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FDA approves ibrexafungerp for vaginal yeast infection
Ibrexafungerp is the first drug approved in a new antifungal class for vulvovaginal candidiasis (VVC) in more than 20 years, the drug’s manufacturer Scynexis said in a press release. It becomes the first and only nonazole treatment for vaginal yeast infections.
The biotechnology company said approval came after positive results from two phase 3 studies in which oral ibrexafungerp demonstrated efficacy and tolerability. The most common reactions observed in clinical trials were diarrhea, nausea, abdominal pain, dizziness, and vomiting.
There are few other treatments for vaginal yeast infections, which is the second most common cause of vaginitis. Those previously approved agents include several topical azole antifungals and oral fluconazole (Diflucan), which, Scynexis said, is the only other orally administered antifungal approved for the treatment of VVC in the United States and has accounted for over more than 90% of prescriptions written for the condition each year.
However, the company noted, oral fluconazole reports a 55% therapeutic cure rate on its label, which now also includes warnings of potential fetal harm, demonstrating the need for new oral options.
The new drug may not fill that need for pregnant women, however, as the company noted that ibrexafungerp should not be used during pregnancy, and administration during pregnancy “may cause fetal harm based on animal studies.”
Because of possible teratogenic effects, the company advised clinicians to verify pregnancy status in females of reproductive potential before prescribing ibrexafungerp and advises effective contraception during treatment.
VVC can come with substantial morbidity, including genital pain, itching and burning, reduced sexual pleasure, and psychological distress.
David Angulo, MD, chief medical officer for Scynexis, said in a statement the tablets brings new benefits.
Dr. Angulo said the drug “has a differentiated fungicidal mechanism of action that kills a broad range of Candida species, including azole-resistant strains. We are working on completing our CANDLE study investigating ibrexafungerp for the prevention of recurrent VVC and expect we will be submitting a supplemental NDA [new drug application] in the first half of 2022.”
Scynexis said it partnered with Amplity Health, a Pennsylvania-based pharmaceutical company, to support U.S. marketing of the drug. The commercial launch will follow the approval.
Ibrexafungerp was granted approval through both the FDA’s Qualified Infectious Disease Product and Fast Track designations. It is expected to be marketed exclusively in the United States for 10 years.
A version of this article first appeared on Medscape.com.
Ibrexafungerp is the first drug approved in a new antifungal class for vulvovaginal candidiasis (VVC) in more than 20 years, the drug’s manufacturer Scynexis said in a press release. It becomes the first and only nonazole treatment for vaginal yeast infections.
The biotechnology company said approval came after positive results from two phase 3 studies in which oral ibrexafungerp demonstrated efficacy and tolerability. The most common reactions observed in clinical trials were diarrhea, nausea, abdominal pain, dizziness, and vomiting.
There are few other treatments for vaginal yeast infections, which is the second most common cause of vaginitis. Those previously approved agents include several topical azole antifungals and oral fluconazole (Diflucan), which, Scynexis said, is the only other orally administered antifungal approved for the treatment of VVC in the United States and has accounted for over more than 90% of prescriptions written for the condition each year.
However, the company noted, oral fluconazole reports a 55% therapeutic cure rate on its label, which now also includes warnings of potential fetal harm, demonstrating the need for new oral options.
The new drug may not fill that need for pregnant women, however, as the company noted that ibrexafungerp should not be used during pregnancy, and administration during pregnancy “may cause fetal harm based on animal studies.”
Because of possible teratogenic effects, the company advised clinicians to verify pregnancy status in females of reproductive potential before prescribing ibrexafungerp and advises effective contraception during treatment.
VVC can come with substantial morbidity, including genital pain, itching and burning, reduced sexual pleasure, and psychological distress.
David Angulo, MD, chief medical officer for Scynexis, said in a statement the tablets brings new benefits.
Dr. Angulo said the drug “has a differentiated fungicidal mechanism of action that kills a broad range of Candida species, including azole-resistant strains. We are working on completing our CANDLE study investigating ibrexafungerp for the prevention of recurrent VVC and expect we will be submitting a supplemental NDA [new drug application] in the first half of 2022.”
Scynexis said it partnered with Amplity Health, a Pennsylvania-based pharmaceutical company, to support U.S. marketing of the drug. The commercial launch will follow the approval.
Ibrexafungerp was granted approval through both the FDA’s Qualified Infectious Disease Product and Fast Track designations. It is expected to be marketed exclusively in the United States for 10 years.
A version of this article first appeared on Medscape.com.
Ibrexafungerp is the first drug approved in a new antifungal class for vulvovaginal candidiasis (VVC) in more than 20 years, the drug’s manufacturer Scynexis said in a press release. It becomes the first and only nonazole treatment for vaginal yeast infections.
The biotechnology company said approval came after positive results from two phase 3 studies in which oral ibrexafungerp demonstrated efficacy and tolerability. The most common reactions observed in clinical trials were diarrhea, nausea, abdominal pain, dizziness, and vomiting.
There are few other treatments for vaginal yeast infections, which is the second most common cause of vaginitis. Those previously approved agents include several topical azole antifungals and oral fluconazole (Diflucan), which, Scynexis said, is the only other orally administered antifungal approved for the treatment of VVC in the United States and has accounted for over more than 90% of prescriptions written for the condition each year.
However, the company noted, oral fluconazole reports a 55% therapeutic cure rate on its label, which now also includes warnings of potential fetal harm, demonstrating the need for new oral options.
The new drug may not fill that need for pregnant women, however, as the company noted that ibrexafungerp should not be used during pregnancy, and administration during pregnancy “may cause fetal harm based on animal studies.”
Because of possible teratogenic effects, the company advised clinicians to verify pregnancy status in females of reproductive potential before prescribing ibrexafungerp and advises effective contraception during treatment.
VVC can come with substantial morbidity, including genital pain, itching and burning, reduced sexual pleasure, and psychological distress.
David Angulo, MD, chief medical officer for Scynexis, said in a statement the tablets brings new benefits.
Dr. Angulo said the drug “has a differentiated fungicidal mechanism of action that kills a broad range of Candida species, including azole-resistant strains. We are working on completing our CANDLE study investigating ibrexafungerp for the prevention of recurrent VVC and expect we will be submitting a supplemental NDA [new drug application] in the first half of 2022.”
Scynexis said it partnered with Amplity Health, a Pennsylvania-based pharmaceutical company, to support U.S. marketing of the drug. The commercial launch will follow the approval.
Ibrexafungerp was granted approval through both the FDA’s Qualified Infectious Disease Product and Fast Track designations. It is expected to be marketed exclusively in the United States for 10 years.
A version of this article first appeared on Medscape.com.
Vaping and pregnancy: Inhaled toxins among reasons for pause
Researchers are trying to understand how e-cigarette use affects pregnancy and birth outcomes. This question may become more relevant as younger vapers, among whom the devices gained considerable popularity, start having children.
Limited emerging data from animal experiments and human epidemiologic studies suggest that vaping may have negative effects on fertility and pregnancy. “Even if these impacts are less severe than conventional smoking, we really should be thinking about alternate options that may be safer for our patients than inhalation of this aerosol,” said Blair J. Wylie, MD, MPH, a maternal-fetal medicine physician at Beth Israel Deaconess Medical Center in Boston.
Dr. Wylie reviewed what is known about vaping, including chemicals other than nicotine that have been detected in vape aerosols, and pregnancy at the 2021 virtual meeting of the American College of Obstetricians and Gynecologists.
“There’s a lot we don’t know,” she said. “These products were only introduced recently, in 2003. They are marketed aggressively to our youth and have gained tremendous popularity among that population. And it’s only a matter of time, I think, before we see a lot of use in our own patient population.”
In a separate study presented at the ACOG meeting, Nicole Izhakoff, a researcher at Florida International University, Miami, and colleagues evaluated the association between e-cigarette use during pregnancy and unfavorable birth outcomes, such as preterm birth, low birth weight, or extended hospital stay for the newborn.
The investigators used 2016-2017 survey data from the Pregnancy Risk Assessment Monitoring System. In all, 71,940 women completed the survey, including 859 who reported e-cigarette use during pregnancy.
After adjusting for age, race, ethnicity, insurance, maternal education, prenatal care, abuse during pregnancy, and complications during pregnancy, the researchers estimated that the odds of an unfavorable birth outcome were 62% greater among women who used e-cigarettes during pregnancy, compared with those who did not.
The researchers lacked information about simultaneous use of alcohol, traditional tobacco, or other drugs, however.
“Physicians of all subspecialties, especially those of obstetrics-gynecology and pediatrics, need to increase the implementation of screening for past or current e-cigarette use in at-risk patients,” Ms. Izhakoff and coauthors concluded. “Further research regarding the long-term health effects of e-cigarettes is warranted.”
Dr. Wylie coauthored another study related to this topic that was published online May 24, 2021, in the Journal of Maternal-Fetal & Neonatal Medicine.
The researchers examined birth weights of children whose mothers use e-cigarettes alone, those whose mothers used both e-cigarettes and conventional cigarettes, and those whose mothers smoked conventional cigarettes only. Their estimates were imprecise, but signaled that e-cigarette use may reduce birth weight. The use of e-cigarettes alone appeared to have less of an impact on birth weight than the dual use of conventional cigarettes and e-cigarettes did.
Dr. Wylie cautioned that outcomes like birth weight are “pretty crude measures of whether an exposure is okay or not in pregnancy. Many of these toxins that we know that are in the aerosols can cause harm, but they may not be reflected in the absolute value of the birth weight.”
In addition, clinicians should avoid focusing on the wrong question when caring for patients.
“I think the wrong question is: Is vaping safer than smoking?” Dr. Wylie said in an interview. “Metals are going into your lungs. Plastics are going into your lungs. It is hard for me to think that we are going to identify that as our champion smoking cessation strategy in pregnancy.”
Rapidly changing landscape
Answering the question of which is safer is a challenge anyway because researchers likely have incomplete information about who vapes, who smokes, and who does both.
Still, the new research illustrates that “people are starting to think about this and beginning to do some analysis that is really hypothesis generating at this point,” Dr. Wylie said. Such studies may prompt clinicians to ask their patients about e-cigarette use. “Marijuana is sort of a similar thing where patients’ perception of safety, because things are legal, can lead to use during pregnancy without ... letting their care teams know,” she said. “Things are changing so rapidly in terms of what’s available to people to use that we need to stay on top of that as obstetricians and ask the right questions and try to understand what the risks are and potential benefits.”
Dr. Wylie is an obstetric consultant to the New England Pediatric Environmental Health Specialty Unit, which is where she heard pediatricians discussing widespread e-cigarette use among youth. It occurred to her that some of these teens eventually would be seeing obstetricians. She also saw parallels to prior research she conducted that focused on household air pollution or cooking from wood-burning fires in Africa.
“What is frightening, I think, about these electronic cigarettes is that you’re heating this liquid to extraordinarily high temperatures to create the vapor,” and the extreme heat vaporizes plastics and metals as well as nicotine, Dr. Wylie said.
An ACOG committee opinion discusses approaches to smoking and vaping cessation such as counseling, behavioral therapy, and medication.
The publication also lists a host of elements have been isolated from vape aerosol, including “carbonyl compounds (formaldehyde, acetaldehyde, acetone, and acrolein); volatile organic compounds (benzene and toluene); nitrosamines; particulate matter; and heavy metals such as copper, lead, zinc, and tin.”
In addition to the nicotine in e-cigarette liquids, which is harmful in itself, there is “all of this other company that it keeps,” including solvent byproducts, known carcinogens, and lung irritants, Dr. Wylie said. Fine particulate matter “can land in the small airways and cause inflammation, even translocate into the systemic circulation and cause systemic inflammation.”
The use of flavoring “likely alters perceptions of harm” and contributes to the popularity of vaping, Dr. Wylie noted. At the same time, the use of flavoring also has little regulatory oversight. Flavors usually are approved for marketing based on safety for ingestion, but that may not translate into safety for inhalation.
Parsing the health effects
People who vape have increased cough, wheezing, and phlegm production, compared with people who do not vape. Vaping also may worsen underlying lung disease like asthma. Lung function on spirometry decreases after e-cigarette use, studies have shown.
In 2019, researchers described e-cigarette or vaping product use–related acute lung injury (EVALI), which has caused more than 60 deaths in the United States. The condition may be related to vitamin E acetate, a component that had been used in some liquids used by patients with EVALI.
And the nicotine in e-cigarettes can accelerate atherogenesis and affect blood pressure, heart rate, and arterial stiffness.
Initially introduced as a smoking cessation tool, e-cigarettes now often are used on their own or in addition to cigarettes, rather than strictly for smoking cessation.
A Cochrane review suggests that e-cigarettes may be more effective than other approaches to smoking cessation. But “the effect is modest at best,” Dr. Wylie said. Among 100 people attempting to quit cigarette smoking, there might four to six more quitters with the use of e-cigarettes as a smoking cessation intervention, compared with other approaches.
Animal models provide other reasons for caution. One experiment in mice showed that exposure to e-cigarette aerosol impaired implantation and fetal health. The results suggest “that there might be some negative impacts across generations,” Dr. Wylie said.
Another study has suggested the possibility that women who currently use e-cigarettes may have slightly diminished fecundability. The results were not statistically significant, but the study “gives us pause about whether there could be some impact on early pregnancy and fertility,” Dr. Wylie said.
In mouse models, prenatal exposure to e-cigarette aerosol has decreased fetal weight and length, altered neurodevelopment and neuroregulatory gene expression, and increased proinflammatory cytokines. E-cigarette aerosol also has caused birth defects in zebrafish and facial clefting in frogs. Whether and how these data relate to human pregnancy is unclear.
While e-cigarette ads may convey a sense of style and harmlessness, clinicians have reasons to worry about the effects. “We have to be a little bit more cautious when we are talking about this with our patients,” Dr. Wylie said.
Dr. Wylie had no relevant financial disclosures. She is a Society for Maternal-Fetal Medicine board member and receives grant support related to research of household air pollution and pregnancy, prenatal pesticide exposure, preeclampsia in low income settings, and malaria during pregnancy. Ms. Izhakoff and coauthors had no disclosures.
Researchers are trying to understand how e-cigarette use affects pregnancy and birth outcomes. This question may become more relevant as younger vapers, among whom the devices gained considerable popularity, start having children.
Limited emerging data from animal experiments and human epidemiologic studies suggest that vaping may have negative effects on fertility and pregnancy. “Even if these impacts are less severe than conventional smoking, we really should be thinking about alternate options that may be safer for our patients than inhalation of this aerosol,” said Blair J. Wylie, MD, MPH, a maternal-fetal medicine physician at Beth Israel Deaconess Medical Center in Boston.
Dr. Wylie reviewed what is known about vaping, including chemicals other than nicotine that have been detected in vape aerosols, and pregnancy at the 2021 virtual meeting of the American College of Obstetricians and Gynecologists.
“There’s a lot we don’t know,” she said. “These products were only introduced recently, in 2003. They are marketed aggressively to our youth and have gained tremendous popularity among that population. And it’s only a matter of time, I think, before we see a lot of use in our own patient population.”
In a separate study presented at the ACOG meeting, Nicole Izhakoff, a researcher at Florida International University, Miami, and colleagues evaluated the association between e-cigarette use during pregnancy and unfavorable birth outcomes, such as preterm birth, low birth weight, or extended hospital stay for the newborn.
The investigators used 2016-2017 survey data from the Pregnancy Risk Assessment Monitoring System. In all, 71,940 women completed the survey, including 859 who reported e-cigarette use during pregnancy.
After adjusting for age, race, ethnicity, insurance, maternal education, prenatal care, abuse during pregnancy, and complications during pregnancy, the researchers estimated that the odds of an unfavorable birth outcome were 62% greater among women who used e-cigarettes during pregnancy, compared with those who did not.
The researchers lacked information about simultaneous use of alcohol, traditional tobacco, or other drugs, however.
“Physicians of all subspecialties, especially those of obstetrics-gynecology and pediatrics, need to increase the implementation of screening for past or current e-cigarette use in at-risk patients,” Ms. Izhakoff and coauthors concluded. “Further research regarding the long-term health effects of e-cigarettes is warranted.”
Dr. Wylie coauthored another study related to this topic that was published online May 24, 2021, in the Journal of Maternal-Fetal & Neonatal Medicine.
The researchers examined birth weights of children whose mothers use e-cigarettes alone, those whose mothers used both e-cigarettes and conventional cigarettes, and those whose mothers smoked conventional cigarettes only. Their estimates were imprecise, but signaled that e-cigarette use may reduce birth weight. The use of e-cigarettes alone appeared to have less of an impact on birth weight than the dual use of conventional cigarettes and e-cigarettes did.
Dr. Wylie cautioned that outcomes like birth weight are “pretty crude measures of whether an exposure is okay or not in pregnancy. Many of these toxins that we know that are in the aerosols can cause harm, but they may not be reflected in the absolute value of the birth weight.”
In addition, clinicians should avoid focusing on the wrong question when caring for patients.
“I think the wrong question is: Is vaping safer than smoking?” Dr. Wylie said in an interview. “Metals are going into your lungs. Plastics are going into your lungs. It is hard for me to think that we are going to identify that as our champion smoking cessation strategy in pregnancy.”
Rapidly changing landscape
Answering the question of which is safer is a challenge anyway because researchers likely have incomplete information about who vapes, who smokes, and who does both.
Still, the new research illustrates that “people are starting to think about this and beginning to do some analysis that is really hypothesis generating at this point,” Dr. Wylie said. Such studies may prompt clinicians to ask their patients about e-cigarette use. “Marijuana is sort of a similar thing where patients’ perception of safety, because things are legal, can lead to use during pregnancy without ... letting their care teams know,” she said. “Things are changing so rapidly in terms of what’s available to people to use that we need to stay on top of that as obstetricians and ask the right questions and try to understand what the risks are and potential benefits.”
Dr. Wylie is an obstetric consultant to the New England Pediatric Environmental Health Specialty Unit, which is where she heard pediatricians discussing widespread e-cigarette use among youth. It occurred to her that some of these teens eventually would be seeing obstetricians. She also saw parallels to prior research she conducted that focused on household air pollution or cooking from wood-burning fires in Africa.
“What is frightening, I think, about these electronic cigarettes is that you’re heating this liquid to extraordinarily high temperatures to create the vapor,” and the extreme heat vaporizes plastics and metals as well as nicotine, Dr. Wylie said.
An ACOG committee opinion discusses approaches to smoking and vaping cessation such as counseling, behavioral therapy, and medication.
The publication also lists a host of elements have been isolated from vape aerosol, including “carbonyl compounds (formaldehyde, acetaldehyde, acetone, and acrolein); volatile organic compounds (benzene and toluene); nitrosamines; particulate matter; and heavy metals such as copper, lead, zinc, and tin.”
In addition to the nicotine in e-cigarette liquids, which is harmful in itself, there is “all of this other company that it keeps,” including solvent byproducts, known carcinogens, and lung irritants, Dr. Wylie said. Fine particulate matter “can land in the small airways and cause inflammation, even translocate into the systemic circulation and cause systemic inflammation.”
The use of flavoring “likely alters perceptions of harm” and contributes to the popularity of vaping, Dr. Wylie noted. At the same time, the use of flavoring also has little regulatory oversight. Flavors usually are approved for marketing based on safety for ingestion, but that may not translate into safety for inhalation.
Parsing the health effects
People who vape have increased cough, wheezing, and phlegm production, compared with people who do not vape. Vaping also may worsen underlying lung disease like asthma. Lung function on spirometry decreases after e-cigarette use, studies have shown.
In 2019, researchers described e-cigarette or vaping product use–related acute lung injury (EVALI), which has caused more than 60 deaths in the United States. The condition may be related to vitamin E acetate, a component that had been used in some liquids used by patients with EVALI.
And the nicotine in e-cigarettes can accelerate atherogenesis and affect blood pressure, heart rate, and arterial stiffness.
Initially introduced as a smoking cessation tool, e-cigarettes now often are used on their own or in addition to cigarettes, rather than strictly for smoking cessation.
A Cochrane review suggests that e-cigarettes may be more effective than other approaches to smoking cessation. But “the effect is modest at best,” Dr. Wylie said. Among 100 people attempting to quit cigarette smoking, there might four to six more quitters with the use of e-cigarettes as a smoking cessation intervention, compared with other approaches.
Animal models provide other reasons for caution. One experiment in mice showed that exposure to e-cigarette aerosol impaired implantation and fetal health. The results suggest “that there might be some negative impacts across generations,” Dr. Wylie said.
Another study has suggested the possibility that women who currently use e-cigarettes may have slightly diminished fecundability. The results were not statistically significant, but the study “gives us pause about whether there could be some impact on early pregnancy and fertility,” Dr. Wylie said.
In mouse models, prenatal exposure to e-cigarette aerosol has decreased fetal weight and length, altered neurodevelopment and neuroregulatory gene expression, and increased proinflammatory cytokines. E-cigarette aerosol also has caused birth defects in zebrafish and facial clefting in frogs. Whether and how these data relate to human pregnancy is unclear.
While e-cigarette ads may convey a sense of style and harmlessness, clinicians have reasons to worry about the effects. “We have to be a little bit more cautious when we are talking about this with our patients,” Dr. Wylie said.
Dr. Wylie had no relevant financial disclosures. She is a Society for Maternal-Fetal Medicine board member and receives grant support related to research of household air pollution and pregnancy, prenatal pesticide exposure, preeclampsia in low income settings, and malaria during pregnancy. Ms. Izhakoff and coauthors had no disclosures.
Researchers are trying to understand how e-cigarette use affects pregnancy and birth outcomes. This question may become more relevant as younger vapers, among whom the devices gained considerable popularity, start having children.
Limited emerging data from animal experiments and human epidemiologic studies suggest that vaping may have negative effects on fertility and pregnancy. “Even if these impacts are less severe than conventional smoking, we really should be thinking about alternate options that may be safer for our patients than inhalation of this aerosol,” said Blair J. Wylie, MD, MPH, a maternal-fetal medicine physician at Beth Israel Deaconess Medical Center in Boston.
Dr. Wylie reviewed what is known about vaping, including chemicals other than nicotine that have been detected in vape aerosols, and pregnancy at the 2021 virtual meeting of the American College of Obstetricians and Gynecologists.
“There’s a lot we don’t know,” she said. “These products were only introduced recently, in 2003. They are marketed aggressively to our youth and have gained tremendous popularity among that population. And it’s only a matter of time, I think, before we see a lot of use in our own patient population.”
In a separate study presented at the ACOG meeting, Nicole Izhakoff, a researcher at Florida International University, Miami, and colleagues evaluated the association between e-cigarette use during pregnancy and unfavorable birth outcomes, such as preterm birth, low birth weight, or extended hospital stay for the newborn.
The investigators used 2016-2017 survey data from the Pregnancy Risk Assessment Monitoring System. In all, 71,940 women completed the survey, including 859 who reported e-cigarette use during pregnancy.
After adjusting for age, race, ethnicity, insurance, maternal education, prenatal care, abuse during pregnancy, and complications during pregnancy, the researchers estimated that the odds of an unfavorable birth outcome were 62% greater among women who used e-cigarettes during pregnancy, compared with those who did not.
The researchers lacked information about simultaneous use of alcohol, traditional tobacco, or other drugs, however.
“Physicians of all subspecialties, especially those of obstetrics-gynecology and pediatrics, need to increase the implementation of screening for past or current e-cigarette use in at-risk patients,” Ms. Izhakoff and coauthors concluded. “Further research regarding the long-term health effects of e-cigarettes is warranted.”
Dr. Wylie coauthored another study related to this topic that was published online May 24, 2021, in the Journal of Maternal-Fetal & Neonatal Medicine.
The researchers examined birth weights of children whose mothers use e-cigarettes alone, those whose mothers used both e-cigarettes and conventional cigarettes, and those whose mothers smoked conventional cigarettes only. Their estimates were imprecise, but signaled that e-cigarette use may reduce birth weight. The use of e-cigarettes alone appeared to have less of an impact on birth weight than the dual use of conventional cigarettes and e-cigarettes did.
Dr. Wylie cautioned that outcomes like birth weight are “pretty crude measures of whether an exposure is okay or not in pregnancy. Many of these toxins that we know that are in the aerosols can cause harm, but they may not be reflected in the absolute value of the birth weight.”
In addition, clinicians should avoid focusing on the wrong question when caring for patients.
“I think the wrong question is: Is vaping safer than smoking?” Dr. Wylie said in an interview. “Metals are going into your lungs. Plastics are going into your lungs. It is hard for me to think that we are going to identify that as our champion smoking cessation strategy in pregnancy.”
Rapidly changing landscape
Answering the question of which is safer is a challenge anyway because researchers likely have incomplete information about who vapes, who smokes, and who does both.
Still, the new research illustrates that “people are starting to think about this and beginning to do some analysis that is really hypothesis generating at this point,” Dr. Wylie said. Such studies may prompt clinicians to ask their patients about e-cigarette use. “Marijuana is sort of a similar thing where patients’ perception of safety, because things are legal, can lead to use during pregnancy without ... letting their care teams know,” she said. “Things are changing so rapidly in terms of what’s available to people to use that we need to stay on top of that as obstetricians and ask the right questions and try to understand what the risks are and potential benefits.”
Dr. Wylie is an obstetric consultant to the New England Pediatric Environmental Health Specialty Unit, which is where she heard pediatricians discussing widespread e-cigarette use among youth. It occurred to her that some of these teens eventually would be seeing obstetricians. She also saw parallels to prior research she conducted that focused on household air pollution or cooking from wood-burning fires in Africa.
“What is frightening, I think, about these electronic cigarettes is that you’re heating this liquid to extraordinarily high temperatures to create the vapor,” and the extreme heat vaporizes plastics and metals as well as nicotine, Dr. Wylie said.
An ACOG committee opinion discusses approaches to smoking and vaping cessation such as counseling, behavioral therapy, and medication.
The publication also lists a host of elements have been isolated from vape aerosol, including “carbonyl compounds (formaldehyde, acetaldehyde, acetone, and acrolein); volatile organic compounds (benzene and toluene); nitrosamines; particulate matter; and heavy metals such as copper, lead, zinc, and tin.”
In addition to the nicotine in e-cigarette liquids, which is harmful in itself, there is “all of this other company that it keeps,” including solvent byproducts, known carcinogens, and lung irritants, Dr. Wylie said. Fine particulate matter “can land in the small airways and cause inflammation, even translocate into the systemic circulation and cause systemic inflammation.”
The use of flavoring “likely alters perceptions of harm” and contributes to the popularity of vaping, Dr. Wylie noted. At the same time, the use of flavoring also has little regulatory oversight. Flavors usually are approved for marketing based on safety for ingestion, but that may not translate into safety for inhalation.
Parsing the health effects
People who vape have increased cough, wheezing, and phlegm production, compared with people who do not vape. Vaping also may worsen underlying lung disease like asthma. Lung function on spirometry decreases after e-cigarette use, studies have shown.
