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Multiple sclerosis may not flare up after pregnancy
PHILADELPHIA – according to a study to be presented at the annual meeting of the American Academy of Neurology.
“We did not observe any rebound disease activity,” said Annette Langer-Gould, MD, PhD, and her research colleagues in their report.
The findings contrast with those of 20-year-old studies that first identified a lower risk of relapse during pregnancy but signficant rebound disease activity in the early postpartum period. The initial studies were conducted before disease-modifying treatments (DMTs) were available and before neurologists used MRI to help diagnose MS after one attack, noted Dr. Langer-Gould in a statement.
In the large, contemporary cohort of patients with MS, the annualized relapse rate was 0.39 pre-pregnancy, 0.07-0.14 during pregnancy, 0.27 in the first 3 months postpartum, and 0.37 at 4-6 months postpartum. Exclusive breastfeeding significantly reduced the risk of postpartum relapses by 42% (adjusted hazard ratio = 0.58). Women who supplemented breast milk with formula within 2 months of delivery had the same risk of relapse as women who did not breastfeed, however.
“These results are exciting, as MS is more common among women of childbearing age than in any other group,” said Dr. Langer-Gould, who is regional lead for clinical and translational neuroscience at Kaiser Permanente Southern California in Pasadena, in the statement. “This shows us that women with MS today can have children, breastfeed, and resume their treatment without experiencing an increased risk of relapses during the postpartum period.”
To describe the risk of postpartum relapses and identify potential risk factors for relapse the investigators analyzed prospectively collected data from 466 pregnancies among 375 women with MS from the complete electronic health record at Kaiser Permanente Southern and Northern California between 2008 and 2016. The researchers also used surveys to collect information about treatment history, breastfeeding, and relapses. They used multivariable models to account for intraclass clustering and disease severity.
In 38% of the pregnancies, the mother had not received treatment in the year before conception. In 14.6%, the mother had a clinically isolated syndrome; in 8.4%, the mother had a relapse during pregnancy.
Resuming modestly effective DMTs such as interferon-betas and glatiramer acetate did not affect relapse risk.
In the postpartum year, 26.4% of mothers relapsed, 87% breastfed, 35% breastfed exclusively, and 41.2% resumed using DMT.
The lack of rebound disease activity in this cohort could be related to the high rate of exclusive breastfeeding, as well as the inclusion of women from a population-based setting and the inclusion of women who had incorrectly been diagnosed with MS after a single relapse. Few patients in this cohort had been treated with natalizumab or fingolimod prior to pregnancy, so the study does not address the potential harms of stopping these drugs or the potential benefits of breastfeeding among patients treated with these drugs.
The study was supported by the National Multiple Sclerosis Society. The researchers had no disclosures.
SOURCE: Langer-Gould A et al. AAN 2019, Abstract S6.007.
PHILADELPHIA – according to a study to be presented at the annual meeting of the American Academy of Neurology.
“We did not observe any rebound disease activity,” said Annette Langer-Gould, MD, PhD, and her research colleagues in their report.
The findings contrast with those of 20-year-old studies that first identified a lower risk of relapse during pregnancy but signficant rebound disease activity in the early postpartum period. The initial studies were conducted before disease-modifying treatments (DMTs) were available and before neurologists used MRI to help diagnose MS after one attack, noted Dr. Langer-Gould in a statement.
In the large, contemporary cohort of patients with MS, the annualized relapse rate was 0.39 pre-pregnancy, 0.07-0.14 during pregnancy, 0.27 in the first 3 months postpartum, and 0.37 at 4-6 months postpartum. Exclusive breastfeeding significantly reduced the risk of postpartum relapses by 42% (adjusted hazard ratio = 0.58). Women who supplemented breast milk with formula within 2 months of delivery had the same risk of relapse as women who did not breastfeed, however.
“These results are exciting, as MS is more common among women of childbearing age than in any other group,” said Dr. Langer-Gould, who is regional lead for clinical and translational neuroscience at Kaiser Permanente Southern California in Pasadena, in the statement. “This shows us that women with MS today can have children, breastfeed, and resume their treatment without experiencing an increased risk of relapses during the postpartum period.”
To describe the risk of postpartum relapses and identify potential risk factors for relapse the investigators analyzed prospectively collected data from 466 pregnancies among 375 women with MS from the complete electronic health record at Kaiser Permanente Southern and Northern California between 2008 and 2016. The researchers also used surveys to collect information about treatment history, breastfeeding, and relapses. They used multivariable models to account for intraclass clustering and disease severity.
In 38% of the pregnancies, the mother had not received treatment in the year before conception. In 14.6%, the mother had a clinically isolated syndrome; in 8.4%, the mother had a relapse during pregnancy.
Resuming modestly effective DMTs such as interferon-betas and glatiramer acetate did not affect relapse risk.
In the postpartum year, 26.4% of mothers relapsed, 87% breastfed, 35% breastfed exclusively, and 41.2% resumed using DMT.
The lack of rebound disease activity in this cohort could be related to the high rate of exclusive breastfeeding, as well as the inclusion of women from a population-based setting and the inclusion of women who had incorrectly been diagnosed with MS after a single relapse. Few patients in this cohort had been treated with natalizumab or fingolimod prior to pregnancy, so the study does not address the potential harms of stopping these drugs or the potential benefits of breastfeeding among patients treated with these drugs.
The study was supported by the National Multiple Sclerosis Society. The researchers had no disclosures.
SOURCE: Langer-Gould A et al. AAN 2019, Abstract S6.007.
PHILADELPHIA – according to a study to be presented at the annual meeting of the American Academy of Neurology.
“We did not observe any rebound disease activity,” said Annette Langer-Gould, MD, PhD, and her research colleagues in their report.
The findings contrast with those of 20-year-old studies that first identified a lower risk of relapse during pregnancy but signficant rebound disease activity in the early postpartum period. The initial studies were conducted before disease-modifying treatments (DMTs) were available and before neurologists used MRI to help diagnose MS after one attack, noted Dr. Langer-Gould in a statement.
In the large, contemporary cohort of patients with MS, the annualized relapse rate was 0.39 pre-pregnancy, 0.07-0.14 during pregnancy, 0.27 in the first 3 months postpartum, and 0.37 at 4-6 months postpartum. Exclusive breastfeeding significantly reduced the risk of postpartum relapses by 42% (adjusted hazard ratio = 0.58). Women who supplemented breast milk with formula within 2 months of delivery had the same risk of relapse as women who did not breastfeed, however.
“These results are exciting, as MS is more common among women of childbearing age than in any other group,” said Dr. Langer-Gould, who is regional lead for clinical and translational neuroscience at Kaiser Permanente Southern California in Pasadena, in the statement. “This shows us that women with MS today can have children, breastfeed, and resume their treatment without experiencing an increased risk of relapses during the postpartum period.”
To describe the risk of postpartum relapses and identify potential risk factors for relapse the investigators analyzed prospectively collected data from 466 pregnancies among 375 women with MS from the complete electronic health record at Kaiser Permanente Southern and Northern California between 2008 and 2016. The researchers also used surveys to collect information about treatment history, breastfeeding, and relapses. They used multivariable models to account for intraclass clustering and disease severity.
In 38% of the pregnancies, the mother had not received treatment in the year before conception. In 14.6%, the mother had a clinically isolated syndrome; in 8.4%, the mother had a relapse during pregnancy.
Resuming modestly effective DMTs such as interferon-betas and glatiramer acetate did not affect relapse risk.
In the postpartum year, 26.4% of mothers relapsed, 87% breastfed, 35% breastfed exclusively, and 41.2% resumed using DMT.
The lack of rebound disease activity in this cohort could be related to the high rate of exclusive breastfeeding, as well as the inclusion of women from a population-based setting and the inclusion of women who had incorrectly been diagnosed with MS after a single relapse. Few patients in this cohort had been treated with natalizumab or fingolimod prior to pregnancy, so the study does not address the potential harms of stopping these drugs or the potential benefits of breastfeeding among patients treated with these drugs.
The study was supported by the National Multiple Sclerosis Society. The researchers had no disclosures.
SOURCE: Langer-Gould A et al. AAN 2019, Abstract S6.007.
FROM AAN 2019
ACOG guidance addresses cardiac contributors to maternal mortality
NASHVILLE, TENN. – according to new comprehensive guidance from the American College of Obstetricians and Gynecologists.
The toolkit algorithm is called the California Improving Health Care Response to Cardiovascular Disease in Pregnancy and Postpartum Toolkit. It was developed by the Cardiovascular Disease in Pregnancy Postpartum Task Force to serve as a resource for obstetrics, primary care and emergency medicine providers who provide prenatal care or interact with women during the postpartum period. It incldues an overview of clinical assessment and comprehensive management strategies for cardiovascular disease based on risk factors and presenting symptoms.
The guidance also calls for all pregnant and postpartum women with known or suspected CVD to undergo further evaluation by a “Pregnancy Heart Team that includes a cardiologist and maternal–fetal medicine subspecialist, or both, and other subspecialists as necessary.” The guidance was issued in Practice Bulletin 212, Pregnancy and Heart Disease, which is published in the May edition of Obstetrics & Gynecology (Obstet Gynecol. 2019 May;133[5]:e320-e356).
In all, 27 specific recommendations and conclusions relating to screening, diagnosis, and management of CVD for women during the prepregnancy period through the postpartum period are included in the guidance.
ACOG president Lisa Hollier, MD, convened the task force that developed this guidance to address cardiac contributors to maternal mortality, she said during a press briefing at the ACOG annual clinical and scientific meeting.
“When I began my presidency a year ago, my goal was to bring together a multidisciplinary group of clinicians ... to create clinical guidance that would make a difference in the lives of women," said Dr. Hollier, who is also a professor of obstetrics and gynecology at Baylor College of Medicine, Houston. 
Part of her presidential initiative was centered on eliminating preventable maternal death, and this guidance has the potential to make strides toward that goal, she said. When it comes to CVD in pregnancy, “there is so much we can do to prevent negative outcomes and ensure that moms go home with their babies and are around to see them grow up,” she noted.
CVD is the leading cause of death in pregnant women and women in the postpartum period, accounting for 26.5% of U.S. pregnancy-related deaths.
“It’s critical that we as physicians and health care professionals develop expertise in recognizing the signs and symptoms so that we can save women’s lives,” she said in the press breifing. Dr. Hollier also implored her colleagues to “start using this guidance immediately and prevent more women from dying from cardiovascular complications of pregnancy.”
In this video interview, Dr. Hollier further explains the need for the guidance and its potential for improving maternal mortality rates.
Dr. Hollier reported having no relevant disclosures.
SOURCE: Hollier L et al., Obstet Gynecol. 2019 May;133[5]:e320-56.
NASHVILLE, TENN. – according to new comprehensive guidance from the American College of Obstetricians and Gynecologists.
The toolkit algorithm is called the California Improving Health Care Response to Cardiovascular Disease in Pregnancy and Postpartum Toolkit. It was developed by the Cardiovascular Disease in Pregnancy Postpartum Task Force to serve as a resource for obstetrics, primary care and emergency medicine providers who provide prenatal care or interact with women during the postpartum period. It incldues an overview of clinical assessment and comprehensive management strategies for cardiovascular disease based on risk factors and presenting symptoms.
The guidance also calls for all pregnant and postpartum women with known or suspected CVD to undergo further evaluation by a “Pregnancy Heart Team that includes a cardiologist and maternal–fetal medicine subspecialist, or both, and other subspecialists as necessary.” The guidance was issued in Practice Bulletin 212, Pregnancy and Heart Disease, which is published in the May edition of Obstetrics & Gynecology (Obstet Gynecol. 2019 May;133[5]:e320-e356).
In all, 27 specific recommendations and conclusions relating to screening, diagnosis, and management of CVD for women during the prepregnancy period through the postpartum period are included in the guidance.
ACOG president Lisa Hollier, MD, convened the task force that developed this guidance to address cardiac contributors to maternal mortality, she said during a press briefing at the ACOG annual clinical and scientific meeting.
“When I began my presidency a year ago, my goal was to bring together a multidisciplinary group of clinicians ... to create clinical guidance that would make a difference in the lives of women," said Dr. Hollier, who is also a professor of obstetrics and gynecology at Baylor College of Medicine, Houston.
Part of her presidential initiative was centered on eliminating preventable maternal death, and this guidance has the potential to make strides toward that goal, she said. When it comes to CVD in pregnancy, “there is so much we can do to prevent negative outcomes and ensure that moms go home with their babies and are around to see them grow up,” she noted.
CVD is the leading cause of death in pregnant women and women in the postpartum period, accounting for 26.5% of U.S. pregnancy-related deaths.
“It’s critical that we as physicians and health care professionals develop expertise in recognizing the signs and symptoms so that we can save women’s lives,” she said in the press breifing. Dr. Hollier also implored her colleagues to “start using this guidance immediately and prevent more women from dying from cardiovascular complications of pregnancy.”
In this video interview, Dr. Hollier further explains the need for the guidance and its potential for improving maternal mortality rates.
Dr. Hollier reported having no relevant disclosures.
SOURCE: Hollier L et al., Obstet Gynecol. 2019 May;133[5]:e320-56.
NASHVILLE, TENN. – according to new comprehensive guidance from the American College of Obstetricians and Gynecologists.
The toolkit algorithm is called the California Improving Health Care Response to Cardiovascular Disease in Pregnancy and Postpartum Toolkit. It was developed by the Cardiovascular Disease in Pregnancy Postpartum Task Force to serve as a resource for obstetrics, primary care and emergency medicine providers who provide prenatal care or interact with women during the postpartum period. It incldues an overview of clinical assessment and comprehensive management strategies for cardiovascular disease based on risk factors and presenting symptoms.
The guidance also calls for all pregnant and postpartum women with known or suspected CVD to undergo further evaluation by a “Pregnancy Heart Team that includes a cardiologist and maternal–fetal medicine subspecialist, or both, and other subspecialists as necessary.” The guidance was issued in Practice Bulletin 212, Pregnancy and Heart Disease, which is published in the May edition of Obstetrics & Gynecology (Obstet Gynecol. 2019 May;133[5]:e320-e356).
In all, 27 specific recommendations and conclusions relating to screening, diagnosis, and management of CVD for women during the prepregnancy period through the postpartum period are included in the guidance.
ACOG president Lisa Hollier, MD, convened the task force that developed this guidance to address cardiac contributors to maternal mortality, she said during a press briefing at the ACOG annual clinical and scientific meeting.
“When I began my presidency a year ago, my goal was to bring together a multidisciplinary group of clinicians ... to create clinical guidance that would make a difference in the lives of women," said Dr. Hollier, who is also a professor of obstetrics and gynecology at Baylor College of Medicine, Houston.
Part of her presidential initiative was centered on eliminating preventable maternal death, and this guidance has the potential to make strides toward that goal, she said. When it comes to CVD in pregnancy, “there is so much we can do to prevent negative outcomes and ensure that moms go home with their babies and are around to see them grow up,” she noted.
CVD is the leading cause of death in pregnant women and women in the postpartum period, accounting for 26.5% of U.S. pregnancy-related deaths.
“It’s critical that we as physicians and health care professionals develop expertise in recognizing the signs and symptoms so that we can save women’s lives,” she said in the press breifing. Dr. Hollier also implored her colleagues to “start using this guidance immediately and prevent more women from dying from cardiovascular complications of pregnancy.”
In this video interview, Dr. Hollier further explains the need for the guidance and its potential for improving maternal mortality rates.
Dr. Hollier reported having no relevant disclosures.
SOURCE: Hollier L et al., Obstet Gynecol. 2019 May;133[5]:e320-56.
REPORTING FROM ACOG 2019
FDA opts not to ban textured breast implants
The Food and Drug Administration decided to continue to allow U.S. sales of textured breast implants, which have been identified as the cause of a rare but significant cancer, breast implant–associated anaplastic large cell lymphoma.
A statement the agency released on May 2 said “The FDA does not believe that, on the basis of available data and information, the device [textured implants] meets the banning standard set forth in the Federal Food and Drug Cosmetic Act.” roughly half of them in the United States.
In coming to this decision, following 2 days of public testimony and discussions by an advisory committee in late March, the FDA is bucking the path taken by regulatory bodies of the European Union as well as several other counties. The EU acted in December 2018 to produce the equivalent of a ban on sales of textured breast implants marketed by Allergan. Then in April 2019, the French drug and device regulatory agency expanded this ban to textured breast implants sold by five other companies.
During the FDA advisory committee meeting in March, one of the world’s experts on BIA-ALCL, Mark W. Clemens, MD, a plastic surgeon at MD Anderson Cancer Center in Houston, said that of about 500 case reports received by the FDA, not one had involved a confirmed and “pure” episode of BIA-ALCL linked with a smooth breast implant. A team of experts recently reached the same conclusion when reviewing the reported worldwide incidence of BIA-ALCL in a published review (Plast Reconstr Surg. 2019 March;143[3S]:30S-40S).
Despite these reports, the FDA said in its new statement that “While the majority of women who develop BIA-ALCL have had textured implants, there are known cases in women with smooth-surface breast implants, and many reports do not include the surface texture of the implant at the time of diagnosis.” The agency added that it is “focused on strengthening the evidence generated to help inform future regulatory action.” During the March advisory committee meeting, some members of the panel spoke against a marketing ban on textured implants for reasons such as the modest number of reported cases and because of the importance of having a textured implant option available.
The FDA took several other notable steps in its May 2 statement:
The agency formally acknowledged that many breast implant recipients have reported experiencing adverse effects that include chronic fatigue, cognitive issues, and joint and muscle pain. “While the FDA doesn’t have definitive evidence demonstrating breast implants cause these symptoms, the current evidence supports that some women experience systemic symptoms that may resolve when their breast implants are removed.” The agency also cited the term that patients have coined for these symptoms: Breast Implant Illness.
The FDA made a commitment to “take steps to improve the information available to women and health care professionals about the risks of breast implants,” including the risk for BIA-ALCL, the increased risk for this cancer with textured implants, and the risk for systemic symptoms. The agency said it would work with stakeholders on possible changes to breast implant labeling, including a possible boxed warning, and a patient-decision checklist.
The FDA announced a change in how manufacturers will file medical device reports for breast implants. The agency will no longer allow these filings to be “summary” reports and will instead require manufacturers to file full individual medical device reports for each case that will be publicly available, with the intent to make reporting more transparent and complete.
Finally, the FDA announced that it would partner with two U.S. breast implant registries, the PROFILE registry of BIA-ALCL cases, and the National Breast Implant Registry, both run by the Plastic Surgery Foundation.
The FDA did not address in its statement other issues that came up during the March advisory committee hearings, including a panel recommendation to change follow-up imaging from MRI to ultrasound for monitoring women with implants for rupture, and the extensive, off-label use of surgical mesh during breast implant surgery.
The Food and Drug Administration decided to continue to allow U.S. sales of textured breast implants, which have been identified as the cause of a rare but significant cancer, breast implant–associated anaplastic large cell lymphoma.
A statement the agency released on May 2 said “The FDA does not believe that, on the basis of available data and information, the device [textured implants] meets the banning standard set forth in the Federal Food and Drug Cosmetic Act.” roughly half of them in the United States.
In coming to this decision, following 2 days of public testimony and discussions by an advisory committee in late March, the FDA is bucking the path taken by regulatory bodies of the European Union as well as several other counties. The EU acted in December 2018 to produce the equivalent of a ban on sales of textured breast implants marketed by Allergan. Then in April 2019, the French drug and device regulatory agency expanded this ban to textured breast implants sold by five other companies.
During the FDA advisory committee meeting in March, one of the world’s experts on BIA-ALCL, Mark W. Clemens, MD, a plastic surgeon at MD Anderson Cancer Center in Houston, said that of about 500 case reports received by the FDA, not one had involved a confirmed and “pure” episode of BIA-ALCL linked with a smooth breast implant. A team of experts recently reached the same conclusion when reviewing the reported worldwide incidence of BIA-ALCL in a published review (Plast Reconstr Surg. 2019 March;143[3S]:30S-40S).
Despite these reports, the FDA said in its new statement that “While the majority of women who develop BIA-ALCL have had textured implants, there are known cases in women with smooth-surface breast implants, and many reports do not include the surface texture of the implant at the time of diagnosis.” The agency added that it is “focused on strengthening the evidence generated to help inform future regulatory action.” During the March advisory committee meeting, some members of the panel spoke against a marketing ban on textured implants for reasons such as the modest number of reported cases and because of the importance of having a textured implant option available.
The FDA took several other notable steps in its May 2 statement:
The agency formally acknowledged that many breast implant recipients have reported experiencing adverse effects that include chronic fatigue, cognitive issues, and joint and muscle pain. “While the FDA doesn’t have definitive evidence demonstrating breast implants cause these symptoms, the current evidence supports that some women experience systemic symptoms that may resolve when their breast implants are removed.” The agency also cited the term that patients have coined for these symptoms: Breast Implant Illness.
The FDA made a commitment to “take steps to improve the information available to women and health care professionals about the risks of breast implants,” including the risk for BIA-ALCL, the increased risk for this cancer with textured implants, and the risk for systemic symptoms. The agency said it would work with stakeholders on possible changes to breast implant labeling, including a possible boxed warning, and a patient-decision checklist.
The FDA announced a change in how manufacturers will file medical device reports for breast implants. The agency will no longer allow these filings to be “summary” reports and will instead require manufacturers to file full individual medical device reports for each case that will be publicly available, with the intent to make reporting more transparent and complete.
Finally, the FDA announced that it would partner with two U.S. breast implant registries, the PROFILE registry of BIA-ALCL cases, and the National Breast Implant Registry, both run by the Plastic Surgery Foundation.
The FDA did not address in its statement other issues that came up during the March advisory committee hearings, including a panel recommendation to change follow-up imaging from MRI to ultrasound for monitoring women with implants for rupture, and the extensive, off-label use of surgical mesh during breast implant surgery.
The Food and Drug Administration decided to continue to allow U.S. sales of textured breast implants, which have been identified as the cause of a rare but significant cancer, breast implant–associated anaplastic large cell lymphoma.
A statement the agency released on May 2 said “The FDA does not believe that, on the basis of available data and information, the device [textured implants] meets the banning standard set forth in the Federal Food and Drug Cosmetic Act.” roughly half of them in the United States.
In coming to this decision, following 2 days of public testimony and discussions by an advisory committee in late March, the FDA is bucking the path taken by regulatory bodies of the European Union as well as several other counties. The EU acted in December 2018 to produce the equivalent of a ban on sales of textured breast implants marketed by Allergan. Then in April 2019, the French drug and device regulatory agency expanded this ban to textured breast implants sold by five other companies.
During the FDA advisory committee meeting in March, one of the world’s experts on BIA-ALCL, Mark W. Clemens, MD, a plastic surgeon at MD Anderson Cancer Center in Houston, said that of about 500 case reports received by the FDA, not one had involved a confirmed and “pure” episode of BIA-ALCL linked with a smooth breast implant. A team of experts recently reached the same conclusion when reviewing the reported worldwide incidence of BIA-ALCL in a published review (Plast Reconstr Surg. 2019 March;143[3S]:30S-40S).
