrophy, infections, and allergic contact dermatitis if the steroid itself or the cream it’s in is an allergen. If stinging or burning occurs, switch to a steroid without propylene glycol, she added.
If no changes occur in the skin, clinicians may have to consider the existence of neuropathic pruritus diagnosis, an injury or dysfunction along the afferent itch pathway. Burning is more common with this neuropathy, but itching can occur too.
Other issues include symptoms that worsen with sitting and pain that worsens throughout the day. Causes can include childbirth, surgery, pelvic trauma, infection, and chemoradiation, and diagnosis requires imaging to rule out other possible causes. Treatment involves pelvic floor physical therapy, pudendal nerve block, or gabapentin.
Dr. Kornik wrapped up with a reminder that vulvar itch is often multifactorial, so clinicians need to chip away at the potential causes – sometimes with cultures, scrapes, and biopsies as needed.
She reported no financial disclosures.
Correction, 10/26/18: Dr. Kornik's treatment recommendations for lichen sclerosus were misstated.
CHICAGO – Diagnosing the cause of vaginal itching, which can have a significant negative impact on a woman’s quality of life, can be particularly difficult for multiple reasons, according to Rachel Kornik, MD, of the departments of dermatology and obstetrics and gynecology at the University of Wisconsin, Madison.
“The anatomy is really challenging in this area, and there’s a broad differential. Often there’s more than one thing happening,” Dr. Kornik said during a session on diagnosing and managing genital pruritus in women at the American Academy of Dermatology summer meeting. Like hair loss, vaginal pruritus is also very emotionally distressing.
“Patients are very anxious when they have all this itching,” she said. “It has an impact on personal relationships. Some patients find it difficult to talk about because it’s a taboo subject, so we have to make them comfortable.”
Dr. Kornik showed a chart of the inflammatory, neoplastic, infections, infestations, environmental, neuropathic, and hormonal. But she focused her presentation primarily on the most common causes: contact dermatitis, lichen sclerosus, and lichen simplex chronicus.
Contact dermatitis
The most common factors that contribute to contact dermatitis are friction, hygiene practices, unique body exposures (such as body fluids and menstrual and personal care products), and occlusion/maceration, which facilitates penetration of external agents. Estrogen deficiency may also play a role.
Taking a thorough history from the patient is key to finding out possible causes. Dr. Kornik provided a list of common irritants to consider.
- Hygiene-related irritants, such as frequent washing and the use of soaps, wash cloths, loofahs, wipes, bath oil, bubbles, and water.
- Laundry products, such as fabric softeners or dryer sheets.
- Menstrual products, such as panty liners, pads, and scents or additives for retaining moisture.
- Over-the-counter itch products, such as those containing benzocaine.
- Medications, such as alcohol-based creams and gels, trichloroacetic acid, fluorouracil (Efudex), imiquimod, and topical antifungals.
- Heat-related irritants, such as use of hair dryers and heating pads.
- Body fluids, including urine, feces, menstrual blood, sweat, semen, and excessive discharge.
It’s also important to consider whether there is an allergic cause. “Contact dermatitis and allergic dermatitis can look very similar both clinically and histologically, and patients can even have them both at the same time,” Dr. Kornik said. “So really, patch testing is essential sometimes to identify a true allergic contact dermatitis.”
She cited a study that identified the top five most common allergens as fragrance mixes, balsam of Peru, benzocaine, terconazole, and quaternium-15 (a formaldehyde-releasing preservative) (Dermatitis. 2013 Mar-Apr;24(2):64-72).
“If somebody’s coming into your office and they have vulvar itching for any reason, the No. 1 thing is making sure that they eliminate and not use any products with fragrances,” Dr. Kornik said. “It’s also important to note that over time, industries’ use of preservatives does change, the concentrations change, and so we may see more emerging allergens or different ones over time.”
The causative allergens are rarely consumed orally, but they may be ectopic, such as shampoo or nail polish.
“What I’ve learned over the years in treating patients with vulvar itching is that they don’t always think to tell you about everything they are applying,” Dr. Kornik said. “You have to ask specific questions. Are you using any wipes or using any lubricants? What is the type and brand of menstrual pad you’re using?”
Patients might also think they can eliminate the cause of irritation by changing products, but “there are cross reactants in many preservatives and fragrances in many products, so they might not eliminate exposure, and intermittent exposures can lead to chronic dermatitis,” she pointed out.
One example is wipes: Some women may use them only periodically, such as after a yoga class, and not think of this as a possibility or realize that wipes could perpetuate chronic dermatitis.
Research has also found that it’s very common for patients with allergic contact dermatitis to have a concomitant vulvar diagnosis. In one study, more than half of patients had another condition, the most common of which was lichen sclerosus. Others included simplex chronicus, atopic dermatitis, condyloma acuminatum, psoriasis, and Paget disease.
Therefore, if patients are not responding as expected, it’s important to consider that the condition is multifactorial “and consider allergic contact dermatitis in addition to whatever other underlying dermatosis they have,” Dr. Kornik said.
Lichen sclerosus
Prevalence of the scarring disorder lichen sclerosus ranges from 1.7% to 3% in the research literature and pathogenesis is likely multifactorial.
“It’s a very frustrating condition for patients and for physicians because we don’t know exactly what causes it, but it definitely has a predilection for the vulva area, and it affects women of all ages,” she said. “I also think it’s more common than we think.”
Loss of normal anatomical structures are a key feature, so physicians need to know their anatomy well to look for what’s not there. Lichen sclerosus involves modified mucous membranes and the perianal area, and it may spread to the crural folds and upper thighs. Symptoms can include periclitoral edema, white patches, pale skin, textural changes (such as wrinkling, waxiness, or hyperkeratosis), fissures, melanosis, and sometimes ulcerations or erosions from scratching.
There is no standardized treatment for lichen sclerosus. Research suggests using a high potency topical steroid treatment daily until skin texture normalizes, which can take anywhere from 6 weeks to 5 months, depending on severity, Dr. Kornik said. Few data are available for management if topical steroids do not work, she added.*
If dealing with recalcitrant disease, she recommends first checking the patients’ compliance and then considering alternative diagnoses or secondary conditions. Do patch testing, rule out contact dermatitis, and rebiopsy if needed. Other options are to add tacrolimus ointment, offer intralesional triamcinolone, consider a systemic agent (acitretin, methotrexate, or possibly hydroxychloroquine), or try laser or photodynamic therapy. She emphasizes the importance of demonstrating to the patient where to apply ointment, since they may not be applying to the right areas.*
Lichen simplex chronicus
Lichen simplex chronicus is a clinical description of the result of chronic rubbing and scratching. It might be triggered by something that has now resolved or be linked to other itching conditions, but clinicians need to consider the possibility of neuropathic itch as well.
Features of lichen simplex chronicus can include bilateral or unilateral involvement of the labia majora, erythematous plaques with lichenification, hyper- or hypopigmentation, or angulated excoriations and hypertrophy of labia caused by thickened skin, though the signs may be subtle, she said.
Treatment requires management of the skin problem itself – the underlying cause of the itch – as well as the behavioral component. Topical steroids are first line, plus an antihistamine at night as needed to stop the scratching. If those are insufficient, the next treatments to consider are intralesional triamcinolone (Kenalog), tacrolimus ointment, topical or oral doxepin, mirtazapine, or even selective serotonin reuptake inhibitors.
Women using topical steroids should also be aware of the possible side effects, including atrophy, infections, and allergic contact dermatitis if the steroid itself or the cream it’s in is an allergen. If stinging or burning occurs, switch to a steroid without propylene glycol, she added.
If no changes occur in the skin, clinicians may have to consider the existence of neuropathic pruritus diagnosis, an injury or dysfunction along the afferent itch pathway. Burning is more common with this neuropathy, but itching can occur too.
Other issues include symptoms that worsen with sitting and pain that worsens throughout the day. Causes can include childbirth, surgery, pelvic trauma, infection, and chemoradiation, and diagnosis requires imaging to rule out other possible causes. Treatment involves pelvic floor physical therapy, pudendal nerve block, or gabapentin.
Dr. Kornik wrapped up with a reminder that vulvar itch is often multifactorial, so clinicians need to chip away at the potential causes – sometimes with cultures, scrapes, and biopsies as needed.
She reported no financial disclosures.
Correction, 10/26/18: Dr. Kornik's treatment recommendations for lichen sclerosus were misstated.
EXPERT ANALYSIS FROM SUMMER AAD 2018
No signal for CV, breast effects with bioidentical vaginal estrogen for dyspareunia
that would suggest significant systemic absorption.
The lack of sex hormone binding globulin (SHBG) changes in the subset of women who received this test bolsters support for low systemic absorption from the low-dose vaginal softgel, Lisa Larkin, MD, said at the annual meeting of the North American Menopause Society in Orlando.
These safety data show that the vaginal route for this hormone is meeting a treatment goal for many menopausal women: “One goal of vaginal estrogen is to minimize systemic absorption and potentially reduce related side effects,” Dr. Larkin said.
TX-004HR (Imvexxy) delivers bioidentical solubilized 17 beta-estradiol (E2) via a softgel vaginal insert. It is Food and Drug Administration approved in 4-mcg and 10-mcg doses for the treatment of moderate to severe dyspareunia associated with menopause.
The phase 3 clinical trial (REJOICE) of TX-004HR met the coprimary endpoints of improving vaginal physiology, lowering vaginal pH, and decreasing the severity of dyspareunia at both the 4- and 10-mcg doses, said Dr. Larkin, an internal medicine physician in private practice in Mariemont, Ohio.
Serum estradiol levels for REJOICE participants were “similar to placebo and baseline, and generally within the postmenopausal range,” she said.
The randomized, double-blind, placebo-controlled trial tested 4-, 10-, and 25-mcg doses of TX-004HR. The self-administered vaginal inserts were used once daily for 2 weeks, then twice weekly for an additional 10 weeks.