In 2019, researchers described e-cigarette or vaping product use–related acute lung injury (EVALI), which has caused more than 60 deaths in the United States. The condition may be related to vitamin E acetate, a component that had been used in some liquids used by patients with EVALI.
And the nicotine in e-cigarettes can accelerate atherogenesis and affect blood pressure, heart rate, and arterial stiffness.
Initially introduced as a smoking cessation tool, e-cigarettes now often are used on their own or in addition to cigarettes, rather than strictly for smoking cessation.
A Cochrane review suggests that e-cigarettes may be more effective than other approaches to smoking cessation. But “the effect is modest at best,” Dr. Wylie said. Among 100 people attempting to quit cigarette smoking, there might four to six more quitters with the use of e-cigarettes as a smoking cessation intervention, compared with other approaches.
Animal models provide other reasons for caution. One experiment in mice showed that exposure to e-cigarette aerosol impaired implantation and fetal health. The results suggest “that there might be some negative impacts across generations,” Dr. Wylie said.
Another study has suggested the possibility that women who currently use e-cigarettes may have slightly diminished fecundability. The results were not statistically significant, but the study “gives us pause about whether there could be some impact on early pregnancy and fertility,” Dr. Wylie said.
In mouse models, prenatal exposure to e-cigarette aerosol has decreased fetal weight and length, altered neurodevelopment and neuroregulatory gene expression, and increased proinflammatory cytokines. E-cigarette aerosol also has caused birth defects in zebrafish and facial clefting in frogs. Whether and how these data relate to human pregnancy is unclear.
While e-cigarette ads may convey a sense of style and harmlessness, clinicians have reasons to worry about the effects. “We have to be a little bit more cautious when we are talking about this with our patients,” Dr. Wylie said.
Dr. Wylie had no relevant financial disclosures. She is a Society for Maternal-Fetal Medicine board member and receives grant support related to research of household air pollution and pregnancy, prenatal pesticide exposure, preeclampsia in low income settings, and malaria during pregnancy. Ms. Izhakoff and coauthors had no disclosures.
FROM ACOG 2021
Is Person-Centered Physical Activity–Promoting Intervention for Individuals With CWP More Effective With Digital Support or Telephone Support?
Study Overview
Objective. To determine the effectiveness of a person-centered intervention (comprising personalized and cocreated treatment plans to promote physical activity) for individuals with chronic widespread pain when delivered with digital eHealth support compared with standard telephone follow-up.
Design. Single-blinded multicenter randomized controlled trial.
Settings and participants. Participants with chronic widespread pain (CWP) who had participated in a pain management program from 2010–16 at 5 primary health care rehabilitation centers in 5 cities or towns in the western part of Sweden were invited to join the study between March 2018 and April 2019 via letter providing information about the intervention. The letter was followed by a phone call 1-2 weeks later to screen for inclusion and exclusion criteria and interest in participating. Additional participants were invited to participate via a newspaper advertisement in 1 of the 5 cities.
Inclusion criteria were Swedish-speaking persons aged 20–65 years with CWP (defined as having pain in both sides of the body, pain above and below the waist, and axial pain for at least 3 months). Exclusion criteria included having other severe somatic or psychiatric disorders, dominating causes of pain other than CWP, or other severe disease interfering with the ability to be physically active, pregnancy, not having access to a smartphone or a computer, inability to speak or understand Swedish, ongoing physiotherapy treatment, and already exercising regularly. Of 716 people initially assessed for eligibility, 425 completed telephone screening, and 139 were randomized (using block randomization) to either the intervention arm (n = 69) or the active control arm (n = 70). Due to the nature of the intervention, it was not possible to blind the participants or the physiotherapist to group allocation. All participants provided written informed consent.
The 2 groups underwent the same first individual meeting with a physiotherapist to cocreate a health plan with physical activities, and, if needed, stress management, based on each participant’s individual preferences, obstacles, goals, and resources. The difference between the groups was the type of follow-up support. Participants in the intervention group had 1 follow-up meeting with the physiotherapist a week after the initial meeting (to review and adjust the health plan as needed) and thereafter were supported through a digital e-health platform (accessed via the participant’s smartphone or computer) during the 6-month follow-up period. Participants were encouraged to access the platform once a week to answer questions regarding their health, and the extent to which they had been able to manage their health plan during the previous week. In addition, the participant and physiotherapist could communicate via the platform as needed. Participants in the active control group had 1 follow-up phone call with the physiotherapist 1 month after the initial meeting (similarly to review and adjust the health plan as needed), and no further contact or support from the physiotherapist during the 6-month follow-up period.
Measures and analysis. The primary outcome measure was pain intensity during the previous week assessed with a 0–100 subscale from the Fibromyalgia Impact Questionnaire (FIQ-pain). Secondary outcome measures included overall health status (via FIQ-total with 10 subscales), global fatigue (via FIQ-fatigue subscale), multidimensional fatigue (via Multidimensional Fatigue Inventory, a 20-item questionnaire rated on a 1-5 Likert scale), clinical manifestations of stress (via Stress and Crisis Inventory, a 35-item questionnaire rated on a 0-4 Likert scale), self-efficacy (via General Self-Efficacy Scale, a 10-item questionnaire rated on a 1-4 Likert scale), health-related quality of life (via Short Form 36, specifically the Physical Component Summary composite score), leisure-time physical activity (via Leisure Time Physical Activity Instrument), and physical function (via 1-min chair-stand test). Additional demographic data on age, pain localization, pharmacological treatment, tobacco use, country of birth, level of education, family status, economic status, work status, sick-leave, and disability pension were collected via a questionnaire.
Between-group differences for changes in outcomes from baseline to 6-month follow-up were calculated using the Mann–Whitney U test for continuous data, and Pearson’s χ2 or Fisher’s exact test for categorical data. Significance level was set at 5% with no adjustment for multiple comparisons. All analyses were made according to intention-to-treat by originally assigned group; missing cases were not included in the analysis.
Main results. Participants consisted of primarily middle-age, middle income, educated (> 12 years of education) females, with > 60% of participants working at least part-time (between-group differences in baseline data and demographic data not detailed in the article). A total of 29 participants were lost to follow-up. In the intervention group, lost-to-follow up participants were older, performed fewer hours of physical activity, and had lower mental fatigue at baseline, compared with those who were lost to follow-up in the active control group.
In between-group analyses, there were no significant differences in the primary outcome (pain intensity) from baseline to 6-month follow-up. The only significant difference in secondary outcomes was seen in global fatigue – the active control group improved significantly compared with the intervention group (P = .004).
In the intervention group, 87% of participants used the digital platform. Among these users, 35% contacted the physiotherapist (75% of these communications were health- or study-related issues, 25% were issues with the digital platform), 33% were contacted by the physiotherapist (96% of these communications were about the health plan and physical activity), and 32% never had any contact with the physiotherapist. There was a significant difference in the primary outcome (pain intensity) from baseline to 6-month follow-up between platform users and non-users (P = .03, mean change [SD] 3.8 [19.66] mm vs –20.5 [6.36] mm, respectively).
Conclusion. No significant differences were found between the groups after 6 months (except for a significant decrease in global fatigue in the active control group compared with the intervention group). Further development of interventions to support persons with CWP to maintain regular physical activity is needed.
Commentary
Chronic widespread pain is a disorder characterized by diffuse body pain persisting for at least 3 months.1-2 It has been associated with lost work productivity, mental ill health, and reduced quality of life. The development of clinically effective and cost-effective pain management strategies for CWP is challenging given the syndrome complexity and heterogenous symptomology. Thus, multimodal, multidisciplinary management is widely advocated, often a combination of education and self-management, with integration of physical, non-pharmacological and pharmacological treatments.1-3 Of note, physical exercise and cognitive behavioral therapy are 2 non-pharmacological treatments that hold some promise based on available evidence.
The pervasiveness of technology in nearly all aspects of daily life has corresponded with the development of implementation of a wide range of technology-based interventions for health purposes.4 Examples of electronic health or eHealth modalities include internet-based, telephone supported, interactive voice-response, videoconferencing, mobile apps, and virtual reality. While the use of technology in chronic pain management interventions has increased in recent years, the literature is still limited, heterogenous, and provides limited evidence on the efficacy of eHealth/digital interventions, let alone which specific modalities are most effective.4-9
This study adds to the literature as a randomized controlled trial evaluating the effectiveness of a person-centered intervention for individuals with CWP delivered with digital eHealth support compared with standard telephone follow-up. Results showed no significant difference in the primary outcome of pain intensity and nearly all secondary outcomes between the intervention group (supported by the digital platform) and the active control group (supported by a follow-up phone call). Further, intervention participants who did not use the platform improved significantly more in pain intensity than those who used the platform.
While these results imply that digital support does not contribute to improvements in the outcomes measured, it is important these findings are interpreted with caution given the limitations of the study design as well as limitations with the intervention itself. Importantly, while this study was designed as a randomized controlled trial, the authors indicated that it was not possible to blind the participants or the physiotherapist to group allocation, which may have impacted their behaviors while in the study. In addition, as the authors note, an intervention aimed at increasing physical activity should ideally include an objective measure of activity and this was lacking in this study. The use of an actigraphy device for example would have provided objective, continuous data on movement and could have helped assess an important outcome measure – whether participants reached their physical activity goals or had increased their overall physical activity. In the analysis, there was no adjustment for multiple comparisons or use of imputation methods to handle missing values. Further, it was unclear whether differences in baseline data were evaluated and taken into consideration in between-group analyses. Lastly, results are only attributable to the eHealth mode used in this study (digital web-based with limited mechanisms of behavior change and engagement built-in) and thus should not be generalized to all digital/eHealth interventions persons with CWP.
Applications for Clinical Practice
While the results of this study failed to demonstrate significant differences between a physical activity-promoting intervention for persons with CWP with digital follow-up vs telephone follow-up, it remains important to consider person-centered principles when offering CWP management support. In this spirit, clinicians should consider a management approach that takes into account the individual’s knowledge, resources, and barriers, and also actively involves the patient in treatment planning to enhance the patient’s self-efficacy to manage their health. In addition, individual preference for a specific (or combination of) eHealth/digital modality should be considered and used to guide a comprehensive management plan, as well as used as a complementary modality to face-to-face care/support.
1. Bee, P, McBeth, J, MacFarlane, GJ, Lovell K. Managing chronic widespread pain in primary care: a qualitative study of patient perspectives and implications for treatment delivery. BMC Musculoskelet Disord. 2016;17(1):354.
2. Whibley D, Dean LE, Basu N. Management of Widespread Pain and Fibromyalgia. Curr Treatm Opt Rheumatol. 2016;2(4):312-320.
3. Takai Y, Yamamoto-Mitani N, Abe Y, Suzuki M. Literature review of pain management for people with chronic pain. Jpn J Nurs Sci. 2015;12(3):167-183.
4. Slattery BW, Haugh S, O’Connor L, et al. An Evaluation of the Effectiveness of the Modalities Used to Deliver Electronic Health Interventions for Chronic Pain: Systematic Review With Network Meta-Analysis. J Med Internet Res. 2019;21(7):e11086.
5. Heapy AA, Higgins DM, Cervone D, et al. A Systematic Review of Technology-assisted Self-Management Interventions for Chronic Pain. Clin J Pain. 2015;31(6):470-492.
6. Martin CL, Bakker CJ, Breth MS, et al. The efficacy of mobile health interventions used to manage acute or chronic pain: A systematic review. Res Nurs Health. 2021 Feb;44(1):111-128.
7. Bhattarai P, Phillips JL. The role of digital health technologies in management of pain in older people: An integrative review. Arch Gerontol and Geriatr. 2017;68:14-24.
8. Bhatia A, Kara J, Janmohamed T, et al. User Engagement and Clinical Impact of the Manage My Pain App in Patients With Chronic Pain: A Real-World, Multi-site Trial. JMIR Mhealth Uhealth. 2021;9(3):e26528.
9. Nevedal DC, Wang C, Oberleitner L, et al. Effects of an individually tailored Web-based chronic pain management program on pain severity, psychological health, and functioning. J Med Internet Res. 2013;15(9):e201.
Study Overview
Objective. To determine the effectiveness of a person-centered intervention (comprising personalized and cocreated treatment plans to promote physical activity) for individuals with chronic widespread pain when delivered with digital eHealth support compared with standard telephone follow-up.
Design. Single-blinded multicenter randomized controlled trial.
Settings and participants. Participants with chronic widespread pain (CWP) who had participated in a pain management program from 2010–16 at 5 primary health care rehabilitation centers in 5 cities or towns in the western part of Sweden were invited to join the study between March 2018 and April 2019 via letter providing information about the intervention. The letter was followed by a phone call 1-2 weeks later to screen for inclusion and exclusion criteria and interest in participating. Additional participants were invited to participate via a newspaper advertisement in 1 of the 5 cities.
Inclusion criteria were Swedish-speaking persons aged 20–65 years with CWP (defined as having pain in both sides of the body, pain above and below the waist, and axial pain for at least 3 months). Exclusion criteria included having other severe somatic or psychiatric disorders, dominating causes of pain other than CWP, or other severe disease interfering with the ability to be physically active, pregnancy, not having access to a smartphone or a computer, inability to speak or understand Swedish, ongoing physiotherapy treatment, and already exercising regularly. Of 716 people initially assessed for eligibility, 425 completed telephone screening, and 139 were randomized (using block randomization) to either the intervention arm (n = 69) or the active control arm (n = 70). Due to the nature of the intervention, it was not possible to blind the participants or the physiotherapist to group allocation. All participants provided written informed consent.
The 2 groups underwent the same first individual meeting with a physiotherapist to cocreate a health plan with physical activities, and, if needed, stress management, based on each participant’s individual preferences, obstacles, goals, and resources. The difference between the groups was the type of follow-up support. Participants in the intervention group had 1 follow-up meeting with the physiotherapist a week after the initial meeting (to review and adjust the health plan as needed) and thereafter were supported through a digital e-health platform (accessed via the participant’s smartphone or computer) during the 6-month follow-up period. Participants were encouraged to access the platform once a week to answer questions regarding their health, and the extent to which they had been able to manage their health plan during the previous week. In addition, the participant and physiotherapist could communicate via the platform as needed. Participants in the active control group had 1 follow-up phone call with the physiotherapist 1 month after the initial meeting (similarly to review and adjust the health plan as needed), and no further contact or support from the physiotherapist during the 6-month follow-up period.
Measures and analysis. The primary outcome measure was pain intensity during the previous week assessed with a 0–100 subscale from the Fibromyalgia Impact Questionnaire (FIQ-pain). Secondary outcome measures included overall health status (via FIQ-total with 10 subscales), global fatigue (via FIQ-fatigue subscale), multidimensional fatigue (via Multidimensional Fatigue Inventory, a 20-item questionnaire rated on a 1-5 Likert scale), clinical manifestations of stress (via Stress and Crisis Inventory, a 35-item questionnaire rated on a 0-4 Likert scale), self-efficacy (via General Self-Efficacy Scale, a 10-item questionnaire rated on a 1-4 Likert scale), health-related quality of life (via Short Form 36, specifically the Physical Component Summary composite score), leisure-time physical activity (via Leisure Time Physical Activity Instrument), and physical function (via 1-min chair-stand test). Additional demographic data on age, pain localization, pharmacological treatment, tobacco use, country of birth, level of education, family status, economic status, work status, sick-leave, and disability pension were collected via a questionnaire.
Between-group differences for changes in outcomes from baseline to 6-month follow-up were calculated using the Mann–Whitney U test for continuous data, and Pearson’s χ2 or Fisher’s exact test for categorical data. Significance level was set at 5% with no adjustment for multiple comparisons. All analyses were made according to intention-to-treat by originally assigned group; missing cases were not included in the analysis.
Main results. Participants consisted of primarily middle-age, middle income, educated (> 12 years of education) females, with > 60% of participants working at least part-time (between-group differences in baseline data and demographic data not detailed in the article). A total of 29 participants were lost to follow-up. In the intervention group, lost-to-follow up participants were older, performed fewer hours of physical activity, and had lower mental fatigue at baseline, compared with those who were lost to follow-up in the active control group.
In between-group analyses, there were no significant differences in the primary outcome (pain intensity) from baseline to 6-month follow-up. The only significant difference in secondary outcomes was seen in global fatigue – the active control group improved significantly compared with the intervention group (P = .004).
In the intervention group, 87% of participants used the digital platform. Among these users, 35% contacted the physiotherapist (75% of these communications were health- or study-related issues, 25% were issues with the digital platform), 33% were contacted by the physiotherapist (96% of these communications were about the health plan and physical activity), and 32% never had any contact with the physiotherapist. There was a significant difference in the primary outcome (pain intensity) from baseline to 6-month follow-up between platform users and non-users (P = .03, mean change [SD] 3.8 [19.66] mm vs –20.5 [6.36] mm, respectively).
Conclusion. No significant differences were found between the groups after 6 months (except for a significant decrease in global fatigue in the active control group compared with the intervention group). Further development of interventions to support persons with CWP to maintain regular physical activity is needed.
Commentary
Chronic widespread pain is a disorder characterized by diffuse body pain persisting for at least 3 months.1-2 It has been associated with lost work productivity, mental ill health, and reduced quality of life. The development of clinically effective and cost-effective pain management strategies for CWP is challenging given the syndrome complexity and heterogenous symptomology. Thus, multimodal, multidisciplinary management is widely advocated, often a combination of education and self-management, with integration of physical, non-pharmacological and pharmacological treatments.1-3 Of note, physical exercise and cognitive behavioral therapy are 2 non-pharmacological treatments that hold some promise based on available evidence.
The pervasiveness of technology in nearly all aspects of daily life has corresponded with the development of implementation of a wide range of technology-based interventions for health purposes.4 Examples of electronic health or eHealth modalities include internet-based, telephone supported, interactive voice-response, videoconferencing, mobile apps, and virtual reality. While the use of technology in chronic pain management interventions has increased in recent years, the literature is still limited, heterogenous, and provides limited evidence on the efficacy of eHealth/digital interventions, let alone which specific modalities are most effective.4-9
This study adds to the literature as a randomized controlled trial evaluating the effectiveness of a person-centered intervention for individuals with CWP delivered with digital eHealth support compared with standard telephone follow-up. Results showed no significant difference in the primary outcome of pain intensity and nearly all secondary outcomes between the intervention group (supported by the digital platform) and the active control group (supported by a follow-up phone call). Further, intervention participants who did not use the platform improved significantly more in pain intensity than those who used the platform.
While these results imply that digital support does not contribute to improvements in the outcomes measured, it is important these findings are interpreted with caution given the limitations of the study design as well as limitations with the intervention itself. Importantly, while this study was designed as a randomized controlled trial, the authors indicated that it was not possible to blind the participants or the physiotherapist to group allocation, which may have impacted their behaviors while in the study. In addition, as the authors note, an intervention aimed at increasing physical activity should ideally include an objective measure of activity and this was lacking in this study. The use of an actigraphy device for example would have provided objective, continuous data on movement and could have helped assess an important outcome measure – whether participants reached their physical activity goals or had increased their overall physical activity. In the analysis, there was no adjustment for multiple comparisons or use of imputation methods to handle missing values. Further, it was unclear whether differences in baseline data were evaluated and taken into consideration in between-group analyses. Lastly, results are only attributable to the eHealth mode used in this study (digital web-based with limited mechanisms of behavior change and engagement built-in) and thus should not be generalized to all digital/eHealth interventions persons with CWP.
Applications for Clinical Practice
While the results of this study failed to demonstrate significant differences between a physical activity-promoting intervention for persons with CWP with digital follow-up vs telephone follow-up, it remains important to consider person-centered principles when offering CWP management support. In this spirit, clinicians should consider a management approach that takes into account the individual’s knowledge, resources, and barriers, and also actively involves the patient in treatment planning to enhance the patient’s self-efficacy to manage their health. In addition, individual preference for a specific (or combination of) eHealth/digital modality should be considered and used to guide a comprehensive management plan, as well as used as a complementary modality to face-to-face care/support.
Study Overview
Objective. To determine the effectiveness of a person-centered intervention (comprising personalized and cocreated treatment plans to promote physical activity) for individuals with chronic widespread pain when delivered with digital eHealth support compared with standard telephone follow-up.
Design. Single-blinded multicenter randomized controlled trial.
Settings and participants. Participants with chronic widespread pain (CWP) who had participated in a pain management program from 2010–16 at 5 primary health care rehabilitation centers in 5 cities or towns in the western part of Sweden were invited to join the study between March 2018 and April 2019 via letter providing information about the intervention. The letter was followed by a phone call 1-2 weeks later to screen for inclusion and exclusion criteria and interest in participating. Additional participants were invited to participate via a newspaper advertisement in 1 of the 5 cities.
Inclusion criteria were Swedish-speaking persons aged 20–65 years with CWP (defined as having pain in both sides of the body, pain above and below the waist, and axial pain for at least 3 months). Exclusion criteria included having other severe somatic or psychiatric disorders, dominating causes of pain other than CWP, or other severe disease interfering with the ability to be physically active, pregnancy, not having access to a smartphone or a computer, inability to speak or understand Swedish, ongoing physiotherapy treatment, and already exercising regularly. Of 716 people initially assessed for eligibility, 425 completed telephone screening, and 139 were randomized (using block randomization) to either the intervention arm (n = 69) or the active control arm (n = 70). Due to the nature of the intervention, it was not possible to blind the participants or the physiotherapist to group allocation. All participants provided written informed consent.
The 2 groups underwent the same first individual meeting with a physiotherapist to cocreate a health plan with physical activities, and, if needed, stress management, based on each participant’s individual preferences, obstacles, goals, and resources. The difference between the groups was the type of follow-up support. Participants in the intervention group had 1 follow-up meeting with the physiotherapist a week after the initial meeting (to review and adjust the health plan as needed) and thereafter were supported through a digital e-health platform (accessed via the participant’s smartphone or computer) during the 6-month follow-up period. Participants were encouraged to access the platform once a week to answer questions regarding their health, and the extent to which they had been able to manage their health plan during the previous week. In addition, the participant and physiotherapist could communicate via the platform as needed. Participants in the active control group had 1 follow-up phone call with the physiotherapist 1 month after the initial meeting (similarly to review and adjust the health plan as needed), and no further contact or support from the physiotherapist during the 6-month follow-up period.
Measures and analysis. The primary outcome measure was pain intensity during the previous week assessed with a 0–100 subscale from the Fibromyalgia Impact Questionnaire (FIQ-pain). Secondary outcome measures included overall health status (via FIQ-total with 10 subscales), global fatigue (via FIQ-fatigue subscale), multidimensional fatigue (via Multidimensional Fatigue Inventory, a 20-item questionnaire rated on a 1-5 Likert scale), clinical manifestations of stress (via Stress and Crisis Inventory, a 35-item questionnaire rated on a 0-4 Likert scale), self-efficacy (via General Self-Efficacy Scale, a 10-item questionnaire rated on a 1-4 Likert scale), health-related quality of life (via Short Form 36, specifically the Physical Component Summary composite score), leisure-time physical activity (via Leisure Time Physical Activity Instrument), and physical function (via 1-min chair-stand test). Additional demographic data on age, pain localization, pharmacological treatment, tobacco use, country of birth, level of education, family status, economic status, work status, sick-leave, and disability pension were collected via a questionnaire.
Between-group differences for changes in outcomes from baseline to 6-month follow-up were calculated using the Mann–Whitney U test for continuous data, and Pearson’s χ2 or Fisher’s exact test for categorical data. Significance level was set at 5% with no adjustment for multiple comparisons. All analyses were made according to intention-to-treat by originally assigned group; missing cases were not included in the analysis.
Main results. Participants consisted of primarily middle-age, middle income, educated (> 12 years of education) females, with > 60% of participants working at least part-time (between-group differences in baseline data and demographic data not detailed in the article). A total of 29 participants were lost to follow-up. In the intervention group, lost-to-follow up participants were older, performed fewer hours of physical activity, and had lower mental fatigue at baseline, compared with those who were lost to follow-up in the active control group.
In between-group analyses, there were no significant differences in the primary outcome (pain intensity) from baseline to 6-month follow-up. The only significant difference in secondary outcomes was seen in global fatigue – the active control group improved significantly compared with the intervention group (P = .004).
In the intervention group, 87% of participants used the digital platform. Among these users, 35% contacted the physiotherapist (75% of these communications were health- or study-related issues, 25% were issues with the digital platform), 33% were contacted by the physiotherapist (96% of these communications were about the health plan and physical activity), and 32% never had any contact with the physiotherapist. There was a significant difference in the primary outcome (pain intensity) from baseline to 6-month follow-up between platform users and non-users (P = .03, mean change [SD] 3.8 [19.66] mm vs –20.5 [6.36] mm, respectively).
Conclusion. No significant differences were found between the groups after 6 months (except for a significant decrease in global fatigue in the active control group compared with the intervention group). Further development of interventions to support persons with CWP to maintain regular physical activity is needed.
Commentary
Chronic widespread pain is a disorder characterized by diffuse body pain persisting for at least 3 months.1-2 It has been associated with lost work productivity, mental ill health, and reduced quality of life. The development of clinically effective and cost-effective pain management strategies for CWP is challenging given the syndrome complexity and heterogenous symptomology. Thus, multimodal, multidisciplinary management is widely advocated, often a combination of education and self-management, with integration of physical, non-pharmacological and pharmacological treatments.1-3 Of note, physical exercise and cognitive behavioral therapy are 2 non-pharmacological treatments that hold some promise based on available evidence.
The pervasiveness of technology in nearly all aspects of daily life has corresponded with the development of implementation of a wide range of technology-based interventions for health purposes.4 Examples of electronic health or eHealth modalities include internet-based, telephone supported, interactive voice-response, videoconferencing, mobile apps, and virtual reality. While the use of technology in chronic pain management interventions has increased in recent years, the literature is still limited, heterogenous, and provides limited evidence on the efficacy of eHealth/digital interventions, let alone which specific modalities are most effective.4-9
This study adds to the literature as a randomized controlled trial evaluating the effectiveness of a person-centered intervention for individuals with CWP delivered with digital eHealth support compared with standard telephone follow-up. Results showed no significant difference in the primary outcome of pain intensity and nearly all secondary outcomes between the intervention group (supported by the digital platform) and the active control group (supported by a follow-up phone call). Further, intervention participants who did not use the platform improved significantly more in pain intensity than those who used the platform.
While these results imply that digital support does not contribute to improvements in the outcomes measured, it is important these findings are interpreted with caution given the limitations of the study design as well as limitations with the intervention itself. Importantly, while this study was designed as a randomized controlled trial, the authors indicated that it was not possible to blind the participants or the physiotherapist to group allocation, which may have impacted their behaviors while in the study. In addition, as the authors note, an intervention aimed at increasing physical activity should ideally include an objective measure of activity and this was lacking in this study. The use of an actigraphy device for example would have provided objective, continuous data on movement and could have helped assess an important outcome measure – whether participants reached their physical activity goals or had increased their overall physical activity. In the analysis, there was no adjustment for multiple comparisons or use of imputation methods to handle missing values. Further, it was unclear whether differences in baseline data were evaluated and taken into consideration in between-group analyses. Lastly, results are only attributable to the eHealth mode used in this study (digital web-based with limited mechanisms of behavior change and engagement built-in) and thus should not be generalized to all digital/eHealth interventions persons with CWP.