Despite these reports, the FDA said in its new statement that “While the majority of women who develop BIA-ALCL have had textured implants, there are known cases in women with smooth-surface breast implants, and many reports do not include the surface texture of the implant at the time of diagnosis.” The agency added that it is “focused on strengthening the evidence generated to help inform future regulatory action.” During the March advisory committee meeting, some members of the panel spoke against a marketing ban on textured implants for reasons such as the modest number of reported cases and because of the importance of having a textured implant option available.
The FDA took several other notable steps in its May 2 statement:
The agency formally acknowledged that many breast implant recipients have reported experiencing adverse effects that include chronic fatigue, cognitive issues, and joint and muscle pain. “While the FDA doesn’t have definitive evidence demonstrating breast implants cause these symptoms, the current evidence supports that some women experience systemic symptoms that may resolve when their breast implants are removed.” The agency also cited the term that patients have coined for these symptoms: Breast Implant Illness.
The FDA made a commitment to “take steps to improve the information available to women and health care professionals about the risks of breast implants,” including the risk for BIA-ALCL, the increased risk for this cancer with textured implants, and the risk for systemic symptoms. The agency said it would work with stakeholders on possible changes to breast implant labeling, including a possible boxed warning, and a patient-decision checklist.
The FDA announced a change in how manufacturers will file medical device reports for breast implants. The agency will no longer allow these filings to be “summary” reports and will instead require manufacturers to file full individual medical device reports for each case that will be publicly available, with the intent to make reporting more transparent and complete.
Finally, the FDA announced that it would partner with two U.S. breast implant registries, the PROFILE registry of BIA-ALCL cases, and the National Breast Implant Registry, both run by the Plastic Surgery Foundation.
The FDA did not address in its statement other issues that came up during the March advisory committee hearings, including a panel recommendation to change follow-up imaging from MRI to ultrasound for monitoring women with implants for rupture, and the extensive, off-label use of surgical mesh during breast implant surgery.
HHS finalizes controversial conscience regulation
Health care professionals may not be compelled to provide medical care, including abortion services or even referrals, if they object on religious or moral grounds under a federal regulation finalized May 2.
The regulation also requires health care entities that receive federal funding to alert their employees to their federal conscience rights.
This final rule “replaces a 2011 rule that has proven inadequate, and ensures that HHS implements the full set of tools appropriate for enforcing the conscience protections passed by Congress,” HHS officials said in a statement. “These federal laws protect providers, individuals, and other health care entities from having to provide, participate in, pay for, provide coverage of, or refer for, services such as abortion, sterilization, or assisted suicide. It also includes conscience protections with respect to advance directives.”
The regulation was first proposed in January 2018, shortly after the formation of the Conscience and Religious Freedom Division within the HHS Office of Civil Rights (OCR).
Application of the regulation extends beyond the clinic and hospital. The regulation notes that, on a case-by-case basis, those providing emergency services such as EMTs or even ambulance drivers could be protected should they choose to exercise their conscience and not provide services based on their religious beliefs.
“With this final rule, the Department seeks to educate protected entities and covered entities as to their legal rights and obligations; to encourage individuals and organizations with religious beliefs or moral convictions to enter, or remain in, the health care industry; and to prevent others from being dissuaded from filing complaints due to prior OCR complaint resolutions or sub-regulatory guidance that no reflect the views of the Department,” according to the regulation.
HHS officials denied accusations that the regulation puts the needs of providers over those of patients.
By “protecting a diversity of beliefs among health care providers, these protections ensure that options are available to patients who desire, and would feel most comfortable with, a provider whose religious beliefs or moral convictions match their own. Even where a patient and provider do not share the same religious beliefs or moral convictions, it is not necessarily the case that patients would want providers to be forced to violate their religious beliefs or moral convictions,” according to the regulation.
However, the American Civil Liberties Union and others see the new regulation as license to discriminate.
“Once again, this administration shows itself to be determined to use religious liberty to harm communities it deems less worthy of equal treatment under the law,” Louise Melling, ACLU deputy legal director, said in a statement. “This rule threatens to prevent people from accessing critical medical care and may endanger people’s lives. Religious liberty is a fundamental right, but it does not include the right to discriminate or harm others. Denying patients health care is not religious liberty. Discriminating against patients based on their gender or gender expression is not religious liberty. Medical standards, not religious beliefs, should guide medical care.”
The regulation does not yet have a scheduled publication date in the Federal Register, nor has it been posted as a preview document on the publication’s website. It will become effective 60 days after publication.
Health care professionals may not be compelled to provide medical care, including abortion services or even referrals, if they object on religious or moral grounds under a federal regulation finalized May 2.
The regulation also requires health care entities that receive federal funding to alert their employees to their federal conscience rights.
This final rule “replaces a 2011 rule that has proven inadequate, and ensures that HHS implements the full set of tools appropriate for enforcing the conscience protections passed by Congress,” HHS officials said in a statement. “These federal laws protect providers, individuals, and other health care entities from having to provide, participate in, pay for, provide coverage of, or refer for, services such as abortion, sterilization, or assisted suicide. It also includes conscience protections with respect to advance directives.”
The regulation was first proposed in January 2018, shortly after the formation of the Conscience and Religious Freedom Division within the HHS Office of Civil Rights (OCR).
Application of the regulation extends beyond the clinic and hospital. The regulation notes that, on a case-by-case basis, those providing emergency services such as EMTs or even ambulance drivers could be protected should they choose to exercise their conscience and not provide services based on their religious beliefs.
“With this final rule, the Department seeks to educate protected entities and covered entities as to their legal rights and obligations; to encourage individuals and organizations with religious beliefs or moral convictions to enter, or remain in, the health care industry; and to prevent others from being dissuaded from filing complaints due to prior OCR complaint resolutions or sub-regulatory guidance that no reflect the views of the Department,” according to the regulation.
HHS officials denied accusations that the regulation puts the needs of providers over those of patients.
By “protecting a diversity of beliefs among health care providers, these protections ensure that options are available to patients who desire, and would feel most comfortable with, a provider whose religious beliefs or moral convictions match their own. Even where a patient and provider do not share the same religious beliefs or moral convictions, it is not necessarily the case that patients would want providers to be forced to violate their religious beliefs or moral convictions,” according to the regulation.
However, the American Civil Liberties Union and others see the new regulation as license to discriminate.
“Once again, this administration shows itself to be determined to use religious liberty to harm communities it deems less worthy of equal treatment under the law,” Louise Melling, ACLU deputy legal director, said in a statement. “This rule threatens to prevent people from accessing critical medical care and may endanger people’s lives. Religious liberty is a fundamental right, but it does not include the right to discriminate or harm others. Denying patients health care is not religious liberty. Discriminating against patients based on their gender or gender expression is not religious liberty. Medical standards, not religious beliefs, should guide medical care.”
The regulation does not yet have a scheduled publication date in the Federal Register, nor has it been posted as a preview document on the publication’s website. It will become effective 60 days after publication.
Health care professionals may not be compelled to provide medical care, including abortion services or even referrals, if they object on religious or moral grounds under a federal regulation finalized May 2.
The regulation also requires health care entities that receive federal funding to alert their employees to their federal conscience rights.
This final rule “replaces a 2011 rule that has proven inadequate, and ensures that HHS implements the full set of tools appropriate for enforcing the conscience protections passed by Congress,” HHS officials said in a statement. “These federal laws protect providers, individuals, and other health care entities from having to provide, participate in, pay for, provide coverage of, or refer for, services such as abortion, sterilization, or assisted suicide. It also includes conscience protections with respect to advance directives.”
The regulation was first proposed in January 2018, shortly after the formation of the Conscience and Religious Freedom Division within the HHS Office of Civil Rights (OCR).
Application of the regulation extends beyond the clinic and hospital. The regulation notes that, on a case-by-case basis, those providing emergency services such as EMTs or even ambulance drivers could be protected should they choose to exercise their conscience and not provide services based on their religious beliefs.
“With this final rule, the Department seeks to educate protected entities and covered entities as to their legal rights and obligations; to encourage individuals and organizations with religious beliefs or moral convictions to enter, or remain in, the health care industry; and to prevent others from being dissuaded from filing complaints due to prior OCR complaint resolutions or sub-regulatory guidance that no reflect the views of the Department,” according to the regulation.
HHS officials denied accusations that the regulation puts the needs of providers over those of patients.
By “protecting a diversity of beliefs among health care providers, these protections ensure that options are available to patients who desire, and would feel most comfortable with, a provider whose religious beliefs or moral convictions match their own. Even where a patient and provider do not share the same religious beliefs or moral convictions, it is not necessarily the case that patients would want providers to be forced to violate their religious beliefs or moral convictions,” according to the regulation.
However, the American Civil Liberties Union and others see the new regulation as license to discriminate.
“Once again, this administration shows itself to be determined to use religious liberty to harm communities it deems less worthy of equal treatment under the law,” Louise Melling, ACLU deputy legal director, said in a statement. “This rule threatens to prevent people from accessing critical medical care and may endanger people’s lives. Religious liberty is a fundamental right, but it does not include the right to discriminate or harm others. Denying patients health care is not religious liberty. Discriminating against patients based on their gender or gender expression is not religious liberty. Medical standards, not religious beliefs, should guide medical care.”
The regulation does not yet have a scheduled publication date in the Federal Register, nor has it been posted as a preview document on the publication’s website. It will become effective 60 days after publication.
Ulipristal acetate tops placebo for uterine leiomyomas
according to a study of the intention-to-treat populations of the randomized, double-blind, phase III VENUS I and VENUS II trials.
In these pivotal studies, ulipristal (Ella) at either 5 mg or 10 mg significantly improved both rate of and time to amenorrhea, noted Andrea S. Lukes, MD, of Carolina Women’s Research and Wellness Center in Durham, N.C. To assess effects on quality of life, she and her associates analyzed baseline and 12-week responses to the widely validated Uterine Fibroid Symptom Health-Related Quality of Life (UFS-QOL) questionnaire, which examined factors such as symptom severity, energy and mood, physical and social activities, self-consciousness, and sexual functioning.
Among 589 patients in the analysis, 169 received placebo, 215 received 5 mg ulipristal, and 205 received 10 mg ulipristal. At baseline, average total quality of life scores on UFS-QOL were 33 (standard deviation, 220), 32 (SD, 21), and 36 (SD, 23), respectively, the researchers wrote in Obstetrics & Gynecology.
After 12 weeks of treatment, both doses of ulipristal were associated with significantly greater improvements on all UFS-QOL scales, compared with placebo (P less than .001). For example, on a scale of 0-100, symptom severity improved by a mean of 23 with ulipristal 5 mg and by a mean of 30 with ulipristal 10 mg (both P less than .001 versus placebo).
“Although a small proportion of patients experienced no change or some worsening in these outcomes, the majority of women reported clear improvements; for example, more than 70% of patients in the ulipristal treatment arms achieved a meaningful improvement of 30 or more points on the Revised Activities subscale,” the researchers wrote.
Additionally, significantly greater improvements in physical and social activities were seen for both ulipristal doses, compared with placebo, from baseline to the end of treatment.
The VENUS II trial included two 12-week treatment courses. In this trial, women who switched from ulipristal to placebo experienced some worsening in quality of life, while those who switched from placebo to ulipristal improved their UFS-QOL scores, the investigators said. Patients who stayed on ulipristal throughout continued to benefit from one treatment course to the next.
The researchers concluded that the findings, “taken together with the significant improvements in amenorrhea, suggest that ulipristal is a promising, noninvasive treatment option for women suffering from symptomatic uterine leiomyomas.”
Allergan provided funding. Dr. Lukes disclosed ties to Allergan, AbbVie, Myovant, Merck, and several other companies. Four of the coauthors are employees of Allergan, and the two remaining coauthors had links to a number of pharmaceutical companies.
SOURCE: Lukes AS et al. Obstet Gynecol 2019;133 (5):869-78.
In this study, 77%-87% of women who received ulipristal acetate reported more than a 20-point improvement in health-related quality of life, compared with only 36% of placebo recipients, Joanna L. Hatfield, MD, wrote in an accompanying editorial.
“However, women with leiomyomas report a 51-point mean improvement after hysterectomy,” she noted. “Clinicians need to keep this difference in mind when counseling women with leiomyomas.”
Ulipristal can cause fatigue and weight gain leading to treatment discontinuation, she noted. Very rare cases of liver failure also have been reported, and there is no evidence that liver enzyme screening identifies patients at risk.
Nonetheless, for the approximately half of women with symptomatic leiomyomas who desire uterine-sparing treatment, selective progesterone receptor modulators like ulipristal offer “a noninvasive way to manage bleeding and bulk symptoms,” Dr. Hatfield said.
She advocated for long-term safety studies and a large pregnancy registry, calling ulipristal “neither a panacea nor a Pandora’s box,” but a choice that “lies somewhere in the middle, just [like] nearly all options that present themselves in a woman’s life.”
Dr. Hatfield is director of the fibroid program at Oregon Health & Science University in Portland. She did not report having conflicts of interest. She wrote an editorial accompanying the article by AS Lukes et al. (Obstet Gynecol. 2019 May;133[5]:867-8).
In this study, 77%-87% of women who received ulipristal acetate reported more than a 20-point improvement in health-related quality of life, compared with only 36% of placebo recipients, Joanna L. Hatfield, MD, wrote in an accompanying editorial.
“However, women with leiomyomas report a 51-point mean improvement after hysterectomy,” she noted. “Clinicians need to keep this difference in mind when counseling women with leiomyomas.”
Ulipristal can cause fatigue and weight gain leading to treatment discontinuation, she noted. Very rare cases of liver failure also have been reported, and there is no evidence that liver enzyme screening identifies patients at risk.
Nonetheless, for the approximately half of women with symptomatic leiomyomas who desire uterine-sparing treatment, selective progesterone receptor modulators like ulipristal offer “a noninvasive way to manage bleeding and bulk symptoms,” Dr. Hatfield said.
She advocated for long-term safety studies and a large pregnancy registry, calling ulipristal “neither a panacea nor a Pandora’s box,” but a choice that “lies somewhere in the middle, just [like] nearly all options that present themselves in a woman’s life.”
Dr. Hatfield is director of the fibroid program at Oregon Health & Science University in Portland. She did not report having conflicts of interest. She wrote an editorial accompanying the article by AS Lukes et al. (Obstet Gynecol. 2019 May;133[5]:867-8).
In this study, 77%-87% of women who received ulipristal acetate reported more than a 20-point improvement in health-related quality of life, compared with only 36% of placebo recipients, Joanna L. Hatfield, MD, wrote in an accompanying editorial.
“However, women with leiomyomas report a 51-point mean improvement after hysterectomy,” she noted. “Clinicians need to keep this difference in mind when counseling women with leiomyomas.”
Ulipristal can cause fatigue and weight gain leading to treatment discontinuation, she noted. Very rare cases of liver failure also have been reported, and there is no evidence that liver enzyme screening identifies patients at risk.
Nonetheless, for the approximately half of women with symptomatic leiomyomas who desire uterine-sparing treatment, selective progesterone receptor modulators like ulipristal offer “a noninvasive way to manage bleeding and bulk symptoms,” Dr. Hatfield said.
She advocated for long-term safety studies and a large pregnancy registry, calling ulipristal “neither a panacea nor a Pandora’s box,” but a choice that “lies somewhere in the middle, just [like] nearly all options that present themselves in a woman’s life.”
Dr. Hatfield is director of the fibroid program at Oregon Health & Science University in Portland. She did not report having conflicts of interest. She wrote an editorial accompanying the article by AS Lukes et al. (Obstet Gynecol. 2019 May;133[5]:867-8).
according to a study of the intention-to-treat populations of the randomized, double-blind, phase III VENUS I and VENUS II trials.
In these pivotal studies, ulipristal (Ella) at either 5 mg or 10 mg significantly improved both rate of and time to amenorrhea, noted Andrea S. Lukes, MD, of Carolina Women’s Research and Wellness Center in Durham, N.C. To assess effects on quality of life, she and her associates analyzed baseline and 12-week responses to the widely validated Uterine Fibroid Symptom Health-Related Quality of Life (UFS-QOL) questionnaire, which examined factors such as symptom severity, energy and mood, physical and social activities, self-consciousness, and sexual functioning.
Among 589 patients in the analysis, 169 received placebo, 215 received 5 mg ulipristal, and 205 received 10 mg ulipristal. At baseline, average total quality of life scores on UFS-QOL were 33 (standard deviation, 220), 32 (SD, 21), and 36 (SD, 23), respectively, the researchers wrote in Obstetrics & Gynecology.
After 12 weeks of treatment, both doses of ulipristal were associated with significantly greater improvements on all UFS-QOL scales, compared with placebo (P less than .001). For example, on a scale of 0-100, symptom severity improved by a mean of 23 with ulipristal 5 mg and by a mean of 30 with ulipristal 10 mg (both P less than .001 versus placebo).
“Although a small proportion of patients experienced no change or some worsening in these outcomes, the majority of women reported clear improvements; for example, more than 70% of patients in the ulipristal treatment arms achieved a meaningful improvement of 30 or more points on the Revised Activities subscale,” the researchers wrote.
Additionally, significantly greater improvements in physical and social activities were seen for both ulipristal doses, compared with placebo, from baseline to the end of treatment.
The VENUS II trial included two 12-week treatment courses. In this trial, women who switched from ulipristal to placebo experienced some worsening in quality of life, while those who switched from placebo to ulipristal improved their UFS-QOL scores, the investigators said. Patients who stayed on ulipristal throughout continued to benefit from one treatment course to the next.
The researchers concluded that the findings, “taken together with the significant improvements in amenorrhea, suggest that ulipristal is a promising, noninvasive treatment option for women suffering from symptomatic uterine leiomyomas.”
Allergan provided funding. Dr. Lukes disclosed ties to Allergan, AbbVie, Myovant, Merck, and several other companies. Four of the coauthors are employees of Allergan, and the two remaining coauthors had links to a number of pharmaceutical companies.
SOURCE: Lukes AS et al. Obstet Gynecol 2019;133 (5):869-78.
according to a study of the intention-to-treat populations of the randomized, double-blind, phase III VENUS I and VENUS II trials.
In these pivotal studies, ulipristal (Ella) at either 5 mg or 10 mg significantly improved both rate of and time to amenorrhea, noted Andrea S. Lukes, MD, of Carolina Women’s Research and Wellness Center in Durham, N.C. To assess effects on quality of life, she and her associates analyzed baseline and 12-week responses to the widely validated Uterine Fibroid Symptom Health-Related Quality of Life (UFS-QOL) questionnaire, which examined factors such as symptom severity, energy and mood, physical and social activities, self-consciousness, and sexual functioning.
Among 589 patients in the analysis, 169 received placebo, 215 received 5 mg ulipristal, and 205 received 10 mg ulipristal. At baseline, average total quality of life scores on UFS-QOL were 33 (standard deviation, 220), 32 (SD, 21), and 36 (SD, 23), respectively, the researchers wrote in Obstetrics & Gynecology.
After 12 weeks of treatment, both doses of ulipristal were associated with significantly greater improvements on all UFS-QOL scales, compared with placebo (P less than .001). For example, on a scale of 0-100, symptom severity improved by a mean of 23 with ulipristal 5 mg and by a mean of 30 with ulipristal 10 mg (both P less than .001 versus placebo).
“Although a small proportion of patients experienced no change or some worsening in these outcomes, the majority of women reported clear improvements; for example, more than 70% of patients in the ulipristal treatment arms achieved a meaningful improvement of 30 or more points on the Revised Activities subscale,” the researchers wrote.
Additionally, significantly greater improvements in physical and social activities were seen for both ulipristal doses, compared with placebo, from baseline to the end of treatment.
The VENUS II trial included two 12-week treatment courses. In this trial, women who switched from ulipristal to placebo experienced some worsening in quality of life, while those who switched from placebo to ulipristal improved their UFS-QOL scores, the investigators said. Patients who stayed on ulipristal throughout continued to benefit from one treatment course to the next.
The researchers concluded that the findings, “taken together with the significant improvements in amenorrhea, suggest that ulipristal is a promising, noninvasive treatment option for women suffering from symptomatic uterine leiomyomas.”
Allergan provided funding. Dr. Lukes disclosed ties to Allergan, AbbVie, Myovant, Merck, and several other companies. Four of the coauthors are employees of Allergan, and the two remaining coauthors had links to a number of pharmaceutical companies.
SOURCE: Lukes AS et al. Obstet Gynecol 2019;133 (5):869-78.
FROM OBSTETRICS & GYNECOLOGY
Key clinical point: For women with symptomatic uterine leiomyomas, ulipristal at either 5 mg or 10 mg significantly improved both the rate of and time to amenorrhea, compared with placebo.
Major finding: Patients who received 5 or 10 mg ulipristal showed significant improvements in Uterine Fibroid Symptom Health-Related Quality of Life scales, compared with those who received placebo (P less than .001).
Study details: VENUS I and II, 12-week randomized controlled trials of ulipristal acetate or placebo in 589 women with symptomatic uterine leiomyomas and abnormal uterine bleeding.
Disclosures: Allergan provided funding. Dr. Lukes disclosed ties to Allergan, AbbVie, Myovant, Merck, and several other companies. Four of the coauthors are employees of Allergan, and the two remaining coauthors had links to a number of pharmaceutical companies.
Source: Lukes AS et al. Obstet Gynecol. 2019 May;133(5):869-78.
Version success more likely in lower BMI, multiparous breech pregnancies
according to results of a single-center retrospective study.
Writing in Obstetrics & Gynecology, Ofer Isakov, MD, PhD, and colleagues from the Sourasky Medical Center, Tel Aviv, reported the results of a study of 250 women with singleton pregnancies and breech presentation who underwent external cephalic version (ECV) to turn the baby at 36-41 weeks’ gestation.
The overall success rate of the procedure was 65%. However, women with no forebag – the pocket of amniotic fluid in front of the fetal presenting part – had a 3%-10% chance of successful version, while those with a forebag size greater than 1 cm had a 96%-97% probability of success.
Women with a BMI greater than 29 had a very low chance of success, which the authors suggested was likely attributable to a thicker abdominal wall that made manipulation more difficult. However, among women with a BMI of 29 or below, success was significantly associated with forebag size.
Among women with a forebag of 1 cm in size, multiparous women had a significantly higher chance of success than nulliparous women (81%-91% vs. 0%-24%, respectively).
Dr. Isakov and colleagues suggested that the impact of multiparity could relate to late engagement or the relative laxity of the abdomen in women who had experienced previous births.
The authors then developed a decision tree predictive model of success for ECV, which had a prediction accuracy of 92%.
“External version is a simple and effective procedure that can reduce the cesarean delivery rate, but counseling patients on the risks and success rates of version is challenging owing to the lack of validated models to predict success,” Dr. Isakov and colleagues wrote. “The ability to predict the outcome of an ECV attempt may improve the rates of patient consent and prevent the performance of many unpleasant procedures with low chance for success.”
They noted that their success rate was higher than that seen in other studies of ECV and suggested this may be because all the procedures were performed by a single experienced practitioner, and the mean BMI of the cohort was lower than that in earlier studies.
None of the authors declared any relevant financial disclosures, and there was no external funding.
SOURCE: Isakov O et al. Obstet Gynecol. 2019;133:869-78.