In looking at treatment emergent adverse events (TEAEs), the REJOICE investigators were particularly interested in tracking cardiovascular and breast events, Dr. Larkin said. Participants received ECGs and clinical breast exams at baseline, and at study week 12. In addition, 72 of the women had SHBG measured at baseline and at weeks 2 and 12. The trial had a high completion rate of 94% at 12 weeks. The mean age of the women was 59 years, and the mean body mass index was 26.7 kg/m2. African American women made up 12% of the study; the remainder of the women were white.
In the end, 784 menopausal women with moderate to severe dyspareunia were randomized 1:1:1:1 to placebo or to receive one of the three dose levels of TX-004HR. Overall, “no clinically significant differences in adverse events were observed between treatment and placebo groups,” Dr. Larkin said. Only headache, vaginal discharge, and vulvovaginal pruritus occurred in at least 3% of the women in any treatment arm, with no differences between those taking TX-004HR and placebo. There were no malignancies or endometrial hyperplasia among the REJOICE participants: “There was no signal of estrogenic stimulation of the endometrium,” she said.
Looking at cardiovascular-related TEAEs, the five events that occurred were judged to be mild, and mostly not related to treatment. One case of first degree atrioventricular block and one case of sinus bradycardia were reported by the same woman, who was taking the 4-mcg dose of TX-004HR. One additional woman on that dose experienced palpitations, as did one woman taking placebo. “No coronary heart disease, venous thromboembolism, or other thrombotic episodes were noted” during the REJOICE trial, Dr. Larkin said. There were no clinically significant ECG changes during the study period that were judged related to treatment. Blood pressure was mildly increased in three women, one each in the 4-mcg, 10-mcg, and placebo study arms. The elevation was considered possibly related to the study in the 4-mcg and placebo takers. Two other women in the 4-mcg group experienced mild incident hypertension, with one woman’s hypertension judged possibly related to treatment.
Blood chemistry showed incident hypercholesterolemia for one woman in the 4-mcg group and one in the placebo group, and one woman taking the 10-mcg TX-0400HR dose and two taking placebo had increases in serum triglycerides.
Seven women reported breast-related TEAEs, with five of these considered possibly or probably treatment related. One woman on the 10-mcg dose had breast tenderness; all other events were among placebo takers.
Finally, among the subset of women whose SHBG levels were tested, “no dose-related pattern was apparent, and changes with TX-004HR were comparable to changes with placebo,” said Dr. Larkin, noting that there was no suggestion of significant systemic absorption.
“These safety data, in conjunction with the improved moderate to severe dyspareunia efficacy data and minimal estradiol absorption, support a local effect of the TX-004HR vaginal insert,” she said.
The study was sponsored by TherapeuticsMD, the manufacturer of TH-004HR. Dr. Larkin disclosed that she is an advisory board member and on the speaker’s bureau for Valeant pharmaceuticals, is a consultant for TherapeuticsMD, and is an advisory board member for AMAG and Palatin Technologies.
SOURCE: Larkin L et al. NAMS 2018, Thursday concurrent session 1.
that would suggest significant systemic absorption.
The lack of sex hormone binding globulin (SHBG) changes in the subset of women who received this test bolsters support for low systemic absorption from the low-dose vaginal softgel, Lisa Larkin, MD, said at the annual meeting of the North American Menopause Society in Orlando.
These safety data show that the vaginal route for this hormone is meeting a treatment goal for many menopausal women: “One goal of vaginal estrogen is to minimize systemic absorption and potentially reduce related side effects,” Dr. Larkin said.
TX-004HR (Imvexxy) delivers bioidentical solubilized 17 beta-estradiol (E2) via a softgel vaginal insert. It is Food and Drug Administration approved in 4-mcg and 10-mcg doses for the treatment of moderate to severe dyspareunia associated with menopause.
The phase 3 clinical trial (REJOICE) of TX-004HR met the coprimary endpoints of improving vaginal physiology, lowering vaginal pH, and decreasing the severity of dyspareunia at both the 4- and 10-mcg doses, said Dr. Larkin, an internal medicine physician in private practice in Mariemont, Ohio.
Serum estradiol levels for REJOICE participants were “similar to placebo and baseline, and generally within the postmenopausal range,” she said.
The randomized, double-blind, placebo-controlled trial tested 4-, 10-, and 25-mcg doses of TX-004HR. The self-administered vaginal inserts were used once daily for 2 weeks, then twice weekly for an additional 10 weeks.
In looking at treatment emergent adverse events (TEAEs), the REJOICE investigators were particularly interested in tracking cardiovascular and breast events, Dr. Larkin said. Participants received ECGs and clinical breast exams at baseline, and at study week 12. In addition, 72 of the women had SHBG measured at baseline and at weeks 2 and 12. The trial had a high completion rate of 94% at 12 weeks. The mean age of the women was 59 years, and the mean body mass index was 26.7 kg/m2. African American women made up 12% of the study; the remainder of the women were white.
In the end, 784 menopausal women with moderate to severe dyspareunia were randomized 1:1:1:1 to placebo or to receive one of the three dose levels of TX-004HR. Overall, “no clinically significant differences in adverse events were observed between treatment and placebo groups,” Dr. Larkin said. Only headache, vaginal discharge, and vulvovaginal pruritus occurred in at least 3% of the women in any treatment arm, with no differences between those taking TX-004HR and placebo. There were no malignancies or endometrial hyperplasia among the REJOICE participants: “There was no signal of estrogenic stimulation of the endometrium,” she said.
Looking at cardiovascular-related TEAEs, the five events that occurred were judged to be mild, and mostly not related to treatment. One case of first degree atrioventricular block and one case of sinus bradycardia were reported by the same woman, who was taking the 4-mcg dose of TX-004HR. One additional woman on that dose experienced palpitations, as did one woman taking placebo. “No coronary heart disease, venous thromboembolism, or other thrombotic episodes were noted” during the REJOICE trial, Dr. Larkin said. There were no clinically significant ECG changes during the study period that were judged related to treatment. Blood pressure was mildly increased in three women, one each in the 4-mcg, 10-mcg, and placebo study arms. The elevation was considered possibly related to the study in the 4-mcg and placebo takers. Two other women in the 4-mcg group experienced mild incident hypertension, with one woman’s hypertension judged possibly related to treatment.
Blood chemistry showed incident hypercholesterolemia for one woman in the 4-mcg group and one in the placebo group, and one woman taking the 10-mcg TX-0400HR dose and two taking placebo had increases in serum triglycerides.
Seven women reported breast-related TEAEs, with five of these considered possibly or probably treatment related. One woman on the 10-mcg dose had breast tenderness; all other events were among placebo takers.
Finally, among the subset of women whose SHBG levels were tested, “no dose-related pattern was apparent, and changes with TX-004HR were comparable to changes with placebo,” said Dr. Larkin, noting that there was no suggestion of significant systemic absorption.
“These safety data, in conjunction with the improved moderate to severe dyspareunia efficacy data and minimal estradiol absorption, support a local effect of the TX-004HR vaginal insert,” she said.
The study was sponsored by TherapeuticsMD, the manufacturer of TH-004HR. Dr. Larkin disclosed that she is an advisory board member and on the speaker’s bureau for Valeant pharmaceuticals, is a consultant for TherapeuticsMD, and is an advisory board member for AMAG and Palatin Technologies.
SOURCE: Larkin L et al. NAMS 2018, Thursday concurrent session 1.
that would suggest significant systemic absorption.
The lack of sex hormone binding globulin (SHBG) changes in the subset of women who received this test bolsters support for low systemic absorption from the low-dose vaginal softgel, Lisa Larkin, MD, said at the annual meeting of the North American Menopause Society in Orlando.
These safety data show that the vaginal route for this hormone is meeting a treatment goal for many menopausal women: “One goal of vaginal estrogen is to minimize systemic absorption and potentially reduce related side effects,” Dr. Larkin said.
TX-004HR (Imvexxy) delivers bioidentical solubilized 17 beta-estradiol (E2) via a softgel vaginal insert. It is Food and Drug Administration approved in 4-mcg and 10-mcg doses for the treatment of moderate to severe dyspareunia associated with menopause.
The phase 3 clinical trial (REJOICE) of TX-004HR met the coprimary endpoints of improving vaginal physiology, lowering vaginal pH, and decreasing the severity of dyspareunia at both the 4- and 10-mcg doses, said Dr. Larkin, an internal medicine physician in private practice in Mariemont, Ohio.
Serum estradiol levels for REJOICE participants were “similar to placebo and baseline, and generally within the postmenopausal range,” she said.
The randomized, double-blind, placebo-controlled trial tested 4-, 10-, and 25-mcg doses of TX-004HR. The self-administered vaginal inserts were used once daily for 2 weeks, then twice weekly for an additional 10 weeks.
In looking at treatment emergent adverse events (TEAEs), the REJOICE investigators were particularly interested in tracking cardiovascular and breast events, Dr. Larkin said. Participants received ECGs and clinical breast exams at baseline, and at study week 12. In addition, 72 of the women had SHBG measured at baseline and at weeks 2 and 12. The trial had a high completion rate of 94% at 12 weeks. The mean age of the women was 59 years, and the mean body mass index was 26.7 kg/m2. African American women made up 12% of the study; the remainder of the women were white.
In the end, 784 menopausal women with moderate to severe dyspareunia were randomized 1:1:1:1 to placebo or to receive one of the three dose levels of TX-004HR. Overall, “no clinically significant differences in adverse events were observed between treatment and placebo groups,” Dr. Larkin said. Only headache, vaginal discharge, and vulvovaginal pruritus occurred in at least 3% of the women in any treatment arm, with no differences between those taking TX-004HR and placebo. There were no malignancies or endometrial hyperplasia among the REJOICE participants: “There was no signal of estrogenic stimulation of the endometrium,” she said.
Looking at cardiovascular-related TEAEs, the five events that occurred were judged to be mild, and mostly not related to treatment. One case of first degree atrioventricular block and one case of sinus bradycardia were reported by the same woman, who was taking the 4-mcg dose of TX-004HR. One additional woman on that dose experienced palpitations, as did one woman taking placebo. “No coronary heart disease, venous thromboembolism, or other thrombotic episodes were noted” during the REJOICE trial, Dr. Larkin said. There were no clinically significant ECG changes during the study period that were judged related to treatment. Blood pressure was mildly increased in three women, one each in the 4-mcg, 10-mcg, and placebo study arms. The elevation was considered possibly related to the study in the 4-mcg and placebo takers. Two other women in the 4-mcg group experienced mild incident hypertension, with one woman’s hypertension judged possibly related to treatment.