Applications for Clinical Practice
While the results of this study failed to demonstrate significant differences between a physical activity-promoting intervention for persons with CWP with digital follow-up vs telephone follow-up, it remains important to consider person-centered principles when offering CWP management support. In this spirit, clinicians should consider a management approach that takes into account the individual’s knowledge, resources, and barriers, and also actively involves the patient in treatment planning to enhance the patient’s self-efficacy to manage their health. In addition, individual preference for a specific (or combination of) eHealth/digital modality should be considered and used to guide a comprehensive management plan, as well as used as a complementary modality to face-to-face care/support.
1. Bee, P, McBeth, J, MacFarlane, GJ, Lovell K. Managing chronic widespread pain in primary care: a qualitative study of patient perspectives and implications for treatment delivery. BMC Musculoskelet Disord. 2016;17(1):354.
2. Whibley D, Dean LE, Basu N. Management of Widespread Pain and Fibromyalgia. Curr Treatm Opt Rheumatol. 2016;2(4):312-320.
3. Takai Y, Yamamoto-Mitani N, Abe Y, Suzuki M. Literature review of pain management for people with chronic pain. Jpn J Nurs Sci. 2015;12(3):167-183.
4. Slattery BW, Haugh S, O’Connor L, et al. An Evaluation of the Effectiveness of the Modalities Used to Deliver Electronic Health Interventions for Chronic Pain: Systematic Review With Network Meta-Analysis. J Med Internet Res. 2019;21(7):e11086.
5. Heapy AA, Higgins DM, Cervone D, et al. A Systematic Review of Technology-assisted Self-Management Interventions for Chronic Pain. Clin J Pain. 2015;31(6):470-492.
6. Martin CL, Bakker CJ, Breth MS, et al. The efficacy of mobile health interventions used to manage acute or chronic pain: A systematic review. Res Nurs Health. 2021 Feb;44(1):111-128.
7. Bhattarai P, Phillips JL. The role of digital health technologies in management of pain in older people: An integrative review. Arch Gerontol and Geriatr. 2017;68:14-24.
8. Bhatia A, Kara J, Janmohamed T, et al. User Engagement and Clinical Impact of the Manage My Pain App in Patients With Chronic Pain: A Real-World, Multi-site Trial. JMIR Mhealth Uhealth. 2021;9(3):e26528.
9. Nevedal DC, Wang C, Oberleitner L, et al. Effects of an individually tailored Web-based chronic pain management program on pain severity, psychological health, and functioning. J Med Internet Res. 2013;15(9):e201.
1. Bee, P, McBeth, J, MacFarlane, GJ, Lovell K. Managing chronic widespread pain in primary care: a qualitative study of patient perspectives and implications for treatment delivery. BMC Musculoskelet Disord. 2016;17(1):354.
2. Whibley D, Dean LE, Basu N. Management of Widespread Pain and Fibromyalgia. Curr Treatm Opt Rheumatol. 2016;2(4):312-320.
3. Takai Y, Yamamoto-Mitani N, Abe Y, Suzuki M. Literature review of pain management for people with chronic pain. Jpn J Nurs Sci. 2015;12(3):167-183.
4. Slattery BW, Haugh S, O’Connor L, et al. An Evaluation of the Effectiveness of the Modalities Used to Deliver Electronic Health Interventions for Chronic Pain: Systematic Review With Network Meta-Analysis. J Med Internet Res. 2019;21(7):e11086.
5. Heapy AA, Higgins DM, Cervone D, et al. A Systematic Review of Technology-assisted Self-Management Interventions for Chronic Pain. Clin J Pain. 2015;31(6):470-492.
6. Martin CL, Bakker CJ, Breth MS, et al. The efficacy of mobile health interventions used to manage acute or chronic pain: A systematic review. Res Nurs Health. 2021 Feb;44(1):111-128.
7. Bhattarai P, Phillips JL. The role of digital health technologies in management of pain in older people: An integrative review. Arch Gerontol and Geriatr. 2017;68:14-24.
8. Bhatia A, Kara J, Janmohamed T, et al. User Engagement and Clinical Impact of the Manage My Pain App in Patients With Chronic Pain: A Real-World, Multi-site Trial. JMIR Mhealth Uhealth. 2021;9(3):e26528.
9. Nevedal DC, Wang C, Oberleitner L, et al. Effects of an individually tailored Web-based chronic pain management program on pain severity, psychological health, and functioning. J Med Internet Res. 2013;15(9):e201.
USPSTF recommends clinicians counsel pregnant patients to limit gestational weight gain
The U.S. Preventive Services Task Force has recommended clinicians counsel their adolescent and adult pregnant patients in primary care settings to use interventions to limit excess gestational weight gain.
Counseling pregnant persons on gestational weight gain (GWG) carries a B recommendation from the U.S. Preventive Services Task Force (USPSTF), meaning there is “moderate certainty that behavioral counseling interventions aimed at promoting healthy weight gain and preventing excess GWG in pregnancy have a moderate net benefit for pregnant persons,” the task force said in its recommendation statement, which was published in JAMA on May 25.
While the USPSTF has made other recommendations on screening for obesity in adults and gestational diabetes, this is the first recommendation from the task force on behavioral counseling interventions for pregnant persons to promote a healthy weight and limit GWG. The recommendation is important, the USPSTF said, because half of individuals entered pregnancy while either overweight (24%) or obese (24%) in 2015, with the prevalence of prepregnancy obesity higher among Alaska Native/American Indian (36.4%), Black (34.7%), and Hispanic (27.3%) women.
To define gestational weight gain, the USPSTF used National Academy of Medicine recommendations of weight change of 28-40 pounds in the underweight category (body mass index [BMI], < 18.5 kg/m2), 25-35 pounds in the normal-weight category (BMI, 18.5-24.9 kg/m2), 15-25 pounds in the overweight category (BMI, 25-29.9 kg/m2), and 11-20 pounds in the obese category (≥ 30 kg/m2).
Implementations of this recommendation include content with a focus on nutrition, physical activity, lifestyle change, or behavioral change. The counseling should be performed at the end of the first trimester or start of the second trimester and should stop shortly before delivery. “The most common types of behavioral counseling interventions included active or supervised exercise or counseling about diet and physical activity,” the USPSTF said.
The average duration of counseling sessions was between 15 and 120 minutes, varying from less than 2 contacts to more than 12 contacts involved in the intervention. Primary care clinicians can deliver these interventions themselves or refer the patient out to an intervention in another setting. “Effective behavioral counseling interventions often referred participants to various interventionists in different settings,” such as a local community fitness center, the authors wrote. “Participants were counseled on healthy diet and exercise through individual or group education sessions. Some interventions provided medically supervised group exercise classes with or without counseling.”
In their evidence report for the USPSTF recommendation, Amy G. Cantor, MD, of the Pacific Northwest Evidence-Based Practice Center, department of medical informatics and clinical epidemiology at Oregon Health & Science University in Portland, and colleagues performed a systematic review of 68 studies in the Ovid MEDLINE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews evaluating the effect of diet, exercise, and/or behavioral counseling interventions for 25,789 pregnant patients with GWG. The results were current up to February 2021 when the last search was performed. The mean ages of patients across all studies were 18.6 to 33.8 years, and 41% of studies contained patients from “diverse backgrounds.”
The results of the systematic review showed use of an intervention to limit GWG decreased the risk of gestational diabetes compared with a control group in 43 trials (relative risk, 0.87; 95% confidence interval, 0.79-0.95), emergency cesarean delivery in 14 trials (RR, 0.85; 95% CI, 0.74-0.96), macrosomia in 25 trials (RR, 0.77; 95% CI, 0.65-0.92), and large for gestational age infants in 26 trials (RR, 0.89; 95% CI, 0.80-0.99). There was not an association between GWG interventions and reduced gestational hypertension in 28 trials (RR, 0.87; 95% CI, 0.70-1.04), preeclampsia in 27 trials (RR, 0.98; 95% CI, 0.84-1.13), and lower risk of preterm birth in 33 trials (RR, 0.93; 95% CI, 0.81-1.07), as well as other outcomes such as respiratory distress syndrome, shoulder dystocia, neonatal intensive care unit admission, neonatal death, or infant growth during the first year.
In terms of the types of interventions used, Dr. Canton and colleagues found the greatest impact on GWG occurred when a high-intensity intervention with 12 or more sessions was used in 28 trials (−1.47 kg; 95% CI, −1.78 to −1.22) than in moderate-intensity interventions in 18 trials (−0.32 kg; 95% CI, −0.71 to −0.04) and low-intensity interventions in 9 trials (−0.64 kg; 94% CI, −1.44 to 0.02).
Implementing these interventions could be challenging
D. Yvette LaCoursiere, MD, of the department of obstetrics, gynecology, and reproductive sciences at the University of California, San Diego, in La Jolla, Calif., wrote in an accompanying editorial that the USPSTF recommendation supports the recommendation of the American College of Obstetricians and Gynecologists (ACOG) of offering nutritional and exercise-based support for patients with “excessive GWG,” but noted that leaving implementation of behavioral counseling interventions to the clinicians “is where challenges lie.”
“The USPSTF recommendations will require lengthening already time-constrained prenatal visits or relying on adjunctive professionals,” she said.
Dr. LaCoursiere highlighted the amount of time the behavioral counseling interventions took to implement, with the shortest intervention lasting 15 minutes. “With the exception of those in group prenatal care practices, clinicians conducting the standard prenatal visit will find it difficult to accommodate moderate- or high-intensity interventions. On a similar note, the topics included in many of the interventions are broad and not necessarily in the purview of clinicians who provide prenatal care,” she said.
In addition, behavioral counseling interventions may not be covered by some patients’ insurance plans, Dr. LaCoursiere explained. “While it is a federal requirement for states to provide pregnant Medicaid enrollees smoking cessation counseling and prescription drugs, there is no such mandate for nutrition or physical activity counseling. Neither is it required that states provide these services to nonpregnant enrollees,” she said. “These are not insurmountable challenges, but more groundwork is necessary to ensure an effective and efficient implementation.”
Commenting on how a clinician could fit a behavioral counseling intervention into the prenatal care model, Dr. LaCoursiere said creativity may be needed. Some researchers in the systematic review used Internet or telehealth-based programs for dietary education, exercise support, health information, and goal setting, for example, which could help with continuity of care during the COVID-19 pandemic. “These types of interventions may help overcome the obstacle of insufficient clinic time by separating the primary implementation phase from the traditional clinical setting,” she said.
While the evidence supports the implementation of these interventions, “additional work remains for clinicians and researchers to identify high-yield components and determine best practices for the delivery of GWG interventions,” she said.
“The success of this intervention will depend on improving resources for clinicians to facilitate provision of direct counseling or to refer patients to skilled professionals and explore novel alternatives. Promising innovative approaches such as the use of telehealth, technology-based delivery systems, and group prenatal care are under investigation and may expand the ability to successfully implement these recommendations and ultimately improve outcomes for pregnant persons and their infants,” Dr. LaCoursiere concluded.
This research was funded by contracts from the Agency for Healthcare Research and Quality and U.S. Department of Health and Human Services. The authors report no relevant conflict of interest.
The U.S. Preventive Services Task Force has recommended clinicians counsel their adolescent and adult pregnant patients in primary care settings to use interventions to limit excess gestational weight gain.
Counseling pregnant persons on gestational weight gain (GWG) carries a B recommendation from the U.S. Preventive Services Task Force (USPSTF), meaning there is “moderate certainty that behavioral counseling interventions aimed at promoting healthy weight gain and preventing excess GWG in pregnancy have a moderate net benefit for pregnant persons,” the task force said in its recommendation statement, which was published in JAMA on May 25.
While the USPSTF has made other recommendations on screening for obesity in adults and gestational diabetes, this is the first recommendation from the task force on behavioral counseling interventions for pregnant persons to promote a healthy weight and limit GWG. The recommendation is important, the USPSTF said, because half of individuals entered pregnancy while either overweight (24%) or obese (24%) in 2015, with the prevalence of prepregnancy obesity higher among Alaska Native/American Indian (36.4%), Black (34.7%), and Hispanic (27.3%) women.
To define gestational weight gain, the USPSTF used National Academy of Medicine recommendations of weight change of 28-40 pounds in the underweight category (body mass index [BMI], < 18.5 kg/m2), 25-35 pounds in the normal-weight category (BMI, 18.5-24.9 kg/m2), 15-25 pounds in the overweight category (BMI, 25-29.9 kg/m2), and 11-20 pounds in the obese category (≥ 30 kg/m2).
Implementations of this recommendation include content with a focus on nutrition, physical activity, lifestyle change, or behavioral change. The counseling should be performed at the end of the first trimester or start of the second trimester and should stop shortly before delivery. “The most common types of behavioral counseling interventions included active or supervised exercise or counseling about diet and physical activity,” the USPSTF said.
The average duration of counseling sessions was between 15 and 120 minutes, varying from less than 2 contacts to more than 12 contacts involved in the intervention. Primary care clinicians can deliver these interventions themselves or refer the patient out to an intervention in another setting. “Effective behavioral counseling interventions often referred participants to various interventionists in different settings,” such as a local community fitness center, the authors wrote. “Participants were counseled on healthy diet and exercise through individual or group education sessions. Some interventions provided medically supervised group exercise classes with or without counseling.”
In their evidence report for the USPSTF recommendation, Amy G. Cantor, MD, of the Pacific Northwest Evidence-Based Practice Center, department of medical informatics and clinical epidemiology at Oregon Health & Science University in Portland, and colleagues performed a systematic review of 68 studies in the Ovid MEDLINE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews evaluating the effect of diet, exercise, and/or behavioral counseling interventions for 25,789 pregnant patients with GWG. The results were current up to February 2021 when the last search was performed. The mean ages of patients across all studies were 18.6 to 33.8 years, and 41% of studies contained patients from “diverse backgrounds.”
The results of the systematic review showed use of an intervention to limit GWG decreased the risk of gestational diabetes compared with a control group in 43 trials (relative risk, 0.87; 95% confidence interval, 0.79-0.95), emergency cesarean delivery in 14 trials (RR, 0.85; 95% CI, 0.74-0.96), macrosomia in 25 trials (RR, 0.77; 95% CI, 0.65-0.92), and large for gestational age infants in 26 trials (RR, 0.89; 95% CI, 0.80-0.99). There was not an association between GWG interventions and reduced gestational hypertension in 28 trials (RR, 0.87; 95% CI, 0.70-1.04), preeclampsia in 27 trials (RR, 0.98; 95% CI, 0.84-1.13), and lower risk of preterm birth in 33 trials (RR, 0.93; 95% CI, 0.81-1.07), as well as other outcomes such as respiratory distress syndrome, shoulder dystocia, neonatal intensive care unit admission, neonatal death, or infant growth during the first year.
In terms of the types of interventions used, Dr. Canton and colleagues found the greatest impact on GWG occurred when a high-intensity intervention with 12 or more sessions was used in 28 trials (−1.47 kg; 95% CI, −1.78 to −1.22) than in moderate-intensity interventions in 18 trials (−0.32 kg; 95% CI, −0.71 to −0.04) and low-intensity interventions in 9 trials (−0.64 kg; 94% CI, −1.44 to 0.02).
Implementing these interventions could be challenging
D. Yvette LaCoursiere, MD, of the department of obstetrics, gynecology, and reproductive sciences at the University of California, San Diego, in La Jolla, Calif., wrote in an accompanying editorial that the USPSTF recommendation supports the recommendation of the American College of Obstetricians and Gynecologists (ACOG) of offering nutritional and exercise-based support for patients with “excessive GWG,” but noted that leaving implementation of behavioral counseling interventions to the clinicians “is where challenges lie.”
“The USPSTF recommendations will require lengthening already time-constrained prenatal visits or relying on adjunctive professionals,” she said.
Dr. LaCoursiere highlighted the amount of time the behavioral counseling interventions took to implement, with the shortest intervention lasting 15 minutes. “With the exception of those in group prenatal care practices, clinicians conducting the standard prenatal visit will find it difficult to accommodate moderate- or high-intensity interventions. On a similar note, the topics included in many of the interventions are broad and not necessarily in the purview of clinicians who provide prenatal care,” she said.
In addition, behavioral counseling interventions may not be covered by some patients’ insurance plans, Dr. LaCoursiere explained. “While it is a federal requirement for states to provide pregnant Medicaid enrollees smoking cessation counseling and prescription drugs, there is no such mandate for nutrition or physical activity counseling. Neither is it required that states provide these services to nonpregnant enrollees,” she said. “These are not insurmountable challenges, but more groundwork is necessary to ensure an effective and efficient implementation.”
Commenting on how a clinician could fit a behavioral counseling intervention into the prenatal care model, Dr. LaCoursiere said creativity may be needed. Some researchers in the systematic review used Internet or telehealth-based programs for dietary education, exercise support, health information, and goal setting, for example, which could help with continuity of care during the COVID-19 pandemic. “These types of interventions may help overcome the obstacle of insufficient clinic time by separating the primary implementation phase from the traditional clinical setting,” she said.
While the evidence supports the implementation of these interventions, “additional work remains for clinicians and researchers to identify high-yield components and determine best practices for the delivery of GWG interventions,” she said.
“The success of this intervention will depend on improving resources for clinicians to facilitate provision of direct counseling or to refer patients to skilled professionals and explore novel alternatives. Promising innovative approaches such as the use of telehealth, technology-based delivery systems, and group prenatal care are under investigation and may expand the ability to successfully implement these recommendations and ultimately improve outcomes for pregnant persons and their infants,” Dr. LaCoursiere concluded.
This research was funded by contracts from the Agency for Healthcare Research and Quality and U.S. Department of Health and Human Services. The authors report no relevant conflict of interest.
The U.S. Preventive Services Task Force has recommended clinicians counsel their adolescent and adult pregnant patients in primary care settings to use interventions to limit excess gestational weight gain.
Counseling pregnant persons on gestational weight gain (GWG) carries a B recommendation from the U.S. Preventive Services Task Force (USPSTF), meaning there is “moderate certainty that behavioral counseling interventions aimed at promoting healthy weight gain and preventing excess GWG in pregnancy have a moderate net benefit for pregnant persons,” the task force said in its recommendation statement, which was published in JAMA on May 25.
While the USPSTF has made other recommendations on screening for obesity in adults and gestational diabetes, this is the first recommendation from the task force on behavioral counseling interventions for pregnant persons to promote a healthy weight and limit GWG. The recommendation is important, the USPSTF said, because half of individuals entered pregnancy while either overweight (24%) or obese (24%) in 2015, with the prevalence of prepregnancy obesity higher among Alaska Native/American Indian (36.4%), Black (34.7%), and Hispanic (27.3%) women.
To define gestational weight gain, the USPSTF used National Academy of Medicine recommendations of weight change of 28-40 pounds in the underweight category (body mass index [BMI], < 18.5 kg/m2), 25-35 pounds in the normal-weight category (BMI, 18.5-24.9 kg/m2), 15-25 pounds in the overweight category (BMI, 25-29.9 kg/m2), and 11-20 pounds in the obese category (≥ 30 kg/m2).
Implementations of this recommendation include content with a focus on nutrition, physical activity, lifestyle change, or behavioral change. The counseling should be performed at the end of the first trimester or start of the second trimester and should stop shortly before delivery. “The most common types of behavioral counseling interventions included active or supervised exercise or counseling about diet and physical activity,” the USPSTF said.
The average duration of counseling sessions was between 15 and 120 minutes, varying from less than 2 contacts to more than 12 contacts involved in the intervention. Primary care clinicians can deliver these interventions themselves or refer the patient out to an intervention in another setting. “Effective behavioral counseling interventions often referred participants to various interventionists in different settings,” such as a local community fitness center, the authors wrote. “Participants were counseled on healthy diet and exercise through individual or group education sessions. Some interventions provided medically supervised group exercise classes with or without counseling.”
In their evidence report for the USPSTF recommendation, Amy G. Cantor, MD, of the Pacific Northwest Evidence-Based Practice Center, department of medical informatics and clinical epidemiology at Oregon Health & Science University in Portland, and colleagues performed a systematic review of 68 studies in the Ovid MEDLINE, Cochrane Central Register of Controlled Trials, and Cochrane Database of Systematic Reviews evaluating the effect of diet, exercise, and/or behavioral counseling interventions for 25,789 pregnant patients with GWG. The results were current up to February 2021 when the last search was performed. The mean ages of patients across all studies were 18.6 to 33.8 years, and 41% of studies contained patients from “diverse backgrounds.”
The results of the systematic review showed use of an intervention to limit GWG decreased the risk of gestational diabetes compared with a control group in 43 trials (relative risk, 0.87; 95% confidence interval, 0.79-0.95), emergency cesarean delivery in 14 trials (RR, 0.85; 95% CI, 0.74-0.96), macrosomia in 25 trials (RR, 0.77; 95% CI, 0.65-0.92), and large for gestational age infants in 26 trials (RR, 0.89; 95% CI, 0.80-0.99). There was not an association between GWG interventions and reduced gestational hypertension in 28 trials (RR, 0.87; 95% CI, 0.70-1.04), preeclampsia in 27 trials (RR, 0.98; 95% CI, 0.84-1.13), and lower risk of preterm birth in 33 trials (RR, 0.93; 95% CI, 0.81-1.07), as well as other outcomes such as respiratory distress syndrome, shoulder dystocia, neonatal intensive care unit admission, neonatal death, or infant growth during the first year.
In terms of the types of interventions used, Dr. Canton and colleagues found the greatest impact on GWG occurred when a high-intensity intervention with 12 or more sessions was used in 28 trials (−1.47 kg; 95% CI, −1.78 to −1.22) than in moderate-intensity interventions in 18 trials (−0.32 kg; 95% CI, −0.71 to −0.04) and low-intensity interventions in 9 trials (−0.64 kg; 94% CI, −1.44 to 0.02).
Implementing these interventions could be challenging
D. Yvette LaCoursiere, MD, of the department of obstetrics, gynecology, and reproductive sciences at the University of California, San Diego, in La Jolla, Calif., wrote in an accompanying editorial that the USPSTF recommendation supports the recommendation of the American College of Obstetricians and Gynecologists (ACOG) of offering nutritional and exercise-based support for patients with “excessive GWG,” but noted that leaving implementation of behavioral counseling interventions to the clinicians “is where challenges lie.”
“The USPSTF recommendations will require lengthening already time-constrained prenatal visits or relying on adjunctive professionals,” she said.
Dr. LaCoursiere highlighted the amount of time the behavioral counseling interventions took to implement, with the shortest intervention lasting 15 minutes. “With the exception of those in group prenatal care practices, clinicians conducting the standard prenatal visit will find it difficult to accommodate moderate- or high-intensity interventions. On a similar note, the topics included in many of the interventions are broad and not necessarily in the purview of clinicians who provide prenatal care,” she said.
In addition, behavioral counseling interventions may not be covered by some patients’ insurance plans, Dr. LaCoursiere explained. “While it is a federal requirement for states to provide pregnant Medicaid enrollees smoking cessation counseling and prescription drugs, there is no such mandate for nutrition or physical activity counseling. Neither is it required that states provide these services to nonpregnant enrollees,” she said. “These are not insurmountable challenges, but more groundwork is necessary to ensure an effective and efficient implementation.”
Commenting on how a clinician could fit a behavioral counseling intervention into the prenatal care model, Dr. LaCoursiere said creativity may be needed. Some researchers in the systematic review used Internet or telehealth-based programs for dietary education, exercise support, health information, and goal setting, for example, which could help with continuity of care during the COVID-19 pandemic. “These types of interventions may help overcome the obstacle of insufficient clinic time by separating the primary implementation phase from the traditional clinical setting,” she said.
While the evidence supports the implementation of these interventions, “additional work remains for clinicians and researchers to identify high-yield components and determine best practices for the delivery of GWG interventions,” she said.
“The success of this intervention will depend on improving resources for clinicians to facilitate provision of direct counseling or to refer patients to skilled professionals and explore novel alternatives. Promising innovative approaches such as the use of telehealth, technology-based delivery systems, and group prenatal care are under investigation and may expand the ability to successfully implement these recommendations and ultimately improve outcomes for pregnant persons and their infants,” Dr. LaCoursiere concluded.
This research was funded by contracts from the Agency for Healthcare Research and Quality and U.S. Department of Health and Human Services. The authors report no relevant conflict of interest.
FROM JAMA
Novel drug approvals of 2020
In 2020, the Food and Drug Administration approved 53 new drugs for humans. One of these agents, Annovera (segesterone and ethinyl estradiol), is a vaginal ring to prevent pregnancy and is not relevant in this article. A second drug, Asparlas (calaspargase pegol), indicated to treat acute lymphoblastic leukemia, has not yet been released by its manufacturer. Orgovyx (relugolix) is used for prostate cancer and Lampit (nifurtimox) is drug used in children – neither of these two agents will be covered. The remaining 49 are covered below. The agents with molecular weights less than 1,000 probably cross the placenta in the first half of pregnancy, but nearly all, regardless of MW, will cross in the second half of pregnancy.
No human pregnancy data for these agents has been found, but there are five drugs included in pregnancy registries. It will take some time before the outcomes of these drugs are published. The routine absence of pregnancy data for most drugs was pointed out in an article that I coauthored, “Should pregnant women be included in phase 4 clinical drug trials?”. The article makes a strong argument for including some pregnant women in these trials.
Anti-infectives
Artesunate (384)
The drug appears low risk when used in the second and third trimesters. There is inadequate information regarding its use in the first trimester, so the safest course for the embryo appears to be avoiding its use during this period. A single intravenous dose given to rats early in gestation resulted in embryolethality.
Ebanga (ansuvimab) (147,000)
Studies on its use in pregnant animals have not been conducted.
Inmazeb (atoltivimab, maftivimab, odesivimab) (144,000-146,000)
Inmazeb is a combination of the three agents. Studies on its use in pregnant animals have not been conducted.
Veklury (remdesivir) (603)
Veklury is indicated for the treatment of pregnant women hospitalized with COVID-19 who are at risk for serious morbidity and mortality. The drug should be used during pregnancy only if the potential benefit justifies the potential risk for the mother and the fetus.
Antineoplastics
Ayvakit (avapritinib) (499)
The drug may cause fetal harm. The drug was teratogenic in animals.
Blenrep (belantamab mafodotin-blmf) (152,000)
A B-cell maturation antigen, it is indicated for the treatment of multiple myeloma. No human or animal pregnancy data have been located.
Danyelza (naxitamab-gqgk) (144,000)
This agent is used for the treatment of neuroblastoma. Based on its mechanism of action it may cause fetal harm if used in pregnancy.
Gavreto (pralsetinib) (534)
Gavreto is indicated for the treatment of small cell lung cancer. It may cause embryo-fetal harm if used in pregnancy.