With cesarean delivery rates rising, there is a need for vigilance to prevent them from returning to the 2009 peak of 33% of deliveries, and ECV is one strategy to help reduce cesarean rates. While there are some risks associated with ECV, which could contribute to negative attitudes, the lack of acceptance of this procedure may be improved if clinicians can provide an individualized estimate for the chance of success. This study proposes creating a predictive model that discriminates between poor and good changes of ECV success.
The fact that this study is a single-center study with a single physician performing all the procedures does limit its generalizability. However the authors’ use of ultrasound measurements of the forebag is a novel contribution that provides an objective measure of this factor, as well as an objective estimate of the engagement of the breech, which has been lacking.
Dr. Gayle Olson Koutrouvelis is a professor of obstetrics, gynecology, and maternal-fetal medicine at the University of Texas Medical Branch in Galveston. These comments are adapted from an editorial accompanying the article by Isakov et al. (Obstet Gynecol. 2019; 133:855-6.). She declared no conflicts of interest.
With cesarean delivery rates rising, there is a need for vigilance to prevent them from returning to the 2009 peak of 33% of deliveries, and ECV is one strategy to help reduce cesarean rates. While there are some risks associated with ECV, which could contribute to negative attitudes, the lack of acceptance of this procedure may be improved if clinicians can provide an individualized estimate for the chance of success. This study proposes creating a predictive model that discriminates between poor and good changes of ECV success.
The fact that this study is a single-center study with a single physician performing all the procedures does limit its generalizability. However the authors’ use of ultrasound measurements of the forebag is a novel contribution that provides an objective measure of this factor, as well as an objective estimate of the engagement of the breech, which has been lacking.
Dr. Gayle Olson Koutrouvelis is a professor of obstetrics, gynecology, and maternal-fetal medicine at the University of Texas Medical Branch in Galveston. These comments are adapted from an editorial accompanying the article by Isakov et al. (Obstet Gynecol. 2019; 133:855-6.). She declared no conflicts of interest.
With cesarean delivery rates rising, there is a need for vigilance to prevent them from returning to the 2009 peak of 33% of deliveries, and ECV is one strategy to help reduce cesarean rates. While there are some risks associated with ECV, which could contribute to negative attitudes, the lack of acceptance of this procedure may be improved if clinicians can provide an individualized estimate for the chance of success. This study proposes creating a predictive model that discriminates between poor and good changes of ECV success.
The fact that this study is a single-center study with a single physician performing all the procedures does limit its generalizability. However the authors’ use of ultrasound measurements of the forebag is a novel contribution that provides an objective measure of this factor, as well as an objective estimate of the engagement of the breech, which has been lacking.
Dr. Gayle Olson Koutrouvelis is a professor of obstetrics, gynecology, and maternal-fetal medicine at the University of Texas Medical Branch in Galveston. These comments are adapted from an editorial accompanying the article by Isakov et al. (Obstet Gynecol. 2019; 133:855-6.). She declared no conflicts of interest.
according to results of a single-center retrospective study.
Writing in Obstetrics & Gynecology, Ofer Isakov, MD, PhD, and colleagues from the Sourasky Medical Center, Tel Aviv, reported the results of a study of 250 women with singleton pregnancies and breech presentation who underwent external cephalic version (ECV) to turn the baby at 36-41 weeks’ gestation.
The overall success rate of the procedure was 65%. However, women with no forebag – the pocket of amniotic fluid in front of the fetal presenting part – had a 3%-10% chance of successful version, while those with a forebag size greater than 1 cm had a 96%-97% probability of success.
Women with a BMI greater than 29 had a very low chance of success, which the authors suggested was likely attributable to a thicker abdominal wall that made manipulation more difficult. However, among women with a BMI of 29 or below, success was significantly associated with forebag size.
Among women with a forebag of 1 cm in size, multiparous women had a significantly higher chance of success than nulliparous women (81%-91% vs. 0%-24%, respectively).
Dr. Isakov and colleagues suggested that the impact of multiparity could relate to late engagement or the relative laxity of the abdomen in women who had experienced previous births.
The authors then developed a decision tree predictive model of success for ECV, which had a prediction accuracy of 92%.
“External version is a simple and effective procedure that can reduce the cesarean delivery rate, but counseling patients on the risks and success rates of version is challenging owing to the lack of validated models to predict success,” Dr. Isakov and colleagues wrote. “The ability to predict the outcome of an ECV attempt may improve the rates of patient consent and prevent the performance of many unpleasant procedures with low chance for success.”
They noted that their success rate was higher than that seen in other studies of ECV and suggested this may be because all the procedures were performed by a single experienced practitioner, and the mean BMI of the cohort was lower than that in earlier studies.
None of the authors declared any relevant financial disclosures, and there was no external funding.
SOURCE: Isakov O et al. Obstet Gynecol. 2019;133:869-78.
according to results of a single-center retrospective study.
Writing in Obstetrics & Gynecology, Ofer Isakov, MD, PhD, and colleagues from the Sourasky Medical Center, Tel Aviv, reported the results of a study of 250 women with singleton pregnancies and breech presentation who underwent external cephalic version (ECV) to turn the baby at 36-41 weeks’ gestation.
The overall success rate of the procedure was 65%. However, women with no forebag – the pocket of amniotic fluid in front of the fetal presenting part – had a 3%-10% chance of successful version, while those with a forebag size greater than 1 cm had a 96%-97% probability of success.
Women with a BMI greater than 29 had a very low chance of success, which the authors suggested was likely attributable to a thicker abdominal wall that made manipulation more difficult. However, among women with a BMI of 29 or below, success was significantly associated with forebag size.
Among women with a forebag of 1 cm in size, multiparous women had a significantly higher chance of success than nulliparous women (81%-91% vs. 0%-24%, respectively).
Dr. Isakov and colleagues suggested that the impact of multiparity could relate to late engagement or the relative laxity of the abdomen in women who had experienced previous births.
The authors then developed a decision tree predictive model of success for ECV, which had a prediction accuracy of 92%.
“External version is a simple and effective procedure that can reduce the cesarean delivery rate, but counseling patients on the risks and success rates of version is challenging owing to the lack of validated models to predict success,” Dr. Isakov and colleagues wrote. “The ability to predict the outcome of an ECV attempt may improve the rates of patient consent and prevent the performance of many unpleasant procedures with low chance for success.”
They noted that their success rate was higher than that seen in other studies of ECV and suggested this may be because all the procedures were performed by a single experienced practitioner, and the mean BMI of the cohort was lower than that in earlier studies.
None of the authors declared any relevant financial disclosures, and there was no external funding.
SOURCE: Isakov O et al. Obstet Gynecol. 2019;133:869-78.
FROM OBSTETRICS & GYNECOLOGY
Key clinical point: Multiparity, larger forebag size, and lower BMI are predictors of external cephalic version success.
Major finding: Model of external cephalic version success shows prediction accuracy of 92%.
Study details: A single-center retrospective cohort study in 250 women with breech presentation.
Disclosures: None of the authors declared any relevant financial disclosures, and there was no external funding.
Source: Isakov O et al. Obstet Gynecol. 2019;133:869-78.
Bipolar disorder during pregnancy: Lessons learned
Careful management of bipolar disorder during pregnancy is critical because for so many patients with this illness, the road to emotional well-being has been a long one, requiring a combination of careful pharmacologic and nonpharmacologic strategies.
Half of referrals to our Center for Women’s Mental Health – where we evaluate and treat women before, during, and after pregnancy – are for women who have histories of bipolar disorder. My colleagues and I are asked at continuing medical education programs what we “always do” and “never do” with respect to the treatment of these patients.
What about discontinuation of mood stabilizers during pregnancy and risk of relapse?
We never abruptly stop mood stabilizers if a patient has an unplanned pregnancy – a common scenario, with 50% of pregnancies across the country being unplanned across sociodemographic lines – save for sodium valproate, which is a clearly a documented teratogen; it increases risk for organ malformation and behavioral difficulties in exposed offspring. In our center, we typically view the use of sodium valproate in reproductive age women as contraindicated.
One may then question the circumstances under which lithium might be used during pregnancy, because many clinicians are faced with patients who have been exquisite responders to lithium. Such a patient may present with a history of mania, but there are obvious concerns given the historical literature, and even some more recent reports, that describe an increased risk of teratogenicity with fetal exposure to lithium.
not only to decrease the risk of relapse following discontinuation of mood stabilizers, but because recurrence of illness during pregnancy for these patients is a very strong predictor of risk for postpartum depression. Women with bipolar disorder already are at a fivefold increased risk for postpartum depression, so discussion of sustaining euthymia during pregnancy for bipolar women is particularly timely given the focus nationally on treatment and prevention of postpartum depression.
In patients with history of mania, what about stopping treatment with lithium and other effective treatments during pregnancy?
Historically, we sometimes divided patients with bipolar disorder into those with “more severe recurrent disease” compared with those with more distant, circumscribed disease. In patients with more remote histories of mood dysregulation, we tended to discontinue treatment with mood stabilizers such as lithium or even newer second-generation atypical antipsychotics to see if patients could at least get through earlier stages of pregnancy before going back on anti-manic treatment.
Our experience now over several decades has revealed that this can be a risky clinical move. What we see is that even in patients with histories of mania years in the past (i.e., a circumscribed episode of mania during college in a woman now 35 years old with intervening sustained well-being), discontinuation of treatment that got patients well can lead to recurrence. Hence, we should not confuse an exquisite response to treatment with long periods of well-being as suggesting that the patient has a less severe form of bipolar disorder and hence the capacity to sustain that well-being when treatment is removed.
What about increasing/decreasing lithium dose during pregnancy and around time of delivery?
Select patients may be sensitive to changes in plasma levels of lithium, but the literature suggests that the clinical utility of arbitrarily sustaining plasma levels at the upper limit of the accepted range may be of only modest advantage, if any. With this as a backdrop and even while knowing that increased plasma volume of pregnancy is associated with a fall in plasma level of most medications, we do not arbitrarily increase the dose of lithium across pregnancy merely to sustain a level in the absence of a change in clinical symptoms. Indeed, to my knowledge, currently available data supporting a clear correlation of decline in plasma levels and frank change in symptoms during pregnancy are very sparse, if existent.
Earlier work had suggested that lithium dosage should be reduced proximate to delivery, a period characterized by rapid shifts in plasma volume during the acute peripartum period. Because physicians in our center do not alter lithium dose across pregnancy, we never reduce the dose of lithium proximate to delivery because of a theoretical concern for increased risk of either neonatal toxicity or maternal lithium toxicity, which is essentially nonexistent in terms of systematic reports in the literature.
Obvious concerns about lithium during pregnancy have focused on increased risk of teratogenesis, with the earliest reports supporting an increased risk of Epstein’s anomaly (0.05%-0.1%). More recent reports suggest an increased risk of cardiovascular malformations, which according to some investigators may be dose dependent.
For those patients who are exquisitely responsive to lithium, we typically leave them on the medicine and avail ourselves of current fetal echocardiographic evaluation at 16 weeks to 18 weeks to document the integrity of the fetal cardiac anatomy. Although the risk for cardiac malformations associated with lithium exposure during the first trimester is still exceedingly small, it is still extremely reassuring to patients to know that they are safely on the other side of a teratogenic window.
What about lamotrigine levels across pregnancy?
The last decade has seen a dramatic decrease in the administration of lithium to women with bipolar disorder, and growing use of both lamotrigine and second-generation atypical antipsychotics (frequently in combination) as an alternative. The changes in plasma level of lamotrigine across pregnancy are being increasingly well documented based on rigorous studies (Obstet Gynecol Clin North Am. 2018 Sep;45[3]:403-17).
These are welcome data, but the correlation between plasma concentration of lamotrigine and clinical response is a poor one. To date, there are sparse data to suggest that maintaining plasma levels of lithium or lamotrigine at a certain level during pregnancy changes clinical outcome. Following lamotrigine plasma levels during pregnancy seems more like an academic exercise than a procedure associated with particular clinical value.
As in the case of lithium, we never change lamotrigine doses proximate to pregnancy because of the absence of reports of neonatal toxicity associated with using lamotrigine during the peripartum period. The rationale for removing or minimizing the use of an effective medicine proximate to delivery, a period of risk for bipolar women, is lacking.
In 2019, we clearly are seeing a growing use of atypical antipsychotics for the treatment of bipolar disorder during pregnancy frequently coadministered with medicines such as lamotrigine as opposed to lithium. The accumulated data to date on second-generation atypical antipsychotics are not definitive, but increasingly are reassuring in terms of absence of a clear signal for teratogenicity; hence, our comfort in using this class of medicines is only growing, which is important given the prevalence of use of these agents in reproductive-age women.
If there is a single critical guiding principle for the clinician when it comes to managing bipolar women during pregnancy and the postpartum period, it is sustaining euthymia. With the recent focus of the U.S. Preventive Services Task Force on prevention of postpartum depression, nothing is more helpful perhaps than keeping women with bipolar disorder well, both proximate to pregnancy and during an actual pregnancy. Keeping those patients well maximizes the likelihood that they will proceed across the peripartum and into the postpartum period with a level of emotional well-being that optimizes and maximizes positive long-term outcomes for both patients and families.
Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He is also the Edmund and Carroll Carpenter professor of psychiatry at Harvard Medical School. He has been a consultant to manufacturers of psychiatric medications. Email Dr. Cohen at [email protected].
Careful management of bipolar disorder during pregnancy is critical because for so many patients with this illness, the road to emotional well-being has been a long one, requiring a combination of careful pharmacologic and nonpharmacologic strategies.
Half of referrals to our Center for Women’s Mental Health – where we evaluate and treat women before, during, and after pregnancy – are for women who have histories of bipolar disorder. My colleagues and I are asked at continuing medical education programs what we “always do” and “never do” with respect to the treatment of these patients.
What about discontinuation of mood stabilizers during pregnancy and risk of relapse?
We never abruptly stop mood stabilizers if a patient has an unplanned pregnancy – a common scenario, with 50% of pregnancies across the country being unplanned across sociodemographic lines – save for sodium valproate, which is a clearly a documented teratogen; it increases risk for organ malformation and behavioral difficulties in exposed offspring. In our center, we typically view the use of sodium valproate in reproductive age women as contraindicated.
One may then question the circumstances under which lithium might be used during pregnancy, because many clinicians are faced with patients who have been exquisite responders to lithium. Such a patient may present with a history of mania, but there are obvious concerns given the historical literature, and even some more recent reports, that describe an increased risk of teratogenicity with fetal exposure to lithium.
not only to decrease the risk of relapse following discontinuation of mood stabilizers, but because recurrence of illness during pregnancy for these patients is a very strong predictor of risk for postpartum depression. Women with bipolar disorder already are at a fivefold increased risk for postpartum depression, so discussion of sustaining euthymia during pregnancy for bipolar women is particularly timely given the focus nationally on treatment and prevention of postpartum depression.
In patients with history of mania, what about stopping treatment with lithium and other effective treatments during pregnancy?
Historically, we sometimes divided patients with bipolar disorder into those with “more severe recurrent disease” compared with those with more distant, circumscribed disease. In patients with more remote histories of mood dysregulation, we tended to discontinue treatment with mood stabilizers such as lithium or even newer second-generation atypical antipsychotics to see if patients could at least get through earlier stages of pregnancy before going back on anti-manic treatment.
Our experience now over several decades has revealed that this can be a risky clinical move. What we see is that even in patients with histories of mania years in the past (i.e., a circumscribed episode of mania during college in a woman now 35 years old with intervening sustained well-being), discontinuation of treatment that got patients well can lead to recurrence. Hence, we should not confuse an exquisite response to treatment with long periods of well-being as suggesting that the patient has a less severe form of bipolar disorder and hence the capacity to sustain that well-being when treatment is removed.
What about increasing/decreasing lithium dose during pregnancy and around time of delivery?
Select patients may be sensitive to changes in plasma levels of lithium, but the literature suggests that the clinical utility of arbitrarily sustaining plasma levels at the upper limit of the accepted range may be of only modest advantage, if any. With this as a backdrop and even while knowing that increased plasma volume of pregnancy is associated with a fall in plasma level of most medications, we do not arbitrarily increase the dose of lithium across pregnancy merely to sustain a level in the absence of a change in clinical symptoms. Indeed, to my knowledge, currently available data supporting a clear correlation of decline in plasma levels and frank change in symptoms during pregnancy are very sparse, if existent.
Earlier work had suggested that lithium dosage should be reduced proximate to delivery, a period characterized by rapid shifts in plasma volume during the acute peripartum period. Because physicians in our center do not alter lithium dose across pregnancy, we never reduce the dose of lithium proximate to delivery because of a theoretical concern for increased risk of either neonatal toxicity or maternal lithium toxicity, which is essentially nonexistent in terms of systematic reports in the literature.
Obvious concerns about lithium during pregnancy have focused on increased risk of teratogenesis, with the earliest reports supporting an increased risk of Epstein’s anomaly (0.05%-0.1%). More recent reports suggest an increased risk of cardiovascular malformations, which according to some investigators may be dose dependent.
For those patients who are exquisitely responsive to lithium, we typically leave them on the medicine and avail ourselves of current fetal echocardiographic evaluation at 16 weeks to 18 weeks to document the integrity of the fetal cardiac anatomy. Although the risk for cardiac malformations associated with lithium exposure during the first trimester is still exceedingly small, it is still extremely reassuring to patients to know that they are safely on the other side of a teratogenic window.
What about lamotrigine levels across pregnancy?
The last decade has seen a dramatic decrease in the administration of lithium to women with bipolar disorder, and growing use of both lamotrigine and second-generation atypical antipsychotics (frequently in combination) as an alternative. The changes in plasma level of lamotrigine across pregnancy are being increasingly well documented based on rigorous studies (Obstet Gynecol Clin North Am. 2018 Sep;45[3]:403-17).
These are welcome data, but the correlation between plasma concentration of lamotrigine and clinical response is a poor one. To date, there are sparse data to suggest that maintaining plasma levels of lithium or lamotrigine at a certain level during pregnancy changes clinical outcome. Following lamotrigine plasma levels during pregnancy seems more like an academic exercise than a procedure associated with particular clinical value.
As in the case of lithium, we never change lamotrigine doses proximate to pregnancy because of the absence of reports of neonatal toxicity associated with using lamotrigine during the peripartum period. The rationale for removing or minimizing the use of an effective medicine proximate to delivery, a period of risk for bipolar women, is lacking.
In 2019, we clearly are seeing a growing use of atypical antipsychotics for the treatment of bipolar disorder during pregnancy frequently coadministered with medicines such as lamotrigine as opposed to lithium. The accumulated data to date on second-generation atypical antipsychotics are not definitive, but increasingly are reassuring in terms of absence of a clear signal for teratogenicity; hence, our comfort in using this class of medicines is only growing, which is important given the prevalence of use of these agents in reproductive-age women.
If there is a single critical guiding principle for the clinician when it comes to managing bipolar women during pregnancy and the postpartum period, it is sustaining euthymia. With the recent focus of the U.S. Preventive Services Task Force on prevention of postpartum depression, nothing is more helpful perhaps than keeping women with bipolar disorder well, both proximate to pregnancy and during an actual pregnancy. Keeping those patients well maximizes the likelihood that they will proceed across the peripartum and into the postpartum period with a level of emotional well-being that optimizes and maximizes positive long-term outcomes for both patients and families.
Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He is also the Edmund and Carroll Carpenter professor of psychiatry at Harvard Medical School. He has been a consultant to manufacturers of psychiatric medications. Email Dr. Cohen at [email protected].
Careful management of bipolar disorder during pregnancy is critical because for so many patients with this illness, the road to emotional well-being has been a long one, requiring a combination of careful pharmacologic and nonpharmacologic strategies.
Half of referrals to our Center for Women’s Mental Health – where we evaluate and treat women before, during, and after pregnancy – are for women who have histories of bipolar disorder. My colleagues and I are asked at continuing medical education programs what we “always do” and “never do” with respect to the treatment of these patients.
What about discontinuation of mood stabilizers during pregnancy and risk of relapse?
We never abruptly stop mood stabilizers if a patient has an unplanned pregnancy – a common scenario, with 50% of pregnancies across the country being unplanned across sociodemographic lines – save for sodium valproate, which is a clearly a documented teratogen; it increases risk for organ malformation and behavioral difficulties in exposed offspring. In our center, we typically view the use of sodium valproate in reproductive age women as contraindicated.
One may then question the circumstances under which lithium might be used during pregnancy, because many clinicians are faced with patients who have been exquisite responders to lithium. Such a patient may present with a history of mania, but there are obvious concerns given the historical literature, and even some more recent reports, that describe an increased risk of teratogenicity with fetal exposure to lithium.
not only to decrease the risk of relapse following discontinuation of mood stabilizers, but because recurrence of illness during pregnancy for these patients is a very strong predictor of risk for postpartum depression. Women with bipolar disorder already are at a fivefold increased risk for postpartum depression, so discussion of sustaining euthymia during pregnancy for bipolar women is particularly timely given the focus nationally on treatment and prevention of postpartum depression.
In patients with history of mania, what about stopping treatment with lithium and other effective treatments during pregnancy?
Historically, we sometimes divided patients with bipolar disorder into those with “more severe recurrent disease” compared with those with more distant, circumscribed disease. In patients with more remote histories of mood dysregulation, we tended to discontinue treatment with mood stabilizers such as lithium or even newer second-generation atypical antipsychotics to see if patients could at least get through earlier stages of pregnancy before going back on anti-manic treatment.
Our experience now over several decades has revealed that this can be a risky clinical move. What we see is that even in patients with histories of mania years in the past (i.e., a circumscribed episode of mania during college in a woman now 35 years old with intervening sustained well-being), discontinuation of treatment that got patients well can lead to recurrence. Hence, we should not confuse an exquisite response to treatment with long periods of well-being as suggesting that the patient has a less severe form of bipolar disorder and hence the capacity to sustain that well-being when treatment is removed.
What about increasing/decreasing lithium dose during pregnancy and around time of delivery?
Select patients may be sensitive to changes in plasma levels of lithium, but the literature suggests that the clinical utility of arbitrarily sustaining plasma levels at the upper limit of the accepted range may be of only modest advantage, if any. With this as a backdrop and even while knowing that increased plasma volume of pregnancy is associated with a fall in plasma level of most medications, we do not arbitrarily increase the dose of lithium across pregnancy merely to sustain a level in the absence of a change in clinical symptoms. Indeed, to my knowledge, currently available data supporting a clear correlation of decline in plasma levels and frank change in symptoms during pregnancy are very sparse, if existent.
Earlier work had suggested that lithium dosage should be reduced proximate to delivery, a period characterized by rapid shifts in plasma volume during the acute peripartum period. Because physicians in our center do not alter lithium dose across pregnancy, we never reduce the dose of lithium proximate to delivery because of a theoretical concern for increased risk of either neonatal toxicity or maternal lithium toxicity, which is essentially nonexistent in terms of systematic reports in the literature.
Obvious concerns about lithium during pregnancy have focused on increased risk of teratogenesis, with the earliest reports supporting an increased risk of Epstein’s anomaly (0.05%-0.1%). More recent reports suggest an increased risk of cardiovascular malformations, which according to some investigators may be dose dependent.