Blood chemistry showed incident hypercholesterolemia for one woman in the 4-mcg group and one in the placebo group, and one woman taking the 10-mcg TX-0400HR dose and two taking placebo had increases in serum triglycerides.
Seven women reported breast-related TEAEs, with five of these considered possibly or probably treatment related. One woman on the 10-mcg dose had breast tenderness; all other events were among placebo takers.
Finally, among the subset of women whose SHBG levels were tested, “no dose-related pattern was apparent, and changes with TX-004HR were comparable to changes with placebo,” said Dr. Larkin, noting that there was no suggestion of significant systemic absorption.
“These safety data, in conjunction with the improved moderate to severe dyspareunia efficacy data and minimal estradiol absorption, support a local effect of the TX-004HR vaginal insert,” she said.
The study was sponsored by TherapeuticsMD, the manufacturer of TH-004HR. Dr. Larkin disclosed that she is an advisory board member and on the speaker’s bureau for Valeant pharmaceuticals, is a consultant for TherapeuticsMD, and is an advisory board member for AMAG and Palatin Technologies.
SOURCE: Larkin L et al. NAMS 2018, Thursday concurrent session 1.
FROM NAMS 2018
Key clinical point: Safety data from clinical trials of a bioidentical vaginal estrogen for dyspareunia in menopausal women showed no signs of CV or breast risks.
Major finding: There were no cardiovascular events or thrombotic episodes among menopausal women with dyspareunia treated with TX-004HR.
Study details: Randomized, double-blind, placebo-controlled trial of 784 menopausal women with moderate to severe dyspareunia.
Disclosures: The study was sponsored by TherapeuticsMD, the manufacturer of TH-004HR. Dr. Larkin reported financial relationships with several pharmaceutical companies, including TherapeuticsMD.
Source: Larkin L et al. NAMS 2018, Thursday concurrent session 1.
With more mindfulness, menopausal symptoms wane
An observational Furthermore, mindfulness had the greatest positive effect on menopausal symptoms for those women with the highest self-reported stress levels.
“In this cross-sectional study, mindfulness was associated with lower menopausal symptom burden. In women with higher stress, the magnitude of association between mindfulness and menopausal symptoms appeared more robust,” said Richa Sood, MD, speaking at the annual meeting of the North American Menopause Society.
Menopausal symptoms can exist alongside many other midlife issues because women often are trying to keep many balls in the air: This age group may be facing aging parents, a household with teenagers, and work-related pressures, she noted.
Thus, menopausal symptoms can be amplified by stressors. New mood problems – or worsening of preexisting ones – can interfere with work productivity and negatively affect relationships. Life satisfaction can take a steep dive during midlife for some women, said Dr. Sood of the Mayo Clinic, Rochester, Minn.
Could mindfulness be effective for stress management in this complex landscape of physiological and lifespan changes? “Mindfulness is paying attention,” said Dr. Sood. Practitioners of mindfulness focus on purposeful attention, staying in the present moment, and avoiding judgment.
Mindfulness may work as a stress-management tool for a variety of reasons, said Dr. Sood. The technique can help retrain people with tendencies for emotional reactivity in stressful situations; additionally, the focus on the present and on observation, rather than judgment, may help avoid maladaptive rumination.
To see how mindfulness in everyday life could affect the burden of menopausal symptoms, Dr. Sood and her collaborators designed an observational, cross-sectional study of 1,744 women aged 40-64 years.
The investigators used three scales in their assessments. The first, the Menopause Rating Scale (MRS), is an 11-item scale ranging from 0 to 44 that assesses psychological, somatovegetative, and urogenital domains. The second, the Perceived Stress Scale 4 (PSS-4), is a four-item scale that is a global measure of stress over the last 4 weeks, with tallied scores in the 0-16 range. Finally, the Mindful Attention Awareness Scale (MAAS) is a 15-item scale that captures how frequently respondents are in a mindful state during their daily life, with higher scores meaning more mindfulness.
The 1,744 women were seen in a women’s health clinic over the period of one year. Participants were a mean 53.4 years old (standard deviation, 6.1 years). Almost all were white (93%), most were married (82.7%), and most also had at least a 4-year college degree (64.6%) and were employed (65.3%).
The investigators mapped each scale against each of the others, which yielded three plots. In the first, higher MAAS scores were correlated with lower MRS scores (correlation, –0.49; P less than .001), which means that more time in a mindful state was associated with less severe menopausal symptoms.
In the second plot, lower MRS scores were associated with lower PSS-4 scores (correlation, 0.55; P less than .001). The last plot mapped PSS-4 scores against MAAS scores, showing that higher MAAS scores were correlated with lower PSS-4 scores, which means that more time in a mindful state was also associated with less perceived stress (correlation, –0.53; P less than .001).
Most of these associations remained statistically significant after multivariable linear regression analysis and breaking out the subscales of the MRS. Only the association between higher MAAS scores and the somatovegetative domain of the PSS-4 lost significance (P = 0.44).
Next, Dr. Sood and her collaborators probed how higher perceived stress, as measured by higher PSS-4 scores, altered the effects that mindful activity had on menopausal symptoms (as measured by the MRS).
The effect of mindfulness became stronger in the milieu of higher perceived stress. At a relatively low PSS-4 value of 4, the MRS score dropped 1.53 points for each one-point increase in the MAAS total score. However, with a PSS-4 score of 12, the decrease in MRS was 2.27 points for each one-point increase in MAAS, and with the maximum perceived stress score of 16, the MRS fell 2.64 points for each one-point increase in the MAAS score.
These findings are set against the backdrop of previous literature linking mindfulness to positive health behaviors and outcomes, she said, noting that work looking specifically at mindfulness-based stress reduction in peri- and postmenopausal women showed a halving of symptoms and improved quality of life.
Dr. Sood said that the present study was observational only, noting that it looked only at time spent in a mindful state in an untrained cohort of women in midlife. “Trait, or dispositional, mindfulness appears to be protective against stress and symptoms in midlife women,” she commented. “More mindful women may be choosing to shift their attention to more pleasant aspects of life, rather than their symptoms.”
“If you allow me to speculate a bit,” Dr. Sood continued, “the underpinnings of psychological symptoms rest in threat-focused attention and emotional reactivity – so the mindfulness approach appears to fit very well to impact such a change.”
Mindfulness, she added, “might be a tool to impact the emotional component of the overall experience, thereby decreasing the total suffering.” However, she noted that what’s needed are studies with a more heterogeneous population, as well as ones designed to tease out causality. Still, “the current study adds to the wealth of data supporting the role of mindfulness in various settings for impacting positive change in health and behaviors.”
Dr. Sood reported that she has ownership stake in the Global Center for Resiliency and Well-Being.
SOURCE: Sood R et al. NAMS 2018, Top-Scoring Abstract Session.
An observational Furthermore, mindfulness had the greatest positive effect on menopausal symptoms for those women with the highest self-reported stress levels.
“In this cross-sectional study, mindfulness was associated with lower menopausal symptom burden. In women with higher stress, the magnitude of association between mindfulness and menopausal symptoms appeared more robust,” said Richa Sood, MD, speaking at the annual meeting of the North American Menopause Society.
Menopausal symptoms can exist alongside many other midlife issues because women often are trying to keep many balls in the air: This age group may be facing aging parents, a household with teenagers, and work-related pressures, she noted.
Thus, menopausal symptoms can be amplified by stressors. New mood problems – or worsening of preexisting ones – can interfere with work productivity and negatively affect relationships. Life satisfaction can take a steep dive during midlife for some women, said Dr. Sood of the Mayo Clinic, Rochester, Minn.
Could mindfulness be effective for stress management in this complex landscape of physiological and lifespan changes? “Mindfulness is paying attention,” said Dr. Sood. Practitioners of mindfulness focus on purposeful attention, staying in the present moment, and avoiding judgment.
Mindfulness may work as a stress-management tool for a variety of reasons, said Dr. Sood. The technique can help retrain people with tendencies for emotional reactivity in stressful situations; additionally, the focus on the present and on observation, rather than judgment, may help avoid maladaptive rumination.
To see how mindfulness in everyday life could affect the burden of menopausal symptoms, Dr. Sood and her collaborators designed an observational, cross-sectional study of 1,744 women aged 40-64 years.
The investigators used three scales in their assessments. The first, the Menopause Rating Scale (MRS), is an 11-item scale ranging from 0 to 44 that assesses psychological, somatovegetative, and urogenital domains. The second, the Perceived Stress Scale 4 (PSS-4), is a four-item scale that is a global measure of stress over the last 4 weeks, with tallied scores in the 0-16 range. Finally, the Mindful Attention Awareness Scale (MAAS) is a 15-item scale that captures how frequently respondents are in a mindful state during their daily life, with higher scores meaning more mindfulness.
The 1,744 women were seen in a women’s health clinic over the period of one year. Participants were a mean 53.4 years old (standard deviation, 6.1 years). Almost all were white (93%), most were married (82.7%), and most also had at least a 4-year college degree (64.6%) and were employed (65.3%).
The investigators mapped each scale against each of the others, which yielded three plots. In the first, higher MAAS scores were correlated with lower MRS scores (correlation, –0.49; P less than .001), which means that more time in a mindful state was associated with less severe menopausal symptoms.
In the second plot, lower MRS scores were associated with lower PSS-4 scores (correlation, 0.55; P less than .001). The last plot mapped PSS-4 scores against MAAS scores, showing that higher MAAS scores were correlated with lower PSS-4 scores, which means that more time in a mindful state was also associated with less perceived stress (correlation, –0.53; P less than .001).
Most of these associations remained statistically significant after multivariable linear regression analysis and breaking out the subscales of the MRS. Only the association between higher MAAS scores and the somatovegetative domain of the PSS-4 lost significance (P = 0.44).