Inqovi (cedazuridine + decitabine) (268,228)
The drug combination can cause fetal harm in human pregnancy. It is toxic in pregnant animals.
Margenza (margetuximab-cmkb) (149,000)
Although there are no data on the use of this drug in human pregnancy, the findings in animals and mechanism of action suggest that it will cause fetal harm.
Monjuvi (tafasitamab-cxix) (150,000)
This drug is a cytolytic antibody that is indicated in combination with lenalidomide. The combination may cause fetal harm.
Pemazyre (pemigatinib) (488)
It is indicated for the treatment of cholangiocarcinoma. In an animal study, the drug caused fetal defects, fetal growth retardation, and embryo-fetal death at maternal exposures lower than the human exposure.
Qinlock (ripretinib) (510)
This drug is used for the treatment of patients with advanced gastrointestinal stromal tumor. The drug was teratogenic in pregnant animals.
Retevmo (selpercatinib) (526)
This is a kinase inhibitor used for the treatment of small cell lung cancer. The drug is teratogenic in animals.
Sarclisa (isatuximab-irfc) (148,000)This drug is used in combination with pomalidomide and dexamethasone. The combination would probably cause major toxicity in an embryo or fetus.
Tabrecta (capmatinib) (412 – free base)Capmatinib is a kinase inhibitor used for the treatment of metastatic non–small cell lung cancer. It is teratogenic in animals.
Tazverik (tazemetostat) (654)Tazemetostat is indicated for the treatment of epithelioid sarcoma and follicular lymphoma, The drug is teratogenic in animals.
Trodelvy (sacituzumab govitecan-hziy) (1,602)This agent is used for the treatment of breast cancer. The drug has not been tested in pregnant animals. However, according to the manufacturer, there is a high possibility of human teratogenicity if it is given to a pregnant woman.
Tukysa (tucatinib) (481)
Tukysa is a tyrosine kinase inhibitor that is used in combination with trastuzumab and capecitabine for the treatment of breast cancer. The drug is teratogenic in animals.
Zeposia (ozanimod) (441)
Zeposia is indicated for the treatment of multiple sclerosis. The drug takes about 3 months to eliminate from the body. The drug is teratogenic in animals.
Zepzelca (lurbinectedin) (785)
This agent is used for the treatment of metastatic small cell lung cancer. The drug is teratogenic in animals.
Antiemetics
Barhemsys (amisulpride) (369)
This agent is Indicated to prevent nausea and vomiting. Animal data suggest low risk of embryo/fetal birth defects.
Antimigraine
Nurtec (rimegepant) (611)
Nurtec is indicated for acute treatment of migraine. Development toxicity was not observed in animals given doses similar to those used in humans.
Vyepti (eptinezumab-jjmr) (143,000)
A humanized monoclonal antibody that is given every 3 months to prevent migraine. There was no embryo-fetal harm in animals given the drug.
CNS
Byfavo (remimazolam) (493 – free base)
This drug is indicated for procedural sedation in adults undergoing procedures lasting 30 minutes or less. No defects were observed in animals.
Diagnostics
Cerianna (fluoroestradiol F 18) (289)
It is indicated for use with PET for characterization of estrogen receptor status in patients with ER-positive breast cancer. It has the potential to cause fetal harm depending on the fetal stage of development and the magnitude of radiation dose. There are no data on its use in pregnant women or animals.
Detectnet (copper CU-64 dotatate) (1,497)
All radiopharmaceuticals have the potential to cause fetal harm depending on the fetal stage of development and the magnitude of the radiation dose. There are no pregnancy data in humans or animals
Miscellaneous
Dojolvi (triheptanoin) (429)
This agent is indicated as a source of calories and fatty acids for the treatment of pediatric and adult patients with molecularly confirmed long-chain fatty acid oxidation disorders. Advise patients that there is a pregnancy safety study that collects pregnancy outcome data in women taking Dojolvi during pregnancy. Pregnant patients can enroll in the study by calling 1-888-756-8657.
Enspryng (satralizumab-mwge) (143,000)
It is indicated for the treatment of neuromyelitis optica spectrum disorder in adult patients who are anti–aquaporin-4 (AQP4) antibody positive. No information is available on the risks, if any, in pregnancy. No adverse effects on maternal or fetal development were observed in pregnant monkeys and their offspring.
Evrysdi (risdiplam) (401)
This is a prescription medicine used to treat spinal muscular atrophy in adults and children aged 2 months and older. In pregnant animals the drug caused adverse effects on fetal development.
Gemtesa (vibegron) (445)
Gemtesa is used in adults to treat the symptoms of overactive bladder. The drug had no adverse effects on pregnant animals.
Imcivree (setmelanotide) (1,117)
This drug is indicated for chronic weight management in adult and pediatric patients aged 6 years and older with obesity because of proopiomelanocortin, proprotein convertase subtilisin/kexin type 1, or leptin receptor deficiency. The drug was not embryo toxic in animals.
Isturisa (osilodrostat) (325)
Isturisa is a cortisol synthesis inhibitor indicated for the treatment of adult patients with Cushing’s disease. No adverse fetal effects were observed in pregnant animals.
Klisyri (tirbanibulin) (431)
Tirbanibulin ointment is a microtubule inhibitor that is used to treat actinic keratosis. Information on its effects in pregnancy is not available.
Koselugo (selumetinib) (556)
This is a kinase inhibitor indicated for the treatment of pediatric patients aged 2 years and older. The drug is toxic in pregnant animals but its effects in human pregnancy are not known.
Nexletol (bempedoic acid) (344)
Nexletol is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease who require additional lowering of LDL cholesterol. The drug was not teratogenic in animals. Discontinue Nexletol when pregnancy is recognized unless the benefits of therapy outweigh the potential risks to the fetus.
Olinvyk (oliceridine) (503)
Olinvyk injection is indicated in adults for the management of acute pain severe enough to require an intravenous opioid analgesic. Prolonged use of Olinvyk during pregnancy can result in neonatal opioid withdrawal syndrome. The drug was not teratogenic in animals.
Ongentys (opicapone) (413)
Ongentys is indicated as adjunctive treatment to levodopa/carbidopa in patients with Parkinson’s disease experiencing “off” episodes. The drug was teratogenic in rabbits but not in rats.
Orladeyo (berotralstat) (635)
This drug is a plasma kallikrein inhibitor indicated for prophylaxis to prevent attacks of hereditary angioedema. It was not teratogenic in animals.
Oxlumo (lumasiran) (17,286)
Oxlumo is a HAO1-directed small interfering ribonucleic acid indicated for the treatment of primary hyperoxaluria type 1 to lower urinary oxalate levels. No adverse effects on pregnancy or embryo-fetal development related to the drug were observed in animals.
Pizensy (lactitol) (344)
Lactitol is minimally absorbed systemically following oral administration. It is unknown whether maternal use will result in fetal exposure to the drug. No effects on embryo-fetal development were observed in animals at doses much higher than the maximum recommended human dosage.
Rukobia (fostemsavir) (705; 584 for free acid)
This drug is an HIV-1–directed attachment inhibitor, in combination with other antiretrovirals. There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to the drug during pregnancy. Health care providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry at 1-800-258-4263.
Sogroya (somapacitan-beco) (23,305)
This is a human growth hormone analog indicated for replacement of endogenous growth hormone in adults with growth hormone deficiency. The drug was not teratogenic in animals.
Tepezza (teprotumumab-trbw) (148,000)
Drug is indicated for the treatment of thyroid eye disease. The drug was teratogenic in cynomolgus monkeys. The manufacturer states that because of the risk, the drug should not be used in pregnancy.
Tauvid (flortaucipir F-18) (262)
This drug is indicated for use with PET imaging of the brain to evaluate for Alzheimer’s disease. It is a radioactive drug and should not be used in pregnant women.
Uplizna (inebilizumab-cdon) (149,000)
Uplizna is indicated for the treatment of neuromyelitis optica spectrum disorder in adult patients who are anti-AQP4 antibody positive. It is a humanized IgG1 monoclonal antibody and immunoglobulins are known to cross the placental barrier. Based on animal data, the drug can cause fetal harm because of B-cell lymphopenia and reduce antibody response in offspring exposed to the drug. Women of childbearing potential should use contraception while receiving Uplizna and for 6 months after the last dose.
Winlevi (clascoterone) (403)
This cream is an androgen receptor inhibitor that is indicated for the topical treatment of acne vulgaris in patients aged 12 years and older. Subcutaneous use in animals was associated with fetal defects.
Xeglyze (abametapir) (1,840)
Xeglyze is indicated for the topical treatment of head lice infestation in patients aged 6 months and older. The drug was not teratogenic in animals.
Zokinvy (lonafarnib) (639)
Zokinvy is indicated in patients 12 months or older to reduce the risk of mortality in several conditions. Animal studies have found embryo-fetal harm.
Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. Mr. Briggs said he had no relevant financial disclosures. Email him at obnews@mdedge.com.
In 2020, the Food and Drug Administration approved 53 new drugs for humans. One of these agents, Annovera (segesterone and ethinyl estradiol), is a vaginal ring to prevent pregnancy and is not relevant in this article. A second drug, Asparlas (calaspargase pegol), indicated to treat acute lymphoblastic leukemia, has not yet been released by its manufacturer. Orgovyx (relugolix) is used for prostate cancer and Lampit (nifurtimox) is drug used in children – neither of these two agents will be covered. The remaining 49 are covered below. The agents with molecular weights less than 1,000 probably cross the placenta in the first half of pregnancy, but nearly all, regardless of MW, will cross in the second half of pregnancy.
No human pregnancy data for these agents has been found, but there are five drugs included in pregnancy registries. It will take some time before the outcomes of these drugs are published. The routine absence of pregnancy data for most drugs was pointed out in an article that I coauthored, “Should pregnant women be included in phase 4 clinical drug trials?”. The article makes a strong argument for including some pregnant women in these trials.
Anti-infectives
Artesunate (384)
The drug appears low risk when used in the second and third trimesters. There is inadequate information regarding its use in the first trimester, so the safest course for the embryo appears to be avoiding its use during this period. A single intravenous dose given to rats early in gestation resulted in embryolethality.
Ebanga (ansuvimab) (147,000)
Studies on its use in pregnant animals have not been conducted.
Inmazeb (atoltivimab, maftivimab, odesivimab) (144,000-146,000)
Inmazeb is a combination of the three agents. Studies on its use in pregnant animals have not been conducted.
Veklury (remdesivir) (603)
Veklury is indicated for the treatment of pregnant women hospitalized with COVID-19 who are at risk for serious morbidity and mortality. The drug should be used during pregnancy only if the potential benefit justifies the potential risk for the mother and the fetus.
Antineoplastics
Ayvakit (avapritinib) (499)
The drug may cause fetal harm. The drug was teratogenic in animals.
Blenrep (belantamab mafodotin-blmf) (152,000)
A B-cell maturation antigen, it is indicated for the treatment of multiple myeloma. No human or animal pregnancy data have been located.
Danyelza (naxitamab-gqgk) (144,000)
This agent is used for the treatment of neuroblastoma. Based on its mechanism of action it may cause fetal harm if used in pregnancy.
Gavreto (pralsetinib) (534)
Gavreto is indicated for the treatment of small cell lung cancer. It may cause embryo-fetal harm if used in pregnancy.
Inqovi (cedazuridine + decitabine) (268,228)
The drug combination can cause fetal harm in human pregnancy. It is toxic in pregnant animals.
Margenza (margetuximab-cmkb) (149,000)
Although there are no data on the use of this drug in human pregnancy, the findings in animals and mechanism of action suggest that it will cause fetal harm.
Monjuvi (tafasitamab-cxix) (150,000)
This drug is a cytolytic antibody that is indicated in combination with lenalidomide. The combination may cause fetal harm.
Pemazyre (pemigatinib) (488)
It is indicated for the treatment of cholangiocarcinoma. In an animal study, the drug caused fetal defects, fetal growth retardation, and embryo-fetal death at maternal exposures lower than the human exposure.
Qinlock (ripretinib) (510)
This drug is used for the treatment of patients with advanced gastrointestinal stromal tumor. The drug was teratogenic in pregnant animals.
Retevmo (selpercatinib) (526)
This is a kinase inhibitor used for the treatment of small cell lung cancer. The drug is teratogenic in animals.
Sarclisa (isatuximab-irfc) (148,000)This drug is used in combination with pomalidomide and dexamethasone. The combination would probably cause major toxicity in an embryo or fetus.
Tabrecta (capmatinib) (412 – free base)Capmatinib is a kinase inhibitor used for the treatment of metastatic non–small cell lung cancer. It is teratogenic in animals.
Tazverik (tazemetostat) (654)Tazemetostat is indicated for the treatment of epithelioid sarcoma and follicular lymphoma, The drug is teratogenic in animals.
Trodelvy (sacituzumab govitecan-hziy) (1,602)This agent is used for the treatment of breast cancer. The drug has not been tested in pregnant animals. However, according to the manufacturer, there is a high possibility of human teratogenicity if it is given to a pregnant woman.
Tukysa (tucatinib) (481)
Tukysa is a tyrosine kinase inhibitor that is used in combination with trastuzumab and capecitabine for the treatment of breast cancer. The drug is teratogenic in animals.
Zeposia (ozanimod) (441)
Zeposia is indicated for the treatment of multiple sclerosis. The drug takes about 3 months to eliminate from the body. The drug is teratogenic in animals.
Zepzelca (lurbinectedin) (785)
This agent is used for the treatment of metastatic small cell lung cancer. The drug is teratogenic in animals.
Antiemetics
Barhemsys (amisulpride) (369)
This agent is Indicated to prevent nausea and vomiting. Animal data suggest low risk of embryo/fetal birth defects.
Antimigraine
Nurtec (rimegepant) (611)
Nurtec is indicated for acute treatment of migraine. Development toxicity was not observed in animals given doses similar to those used in humans.
Vyepti (eptinezumab-jjmr) (143,000)
A humanized monoclonal antibody that is given every 3 months to prevent migraine. There was no embryo-fetal harm in animals given the drug.
CNS
Byfavo (remimazolam) (493 – free base)
This drug is indicated for procedural sedation in adults undergoing procedures lasting 30 minutes or less. No defects were observed in animals.
Diagnostics
Cerianna (fluoroestradiol F 18) (289)
It is indicated for use with PET for characterization of estrogen receptor status in patients with ER-positive breast cancer. It has the potential to cause fetal harm depending on the fetal stage of development and the magnitude of radiation dose. There are no data on its use in pregnant women or animals.
Detectnet (copper CU-64 dotatate) (1,497)
All radiopharmaceuticals have the potential to cause fetal harm depending on the fetal stage of development and the magnitude of the radiation dose. There are no pregnancy data in humans or animals
Miscellaneous
Dojolvi (triheptanoin) (429)
This agent is indicated as a source of calories and fatty acids for the treatment of pediatric and adult patients with molecularly confirmed long-chain fatty acid oxidation disorders. Advise patients that there is a pregnancy safety study that collects pregnancy outcome data in women taking Dojolvi during pregnancy. Pregnant patients can enroll in the study by calling 1-888-756-8657.
Enspryng (satralizumab-mwge) (143,000)
It is indicated for the treatment of neuromyelitis optica spectrum disorder in adult patients who are anti–aquaporin-4 (AQP4) antibody positive. No information is available on the risks, if any, in pregnancy. No adverse effects on maternal or fetal development were observed in pregnant monkeys and their offspring.
Evrysdi (risdiplam) (401)
This is a prescription medicine used to treat spinal muscular atrophy in adults and children aged 2 months and older. In pregnant animals the drug caused adverse effects on fetal development.
Gemtesa (vibegron) (445)
Gemtesa is used in adults to treat the symptoms of overactive bladder. The drug had no adverse effects on pregnant animals.
Imcivree (setmelanotide) (1,117)
This drug is indicated for chronic weight management in adult and pediatric patients aged 6 years and older with obesity because of proopiomelanocortin, proprotein convertase subtilisin/kexin type 1, or leptin receptor deficiency. The drug was not embryo toxic in animals.
Isturisa (osilodrostat) (325)
Isturisa is a cortisol synthesis inhibitor indicated for the treatment of adult patients with Cushing’s disease. No adverse fetal effects were observed in pregnant animals.
Klisyri (tirbanibulin) (431)
Tirbanibulin ointment is a microtubule inhibitor that is used to treat actinic keratosis. Information on its effects in pregnancy is not available.
Koselugo (selumetinib) (556)
This is a kinase inhibitor indicated for the treatment of pediatric patients aged 2 years and older. The drug is toxic in pregnant animals but its effects in human pregnancy are not known.
Nexletol (bempedoic acid) (344)
Nexletol is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease who require additional lowering of LDL cholesterol. The drug was not teratogenic in animals. Discontinue Nexletol when pregnancy is recognized unless the benefits of therapy outweigh the potential risks to the fetus.
Olinvyk (oliceridine) (503)
Olinvyk injection is indicated in adults for the management of acute pain severe enough to require an intravenous opioid analgesic. Prolonged use of Olinvyk during pregnancy can result in neonatal opioid withdrawal syndrome. The drug was not teratogenic in animals.
Ongentys (opicapone) (413)
Ongentys is indicated as adjunctive treatment to levodopa/carbidopa in patients with Parkinson’s disease experiencing “off” episodes. The drug was teratogenic in rabbits but not in rats.
Orladeyo (berotralstat) (635)
This drug is a plasma kallikrein inhibitor indicated for prophylaxis to prevent attacks of hereditary angioedema. It was not teratogenic in animals.
Oxlumo (lumasiran) (17,286)
Oxlumo is a HAO1-directed small interfering ribonucleic acid indicated for the treatment of primary hyperoxaluria type 1 to lower urinary oxalate levels. No adverse effects on pregnancy or embryo-fetal development related to the drug were observed in animals.
Pizensy (lactitol) (344)
Lactitol is minimally absorbed systemically following oral administration. It is unknown whether maternal use will result in fetal exposure to the drug. No effects on embryo-fetal development were observed in animals at doses much higher than the maximum recommended human dosage.
Rukobia (fostemsavir) (705; 584 for free acid)
This drug is an HIV-1–directed attachment inhibitor, in combination with other antiretrovirals. There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to the drug during pregnancy. Health care providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry at 1-800-258-4263.
Sogroya (somapacitan-beco) (23,305)
This is a human growth hormone analog indicated for replacement of endogenous growth hormone in adults with growth hormone deficiency. The drug was not teratogenic in animals.
Tepezza (teprotumumab-trbw) (148,000)
Drug is indicated for the treatment of thyroid eye disease. The drug was teratogenic in cynomolgus monkeys. The manufacturer states that because of the risk, the drug should not be used in pregnancy.
Tauvid (flortaucipir F-18) (262)
This drug is indicated for use with PET imaging of the brain to evaluate for Alzheimer’s disease. It is a radioactive drug and should not be used in pregnant women.
Uplizna (inebilizumab-cdon) (149,000)
Uplizna is indicated for the treatment of neuromyelitis optica spectrum disorder in adult patients who are anti-AQP4 antibody positive. It is a humanized IgG1 monoclonal antibody and immunoglobulins are known to cross the placental barrier. Based on animal data, the drug can cause fetal harm because of B-cell lymphopenia and reduce antibody response in offspring exposed to the drug. Women of childbearing potential should use contraception while receiving Uplizna and for 6 months after the last dose.
Winlevi (clascoterone) (403)
This cream is an androgen receptor inhibitor that is indicated for the topical treatment of acne vulgaris in patients aged 12 years and older. Subcutaneous use in animals was associated with fetal defects.
Xeglyze (abametapir) (1,840)
Xeglyze is indicated for the topical treatment of head lice infestation in patients aged 6 months and older. The drug was not teratogenic in animals.
Zokinvy (lonafarnib) (639)
Zokinvy is indicated in patients 12 months or older to reduce the risk of mortality in several conditions. Animal studies have found embryo-fetal harm.
Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. Mr. Briggs said he had no relevant financial disclosures. Email him at obnews@mdedge.com.
In 2020, the Food and Drug Administration approved 53 new drugs for humans. One of these agents, Annovera (segesterone and ethinyl estradiol), is a vaginal ring to prevent pregnancy and is not relevant in this article. A second drug, Asparlas (calaspargase pegol), indicated to treat acute lymphoblastic leukemia, has not yet been released by its manufacturer. Orgovyx (relugolix) is used for prostate cancer and Lampit (nifurtimox) is drug used in children – neither of these two agents will be covered. The remaining 49 are covered below. The agents with molecular weights less than 1,000 probably cross the placenta in the first half of pregnancy, but nearly all, regardless of MW, will cross in the second half of pregnancy.
No human pregnancy data for these agents has been found, but there are five drugs included in pregnancy registries. It will take some time before the outcomes of these drugs are published. The routine absence of pregnancy data for most drugs was pointed out in an article that I coauthored, “Should pregnant women be included in phase 4 clinical drug trials?”. The article makes a strong argument for including some pregnant women in these trials.
Anti-infectives
Artesunate (384)
The drug appears low risk when used in the second and third trimesters. There is inadequate information regarding its use in the first trimester, so the safest course for the embryo appears to be avoiding its use during this period. A single intravenous dose given to rats early in gestation resulted in embryolethality.
Ebanga (ansuvimab) (147,000)
Studies on its use in pregnant animals have not been conducted.
Inmazeb (atoltivimab, maftivimab, odesivimab) (144,000-146,000)
Inmazeb is a combination of the three agents. Studies on its use in pregnant animals have not been conducted.
Veklury (remdesivir) (603)
Veklury is indicated for the treatment of pregnant women hospitalized with COVID-19 who are at risk for serious morbidity and mortality. The drug should be used during pregnancy only if the potential benefit justifies the potential risk for the mother and the fetus.
Antineoplastics
Ayvakit (avapritinib) (499)
The drug may cause fetal harm. The drug was teratogenic in animals.
Blenrep (belantamab mafodotin-blmf) (152,000)
A B-cell maturation antigen, it is indicated for the treatment of multiple myeloma. No human or animal pregnancy data have been located.
Danyelza (naxitamab-gqgk) (144,000)
This agent is used for the treatment of neuroblastoma. Based on its mechanism of action it may cause fetal harm if used in pregnancy.
Gavreto (pralsetinib) (534)
Gavreto is indicated for the treatment of small cell lung cancer. It may cause embryo-fetal harm if used in pregnancy.
Inqovi (cedazuridine + decitabine) (268,228)
The drug combination can cause fetal harm in human pregnancy. It is toxic in pregnant animals.
Margenza (margetuximab-cmkb) (149,000)
Although there are no data on the use of this drug in human pregnancy, the findings in animals and mechanism of action suggest that it will cause fetal harm.
Monjuvi (tafasitamab-cxix) (150,000)
This drug is a cytolytic antibody that is indicated in combination with lenalidomide. The combination may cause fetal harm.
Pemazyre (pemigatinib) (488)
It is indicated for the treatment of cholangiocarcinoma. In an animal study, the drug caused fetal defects, fetal growth retardation, and embryo-fetal death at maternal exposures lower than the human exposure.
Qinlock (ripretinib) (510)
This drug is used for the treatment of patients with advanced gastrointestinal stromal tumor. The drug was teratogenic in pregnant animals.
Retevmo (selpercatinib) (526)
This is a kinase inhibitor used for the treatment of small cell lung cancer. The drug is teratogenic in animals.
Sarclisa (isatuximab-irfc) (148,000)This drug is used in combination with pomalidomide and dexamethasone. The combination would probably cause major toxicity in an embryo or fetus.
Tabrecta (capmatinib) (412 – free base)Capmatinib is a kinase inhibitor used for the treatment of metastatic non–small cell lung cancer. It is teratogenic in animals.
Tazverik (tazemetostat) (654)Tazemetostat is indicated for the treatment of epithelioid sarcoma and follicular lymphoma, The drug is teratogenic in animals.
Trodelvy (sacituzumab govitecan-hziy) (1,602)This agent is used for the treatment of breast cancer. The drug has not been tested in pregnant animals. However, according to the manufacturer, there is a high possibility of human teratogenicity if it is given to a pregnant woman.
Tukysa (tucatinib) (481)
Tukysa is a tyrosine kinase inhibitor that is used in combination with trastuzumab and capecitabine for the treatment of breast cancer. The drug is teratogenic in animals.
Zeposia (ozanimod) (441)
Zeposia is indicated for the treatment of multiple sclerosis. The drug takes about 3 months to eliminate from the body. The drug is teratogenic in animals.
Zepzelca (lurbinectedin) (785)
This agent is used for the treatment of metastatic small cell lung cancer. The drug is teratogenic in animals.
Antiemetics
Barhemsys (amisulpride) (369)
This agent is Indicated to prevent nausea and vomiting. Animal data suggest low risk of embryo/fetal birth defects.
Antimigraine
Nurtec (rimegepant) (611)
Nurtec is indicated for acute treatment of migraine. Development toxicity was not observed in animals given doses similar to those used in humans.
Vyepti (eptinezumab-jjmr) (143,000)
A humanized monoclonal antibody that is given every 3 months to prevent migraine. There was no embryo-fetal harm in animals given the drug.
CNS
Byfavo (remimazolam) (493 – free base)
This drug is indicated for procedural sedation in adults undergoing procedures lasting 30 minutes or less. No defects were observed in animals.
Diagnostics
Cerianna (fluoroestradiol F 18) (289)
It is indicated for use with PET for characterization of estrogen receptor status in patients with ER-positive breast cancer. It has the potential to cause fetal harm depending on the fetal stage of development and the magnitude of radiation dose. There are no data on its use in pregnant women or animals.
Detectnet (copper CU-64 dotatate) (1,497)
All radiopharmaceuticals have the potential to cause fetal harm depending on the fetal stage of development and the magnitude of the radiation dose. There are no pregnancy data in humans or animals
Miscellaneous
Dojolvi (triheptanoin) (429)
This agent is indicated as a source of calories and fatty acids for the treatment of pediatric and adult patients with molecularly confirmed long-chain fatty acid oxidation disorders. Advise patients that there is a pregnancy safety study that collects pregnancy outcome data in women taking Dojolvi during pregnancy. Pregnant patients can enroll in the study by calling 1-888-756-8657.
Enspryng (satralizumab-mwge) (143,000)
It is indicated for the treatment of neuromyelitis optica spectrum disorder in adult patients who are anti–aquaporin-4 (AQP4) antibody positive. No information is available on the risks, if any, in pregnancy. No adverse effects on maternal or fetal development were observed in pregnant monkeys and their offspring.
Evrysdi (risdiplam) (401)
This is a prescription medicine used to treat spinal muscular atrophy in adults and children aged 2 months and older. In pregnant animals the drug caused adverse effects on fetal development.
Gemtesa (vibegron) (445)
Gemtesa is used in adults to treat the symptoms of overactive bladder. The drug had no adverse effects on pregnant animals.