For those patients who are exquisitely responsive to lithium, we typically leave them on the medicine and avail ourselves of current fetal echocardiographic evaluation at 16 weeks to 18 weeks to document the integrity of the fetal cardiac anatomy. Although the risk for cardiac malformations associated with lithium exposure during the first trimester is still exceedingly small, it is still extremely reassuring to patients to know that they are safely on the other side of a teratogenic window.
What about lamotrigine levels across pregnancy?
The last decade has seen a dramatic decrease in the administration of lithium to women with bipolar disorder, and growing use of both lamotrigine and second-generation atypical antipsychotics (frequently in combination) as an alternative. The changes in plasma level of lamotrigine across pregnancy are being increasingly well documented based on rigorous studies (Obstet Gynecol Clin North Am. 2018 Sep;45[3]:403-17).
These are welcome data, but the correlation between plasma concentration of lamotrigine and clinical response is a poor one. To date, there are sparse data to suggest that maintaining plasma levels of lithium or lamotrigine at a certain level during pregnancy changes clinical outcome. Following lamotrigine plasma levels during pregnancy seems more like an academic exercise than a procedure associated with particular clinical value.
As in the case of lithium, we never change lamotrigine doses proximate to pregnancy because of the absence of reports of neonatal toxicity associated with using lamotrigine during the peripartum period. The rationale for removing or minimizing the use of an effective medicine proximate to delivery, a period of risk for bipolar women, is lacking.
In 2019, we clearly are seeing a growing use of atypical antipsychotics for the treatment of bipolar disorder during pregnancy frequently coadministered with medicines such as lamotrigine as opposed to lithium. The accumulated data to date on second-generation atypical antipsychotics are not definitive, but increasingly are reassuring in terms of absence of a clear signal for teratogenicity; hence, our comfort in using this class of medicines is only growing, which is important given the prevalence of use of these agents in reproductive-age women.
If there is a single critical guiding principle for the clinician when it comes to managing bipolar women during pregnancy and the postpartum period, it is sustaining euthymia. With the recent focus of the U.S. Preventive Services Task Force on prevention of postpartum depression, nothing is more helpful perhaps than keeping women with bipolar disorder well, both proximate to pregnancy and during an actual pregnancy. Keeping those patients well maximizes the likelihood that they will proceed across the peripartum and into the postpartum period with a level of emotional well-being that optimizes and maximizes positive long-term outcomes for both patients and families.
Dr. Cohen is the director of the Ammon-Pinizzotto Center for Women’s Mental Health at Massachusetts General Hospital in Boston, which provides information resources and conducts clinical care and research in reproductive mental health. He is also the Edmund and Carroll Carpenter professor of psychiatry at Harvard Medical School. He has been a consultant to manufacturers of psychiatric medications. Email Dr. Cohen at [email protected].
Knowledge gaps about long-term osteoporosis drug therapy benefits, risks remain large
Long-term use of alendronate and zoledronic acid for more than 3 years reduces the rate of vertebral fracture in treatment-naive postmenopausal women with notable, yet rare, adverse events, but too little evidence exists to make determinations on the long-term benefit/risk profile of other bisphosphonates or other osteoporosis drugs besides raloxifene and oral hormone therapy, according to a report coming out of a recent National Institutes of Health workshop.
This situation leaves a large research gap that authors of an accompanying position paper hope to bridge with recommendations for studying therapy discontinuation and drug holidays during long-term osteoporosis drug treatment.
The NIH’s Pathways to Prevention (P2P) Workshop: Appropriate Use of Drug Therapies for Osteoporotic Fracture Prevention outlined the findings of the systematic review of long-term osteoporosis drug treatment (ODT), which was commissioned by the NIH Office of Disease Prevention. The systematic review and a position paper summarizing the workshop were published April 23 in Annals of Internal Medicine.
“Clinicians and patients need increased information on benefits and risks to inform shared decision making about the use of these treatments, taking into account patients’ values and preferences,” Albert Siu, MD, of the Brookdale Department of Geriatrics and Palliative Medicine at the Icahn School of Medicine at Mount Sinai in New York, and his colleagues wrote in the position paper (Ann Intern Med. 2019 Apr 23. doi: 10.7326/M19-0961). “The research ... is urgently needed to advance prevention of osteoporosis-related mortality and morbidity.”
In the systematic review, by a group of researchers separate from the workshop, 48 studies were identified (35 trials, 13 observational studies) that compared men and postmenopausal women 50 years or older who used treatments such as alendronate, raloxifene, zoledronic acid, and hormone therapy. The researchers found that use of alendronate for 4 years reduced the rate of clinical fractures (hazard ratio, 0.64; 95% confidence interval, 0.50-0.82) and radiographic vertebral fractures (HR, 0.50; 95% CI, 0.31-0.82) in women with osteoporosis. Raloxifene use for 4 years reduced the rate of clinical vertebral fractures (relative risk, 0.58; 95% CI, 0.43-0.79) and radiographic vertebral fractures (RR, 0.64; 95% CI, 0.53-0.76) but not nonvertebral fractures. Zoledronic acid use for 6 years was associated with a lower rate of nonvertebral fractures (HR, 0.66; 95% CI, 0.51-0.85) and clinical vertebral fractures (HR, 0.41; 95% CI, 0.22-0.75) in women with both osteoporosis and osteopenia. Estrogen-progestin use for 5.6 years and unopposed estrogen for 7 years was associated with clinical fracture reduction in women with unspecified osteoporosis and osteopenia when compared with placebo (Ann Intern Med. 2019 April 23. doi: 10.7326/M19-0533).
Controlled observational studies collectively show that long-term use of alendronate and of bisphosphonates as a class increased risk for radiologically confirmed atypical femoral fracture but by a small absolute amount, with less evidence for risks of subtrochanteric or femoral shaft fractures without radiologically confirmed atypical femoral fracture features and osteonecrosis of the jaw. However, there were no eligible observational studies with long-term use of zoledronic acid that evaluated risk for these adverse events.
Long-term raloxifene therapy was associated with a threefold increased risk for deep venous thrombosis and a three- to fourfold increased risk for pulmonary embolism, although not all results were statistically significant, the researchers said. In two long-term trials, both estrogen and estrogen-progestin compared with placebo increased risk for cardiovascular disease and cognitive impairment. Estrogen-progestin also increased risk for invasive breast cancer.
The researchers also studied abaloparatide, denosumab, ibandronate, risedronate, and teriparatide, but noted there were insufficient data to show the long-term effects of their use on fractures and other harms.
Dr. Siu and coauthors on the position paper made the following recommendations with regard to future research on long-term ODT:
• Using “innovative designs and approaches” for new research such as modeling studies, clinical trials, and observational studies of existing and potential treatments.
• Evaluating new agents or multicomponent interventions, such as fracture liaison services and oral care, that do not carry the downsides of antiresorptive therapies.
• Researching and preventing atypical femoral fracture and osteonecrosis of the jaw, particularly when associated with long-term denosumab or bisphosphonate use.
• Determining which patients are indicated for drug holidays, sequential therapies, and strategies for avoiding serious adverse events.
• Studying barriers to ODT.
“When we have information on these outcomes, such as how medication use after a fragility fracture is linked to future fractures or survival rates, we need to understand how to convey that information to patients so they can make more informed decisions about their care,” noted Dr. Siu and colleagues.
In an editorial related to both the position paper and the systematic review, Carolyn J. Crandall, MD, of the University of California, Los Angeles, agreed that clinical trial data do not answer questions about shared decision making for women with multiple comorbid conditions, the long-term effects of ODT with regard to rare fracture risk, and which patients are well-suited for drug holidays.
“The National Institutes of Health should support research to answer these high-impact clinical questions, in addition to encouraging approaches for clinicians to determine which individual patients are at greater risk for harms related to long-term bisphosphonate use,” she said. “The need to rigorously study patient preferences in the context of ODT is pressing because of the complex dosing instructions of oral bisphosphonates and the dramatic underutilization of ODT among persons who have already had a vertebral or hip fracture.”
The systematic review was funded by the National Institutes of Health and the Agency for Healthcare Research and Quality. The authors of the position paper and Dr. Crandall reported no conflicts of interest.
SOURCE: Siu A et al. Ann Intern Med. 2019 April 23. doi: 10.7326/M19-0961.
Long-term use of alendronate and zoledronic acid for more than 3 years reduces the rate of vertebral fracture in treatment-naive postmenopausal women with notable, yet rare, adverse events, but too little evidence exists to make determinations on the long-term benefit/risk profile of other bisphosphonates or other osteoporosis drugs besides raloxifene and oral hormone therapy, according to a report coming out of a recent National Institutes of Health workshop.
This situation leaves a large research gap that authors of an accompanying position paper hope to bridge with recommendations for studying therapy discontinuation and drug holidays during long-term osteoporosis drug treatment.
The NIH’s Pathways to Prevention (P2P) Workshop: Appropriate Use of Drug Therapies for Osteoporotic Fracture Prevention outlined the findings of the systematic review of long-term osteoporosis drug treatment (ODT), which was commissioned by the NIH Office of Disease Prevention. The systematic review and a position paper summarizing the workshop were published April 23 in Annals of Internal Medicine.
“Clinicians and patients need increased information on benefits and risks to inform shared decision making about the use of these treatments, taking into account patients’ values and preferences,” Albert Siu, MD, of the Brookdale Department of Geriatrics and Palliative Medicine at the Icahn School of Medicine at Mount Sinai in New York, and his colleagues wrote in the position paper (Ann Intern Med. 2019 Apr 23. doi: 10.7326/M19-0961). “The research ... is urgently needed to advance prevention of osteoporosis-related mortality and morbidity.”
In the systematic review, by a group of researchers separate from the workshop, 48 studies were identified (35 trials, 13 observational studies) that compared men and postmenopausal women 50 years or older who used treatments such as alendronate, raloxifene, zoledronic acid, and hormone therapy. The researchers found that use of alendronate for 4 years reduced the rate of clinical fractures (hazard ratio, 0.64; 95% confidence interval, 0.50-0.82) and radiographic vertebral fractures (HR, 0.50; 95% CI, 0.31-0.82) in women with osteoporosis. Raloxifene use for 4 years reduced the rate of clinical vertebral fractures (relative risk, 0.58; 95% CI, 0.43-0.79) and radiographic vertebral fractures (RR, 0.64; 95% CI, 0.53-0.76) but not nonvertebral fractures. Zoledronic acid use for 6 years was associated with a lower rate of nonvertebral fractures (HR, 0.66; 95% CI, 0.51-0.85) and clinical vertebral fractures (HR, 0.41; 95% CI, 0.22-0.75) in women with both osteoporosis and osteopenia. Estrogen-progestin use for 5.6 years and unopposed estrogen for 7 years was associated with clinical fracture reduction in women with unspecified osteoporosis and osteopenia when compared with placebo (Ann Intern Med. 2019 April 23. doi: 10.7326/M19-0533).
Controlled observational studies collectively show that long-term use of alendronate and of bisphosphonates as a class increased risk for radiologically confirmed atypical femoral fracture but by a small absolute amount, with less evidence for risks of subtrochanteric or femoral shaft fractures without radiologically confirmed atypical femoral fracture features and osteonecrosis of the jaw. However, there were no eligible observational studies with long-term use of zoledronic acid that evaluated risk for these adverse events.
Long-term raloxifene therapy was associated with a threefold increased risk for deep venous thrombosis and a three- to fourfold increased risk for pulmonary embolism, although not all results were statistically significant, the researchers said. In two long-term trials, both estrogen and estrogen-progestin compared with placebo increased risk for cardiovascular disease and cognitive impairment. Estrogen-progestin also increased risk for invasive breast cancer.
The researchers also studied abaloparatide, denosumab, ibandronate, risedronate, and teriparatide, but noted there were insufficient data to show the long-term effects of their use on fractures and other harms.
Dr. Siu and coauthors on the position paper made the following recommendations with regard to future research on long-term ODT:
• Using “innovative designs and approaches” for new research such as modeling studies, clinical trials, and observational studies of existing and potential treatments.
• Evaluating new agents or multicomponent interventions, such as fracture liaison services and oral care, that do not carry the downsides of antiresorptive therapies.
• Researching and preventing atypical femoral fracture and osteonecrosis of the jaw, particularly when associated with long-term denosumab or bisphosphonate use.
• Determining which patients are indicated for drug holidays, sequential therapies, and strategies for avoiding serious adverse events.
• Studying barriers to ODT.
“When we have information on these outcomes, such as how medication use after a fragility fracture is linked to future fractures or survival rates, we need to understand how to convey that information to patients so they can make more informed decisions about their care,” noted Dr. Siu and colleagues.
In an editorial related to both the position paper and the systematic review, Carolyn J. Crandall, MD, of the University of California, Los Angeles, agreed that clinical trial data do not answer questions about shared decision making for women with multiple comorbid conditions, the long-term effects of ODT with regard to rare fracture risk, and which patients are well-suited for drug holidays.
“The National Institutes of Health should support research to answer these high-impact clinical questions, in addition to encouraging approaches for clinicians to determine which individual patients are at greater risk for harms related to long-term bisphosphonate use,” she said. “The need to rigorously study patient preferences in the context of ODT is pressing because of the complex dosing instructions of oral bisphosphonates and the dramatic underutilization of ODT among persons who have already had a vertebral or hip fracture.”
The systematic review was funded by the National Institutes of Health and the Agency for Healthcare Research and Quality. The authors of the position paper and Dr. Crandall reported no conflicts of interest.
SOURCE: Siu A et al. Ann Intern Med. 2019 April 23. doi: 10.7326/M19-0961.
Long-term use of alendronate and zoledronic acid for more than 3 years reduces the rate of vertebral fracture in treatment-naive postmenopausal women with notable, yet rare, adverse events, but too little evidence exists to make determinations on the long-term benefit/risk profile of other bisphosphonates or other osteoporosis drugs besides raloxifene and oral hormone therapy, according to a report coming out of a recent National Institutes of Health workshop.
This situation leaves a large research gap that authors of an accompanying position paper hope to bridge with recommendations for studying therapy discontinuation and drug holidays during long-term osteoporosis drug treatment.
The NIH’s Pathways to Prevention (P2P) Workshop: Appropriate Use of Drug Therapies for Osteoporotic Fracture Prevention outlined the findings of the systematic review of long-term osteoporosis drug treatment (ODT), which was commissioned by the NIH Office of Disease Prevention. The systematic review and a position paper summarizing the workshop were published April 23 in Annals of Internal Medicine.
“Clinicians and patients need increased information on benefits and risks to inform shared decision making about the use of these treatments, taking into account patients’ values and preferences,” Albert Siu, MD, of the Brookdale Department of Geriatrics and Palliative Medicine at the Icahn School of Medicine at Mount Sinai in New York, and his colleagues wrote in the position paper (Ann Intern Med. 2019 Apr 23. doi: 10.7326/M19-0961). “The research ... is urgently needed to advance prevention of osteoporosis-related mortality and morbidity.”
In the systematic review, by a group of researchers separate from the workshop, 48 studies were identified (35 trials, 13 observational studies) that compared men and postmenopausal women 50 years or older who used treatments such as alendronate, raloxifene, zoledronic acid, and hormone therapy. The researchers found that use of alendronate for 4 years reduced the rate of clinical fractures (hazard ratio, 0.64; 95% confidence interval, 0.50-0.82) and radiographic vertebral fractures (HR, 0.50; 95% CI, 0.31-0.82) in women with osteoporosis. Raloxifene use for 4 years reduced the rate of clinical vertebral fractures (relative risk, 0.58; 95% CI, 0.43-0.79) and radiographic vertebral fractures (RR, 0.64; 95% CI, 0.53-0.76) but not nonvertebral fractures. Zoledronic acid use for 6 years was associated with a lower rate of nonvertebral fractures (HR, 0.66; 95% CI, 0.51-0.85) and clinical vertebral fractures (HR, 0.41; 95% CI, 0.22-0.75) in women with both osteoporosis and osteopenia. Estrogen-progestin use for 5.6 years and unopposed estrogen for 7 years was associated with clinical fracture reduction in women with unspecified osteoporosis and osteopenia when compared with placebo (Ann Intern Med. 2019 April 23. doi: 10.7326/M19-0533).
Controlled observational studies collectively show that long-term use of alendronate and of bisphosphonates as a class increased risk for radiologically confirmed atypical femoral fracture but by a small absolute amount, with less evidence for risks of subtrochanteric or femoral shaft fractures without radiologically confirmed atypical femoral fracture features and osteonecrosis of the jaw. However, there were no eligible observational studies with long-term use of zoledronic acid that evaluated risk for these adverse events.
Long-term raloxifene therapy was associated with a threefold increased risk for deep venous thrombosis and a three- to fourfold increased risk for pulmonary embolism, although not all results were statistically significant, the researchers said. In two long-term trials, both estrogen and estrogen-progestin compared with placebo increased risk for cardiovascular disease and cognitive impairment. Estrogen-progestin also increased risk for invasive breast cancer.
The researchers also studied abaloparatide, denosumab, ibandronate, risedronate, and teriparatide, but noted there were insufficient data to show the long-term effects of their use on fractures and other harms.
Dr. Siu and coauthors on the position paper made the following recommendations with regard to future research on long-term ODT:
• Using “innovative designs and approaches” for new research such as modeling studies, clinical trials, and observational studies of existing and potential treatments.
• Evaluating new agents or multicomponent interventions, such as fracture liaison services and oral care, that do not carry the downsides of antiresorptive therapies.
• Researching and preventing atypical femoral fracture and osteonecrosis of the jaw, particularly when associated with long-term denosumab or bisphosphonate use.
• Determining which patients are indicated for drug holidays, sequential therapies, and strategies for avoiding serious adverse events.
• Studying barriers to ODT.
“When we have information on these outcomes, such as how medication use after a fragility fracture is linked to future fractures or survival rates, we need to understand how to convey that information to patients so they can make more informed decisions about their care,” noted Dr. Siu and colleagues.
In an editorial related to both the position paper and the systematic review, Carolyn J. Crandall, MD, of the University of California, Los Angeles, agreed that clinical trial data do not answer questions about shared decision making for women with multiple comorbid conditions, the long-term effects of ODT with regard to rare fracture risk, and which patients are well-suited for drug holidays.
“The National Institutes of Health should support research to answer these high-impact clinical questions, in addition to encouraging approaches for clinicians to determine which individual patients are at greater risk for harms related to long-term bisphosphonate use,” she said. “The need to rigorously study patient preferences in the context of ODT is pressing because of the complex dosing instructions of oral bisphosphonates and the dramatic underutilization of ODT among persons who have already had a vertebral or hip fracture.”
The systematic review was funded by the National Institutes of Health and the Agency for Healthcare Research and Quality. The authors of the position paper and Dr. Crandall reported no conflicts of interest.
SOURCE: Siu A et al. Ann Intern Med. 2019 April 23. doi: 10.7326/M19-0961.
FROM ANNALS OF INTERNAL MEDICINE
Evaluating and managing postural tachycardia syndrome
Some people, most of them relatively young women, experience lightheadedness, a racing heart, and other symptoms (but not hypotension) when they stand up, in a condition known as postural tachycardia syndrome (POTS).1 Although not known to shorten life,1 it can be physically and mentally debilitating.2,3 Therapy rarely cures it, but a multifaceted approach can substantially improve quality of life.
This review outlines the evaluation and diagnosis of POTS and provides guidance for a therapy regimen.
HOW IS POTS DEFINED?
POTS is a multifactorial syndrome rather than a specific disease. It is characterized by all of the following1,4–6:
- An increase in heart rate of ≥ 30 bpm, or ≥ 40 bpm for those under age 19, within 10 minutes of standing from a supine position
- Sustained tachycardia (> 30 seconds)
- Absence of orthostatic hypotension (a fall in blood pressure of ≥ 20/10 mm Hg)
- Frequent and chronic duration (≥ 6 months).
These features are critical to diagnosis. Hemodynamic criteria in isolation may describe postural tachycardia but are not sufficient to diagnose POTS.
The prevalence of POTS is estimated to be between 0.2% and 1.0%,7 affecting up to 3 million people in the United States. Most cases arise between ages 13 and 50, with a female-to-male ratio of 5:1.8
MANY NAMES, SAME CONDITION
In 1871, Da Costa9 described a condition he called “irritable heart syndrome” that had characteristics similar to those of POTS, including extreme fatigue and exercise intolerance. Decades later, Lewis10 and Wood11 provided more detailed descriptions of the disorder, renaming it “soldier’s heart” or “Da Costa syndrome.” As other cases were documented, more terms arose, including “effort syndrome” and “mitral valve prolapse syndrome.”
In 1982, Rosen and Cryer12 were the first to use the term “postural tachycardia syndrome” for patients with disabling tachycardia upon standing without orthostatic hypotension. In 1986, Fouad et al13 described patients with postural tachycardia, orthostatic intolerance, and a small degree of hypotension as having “idiopathic hypovolemia.”
In 1993, Schondorf and Low14 established the current definition of POTS, leading to increased awareness and research efforts to understand its pathophysiology.
MULTIFACTORIAL PATHOPHYSIOLOGY
During the last 2 decades, several often-overlapping forms of POTS have been recognized, all of which share a final common pathway of sustained orthostatic tachycardia.15–19 In addition, a number of common comorbidities were identified through review of large clinic populations of POTS.20,21
Hypovolemic POTS
Up to 70% of patients with POTS have hypovolemia. The average plasma volume deficit is about 13%, which typically causes only insignificant changes in heart rate and norepinephrine levels while a patient is supine. However, blood pooling associated with upright posture further compromises cardiac output and consequently increases sympathetic nerve activity. Abnormalities in the renin-angiotensin-aldosterone volume regulation system are also suspected to impair sodium retention, contributing to hypovolemia.1,22
Neuropathic POTS
About half of patients with POTS have partial sympathetic denervation (particularly in the lower limbs) and inadequate vasoconstriction upon standing, leading to reduced venous return and stroke volume.17,23 A compensatory increase in sympathetic tone results in tachycardia to maintain cardiac output and blood pressure.
Hyperadrenergic POTS
Up to 50% of patients with POTS have high norepinephrine levels (≥ 600 pg/mL) when upright. This subtype, hyperadrenergic POTS, is characterized by an increase in systolic blood pressure of at least 10 mm Hg within 10 minutes of standing, with concomitant tachycardia that can be similar to or greater than that seen in nonhyperadrenergic POTS. Patients with hyperadrenergic POTS tend to report more prominent symptoms of sympathetic activation, such as palpitations, anxiety, and tremulousness.24,25
Norepinephrine transporter deficiency
The norepinephrine transporter (NET) is on the presynaptic cleft of sympathetic neurons and serves to clear synaptic norepinephrine. NET deficiency leads to a hyperadrenergic state and elevated sympathetic nerve activation.18 NET deficiency may be induced by common antidepressants (eg, tricyclic antidepressants and serotonin-norepinephrine reuptake inhibitors) and attention-deficit disorder medications.4
Mast cell activation syndrome
The relationship between mast cell activation syndrome and POTS is poorly understood.4,26 Mast cell activation syndrome has been described in a subset of patients with POTS who have sinus tachycardia accompanied by severe episodic flushing. Patients with this subtype have a hyperadrenergic response to postural change and elevated urine methylhistamine during flushing episodes.