Next, Dr. Sood and her collaborators probed how higher perceived stress, as measured by higher PSS-4 scores, altered the effects that mindful activity had on menopausal symptoms (as measured by the MRS).
The effect of mindfulness became stronger in the milieu of higher perceived stress. At a relatively low PSS-4 value of 4, the MRS score dropped 1.53 points for each one-point increase in the MAAS total score. However, with a PSS-4 score of 12, the decrease in MRS was 2.27 points for each one-point increase in MAAS, and with the maximum perceived stress score of 16, the MRS fell 2.64 points for each one-point increase in the MAAS score.
These findings are set against the backdrop of previous literature linking mindfulness to positive health behaviors and outcomes, she said, noting that work looking specifically at mindfulness-based stress reduction in peri- and postmenopausal women showed a halving of symptoms and improved quality of life.
Dr. Sood said that the present study was observational only, noting that it looked only at time spent in a mindful state in an untrained cohort of women in midlife. “Trait, or dispositional, mindfulness appears to be protective against stress and symptoms in midlife women,” she commented. “More mindful women may be choosing to shift their attention to more pleasant aspects of life, rather than their symptoms.”
“If you allow me to speculate a bit,” Dr. Sood continued, “the underpinnings of psychological symptoms rest in threat-focused attention and emotional reactivity – so the mindfulness approach appears to fit very well to impact such a change.”
Mindfulness, she added, “might be a tool to impact the emotional component of the overall experience, thereby decreasing the total suffering.” However, she noted that what’s needed are studies with a more heterogeneous population, as well as ones designed to tease out causality. Still, “the current study adds to the wealth of data supporting the role of mindfulness in various settings for impacting positive change in health and behaviors.”
Dr. Sood reported that she has ownership stake in the Global Center for Resiliency and Well-Being.
SOURCE: Sood R et al. NAMS 2018, Top-Scoring Abstract Session.
An observational Furthermore, mindfulness had the greatest positive effect on menopausal symptoms for those women with the highest self-reported stress levels.
“In this cross-sectional study, mindfulness was associated with lower menopausal symptom burden. In women with higher stress, the magnitude of association between mindfulness and menopausal symptoms appeared more robust,” said Richa Sood, MD, speaking at the annual meeting of the North American Menopause Society.
Menopausal symptoms can exist alongside many other midlife issues because women often are trying to keep many balls in the air: This age group may be facing aging parents, a household with teenagers, and work-related pressures, she noted.
Thus, menopausal symptoms can be amplified by stressors. New mood problems – or worsening of preexisting ones – can interfere with work productivity and negatively affect relationships. Life satisfaction can take a steep dive during midlife for some women, said Dr. Sood of the Mayo Clinic, Rochester, Minn.
Could mindfulness be effective for stress management in this complex landscape of physiological and lifespan changes? “Mindfulness is paying attention,” said Dr. Sood. Practitioners of mindfulness focus on purposeful attention, staying in the present moment, and avoiding judgment.
Mindfulness may work as a stress-management tool for a variety of reasons, said Dr. Sood. The technique can help retrain people with tendencies for emotional reactivity in stressful situations; additionally, the focus on the present and on observation, rather than judgment, may help avoid maladaptive rumination.
To see how mindfulness in everyday life could affect the burden of menopausal symptoms, Dr. Sood and her collaborators designed an observational, cross-sectional study of 1,744 women aged 40-64 years.
The investigators used three scales in their assessments. The first, the Menopause Rating Scale (MRS), is an 11-item scale ranging from 0 to 44 that assesses psychological, somatovegetative, and urogenital domains. The second, the Perceived Stress Scale 4 (PSS-4), is a four-item scale that is a global measure of stress over the last 4 weeks, with tallied scores in the 0-16 range. Finally, the Mindful Attention Awareness Scale (MAAS) is a 15-item scale that captures how frequently respondents are in a mindful state during their daily life, with higher scores meaning more mindfulness.
The 1,744 women were seen in a women’s health clinic over the period of one year. Participants were a mean 53.4 years old (standard deviation, 6.1 years). Almost all were white (93%), most were married (82.7%), and most also had at least a 4-year college degree (64.6%) and were employed (65.3%).
The investigators mapped each scale against each of the others, which yielded three plots. In the first, higher MAAS scores were correlated with lower MRS scores (correlation, –0.49; P less than .001), which means that more time in a mindful state was associated with less severe menopausal symptoms.
In the second plot, lower MRS scores were associated with lower PSS-4 scores (correlation, 0.55; P less than .001). The last plot mapped PSS-4 scores against MAAS scores, showing that higher MAAS scores were correlated with lower PSS-4 scores, which means that more time in a mindful state was also associated with less perceived stress (correlation, –0.53; P less than .001).
Most of these associations remained statistically significant after multivariable linear regression analysis and breaking out the subscales of the MRS. Only the association between higher MAAS scores and the somatovegetative domain of the PSS-4 lost significance (P = 0.44).
Next, Dr. Sood and her collaborators probed how higher perceived stress, as measured by higher PSS-4 scores, altered the effects that mindful activity had on menopausal symptoms (as measured by the MRS).
The effect of mindfulness became stronger in the milieu of higher perceived stress. At a relatively low PSS-4 value of 4, the MRS score dropped 1.53 points for each one-point increase in the MAAS total score. However, with a PSS-4 score of 12, the decrease in MRS was 2.27 points for each one-point increase in MAAS, and with the maximum perceived stress score of 16, the MRS fell 2.64 points for each one-point increase in the MAAS score.
These findings are set against the backdrop of previous literature linking mindfulness to positive health behaviors and outcomes, she said, noting that work looking specifically at mindfulness-based stress reduction in peri- and postmenopausal women showed a halving of symptoms and improved quality of life.
Dr. Sood said that the present study was observational only, noting that it looked only at time spent in a mindful state in an untrained cohort of women in midlife. “Trait, or dispositional, mindfulness appears to be protective against stress and symptoms in midlife women,” she commented. “More mindful women may be choosing to shift their attention to more pleasant aspects of life, rather than their symptoms.”
“If you allow me to speculate a bit,” Dr. Sood continued, “the underpinnings of psychological symptoms rest in threat-focused attention and emotional reactivity – so the mindfulness approach appears to fit very well to impact such a change.”
Mindfulness, she added, “might be a tool to impact the emotional component of the overall experience, thereby decreasing the total suffering.” However, she noted that what’s needed are studies with a more heterogeneous population, as well as ones designed to tease out causality. Still, “the current study adds to the wealth of data supporting the role of mindfulness in various settings for impacting positive change in health and behaviors.”
Dr. Sood reported that she has ownership stake in the Global Center for Resiliency and Well-Being.
SOURCE: Sood R et al. NAMS 2018, Top-Scoring Abstract Session.
FROM NAMS 2018
Key clinical point: Time spent in a mindful state was associated with fewer menopause symptoms.
Major finding: With maximum stress, each 1-point increase in mindfulness was associated with a 2.64-point drop in menopausal symptoms.
Study details: A cross-sectional, single-center study of 1,744 women aged 40-64 years.
Disclosures: Dr. Sood reported that she has ownership stake in the Global Center for Resiliency and Well-Being.
Source: Sood R et al. NAMS 2018, Top-Scoring Abstract Session.
Delayed pushing during labor does not benefit mother or baby, study finds
according to the results of a randomized trial.
“The optimal technique for managing maternal pushing during the second stage of labor is unknown,” wrote Alison G. Cahill, MD, of Washington University, St. Louis, and her coauthors, who published their study in JAMA on Oct. 9. “The two most common approaches to the second stage of labor management are to either initiate pushing with uterine contractions once complete cervical dilation occurs (immediate pushing) or to allow for spontaneous descent (delayed pushing),” they noted. “Both approaches are commonly used, and neither is considered the gold standard.”
They addressed this question in the multicenter trial of nulliparous women (mean age, 26.5 years) who, during May 2014 to December 2017, were at or past 37 weeks’ gestation and had received neuraxial analgesia. The primary outcome was the rate of spontaneous vaginal delivery; secondary outcomes included maternal and neonatal morbidity outcomes. When they reached complete cervical dilation, women were randomized to immediate pushing or delayed pushing, in which they were instructed to wait 60 minutes.
The study was terminated after the data and safety monitoring board conducted a planned interim analysis; the analysis found futility in the delayed pushing group and raised concerns about increased morbidity in that group.
Among the 1,031 women in the immediate pushing group, the rate of spontaneous vaginal delivery was 85.9%; the rate was 86.5% among the 1,041 women in the delayed pushing group (P = .67).
The mean duration of the second stage of labor was significantly shorter in the immediate pushing group (102.4 minutes), compared with that seen in the delayed pushing group (134.2 minutes; P less than .001). The mean duration of active pushing was significantly longer in the immediate pushing group (83.7 minutes), compared with that seen in the delayed pushing group (74.5 minutes; P less than .001).
In terms of secondary outcomes, rates of postpartum hemorrhage were lower in the immediate pushing group (2.3%), compared with the rate among those in the delayed pushing group (4%; P = .03). During the second stage of labor, chorioamnionitis was significantly more common among women in the delayed pushing group (9.1%), compared with rate among women in the immediate pushing group (6.7%; P = .005). There was no significant difference between the two groups in the rates of a composite neonatal morbidity outcome (which included birth injury, respiratory distress, and neonatal acidemia), which was 7.3% in the immediate pushing group and 9.9% in the delayed pushing group. There were no neonatal deaths.
Among prespecified exploratory outcomes, the rates of neonatal acidemia and suspected neonatal sepsis were significantly higher in the delayed pushing group, whereas the rate of third-degree perineal lacerations was significantly higher in the immediate pushing group.
“The finding of no effect on spontaneous vaginal delivery for pushing timing during the second stage of labor and the evidence suggesting increased maternal and neonatal complications in the delayed pushing group support the view that women immediately pushing after complete cervical dilation may be preferred because women without neuraxial analgesia reflexively push immediately,” the authors pointed out. Their results, they concluded, “may help inform decisions about the preferred timing of second stage pushing efforts when considered with other maternal and neonatal outcomes.”