Imcivree (setmelanotide) (1,117)
This drug is indicated for chronic weight management in adult and pediatric patients aged 6 years and older with obesity because of proopiomelanocortin, proprotein convertase subtilisin/kexin type 1, or leptin receptor deficiency. The drug was not embryo toxic in animals.
Isturisa (osilodrostat) (325)
Isturisa is a cortisol synthesis inhibitor indicated for the treatment of adult patients with Cushing’s disease. No adverse fetal effects were observed in pregnant animals.
Klisyri (tirbanibulin) (431)
Tirbanibulin ointment is a microtubule inhibitor that is used to treat actinic keratosis. Information on its effects in pregnancy is not available.
Koselugo (selumetinib) (556)
This is a kinase inhibitor indicated for the treatment of pediatric patients aged 2 years and older. The drug is toxic in pregnant animals but its effects in human pregnancy are not known.
Nexletol (bempedoic acid) (344)
Nexletol is indicated as an adjunct to diet and maximally tolerated statin therapy for the treatment of adults with heterozygous familial hypercholesterolemia or established atherosclerotic cardiovascular disease who require additional lowering of LDL cholesterol. The drug was not teratogenic in animals. Discontinue Nexletol when pregnancy is recognized unless the benefits of therapy outweigh the potential risks to the fetus.
Olinvyk (oliceridine) (503)
Olinvyk injection is indicated in adults for the management of acute pain severe enough to require an intravenous opioid analgesic. Prolonged use of Olinvyk during pregnancy can result in neonatal opioid withdrawal syndrome. The drug was not teratogenic in animals.
Ongentys (opicapone) (413)
Ongentys is indicated as adjunctive treatment to levodopa/carbidopa in patients with Parkinson’s disease experiencing “off” episodes. The drug was teratogenic in rabbits but not in rats.
Orladeyo (berotralstat) (635)
This drug is a plasma kallikrein inhibitor indicated for prophylaxis to prevent attacks of hereditary angioedema. It was not teratogenic in animals.
Oxlumo (lumasiran) (17,286)
Oxlumo is a HAO1-directed small interfering ribonucleic acid indicated for the treatment of primary hyperoxaluria type 1 to lower urinary oxalate levels. No adverse effects on pregnancy or embryo-fetal development related to the drug were observed in animals.
Pizensy (lactitol) (344)
Lactitol is minimally absorbed systemically following oral administration. It is unknown whether maternal use will result in fetal exposure to the drug. No effects on embryo-fetal development were observed in animals at doses much higher than the maximum recommended human dosage.
Rukobia (fostemsavir) (705; 584 for free acid)
This drug is an HIV-1–directed attachment inhibitor, in combination with other antiretrovirals. There is a pregnancy exposure registry that monitors pregnancy outcomes in individuals exposed to the drug during pregnancy. Health care providers are encouraged to register patients by calling the Antiretroviral Pregnancy Registry at 1-800-258-4263.
Sogroya (somapacitan-beco) (23,305)
This is a human growth hormone analog indicated for replacement of endogenous growth hormone in adults with growth hormone deficiency. The drug was not teratogenic in animals.
Tepezza (teprotumumab-trbw) (148,000)
Drug is indicated for the treatment of thyroid eye disease. The drug was teratogenic in cynomolgus monkeys. The manufacturer states that because of the risk, the drug should not be used in pregnancy.
Tauvid (flortaucipir F-18) (262)
This drug is indicated for use with PET imaging of the brain to evaluate for Alzheimer’s disease. It is a radioactive drug and should not be used in pregnant women.
Uplizna (inebilizumab-cdon) (149,000)
Uplizna is indicated for the treatment of neuromyelitis optica spectrum disorder in adult patients who are anti-AQP4 antibody positive. It is a humanized IgG1 monoclonal antibody and immunoglobulins are known to cross the placental barrier. Based on animal data, the drug can cause fetal harm because of B-cell lymphopenia and reduce antibody response in offspring exposed to the drug. Women of childbearing potential should use contraception while receiving Uplizna and for 6 months after the last dose.
Winlevi (clascoterone) (403)
This cream is an androgen receptor inhibitor that is indicated for the topical treatment of acne vulgaris in patients aged 12 years and older. Subcutaneous use in animals was associated with fetal defects.
Xeglyze (abametapir) (1,840)
Xeglyze is indicated for the topical treatment of head lice infestation in patients aged 6 months and older. The drug was not teratogenic in animals.
Zokinvy (lonafarnib) (639)
Zokinvy is indicated in patients 12 months or older to reduce the risk of mortality in several conditions. Animal studies have found embryo-fetal harm.
Mr. Briggs is clinical professor of pharmacy at the University of California, San Francisco, and adjunct professor of pharmacy at the University of Southern California, Los Angeles, as well as at Washington State University, Spokane. Mr. Briggs said he had no relevant financial disclosures. Email him at obnews@mdedge.com.
New targeted treatments are major advances for HER2-positive breast cancer
Before 2001, HER2/neu-positive breast cancer (HER2+) was one of the most dreaded diagnoses a woman could face, as treatment was largely ineffective. The discovery of trastuzumab changed that dramatically.
Over the next 20 years, two additional HER2-targeted therapies – lapatinib and trastuzumab emtansine (TDM-1) – earned approval from the Food and Drug Administration for selected patients with early and late HER2+ breast cancer.
Since 2019, four additional HER2-targeted therapies have been approved by the FDA for HER2+ metastatic breast cancer (MBC), changing the treatment paradigm for those patients substantially.
The new agents are especially useful in certain patient populations. The agents offer the promise of improved survival for patients with recurrent metastatic disease and the potential for further reductions in relapse rates in earlier settings.
Trastuzumab deruxtecan
Trastuzumab deruxtecan is an antibody-drug conjugate that links three components: an anti-HER2 monoclonal antibody, a highly potent topoisomerase I inhibitor payload, and a tetrapeptide-based cleavable linker.
Trastuzumab deruxtecan has a high drug-to-antibody ratio. A membrane-permeable payload offers the potential for activity against adjacent HER2-negative cells in heterogeneous tumors. It has a long half-life (6 days).
Trastuzumab deruxtecan received accelerated approval from the FDA in December 2019 to treat patients with HER2+ MBC who have received two or more prior HER2-targeted regimens, based on the results of the DESTINY-Breast 01 trial.
DESTINY-Breast 01 trial
In the phase 2 DESTINY-Breast 01 trial, 184 patients with a median of six previous treatments received trastuzumab deruxtecan (5.4 mg/kg) intravenously every 21 days. There were 24 patients with treated, asymptomatic brain metastases who participated. Patients with untreated or symptomatic brain metastases were excluded.
Overall, a response to therapy was reported in 112 patients (60.9%), with 6.0% complete and 54.9% partial responses. Most of the patients for whom both baseline and postbaseline data were available had a reduction in tumor size.
The median time until response was 1.6 months, an interval that corresponded to the time until the first scheduled imaging. Three patients (1.6%) had progressive disease, and two patients (1.1%) could not be evaluated.
The median duration of follow-up was 11.1 months, and the median response duration was 14.8 months.
The median progression-free survival (PFS) was 16.4 months, and the median overall survival (OS) was not reached. The median PFS in the patients with brain involvement was 18.1 months.
The most common adverse events of grade 3 or higher were a decreased neutrophil count (20.7%), anemia (8.7%), and nausea (7.6%). Most concerning was that trastuzumab deruxtecan was associated with interstitial lung disease in 13.6% of patients.
Tucatinib
Tucatinib is an oral, highly selective HER2 tyrosine kinase inhibitor (TKI). In April 2020, it was approved by the FDA, in combination with trastuzumab and capecitabine, for adult patients with advanced unresectable or metastatic HER2+ breast cancer who have received one or more prior anti-HER2–based regimens for MBC. The approval included patients with brain metastases.
The recommended tucatinib dose is 300 mg orally twice a day in combination with trastuzumab (at the standard dose) and capecitabine (1,000 mg/m2 given orally twice daily on days 1-14) on a 21-day cycle, until disease progression or unacceptable toxicity.
HER2CLIMB trial
The study that led to the approval of tucatinib was the HER2CLIMB trial. The trial enrolled 612 HER2+ MBC patients who had prior treatment with trastuzumab, pertuzumab, and T-DM1. Patients had received a median of 4 (range, 2-17) prior lines of HER2-targeted therapy.
The patients were randomized 2:1 to receive trastuzumab plus capecitabine and either tucatinib or an identical placebo twice daily.
The primary endpoint was PFS, evaluated in the initial 480 randomized patients. The median PFS was 7.8 months in the tucatinib arm and 5.6 months in the control arm (hazard ratio, 0.54; 95% confidence interval, 0.42-0.71; P < .001).
The confirmed overall response rate for patients with measurable disease was 40.6% in the tucatinib arm and 22.8% in the control arm (P = .001). The proportion of patients still in response at 12 months was 33.1% and 12.3%, respectively.
The median OS was 21.9 months in the tucatinib arm and 17.4 months in the placebo arm (HR, 0.66; 95% CI, 0.50-0.88; P = .005). At 24 months, 44.9% and 26.6% of patients, respectively, were still alive.
The most common grade 3 or higher adverse events (in the tucatinib and placebo arms, respectively) were palmar-plantar erythrodysesthesia syndrome (13.1% vs. 9.1%), diarrhea (12.9% vs. 8.6%), elevations in ALT and AST (approximately 5% vs. 0.5% for each), and fatigue (4.7% vs. 4.1%).
Tucatinib in patients with brain involvement
A unique feature of the HER2CLIMB study was that patients with MBC and untreated, symptomatic brain metastases were eligible. Patients with active, untreated central nervous system disease are excluded from virtually all other trials, especially drug-approval trials.
There were 291 patients with brain metastases in HER2CLIMB, 198 (48%) in the tucatinib arm and 93 (46%) in the control arm.
The risk of intracranial progression or death was reduced by 68% in the tucatinib arm (HR, 0.32; 95% CI, 0.22 to 0.48; P < .0001).
The 1-year CNS-PFS rate was 40.2% in the tucatinib arm and 0% in the placebo arm. The median duration of CNS-PFS was 9.9 months and 4.2 months, respectively.
The risk of death was reduced by 42% in the tucatinib arm (HR, 0.58; 95% CI, 0.40-0.85; P = .005). The median OS was 18.1 months and 12.0 months, respectively.
There were more objective responses in the brain with tucatinib (47.3%) than with placebo (20.0%; P = .03). The median duration of response was 6.8 months and 3.0 months, respectively.
Particularly because of its CNS activity and lack of serious, long-term toxicity, tucatinib combination therapy represents an attractive new option for patients with HER2+ MBC.
Neratinib
Neratinib is an irreversible pan-HER TKI that was approved by the FDA in July 2017 for extended adjuvant therapy in patients with early-stage HER2+ breast cancer, following the use of trastuzumab-based therapy.
Long-term results of the ExteNet study led to the approval for use as extended adjuvant therapy.
In February 2020, neratinib was FDA approved in combination with capecitabine for patients with HER2+ MBC after two or more prior anti-HER2–based regimens. The more recent FDA approval was based on results of the NALA trial.
NALA trial
The phase 3 NALA trial included 621 patients with HER2+ MBC who had received at least two prior anti-HER2 based regimens.
Patients were randomized 1:1 to receive neratinib at 240 mg orally once daily on days 1-21 with capecitabine at 750 mg/m2 orally twice daily on days 1-14 or lapatinib at 1,250 mg orally once daily on days 1-21 with capecitabine at 1,000 mg/m2 orally twice daily on days 1-14 for each 21-day cycle. Patients were treated until disease progression or unacceptable toxicity.
The primary endpoints were PFS and OS by blinded, independent, central review.
The median PFS was 5.6 months in the neratinib arm and 5.5 months in the lapatinib arm (HR, 0.76; 95% CI, 0.63-0.93; P = .0059). The PFS rate at 12 months was 28.8% and 14.8%, respectively.
The median OS was 21.0 months in the neratinib arm and 18.7 months in the lapatinib arm (HR, 0.88; 95% CI, 0.72-1.07; P = .2086). The ORR was 32.8% and 26.7%, respectively. The median response duration was 8.5 months and 5.6 months, respectively.
Fewer interventions for CNS disease were required in the neratinib arm than in the lapatinib arm (cumulative incidence, 22.8% vs. 29.2%; P = .043).
The most frequently reported grade 3-4 adverse reactions for the neratinib combination were diarrhea, nausea, vomiting, fatigue, and decreased appetite.
Grade 3 diarrhea occurred in 24.4% of those in the neratinib arm and 12.5% of those in the lapatinib arm. Antidiarrheal medication was used by 98.3% of patients receiving neratinib and 62.1% of patients receiving lapatinib.
Margetuximab-cmkb
Margetuximab is a chimeric Fc-engineered anti-HER2 monoclonal antibody that targets the same epitope as trastuzumab and exerts similar antiproliferative effects.
Compared with trastuzumab, margetuximab has higher affinity for both 158V (high-binding) and 158F (low-binding) alleles of the activating Fc receptor, CD16A. As a result, margetuximab enhances innate immunity, including CD16A-mediated antibody-dependent cellular cytotoxicity, more effectively than trastuzumab. Margetuximab also potentiates adaptive immunity, including enhanced clonality of the T-cell repertoire and induction of HER2-specific T- and B-cell responses.
In December 2020, margetuximab, in combination with chemotherapy, was approved by the FDA for patients with HER2+ MBC after two or more prior anti-HER2 regimens, at least one of which was for metastatic disease. The approved dose is 15 mg/kg IV every 3 weeks.
The study that led to margetuximab’s approval was the phase 3 SOPHIA trial.
SOPHIA trial
SOPHIA was a randomized trial of 536 patients with HER2+ MBC who had received prior treatment with other anti-HER2 therapies, including one to three lines of therapy for MBC.
Patients were randomly assigned 1:1 to receive margetuximab plus chemotherapy or trastuzumab plus chemotherapy. Assignment was stratified by chemotherapy choice (capecitabine, eribulin, gemcitabine, or vinorelbine), the number of previous lines of therapy for MBC, and disease extent.
Co–primary outcome measures were PFS by blinded, independent, central review and OS.
At the second interim analysis, the median PFS was 5.8 months in the margetuximab arm and 4.9 months in the trastuzumab arm (HR, 0.76; 95% CI, 0.59-0.98; P = .033). Results were more impressive in patients with CD16A genotypes containing a 158F allele. In this group, the median PFS was 6.9 months with margetuximab and 5.1 months with trastuzumab (HR, 0.68, 95% CI, 0.52-0.90; P = .005).
At the second interim analysis, the median OS was 21.6 months in the margetuximab arm and 19.8 months in the trastuzumab arm (HR, 0.89; 95% CI, 0.69-1.13; P = .33).
Subgroup data showed no differences in OS between the two arms for any subgroup except HER2+ MBC patients with an IHC score of 2 or higher. This is consistent with the postulated mechanism of action of margetuximab.
The confirmed ORR was 25% in the margetuximab arm and 14% in the trastuzumab arm, with similar durations of response between the study arms.
The most common adverse events in both arms (≥20%), regardless of causality, were fatigue, nausea, diarrhea, and neutropenia. Vomiting was common in the margetuximab arm, and anemia was common in the trastuzumab arm.
Grade 3 or higher adverse events occurred in 53.8% of patients receiving margetuximab and 52.6% of those receiving trastuzumab.
In view of margetuximab’s modest benefits in the SOPHIA trial, the ultimate role for margetuximab in HER2+ MBC may be restricted to patients with the CD16A-158F allele. A neoadjuvant trial is planned in that population.
Take-home messages
There are legitimate arguments regarding whether curing MBC is within reach for certain patient subsets, but there is no argument about whether the outlook for patients with HER2+ MBC has improved dramatically in recent years; it has.
The approval of four unique, new agents for the treatment of women with HER2+ MBC in relapse provides further improvements in outcome for these patients and distinctly different opportunities for tailoring treatment to the special circumstances of each patient (e.g., whether brain metastases are present, desire for oral therapy, comorbidities, experience with prior chemotherapy, etc).
When considered along with the potential for incorporating these drugs in earlier settings in well-designed clinical trials, these new drugs offer great promise to a group of patients who faced a dismal outcome just 2 decades ago.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
Before 2001, HER2/neu-positive breast cancer (HER2+) was one of the most dreaded diagnoses a woman could face, as treatment was largely ineffective. The discovery of trastuzumab changed that dramatically.
Over the next 20 years, two additional HER2-targeted therapies – lapatinib and trastuzumab emtansine (TDM-1) – earned approval from the Food and Drug Administration for selected patients with early and late HER2+ breast cancer.
Since 2019, four additional HER2-targeted therapies have been approved by the FDA for HER2+ metastatic breast cancer (MBC), changing the treatment paradigm for those patients substantially.
The new agents are especially useful in certain patient populations. The agents offer the promise of improved survival for patients with recurrent metastatic disease and the potential for further reductions in relapse rates in earlier settings.
Trastuzumab deruxtecan
Trastuzumab deruxtecan is an antibody-drug conjugate that links three components: an anti-HER2 monoclonal antibody, a highly potent topoisomerase I inhibitor payload, and a tetrapeptide-based cleavable linker.
Trastuzumab deruxtecan has a high drug-to-antibody ratio. A membrane-permeable payload offers the potential for activity against adjacent HER2-negative cells in heterogeneous tumors. It has a long half-life (6 days).
Trastuzumab deruxtecan received accelerated approval from the FDA in December 2019 to treat patients with HER2+ MBC who have received two or more prior HER2-targeted regimens, based on the results of the DESTINY-Breast 01 trial.
DESTINY-Breast 01 trial
In the phase 2 DESTINY-Breast 01 trial, 184 patients with a median of six previous treatments received trastuzumab deruxtecan (5.4 mg/kg) intravenously every 21 days. There were 24 patients with treated, asymptomatic brain metastases who participated. Patients with untreated or symptomatic brain metastases were excluded.
Overall, a response to therapy was reported in 112 patients (60.9%), with 6.0% complete and 54.9% partial responses. Most of the patients for whom both baseline and postbaseline data were available had a reduction in tumor size.
The median time until response was 1.6 months, an interval that corresponded to the time until the first scheduled imaging. Three patients (1.6%) had progressive disease, and two patients (1.1%) could not be evaluated.
The median duration of follow-up was 11.1 months, and the median response duration was 14.8 months.
The median progression-free survival (PFS) was 16.4 months, and the median overall survival (OS) was not reached. The median PFS in the patients with brain involvement was 18.1 months.
The most common adverse events of grade 3 or higher were a decreased neutrophil count (20.7%), anemia (8.7%), and nausea (7.6%). Most concerning was that trastuzumab deruxtecan was associated with interstitial lung disease in 13.6% of patients.
Tucatinib
Tucatinib is an oral, highly selective HER2 tyrosine kinase inhibitor (TKI). In April 2020, it was approved by the FDA, in combination with trastuzumab and capecitabine, for adult patients with advanced unresectable or metastatic HER2+ breast cancer who have received one or more prior anti-HER2–based regimens for MBC. The approval included patients with brain metastases.
The recommended tucatinib dose is 300 mg orally twice a day in combination with trastuzumab (at the standard dose) and capecitabine (1,000 mg/m2 given orally twice daily on days 1-14) on a 21-day cycle, until disease progression or unacceptable toxicity.
HER2CLIMB trial
The study that led to the approval of tucatinib was the HER2CLIMB trial. The trial enrolled 612 HER2+ MBC patients who had prior treatment with trastuzumab, pertuzumab, and T-DM1. Patients had received a median of 4 (range, 2-17) prior lines of HER2-targeted therapy.
The patients were randomized 2:1 to receive trastuzumab plus capecitabine and either tucatinib or an identical placebo twice daily.
The primary endpoint was PFS, evaluated in the initial 480 randomized patients. The median PFS was 7.8 months in the tucatinib arm and 5.6 months in the control arm (hazard ratio, 0.54; 95% confidence interval, 0.42-0.71; P < .001).
The confirmed overall response rate for patients with measurable disease was 40.6% in the tucatinib arm and 22.8% in the control arm (P = .001). The proportion of patients still in response at 12 months was 33.1% and 12.3%, respectively.
The median OS was 21.9 months in the tucatinib arm and 17.4 months in the placebo arm (HR, 0.66; 95% CI, 0.50-0.88; P = .005). At 24 months, 44.9% and 26.6% of patients, respectively, were still alive.
The most common grade 3 or higher adverse events (in the tucatinib and placebo arms, respectively) were palmar-plantar erythrodysesthesia syndrome (13.1% vs. 9.1%), diarrhea (12.9% vs. 8.6%), elevations in ALT and AST (approximately 5% vs. 0.5% for each), and fatigue (4.7% vs. 4.1%).
Tucatinib in patients with brain involvement
A unique feature of the HER2CLIMB study was that patients with MBC and untreated, symptomatic brain metastases were eligible. Patients with active, untreated central nervous system disease are excluded from virtually all other trials, especially drug-approval trials.
There were 291 patients with brain metastases in HER2CLIMB, 198 (48%) in the tucatinib arm and 93 (46%) in the control arm.
The risk of intracranial progression or death was reduced by 68% in the tucatinib arm (HR, 0.32; 95% CI, 0.22 to 0.48; P < .0001).
The 1-year CNS-PFS rate was 40.2% in the tucatinib arm and 0% in the placebo arm. The median duration of CNS-PFS was 9.9 months and 4.2 months, respectively.
The risk of death was reduced by 42% in the tucatinib arm (HR, 0.58; 95% CI, 0.40-0.85; P = .005). The median OS was 18.1 months and 12.0 months, respectively.
There were more objective responses in the brain with tucatinib (47.3%) than with placebo (20.0%; P = .03). The median duration of response was 6.8 months and 3.0 months, respectively.
Particularly because of its CNS activity and lack of serious, long-term toxicity, tucatinib combination therapy represents an attractive new option for patients with HER2+ MBC.
Neratinib
Neratinib is an irreversible pan-HER TKI that was approved by the FDA in July 2017 for extended adjuvant therapy in patients with early-stage HER2+ breast cancer, following the use of trastuzumab-based therapy.
Long-term results of the ExteNet study led to the approval for use as extended adjuvant therapy.
In February 2020, neratinib was FDA approved in combination with capecitabine for patients with HER2+ MBC after two or more prior anti-HER2–based regimens. The more recent FDA approval was based on results of the NALA trial.
NALA trial
The phase 3 NALA trial included 621 patients with HER2+ MBC who had received at least two prior anti-HER2 based regimens.
Patients were randomized 1:1 to receive neratinib at 240 mg orally once daily on days 1-21 with capecitabine at 750 mg/m2 orally twice daily on days 1-14 or lapatinib at 1,250 mg orally once daily on days 1-21 with capecitabine at 1,000 mg/m2 orally twice daily on days 1-14 for each 21-day cycle. Patients were treated until disease progression or unacceptable toxicity.
The primary endpoints were PFS and OS by blinded, independent, central review.
The median PFS was 5.6 months in the neratinib arm and 5.5 months in the lapatinib arm (HR, 0.76; 95% CI, 0.63-0.93; P = .0059). The PFS rate at 12 months was 28.8% and 14.8%, respectively.
The median OS was 21.0 months in the neratinib arm and 18.7 months in the lapatinib arm (HR, 0.88; 95% CI, 0.72-1.07; P = .2086). The ORR was 32.8% and 26.7%, respectively. The median response duration was 8.5 months and 5.6 months, respectively.
Fewer interventions for CNS disease were required in the neratinib arm than in the lapatinib arm (cumulative incidence, 22.8% vs. 29.2%; P = .043).
The most frequently reported grade 3-4 adverse reactions for the neratinib combination were diarrhea, nausea, vomiting, fatigue, and decreased appetite.
Grade 3 diarrhea occurred in 24.4% of those in the neratinib arm and 12.5% of those in the lapatinib arm. Antidiarrheal medication was used by 98.3% of patients receiving neratinib and 62.1% of patients receiving lapatinib.
Margetuximab-cmkb
Margetuximab is a chimeric Fc-engineered anti-HER2 monoclonal antibody that targets the same epitope as trastuzumab and exerts similar antiproliferative effects.
Compared with trastuzumab, margetuximab has higher affinity for both 158V (high-binding) and 158F (low-binding) alleles of the activating Fc receptor, CD16A. As a result, margetuximab enhances innate immunity, including CD16A-mediated antibody-dependent cellular cytotoxicity, more effectively than trastuzumab. Margetuximab also potentiates adaptive immunity, including enhanced clonality of the T-cell repertoire and induction of HER2-specific T- and B-cell responses.
In December 2020, margetuximab, in combination with chemotherapy, was approved by the FDA for patients with HER2+ MBC after two or more prior anti-HER2 regimens, at least one of which was for metastatic disease. The approved dose is 15 mg/kg IV every 3 weeks.
The study that led to margetuximab’s approval was the phase 3 SOPHIA trial.
SOPHIA trial
SOPHIA was a randomized trial of 536 patients with HER2+ MBC who had received prior treatment with other anti-HER2 therapies, including one to three lines of therapy for MBC.
Patients were randomly assigned 1:1 to receive margetuximab plus chemotherapy or trastuzumab plus chemotherapy. Assignment was stratified by chemotherapy choice (capecitabine, eribulin, gemcitabine, or vinorelbine), the number of previous lines of therapy for MBC, and disease extent.
Co–primary outcome measures were PFS by blinded, independent, central review and OS.
At the second interim analysis, the median PFS was 5.8 months in the margetuximab arm and 4.9 months in the trastuzumab arm (HR, 0.76; 95% CI, 0.59-0.98; P = .033). Results were more impressive in patients with CD16A genotypes containing a 158F allele. In this group, the median PFS was 6.9 months with margetuximab and 5.1 months with trastuzumab (HR, 0.68, 95% CI, 0.52-0.90; P = .005).
At the second interim analysis, the median OS was 21.6 months in the margetuximab arm and 19.8 months in the trastuzumab arm (HR, 0.89; 95% CI, 0.69-1.13; P = .33).
Subgroup data showed no differences in OS between the two arms for any subgroup except HER2+ MBC patients with an IHC score of 2 or higher. This is consistent with the postulated mechanism of action of margetuximab.
The confirmed ORR was 25% in the margetuximab arm and 14% in the trastuzumab arm, with similar durations of response between the study arms.
The most common adverse events in both arms (≥20%), regardless of causality, were fatigue, nausea, diarrhea, and neutropenia. Vomiting was common in the margetuximab arm, and anemia was common in the trastuzumab arm.
Grade 3 or higher adverse events occurred in 53.8% of patients receiving margetuximab and 52.6% of those receiving trastuzumab.
In view of margetuximab’s modest benefits in the SOPHIA trial, the ultimate role for margetuximab in HER2+ MBC may be restricted to patients with the CD16A-158F allele. A neoadjuvant trial is planned in that population.
Take-home messages
There are legitimate arguments regarding whether curing MBC is within reach for certain patient subsets, but there is no argument about whether the outlook for patients with HER2+ MBC has improved dramatically in recent years; it has.