Patients with mast cell activation syndrome tend to have strong allergic symptoms and may also have severe gastrointestinal problems, food sensitivities, dermatographism, and neuropathy. Diagnosis can be difficult, as the condition is associated with numerous markers with varying sensitivity and specificity.
Autoimmune origin
A significant minority of patients report a viral-like illness before the onset of POTS symptoms, suggesting a possible autoimmune-mediated or inflammatory cause. Also, some autoimmune disorders (eg, Sjögren syndrome) can present with a POTS-like manifestation.
Research into the role of autoantibodies in the pathophysiology of POTS offers the potential to develop novel therapeutic targets. Autoantibodies that have been reported in POTS include those against M1 to M3 muscarinic receptors (present in over 87% of patients with POTS),27 cardiac lipid raft-associated proteins,28 adrenergic G-protein coupled receptors, alpha-1-adrenergic receptors, and beta-1- and beta-2-adrenergic receptors.29 Although commercial enzyme-linked immunosorbent assays can assess for these antibody fragments, it is not known whether targeting the antibodies improves outcomes. At this time, antibody testing for POTS should be confined to the research setting.
LINKS TO OTHER SYNDROMES
POTS is often associated with other conditions whose symptoms cannot be explained by postural intolerance or tachycardia.
Ehlers-Danlos syndromes are a group of inherited heterogeneous disorders involving joint hypermobility, skin hyperextensibility, and tissue fragility.30 The hypermobile subtype is most commonly associated with POTS, with patients often having symptoms of autonomic dysregulation and autonomic test abnormalities.31–33 Patients with POTS may have a history of joint subluxations, joint pain, cervical instability, and spontaneous epidural leaks. The reason for the overlap between the two syndromes is not clear.
Chronic fatigue syndrome is characterized by persistent fatigue that does not resolve with rest and is not necessarily associated with orthostatic changes. More than 75% of patients with POTS report general fatigue as a major complaint, and up to 23% meet the full criteria for chronic fatigue syndrome.34
DIAGNOSTIC STRATEGY
A patient presenting with symptoms suggestive of POTS should first undergo a detailed history and physical examination. Other causes of sinus tachycardia should be considered.
Detailed history, symptom review
The history should focus on determining symptom burden, including tachycardia onset, frequency, severity, and triggers; the presence of syncope; and the impact of symptoms on daily function and quality of life.
Presyncope and its associated symptoms occur in less than one-third of patients with POTS, and syncope is not a principal feature.4 If syncope is the predominant complaint, alternative causes should be investigated. The usual cause of syncope in the general population is thought to be vasovagal.
In addition to orthostatic intolerance, gastrointestinal disturbances are common in POTS, presenting as abdominal pain, heartburn, irregular bowel movements, diarrhea, or constipation. Symptoms of gastroparesis are less common. Gastrointestinal symptoms tend to be prolonged, lasting hours and occurring multiple times a week. They tend not to improve in the supine position.35
POTS-associated symptoms may develop insidiously, but patients often report onset after an acute stressor such as pregnancy, major surgery, or a presumed viral illness.4 Whether these putative triggers are causative or coincidental is unknown. Symptoms of orthostatic intolerance tend to be exacerbated by dehydration, heat, alcohol, exercise, and menstruation.36,37
Consider the family history: 1 in 8 patients with POTS reports familial orthostatic intolerance,38 suggesting a genetic role in some patients. Inquire about symptoms or a previous diagnosis of Ehlers-Danlos syndrome and mast cell activation syndrome.
Consider other conditions
Pheochromocytoma causes hyperadrenergic symptoms (eg, palpitations, lightheadedness) like those in POTS, but patients with pheochromocytoma typically have these symptoms while supine. Pheochromocytoma is also characterized by plasma norepinephrine levels much higher than in POTS.4 Plasma metanephrine testing helps diagnose or rule out pheochromocytoma.5
Inappropriate sinus tachycardia, like pheochromocytoma, also has clinical features similar to those of POTS, as well as tachycardia present when supine. It involves higher sympathetic tone and lower parasympathetic tone compared with POTS; patients commonly have a daytime resting heart rate of at least 100 bpm or a 24-hour mean heart rate of at least 90 bpm.1,42 While the intrinsic heart rate is heightened in inappropriate sinus tachycardia, it is not different between POTS patients and healthy individuals.42,43 Distinguishing POTS from inappropriate sinus tachycardia is further complicated by the broad inclusion criteria of most studies of inappropriate sinus tachycardia, which failed to exclude patients with POTS.44 The Heart Rhythm Society recently adopted distinct definitions for the 2 conditions.1
Physical examination: Focus on vital signs
Dependent acrocyanosis—dark red-blue discoloration of the lower legs that is cold to the touch—occurs in about half of patients with POTS upon standing.4 Dependent acrocyanosis is associated with joint hypermobility and Ehlers-Danlos syndrome, so these conditions should also be considered if findings are positive.
Laboratory testing for other causes
Laboratory testing is used mainly to detect primary causes of sinus tachycardia. Tests should include:
- Complete blood cell count with hematocrit (for severe anemia)
- Thyroid-stimulating hormone level (for hyperthyroidism)
- Electrolyte panel (for significant electrolyte disturbances).
Evidence is insufficient to support routinely measuring the vitamin B12 level, iron indices, and serum markers for celiac disease, although these may be done if the history or physical examination suggests related problems.4 Sicca symptoms (severe dry eye or dry mouth) should trigger evaluation for Sjögren syndrome.
Electrocardiography needed
Electrocardiography should be performed to investigate for cardiac conduction abnormalities as well as for resting markers of a supraventricular tachyarrhythmia. Extended ambulatory (Holter) monitoring may be useful to evaluate for a transient reentrant tachyarrhythmia4; however, it does not record body position, so it can be difficult to determine if detected episodes of tachycardia are related to posture.
Additional testing for select cases
Further investigation is usually not needed to diagnose POTS but should be considered in some cases. Advanced tests are typically performed at a tertiary care referral center and include:
- Quantitative sensory testing to evaluate for small-fiber neuropathy (ie, Quantitative Sudomotor Axon Reflex Test, or QSART), which occurs in the neuropathic POTS subtype
- Formal autonomic function testing to characterize neurovascular responsiveness
- Supine and standing plasma norepinephrine levels (fractionated catecholamines) to characterize the net activation of the sympathetic nervous system
- Blood volume assessments to assess hypovolemia
- Formal exercise testing to objectively quantify exercise capacity.
GRADED MANAGEMENT
No single universal gold-standard therapy exists for POTS, and management should be individually determined with the primary goals of treating symptoms and restoring function. A graded approach should be used, starting with conservative nonpharmacologic therapies and adding medications as needed.
While the disease course varies substantially from patient to patient, proper management is strongly associated with eventual symptom improvement.1
NONPHARMACOLOGIC STEPS FIRST
Education
Patients should be informed of the nature of their condition and referred to appropriate healthcare personnel. POTS is a chronic illness requiring individualized coping strategies, intensive physician interaction, and support of a multidisciplinary team. Patients and family members can be reassured that most symptoms improve over time with appropriate diagnosis and treatment.1 Patients should be advised to avoid aggravating triggers and activities.
Exercise
Exercise programs are encouraged but should be introduced gradually, as physical activity can exacerbate symptoms, especially at the outset. Several studies have reported benefits from a short-term (3-month) program, in which the patient gradually progresses from non-upright exercise (eg, rowing machine, recumbent cycle, swimming) to upright endurance exercises. At the end of these programs, significant cardiac remodeling, improved quality of life, and reduced heart rate responses to standing have been reported, and benefits have been reported to persist in patients who continued exercising after the 3-month study period.46,47
Despite the benefits of exercise interventions, compliance is low.46,47 To prevent early discouragement, patients should be advised that it can take 4 to 6 weeks of continued exercise before benefits appear. Patients are encouraged to exercise every other day for 30 minutes or more. Regimens should primarily focus on aerobic conditioning, but resistance training, concentrating on thigh muscles, can also help. Exercise is a treatment and not a cure, and benefits can rapidly disappear if regular activity (at least 3 times per week) is stopped.48
Compression stockings
Compression stockings help reduce peripheral venous pooling and enhance venous return to the heart. Waist-high stockings with compression of at least 30 to 40 mm Hg offer the best results.
Diet
Increased fluid and salt intake is advisable for patients with suspected hypovolemia. At least 2 to 3 L of water accompanied by 10 to 12 g of daily sodium intake is recommended.1 This can usually be accomplished with diet and salt added to food, but salt tablets can be used if the patient prefers. The resultant plasma volume expansion may help reduce the reflex tachycardia upon standing.49
Check medications
Rescue therapy with saline infusion
Intravenous saline infusion can augment blood volume in patients who are clinically decompensated and present with severe symptoms.1 Intermittent infusion of 1 L of normal saline has been found to significantly reduce orthostatic tachycardia and related symptoms in patients with POTS, contributing to improved quality of life.51,52
Chronic saline infusions are not recommended for long-term care because of the risk of access complications and infection.1 Moak et al53 reported a high rate of bacteremia in a cohort of children with POTS with regular saline infusions, most of whom had a central line. On the other hand, Ruzieh et al54 reported significantly improved symptoms with regular saline infusions without a high rate of complications, but patients in this study received infusions for only a few months and through a peripheral intravenous catheter.
DRUG THERAPY
No medications are approved by the US Food and Drug Administration (FDA) or Health Canada specifically for treating POTS, making all pharmacologic recommendations off-label. Although the drugs discussed below have been evaluated for POTS in controlled laboratory settings, they have yet to be tested in robust clinical trials.
Blood volume expansion
Several drugs expand blood volume, which may reduce orthostatic tachycardia.
Fludrocortisone is a synthetic aldosterone analogue that enhances sodium and water retention. Although one observational study found that it normalizes hemodynamic changes in response to orthostatic stress, no high-level evidence exists for its effectiveness for POTS.55 It is generally well tolerated, although possible adverse effects include hyperkalemia, hypertension, fatigue, nausea, headache, and edema.5,56
Desmopressin is a synthetic version of a natural antidiuretic hormone that increases kidney-mediated free-water reabsorption without sodium retention. It significantly reduces upright heart rate in patients with POTS and improves symptom burden. Although potential adverse effects include edema and headache, hyponatremia is the primary concern with daily use, especially with the increased water intake advised for POTS.57 Patients should be advised to use desmopressin no more than once a week for the acute improvement of symptoms. Intermittent monitoring of serum sodium levels is recommended for safety.
Erythropoietin replacement has been suggested for treating POTS to address the significant deficit in red blood cell volume. Although erythropoietin therapy has a direct vasoconstrictive effect and largely improves red blood cell volume in patients with POTS, it does not expand plasma volume, so orthostatic tachycardia is not itself reduced.22 Nevertheless, it may significantly improve POTS symptoms refractory to more common methods of treatment, and it should be reserved for such cases. In addition to the lack of effect on orthostatic tachycardia, drawbacks to using erythropoietin include its high cost, the need for subcutaneous administration, and the risk of life-threatening complications such as myocardial infarction and stroke.58,59
Heart rate-lowering agents
Propranolol, a nonselective beta-adrenergic antagonist, can significantly reduce standing heart rate and improve symptoms at low dosages (10–20 mg). Higher dosages can further restrain orthostatic tachycardia but are not as well tolerated, mainly due to hypotension and worsening of existing symptoms such as fatigue.60 Regular-acting propranolol works for about 4 to 5 hours per dose, so full-day coverage often requires dosing 4 times per day.
Ivabradine is a selective blocker of the “funny” (If) channel that reduces the sinus node firing rate without affecting blood pressure, so it slows heart rate without causing supine hypertension or orthostatic hypotension.
A retrospective case series found that 60% of patients with POTS treated with ivabradine reported symptomatic improvement, and all patients experienced reduced tachycardia with continued use.61 Ivabradine has not been compared with placebo or propranolol in a randomized controlled trial, and it has not been well studied in pregnancy and so should be avoided because of potential teratogenic effects.
When prescribing ivabradine for women of childbearing age, a negative pregnancy test may be documented prior to initiation of therapy, and the use of highly effective methods of contraception is recommended. Ivabradine should be avoided in women contemplating pregnancy. Insurance coverage can limit access to ivabradine in the United States.
Central nervous system sympatholytics
Patients with prominent hyperadrenergic features may benefit from central sympatholytic agents. However, these drugs may not be well tolerated in patients with neuropathic POTS because of the effects of reduced systemic vascular resistance5 and the possible exacerbation of drowsiness, fatigue, and mental clouding.4 Patients can be extremely sensitive to these medications, so they should initially be prescribed at the lowest dose, then gradually increased as tolerated.
Clonidine, an alpha-2-adrenergic agonist, decreases central sympathetic tone. In hyperadrenergic patients, clonidine can stabilize heart rate and blood pressure, thereby reducing orthostatic symptoms.62
Methyldopa has effects similar to those of clonidine but is easier to titrate owing to its longer half-life.63 Methyldopa is typically started at 125 mg at bedtime and increased to 125 mg twice daily, if tolerated.
Other agents
Midodrine is a prodrug. The active form, an alpha-1-adrenergic agonist, constricts peripheral veins and arteries to increase vascular resistance and venous return, thereby reducing orthostatic tachycardia.52 It is most useful in patients with impaired peripheral vasoconstriction (eg, neuropathic POTS) and may be less effective in those with hyperadrenergic POTS.64 Major limitations of midodrine include worsening supine hypertension and possible urinary retention.39
Because of midodrine’s short half-life, frequent dosing is required during daytime hours (eg, 8 AM, noon, and 4 PM), but it should not be taken within 4 to 5 hours of sleep because of the risk of supine hypertension. Midodrine is typically started at 2.5 to 5 mg per dose and can be titrated up to 15 mg per dose.
Midodrine is an FDA pregnancy category C drug (adverse effects in pregnancy seen in animal models, but evidence lacking in humans). While ideally it should be avoided, we have used it safely in pregnant women with disabling POTS symptoms.
Pyridostigmine, an acetylcholinesterase inhibitor, increases cardiovagal tone and possibly sympathetic tone. It has been reported to significantly reduce standing heart rate and improve symptom burden in patients with POTS.65 However, pyridostigmine increases gastrointestinal mobility, leading to severe adverse effects in over 20% of patients, including abdominal cramps, nausea, and diarrhea.66
Droxidopa, a synthetic amino acid precursor of norepinephrine, improves dizziness and fatigue in POTS with minimal effects on blood pressure.67
Modafinil, a psychostimulant, may improve POTS-associated cognitive symptoms.4 It also raises upright blood pressure without significantly worsening standing heart rate or acute orthostatic symptoms.68
EFFECTS OF COMORBID DISORDERS ON MANAGEMENT
Ehlers-Danlos syndrome
Pharmacologic approaches to POTS should not be altered based on the presence of Ehlers-Danlos syndrome, but because many of these patients are prone to joint dislocation, exercise prescriptions may need adjusting.
A medical genetics consult is recommended for patients with Ehlers-Danlos syndrome. Although the hypermobile type (the form most commonly associated with POTS) is not associated with aortopathy, it can be confused with classical and vascular Ehlers-Danlos syndromes, which require serial aortic screening.30
Mast cell activation syndrome
Consultation with an allergist or immunologist may help patients with severe symptoms.
Autoantibodies and autoimmunity
Treatment of the underlying disorder is recommended and can result in significantly improved POTS symptoms.
SPECIALTY CARE REFERRAL
POTS can be challenging to manage. Given the range of physiologic, emotional, and functional distress patients experience, it often requires significant physician time and multidisciplinary care. Patients with continued severe or debilitating symptoms may benefit from referral to a tertiary-care center with experience in autonomic nervous system disorders.
PROGNOSIS
Limited data are available on the long-term prognosis of POTS, and more studies are needed in pediatric and adult populations. No deaths have been reported in the handful of published cases of POTS in patients older than 50.1 Some pediatric studies suggest that some teenagers “outgrow” their POTS. However, these data are not robust, and an alternative explanation is that as they get older, they see adult physicians for their POTS symptoms and so are lost to study follow-up.6,44,69
We have not often seen POTS simply resolve without ongoing treatment. However, in our experience, most patients have improved symptoms and function with multimodal treatment (ie, exercise, salt, water, stockings, and some medications) and time.
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- Ross AJ, Ocon AJ, Medow MS, Stewart JM. A double-blind placebo-controlled cross-over study of the vascular effects of midodrine in neuropathic compared with hyperadrenergic postural tachycardia syndrome. Clin Sci (Lond) 2014; 126(4):289–296. doi:10.1042/CS20130222
- Raj SR, Black BK, Biaggioni I, Harris PA, Robertson D. Acetylcholinesterase inhibition improves tachycardia in postural tachycardia syndrome. Circulation 2005; 111(21):2734–2340. doi:10.1161/CIRCULATIONAHA.104.497594
- Kanjwal K, Karabin B, Sheikh M, et al. Pyridostigmine in the treatment of postural orthostatic tachycardia: A single-center experience. Pacing Clin Electrophysiol 2011; 34(6):750–755. doi:10.1111/j.1540-8159.2011.03047.x
- Ruzieh M, Dasa O, Pacenta A, Karabin B, Grubb B. Droxidopa in the treatment of postural orthostatic tachycardia syndrome. Am J Ther 2017; 24(2):e157–e161. doi:10.1097/MJT.0000000000000468
- Kpaeyeh AG Jr, Mar PL, Raj V, et al. Hemodynamic profiles and tolerability of modafinil in the treatment of POTS: a randomized placebo-controlled trial. J Clin Psychopharmacol 2014; 34(6):738–741. doi:10.1097/JCP.0000000000000221
- Lai CC, Fischer PR, Brands CK, et al. Outcomes in adolescents with postural orthostatic tachycardia syndrome treated with midodrine and beta-blockers. Pacing Clin Electrophysiol 2009; 32(2):234–238. doi:10.1111/j.1540-8159.2008.02207.x
Some people, most of them relatively young women, experience lightheadedness, a racing heart, and other symptoms (but not hypotension) when they stand up, in a condition known as postural tachycardia syndrome (POTS).1 Although not known to shorten life,1 it can be physically and mentally debilitating.2,3 Therapy rarely cures it, but a multifaceted approach can substantially improve quality of life.
This review outlines the evaluation and diagnosis of POTS and provides guidance for a therapy regimen.
HOW IS POTS DEFINED?
POTS is a multifactorial syndrome rather than a specific disease. It is characterized by all of the following1,4–6:
- An increase in heart rate of ≥ 30 bpm, or ≥ 40 bpm for those under age 19, within 10 minutes of standing from a supine position
- Sustained tachycardia (> 30 seconds)
- Absence of orthostatic hypotension (a fall in blood pressure of ≥ 20/10 mm Hg)
- Frequent and chronic duration (≥ 6 months).
These features are critical to diagnosis. Hemodynamic criteria in isolation may describe postural tachycardia but are not sufficient to diagnose POTS.
The prevalence of POTS is estimated to be between 0.2% and 1.0%,7 affecting up to 3 million people in the United States. Most cases arise between ages 13 and 50, with a female-to-male ratio of 5:1.8
MANY NAMES, SAME CONDITION
In 1871, Da Costa9 described a condition he called “irritable heart syndrome” that had characteristics similar to those of POTS, including extreme fatigue and exercise intolerance. Decades later, Lewis10 and Wood11 provided more detailed descriptions of the disorder, renaming it “soldier’s heart” or “Da Costa syndrome.” As other cases were documented, more terms arose, including “effort syndrome” and “mitral valve prolapse syndrome.”
In 1982, Rosen and Cryer12 were the first to use the term “postural tachycardia syndrome” for patients with disabling tachycardia upon standing without orthostatic hypotension. In 1986, Fouad et al13 described patients with postural tachycardia, orthostatic intolerance, and a small degree of hypotension as having “idiopathic hypovolemia.”
In 1993, Schondorf and Low14 established the current definition of POTS, leading to increased awareness and research efforts to understand its pathophysiology.
MULTIFACTORIAL PATHOPHYSIOLOGY
During the last 2 decades, several often-overlapping forms of POTS have been recognized, all of which share a final common pathway of sustained orthostatic tachycardia.15–19 In addition, a number of common comorbidities were identified through review of large clinic populations of POTS.20,21
Hypovolemic POTS
Up to 70% of patients with POTS have hypovolemia. The average plasma volume deficit is about 13%, which typically causes only insignificant changes in heart rate and norepinephrine levels while a patient is supine. However, blood pooling associated with upright posture further compromises cardiac output and consequently increases sympathetic nerve activity. Abnormalities in the renin-angiotensin-aldosterone volume regulation system are also suspected to impair sodium retention, contributing to hypovolemia.1,22
Neuropathic POTS
About half of patients with POTS have partial sympathetic denervation (particularly in the lower limbs) and inadequate vasoconstriction upon standing, leading to reduced venous return and stroke volume.17,23 A compensatory increase in sympathetic tone results in tachycardia to maintain cardiac output and blood pressure.
Hyperadrenergic POTS
Up to 50% of patients with POTS have high norepinephrine levels (≥ 600 pg/mL) when upright. This subtype, hyperadrenergic POTS, is characterized by an increase in systolic blood pressure of at least 10 mm Hg within 10 minutes of standing, with concomitant tachycardia that can be similar to or greater than that seen in nonhyperadrenergic POTS. Patients with hyperadrenergic POTS tend to report more prominent symptoms of sympathetic activation, such as palpitations, anxiety, and tremulousness.24,25
Norepinephrine transporter deficiency
The norepinephrine transporter (NET) is on the presynaptic cleft of sympathetic neurons and serves to clear synaptic norepinephrine. NET deficiency leads to a hyperadrenergic state and elevated sympathetic nerve activation.18 NET deficiency may be induced by common antidepressants (eg, tricyclic antidepressants and serotonin-norepinephrine reuptake inhibitors) and attention-deficit disorder medications.4
Mast cell activation syndrome
The relationship between mast cell activation syndrome and POTS is poorly understood.4,26 Mast cell activation syndrome has been described in a subset of patients with POTS who have sinus tachycardia accompanied by severe episodic flushing. Patients with this subtype have a hyperadrenergic response to postural change and elevated urine methylhistamine during flushing episodes.
Patients with mast cell activation syndrome tend to have strong allergic symptoms and may also have severe gastrointestinal problems, food sensitivities, dermatographism, and neuropathy. Diagnosis can be difficult, as the condition is associated with numerous markers with varying sensitivity and specificity.
Autoimmune origin
A significant minority of patients report a viral-like illness before the onset of POTS symptoms, suggesting a possible autoimmune-mediated or inflammatory cause. Also, some autoimmune disorders (eg, Sjögren syndrome) can present with a POTS-like manifestation.
Research into the role of autoantibodies in the pathophysiology of POTS offers the potential to develop novel therapeutic targets. Autoantibodies that have been reported in POTS include those against M1 to M3 muscarinic receptors (present in over 87% of patients with POTS),27 cardiac lipid raft-associated proteins,28 adrenergic G-protein coupled receptors, alpha-1-adrenergic receptors, and beta-1- and beta-2-adrenergic receptors.29 Although commercial enzyme-linked immunosorbent assays can assess for these antibody fragments, it is not known whether targeting the antibodies improves outcomes. At this time, antibody testing for POTS should be confined to the research setting.