They noted that the trial had several limitations, including the unblinded design, which raised the possibility of bias that may have influenced the management of patients or diagnoses.
The authors had no disclosures. The study was supported by a grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and by funding from the department of obstetrics and gynecology at Washington University, St. Louis.
SOURCE: Cahill AG et al. JAMA. 2018;320(14):1444-54.
Of the almost 4 million births in the United States each year, 68% are vaginal deliveries, which illustrates how important it is to have additional evidence to guide the management of labor, Jeffrey D. Sperling, MD, and Dana R. Gossett, MD, wrote in an accompanying editorial. They noted that, despite a lack of blinding and other limitations, as well as the fact there is no one risk-free solution regarding labor management or route of delivery, the results of this study have improved the understanding “of the risks and benefits of different strategies of labor management.”
The study, they added, “presents the only contemporary level 1 evidence available on the topic of whether the timing of pushing in the second stage of labor can have an effect on outcomes.”
The data “contribute to a growing body of literature on how to optimally manage labor in an evidenced-based fashion and improve perinatal outcomes without compromising maternal satisfaction,” they wrote. They recommended that future research should include exploring the effects and outcomes of delaying pushing among multiparous women, women with a previous cesarean delivery, and women who have not received epidural analgesia.
Dr. Sperling and Dr. Gossett are with the department of obstetrics, gynecology, and reproductive sciences at the University of California, San Francisco. Dr. Gossett reported serving as a consultant to Bayer Pharmaceuticals. No other disclosures were reported (JAMA. 2018;320[14]:1439-40).
Of the almost 4 million births in the United States each year, 68% are vaginal deliveries, which illustrates how important it is to have additional evidence to guide the management of labor, Jeffrey D. Sperling, MD, and Dana R. Gossett, MD, wrote in an accompanying editorial. They noted that, despite a lack of blinding and other limitations, as well as the fact there is no one risk-free solution regarding labor management or route of delivery, the results of this study have improved the understanding “of the risks and benefits of different strategies of labor management.”
The study, they added, “presents the only contemporary level 1 evidence available on the topic of whether the timing of pushing in the second stage of labor can have an effect on outcomes.”
The data “contribute to a growing body of literature on how to optimally manage labor in an evidenced-based fashion and improve perinatal outcomes without compromising maternal satisfaction,” they wrote. They recommended that future research should include exploring the effects and outcomes of delaying pushing among multiparous women, women with a previous cesarean delivery, and women who have not received epidural analgesia.
Dr. Sperling and Dr. Gossett are with the department of obstetrics, gynecology, and reproductive sciences at the University of California, San Francisco. Dr. Gossett reported serving as a consultant to Bayer Pharmaceuticals. No other disclosures were reported (JAMA. 2018;320[14]:1439-40).
Of the almost 4 million births in the United States each year, 68% are vaginal deliveries, which illustrates how important it is to have additional evidence to guide the management of labor, Jeffrey D. Sperling, MD, and Dana R. Gossett, MD, wrote in an accompanying editorial. They noted that, despite a lack of blinding and other limitations, as well as the fact there is no one risk-free solution regarding labor management or route of delivery, the results of this study have improved the understanding “of the risks and benefits of different strategies of labor management.”
The study, they added, “presents the only contemporary level 1 evidence available on the topic of whether the timing of pushing in the second stage of labor can have an effect on outcomes.”
The data “contribute to a growing body of literature on how to optimally manage labor in an evidenced-based fashion and improve perinatal outcomes without compromising maternal satisfaction,” they wrote. They recommended that future research should include exploring the effects and outcomes of delaying pushing among multiparous women, women with a previous cesarean delivery, and women who have not received epidural analgesia.
Dr. Sperling and Dr. Gossett are with the department of obstetrics, gynecology, and reproductive sciences at the University of California, San Francisco. Dr. Gossett reported serving as a consultant to Bayer Pharmaceuticals. No other disclosures were reported (JAMA. 2018;320[14]:1439-40).
according to the results of a randomized trial.
“The optimal technique for managing maternal pushing during the second stage of labor is unknown,” wrote Alison G. Cahill, MD, of Washington University, St. Louis, and her coauthors, who published their study in JAMA on Oct. 9. “The two most common approaches to the second stage of labor management are to either initiate pushing with uterine contractions once complete cervical dilation occurs (immediate pushing) or to allow for spontaneous descent (delayed pushing),” they noted. “Both approaches are commonly used, and neither is considered the gold standard.”
They addressed this question in the multicenter trial of nulliparous women (mean age, 26.5 years) who, during May 2014 to December 2017, were at or past 37 weeks’ gestation and had received neuraxial analgesia. The primary outcome was the rate of spontaneous vaginal delivery; secondary outcomes included maternal and neonatal morbidity outcomes. When they reached complete cervical dilation, women were randomized to immediate pushing or delayed pushing, in which they were instructed to wait 60 minutes.
The study was terminated after the data and safety monitoring board conducted a planned interim analysis; the analysis found futility in the delayed pushing group and raised concerns about increased morbidity in that group.
Among the 1,031 women in the immediate pushing group, the rate of spontaneous vaginal delivery was 85.9%; the rate was 86.5% among the 1,041 women in the delayed pushing group (P = .67).
The mean duration of the second stage of labor was significantly shorter in the immediate pushing group (102.4 minutes), compared with that seen in the delayed pushing group (134.2 minutes; P less than .001). The mean duration of active pushing was significantly longer in the immediate pushing group (83.7 minutes), compared with that seen in the delayed pushing group (74.5 minutes; P less than .001).
In terms of secondary outcomes, rates of postpartum hemorrhage were lower in the immediate pushing group (2.3%), compared with the rate among those in the delayed pushing group (4%; P = .03). During the second stage of labor, chorioamnionitis was significantly more common among women in the delayed pushing group (9.1%), compared with rate among women in the immediate pushing group (6.7%; P = .005). There was no significant difference between the two groups in the rates of a composite neonatal morbidity outcome (which included birth injury, respiratory distress, and neonatal acidemia), which was 7.3% in the immediate pushing group and 9.9% in the delayed pushing group. There were no neonatal deaths.
Among prespecified exploratory outcomes, the rates of neonatal acidemia and suspected neonatal sepsis were significantly higher in the delayed pushing group, whereas the rate of third-degree perineal lacerations was significantly higher in the immediate pushing group.
“The finding of no effect on spontaneous vaginal delivery for pushing timing during the second stage of labor and the evidence suggesting increased maternal and neonatal complications in the delayed pushing group support the view that women immediately pushing after complete cervical dilation may be preferred because women without neuraxial analgesia reflexively push immediately,” the authors pointed out. Their results, they concluded, “may help inform decisions about the preferred timing of second stage pushing efforts when considered with other maternal and neonatal outcomes.”
They noted that the trial had several limitations, including the unblinded design, which raised the possibility of bias that may have influenced the management of patients or diagnoses.
The authors had no disclosures. The study was supported by a grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and by funding from the department of obstetrics and gynecology at Washington University, St. Louis.
SOURCE: Cahill AG et al. JAMA. 2018;320(14):1444-54.
according to the results of a randomized trial.
“The optimal technique for managing maternal pushing during the second stage of labor is unknown,” wrote Alison G. Cahill, MD, of Washington University, St. Louis, and her coauthors, who published their study in JAMA on Oct. 9. “The two most common approaches to the second stage of labor management are to either initiate pushing with uterine contractions once complete cervical dilation occurs (immediate pushing) or to allow for spontaneous descent (delayed pushing),” they noted. “Both approaches are commonly used, and neither is considered the gold standard.”
They addressed this question in the multicenter trial of nulliparous women (mean age, 26.5 years) who, during May 2014 to December 2017, were at or past 37 weeks’ gestation and had received neuraxial analgesia. The primary outcome was the rate of spontaneous vaginal delivery; secondary outcomes included maternal and neonatal morbidity outcomes. When they reached complete cervical dilation, women were randomized to immediate pushing or delayed pushing, in which they were instructed to wait 60 minutes.
The study was terminated after the data and safety monitoring board conducted a planned interim analysis; the analysis found futility in the delayed pushing group and raised concerns about increased morbidity in that group.
Among the 1,031 women in the immediate pushing group, the rate of spontaneous vaginal delivery was 85.9%; the rate was 86.5% among the 1,041 women in the delayed pushing group (P = .67).
The mean duration of the second stage of labor was significantly shorter in the immediate pushing group (102.4 minutes), compared with that seen in the delayed pushing group (134.2 minutes; P less than .001). The mean duration of active pushing was significantly longer in the immediate pushing group (83.7 minutes), compared with that seen in the delayed pushing group (74.5 minutes; P less than .001).
In terms of secondary outcomes, rates of postpartum hemorrhage were lower in the immediate pushing group (2.3%), compared with the rate among those in the delayed pushing group (4%; P = .03). During the second stage of labor, chorioamnionitis was significantly more common among women in the delayed pushing group (9.1%), compared with rate among women in the immediate pushing group (6.7%; P = .005). There was no significant difference between the two groups in the rates of a composite neonatal morbidity outcome (which included birth injury, respiratory distress, and neonatal acidemia), which was 7.3% in the immediate pushing group and 9.9% in the delayed pushing group. There were no neonatal deaths.
Among prespecified exploratory outcomes, the rates of neonatal acidemia and suspected neonatal sepsis were significantly higher in the delayed pushing group, whereas the rate of third-degree perineal lacerations was significantly higher in the immediate pushing group.
“The finding of no effect on spontaneous vaginal delivery for pushing timing during the second stage of labor and the evidence suggesting increased maternal and neonatal complications in the delayed pushing group support the view that women immediately pushing after complete cervical dilation may be preferred because women without neuraxial analgesia reflexively push immediately,” the authors pointed out. Their results, they concluded, “may help inform decisions about the preferred timing of second stage pushing efforts when considered with other maternal and neonatal outcomes.”
They noted that the trial had several limitations, including the unblinded design, which raised the possibility of bias that may have influenced the management of patients or diagnoses.