The approval of four unique, new agents for the treatment of women with HER2+ MBC in relapse provides further improvements in outcome for these patients and distinctly different opportunities for tailoring treatment to the special circumstances of each patient (e.g., whether brain metastases are present, desire for oral therapy, comorbidities, experience with prior chemotherapy, etc).
When considered along with the potential for incorporating these drugs in earlier settings in well-designed clinical trials, these new drugs offer great promise to a group of patients who faced a dismal outcome just 2 decades ago.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
Before 2001, HER2/neu-positive breast cancer (HER2+) was one of the most dreaded diagnoses a woman could face, as treatment was largely ineffective. The discovery of trastuzumab changed that dramatically.
Over the next 20 years, two additional HER2-targeted therapies – lapatinib and trastuzumab emtansine (TDM-1) – earned approval from the Food and Drug Administration for selected patients with early and late HER2+ breast cancer.
Since 2019, four additional HER2-targeted therapies have been approved by the FDA for HER2+ metastatic breast cancer (MBC), changing the treatment paradigm for those patients substantially.
The new agents are especially useful in certain patient populations. The agents offer the promise of improved survival for patients with recurrent metastatic disease and the potential for further reductions in relapse rates in earlier settings.
Trastuzumab deruxtecan
Trastuzumab deruxtecan is an antibody-drug conjugate that links three components: an anti-HER2 monoclonal antibody, a highly potent topoisomerase I inhibitor payload, and a tetrapeptide-based cleavable linker.
Trastuzumab deruxtecan has a high drug-to-antibody ratio. A membrane-permeable payload offers the potential for activity against adjacent HER2-negative cells in heterogeneous tumors. It has a long half-life (6 days).
Trastuzumab deruxtecan received accelerated approval from the FDA in December 2019 to treat patients with HER2+ MBC who have received two or more prior HER2-targeted regimens, based on the results of the DESTINY-Breast 01 trial.
DESTINY-Breast 01 trial
In the phase 2 DESTINY-Breast 01 trial, 184 patients with a median of six previous treatments received trastuzumab deruxtecan (5.4 mg/kg) intravenously every 21 days. There were 24 patients with treated, asymptomatic brain metastases who participated. Patients with untreated or symptomatic brain metastases were excluded.
Overall, a response to therapy was reported in 112 patients (60.9%), with 6.0% complete and 54.9% partial responses. Most of the patients for whom both baseline and postbaseline data were available had a reduction in tumor size.
The median time until response was 1.6 months, an interval that corresponded to the time until the first scheduled imaging. Three patients (1.6%) had progressive disease, and two patients (1.1%) could not be evaluated.
The median duration of follow-up was 11.1 months, and the median response duration was 14.8 months.
The median progression-free survival (PFS) was 16.4 months, and the median overall survival (OS) was not reached. The median PFS in the patients with brain involvement was 18.1 months.
The most common adverse events of grade 3 or higher were a decreased neutrophil count (20.7%), anemia (8.7%), and nausea (7.6%). Most concerning was that trastuzumab deruxtecan was associated with interstitial lung disease in 13.6% of patients.
Tucatinib
Tucatinib is an oral, highly selective HER2 tyrosine kinase inhibitor (TKI). In April 2020, it was approved by the FDA, in combination with trastuzumab and capecitabine, for adult patients with advanced unresectable or metastatic HER2+ breast cancer who have received one or more prior anti-HER2–based regimens for MBC. The approval included patients with brain metastases.
The recommended tucatinib dose is 300 mg orally twice a day in combination with trastuzumab (at the standard dose) and capecitabine (1,000 mg/m2 given orally twice daily on days 1-14) on a 21-day cycle, until disease progression or unacceptable toxicity.
HER2CLIMB trial
The study that led to the approval of tucatinib was the HER2CLIMB trial. The trial enrolled 612 HER2+ MBC patients who had prior treatment with trastuzumab, pertuzumab, and T-DM1. Patients had received a median of 4 (range, 2-17) prior lines of HER2-targeted therapy.
The patients were randomized 2:1 to receive trastuzumab plus capecitabine and either tucatinib or an identical placebo twice daily.
The primary endpoint was PFS, evaluated in the initial 480 randomized patients. The median PFS was 7.8 months in the tucatinib arm and 5.6 months in the control arm (hazard ratio, 0.54; 95% confidence interval, 0.42-0.71; P < .001).
The confirmed overall response rate for patients with measurable disease was 40.6% in the tucatinib arm and 22.8% in the control arm (P = .001). The proportion of patients still in response at 12 months was 33.1% and 12.3%, respectively.
The median OS was 21.9 months in the tucatinib arm and 17.4 months in the placebo arm (HR, 0.66; 95% CI, 0.50-0.88; P = .005). At 24 months, 44.9% and 26.6% of patients, respectively, were still alive.
The most common grade 3 or higher adverse events (in the tucatinib and placebo arms, respectively) were palmar-plantar erythrodysesthesia syndrome (13.1% vs. 9.1%), diarrhea (12.9% vs. 8.6%), elevations in ALT and AST (approximately 5% vs. 0.5% for each), and fatigue (4.7% vs. 4.1%).
Tucatinib in patients with brain involvement
A unique feature of the HER2CLIMB study was that patients with MBC and untreated, symptomatic brain metastases were eligible. Patients with active, untreated central nervous system disease are excluded from virtually all other trials, especially drug-approval trials.
There were 291 patients with brain metastases in HER2CLIMB, 198 (48%) in the tucatinib arm and 93 (46%) in the control arm.
The risk of intracranial progression or death was reduced by 68% in the tucatinib arm (HR, 0.32; 95% CI, 0.22 to 0.48; P < .0001).
The 1-year CNS-PFS rate was 40.2% in the tucatinib arm and 0% in the placebo arm. The median duration of CNS-PFS was 9.9 months and 4.2 months, respectively.
The risk of death was reduced by 42% in the tucatinib arm (HR, 0.58; 95% CI, 0.40-0.85; P = .005). The median OS was 18.1 months and 12.0 months, respectively.
There were more objective responses in the brain with tucatinib (47.3%) than with placebo (20.0%; P = .03). The median duration of response was 6.8 months and 3.0 months, respectively.
Particularly because of its CNS activity and lack of serious, long-term toxicity, tucatinib combination therapy represents an attractive new option for patients with HER2+ MBC.
Neratinib
Neratinib is an irreversible pan-HER TKI that was approved by the FDA in July 2017 for extended adjuvant therapy in patients with early-stage HER2+ breast cancer, following the use of trastuzumab-based therapy.
Long-term results of the ExteNet study led to the approval for use as extended adjuvant therapy.
In February 2020, neratinib was FDA approved in combination with capecitabine for patients with HER2+ MBC after two or more prior anti-HER2–based regimens. The more recent FDA approval was based on results of the NALA trial.
NALA trial
The phase 3 NALA trial included 621 patients with HER2+ MBC who had received at least two prior anti-HER2 based regimens.
Patients were randomized 1:1 to receive neratinib at 240 mg orally once daily on days 1-21 with capecitabine at 750 mg/m2 orally twice daily on days 1-14 or lapatinib at 1,250 mg orally once daily on days 1-21 with capecitabine at 1,000 mg/m2 orally twice daily on days 1-14 for each 21-day cycle. Patients were treated until disease progression or unacceptable toxicity.
The primary endpoints were PFS and OS by blinded, independent, central review.
The median PFS was 5.6 months in the neratinib arm and 5.5 months in the lapatinib arm (HR, 0.76; 95% CI, 0.63-0.93; P = .0059). The PFS rate at 12 months was 28.8% and 14.8%, respectively.
The median OS was 21.0 months in the neratinib arm and 18.7 months in the lapatinib arm (HR, 0.88; 95% CI, 0.72-1.07; P = .2086). The ORR was 32.8% and 26.7%, respectively. The median response duration was 8.5 months and 5.6 months, respectively.
Fewer interventions for CNS disease were required in the neratinib arm than in the lapatinib arm (cumulative incidence, 22.8% vs. 29.2%; P = .043).
The most frequently reported grade 3-4 adverse reactions for the neratinib combination were diarrhea, nausea, vomiting, fatigue, and decreased appetite.
Grade 3 diarrhea occurred in 24.4% of those in the neratinib arm and 12.5% of those in the lapatinib arm. Antidiarrheal medication was used by 98.3% of patients receiving neratinib and 62.1% of patients receiving lapatinib.
Margetuximab-cmkb
Margetuximab is a chimeric Fc-engineered anti-HER2 monoclonal antibody that targets the same epitope as trastuzumab and exerts similar antiproliferative effects.
Compared with trastuzumab, margetuximab has higher affinity for both 158V (high-binding) and 158F (low-binding) alleles of the activating Fc receptor, CD16A. As a result, margetuximab enhances innate immunity, including CD16A-mediated antibody-dependent cellular cytotoxicity, more effectively than trastuzumab. Margetuximab also potentiates adaptive immunity, including enhanced clonality of the T-cell repertoire and induction of HER2-specific T- and B-cell responses.
In December 2020, margetuximab, in combination with chemotherapy, was approved by the FDA for patients with HER2+ MBC after two or more prior anti-HER2 regimens, at least one of which was for metastatic disease. The approved dose is 15 mg/kg IV every 3 weeks.
The study that led to margetuximab’s approval was the phase 3 SOPHIA trial.
SOPHIA trial
SOPHIA was a randomized trial of 536 patients with HER2+ MBC who had received prior treatment with other anti-HER2 therapies, including one to three lines of therapy for MBC.
Patients were randomly assigned 1:1 to receive margetuximab plus chemotherapy or trastuzumab plus chemotherapy. Assignment was stratified by chemotherapy choice (capecitabine, eribulin, gemcitabine, or vinorelbine), the number of previous lines of therapy for MBC, and disease extent.
Co–primary outcome measures were PFS by blinded, independent, central review and OS.
At the second interim analysis, the median PFS was 5.8 months in the margetuximab arm and 4.9 months in the trastuzumab arm (HR, 0.76; 95% CI, 0.59-0.98; P = .033). Results were more impressive in patients with CD16A genotypes containing a 158F allele. In this group, the median PFS was 6.9 months with margetuximab and 5.1 months with trastuzumab (HR, 0.68, 95% CI, 0.52-0.90; P = .005).
At the second interim analysis, the median OS was 21.6 months in the margetuximab arm and 19.8 months in the trastuzumab arm (HR, 0.89; 95% CI, 0.69-1.13; P = .33).
Subgroup data showed no differences in OS between the two arms for any subgroup except HER2+ MBC patients with an IHC score of 2 or higher. This is consistent with the postulated mechanism of action of margetuximab.
The confirmed ORR was 25% in the margetuximab arm and 14% in the trastuzumab arm, with similar durations of response between the study arms.
The most common adverse events in both arms (≥20%), regardless of causality, were fatigue, nausea, diarrhea, and neutropenia. Vomiting was common in the margetuximab arm, and anemia was common in the trastuzumab arm.
Grade 3 or higher adverse events occurred in 53.8% of patients receiving margetuximab and 52.6% of those receiving trastuzumab.
In view of margetuximab’s modest benefits in the SOPHIA trial, the ultimate role for margetuximab in HER2+ MBC may be restricted to patients with the CD16A-158F allele. A neoadjuvant trial is planned in that population.
Take-home messages
There are legitimate arguments regarding whether curing MBC is within reach for certain patient subsets, but there is no argument about whether the outlook for patients with HER2+ MBC has improved dramatically in recent years; it has.
The approval of four unique, new agents for the treatment of women with HER2+ MBC in relapse provides further improvements in outcome for these patients and distinctly different opportunities for tailoring treatment to the special circumstances of each patient (e.g., whether brain metastases are present, desire for oral therapy, comorbidities, experience with prior chemotherapy, etc).
When considered along with the potential for incorporating these drugs in earlier settings in well-designed clinical trials, these new drugs offer great promise to a group of patients who faced a dismal outcome just 2 decades ago.
Dr. Lyss was a community-based medical oncologist and clinical researcher for more than 35 years before his recent retirement. His clinical and research interests were focused on breast and lung cancers, as well as expanding clinical trial access to medically underserved populations. He is based in St. Louis. He has no conflicts of interest.
Polycystic ovary syndrome: It’s not just about fertility
Polycystic ovary syndrome, the most common endocrinopathy and most common cause of female infertility, affects 8%-13% of reproductive-aged women. PCOS has a profound impact on a woman’s life yet its diagnosis and management remain confusing despite being first described nearly a century ago by Stein and Leventhal.
To illustrate, in a global survey of 1,385 women with PCOS, one-third or more reported a delay of greater than 2 years and nearly half required evaluation by at least three health professionals before a diagnosis was established (J Clin Endocrinol Metab. 2017;102[2]:604-12). A vital health problem that urgently requires a gap analysis and needs assessment, PCOS is not “just about fertility” but has extensive gynecologic and metabolic consequences that require a personalized approach to care coordinated among the fields of internal medicine, pediatrics, dermatology, and, of course, gynecology.
Diagnosis in adults and adolescence
Normal menstrual intervals do not always equate with ovulation. Up to 40% of hirsute women with monthly cycles may not ovulate regularly. The Rotterdam criteria are used to confirm PCOS and require two of the following three: 1) ovulation dysfunction (cycle interval > 35 d or < 8 cycles/year); 2) hyperandrogenism (i.e., elevated total or free testosterone, DHEAS, or signs of hirsutism or acne with Ferriman-Gallwey score greater than 6); 3) polycystic ovaries on ultrasound (20 or more 2- to 9-mm follicles on at least one ovary, and/or increased ovarian volume (> 10 mL) – all at the exclusion of other etiologies including hyperprolactinemia, thyroid dysfunction, androgen-secreting tumors including Cushing’s syndrome, and nonclassic adrenal hyperplasia mostly easily screened by obtaining 17-hydroxyprogesterone.
For adolescents, by age 14 most will have adult androgen levels. Ovarian ultrasound should not be used as a criterion in this age group given the frequency of this appearance. Due to frequent menstrual irregularity, it is recommended to wait at least 2 years post menarche before consideration of a diagnosis.
Antimüllerian hormone is two- to threefold higher in women with PCOS but this hormone level has not yet been accepted as a diagnostic criterion.
The metabolic connection
A multisystem disorder whose name misdirects its morbidity, PCOS affects the metabolic, reproductive, and psychological system through vicious cycles of distorted feedback signals. Without a consensus of its origin, there appears to be a hypersensitivity of pituitary luteinizing hormone (LH) to hypothalamic gonadotrophin-releasing hormone. Consequently, elevated LH stimulates ovarian theca cells to increase androgens with resultant hyperandrogenic consequences. Parenthetically, the tonic elevation in LH explains the false-positive surges PCOS women experience when testing their urine during ovulation induction.
Elevations in insulin from unexplained damage to the insulin receptor acts synergistically with LH to increase ovarian androgens and inhibit ovulation. Hyperinsulinemia and abdominal fat deposition contribute to impaired glucose tolerance which is threefold higher with PCOS.
The metabolic syndrome, an association of disorders including hypertension, impaired glucose tolerance, dyslipidemia, and obesity, occurs at an increased overall prevalence rate of 43%-47% in women with PCOS, which is twice as high as in women without PCOS. PCOS is associated with low-grade chronic inflammation, which places these women at increased risk of nonalcoholic fatty liver disease. Dyslipidemia is the most common metabolic disorder in PCOS. These metabolic consequences, including obstructive sleep apnea, are worsened by hyperandrogenemia and an elevated BMI.
A genetic link
Multigenetic in origin, PCOS has a fivefold higher risk of inheritance from mothers with PCOS to daughters influenced by prenatal androgen exposure in utero. Genetic studies suggest a causal relationship between PCOS with body mass index, insulin resistance, onset of menopause, depression, and male-pattern balding (PLoS Genet 2018;14[12]:e10007813).
Fifteen genetic risk areas in the human genome seem to predispose to PCOS. New results suggest that altering the gut microbiome via prebiotic or probiotic therapies may be a potential treatment option.
Reproductive and gynecologic management
Due to chronic anovulation, unopposed estrogen can result in abnormal endometrial bleeding, endometrial hyperplasia, and a fourfold risk of endometrial cancer. This underscores the importance of regular progestin withdrawal, combined oral contraception (COC), or a progestin intrauterine device.
PCOS is a leading cause of infertility and is associated with abnormal bleeding, miscarriage, gestational diabetes, and gestational hypertension, all of which are higher based on a hyperandrogenic phenotype.
The rate of infertility in women with PCOS is 70%-80%, with ovulation dysfunction being the dominant cause. For years, the mainstay for ovulation induction was clomiphene citrate; however, letrozole has shown higher pregnancy success rates, particularly in women who have a BMI greater than 30 kg/m2. (N Engl J Med. 2014;371:119-29). Despite multiple studies demonstrating its efficacy and safety, letrozole remains without Food and Drug Administration approval for ovulation induction.
Metformin has been recommended in women with prediabetes or a BMI above 30, and it may improve menstrual regularity but has not been shown to improve live birth rates nor reduce the pregnancy complications of miscarriage or gestational diabetes. Inositol, the ubiquitous endogenous carbohydrate, has not demonstrated clear improvement in reproduction.
Laparoscopic ovarian diathermy (LOD) is a second-line treatment option, as is the use of gonadotropins, to overcome unsuccessful conservative attempts at ovulation induction. LOD is more invasive but outcomes are equivalent to gonadotropin usage while providing a dramatic reduction in multiple gestation, ovarian hyperstimulation syndrome, and cost (not including the surgical procedure). Ultimately, in vitro fertilization is an option for continued infertility in women with PCOS.
Metabolic/gynecologic management
Given the multisystem effect of PCOS, health care providers caring for these women should be vigilant and aggressive at ensuring appropriate monitoring and management. For women with PCOS with an elevated BMI, lifestyle modification is the first line of management. Weight loss alone of only 2%-5% may restore ovulation function.
The combination of dyslipidemia, elevated BMI, and impaired glucose tolerance would presumably predict the risk of cardiovascular events, yet the impact is not proven. Despite an increase in carotid intima media thickness, there are data that suggest only an increase in stroke or myocardial infarction (J Clin Endocrinol Metab. 2019;104[4]:1221-31).
Hyperandrogenism is cosmetically and psychologically disrupting to PCOS patients. The topical application of eflornithine hydrochloride may be of value for mild to moderate facial hair growth. Spironolactone is the preferred first-line agent. (Caution: effective contraception is necessary to avoid feminization of a male fetus). Women with PCOS have a higher risk of disordered eating and body image distress as well as a fivefold higher rate of mental distress such as anxiety and depression.
No specific diet has been determined as part of treatment, yet healthy food selection and caloric intake combined with exercise has been shown to improve metabolic and psychological well-being.
Conclusion
PCOS is a ubiquitous, frustrating, and life-altering disease. Health care providers, particularly those in women’s health, must ensure appropriate counseling and education with evidence-based medicine to empower patients toward improved health.
Dr. Trolice is director of Fertility CARE - The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando. He has no conflicts of interest. Please contact him at obnews@mdedge.com.
Polycystic ovary syndrome, the most common endocrinopathy and most common cause of female infertility, affects 8%-13% of reproductive-aged women. PCOS has a profound impact on a woman’s life yet its diagnosis and management remain confusing despite being first described nearly a century ago by Stein and Leventhal.
To illustrate, in a global survey of 1,385 women with PCOS, one-third or more reported a delay of greater than 2 years and nearly half required evaluation by at least three health professionals before a diagnosis was established (J Clin Endocrinol Metab. 2017;102[2]:604-12). A vital health problem that urgently requires a gap analysis and needs assessment, PCOS is not “just about fertility” but has extensive gynecologic and metabolic consequences that require a personalized approach to care coordinated among the fields of internal medicine, pediatrics, dermatology, and, of course, gynecology.
Diagnosis in adults and adolescence
Normal menstrual intervals do not always equate with ovulation. Up to 40% of hirsute women with monthly cycles may not ovulate regularly. The Rotterdam criteria are used to confirm PCOS and require two of the following three: 1) ovulation dysfunction (cycle interval > 35 d or < 8 cycles/year); 2) hyperandrogenism (i.e., elevated total or free testosterone, DHEAS, or signs of hirsutism or acne with Ferriman-Gallwey score greater than 6); 3) polycystic ovaries on ultrasound (20 or more 2- to 9-mm follicles on at least one ovary, and/or increased ovarian volume (> 10 mL) – all at the exclusion of other etiologies including hyperprolactinemia, thyroid dysfunction, androgen-secreting tumors including Cushing’s syndrome, and nonclassic adrenal hyperplasia mostly easily screened by obtaining 17-hydroxyprogesterone.
For adolescents, by age 14 most will have adult androgen levels. Ovarian ultrasound should not be used as a criterion in this age group given the frequency of this appearance. Due to frequent menstrual irregularity, it is recommended to wait at least 2 years post menarche before consideration of a diagnosis.
Antimüllerian hormone is two- to threefold higher in women with PCOS but this hormone level has not yet been accepted as a diagnostic criterion.
The metabolic connection
A multisystem disorder whose name misdirects its morbidity, PCOS affects the metabolic, reproductive, and psychological system through vicious cycles of distorted feedback signals. Without a consensus of its origin, there appears to be a hypersensitivity of pituitary luteinizing hormone (LH) to hypothalamic gonadotrophin-releasing hormone. Consequently, elevated LH stimulates ovarian theca cells to increase androgens with resultant hyperandrogenic consequences. Parenthetically, the tonic elevation in LH explains the false-positive surges PCOS women experience when testing their urine during ovulation induction.
Elevations in insulin from unexplained damage to the insulin receptor acts synergistically with LH to increase ovarian androgens and inhibit ovulation. Hyperinsulinemia and abdominal fat deposition contribute to impaired glucose tolerance which is threefold higher with PCOS.
The metabolic syndrome, an association of disorders including hypertension, impaired glucose tolerance, dyslipidemia, and obesity, occurs at an increased overall prevalence rate of 43%-47% in women with PCOS, which is twice as high as in women without PCOS. PCOS is associated with low-grade chronic inflammation, which places these women at increased risk of nonalcoholic fatty liver disease. Dyslipidemia is the most common metabolic disorder in PCOS. These metabolic consequences, including obstructive sleep apnea, are worsened by hyperandrogenemia and an elevated BMI.
A genetic link
Multigenetic in origin, PCOS has a fivefold higher risk of inheritance from mothers with PCOS to daughters influenced by prenatal androgen exposure in utero. Genetic studies suggest a causal relationship between PCOS with body mass index, insulin resistance, onset of menopause, depression, and male-pattern balding (PLoS Genet 2018;14[12]:e10007813).
Fifteen genetic risk areas in the human genome seem to predispose to PCOS. New results suggest that altering the gut microbiome via prebiotic or probiotic therapies may be a potential treatment option.
Reproductive and gynecologic management
Due to chronic anovulation, unopposed estrogen can result in abnormal endometrial bleeding, endometrial hyperplasia, and a fourfold risk of endometrial cancer. This underscores the importance of regular progestin withdrawal, combined oral contraception (COC), or a progestin intrauterine device.
PCOS is a leading cause of infertility and is associated with abnormal bleeding, miscarriage, gestational diabetes, and gestational hypertension, all of which are higher based on a hyperandrogenic phenotype.
The rate of infertility in women with PCOS is 70%-80%, with ovulation dysfunction being the dominant cause. For years, the mainstay for ovulation induction was clomiphene citrate; however, letrozole has shown higher pregnancy success rates, particularly in women who have a BMI greater than 30 kg/m2. (N Engl J Med. 2014;371:119-29). Despite multiple studies demonstrating its efficacy and safety, letrozole remains without Food and Drug Administration approval for ovulation induction.
Metformin has been recommended in women with prediabetes or a BMI above 30, and it may improve menstrual regularity but has not been shown to improve live birth rates nor reduce the pregnancy complications of miscarriage or gestational diabetes. Inositol, the ubiquitous endogenous carbohydrate, has not demonstrated clear improvement in reproduction.
Laparoscopic ovarian diathermy (LOD) is a second-line treatment option, as is the use of gonadotropins, to overcome unsuccessful conservative attempts at ovulation induction. LOD is more invasive but outcomes are equivalent to gonadotropin usage while providing a dramatic reduction in multiple gestation, ovarian hyperstimulation syndrome, and cost (not including the surgical procedure). Ultimately, in vitro fertilization is an option for continued infertility in women with PCOS.
Metabolic/gynecologic management
Given the multisystem effect of PCOS, health care providers caring for these women should be vigilant and aggressive at ensuring appropriate monitoring and management. For women with PCOS with an elevated BMI, lifestyle modification is the first line of management. Weight loss alone of only 2%-5% may restore ovulation function.
The combination of dyslipidemia, elevated BMI, and impaired glucose tolerance would presumably predict the risk of cardiovascular events, yet the impact is not proven. Despite an increase in carotid intima media thickness, there are data that suggest only an increase in stroke or myocardial infarction (J Clin Endocrinol Metab. 2019;104[4]:1221-31).
Hyperandrogenism is cosmetically and psychologically disrupting to PCOS patients. The topical application of eflornithine hydrochloride may be of value for mild to moderate facial hair growth. Spironolactone is the preferred first-line agent. (Caution: effective contraception is necessary to avoid feminization of a male fetus). Women with PCOS have a higher risk of disordered eating and body image distress as well as a fivefold higher rate of mental distress such as anxiety and depression.
No specific diet has been determined as part of treatment, yet healthy food selection and caloric intake combined with exercise has been shown to improve metabolic and psychological well-being.
Conclusion
PCOS is a ubiquitous, frustrating, and life-altering disease. Health care providers, particularly those in women’s health, must ensure appropriate counseling and education with evidence-based medicine to empower patients toward improved health.
Dr. Trolice is director of Fertility CARE - The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando. He has no conflicts of interest. Please contact him at obnews@mdedge.com.
Polycystic ovary syndrome, the most common endocrinopathy and most common cause of female infertility, affects 8%-13% of reproductive-aged women. PCOS has a profound impact on a woman’s life yet its diagnosis and management remain confusing despite being first described nearly a century ago by Stein and Leventhal.
To illustrate, in a global survey of 1,385 women with PCOS, one-third or more reported a delay of greater than 2 years and nearly half required evaluation by at least three health professionals before a diagnosis was established (J Clin Endocrinol Metab. 2017;102[2]:604-12). A vital health problem that urgently requires a gap analysis and needs assessment, PCOS is not “just about fertility” but has extensive gynecologic and metabolic consequences that require a personalized approach to care coordinated among the fields of internal medicine, pediatrics, dermatology, and, of course, gynecology.