LINKS TO OTHER SYNDROMES
POTS is often associated with other conditions whose symptoms cannot be explained by postural intolerance or tachycardia.
Ehlers-Danlos syndromes are a group of inherited heterogeneous disorders involving joint hypermobility, skin hyperextensibility, and tissue fragility.30 The hypermobile subtype is most commonly associated with POTS, with patients often having symptoms of autonomic dysregulation and autonomic test abnormalities.31–33 Patients with POTS may have a history of joint subluxations, joint pain, cervical instability, and spontaneous epidural leaks. The reason for the overlap between the two syndromes is not clear.
Chronic fatigue syndrome is characterized by persistent fatigue that does not resolve with rest and is not necessarily associated with orthostatic changes. More than 75% of patients with POTS report general fatigue as a major complaint, and up to 23% meet the full criteria for chronic fatigue syndrome.34
DIAGNOSTIC STRATEGY
A patient presenting with symptoms suggestive of POTS should first undergo a detailed history and physical examination. Other causes of sinus tachycardia should be considered.
Detailed history, symptom review
The history should focus on determining symptom burden, including tachycardia onset, frequency, severity, and triggers; the presence of syncope; and the impact of symptoms on daily function and quality of life.
Presyncope and its associated symptoms occur in less than one-third of patients with POTS, and syncope is not a principal feature.4 If syncope is the predominant complaint, alternative causes should be investigated. The usual cause of syncope in the general population is thought to be vasovagal.
In addition to orthostatic intolerance, gastrointestinal disturbances are common in POTS, presenting as abdominal pain, heartburn, irregular bowel movements, diarrhea, or constipation. Symptoms of gastroparesis are less common. Gastrointestinal symptoms tend to be prolonged, lasting hours and occurring multiple times a week. They tend not to improve in the supine position.35
POTS-associated symptoms may develop insidiously, but patients often report onset after an acute stressor such as pregnancy, major surgery, or a presumed viral illness.4 Whether these putative triggers are causative or coincidental is unknown. Symptoms of orthostatic intolerance tend to be exacerbated by dehydration, heat, alcohol, exercise, and menstruation.36,37
Consider the family history: 1 in 8 patients with POTS reports familial orthostatic intolerance,38 suggesting a genetic role in some patients. Inquire about symptoms or a previous diagnosis of Ehlers-Danlos syndrome and mast cell activation syndrome.
Consider other conditions
Pheochromocytoma causes hyperadrenergic symptoms (eg, palpitations, lightheadedness) like those in POTS, but patients with pheochromocytoma typically have these symptoms while supine. Pheochromocytoma is also characterized by plasma norepinephrine levels much higher than in POTS.4 Plasma metanephrine testing helps diagnose or rule out pheochromocytoma.5
Inappropriate sinus tachycardia, like pheochromocytoma, also has clinical features similar to those of POTS, as well as tachycardia present when supine. It involves higher sympathetic tone and lower parasympathetic tone compared with POTS; patients commonly have a daytime resting heart rate of at least 100 bpm or a 24-hour mean heart rate of at least 90 bpm.1,42 While the intrinsic heart rate is heightened in inappropriate sinus tachycardia, it is not different between POTS patients and healthy individuals.42,43 Distinguishing POTS from inappropriate sinus tachycardia is further complicated by the broad inclusion criteria of most studies of inappropriate sinus tachycardia, which failed to exclude patients with POTS.44 The Heart Rhythm Society recently adopted distinct definitions for the 2 conditions.1
Physical examination: Focus on vital signs
Dependent acrocyanosis—dark red-blue discoloration of the lower legs that is cold to the touch—occurs in about half of patients with POTS upon standing.4 Dependent acrocyanosis is associated with joint hypermobility and Ehlers-Danlos syndrome, so these conditions should also be considered if findings are positive.
Laboratory testing for other causes
Laboratory testing is used mainly to detect primary causes of sinus tachycardia. Tests should include:
- Complete blood cell count with hematocrit (for severe anemia)
- Thyroid-stimulating hormone level (for hyperthyroidism)
- Electrolyte panel (for significant electrolyte disturbances).
Evidence is insufficient to support routinely measuring the vitamin B12 level, iron indices, and serum markers for celiac disease, although these may be done if the history or physical examination suggests related problems.4 Sicca symptoms (severe dry eye or dry mouth) should trigger evaluation for Sjögren syndrome.
Electrocardiography needed
Electrocardiography should be performed to investigate for cardiac conduction abnormalities as well as for resting markers of a supraventricular tachyarrhythmia. Extended ambulatory (Holter) monitoring may be useful to evaluate for a transient reentrant tachyarrhythmia4; however, it does not record body position, so it can be difficult to determine if detected episodes of tachycardia are related to posture.
Additional testing for select cases
Further investigation is usually not needed to diagnose POTS but should be considered in some cases. Advanced tests are typically performed at a tertiary care referral center and include:
- Quantitative sensory testing to evaluate for small-fiber neuropathy (ie, Quantitative Sudomotor Axon Reflex Test, or QSART), which occurs in the neuropathic POTS subtype
- Formal autonomic function testing to characterize neurovascular responsiveness
- Supine and standing plasma norepinephrine levels (fractionated catecholamines) to characterize the net activation of the sympathetic nervous system
- Blood volume assessments to assess hypovolemia
- Formal exercise testing to objectively quantify exercise capacity.
GRADED MANAGEMENT
No single universal gold-standard therapy exists for POTS, and management should be individually determined with the primary goals of treating symptoms and restoring function. A graded approach should be used, starting with conservative nonpharmacologic therapies and adding medications as needed.
While the disease course varies substantially from patient to patient, proper management is strongly associated with eventual symptom improvement.1
NONPHARMACOLOGIC STEPS FIRST
Education
Patients should be informed of the nature of their condition and referred to appropriate healthcare personnel. POTS is a chronic illness requiring individualized coping strategies, intensive physician interaction, and support of a multidisciplinary team. Patients and family members can be reassured that most symptoms improve over time with appropriate diagnosis and treatment.1 Patients should be advised to avoid aggravating triggers and activities.
Exercise
Exercise programs are encouraged but should be introduced gradually, as physical activity can exacerbate symptoms, especially at the outset. Several studies have reported benefits from a short-term (3-month) program, in which the patient gradually progresses from non-upright exercise (eg, rowing machine, recumbent cycle, swimming) to upright endurance exercises. At the end of these programs, significant cardiac remodeling, improved quality of life, and reduced heart rate responses to standing have been reported, and benefits have been reported to persist in patients who continued exercising after the 3-month study period.46,47
Despite the benefits of exercise interventions, compliance is low.46,47 To prevent early discouragement, patients should be advised that it can take 4 to 6 weeks of continued exercise before benefits appear. Patients are encouraged to exercise every other day for 30 minutes or more. Regimens should primarily focus on aerobic conditioning, but resistance training, concentrating on thigh muscles, can also help. Exercise is a treatment and not a cure, and benefits can rapidly disappear if regular activity (at least 3 times per week) is stopped.48
Compression stockings
Compression stockings help reduce peripheral venous pooling and enhance venous return to the heart. Waist-high stockings with compression of at least 30 to 40 mm Hg offer the best results.
Diet
Increased fluid and salt intake is advisable for patients with suspected hypovolemia. At least 2 to 3 L of water accompanied by 10 to 12 g of daily sodium intake is recommended.1 This can usually be accomplished with diet and salt added to food, but salt tablets can be used if the patient prefers. The resultant plasma volume expansion may help reduce the reflex tachycardia upon standing.49
Check medications
Rescue therapy with saline infusion
Intravenous saline infusion can augment blood volume in patients who are clinically decompensated and present with severe symptoms.1 Intermittent infusion of 1 L of normal saline has been found to significantly reduce orthostatic tachycardia and related symptoms in patients with POTS, contributing to improved quality of life.51,52
Chronic saline infusions are not recommended for long-term care because of the risk of access complications and infection.1 Moak et al53 reported a high rate of bacteremia in a cohort of children with POTS with regular saline infusions, most of whom had a central line. On the other hand, Ruzieh et al54 reported significantly improved symptoms with regular saline infusions without a high rate of complications, but patients in this study received infusions for only a few months and through a peripheral intravenous catheter.
DRUG THERAPY
No medications are approved by the US Food and Drug Administration (FDA) or Health Canada specifically for treating POTS, making all pharmacologic recommendations off-label. Although the drugs discussed below have been evaluated for POTS in controlled laboratory settings, they have yet to be tested in robust clinical trials.
Blood volume expansion
Several drugs expand blood volume, which may reduce orthostatic tachycardia.
Fludrocortisone is a synthetic aldosterone analogue that enhances sodium and water retention. Although one observational study found that it normalizes hemodynamic changes in response to orthostatic stress, no high-level evidence exists for its effectiveness for POTS.55 It is generally well tolerated, although possible adverse effects include hyperkalemia, hypertension, fatigue, nausea, headache, and edema.5,56
Desmopressin is a synthetic version of a natural antidiuretic hormone that increases kidney-mediated free-water reabsorption without sodium retention. It significantly reduces upright heart rate in patients with POTS and improves symptom burden. Although potential adverse effects include edema and headache, hyponatremia is the primary concern with daily use, especially with the increased water intake advised for POTS.57 Patients should be advised to use desmopressin no more than once a week for the acute improvement of symptoms. Intermittent monitoring of serum sodium levels is recommended for safety.
Erythropoietin replacement has been suggested for treating POTS to address the significant deficit in red blood cell volume. Although erythropoietin therapy has a direct vasoconstrictive effect and largely improves red blood cell volume in patients with POTS, it does not expand plasma volume, so orthostatic tachycardia is not itself reduced.22 Nevertheless, it may significantly improve POTS symptoms refractory to more common methods of treatment, and it should be reserved for such cases. In addition to the lack of effect on orthostatic tachycardia, drawbacks to using erythropoietin include its high cost, the need for subcutaneous administration, and the risk of life-threatening complications such as myocardial infarction and stroke.58,59
Heart rate-lowering agents
Propranolol, a nonselective beta-adrenergic antagonist, can significantly reduce standing heart rate and improve symptoms at low dosages (10–20 mg). Higher dosages can further restrain orthostatic tachycardia but are not as well tolerated, mainly due to hypotension and worsening of existing symptoms such as fatigue.60 Regular-acting propranolol works for about 4 to 5 hours per dose, so full-day coverage often requires dosing 4 times per day.
Ivabradine is a selective blocker of the “funny” (If) channel that reduces the sinus node firing rate without affecting blood pressure, so it slows heart rate without causing supine hypertension or orthostatic hypotension.
A retrospective case series found that 60% of patients with POTS treated with ivabradine reported symptomatic improvement, and all patients experienced reduced tachycardia with continued use.61 Ivabradine has not been compared with placebo or propranolol in a randomized controlled trial, and it has not been well studied in pregnancy and so should be avoided because of potential teratogenic effects.
When prescribing ivabradine for women of childbearing age, a negative pregnancy test may be documented prior to initiation of therapy, and the use of highly effective methods of contraception is recommended. Ivabradine should be avoided in women contemplating pregnancy. Insurance coverage can limit access to ivabradine in the United States.
Central nervous system sympatholytics
Patients with prominent hyperadrenergic features may benefit from central sympatholytic agents. However, these drugs may not be well tolerated in patients with neuropathic POTS because of the effects of reduced systemic vascular resistance5 and the possible exacerbation of drowsiness, fatigue, and mental clouding.4 Patients can be extremely sensitive to these medications, so they should initially be prescribed at the lowest dose, then gradually increased as tolerated.
Clonidine, an alpha-2-adrenergic agonist, decreases central sympathetic tone. In hyperadrenergic patients, clonidine can stabilize heart rate and blood pressure, thereby reducing orthostatic symptoms.62
Methyldopa has effects similar to those of clonidine but is easier to titrate owing to its longer half-life.63 Methyldopa is typically started at 125 mg at bedtime and increased to 125 mg twice daily, if tolerated.
Other agents
Midodrine is a prodrug. The active form, an alpha-1-adrenergic agonist, constricts peripheral veins and arteries to increase vascular resistance and venous return, thereby reducing orthostatic tachycardia.52 It is most useful in patients with impaired peripheral vasoconstriction (eg, neuropathic POTS) and may be less effective in those with hyperadrenergic POTS.64 Major limitations of midodrine include worsening supine hypertension and possible urinary retention.39
Because of midodrine’s short half-life, frequent dosing is required during daytime hours (eg, 8 AM, noon, and 4 PM), but it should not be taken within 4 to 5 hours of sleep because of the risk of supine hypertension. Midodrine is typically started at 2.5 to 5 mg per dose and can be titrated up to 15 mg per dose.
Midodrine is an FDA pregnancy category C drug (adverse effects in pregnancy seen in animal models, but evidence lacking in humans). While ideally it should be avoided, we have used it safely in pregnant women with disabling POTS symptoms.
Pyridostigmine, an acetylcholinesterase inhibitor, increases cardiovagal tone and possibly sympathetic tone. It has been reported to significantly reduce standing heart rate and improve symptom burden in patients with POTS.65 However, pyridostigmine increases gastrointestinal mobility, leading to severe adverse effects in over 20% of patients, including abdominal cramps, nausea, and diarrhea.66
Droxidopa, a synthetic amino acid precursor of norepinephrine, improves dizziness and fatigue in POTS with minimal effects on blood pressure.67
Modafinil, a psychostimulant, may improve POTS-associated cognitive symptoms.4 It also raises upright blood pressure without significantly worsening standing heart rate or acute orthostatic symptoms.68
EFFECTS OF COMORBID DISORDERS ON MANAGEMENT
Ehlers-Danlos syndrome
Pharmacologic approaches to POTS should not be altered based on the presence of Ehlers-Danlos syndrome, but because many of these patients are prone to joint dislocation, exercise prescriptions may need adjusting.
A medical genetics consult is recommended for patients with Ehlers-Danlos syndrome. Although the hypermobile type (the form most commonly associated with POTS) is not associated with aortopathy, it can be confused with classical and vascular Ehlers-Danlos syndromes, which require serial aortic screening.30
Mast cell activation syndrome
Consultation with an allergist or immunologist may help patients with severe symptoms.
Autoantibodies and autoimmunity
Treatment of the underlying disorder is recommended and can result in significantly improved POTS symptoms.
SPECIALTY CARE REFERRAL
POTS can be challenging to manage. Given the range of physiologic, emotional, and functional distress patients experience, it often requires significant physician time and multidisciplinary care. Patients with continued severe or debilitating symptoms may benefit from referral to a tertiary-care center with experience in autonomic nervous system disorders.
PROGNOSIS
Limited data are available on the long-term prognosis of POTS, and more studies are needed in pediatric and adult populations. No deaths have been reported in the handful of published cases of POTS in patients older than 50.1 Some pediatric studies suggest that some teenagers “outgrow” their POTS. However, these data are not robust, and an alternative explanation is that as they get older, they see adult physicians for their POTS symptoms and so are lost to study follow-up.6,44,69
We have not often seen POTS simply resolve without ongoing treatment. However, in our experience, most patients have improved symptoms and function with multimodal treatment (ie, exercise, salt, water, stockings, and some medications) and time.
Some people, most of them relatively young women, experience lightheadedness, a racing heart, and other symptoms (but not hypotension) when they stand up, in a condition known as postural tachycardia syndrome (POTS).1 Although not known to shorten life,1 it can be physically and mentally debilitating.2,3 Therapy rarely cures it, but a multifaceted approach can substantially improve quality of life.
This review outlines the evaluation and diagnosis of POTS and provides guidance for a therapy regimen.
HOW IS POTS DEFINED?
POTS is a multifactorial syndrome rather than a specific disease. It is characterized by all of the following1,4–6:
- An increase in heart rate of ≥ 30 bpm, or ≥ 40 bpm for those under age 19, within 10 minutes of standing from a supine position
- Sustained tachycardia (> 30 seconds)
- Absence of orthostatic hypotension (a fall in blood pressure of ≥ 20/10 mm Hg)
- Frequent and chronic duration (≥ 6 months).
These features are critical to diagnosis. Hemodynamic criteria in isolation may describe postural tachycardia but are not sufficient to diagnose POTS.
The prevalence of POTS is estimated to be between 0.2% and 1.0%,7 affecting up to 3 million people in the United States. Most cases arise between ages 13 and 50, with a female-to-male ratio of 5:1.8
MANY NAMES, SAME CONDITION
In 1871, Da Costa9 described a condition he called “irritable heart syndrome” that had characteristics similar to those of POTS, including extreme fatigue and exercise intolerance. Decades later, Lewis10 and Wood11 provided more detailed descriptions of the disorder, renaming it “soldier’s heart” or “Da Costa syndrome.” As other cases were documented, more terms arose, including “effort syndrome” and “mitral valve prolapse syndrome.”
In 1982, Rosen and Cryer12 were the first to use the term “postural tachycardia syndrome” for patients with disabling tachycardia upon standing without orthostatic hypotension. In 1986, Fouad et al13 described patients with postural tachycardia, orthostatic intolerance, and a small degree of hypotension as having “idiopathic hypovolemia.”
In 1993, Schondorf and Low14 established the current definition of POTS, leading to increased awareness and research efforts to understand its pathophysiology.
MULTIFACTORIAL PATHOPHYSIOLOGY
During the last 2 decades, several often-overlapping forms of POTS have been recognized, all of which share a final common pathway of sustained orthostatic tachycardia.15–19 In addition, a number of common comorbidities were identified through review of large clinic populations of POTS.20,21
Hypovolemic POTS
Up to 70% of patients with POTS have hypovolemia. The average plasma volume deficit is about 13%, which typically causes only insignificant changes in heart rate and norepinephrine levels while a patient is supine. However, blood pooling associated with upright posture further compromises cardiac output and consequently increases sympathetic nerve activity. Abnormalities in the renin-angiotensin-aldosterone volume regulation system are also suspected to impair sodium retention, contributing to hypovolemia.1,22
Neuropathic POTS
About half of patients with POTS have partial sympathetic denervation (particularly in the lower limbs) and inadequate vasoconstriction upon standing, leading to reduced venous return and stroke volume.17,23 A compensatory increase in sympathetic tone results in tachycardia to maintain cardiac output and blood pressure.
Hyperadrenergic POTS
Up to 50% of patients with POTS have high norepinephrine levels (≥ 600 pg/mL) when upright. This subtype, hyperadrenergic POTS, is characterized by an increase in systolic blood pressure of at least 10 mm Hg within 10 minutes of standing, with concomitant tachycardia that can be similar to or greater than that seen in nonhyperadrenergic POTS. Patients with hyperadrenergic POTS tend to report more prominent symptoms of sympathetic activation, such as palpitations, anxiety, and tremulousness.24,25
Norepinephrine transporter deficiency
The norepinephrine transporter (NET) is on the presynaptic cleft of sympathetic neurons and serves to clear synaptic norepinephrine. NET deficiency leads to a hyperadrenergic state and elevated sympathetic nerve activation.18 NET deficiency may be induced by common antidepressants (eg, tricyclic antidepressants and serotonin-norepinephrine reuptake inhibitors) and attention-deficit disorder medications.4
Mast cell activation syndrome
The relationship between mast cell activation syndrome and POTS is poorly understood.4,26 Mast cell activation syndrome has been described in a subset of patients with POTS who have sinus tachycardia accompanied by severe episodic flushing. Patients with this subtype have a hyperadrenergic response to postural change and elevated urine methylhistamine during flushing episodes.
Patients with mast cell activation syndrome tend to have strong allergic symptoms and may also have severe gastrointestinal problems, food sensitivities, dermatographism, and neuropathy. Diagnosis can be difficult, as the condition is associated with numerous markers with varying sensitivity and specificity.
Autoimmune origin
A significant minority of patients report a viral-like illness before the onset of POTS symptoms, suggesting a possible autoimmune-mediated or inflammatory cause. Also, some autoimmune disorders (eg, Sjögren syndrome) can present with a POTS-like manifestation.
Research into the role of autoantibodies in the pathophysiology of POTS offers the potential to develop novel therapeutic targets. Autoantibodies that have been reported in POTS include those against M1 to M3 muscarinic receptors (present in over 87% of patients with POTS),27 cardiac lipid raft-associated proteins,28 adrenergic G-protein coupled receptors, alpha-1-adrenergic receptors, and beta-1- and beta-2-adrenergic receptors.29 Although commercial enzyme-linked immunosorbent assays can assess for these antibody fragments, it is not known whether targeting the antibodies improves outcomes. At this time, antibody testing for POTS should be confined to the research setting.
LINKS TO OTHER SYNDROMES
POTS is often associated with other conditions whose symptoms cannot be explained by postural intolerance or tachycardia.
Ehlers-Danlos syndromes are a group of inherited heterogeneous disorders involving joint hypermobility, skin hyperextensibility, and tissue fragility.30 The hypermobile subtype is most commonly associated with POTS, with patients often having symptoms of autonomic dysregulation and autonomic test abnormalities.31–33 Patients with POTS may have a history of joint subluxations, joint pain, cervical instability, and spontaneous epidural leaks. The reason for the overlap between the two syndromes is not clear.
Chronic fatigue syndrome is characterized by persistent fatigue that does not resolve with rest and is not necessarily associated with orthostatic changes. More than 75% of patients with POTS report general fatigue as a major complaint, and up to 23% meet the full criteria for chronic fatigue syndrome.34
DIAGNOSTIC STRATEGY
A patient presenting with symptoms suggestive of POTS should first undergo a detailed history and physical examination. Other causes of sinus tachycardia should be considered.
Detailed history, symptom review
The history should focus on determining symptom burden, including tachycardia onset, frequency, severity, and triggers; the presence of syncope; and the impact of symptoms on daily function and quality of life.
Presyncope and its associated symptoms occur in less than one-third of patients with POTS, and syncope is not a principal feature.4 If syncope is the predominant complaint, alternative causes should be investigated. The usual cause of syncope in the general population is thought to be vasovagal.
In addition to orthostatic intolerance, gastrointestinal disturbances are common in POTS, presenting as abdominal pain, heartburn, irregular bowel movements, diarrhea, or constipation. Symptoms of gastroparesis are less common. Gastrointestinal symptoms tend to be prolonged, lasting hours and occurring multiple times a week. They tend not to improve in the supine position.35
POTS-associated symptoms may develop insidiously, but patients often report onset after an acute stressor such as pregnancy, major surgery, or a presumed viral illness.4 Whether these putative triggers are causative or coincidental is unknown. Symptoms of orthostatic intolerance tend to be exacerbated by dehydration, heat, alcohol, exercise, and menstruation.36,37
Consider the family history: 1 in 8 patients with POTS reports familial orthostatic intolerance,38 suggesting a genetic role in some patients. Inquire about symptoms or a previous diagnosis of Ehlers-Danlos syndrome and mast cell activation syndrome.