The authors had no disclosures. The study was supported by a grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and by funding from the department of obstetrics and gynecology at Washington University, St. Louis.
SOURCE: Cahill AG et al. JAMA. 2018;320(14):1444-54.
FROM JAMA
Key clinical point: Delayed pushing during the second stage of labor may not reduce the risk of cesarean delivery and may lengthen the duration of labor.
Major finding: The rate of spontaneous vaginal delivery did not differ between groups (85.9% in the immediate pushing group versus 86.5% in the delayed pushing group).
Study details: A multicenter trial involving 2,414 nulliparous women receiving neuraxial analgesia, who were randomized to immediate pushing or delayed pushing during the second stage of labor.
Disclosures: The study was supported by a grant from the Eunice Kennedy Shriver National Institute of Child Health and Human Development and by funding from the department of obstetrics and gynecology at Washington University, St. Louis.
Source: Cahill AG et al. JAMA. 2018;320(14):1444-54.
Most dermatologic drugs safe for breastfeeding mothers
CHICAGO – A common reason why a women stops breastfeeding is the use of medication her doctor has claimed is unsafe during lactation. But most drugs have little or no effect on an infant’s well-being or milk supply, explained Jenny Eileen Murase, MD, of Palo Alto (Calif.) Foundation Medical Group.
“The bottom line I want you to take away from this [session] is that ,” Dr. Murase told attendees at the American Academy of Dermatology summer meeting. “I really want everyone in this room to understand that most of the time, you should not be recommending that a woman is pumping and dumping her milk or stopping breastfeeding because she’s on an agent.”
Dr. Murase, also affiliated with the University of California, San Francisco, provided an overview of drug safety during lactation for major categories of medications that dermatologists prescribe. She recommended that physicians get a copy of Medications and Mother’s Milk by Thomas Hale, PhD, which she considers the best reference for looking up specific drugs. It categorizes drugs as L1 (safest) to L5 (contraindicated), and L2 as “safer,” L3 as “moderately safe,” and L4 as “possibly hazardous.”
Steroids
Contrary to what many believe, prednisone is not contraindicated in breastfeeding, Dr. Murase said. Instead of advising patients to “pump and dump their milk,” she said, “the only recommendation you need to make is that they wait 4 hours after taking the medicine to breastfeed.” For example, a mother can take prednisone before bed and then wake 4 hours later to nurse. Higher doses, such as more than 40 mg daily over long periods, may have the potential to affect growth and development, but more typical doses don’t pose the same risk.
Topical steroids (except for those that are class 1) also are safe to apply directly to the nipple in breastfeeding women, she noted.
Biologics and immunosuppressants
One of the few medications that are contraindicated are topical pimecrolimus and tacrolimus if applied directly to the nipple, since “oral consumption in the infant could be significant,” Dr. Murase said.
Biologics, on the other hand, are not a concern during lactation. “They have low oral bioavailability because of their large molecular size,” and are broken down in the stomach “in a proteolytic environment,” Dr. Murase explained. The CRADLE study, for example, examined the concentration of certolizumab (Cimzia) in mothers’ mature breast milk and found the highest concentration to be just 0.077 mcg/mL, resulting in an average daily infant dose of less than 0.01 mg/kg per day.
Antihistamines and cosmetic topicals
The major antihistamines – brompheniramine, chlorpheniramine, diphenhydramine, hydroxyzine, cetirizine, fexofenadine and loratadine – are likewise safe as L1-L3 drugs. It is preferable to prescribe nonsedating antihistamines, opting for loratadine as the first-line choice. But dermatologists should be reassured that no data support concerns about milk supply reduction from antihistamines, Dr. Murase said.
It’s best to avoid cosmetic topical products, but hydroquinone (L3), topical minoxidil (L2), and botulinum toxin A (L3) do not pose significant risk to the infant. Neither do the anesthetics lidocaine (L2) and epinephrine (L1) for breastfeeding women who need surgery.
Antibiotics
The vast majority of antibiotics are safe for women to use while breastfeeding, but a few notable exceptions exist, including erythromycin.
“People associate erythromycin as safe in lactation because it’s safe in pregnancy, but that’s not the case,” Dr. Murase pointed out. Erythromycin has been linked to pyloric stenosis in newborns and therefore should be avoided in the early months of breastfeeding. In older infants, however, erythromycin becomes an L1 medication.”
Tetracyclines fall into a borderline category. “Tetracyclines would be fine for a complicated infection,” but should not be used for more than 3 weeks, at which point they are regarded as L4, Dr. Murase said. “So long-term use of the tetracyclines should be avoided.”
Aside from these, topical antibiotics are considered safe. Women taking other oral antibiotics should be monitored for gastrointestinal symptoms or allergic responses.
Antifungals
As for antifungals, topicals are safe, and nystatin and clotrimazole are the best first-line options (both L1). Oral antifungals are similarly fine, with griseofulvin, fluconazole, ketoconazole, itraconazole, and terbinafine all classified as L2 and amphotericin B as L3.
If antifungals or antibiotics are being prescribed for a breast fungal infection or for mastitis, Dr. Murase underscored the importance of not stopping breastfeeding.
“The most important thing is that they continue to actually breastfeed on the affected breast that has the staph infection,” she said. She then reiterated that physicians should “reassure new mothers that the majority of oral and topical medications are safe.”
Dr. Murase disclosed serving on the advisory boards of Dermira, UCB, and Genzyme/Sanofi, and she has consulted for Ferndale and UpToDate.
CHICAGO – A common reason why a women stops breastfeeding is the use of medication her doctor has claimed is unsafe during lactation. But most drugs have little or no effect on an infant’s well-being or milk supply, explained Jenny Eileen Murase, MD, of Palo Alto (Calif.) Foundation Medical Group.
“The bottom line I want you to take away from this [session] is that ,” Dr. Murase told attendees at the American Academy of Dermatology summer meeting. “I really want everyone in this room to understand that most of the time, you should not be recommending that a woman is pumping and dumping her milk or stopping breastfeeding because she’s on an agent.”
Dr. Murase, also affiliated with the University of California, San Francisco, provided an overview of drug safety during lactation for major categories of medications that dermatologists prescribe. She recommended that physicians get a copy of Medications and Mother’s Milk by Thomas Hale, PhD, which she considers the best reference for looking up specific drugs. It categorizes drugs as L1 (safest) to L5 (contraindicated), and L2 as “safer,” L3 as “moderately safe,” and L4 as “possibly hazardous.”
Steroids
Contrary to what many believe, prednisone is not contraindicated in breastfeeding, Dr. Murase said. Instead of advising patients to “pump and dump their milk,” she said, “the only recommendation you need to make is that they wait 4 hours after taking the medicine to breastfeed.” For example, a mother can take prednisone before bed and then wake 4 hours later to nurse. Higher doses, such as more than 40 mg daily over long periods, may have the potential to affect growth and development, but more typical doses don’t pose the same risk.
Topical steroids (except for those that are class 1) also are safe to apply directly to the nipple in breastfeeding women, she noted.
Biologics and immunosuppressants
One of the few medications that are contraindicated are topical pimecrolimus and tacrolimus if applied directly to the nipple, since “oral consumption in the infant could be significant,” Dr. Murase said.
Biologics, on the other hand, are not a concern during lactation. “They have low oral bioavailability because of their large molecular size,” and are broken down in the stomach “in a proteolytic environment,” Dr. Murase explained. The CRADLE study, for example, examined the concentration of certolizumab (Cimzia) in mothers’ mature breast milk and found the highest concentration to be just 0.077 mcg/mL, resulting in an average daily infant dose of less than 0.01 mg/kg per day.
Antihistamines and cosmetic topicals
The major antihistamines – brompheniramine, chlorpheniramine, diphenhydramine, hydroxyzine, cetirizine, fexofenadine and loratadine – are likewise safe as L1-L3 drugs. It is preferable to prescribe nonsedating antihistamines, opting for loratadine as the first-line choice. But dermatologists should be reassured that no data support concerns about milk supply reduction from antihistamines, Dr. Murase said.
It’s best to avoid cosmetic topical products, but hydroquinone (L3), topical minoxidil (L2), and botulinum toxin A (L3) do not pose significant risk to the infant. Neither do the anesthetics lidocaine (L2) and epinephrine (L1) for breastfeeding women who need surgery.
Antibiotics
The vast majority of antibiotics are safe for women to use while breastfeeding, but a few notable exceptions exist, including erythromycin.
“People associate erythromycin as safe in lactation because it’s safe in pregnancy, but that’s not the case,” Dr. Murase pointed out. Erythromycin has been linked to pyloric stenosis in newborns and therefore should be avoided in the early months of breastfeeding. In older infants, however, erythromycin becomes an L1 medication.”
Tetracyclines fall into a borderline category. “Tetracyclines would be fine for a complicated infection,” but should not be used for more than 3 weeks, at which point they are regarded as L4, Dr. Murase said. “So long-term use of the tetracyclines should be avoided.”
Aside from these, topical antibiotics are considered safe. Women taking other oral antibiotics should be monitored for gastrointestinal symptoms or allergic responses.
Antifungals
As for antifungals, topicals are safe, and nystatin and clotrimazole are the best first-line options (both L1). Oral antifungals are similarly fine, with griseofulvin, fluconazole, ketoconazole, itraconazole, and terbinafine all classified as L2 and amphotericin B as L3.
If antifungals or antibiotics are being prescribed for a breast fungal infection or for mastitis, Dr. Murase underscored the importance of not stopping breastfeeding.
“The most important thing is that they continue to actually breastfeed on the affected breast that has the staph infection,” she said. She then reiterated that physicians should “reassure new mothers that the majority of oral and topical medications are safe.”
Dr. Murase disclosed serving on the advisory boards of Dermira, UCB, and Genzyme/Sanofi, and she has consulted for Ferndale and UpToDate.
CHICAGO – A common reason why a women stops breastfeeding is the use of medication her doctor has claimed is unsafe during lactation. But most drugs have little or no effect on an infant’s well-being or milk supply, explained Jenny Eileen Murase, MD, of Palo Alto (Calif.) Foundation Medical Group.