Diagnosis in adults and adolescence
Normal menstrual intervals do not always equate with ovulation. Up to 40% of hirsute women with monthly cycles may not ovulate regularly. The Rotterdam criteria are used to confirm PCOS and require two of the following three: 1) ovulation dysfunction (cycle interval > 35 d or < 8 cycles/year); 2) hyperandrogenism (i.e., elevated total or free testosterone, DHEAS, or signs of hirsutism or acne with Ferriman-Gallwey score greater than 6); 3) polycystic ovaries on ultrasound (20 or more 2- to 9-mm follicles on at least one ovary, and/or increased ovarian volume (> 10 mL) – all at the exclusion of other etiologies including hyperprolactinemia, thyroid dysfunction, androgen-secreting tumors including Cushing’s syndrome, and nonclassic adrenal hyperplasia mostly easily screened by obtaining 17-hydroxyprogesterone.
For adolescents, by age 14 most will have adult androgen levels. Ovarian ultrasound should not be used as a criterion in this age group given the frequency of this appearance. Due to frequent menstrual irregularity, it is recommended to wait at least 2 years post menarche before consideration of a diagnosis.
Antimüllerian hormone is two- to threefold higher in women with PCOS but this hormone level has not yet been accepted as a diagnostic criterion.
The metabolic connection
A multisystem disorder whose name misdirects its morbidity, PCOS affects the metabolic, reproductive, and psychological system through vicious cycles of distorted feedback signals. Without a consensus of its origin, there appears to be a hypersensitivity of pituitary luteinizing hormone (LH) to hypothalamic gonadotrophin-releasing hormone. Consequently, elevated LH stimulates ovarian theca cells to increase androgens with resultant hyperandrogenic consequences. Parenthetically, the tonic elevation in LH explains the false-positive surges PCOS women experience when testing their urine during ovulation induction.
Elevations in insulin from unexplained damage to the insulin receptor acts synergistically with LH to increase ovarian androgens and inhibit ovulation. Hyperinsulinemia and abdominal fat deposition contribute to impaired glucose tolerance which is threefold higher with PCOS.
The metabolic syndrome, an association of disorders including hypertension, impaired glucose tolerance, dyslipidemia, and obesity, occurs at an increased overall prevalence rate of 43%-47% in women with PCOS, which is twice as high as in women without PCOS. PCOS is associated with low-grade chronic inflammation, which places these women at increased risk of nonalcoholic fatty liver disease. Dyslipidemia is the most common metabolic disorder in PCOS. These metabolic consequences, including obstructive sleep apnea, are worsened by hyperandrogenemia and an elevated BMI.
A genetic link
Multigenetic in origin, PCOS has a fivefold higher risk of inheritance from mothers with PCOS to daughters influenced by prenatal androgen exposure in utero. Genetic studies suggest a causal relationship between PCOS with body mass index, insulin resistance, onset of menopause, depression, and male-pattern balding (PLoS Genet 2018;14[12]:e10007813).
Fifteen genetic risk areas in the human genome seem to predispose to PCOS. New results suggest that altering the gut microbiome via prebiotic or probiotic therapies may be a potential treatment option.
Reproductive and gynecologic management
Due to chronic anovulation, unopposed estrogen can result in abnormal endometrial bleeding, endometrial hyperplasia, and a fourfold risk of endometrial cancer. This underscores the importance of regular progestin withdrawal, combined oral contraception (COC), or a progestin intrauterine device.
PCOS is a leading cause of infertility and is associated with abnormal bleeding, miscarriage, gestational diabetes, and gestational hypertension, all of which are higher based on a hyperandrogenic phenotype.
The rate of infertility in women with PCOS is 70%-80%, with ovulation dysfunction being the dominant cause. For years, the mainstay for ovulation induction was clomiphene citrate; however, letrozole has shown higher pregnancy success rates, particularly in women who have a BMI greater than 30 kg/m2. (N Engl J Med. 2014;371:119-29). Despite multiple studies demonstrating its efficacy and safety, letrozole remains without Food and Drug Administration approval for ovulation induction.
Metformin has been recommended in women with prediabetes or a BMI above 30, and it may improve menstrual regularity but has not been shown to improve live birth rates nor reduce the pregnancy complications of miscarriage or gestational diabetes. Inositol, the ubiquitous endogenous carbohydrate, has not demonstrated clear improvement in reproduction.
Laparoscopic ovarian diathermy (LOD) is a second-line treatment option, as is the use of gonadotropins, to overcome unsuccessful conservative attempts at ovulation induction. LOD is more invasive but outcomes are equivalent to gonadotropin usage while providing a dramatic reduction in multiple gestation, ovarian hyperstimulation syndrome, and cost (not including the surgical procedure). Ultimately, in vitro fertilization is an option for continued infertility in women with PCOS.
Metabolic/gynecologic management
Given the multisystem effect of PCOS, health care providers caring for these women should be vigilant and aggressive at ensuring appropriate monitoring and management. For women with PCOS with an elevated BMI, lifestyle modification is the first line of management. Weight loss alone of only 2%-5% may restore ovulation function.
The combination of dyslipidemia, elevated BMI, and impaired glucose tolerance would presumably predict the risk of cardiovascular events, yet the impact is not proven. Despite an increase in carotid intima media thickness, there are data that suggest only an increase in stroke or myocardial infarction (J Clin Endocrinol Metab. 2019;104[4]:1221-31).
Hyperandrogenism is cosmetically and psychologically disrupting to PCOS patients. The topical application of eflornithine hydrochloride may be of value for mild to moderate facial hair growth. Spironolactone is the preferred first-line agent. (Caution: effective contraception is necessary to avoid feminization of a male fetus). Women with PCOS have a higher risk of disordered eating and body image distress as well as a fivefold higher rate of mental distress such as anxiety and depression.
No specific diet has been determined as part of treatment, yet healthy food selection and caloric intake combined with exercise has been shown to improve metabolic and psychological well-being.
Conclusion
PCOS is a ubiquitous, frustrating, and life-altering disease. Health care providers, particularly those in women’s health, must ensure appropriate counseling and education with evidence-based medicine to empower patients toward improved health.
Dr. Trolice is director of Fertility CARE - The IVF Center in Winter Park, Fla., and professor of obstetrics and gynecology at the University of Central Florida, Orlando. He has no conflicts of interest. Please contact him at obnews@mdedge.com.
Addressing today’s racial health inequities requires understanding their roots
The health disparities seen in today’s high rates of Black infant and maternal morbidity and mortality are rooted in health inequities and generational stress dating back centuries in the United States, but today’s obstetricians can make changes in their own practices to address this inequity, according to Haywood L. Brown, MD, professor of ob.gyn. and associate dean of diversity at the Morsani College of Medicine and vice president of institutional equity at the University of South Florida, Tampa.
Dr. Brown delivered his remarks during the Benson and Pamela Harer Seminar on History at the annual meeting of the American College of Obstetricians and Gynecologists on May 2. His talk focused on the origins of perinatal and maternal health inequities and how those original factors play out today in increased maternal and neonatal morbidity and mortality among Black women and their babies.
“Racial and ethnic disparities and inequity in maternal and child health are prevalent and persistent. We have to move beyond the documentation,” Dr. Brown told attendees. “We have to adopt uniform care standards, recognizing our own biases and understanding that the contribution of social determinants of health are important in the care and outcome of women. And we have to work on decreasing the stress of women who give birth.”
Evelyn Nicole Mitchell, MD, faculty chair of the ob.gyn. diversity and inclusion committee at the University of Southern California, found Dr. Brown’s talk compelling and hopes it opens the eyes of others who attended.
“You really have to understand the why behind the problems we have, and it really goes back to slavery and this historical distrust that’s been here from the beginning,” Dr. Mitchell said in an interview. “I hope this allows people to open their eyes and think about this situation from their patients’ shoes, to really put their guard down and explore, ‘how can I contribute to fixing this system that has been here from the beginning?’ I think a lot of people get defensive and think: ‘Oh, I’m not a racist. I just don’t want to talk about this,’ but it’s about a system being racist.” The question then, Dr. Mitchell said, is: “So how do I contribute to that system?”
Dr. Brown frequently returned to the theme of high stress levels in Black mothers contributing to poorer outcomes, such as preterm birth. That stress arises originally from the generational stress brought on by racism and oppression over the centuries but has been compounded by poverty, racial injustice, lack of access to adequate nutrition, lower education levels, environmental factors, and other determinants of health.
“The bottom line, as Dr. Brown said, is that we need to decrease the stress level of Black mothers giving birth,” Dr. Mitchell said. “How can I, as a provider, decrease the stress level of my patients? Well, No. 1, I can identify and eliminate implicit bias that I may harbor.”
Slavery husbandry laid the groundwork for today
The most surprising aspect of Dr. Brown’s lecture for Dr. Mitchell was the fact that enslaved women received a measure of protection that other enslaved people did not to “ensure that they were healthy and that they were able to reproduce in the future,” Dr. Mitchell said. “It was for the wrong reasons – to keep slavery going – but in a sense they were prioritizing Black women to take advantage of their reproductive capacity, compared to nowadays where Black women are facing severe disparities.”
To safeguard enslaved women’s fecundity, plantation owners attempted to reduce stressors in the women’s lives, such as allowing them to cohabitate with a husband and nuclear family, though sexual assault and abuse still occurred. The owners also tracked the enslaved girls’ menstrual cycles after menarche to maximize their “breeding” potential, especially between the ages of 15 and 24. Slave owners delegated older enslaved women as maternity caregivers and midwives, leading to the passing down of midwifery skills through generations of Black American women.
“Pregnant women received the best medical care on the plantation because of the premium placed on reproduction,” Dr. Brown said. Wealthier planters called in doctors for complicated deliveries, which provided J. Marian Sims the ability conduct surgical experiments on Betsey, Lucy, and Anarcha to treat vesicovaginal fistula since fistula “limited her ability to do the maximum work she could in the house or on the plantation,” Dr. Brown said.
After slavery ended, health care access did not improve for Black people. In 1920, there was approximately 1 Black physician for every 3,000 Black people, compared with 1 in 500 for the White population, and grannie midwives continued to be the primary birthing attendants for Black women. Over the next several decades, however, both maternal and infant mortality across all races began steeply dropping. Reasons for the drop included the incorporation of the American Board of Obstetrics and Gynecology in 1930, a shift from home births to hospital births, and the legalization of abortion, which led to an 89% decline in deaths from septic illegal abortions from 1950 to 1973.
Still, Black maternal and infant mortality remained higher than White, and the poverty gap further exacerbated outcomes.
“Substandard maternity care really is the origin of many of the Black maternal and infant morbidity and mortality” complications, such as low birth weight, small for gestational age, growth restriction, and intrauterine starvation, “which we now believe are the origin of things like hypertension, diabetes, and obesity,” Dr. Brown said.
Today, inequities persist because of the systemic racism throughout this history.
“As we talk about health disparities, prematurity, growth restriction, and maternal morbidity, the fetal origins for adult disease in diabetes and hypertension and obesity have generational implications over the last 400 years,” Dr. Brown said. “Generational stress and stresses in lack women from slavery to present times are some of the origins of the things that we see today, including segregation, economic inequities, eugenic sterilizations, the quality of education, and of course, systemic racism on health care access and quality.”
It is this long arc of history that Dr. Mitchell hopes attendees will begin to grasp.
“If you don’t understand all that and have that depth, there’s no way for you to truly understand the problems that are going on and how to solve them,” Dr. Mitchell said. She hopes that especially those who have been more “resistant to accepting these truths” can start to see the big picture. “Hopefully, they can look at it as a systemic problem and then focus on how they can change the system.”
Dr Brown is a contributor to UpToDate and the Merck Manual and serves on the advisory boards of Merck for Mothers Global Women’s Health and BabyScripts. Dr. Mitchell has no disclosures.
The health disparities seen in today’s high rates of Black infant and maternal morbidity and mortality are rooted in health inequities and generational stress dating back centuries in the United States, but today’s obstetricians can make changes in their own practices to address this inequity, according to Haywood L. Brown, MD, professor of ob.gyn. and associate dean of diversity at the Morsani College of Medicine and vice president of institutional equity at the University of South Florida, Tampa.
Dr. Brown delivered his remarks during the Benson and Pamela Harer Seminar on History at the annual meeting of the American College of Obstetricians and Gynecologists on May 2. His talk focused on the origins of perinatal and maternal health inequities and how those original factors play out today in increased maternal and neonatal morbidity and mortality among Black women and their babies.
“Racial and ethnic disparities and inequity in maternal and child health are prevalent and persistent. We have to move beyond the documentation,” Dr. Brown told attendees. “We have to adopt uniform care standards, recognizing our own biases and understanding that the contribution of social determinants of health are important in the care and outcome of women. And we have to work on decreasing the stress of women who give birth.”
Evelyn Nicole Mitchell, MD, faculty chair of the ob.gyn. diversity and inclusion committee at the University of Southern California, found Dr. Brown’s talk compelling and hopes it opens the eyes of others who attended.
“You really have to understand the why behind the problems we have, and it really goes back to slavery and this historical distrust that’s been here from the beginning,” Dr. Mitchell said in an interview. “I hope this allows people to open their eyes and think about this situation from their patients’ shoes, to really put their guard down and explore, ‘how can I contribute to fixing this system that has been here from the beginning?’ I think a lot of people get defensive and think: ‘Oh, I’m not a racist. I just don’t want to talk about this,’ but it’s about a system being racist.” The question then, Dr. Mitchell said, is: “So how do I contribute to that system?”
Dr. Brown frequently returned to the theme of high stress levels in Black mothers contributing to poorer outcomes, such as preterm birth. That stress arises originally from the generational stress brought on by racism and oppression over the centuries but has been compounded by poverty, racial injustice, lack of access to adequate nutrition, lower education levels, environmental factors, and other determinants of health.
“The bottom line, as Dr. Brown said, is that we need to decrease the stress level of Black mothers giving birth,” Dr. Mitchell said. “How can I, as a provider, decrease the stress level of my patients? Well, No. 1, I can identify and eliminate implicit bias that I may harbor.”
Slavery husbandry laid the groundwork for today
The most surprising aspect of Dr. Brown’s lecture for Dr. Mitchell was the fact that enslaved women received a measure of protection that other enslaved people did not to “ensure that they were healthy and that they were able to reproduce in the future,” Dr. Mitchell said. “It was for the wrong reasons – to keep slavery going – but in a sense they were prioritizing Black women to take advantage of their reproductive capacity, compared to nowadays where Black women are facing severe disparities.”
To safeguard enslaved women’s fecundity, plantation owners attempted to reduce stressors in the women’s lives, such as allowing them to cohabitate with a husband and nuclear family, though sexual assault and abuse still occurred. The owners also tracked the enslaved girls’ menstrual cycles after menarche to maximize their “breeding” potential, especially between the ages of 15 and 24. Slave owners delegated older enslaved women as maternity caregivers and midwives, leading to the passing down of midwifery skills through generations of Black American women.
“Pregnant women received the best medical care on the plantation because of the premium placed on reproduction,” Dr. Brown said. Wealthier planters called in doctors for complicated deliveries, which provided J. Marian Sims the ability conduct surgical experiments on Betsey, Lucy, and Anarcha to treat vesicovaginal fistula since fistula “limited her ability to do the maximum work she could in the house or on the plantation,” Dr. Brown said.
After slavery ended, health care access did not improve for Black people. In 1920, there was approximately 1 Black physician for every 3,000 Black people, compared with 1 in 500 for the White population, and grannie midwives continued to be the primary birthing attendants for Black women. Over the next several decades, however, both maternal and infant mortality across all races began steeply dropping. Reasons for the drop included the incorporation of the American Board of Obstetrics and Gynecology in 1930, a shift from home births to hospital births, and the legalization of abortion, which led to an 89% decline in deaths from septic illegal abortions from 1950 to 1973.
Still, Black maternal and infant mortality remained higher than White, and the poverty gap further exacerbated outcomes.
“Substandard maternity care really is the origin of many of the Black maternal and infant morbidity and mortality” complications, such as low birth weight, small for gestational age, growth restriction, and intrauterine starvation, “which we now believe are the origin of things like hypertension, diabetes, and obesity,” Dr. Brown said.
Today, inequities persist because of the systemic racism throughout this history.
“As we talk about health disparities, prematurity, growth restriction, and maternal morbidity, the fetal origins for adult disease in diabetes and hypertension and obesity have generational implications over the last 400 years,” Dr. Brown said. “Generational stress and stresses in lack women from slavery to present times are some of the origins of the things that we see today, including segregation, economic inequities, eugenic sterilizations, the quality of education, and of course, systemic racism on health care access and quality.”
It is this long arc of history that Dr. Mitchell hopes attendees will begin to grasp.
“If you don’t understand all that and have that depth, there’s no way for you to truly understand the problems that are going on and how to solve them,” Dr. Mitchell said. She hopes that especially those who have been more “resistant to accepting these truths” can start to see the big picture. “Hopefully, they can look at it as a systemic problem and then focus on how they can change the system.”
Dr Brown is a contributor to UpToDate and the Merck Manual and serves on the advisory boards of Merck for Mothers Global Women’s Health and BabyScripts. Dr. Mitchell has no disclosures.
The health disparities seen in today’s high rates of Black infant and maternal morbidity and mortality are rooted in health inequities and generational stress dating back centuries in the United States, but today’s obstetricians can make changes in their own practices to address this inequity, according to Haywood L. Brown, MD, professor of ob.gyn. and associate dean of diversity at the Morsani College of Medicine and vice president of institutional equity at the University of South Florida, Tampa.
Dr. Brown delivered his remarks during the Benson and Pamela Harer Seminar on History at the annual meeting of the American College of Obstetricians and Gynecologists on May 2. His talk focused on the origins of perinatal and maternal health inequities and how those original factors play out today in increased maternal and neonatal morbidity and mortality among Black women and their babies.
“Racial and ethnic disparities and inequity in maternal and child health are prevalent and persistent. We have to move beyond the documentation,” Dr. Brown told attendees. “We have to adopt uniform care standards, recognizing our own biases and understanding that the contribution of social determinants of health are important in the care and outcome of women. And we have to work on decreasing the stress of women who give birth.”
Evelyn Nicole Mitchell, MD, faculty chair of the ob.gyn. diversity and inclusion committee at the University of Southern California, found Dr. Brown’s talk compelling and hopes it opens the eyes of others who attended.
“You really have to understand the why behind the problems we have, and it really goes back to slavery and this historical distrust that’s been here from the beginning,” Dr. Mitchell said in an interview. “I hope this allows people to open their eyes and think about this situation from their patients’ shoes, to really put their guard down and explore, ‘how can I contribute to fixing this system that has been here from the beginning?’ I think a lot of people get defensive and think: ‘Oh, I’m not a racist. I just don’t want to talk about this,’ but it’s about a system being racist.” The question then, Dr. Mitchell said, is: “So how do I contribute to that system?”
Dr. Brown frequently returned to the theme of high stress levels in Black mothers contributing to poorer outcomes, such as preterm birth. That stress arises originally from the generational stress brought on by racism and oppression over the centuries but has been compounded by poverty, racial injustice, lack of access to adequate nutrition, lower education levels, environmental factors, and other determinants of health.
“The bottom line, as Dr. Brown said, is that we need to decrease the stress level of Black mothers giving birth,” Dr. Mitchell said. “How can I, as a provider, decrease the stress level of my patients? Well, No. 1, I can identify and eliminate implicit bias that I may harbor.”
Slavery husbandry laid the groundwork for today
The most surprising aspect of Dr. Brown’s lecture for Dr. Mitchell was the fact that enslaved women received a measure of protection that other enslaved people did not to “ensure that they were healthy and that they were able to reproduce in the future,” Dr. Mitchell said. “It was for the wrong reasons – to keep slavery going – but in a sense they were prioritizing Black women to take advantage of their reproductive capacity, compared to nowadays where Black women are facing severe disparities.”
To safeguard enslaved women’s fecundity, plantation owners attempted to reduce stressors in the women’s lives, such as allowing them to cohabitate with a husband and nuclear family, though sexual assault and abuse still occurred. The owners also tracked the enslaved girls’ menstrual cycles after menarche to maximize their “breeding” potential, especially between the ages of 15 and 24. Slave owners delegated older enslaved women as maternity caregivers and midwives, leading to the passing down of midwifery skills through generations of Black American women.
“Pregnant women received the best medical care on the plantation because of the premium placed on reproduction,” Dr. Brown said. Wealthier planters called in doctors for complicated deliveries, which provided J. Marian Sims the ability conduct surgical experiments on Betsey, Lucy, and Anarcha to treat vesicovaginal fistula since fistula “limited her ability to do the maximum work she could in the house or on the plantation,” Dr. Brown said.
After slavery ended, health care access did not improve for Black people. In 1920, there was approximately 1 Black physician for every 3,000 Black people, compared with 1 in 500 for the White population, and grannie midwives continued to be the primary birthing attendants for Black women. Over the next several decades, however, both maternal and infant mortality across all races began steeply dropping. Reasons for the drop included the incorporation of the American Board of Obstetrics and Gynecology in 1930, a shift from home births to hospital births, and the legalization of abortion, which led to an 89% decline in deaths from septic illegal abortions from 1950 to 1973.
Still, Black maternal and infant mortality remained higher than White, and the poverty gap further exacerbated outcomes.
“Substandard maternity care really is the origin of many of the Black maternal and infant morbidity and mortality” complications, such as low birth weight, small for gestational age, growth restriction, and intrauterine starvation, “which we now believe are the origin of things like hypertension, diabetes, and obesity,” Dr. Brown said.
Today, inequities persist because of the systemic racism throughout this history.
“As we talk about health disparities, prematurity, growth restriction, and maternal morbidity, the fetal origins for adult disease in diabetes and hypertension and obesity have generational implications over the last 400 years,” Dr. Brown said. “Generational stress and stresses in lack women from slavery to present times are some of the origins of the things that we see today, including segregation, economic inequities, eugenic sterilizations, the quality of education, and of course, systemic racism on health care access and quality.”
It is this long arc of history that Dr. Mitchell hopes attendees will begin to grasp.
“If you don’t understand all that and have that depth, there’s no way for you to truly understand the problems that are going on and how to solve them,” Dr. Mitchell said. She hopes that especially those who have been more “resistant to accepting these truths” can start to see the big picture. “Hopefully, they can look at it as a systemic problem and then focus on how they can change the system.”
Dr Brown is a contributor to UpToDate and the Merck Manual and serves on the advisory boards of Merck for Mothers Global Women’s Health and BabyScripts. Dr. Mitchell has no disclosures.
FROM ACOG 2021
Lesions in pelvis may be ‘tip of the iceberg’ in endometriosis
Recognizing the systemic effects of endometriosis may help doctors better understand the experiences of patients with the disease and guide the approach to diagnosis and treatment, according to the president of the American Society for Reproductive Medicine (ASRM).
, Hugh S. Taylor, MD, said at the 2021 virtual meeting of the American College of Obstetricians and Gynecologists.
Its systemic manifestations may explain why women with endometriosis tend to have a lower body mass index, compared with women without the disease, Dr. Taylor said.
“Stem cells, microRNAs, and generalized inflammation are some of the mechanisms that mediate these long-range effects on distant organ systems,” he said.
Studies have indicated that lesions in the pelvis do not fully explain the disease, and investigators continue to elucidate how “endometriosis that we see in the pelvis is really just the tip of the iceberg,” said Dr. Taylor, chair of obstetrics, gynecology, and reproductive sciences at Yale University, New Haven, Conn.
Pain, including dysmenorrhea, pelvic pain, and dyspareunia, “can be just as bad with ... stage 1 disease as it can be with stage 4 disease,” he said.
Some patients may not have pain, but have infertility. Other women are asymptomatic, and doctors find endometriosis incidentally.
One common definition of endometriosis – ectopic endometrial glands and stroma predominantly caused by retrograde menstruation – “probably overly simplifies this complex disease,” said Dr. Taylor, who reviewed the current understanding of endometriosis in an article in The Lancet. “The lesions in the pelvis are important. We see them. We treat them. But endometriosis has ... effects throughout the body.”
Dr. Taylor’s research group has shown that stem cells are a potential source of endometriosis. “There are cells from the endometriosis that can be found traveling in the circulation,” but their effects are unclear, he said.
Levels of several microRNAs may be increased or decreased in women with endometriosis, and these altered levels may induce the production of inflammatory cytokines. They also may serve as the basis of a blood test for endometriosis that could be ready for clinical use soon, Dr. Taylor said.
In a mouse model of endometriosis, the disease changes the electrophysiology of the brain and behavior. “We see changes in anxiety induced by endometriosis. We see changes in pain sensitivity induced by endometriosis. And we also see an increase in depression induced by endometriosis in this animal model,” Dr. Taylor said.
Although surgical therapy treats local disease, medical therapy may be needed to treat the systemic manifestations.
During a question-and-answer period after the presentation, Marcelle I. Cedars, MD, asked whether analgesic and hormonal management may be sufficient when a woman has suspected or laparoscopically diagnosed endometriosis and pain is the primary complaint.
“Given the understanding of endometriosis, how would you suggest approaching treatment?” asked Dr. Cedars, president elect of the ASRM and director of the division of reproductive endocrinology and infertility at the University of California, San Francisco.
Analgesic and hormonal therapies remain “the best treatments we have,” Dr. Taylor said. He starts treatment with an oral contraceptive and a nonsteroidal anti-inflammatory medication – “not only for pain relief but to tamp some of the inflammation associated with endometriosis,” he said. If an oral contraceptive does not work, a gonadotropin-releasing hormone antagonist typically is the next step.
Dr. Taylor has disclosed ties to Dot Lab and AbbVie. Dr. Cedars had no disclosures.
Recognizing the systemic effects of endometriosis may help doctors better understand the experiences of patients with the disease and guide the approach to diagnosis and treatment, according to the president of the American Society for Reproductive Medicine (ASRM).
, Hugh S. Taylor, MD, said at the 2021 virtual meeting of the American College of Obstetricians and Gynecologists.
Its systemic manifestations may explain why women with endometriosis tend to have a lower body mass index, compared with women without the disease, Dr. Taylor said.
“Stem cells, microRNAs, and generalized inflammation are some of the mechanisms that mediate these long-range effects on distant organ systems,” he said.
Studies have indicated that lesions in the pelvis do not fully explain the disease, and investigators continue to elucidate how “endometriosis that we see in the pelvis is really just the tip of the iceberg,” said Dr. Taylor, chair of obstetrics, gynecology, and reproductive sciences at Yale University, New Haven, Conn.
Pain, including dysmenorrhea, pelvic pain, and dyspareunia, “can be just as bad with ... stage 1 disease as it can be with stage 4 disease,” he said.
Some patients may not have pain, but have infertility. Other women are asymptomatic, and doctors find endometriosis incidentally.
One common definition of endometriosis – ectopic endometrial glands and stroma predominantly caused by retrograde menstruation – “probably overly simplifies this complex disease,” said Dr. Taylor, who reviewed the current understanding of endometriosis in an article in The Lancet. “The lesions in the pelvis are important. We see them. We treat them. But endometriosis has ... effects throughout the body.”
Dr. Taylor’s research group has shown that stem cells are a potential source of endometriosis. “There are cells from the endometriosis that can be found traveling in the circulation,” but their effects are unclear, he said.