Consider other conditions
Pheochromocytoma causes hyperadrenergic symptoms (eg, palpitations, lightheadedness) like those in POTS, but patients with pheochromocytoma typically have these symptoms while supine. Pheochromocytoma is also characterized by plasma norepinephrine levels much higher than in POTS.4 Plasma metanephrine testing helps diagnose or rule out pheochromocytoma.5
Inappropriate sinus tachycardia, like pheochromocytoma, also has clinical features similar to those of POTS, as well as tachycardia present when supine. It involves higher sympathetic tone and lower parasympathetic tone compared with POTS; patients commonly have a daytime resting heart rate of at least 100 bpm or a 24-hour mean heart rate of at least 90 bpm.1,42 While the intrinsic heart rate is heightened in inappropriate sinus tachycardia, it is not different between POTS patients and healthy individuals.42,43 Distinguishing POTS from inappropriate sinus tachycardia is further complicated by the broad inclusion criteria of most studies of inappropriate sinus tachycardia, which failed to exclude patients with POTS.44 The Heart Rhythm Society recently adopted distinct definitions for the 2 conditions.1
Physical examination: Focus on vital signs
Dependent acrocyanosis—dark red-blue discoloration of the lower legs that is cold to the touch—occurs in about half of patients with POTS upon standing.4 Dependent acrocyanosis is associated with joint hypermobility and Ehlers-Danlos syndrome, so these conditions should also be considered if findings are positive.
Laboratory testing for other causes
Laboratory testing is used mainly to detect primary causes of sinus tachycardia. Tests should include:
- Complete blood cell count with hematocrit (for severe anemia)
- Thyroid-stimulating hormone level (for hyperthyroidism)
- Electrolyte panel (for significant electrolyte disturbances).
Evidence is insufficient to support routinely measuring the vitamin B12 level, iron indices, and serum markers for celiac disease, although these may be done if the history or physical examination suggests related problems.4 Sicca symptoms (severe dry eye or dry mouth) should trigger evaluation for Sjögren syndrome.
Electrocardiography needed
Electrocardiography should be performed to investigate for cardiac conduction abnormalities as well as for resting markers of a supraventricular tachyarrhythmia. Extended ambulatory (Holter) monitoring may be useful to evaluate for a transient reentrant tachyarrhythmia4; however, it does not record body position, so it can be difficult to determine if detected episodes of tachycardia are related to posture.
Additional testing for select cases
Further investigation is usually not needed to diagnose POTS but should be considered in some cases. Advanced tests are typically performed at a tertiary care referral center and include:
- Quantitative sensory testing to evaluate for small-fiber neuropathy (ie, Quantitative Sudomotor Axon Reflex Test, or QSART), which occurs in the neuropathic POTS subtype
- Formal autonomic function testing to characterize neurovascular responsiveness
- Supine and standing plasma norepinephrine levels (fractionated catecholamines) to characterize the net activation of the sympathetic nervous system
- Blood volume assessments to assess hypovolemia
- Formal exercise testing to objectively quantify exercise capacity.
GRADED MANAGEMENT
No single universal gold-standard therapy exists for POTS, and management should be individually determined with the primary goals of treating symptoms and restoring function. A graded approach should be used, starting with conservative nonpharmacologic therapies and adding medications as needed.
While the disease course varies substantially from patient to patient, proper management is strongly associated with eventual symptom improvement.1
NONPHARMACOLOGIC STEPS FIRST
Education
Patients should be informed of the nature of their condition and referred to appropriate healthcare personnel. POTS is a chronic illness requiring individualized coping strategies, intensive physician interaction, and support of a multidisciplinary team. Patients and family members can be reassured that most symptoms improve over time with appropriate diagnosis and treatment.1 Patients should be advised to avoid aggravating triggers and activities.
Exercise
Exercise programs are encouraged but should be introduced gradually, as physical activity can exacerbate symptoms, especially at the outset. Several studies have reported benefits from a short-term (3-month) program, in which the patient gradually progresses from non-upright exercise (eg, rowing machine, recumbent cycle, swimming) to upright endurance exercises. At the end of these programs, significant cardiac remodeling, improved quality of life, and reduced heart rate responses to standing have been reported, and benefits have been reported to persist in patients who continued exercising after the 3-month study period.46,47
Despite the benefits of exercise interventions, compliance is low.46,47 To prevent early discouragement, patients should be advised that it can take 4 to 6 weeks of continued exercise before benefits appear. Patients are encouraged to exercise every other day for 30 minutes or more. Regimens should primarily focus on aerobic conditioning, but resistance training, concentrating on thigh muscles, can also help. Exercise is a treatment and not a cure, and benefits can rapidly disappear if regular activity (at least 3 times per week) is stopped.48
Compression stockings
Compression stockings help reduce peripheral venous pooling and enhance venous return to the heart. Waist-high stockings with compression of at least 30 to 40 mm Hg offer the best results.
Diet
Increased fluid and salt intake is advisable for patients with suspected hypovolemia. At least 2 to 3 L of water accompanied by 10 to 12 g of daily sodium intake is recommended.1 This can usually be accomplished with diet and salt added to food, but salt tablets can be used if the patient prefers. The resultant plasma volume expansion may help reduce the reflex tachycardia upon standing.49
Check medications
Rescue therapy with saline infusion
Intravenous saline infusion can augment blood volume in patients who are clinically decompensated and present with severe symptoms.1 Intermittent infusion of 1 L of normal saline has been found to significantly reduce orthostatic tachycardia and related symptoms in patients with POTS, contributing to improved quality of life.51,52
Chronic saline infusions are not recommended for long-term care because of the risk of access complications and infection.1 Moak et al53 reported a high rate of bacteremia in a cohort of children with POTS with regular saline infusions, most of whom had a central line. On the other hand, Ruzieh et al54 reported significantly improved symptoms with regular saline infusions without a high rate of complications, but patients in this study received infusions for only a few months and through a peripheral intravenous catheter.
DRUG THERAPY
No medications are approved by the US Food and Drug Administration (FDA) or Health Canada specifically for treating POTS, making all pharmacologic recommendations off-label. Although the drugs discussed below have been evaluated for POTS in controlled laboratory settings, they have yet to be tested in robust clinical trials.
Blood volume expansion
Several drugs expand blood volume, which may reduce orthostatic tachycardia.
Fludrocortisone is a synthetic aldosterone analogue that enhances sodium and water retention. Although one observational study found that it normalizes hemodynamic changes in response to orthostatic stress, no high-level evidence exists for its effectiveness for POTS.55 It is generally well tolerated, although possible adverse effects include hyperkalemia, hypertension, fatigue, nausea, headache, and edema.5,56
Desmopressin is a synthetic version of a natural antidiuretic hormone that increases kidney-mediated free-water reabsorption without sodium retention. It significantly reduces upright heart rate in patients with POTS and improves symptom burden. Although potential adverse effects include edema and headache, hyponatremia is the primary concern with daily use, especially with the increased water intake advised for POTS.57 Patients should be advised to use desmopressin no more than once a week for the acute improvement of symptoms. Intermittent monitoring of serum sodium levels is recommended for safety.
Erythropoietin replacement has been suggested for treating POTS to address the significant deficit in red blood cell volume. Although erythropoietin therapy has a direct vasoconstrictive effect and largely improves red blood cell volume in patients with POTS, it does not expand plasma volume, so orthostatic tachycardia is not itself reduced.22 Nevertheless, it may significantly improve POTS symptoms refractory to more common methods of treatment, and it should be reserved for such cases. In addition to the lack of effect on orthostatic tachycardia, drawbacks to using erythropoietin include its high cost, the need for subcutaneous administration, and the risk of life-threatening complications such as myocardial infarction and stroke.58,59
Heart rate-lowering agents
Propranolol, a nonselective beta-adrenergic antagonist, can significantly reduce standing heart rate and improve symptoms at low dosages (10–20 mg). Higher dosages can further restrain orthostatic tachycardia but are not as well tolerated, mainly due to hypotension and worsening of existing symptoms such as fatigue.60 Regular-acting propranolol works for about 4 to 5 hours per dose, so full-day coverage often requires dosing 4 times per day.
Ivabradine is a selective blocker of the “funny” (If) channel that reduces the sinus node firing rate without affecting blood pressure, so it slows heart rate without causing supine hypertension or orthostatic hypotension.
A retrospective case series found that 60% of patients with POTS treated with ivabradine reported symptomatic improvement, and all patients experienced reduced tachycardia with continued use.61 Ivabradine has not been compared with placebo or propranolol in a randomized controlled trial, and it has not been well studied in pregnancy and so should be avoided because of potential teratogenic effects.
When prescribing ivabradine for women of childbearing age, a negative pregnancy test may be documented prior to initiation of therapy, and the use of highly effective methods of contraception is recommended. Ivabradine should be avoided in women contemplating pregnancy. Insurance coverage can limit access to ivabradine in the United States.
Central nervous system sympatholytics
Patients with prominent hyperadrenergic features may benefit from central sympatholytic agents. However, these drugs may not be well tolerated in patients with neuropathic POTS because of the effects of reduced systemic vascular resistance5 and the possible exacerbation of drowsiness, fatigue, and mental clouding.4 Patients can be extremely sensitive to these medications, so they should initially be prescribed at the lowest dose, then gradually increased as tolerated.
Clonidine, an alpha-2-adrenergic agonist, decreases central sympathetic tone. In hyperadrenergic patients, clonidine can stabilize heart rate and blood pressure, thereby reducing orthostatic symptoms.62
Methyldopa has effects similar to those of clonidine but is easier to titrate owing to its longer half-life.63 Methyldopa is typically started at 125 mg at bedtime and increased to 125 mg twice daily, if tolerated.
Other agents
Midodrine is a prodrug. The active form, an alpha-1-adrenergic agonist, constricts peripheral veins and arteries to increase vascular resistance and venous return, thereby reducing orthostatic tachycardia.52 It is most useful in patients with impaired peripheral vasoconstriction (eg, neuropathic POTS) and may be less effective in those with hyperadrenergic POTS.64 Major limitations of midodrine include worsening supine hypertension and possible urinary retention.39
Because of midodrine’s short half-life, frequent dosing is required during daytime hours (eg, 8 AM, noon, and 4 PM), but it should not be taken within 4 to 5 hours of sleep because of the risk of supine hypertension. Midodrine is typically started at 2.5 to 5 mg per dose and can be titrated up to 15 mg per dose.
Midodrine is an FDA pregnancy category C drug (adverse effects in pregnancy seen in animal models, but evidence lacking in humans). While ideally it should be avoided, we have used it safely in pregnant women with disabling POTS symptoms.
Pyridostigmine, an acetylcholinesterase inhibitor, increases cardiovagal tone and possibly sympathetic tone. It has been reported to significantly reduce standing heart rate and improve symptom burden in patients with POTS.65 However, pyridostigmine increases gastrointestinal mobility, leading to severe adverse effects in over 20% of patients, including abdominal cramps, nausea, and diarrhea.66
Droxidopa, a synthetic amino acid precursor of norepinephrine, improves dizziness and fatigue in POTS with minimal effects on blood pressure.67
Modafinil, a psychostimulant, may improve POTS-associated cognitive symptoms.4 It also raises upright blood pressure without significantly worsening standing heart rate or acute orthostatic symptoms.68
EFFECTS OF COMORBID DISORDERS ON MANAGEMENT
Ehlers-Danlos syndrome
Pharmacologic approaches to POTS should not be altered based on the presence of Ehlers-Danlos syndrome, but because many of these patients are prone to joint dislocation, exercise prescriptions may need adjusting.
A medical genetics consult is recommended for patients with Ehlers-Danlos syndrome. Although the hypermobile type (the form most commonly associated with POTS) is not associated with aortopathy, it can be confused with classical and vascular Ehlers-Danlos syndromes, which require serial aortic screening.30
Mast cell activation syndrome
Consultation with an allergist or immunologist may help patients with severe symptoms.
Autoantibodies and autoimmunity
Treatment of the underlying disorder is recommended and can result in significantly improved POTS symptoms.
SPECIALTY CARE REFERRAL
POTS can be challenging to manage. Given the range of physiologic, emotional, and functional distress patients experience, it often requires significant physician time and multidisciplinary care. Patients with continued severe or debilitating symptoms may benefit from referral to a tertiary-care center with experience in autonomic nervous system disorders.
PROGNOSIS
Limited data are available on the long-term prognosis of POTS, and more studies are needed in pediatric and adult populations. No deaths have been reported in the handful of published cases of POTS in patients older than 50.1 Some pediatric studies suggest that some teenagers “outgrow” their POTS. However, these data are not robust, and an alternative explanation is that as they get older, they see adult physicians for their POTS symptoms and so are lost to study follow-up.6,44,69
We have not often seen POTS simply resolve without ongoing treatment. However, in our experience, most patients have improved symptoms and function with multimodal treatment (ie, exercise, salt, water, stockings, and some medications) and time.
- Sheldon RS, Grubb BP 2nd, Olshansky B, et al. 2015 Heart Rhythm Society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope. Heart Rhythm 2015; 12(6):e41–e63. doi:10.1016/j.hrthm.2015.03.029
- Bagai K, Song Y, Ling JF, et al. Sleep disturbances and diminished quality of life in postural tachycardia syndrome. J Clin Sleep Med 2011; 7(2):204–210. pmid:21509337
- Benrud-Larson LM, Dewar MS, Sandroni P, Rummans TA, Haythornthwaite JA, Low PA. Quality of life in patients with postural tachycardia syndrome. Mayo Clin Proc 2002; 77(6):531–537. doi:10.4065/77.6.531
- Raj SR. Postural tachycardia syndrome (POTS). Circulation 2013; 127(23):2336–2342. doi:10.1161/CIRCULATIONAHA.112.144501
- Raj SR. The postural tachycardia syndrome (POTS): pathophysiology, diagnosis & management. Indian Pacing Electrophysiol J 2006; 6(2):84–99. pmid:16943900
- Singer W, Sletten DM, Opfer-Gehrking TL, Brands CK, Fischer PR, Low PA. Postural tachycardia in children and adolescents: what is abnormal? J Pediatr 2012; 160(2):222–226. doi:10.1016/j.jpeds.2011.08.054
- Mar PL, Raj SR. Neuronal and hormonal perturbations in postural tachycardia syndrome. Front Physiol 2014; 5:220. doi:10.3389/fphys.2014.00220
- Garland EM, Raj SR, Black BK, Harris PA, Robertson D. The hemodynamic and neurohumoral phenotype of postural tachycardia syndrome. Neurology 2007; 69(8):790–798. doi:10.1212/01.wnl.0000267663.05398.40
- Da Costa JM. On irritable heart: a clinical study of a form of functional cardiac disorder and its consequences. Am J Med Sci 1871; 61(121):2–52.
- Lewis T. The tolerance of physical exertion, as shown by soldiers suffering from so-called “irritable heart.” Br Med J 1918; 1(2987):363–365. pmid:20768980
- Wood P. Da Costa’s syndrome (or effort syndrome): lecture I. Br Med J 1941; 1(4194):767–772. pmid:20783672
- Rosen SG, Cryer PE. Postural tachycardia syndrome. Reversal of sympathetic hyperresponsiveness and clinical improvement during sodium loading. Am J Med 1982; 72(5):847–850.
- Fouad FM, Tadena-Thome L, Bravo EL, Tarazi RC. Idiopathic hypovolemia. Ann Intern Med 1986; 104(3):298–303. pmid:3511818
- Schondorf R, Low PA. Idiopathic postural orthostatic tachycardia syndrome: an attenuated form of acute pandysautonomia? Neurology 1993; 43(1):132–137. pmid:8423877
- Vernino S, Low PA, Fealey RD, Stewart JD, Farrugia G, Lennon VA. Autoantibodies to ganglionic acetylcholine receptors in autoimmune autonomic neuropathies. N Engl J Med 2000; 343(12):847–855. doi:10.1056/NEJM200009213431204
- Raj SR, Robertson D. Blood volume perturbations in the postural tachycardia syndrome. Am J Med Sci 2007; 334(1):57–60. doi:10.1097/MAJ.0b013e318063c6c0
- Jacob G, Costa F, Shannon JR, et al. The neuropathic postural tachycardia syndrome. N Engl J Med 2000; 343(14):1008–1014. doi:10.1056/NEJM200010053431404
- Shannon JR, Flattem NL, Jordan J, et al. Orthostatic intolerance and tachycardia associated with norepinephrine-transporter deficiency. N Engl J Med 2000; 342(8):541–549. doi:10.1056/NEJM200002243420803
- Jones PK, Shaw BH, Raj SR. Clinical challenges in the diagnosis and management of postural tachycardia syndrome. Pract Neurol 2016; 16(6):431–438. doi:10.1136/practneurol-2016-001405
- Gunning WT, Karabin BL, Blomquist TM, Grubb BP. Postural orthostatic tachycardia syndrome is associated with platelet storage pool deficiency. Medicine (Baltimore) 2016; 95(37):e4849. doi:10.1097/MD.0000000000004849
- Kanjwal K, Sheikh M, Karabin B, Kanjwal Y, Grubb BP. Neurocardiogenic syncope coexisting with postural orthostatic tachycardia syndrome in patients suffering from orthostatic intolerance: a combined form of autonomic dysfunction. Pacing Clin Electrophysiol 2011; 34(5):549–554. doi:10.1111/j.1540-8159.2010.02994.x
- Raj SR, Biaggioni I, Yamhure PC, et al. Renin-aldosterone paradox and perturbed blood volume regulation underlying postural tachycardia syndrome. Circulation 2005; 111(13):1574–1582. doi:10.1161/01.CIR.0000160356.97313.5D
- Gibbons CH, Bonyhay I, Benson A, Wang N, Freeman R. Structural and functional small fiber abnormalities in the neuropathic postural tachycardia syndrome. PLoS One 2013; 8(12):e84716. doi:10.1371/journal.pone.0084716
- Low PA, Sandroni P, Joyner M, Shen WK. Postural tachycardia syndrome (POTS). J Cardiovasc Electrophysiol 2009; 20(3):352–358. doi:10.1111/j.1540-8167.2008.01407.x
- Kanjwal K, Saeed B, Karabin B, Kanjwal Y, Grubb BP. Clinical presentation and management of patients with hyperadrenergic postural orthostatic tachycardia syndrome. A single center experience. Cardiol J 2011; 18(5):527–531. pmid:21947988
- Shibao C, Arzubiaga C, Roberts J, et al. Hyperadrenergic postural tachycardia syndrome in mast cell activation disorders. Hypertension 2005; 45(3):385–390. doi:10.1161/01.HYP.0000158259.68614.40
- Dubey D, Hopkins S, Vernino S. M1 and M2 muscarinic receptor antibodies among patients with postural orthostatic tachycardia syndrome: potential disease biomarker [abstract]. J Clin Neuromuscul Dis 2016; 17(3):179S.
- Wang XL, Ling TY, Charlesworth MC, et al. Autoimmunoreactive IgGs against cardiac lipid raft-associated proteins in patients with postural orthostatic tachycardia syndrome. Transl Res 2013; 162(1):34–44. doi:10.1016/j.trsl.2013.03.002
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- Malfait F, Francomano C, Byers P, et al. The 2017 international classification of the Ehlers-Danlos syndromes. Am J Med Genet C Semin Med Genet 2017; 175(1):8–26. doi:10.1002/ajmg.c.31552
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- De Wandele I, Calders P, Peersman W, et al. Autonomic symptom burden in the hypermobility type of Ehlers-Danlos syndrome: a comparative study with two other EDS types, fibromyalgia, and healthy controls. Semin Arthritis Rheum 2014; 44(3):353–361. doi:10.1016/j.semarthrit.2014.05.013
- Gazit Y, Nahir AM, Grahame R, Jacob G. Dysautonomia in the joint hypermobility syndrome. Am J Med 2003; 115(1):33–40. pmid:12867232
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- Wang LB, Culbertson CJ, Deb A, Morgenshtern K, Huang H, Hohler AD. Gastrointestinal dysfunction in postural tachycardia syndrome. J Neurol Sci 2015; 359(1-2):193–196. doi:10.1016/j.jns.2015.10.052
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- Peggs KJ, Nguyen H, Enayat D, Keller NR, Al-Hendy A, Raj SR. Gynecologic disorders and menstrual cycle lightheadedness in postural tachycardia syndrome. Int J Gynaecol Obstet 2012; 118(3):242–246. doi:10.1016/j.ijgo.2012.04.014
- Thieben MJ, Sandroni P, Sletten DM, et al. Postural orthostatic tachycardia syndrome: the Mayo Clinic experience. Mayo Clin Proc 2007; 82(3):308–313. doi:10.4065/82.3.308
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- Nwazue VC, Paranjape SY, Black BK, et al. Postural tachycardia syndrome and inappropriate sinus tachycardia: role of autonomic modulation and sinus node automaticity. J Am Heart Assoc 2014; 3(2):e000700. doi:10.1161/JAHA.113.000700
- Morillo CA, Klein GJ, Thakur RK, Li H, Zardini M, Yee R. Mechanism of “inappropriate” sinus tachycardia. Role of sympathovagal balance. Circulation 1994; 90(2):873–877. pmid:7913886
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- Bhatia R, Kizilbash SJ, Ahrens SP, et al. Outcomes of adolescent-onset postural orthostatic tachycardia syndrome. J Pediatr 2016; 173:149–153. doi:10.1016/j.jpeds.2016.02.035
- George SA, Bivens TB, Howden EJ, et al. The international POTS registry: evaluating the efficacy of an exercise training intervention in a community setting. Heart Rhythm 2016; 13(4):943–950. doi:10.1016/j.hrthm.2015.12.012
- Fu Q, VanGundy TB, Galbreath MM, et al. Cardiac origins of the postural orthostatic tachycardia syndrome. J Am Coll Cardiol 2010; 55(25):2858–2868. doi:10.1016/j.jacc.2010.02.043
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- Garland EM, Celedonio JE, Raj SR. Postural tachycardia syndrome: beyond orthostatic intolerance. Curr Neurol Neurosci Rep 2015; 15(9):60. doi:10.1007/s11910-015-0583-8
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- Ruzieh M, Baugh A, Dasa O, et al. Effects of intermittent intravenous saline infusions in patients with medication-refractory postural tachycardia syndrome. J Interv Card Electrophysiol 2017; 48(3):255–260. doi:10.1007/s10840-017-0225-y
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- Coffin ST, Black BK, Biaggioni I, et al. Desmopressin acutely decreases tachycardia and improves symptoms in the postural tachycardia syndrome. Heart Rhythm 2012; 9(9):1484–1490. doi:10.1016/j.hrthm.2012.05.002
- Kanjwal K, Saeed B, Karabin B, Kanjwal Y, Sheikh M, Grubb BP. Erythropoietin in the treatment of postural orthostatic tachycardia syndrome. Am J Ther 2012; 19(2):92–95. doi:10.1097/MJT.0b013e3181ef621a
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- Ross AJ, Ocon AJ, Medow MS, Stewart JM. A double-blind placebo-controlled cross-over study of the vascular effects of midodrine in neuropathic compared with hyperadrenergic postural tachycardia syndrome. Clin Sci (Lond) 2014; 126(4):289–296. doi:10.1042/CS20130222
- Raj SR, Black BK, Biaggioni I, Harris PA, Robertson D. Acetylcholinesterase inhibition improves tachycardia in postural tachycardia syndrome. Circulation 2005; 111(21):2734–2340. doi:10.1161/CIRCULATIONAHA.104.497594
- Kanjwal K, Karabin B, Sheikh M, et al. Pyridostigmine in the treatment of postural orthostatic tachycardia: A single-center experience. Pacing Clin Electrophysiol 2011; 34(6):750–755. doi:10.1111/j.1540-8159.2011.03047.x
- Ruzieh M, Dasa O, Pacenta A, Karabin B, Grubb B. Droxidopa in the treatment of postural orthostatic tachycardia syndrome. Am J Ther 2017; 24(2):e157–e161. doi:10.1097/MJT.0000000000000468
- Kpaeyeh AG Jr, Mar PL, Raj V, et al. Hemodynamic profiles and tolerability of modafinil in the treatment of POTS: a randomized placebo-controlled trial. J Clin Psychopharmacol 2014; 34(6):738–741. doi:10.1097/JCP.0000000000000221
- Lai CC, Fischer PR, Brands CK, et al. Outcomes in adolescents with postural orthostatic tachycardia syndrome treated with midodrine and beta-blockers. Pacing Clin Electrophysiol 2009; 32(2):234–238. doi:10.1111/j.1540-8159.2008.02207.x
- Sheldon RS, Grubb BP 2nd, Olshansky B, et al. 2015 Heart Rhythm Society expert consensus statement on the diagnosis and treatment of postural tachycardia syndrome, inappropriate sinus tachycardia, and vasovagal syncope. Heart Rhythm 2015; 12(6):e41–e63. doi:10.1016/j.hrthm.2015.03.029
- Bagai K, Song Y, Ling JF, et al. Sleep disturbances and diminished quality of life in postural tachycardia syndrome. J Clin Sleep Med 2011; 7(2):204–210. pmid:21509337
- Benrud-Larson LM, Dewar MS, Sandroni P, Rummans TA, Haythornthwaite JA, Low PA. Quality of life in patients with postural tachycardia syndrome. Mayo Clin Proc 2002; 77(6):531–537. doi:10.4065/77.6.531
- Raj SR. Postural tachycardia syndrome (POTS). Circulation 2013; 127(23):2336–2342. doi:10.1161/CIRCULATIONAHA.112.144501
- Raj SR. The postural tachycardia syndrome (POTS): pathophysiology, diagnosis & management. Indian Pacing Electrophysiol J 2006; 6(2):84–99. pmid:16943900
- Singer W, Sletten DM, Opfer-Gehrking TL, Brands CK, Fischer PR, Low PA. Postural tachycardia in children and adolescents: what is abnormal? J Pediatr 2012; 160(2):222–226. doi:10.1016/j.jpeds.2011.08.054
- Mar PL, Raj SR. Neuronal and hormonal perturbations in postural tachycardia syndrome. Front Physiol 2014; 5:220. doi:10.3389/fphys.2014.00220
- Garland EM, Raj SR, Black BK, Harris PA, Robertson D. The hemodynamic and neurohumoral phenotype of postural tachycardia syndrome. Neurology 2007; 69(8):790–798. doi:10.1212/01.wnl.0000267663.05398.40
- Da Costa JM. On irritable heart: a clinical study of a form of functional cardiac disorder and its consequences. Am J Med Sci 1871; 61(121):2–52.