“The bottom line I want you to take away from this [session] is that ,” Dr. Murase told attendees at the American Academy of Dermatology summer meeting. “I really want everyone in this room to understand that most of the time, you should not be recommending that a woman is pumping and dumping her milk or stopping breastfeeding because she’s on an agent.”
Dr. Murase, also affiliated with the University of California, San Francisco, provided an overview of drug safety during lactation for major categories of medications that dermatologists prescribe. She recommended that physicians get a copy of Medications and Mother’s Milk by Thomas Hale, PhD, which she considers the best reference for looking up specific drugs. It categorizes drugs as L1 (safest) to L5 (contraindicated), and L2 as “safer,” L3 as “moderately safe,” and L4 as “possibly hazardous.”
Steroids
Contrary to what many believe, prednisone is not contraindicated in breastfeeding, Dr. Murase said. Instead of advising patients to “pump and dump their milk,” she said, “the only recommendation you need to make is that they wait 4 hours after taking the medicine to breastfeed.” For example, a mother can take prednisone before bed and then wake 4 hours later to nurse. Higher doses, such as more than 40 mg daily over long periods, may have the potential to affect growth and development, but more typical doses don’t pose the same risk.
Topical steroids (except for those that are class 1) also are safe to apply directly to the nipple in breastfeeding women, she noted.
Biologics and immunosuppressants
One of the few medications that are contraindicated are topical pimecrolimus and tacrolimus if applied directly to the nipple, since “oral consumption in the infant could be significant,” Dr. Murase said.
Biologics, on the other hand, are not a concern during lactation. “They have low oral bioavailability because of their large molecular size,” and are broken down in the stomach “in a proteolytic environment,” Dr. Murase explained. The CRADLE study, for example, examined the concentration of certolizumab (Cimzia) in mothers’ mature breast milk and found the highest concentration to be just 0.077 mcg/mL, resulting in an average daily infant dose of less than 0.01 mg/kg per day.
Antihistamines and cosmetic topicals
The major antihistamines – brompheniramine, chlorpheniramine, diphenhydramine, hydroxyzine, cetirizine, fexofenadine and loratadine – are likewise safe as L1-L3 drugs. It is preferable to prescribe nonsedating antihistamines, opting for loratadine as the first-line choice. But dermatologists should be reassured that no data support concerns about milk supply reduction from antihistamines, Dr. Murase said.
It’s best to avoid cosmetic topical products, but hydroquinone (L3), topical minoxidil (L2), and botulinum toxin A (L3) do not pose significant risk to the infant. Neither do the anesthetics lidocaine (L2) and epinephrine (L1) for breastfeeding women who need surgery.
Antibiotics
The vast majority of antibiotics are safe for women to use while breastfeeding, but a few notable exceptions exist, including erythromycin.
“People associate erythromycin as safe in lactation because it’s safe in pregnancy, but that’s not the case,” Dr. Murase pointed out. Erythromycin has been linked to pyloric stenosis in newborns and therefore should be avoided in the early months of breastfeeding. In older infants, however, erythromycin becomes an L1 medication.”
Tetracyclines fall into a borderline category. “Tetracyclines would be fine for a complicated infection,” but should not be used for more than 3 weeks, at which point they are regarded as L4, Dr. Murase said. “So long-term use of the tetracyclines should be avoided.”
Aside from these, topical antibiotics are considered safe. Women taking other oral antibiotics should be monitored for gastrointestinal symptoms or allergic responses.
Antifungals
As for antifungals, topicals are safe, and nystatin and clotrimazole are the best first-line options (both L1). Oral antifungals are similarly fine, with griseofulvin, fluconazole, ketoconazole, itraconazole, and terbinafine all classified as L2 and amphotericin B as L3.
If antifungals or antibiotics are being prescribed for a breast fungal infection or for mastitis, Dr. Murase underscored the importance of not stopping breastfeeding.
“The most important thing is that they continue to actually breastfeed on the affected breast that has the staph infection,” she said. She then reiterated that physicians should “reassure new mothers that the majority of oral and topical medications are safe.”
Dr. Murase disclosed serving on the advisory boards of Dermira, UCB, and Genzyme/Sanofi, and she has consulted for Ferndale and UpToDate.
EXPERT ANALYSIS FROM SUMMER AAD 2018
FDA expands approval of 9-valent HPV vaccine
The , men and women aged 27-45 years, the Food and Drug Administration announced on Oct. 5.
The vaccine (Gardasil 9) was previously approved for those aged 9-26 years.
The approval “represents an important opportunity to help prevent HPV-related diseases and cancers in a broader age range,” Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research, said in the FDA statement announcing the approval.
“The Centers for Disease Control and Prevention has stated that HPV vaccination prior to becoming infected with the HPV types covered by the vaccine has the potential to prevent more than 90 percent of these cancers, or 31,200 cases every year, from ever developing,” he added.
Gardasil 9, approved in 2014, covers the four HPV types included in the original Gardasil vaccine approved in 2006, plus five additional HPV types.
The approval is based on the results of a study and follow-up of about 3,200 women aged 27-45 years, followed for an average of 3.5 years, which found that the vaccine was 88% percent effective “in the prevention of a combined endpoint of persistent infection, genital warts, vulvar and vaginal precancerous lesions, cervical precancerous lesions, and cervical cancer related to HPV types covered by the vaccine,” according to the FDA. The vaccine’s effectiveness in men in this age group is “inferred” from these results and from data on Gardasil in men aged 16-26 years, as well as “immunogenicity data from a clinical trial in which 150 men, 27 through 45 years of age, received a 3-dose regimen of Gardasil over 6 months,” the FDA statement noted.
Based on safety data in about 13,000 men and women, injection-site pain, swelling, redness, and headaches are the most common adverse reactions associated with Gardasil 9, the statement said. Gardasil 9 is manufactured by Merck.
The , men and women aged 27-45 years, the Food and Drug Administration announced on Oct. 5.
The vaccine (Gardasil 9) was previously approved for those aged 9-26 years.
The approval “represents an important opportunity to help prevent HPV-related diseases and cancers in a broader age range,” Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research, said in the FDA statement announcing the approval.
“The Centers for Disease Control and Prevention has stated that HPV vaccination prior to becoming infected with the HPV types covered by the vaccine has the potential to prevent more than 90 percent of these cancers, or 31,200 cases every year, from ever developing,” he added.
Gardasil 9, approved in 2014, covers the four HPV types included in the original Gardasil vaccine approved in 2006, plus five additional HPV types.
The approval is based on the results of a study and follow-up of about 3,200 women aged 27-45 years, followed for an average of 3.5 years, which found that the vaccine was 88% percent effective “in the prevention of a combined endpoint of persistent infection, genital warts, vulvar and vaginal precancerous lesions, cervical precancerous lesions, and cervical cancer related to HPV types covered by the vaccine,” according to the FDA. The vaccine’s effectiveness in men in this age group is “inferred” from these results and from data on Gardasil in men aged 16-26 years, as well as “immunogenicity data from a clinical trial in which 150 men, 27 through 45 years of age, received a 3-dose regimen of Gardasil over 6 months,” the FDA statement noted.
Based on safety data in about 13,000 men and women, injection-site pain, swelling, redness, and headaches are the most common adverse reactions associated with Gardasil 9, the statement said. Gardasil 9 is manufactured by Merck.
The , men and women aged 27-45 years, the Food and Drug Administration announced on Oct. 5.
The vaccine (Gardasil 9) was previously approved for those aged 9-26 years.
The approval “represents an important opportunity to help prevent HPV-related diseases and cancers in a broader age range,” Peter Marks, M.D., Ph.D., director of the FDA’s Center for Biologics Evaluation and Research, said in the FDA statement announcing the approval.
“The Centers for Disease Control and Prevention has stated that HPV vaccination prior to becoming infected with the HPV types covered by the vaccine has the potential to prevent more than 90 percent of these cancers, or 31,200 cases every year, from ever developing,” he added.
Gardasil 9, approved in 2014, covers the four HPV types included in the original Gardasil vaccine approved in 2006, plus five additional HPV types.
The approval is based on the results of a study and follow-up of about 3,200 women aged 27-45 years, followed for an average of 3.5 years, which found that the vaccine was 88% percent effective “in the prevention of a combined endpoint of persistent infection, genital warts, vulvar and vaginal precancerous lesions, cervical precancerous lesions, and cervical cancer related to HPV types covered by the vaccine,” according to the FDA. The vaccine’s effectiveness in men in this age group is “inferred” from these results and from data on Gardasil in men aged 16-26 years, as well as “immunogenicity data from a clinical trial in which 150 men, 27 through 45 years of age, received a 3-dose regimen of Gardasil over 6 months,” the FDA statement noted.
Based on safety data in about 13,000 men and women, injection-site pain, swelling, redness, and headaches are the most common adverse reactions associated with Gardasil 9, the statement said. Gardasil 9 is manufactured by Merck.
For dyspareunia, intravaginal prasterone may work best soon after menopause
Neither age nor previous hormone therapy had statistically significant associations with the effect of intravaginal prasterone on dyspareunia severity, according to a new subgroup analysis of clinical trial data. In a trend that did not reach statistical significance, though, said David F. Archer, MD.
“This was an unexpected finding,” he said in an interview.
In a subgroup analysis of data from two clinical trials of intravaginal prasterone (Intrarosa), Dr. Archer and his colleagues sought to investigate whether age, time since menopause, or any previous use of hormone replacement therapy influenced prasterone’s efficacy in treating dyspareunia.
Dr. Archer and his collaborators pooled data from two prospective, randomized, double-blind, placebo-controlled trials (NCT02013544 and NCT01256684) of intravaginal prasterone dosed at 0.50%, 6.5 mg once daily for 12 weeks; he presented the subgroup analyses at the annual meeting of the North American Menopause Society in San Diego.
For each subgroup, Dr. Archer, a professor of obstetrics and gynecology at Eastern Virginia Medical School, Norfolk, and his coinvestigators compared the mean differences in dyspareunia severity score of women who received prasterone and those who received placebo.