- Lewis T. The tolerance of physical exertion, as shown by soldiers suffering from so-called “irritable heart.” Br Med J 1918; 1(2987):363–365. pmid:20768980
- Wood P. Da Costa’s syndrome (or effort syndrome): lecture I. Br Med J 1941; 1(4194):767–772. pmid:20783672
- Rosen SG, Cryer PE. Postural tachycardia syndrome. Reversal of sympathetic hyperresponsiveness and clinical improvement during sodium loading. Am J Med 1982; 72(5):847–850.
- Fouad FM, Tadena-Thome L, Bravo EL, Tarazi RC. Idiopathic hypovolemia. Ann Intern Med 1986; 104(3):298–303. pmid:3511818
- Schondorf R, Low PA. Idiopathic postural orthostatic tachycardia syndrome: an attenuated form of acute pandysautonomia? Neurology 1993; 43(1):132–137. pmid:8423877
- Vernino S, Low PA, Fealey RD, Stewart JD, Farrugia G, Lennon VA. Autoantibodies to ganglionic acetylcholine receptors in autoimmune autonomic neuropathies. N Engl J Med 2000; 343(12):847–855. doi:10.1056/NEJM200009213431204
- Raj SR, Robertson D. Blood volume perturbations in the postural tachycardia syndrome. Am J Med Sci 2007; 334(1):57–60. doi:10.1097/MAJ.0b013e318063c6c0
- Jacob G, Costa F, Shannon JR, et al. The neuropathic postural tachycardia syndrome. N Engl J Med 2000; 343(14):1008–1014. doi:10.1056/NEJM200010053431404
- Shannon JR, Flattem NL, Jordan J, et al. Orthostatic intolerance and tachycardia associated with norepinephrine-transporter deficiency. N Engl J Med 2000; 342(8):541–549. doi:10.1056/NEJM200002243420803
- Jones PK, Shaw BH, Raj SR. Clinical challenges in the diagnosis and management of postural tachycardia syndrome. Pract Neurol 2016; 16(6):431–438. doi:10.1136/practneurol-2016-001405
- Gunning WT, Karabin BL, Blomquist TM, Grubb BP. Postural orthostatic tachycardia syndrome is associated with platelet storage pool deficiency. Medicine (Baltimore) 2016; 95(37):e4849. doi:10.1097/MD.0000000000004849
- Kanjwal K, Sheikh M, Karabin B, Kanjwal Y, Grubb BP. Neurocardiogenic syncope coexisting with postural orthostatic tachycardia syndrome in patients suffering from orthostatic intolerance: a combined form of autonomic dysfunction. Pacing Clin Electrophysiol 2011; 34(5):549–554. doi:10.1111/j.1540-8159.2010.02994.x
- Raj SR, Biaggioni I, Yamhure PC, et al. Renin-aldosterone paradox and perturbed blood volume regulation underlying postural tachycardia syndrome. Circulation 2005; 111(13):1574–1582. doi:10.1161/01.CIR.0000160356.97313.5D
- Gibbons CH, Bonyhay I, Benson A, Wang N, Freeman R. Structural and functional small fiber abnormalities in the neuropathic postural tachycardia syndrome. PLoS One 2013; 8(12):e84716. doi:10.1371/journal.pone.0084716
- Low PA, Sandroni P, Joyner M, Shen WK. Postural tachycardia syndrome (POTS). J Cardiovasc Electrophysiol 2009; 20(3):352–358. doi:10.1111/j.1540-8167.2008.01407.x
- Kanjwal K, Saeed B, Karabin B, Kanjwal Y, Grubb BP. Clinical presentation and management of patients with hyperadrenergic postural orthostatic tachycardia syndrome. A single center experience. Cardiol J 2011; 18(5):527–531. pmid:21947988
- Shibao C, Arzubiaga C, Roberts J, et al. Hyperadrenergic postural tachycardia syndrome in mast cell activation disorders. Hypertension 2005; 45(3):385–390. doi:10.1161/01.HYP.0000158259.68614.40
- Dubey D, Hopkins S, Vernino S. M1 and M2 muscarinic receptor antibodies among patients with postural orthostatic tachycardia syndrome: potential disease biomarker [abstract]. J Clin Neuromuscul Dis 2016; 17(3):179S.
- Wang XL, Ling TY, Charlesworth MC, et al. Autoimmunoreactive IgGs against cardiac lipid raft-associated proteins in patients with postural orthostatic tachycardia syndrome. Transl Res 2013; 162(1):34–44. doi:10.1016/j.trsl.2013.03.002
- Li H, Yu X, Liles C, et al. Autoimmune basis for postural tachycardia syndrome. J Am Heart Assoc 2014; 3(1):e000755. doi:10.1161/JAHA.113.000755
- Malfait F, Francomano C, Byers P, et al. The 2017 international classification of the Ehlers-Danlos syndromes. Am J Med Genet C Semin Med Genet 2017; 175(1):8–26. doi:10.1002/ajmg.c.31552
- Wallman D, Weinberg J, Hohler AD. Ehlers-Danlos syndrome and postural tachycardia syndrome: a relationship study. J Neurol Sci 2014; 340(1-2):99–102. doi:10.1016/j.jns.2014.03.002
- De Wandele I, Calders P, Peersman W, et al. Autonomic symptom burden in the hypermobility type of Ehlers-Danlos syndrome: a comparative study with two other EDS types, fibromyalgia, and healthy controls. Semin Arthritis Rheum 2014; 44(3):353–361. doi:10.1016/j.semarthrit.2014.05.013
- Gazit Y, Nahir AM, Grahame R, Jacob G. Dysautonomia in the joint hypermobility syndrome. Am J Med 2003; 115(1):33–40. pmid:12867232
- Okamoto LE, Raj SR, Peltier A, et al. Neurohumoral and haemodynamic profile in postural tachycardia and chronic fatigue syndromes. Clin Sci (Lond) 2012; 122(4):183–192. doi:10.1042/CS20110200
- Wang LB, Culbertson CJ, Deb A, Morgenshtern K, Huang H, Hohler AD. Gastrointestinal dysfunction in postural tachycardia syndrome. J Neurol Sci 2015; 359(1-2):193–196. doi:10.1016/j.jns.2015.10.052
- Raj S, Sheldon R. Management of postural tachycardia syndrome, inappropriate sinus tachycardia and vasovagal syncope. Arrhythm Electrophysiol Rev 2016; 5(2):122–129. doi:10.15420/AER.2016.7.2
- Peggs KJ, Nguyen H, Enayat D, Keller NR, Al-Hendy A, Raj SR. Gynecologic disorders and menstrual cycle lightheadedness in postural tachycardia syndrome. Int J Gynaecol Obstet 2012; 118(3):242–246. doi:10.1016/j.ijgo.2012.04.014
- Thieben MJ, Sandroni P, Sletten DM, et al. Postural orthostatic tachycardia syndrome: the Mayo Clinic experience. Mayo Clin Proc 2007; 82(3):308–313. doi:10.4065/82.3.308
- Deb A, Morgenshtern K, Culbertson CJ, Wang LB, Hohler AD. A survey-based analysis of symptoms in patients with postural orthostatic tachycardia syndrome. J Am Coll Cardiol 2015; 28(7):157–159. pmid:25829642
- Ertek S, Cicero AF. Hyperthyroidism and cardiovascular complications: a narrative review on the basis of pathophysiology. Arch Med Sci 2013; 9(5):944–952. doi:10.5114/aoms.2013.38685
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- Nwazue VC, Paranjape SY, Black BK, et al. Postural tachycardia syndrome and inappropriate sinus tachycardia: role of autonomic modulation and sinus node automaticity. J Am Heart Assoc 2014; 3(2):e000700. doi:10.1161/JAHA.113.000700
- Morillo CA, Klein GJ, Thakur RK, Li H, Zardini M, Yee R. Mechanism of “inappropriate” sinus tachycardia. Role of sympathovagal balance. Circulation 1994; 90(2):873–877. pmid:7913886
- Grubb BP. Postural tachycardia syndrome. Circulation 2008; 117(21):2814–2817. doi:10.1161/CIRCULATIONAHA.107.761643
- Bhatia R, Kizilbash SJ, Ahrens SP, et al. Outcomes of adolescent-onset postural orthostatic tachycardia syndrome. J Pediatr 2016; 173:149–153. doi:10.1016/j.jpeds.2016.02.035
- George SA, Bivens TB, Howden EJ, et al. The international POTS registry: evaluating the efficacy of an exercise training intervention in a community setting. Heart Rhythm 2016; 13(4):943–950. doi:10.1016/j.hrthm.2015.12.012
- Fu Q, VanGundy TB, Galbreath MM, et al. Cardiac origins of the postural orthostatic tachycardia syndrome. J Am Coll Cardiol 2010; 55(25):2858–2868. doi:10.1016/j.jacc.2010.02.043
- Raj SR. Row, row, row your way to treating postural tachycardia syndrome. Heart Rhythm 2016; 13(4):951–952. doi:10.1016/j.hrthm.2015.12.039
- Celedonio JE, Garland EM, Nwazue VC, et al. Effects of high sodium intake on blood volume and catecholamines in patients with postural tachycardia syndrome and healthy females [abstract]. Clin Auton Res 2014; 24:211.
- Garland EM, Celedonio JE, Raj SR. Postural tachycardia syndrome: beyond orthostatic intolerance. Curr Neurol Neurosci Rep 2015; 15(9):60. doi:10.1007/s11910-015-0583-8
- Gordon VM, Opfer-Gehrking TL, Novak V, Low PA. Hemodynamic and symptomatic effects of acute interventions on tilt in patients with postural tachycardia syndrome. Clin Auton Res 2000; 10:29–33. pmid:10750641
- Jacob G, Shannon JR, Black B, et al. Effects of volume loading and pressor agents in idiopathic orthostatic tachycardia. Circulation 1997; 96(2):575–580. pmid:9244228
- Moak JP, Leong D, Fabian R, et al. Intravenous hydration for management of medication-resistant orthostatic intolerance in the adolescent and young adult. Pediatr Cardiol 2016; 37(2):278–282. doi:10.1007/s00246-015-1274-6
- Ruzieh M, Baugh A, Dasa O, et al. Effects of intermittent intravenous saline infusions in patients with medication-refractory postural tachycardia syndrome. J Interv Card Electrophysiol 2017; 48(3):255–260. doi:10.1007/s10840-017-0225-y
- Freitas J, Santos R, Azevedo E, Costa O, Carvalho M, de Freitas AF. Clinical improvement in patients with orthostatic intolerance after treatment with bisoprolol and fludrocortisone. Clin Auton Res 2000; 10(5):293–299. pmid:11198485
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- Coffin ST, Black BK, Biaggioni I, et al. Desmopressin acutely decreases tachycardia and improves symptoms in the postural tachycardia syndrome. Heart Rhythm 2012; 9(9):1484–1490. doi:10.1016/j.hrthm.2012.05.002
- Kanjwal K, Saeed B, Karabin B, Kanjwal Y, Sheikh M, Grubb BP. Erythropoietin in the treatment of postural orthostatic tachycardia syndrome. Am J Ther 2012; 19(2):92–95. doi:10.1097/MJT.0b013e3181ef621a
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KEY POINTS
- Several POTS subtypes have been recognized, including hypovolemic, neuropathic, and hyperadrenergic forms, overlapping with Ehlers-Danlos syndrome, mast cell activation, and autoimmune syndromes.
- Treatment should take a graded approach, beginning with increasing salt and water intake, exercise, and compression stockings.
- If needed, consider medications to expand blood volume, slow heart rate, or reduce central sympathetic tone.
- Certain medications, including venodilators, diuretics, and serotonin-norepinephrine reuptake inhibitors, can exacerbate symptoms and should be avoided.
Human papillomavirus
To the Editor: I am an active primary care provider. After reading the update on human papillomavirus (HPV) in the March 2019 issue by Zhang and Batur,1 I was hoping for some clarification on a few points.
The statement is made that up to 70% of HPV-related cervical cancer cases can be prevented with vaccination. I have pulled the reference2 but cannot find supporting data for this claim. Is this proven or optimistic thinking based on the decreased incidence of abnormal Papanicolaou (Pap) test results such as noted in the University of New Mexico HPV Pap registry database3? The authors do cite an additional reference4 documenting a decreased incidence of cervical cancer in the United States among 15- to 24-year-olds from 2003–2006 compared with 2011–2014. This study reported a 29% relative risk reduction in the group receiving the vaccine, with the absolute numbers 6 vs 8.4 cases per 1,000,000. Thus, can the authors provide further references to the statement that 70% of cervical cancers can be prevented by vaccination?
The authors also state that vaccine acceptance rates are highest when primary care providers announce that the vaccine is due rather than invite open-ended discussions. At first this shocked me, but then made me pause and wonder how often I do that—and when I do, why. I regularly do it with all the other vaccines recommended by the Advisory Committee on Immunization Practices. When the parent or patient asks for further information, I am armed to provide it. To date, I am struggling to provide data to educate the patient on the efficacy of the HPV vaccine, particularly the claim that it will prevent 70% of cervical cancers. Are there more data that I am missing?
Finally, let me state that I am a “vaccinator”—always have been, and always will be. I discuss the HPV vaccine with my patients and their parents and try to provide data to support my recommendation. However, I am concerned that this current practice regarding the HPV vaccine has been driven by scare tactics and has now turned to “just give it because I say so.” The University of New Mexico Center for HPV prevention reports up to a 50% reduction in cervical intraepithelial neoplasias (precancer lesions) in teens.3 This is exciting information and raises hope for the future successful battle against cervical cancer. I think it is also more accurate than stating to parents and patients that we have proof that we have prevented 70% of cervical cancers. When we explain it in this manner, the majority of parents and patients buy in and, I believe, enjoy and welcome this open-ended discussion.
- Zhang S, Batur P. Human papillomavirus in 2019: an update on cervical cancer prevention and screening guidelines. Cleve Clin J Med 2019; 86(3):173–178. doi:10.3949/ccjm.86a.18018
- Thaxton L, Waxman AG. Cervical cancer prevention: immunization and screening 2015. Med Clin North Am 2015; 99(3): 469-477.
- Benard VB, Castle PE, Jenison SA, et al. Population-based incidence rates of cervical intraepithelial neoplasia in the human papillomavirus vaccine era. JAMA Oncol 2017; 3(6):833–837. doi:10.1001/jamaoncol.2016.3609
- Guo F, Cofie LE, Berenson AB. Cervical cancer incidence in young US females after human papillomavirus vaccine introduction. Am J Prev Med 2018; 55(2):197–204. doi:10.1016/j.amepre.2018.03.013
To the Editor: I am an active primary care provider. After reading the update on human papillomavirus (HPV) in the March 2019 issue by Zhang and Batur,1 I was hoping for some clarification on a few points.
The statement is made that up to 70% of HPV-related cervical cancer cases can be prevented with vaccination. I have pulled the reference2 but cannot find supporting data for this claim. Is this proven or optimistic thinking based on the decreased incidence of abnormal Papanicolaou (Pap) test results such as noted in the University of New Mexico HPV Pap registry database3? The authors do cite an additional reference4 documenting a decreased incidence of cervical cancer in the United States among 15- to 24-year-olds from 2003–2006 compared with 2011–2014. This study reported a 29% relative risk reduction in the group receiving the vaccine, with the absolute numbers 6 vs 8.4 cases per 1,000,000. Thus, can the authors provide further references to the statement that 70% of cervical cancers can be prevented by vaccination?
The authors also state that vaccine acceptance rates are highest when primary care providers announce that the vaccine is due rather than invite open-ended discussions. At first this shocked me, but then made me pause and wonder how often I do that—and when I do, why. I regularly do it with all the other vaccines recommended by the Advisory Committee on Immunization Practices. When the parent or patient asks for further information, I am armed to provide it. To date, I am struggling to provide data to educate the patient on the efficacy of the HPV vaccine, particularly the claim that it will prevent 70% of cervical cancers. Are there more data that I am missing?
Finally, let me state that I am a “vaccinator”—always have been, and always will be. I discuss the HPV vaccine with my patients and their parents and try to provide data to support my recommendation. However, I am concerned that this current practice regarding the HPV vaccine has been driven by scare tactics and has now turned to “just give it because I say so.” The University of New Mexico Center for HPV prevention reports up to a 50% reduction in cervical intraepithelial neoplasias (precancer lesions) in teens.3 This is exciting information and raises hope for the future successful battle against cervical cancer. I think it is also more accurate than stating to parents and patients that we have proof that we have prevented 70% of cervical cancers. When we explain it in this manner, the majority of parents and patients buy in and, I believe, enjoy and welcome this open-ended discussion.
To the Editor: I am an active primary care provider. After reading the update on human papillomavirus (HPV) in the March 2019 issue by Zhang and Batur,1 I was hoping for some clarification on a few points.
The statement is made that up to 70% of HPV-related cervical cancer cases can be prevented with vaccination. I have pulled the reference2 but cannot find supporting data for this claim. Is this proven or optimistic thinking based on the decreased incidence of abnormal Papanicolaou (Pap) test results such as noted in the University of New Mexico HPV Pap registry database3? The authors do cite an additional reference4 documenting a decreased incidence of cervical cancer in the United States among 15- to 24-year-olds from 2003–2006 compared with 2011–2014. This study reported a 29% relative risk reduction in the group receiving the vaccine, with the absolute numbers 6 vs 8.4 cases per 1,000,000. Thus, can the authors provide further references to the statement that 70% of cervical cancers can be prevented by vaccination?
The authors also state that vaccine acceptance rates are highest when primary care providers announce that the vaccine is due rather than invite open-ended discussions. At first this shocked me, but then made me pause and wonder how often I do that—and when I do, why. I regularly do it with all the other vaccines recommended by the Advisory Committee on Immunization Practices. When the parent or patient asks for further information, I am armed to provide it. To date, I am struggling to provide data to educate the patient on the efficacy of the HPV vaccine, particularly the claim that it will prevent 70% of cervical cancers. Are there more data that I am missing?
Finally, let me state that I am a “vaccinator”—always have been, and always will be. I discuss the HPV vaccine with my patients and their parents and try to provide data to support my recommendation. However, I am concerned that this current practice regarding the HPV vaccine has been driven by scare tactics and has now turned to “just give it because I say so.” The University of New Mexico Center for HPV prevention reports up to a 50% reduction in cervical intraepithelial neoplasias (precancer lesions) in teens.3 This is exciting information and raises hope for the future successful battle against cervical cancer. I think it is also more accurate than stating to parents and patients that we have proof that we have prevented 70% of cervical cancers. When we explain it in this manner, the majority of parents and patients buy in and, I believe, enjoy and welcome this open-ended discussion.
- Zhang S, Batur P. Human papillomavirus in 2019: an update on cervical cancer prevention and screening guidelines. Cleve Clin J Med 2019; 86(3):173–178. doi:10.3949/ccjm.86a.18018
- Thaxton L, Waxman AG. Cervical cancer prevention: immunization and screening 2015. Med Clin North Am 2015; 99(3): 469-477.
- Benard VB, Castle PE, Jenison SA, et al. Population-based incidence rates of cervical intraepithelial neoplasia in the human papillomavirus vaccine era. JAMA Oncol 2017; 3(6):833–837. doi:10.1001/jamaoncol.2016.3609
- Guo F, Cofie LE, Berenson AB. Cervical cancer incidence in young US females after human papillomavirus vaccine introduction. Am J Prev Med 2018; 55(2):197–204. doi:10.1016/j.amepre.2018.03.013
- Zhang S, Batur P. Human papillomavirus in 2019: an update on cervical cancer prevention and screening guidelines. Cleve Clin J Med 2019; 86(3):173–178. doi:10.3949/ccjm.86a.18018
- Thaxton L, Waxman AG. Cervical cancer prevention: immunization and screening 2015. Med Clin North Am 2015; 99(3): 469-477.
- Benard VB, Castle PE, Jenison SA, et al. Population-based incidence rates of cervical intraepithelial neoplasia in the human papillomavirus vaccine era. JAMA Oncol 2017; 3(6):833–837. doi:10.1001/jamaoncol.2016.3609
- Guo F, Cofie LE, Berenson AB. Cervical cancer incidence in young US females after human papillomavirus vaccine introduction. Am J Prev Med 2018; 55(2):197–204. doi:10.1016/j.amepre.2018.03.013