All subgroup analyses used the endpoint of improvement in moderate to severe dyspareunia or whether dyspareunia was the most bothersome symptoms for the women participating in the study. The investigators began by looking at the subgroup of 460 women who were 56 years and older at baseline and compared them with the 180 younger participants.
The 283 older participants who received prasterone saw a decrease of 0.36 points in a dyspareunia severity score versus a 0.44 point decrease for the 123 women aged 55 and younger who received prasterone, a nonsignificant difference between subgroups. The decrease compared with placebo-takers was significant in both cases, however (P = .0003 and P =.0031, respectively).
Looking at time since menopause, Dr. Archer and his collaborators divided participants into 33 individuals who were 1 or 2 years post menopause, 86 women who were 3-5 years post menopause, and 521 women who had experienced menopause at least 6 years before study baseline.
In this analysis, 22 of the earliest postmenopause women received prasterone, seeing a 1.59 point drop in dyspareunia severity. For the 59 women in the prasterone study arms who were 3-5 year past menopause, the decrease from baseline was 0.59 points. Finally, among the 325 women who received prasterone and experienced menopause 6 or more years ago, the decrease was 0.27 points.
Although there was a numeric difference in the change in dyspareunia score severity among these groups, the differences were not statistically significant, said Dr. Archer. Again, though, those who took prasterone had a significant reduction in dyspareunia severity scores when compared with those taking placebo (P less than .0001, P = .0136, and P = .0024, respectively).
In the prasterone study arms, 184 had previously used hormone therapy, and 222 had not. After 12 weeks of intravaginal prasterone, there was no statistically significant difference between the two subgroups, with a decreases in dyspareunia severity scores of 0.45 and 0.32, respectively. The decreases in severity scores when compared with those among women who took placebo were again statistically significant for both subgroups, however (P = .0002 and P = .0057, respectively).
Prasterone is a steroid that is also known as dehydroepiandrosterone (DHEA) and is an endogenous hormone that is a precursor for estrogens and androgens. Prasterone’s mechanism of action to reduce vulvar and vaginal atrophy is not completely understood, according to the Food and Drug Administration.
“The nonstatistically significant smaller effect on dyspareunia observed when treatment is initiated after a longer period after menopause suggests that a longer treatment period could be needed to achieve optimal benefit and that treatment of dyspareunia should be initiated as early as possible after menopause,” said Dr. Archer.
Dr. Archer reported grant support from and consulting relationships with several pharmaceutical companies, including Endoceutics, the producer of Intrarosa intravaginal prasterone.
Neither age nor previous hormone therapy had statistically significant associations with the effect of intravaginal prasterone on dyspareunia severity, according to a new subgroup analysis of clinical trial data. In a trend that did not reach statistical significance, though, said David F. Archer, MD.
“This was an unexpected finding,” he said in an interview.
In a subgroup analysis of data from two clinical trials of intravaginal prasterone (Intrarosa), Dr. Archer and his colleagues sought to investigate whether age, time since menopause, or any previous use of hormone replacement therapy influenced prasterone’s efficacy in treating dyspareunia.
Dr. Archer and his collaborators pooled data from two prospective, randomized, double-blind, placebo-controlled trials (NCT02013544 and NCT01256684) of intravaginal prasterone dosed at 0.50%, 6.5 mg once daily for 12 weeks; he presented the subgroup analyses at the annual meeting of the North American Menopause Society in San Diego.
For each subgroup, Dr. Archer, a professor of obstetrics and gynecology at Eastern Virginia Medical School, Norfolk, and his coinvestigators compared the mean differences in dyspareunia severity score of women who received prasterone and those who received placebo.
All subgroup analyses used the endpoint of improvement in moderate to severe dyspareunia or whether dyspareunia was the most bothersome symptoms for the women participating in the study. The investigators began by looking at the subgroup of 460 women who were 56 years and older at baseline and compared them with the 180 younger participants.
The 283 older participants who received prasterone saw a decrease of 0.36 points in a dyspareunia severity score versus a 0.44 point decrease for the 123 women aged 55 and younger who received prasterone, a nonsignificant difference between subgroups. The decrease compared with placebo-takers was significant in both cases, however (P = .0003 and P =.0031, respectively).
Looking at time since menopause, Dr. Archer and his collaborators divided participants into 33 individuals who were 1 or 2 years post menopause, 86 women who were 3-5 years post menopause, and 521 women who had experienced menopause at least 6 years before study baseline.
In this analysis, 22 of the earliest postmenopause women received prasterone, seeing a 1.59 point drop in dyspareunia severity. For the 59 women in the prasterone study arms who were 3-5 year past menopause, the decrease from baseline was 0.59 points. Finally, among the 325 women who received prasterone and experienced menopause 6 or more years ago, the decrease was 0.27 points.
Although there was a numeric difference in the change in dyspareunia score severity among these groups, the differences were not statistically significant, said Dr. Archer. Again, though, those who took prasterone had a significant reduction in dyspareunia severity scores when compared with those taking placebo (P less than .0001, P = .0136, and P = .0024, respectively).
In the prasterone study arms, 184 had previously used hormone therapy, and 222 had not. After 12 weeks of intravaginal prasterone, there was no statistically significant difference between the two subgroups, with a decreases in dyspareunia severity scores of 0.45 and 0.32, respectively. The decreases in severity scores when compared with those among women who took placebo were again statistically significant for both subgroups, however (P = .0002 and P = .0057, respectively).
Prasterone is a steroid that is also known as dehydroepiandrosterone (DHEA) and is an endogenous hormone that is a precursor for estrogens and androgens. Prasterone’s mechanism of action to reduce vulvar and vaginal atrophy is not completely understood, according to the Food and Drug Administration.
“The nonstatistically significant smaller effect on dyspareunia observed when treatment is initiated after a longer period after menopause suggests that a longer treatment period could be needed to achieve optimal benefit and that treatment of dyspareunia should be initiated as early as possible after menopause,” said Dr. Archer.
Dr. Archer reported grant support from and consulting relationships with several pharmaceutical companies, including Endoceutics, the producer of Intrarosa intravaginal prasterone.
Neither age nor previous hormone therapy had statistically significant associations with the effect of intravaginal prasterone on dyspareunia severity, according to a new subgroup analysis of clinical trial data. In a trend that did not reach statistical significance, though, said David F. Archer, MD.
“This was an unexpected finding,” he said in an interview.
In a subgroup analysis of data from two clinical trials of intravaginal prasterone (Intrarosa), Dr. Archer and his colleagues sought to investigate whether age, time since menopause, or any previous use of hormone replacement therapy influenced prasterone’s efficacy in treating dyspareunia.
Dr. Archer and his collaborators pooled data from two prospective, randomized, double-blind, placebo-controlled trials (NCT02013544 and NCT01256684) of intravaginal prasterone dosed at 0.50%, 6.5 mg once daily for 12 weeks; he presented the subgroup analyses at the annual meeting of the North American Menopause Society in San Diego.
For each subgroup, Dr. Archer, a professor of obstetrics and gynecology at Eastern Virginia Medical School, Norfolk, and his coinvestigators compared the mean differences in dyspareunia severity score of women who received prasterone and those who received placebo.
All subgroup analyses used the endpoint of improvement in moderate to severe dyspareunia or whether dyspareunia was the most bothersome symptoms for the women participating in the study. The investigators began by looking at the subgroup of 460 women who were 56 years and older at baseline and compared them with the 180 younger participants.
The 283 older participants who received prasterone saw a decrease of 0.36 points in a dyspareunia severity score versus a 0.44 point decrease for the 123 women aged 55 and younger who received prasterone, a nonsignificant difference between subgroups. The decrease compared with placebo-takers was significant in both cases, however (P = .0003 and P =.0031, respectively).
Looking at time since menopause, Dr. Archer and his collaborators divided participants into 33 individuals who were 1 or 2 years post menopause, 86 women who were 3-5 years post menopause, and 521 women who had experienced menopause at least 6 years before study baseline.
In this analysis, 22 of the earliest postmenopause women received prasterone, seeing a 1.59 point drop in dyspareunia severity. For the 59 women in the prasterone study arms who were 3-5 year past menopause, the decrease from baseline was 0.59 points. Finally, among the 325 women who received prasterone and experienced menopause 6 or more years ago, the decrease was 0.27 points.
Although there was a numeric difference in the change in dyspareunia score severity among these groups, the differences were not statistically significant, said Dr. Archer. Again, though, those who took prasterone had a significant reduction in dyspareunia severity scores when compared with those taking placebo (P less than .0001, P = .0136, and P = .0024, respectively).
In the prasterone study arms, 184 had previously used hormone therapy, and 222 had not. After 12 weeks of intravaginal prasterone, there was no statistically significant difference between the two subgroups, with a decreases in dyspareunia severity scores of 0.45 and 0.32, respectively. The decreases in severity scores when compared with those among women who took placebo were again statistically significant for both subgroups, however (P = .0002 and P = .0057, respectively).
Prasterone is a steroid that is also known as dehydroepiandrosterone (DHEA) and is an endogenous hormone that is a precursor for estrogens and androgens. Prasterone’s mechanism of action to reduce vulvar and vaginal atrophy is not completely understood, according to the Food and Drug Administration.
“The nonstatistically significant smaller effect on dyspareunia observed when treatment is initiated after a longer period after menopause suggests that a longer treatment period could be needed to achieve optimal benefit and that treatment of dyspareunia should be initiated as early as possible after menopause,” said Dr. Archer.
Dr. Archer reported grant support from and consulting relationships with several pharmaceutical companies, including Endoceutics, the producer of Intrarosa intravaginal prasterone.
FROM NAMS 2018
Key clinical point: Dyspareunia improvement was numerically, but not statistically, better soon after menopause.
Major finding: Dyspareunia scores dropped 1.59 points for those within 2 years of menopause, and 0.27 points for those 6 or more years post menopause.
Study details: Subgroup analysis of 640 postmenopausal women taking part in two clinical trials.
Disclosures: Dr. Archer reported receiving support from several pharmaceutical companies, including Endoceutics, the manufacturer of Intrarosa intravaginal prasterone.