Levels of several microRNAs may be increased or decreased in women with endometriosis, and these altered levels may induce the production of inflammatory cytokines. They also may serve as the basis of a blood test for endometriosis that could be ready for clinical use soon, Dr. Taylor said.
In a mouse model of endometriosis, the disease changes the electrophysiology of the brain and behavior. “We see changes in anxiety induced by endometriosis. We see changes in pain sensitivity induced by endometriosis. And we also see an increase in depression induced by endometriosis in this animal model,” Dr. Taylor said.
Although surgical therapy treats local disease, medical therapy may be needed to treat the systemic manifestations.
During a question-and-answer period after the presentation, Marcelle I. Cedars, MD, asked whether analgesic and hormonal management may be sufficient when a woman has suspected or laparoscopically diagnosed endometriosis and pain is the primary complaint.
“Given the understanding of endometriosis, how would you suggest approaching treatment?” asked Dr. Cedars, president elect of the ASRM and director of the division of reproductive endocrinology and infertility at the University of California, San Francisco.
Analgesic and hormonal therapies remain “the best treatments we have,” Dr. Taylor said. He starts treatment with an oral contraceptive and a nonsteroidal anti-inflammatory medication – “not only for pain relief but to tamp some of the inflammation associated with endometriosis,” he said. If an oral contraceptive does not work, a gonadotropin-releasing hormone antagonist typically is the next step.
Dr. Taylor has disclosed ties to Dot Lab and AbbVie. Dr. Cedars had no disclosures.
Recognizing the systemic effects of endometriosis may help doctors better understand the experiences of patients with the disease and guide the approach to diagnosis and treatment, according to the president of the American Society for Reproductive Medicine (ASRM).
, Hugh S. Taylor, MD, said at the 2021 virtual meeting of the American College of Obstetricians and Gynecologists.
Its systemic manifestations may explain why women with endometriosis tend to have a lower body mass index, compared with women without the disease, Dr. Taylor said.
“Stem cells, microRNAs, and generalized inflammation are some of the mechanisms that mediate these long-range effects on distant organ systems,” he said.
Studies have indicated that lesions in the pelvis do not fully explain the disease, and investigators continue to elucidate how “endometriosis that we see in the pelvis is really just the tip of the iceberg,” said Dr. Taylor, chair of obstetrics, gynecology, and reproductive sciences at Yale University, New Haven, Conn.
Pain, including dysmenorrhea, pelvic pain, and dyspareunia, “can be just as bad with ... stage 1 disease as it can be with stage 4 disease,” he said.
Some patients may not have pain, but have infertility. Other women are asymptomatic, and doctors find endometriosis incidentally.
One common definition of endometriosis – ectopic endometrial glands and stroma predominantly caused by retrograde menstruation – “probably overly simplifies this complex disease,” said Dr. Taylor, who reviewed the current understanding of endometriosis in an article in The Lancet. “The lesions in the pelvis are important. We see them. We treat them. But endometriosis has ... effects throughout the body.”
Dr. Taylor’s research group has shown that stem cells are a potential source of endometriosis. “There are cells from the endometriosis that can be found traveling in the circulation,” but their effects are unclear, he said.
Levels of several microRNAs may be increased or decreased in women with endometriosis, and these altered levels may induce the production of inflammatory cytokines. They also may serve as the basis of a blood test for endometriosis that could be ready for clinical use soon, Dr. Taylor said.
In a mouse model of endometriosis, the disease changes the electrophysiology of the brain and behavior. “We see changes in anxiety induced by endometriosis. We see changes in pain sensitivity induced by endometriosis. And we also see an increase in depression induced by endometriosis in this animal model,” Dr. Taylor said.
Although surgical therapy treats local disease, medical therapy may be needed to treat the systemic manifestations.
During a question-and-answer period after the presentation, Marcelle I. Cedars, MD, asked whether analgesic and hormonal management may be sufficient when a woman has suspected or laparoscopically diagnosed endometriosis and pain is the primary complaint.
“Given the understanding of endometriosis, how would you suggest approaching treatment?” asked Dr. Cedars, president elect of the ASRM and director of the division of reproductive endocrinology and infertility at the University of California, San Francisco.
Analgesic and hormonal therapies remain “the best treatments we have,” Dr. Taylor said. He starts treatment with an oral contraceptive and a nonsteroidal anti-inflammatory medication – “not only for pain relief but to tamp some of the inflammation associated with endometriosis,” he said. If an oral contraceptive does not work, a gonadotropin-releasing hormone antagonist typically is the next step.
Dr. Taylor has disclosed ties to Dot Lab and AbbVie. Dr. Cedars had no disclosures.
FROM ACOG 2021
Primary ovarian insufficiency requires long-term management of sequelae
Primary ovarian insufficiency is not your mother’s early menopause, according to Laurie McKenzie, MD, a reproductive endocrinologist and associate professor of ob.gyn. at the University of Texas MD Anderson Cancer Center with a joint appointment at Baylor College of Medicine, both in Houston.
Known previously as primary ovarian failure, the syndrome of primary ovarian insufficiency (POI) no longer refers to a failure in part because of the term’s negative connotations but mostly because it’s not precisely accurate, Dr. McKenzie told attendees at the 2021 annual meeting of the American College of Obstetricians and Gynecologists on May 1.
“Many of these women, especially early on in diagnosis, may be experiencing some intermittent ovarian function, so it may not be a complete failure of the ovaries,” Dr. McKenzie said.
Although the condition is not common, affecting about 1% of the female population, “it’s the kind of thing that when a gynecologist has someone who has this walk into their office, you really need to know how to address it because these women are understandably very distressed.” Lauren Streicher, MD, a clinical professor of obstetrics and gynecology at Northwestern University, Chicago, said in an interview after attending the talk.
Women who develop POI lose ovarian activity before age 40, characterized by menstrual disturbance with raised gonadotropins and low estradiol. Symptoms include the hot flushes and night sweats characteristic of estrogen deficiency as well as vaginal symptoms, including dyspareunia and dryness. Other symptoms can include sleep disturbance, mood changes, poor concentration, stiffness, dry eyes, altered urinary frequency, low libido, and lack of energy.
Dr. McKenzie urged doctors to ask women about their symptoms if they present with amenorrhea because young women with primary amenorrhea rarely experience symptoms at presentation, “implying that these symptoms are due to estrogen withdrawal rather than estrogen deficiency,” she said. Diagnosis involves confirmation of 4-6 months of amenorrhea or oligomenorrhea and two measurements of elevated follicle-stimulating hormone (FSH). Following this work-up, clinicians should seek the cause of the condition.
Etiology of POI and associated conditions
A wide range of conditions or genetic factors can cause POI or be more likely in patients with POI, Dr. McKenzie said. Many women diagnosed with POI have chromosomal abnormalities, and there is no cutoff for genetic testing, she said. Most of these genetic causes (94%) are X chromosome abnormalities, including Turners-associated dysmorphic features, gonadal dysgenesis, and FMR1 anomalies. Autosomal gene mutations could also play a role in POI.
Although women with the full FMR1 mutation (Fragile X syndrome) do not have an increased risk of POI, those with the premutation (55-200 repeats) have a 13%-26% increased risk of developing POI, albeit no increased risk of intellectual disability. About 0.8%-7.5% of women with sporadic POI and up to 13% of women with a family history of POI have this genetic anomaly.
Autoimmune conditions may also develop or be related to POI, including hypothyroidism and adrenal insufficiency, Dr. McKenzie said. About 20% of adults with POI will develop hypothyroidism, so testing every 1-2 years is reasonable, though no formal screening guidelines exist. In women whose cause of POI is unknown or in whom you suspect an immune disorder, clinicians may consider screening for 21OH-Ab or adrenocortical antibodies. Patients with a positive 21OH-Ab or adrenocortical antibodies test should be referred to an endocrinologist to test adrenal function and rule out Addison disease.
Though diabetes mellitus has been linked to POI, not enough evidence exists to recommend screening women with POI for diabetes. There’s similarly no indication for infection screening, but infections can cause POI. Mumps oophoritis, for example, accounts for 3%-7% of POI cases. Cancer therapy, including radiotherapy and chemotherapy, and surgical treatment for cancer can result in POI.
“Smoking, alcohol, nutrition, and exposure to endocrine disruptors are implicated as influencing the age of menopause but are not readily diagnosable causes of POI,” Dr. McKenzie said. “Although not proven to cause POI, cigarette smoking is toxic to the ovaries and has been linked to an earlier age at menopause.” Then there are many women whose cause of POI is unknown.
To take all these possibilities into account, Dr. McKenzie described the complete diagnostic work-up recommended by ACOG:
- Menstrual irregularity for at least 3-4 months
- Test FSH and estradiol
- Test hCG, TSH, and prolactin
- If diagnosis is confirmed, test karyotype, FMR1 premutation, adrenal antibodies, and a pelvic sonogram.
However, she added during the Q&A after her talk, she is not sure why a sonogram is recommended or what additional information it might provide.
Long-term consequences of POI
Dr McKenzie noted that one study found a 2-year reduction in life expectancy among women who developed menopause before age 40. The reduced life expectancy linked to untreated POI is primarily caused by cardiovascular disease, she said. Women who undergo menopause aged between 35 and 40 years have a 50% greater risk of death related to ischemic heart disease than those ages 49-51, after adjusting for other comorbidities and confounders.
“Women with primary ovarian insufficiency should be advised on how to reduce cardiovascular risk factors by not smoking, taking regular exercise, and maintaining a healthy weight,” Dr McKenzie said.
No interventions have been shown to increase ovarian activity
Though fertility is substantially reduced in women with POI, it may not be completely gone. Several studies have found pregnancy rates ranging from 1.5% to 4.8%, and one study found that 25% of women with idiopathic POI had some evidence of ovarian function. Clinicians should therefore recommend women with POI use contraception if they do not want to conceive. Egg donation is an option for preserving fertility in women with POI but only before POI is solidly established.
“No interventions have been reliably shown to increase ovarian activity and natural conception rates,” Dr. McKenzie said.
For women who survive childhood or adolescent cancer and become pregnant, no evidence has shown an increased risk of congenital anomalies, but risk of low birth weight is elevated in babies whose mothers received anthracyclines. Treatment with anthracyclines and mediastinal radiotherapy have also been linked with cardiomyopathy and heart failure, so an echocardiogram prior to pregnancy is indicated in women with exposure to these or high-dose cyclophosphamide.
Abdominopelvic radiotherapy, however, has been linked to poor uterine function with a greater risk of late miscarriage, prematurity, low birth weight, stillbirth, neonatal hemorrhage, and postpartum hemorrhage.
“Pregnancies in women with Turner syndrome are very high risk and may have a maternal mortality as high as 3.5%,” Dr. McKenzie said, so these pregnancies require involvement of a cardiologist.
Other sequelae of POI can include increased bone resorption, net loss of bone (2%-3% annually soon after menopause) and reduced bone mineral density. Women should be getting 1,000 mg/day of calcium and 800 IU/day of vitamin D, but bone screening remains controversial in the field. Finally, providers should not ignore psychosocial effects of POI, including grief, diminished self esteem, and sadness, even more so, potentially, among adolescents.
Treatment of POI
Managing POI involves a two-pronged strategy of providing enough estrogen (estradiol, ethinyl estradiol, or conjugated equine estrogens) to mimic normal physiology and enough progestogen (synthetic or progesterone) to protect the endometrium from the mitogenic effect of estrogen.
The two primary options are hormone therapy and combination oral contraceptives. Hormone therapy might allow ovulation and pregnancy in some women, but combination oral contraceptive may feel less stigmatized in those who are still young, albeit with a potential risk for venous thromboembolism.
Continuous treatment tends to be easier and can involve breakthrough bleeding in younger patients; in postmenopausal women, breast cancer risk is higher but endometrial cancer risk is lower. Cyclic treatment mimics the endometrium’s normal function, resulting in bleeding that may help some women feel more “normal” and aids in knowing about a pregnancy. Those wanting to avoid bleeds and use contraception can use the levonorgestrel IUD off label.
Dr. Streicher said in an interview, “Not only is it critically important to recognize [long-term consequences] in this small group of women, but the lessons learned from young women who go though menopause can absolutely be extrapolated to women who go through menopause at an appropriate time.”
Dr. McKenzie had no disclosures. Dr. Streicher has consulted for Astellas Pharma and Church & Dwight, and she owns investments in InControl Medical and Sermonix Pharmaceutical.
Primary ovarian insufficiency is not your mother’s early menopause, according to Laurie McKenzie, MD, a reproductive endocrinologist and associate professor of ob.gyn. at the University of Texas MD Anderson Cancer Center with a joint appointment at Baylor College of Medicine, both in Houston.
Known previously as primary ovarian failure, the syndrome of primary ovarian insufficiency (POI) no longer refers to a failure in part because of the term’s negative connotations but mostly because it’s not precisely accurate, Dr. McKenzie told attendees at the 2021 annual meeting of the American College of Obstetricians and Gynecologists on May 1.
“Many of these women, especially early on in diagnosis, may be experiencing some intermittent ovarian function, so it may not be a complete failure of the ovaries,” Dr. McKenzie said.
Although the condition is not common, affecting about 1% of the female population, “it’s the kind of thing that when a gynecologist has someone who has this walk into their office, you really need to know how to address it because these women are understandably very distressed.” Lauren Streicher, MD, a clinical professor of obstetrics and gynecology at Northwestern University, Chicago, said in an interview after attending the talk.
Women who develop POI lose ovarian activity before age 40, characterized by menstrual disturbance with raised gonadotropins and low estradiol. Symptoms include the hot flushes and night sweats characteristic of estrogen deficiency as well as vaginal symptoms, including dyspareunia and dryness. Other symptoms can include sleep disturbance, mood changes, poor concentration, stiffness, dry eyes, altered urinary frequency, low libido, and lack of energy.
Dr. McKenzie urged doctors to ask women about their symptoms if they present with amenorrhea because young women with primary amenorrhea rarely experience symptoms at presentation, “implying that these symptoms are due to estrogen withdrawal rather than estrogen deficiency,” she said. Diagnosis involves confirmation of 4-6 months of amenorrhea or oligomenorrhea and two measurements of elevated follicle-stimulating hormone (FSH). Following this work-up, clinicians should seek the cause of the condition.
Etiology of POI and associated conditions
A wide range of conditions or genetic factors can cause POI or be more likely in patients with POI, Dr. McKenzie said. Many women diagnosed with POI have chromosomal abnormalities, and there is no cutoff for genetic testing, she said. Most of these genetic causes (94%) are X chromosome abnormalities, including Turners-associated dysmorphic features, gonadal dysgenesis, and FMR1 anomalies. Autosomal gene mutations could also play a role in POI.
Although women with the full FMR1 mutation (Fragile X syndrome) do not have an increased risk of POI, those with the premutation (55-200 repeats) have a 13%-26% increased risk of developing POI, albeit no increased risk of intellectual disability. About 0.8%-7.5% of women with sporadic POI and up to 13% of women with a family history of POI have this genetic anomaly.
Autoimmune conditions may also develop or be related to POI, including hypothyroidism and adrenal insufficiency, Dr. McKenzie said. About 20% of adults with POI will develop hypothyroidism, so testing every 1-2 years is reasonable, though no formal screening guidelines exist. In women whose cause of POI is unknown or in whom you suspect an immune disorder, clinicians may consider screening for 21OH-Ab or adrenocortical antibodies. Patients with a positive 21OH-Ab or adrenocortical antibodies test should be referred to an endocrinologist to test adrenal function and rule out Addison disease.
Though diabetes mellitus has been linked to POI, not enough evidence exists to recommend screening women with POI for diabetes. There’s similarly no indication for infection screening, but infections can cause POI. Mumps oophoritis, for example, accounts for 3%-7% of POI cases. Cancer therapy, including radiotherapy and chemotherapy, and surgical treatment for cancer can result in POI.
“Smoking, alcohol, nutrition, and exposure to endocrine disruptors are implicated as influencing the age of menopause but are not readily diagnosable causes of POI,” Dr. McKenzie said. “Although not proven to cause POI, cigarette smoking is toxic to the ovaries and has been linked to an earlier age at menopause.” Then there are many women whose cause of POI is unknown.
To take all these possibilities into account, Dr. McKenzie described the complete diagnostic work-up recommended by ACOG:
- Menstrual irregularity for at least 3-4 months
- Test FSH and estradiol
- Test hCG, TSH, and prolactin
- If diagnosis is confirmed, test karyotype, FMR1 premutation, adrenal antibodies, and a pelvic sonogram.
However, she added during the Q&A after her talk, she is not sure why a sonogram is recommended or what additional information it might provide.
Long-term consequences of POI
Dr McKenzie noted that one study found a 2-year reduction in life expectancy among women who developed menopause before age 40. The reduced life expectancy linked to untreated POI is primarily caused by cardiovascular disease, she said. Women who undergo menopause aged between 35 and 40 years have a 50% greater risk of death related to ischemic heart disease than those ages 49-51, after adjusting for other comorbidities and confounders.
“Women with primary ovarian insufficiency should be advised on how to reduce cardiovascular risk factors by not smoking, taking regular exercise, and maintaining a healthy weight,” Dr McKenzie said.
No interventions have been shown to increase ovarian activity
Though fertility is substantially reduced in women with POI, it may not be completely gone. Several studies have found pregnancy rates ranging from 1.5% to 4.8%, and one study found that 25% of women with idiopathic POI had some evidence of ovarian function. Clinicians should therefore recommend women with POI use contraception if they do not want to conceive. Egg donation is an option for preserving fertility in women with POI but only before POI is solidly established.
“No interventions have been reliably shown to increase ovarian activity and natural conception rates,” Dr. McKenzie said.
For women who survive childhood or adolescent cancer and become pregnant, no evidence has shown an increased risk of congenital anomalies, but risk of low birth weight is elevated in babies whose mothers received anthracyclines. Treatment with anthracyclines and mediastinal radiotherapy have also been linked with cardiomyopathy and heart failure, so an echocardiogram prior to pregnancy is indicated in women with exposure to these or high-dose cyclophosphamide.
Abdominopelvic radiotherapy, however, has been linked to poor uterine function with a greater risk of late miscarriage, prematurity, low birth weight, stillbirth, neonatal hemorrhage, and postpartum hemorrhage.
“Pregnancies in women with Turner syndrome are very high risk and may have a maternal mortality as high as 3.5%,” Dr. McKenzie said, so these pregnancies require involvement of a cardiologist.
Other sequelae of POI can include increased bone resorption, net loss of bone (2%-3% annually soon after menopause) and reduced bone mineral density. Women should be getting 1,000 mg/day of calcium and 800 IU/day of vitamin D, but bone screening remains controversial in the field. Finally, providers should not ignore psychosocial effects of POI, including grief, diminished self esteem, and sadness, even more so, potentially, among adolescents.
Treatment of POI
Managing POI involves a two-pronged strategy of providing enough estrogen (estradiol, ethinyl estradiol, or conjugated equine estrogens) to mimic normal physiology and enough progestogen (synthetic or progesterone) to protect the endometrium from the mitogenic effect of estrogen.
The two primary options are hormone therapy and combination oral contraceptives. Hormone therapy might allow ovulation and pregnancy in some women, but combination oral contraceptive may feel less stigmatized in those who are still young, albeit with a potential risk for venous thromboembolism.
Continuous treatment tends to be easier and can involve breakthrough bleeding in younger patients; in postmenopausal women, breast cancer risk is higher but endometrial cancer risk is lower. Cyclic treatment mimics the endometrium’s normal function, resulting in bleeding that may help some women feel more “normal” and aids in knowing about a pregnancy. Those wanting to avoid bleeds and use contraception can use the levonorgestrel IUD off label.
Dr. Streicher said in an interview, “Not only is it critically important to recognize [long-term consequences] in this small group of women, but the lessons learned from young women who go though menopause can absolutely be extrapolated to women who go through menopause at an appropriate time.”
Dr. McKenzie had no disclosures. Dr. Streicher has consulted for Astellas Pharma and Church & Dwight, and she owns investments in InControl Medical and Sermonix Pharmaceutical.
Primary ovarian insufficiency is not your mother’s early menopause, according to Laurie McKenzie, MD, a reproductive endocrinologist and associate professor of ob.gyn. at the University of Texas MD Anderson Cancer Center with a joint appointment at Baylor College of Medicine, both in Houston.
Known previously as primary ovarian failure, the syndrome of primary ovarian insufficiency (POI) no longer refers to a failure in part because of the term’s negative connotations but mostly because it’s not precisely accurate, Dr. McKenzie told attendees at the 2021 annual meeting of the American College of Obstetricians and Gynecologists on May 1.
“Many of these women, especially early on in diagnosis, may be experiencing some intermittent ovarian function, so it may not be a complete failure of the ovaries,” Dr. McKenzie said.
Although the condition is not common, affecting about 1% of the female population, “it’s the kind of thing that when a gynecologist has someone who has this walk into their office, you really need to know how to address it because these women are understandably very distressed.” Lauren Streicher, MD, a clinical professor of obstetrics and gynecology at Northwestern University, Chicago, said in an interview after attending the talk.
Women who develop POI lose ovarian activity before age 40, characterized by menstrual disturbance with raised gonadotropins and low estradiol. Symptoms include the hot flushes and night sweats characteristic of estrogen deficiency as well as vaginal symptoms, including dyspareunia and dryness. Other symptoms can include sleep disturbance, mood changes, poor concentration, stiffness, dry eyes, altered urinary frequency, low libido, and lack of energy.
Dr. McKenzie urged doctors to ask women about their symptoms if they present with amenorrhea because young women with primary amenorrhea rarely experience symptoms at presentation, “implying that these symptoms are due to estrogen withdrawal rather than estrogen deficiency,” she said. Diagnosis involves confirmation of 4-6 months of amenorrhea or oligomenorrhea and two measurements of elevated follicle-stimulating hormone (FSH). Following this work-up, clinicians should seek the cause of the condition.
Etiology of POI and associated conditions
A wide range of conditions or genetic factors can cause POI or be more likely in patients with POI, Dr. McKenzie said. Many women diagnosed with POI have chromosomal abnormalities, and there is no cutoff for genetic testing, she said. Most of these genetic causes (94%) are X chromosome abnormalities, including Turners-associated dysmorphic features, gonadal dysgenesis, and FMR1 anomalies. Autosomal gene mutations could also play a role in POI.
Although women with the full FMR1 mutation (Fragile X syndrome) do not have an increased risk of POI, those with the premutation (55-200 repeats) have a 13%-26% increased risk of developing POI, albeit no increased risk of intellectual disability. About 0.8%-7.5% of women with sporadic POI and up to 13% of women with a family history of POI have this genetic anomaly.
Autoimmune conditions may also develop or be related to POI, including hypothyroidism and adrenal insufficiency, Dr. McKenzie said. About 20% of adults with POI will develop hypothyroidism, so testing every 1-2 years is reasonable, though no formal screening guidelines exist. In women whose cause of POI is unknown or in whom you suspect an immune disorder, clinicians may consider screening for 21OH-Ab or adrenocortical antibodies. Patients with a positive 21OH-Ab or adrenocortical antibodies test should be referred to an endocrinologist to test adrenal function and rule out Addison disease.
Though diabetes mellitus has been linked to POI, not enough evidence exists to recommend screening women with POI for diabetes. There’s similarly no indication for infection screening, but infections can cause POI. Mumps oophoritis, for example, accounts for 3%-7% of POI cases. Cancer therapy, including radiotherapy and chemotherapy, and surgical treatment for cancer can result in POI.
“Smoking, alcohol, nutrition, and exposure to endocrine disruptors are implicated as influencing the age of menopause but are not readily diagnosable causes of POI,” Dr. McKenzie said. “Although not proven to cause POI, cigarette smoking is toxic to the ovaries and has been linked to an earlier age at menopause.” Then there are many women whose cause of POI is unknown.
To take all these possibilities into account, Dr. McKenzie described the complete diagnostic work-up recommended by ACOG:
- Menstrual irregularity for at least 3-4 months
- Test FSH and estradiol
- Test hCG, TSH, and prolactin
- If diagnosis is confirmed, test karyotype, FMR1 premutation, adrenal antibodies, and a pelvic sonogram.
However, she added during the Q&A after her talk, she is not sure why a sonogram is recommended or what additional information it might provide.
Long-term consequences of POI
Dr McKenzie noted that one study found a 2-year reduction in life expectancy among women who developed menopause before age 40. The reduced life expectancy linked to untreated POI is primarily caused by cardiovascular disease, she said. Women who undergo menopause aged between 35 and 40 years have a 50% greater risk of death related to ischemic heart disease than those ages 49-51, after adjusting for other comorbidities and confounders.
“Women with primary ovarian insufficiency should be advised on how to reduce cardiovascular risk factors by not smoking, taking regular exercise, and maintaining a healthy weight,” Dr McKenzie said.
No interventions have been shown to increase ovarian activity
Though fertility is substantially reduced in women with POI, it may not be completely gone. Several studies have found pregnancy rates ranging from 1.5% to 4.8%, and one study found that 25% of women with idiopathic POI had some evidence of ovarian function. Clinicians should therefore recommend women with POI use contraception if they do not want to conceive. Egg donation is an option for preserving fertility in women with POI but only before POI is solidly established.
“No interventions have been reliably shown to increase ovarian activity and natural conception rates,” Dr. McKenzie said.
For women who survive childhood or adolescent cancer and become pregnant, no evidence has shown an increased risk of congenital anomalies, but risk of low birth weight is elevated in babies whose mothers received anthracyclines. Treatment with anthracyclines and mediastinal radiotherapy have also been linked with cardiomyopathy and heart failure, so an echocardiogram prior to pregnancy is indicated in women with exposure to these or high-dose cyclophosphamide.
Abdominopelvic radiotherapy, however, has been linked to poor uterine function with a greater risk of late miscarriage, prematurity, low birth weight, stillbirth, neonatal hemorrhage, and postpartum hemorrhage.
“Pregnancies in women with Turner syndrome are very high risk and may have a maternal mortality as high as 3.5%,” Dr. McKenzie said, so these pregnancies require involvement of a cardiologist.
Other sequelae of POI can include increased bone resorption, net loss of bone (2%-3% annually soon after menopause) and reduced bone mineral density. Women should be getting 1,000 mg/day of calcium and 800 IU/day of vitamin D, but bone screening remains controversial in the field. Finally, providers should not ignore psychosocial effects of POI, including grief, diminished self esteem, and sadness, even more so, potentially, among adolescents.
Treatment of POI
Managing POI involves a two-pronged strategy of providing enough estrogen (estradiol, ethinyl estradiol, or conjugated equine estrogens) to mimic normal physiology and enough progestogen (synthetic or progesterone) to protect the endometrium from the mitogenic effect of estrogen.
The two primary options are hormone therapy and combination oral contraceptives. Hormone therapy might allow ovulation and pregnancy in some women, but combination oral contraceptive may feel less stigmatized in those who are still young, albeit with a potential risk for venous thromboembolism.
Continuous treatment tends to be easier and can involve breakthrough bleeding in younger patients; in postmenopausal women, breast cancer risk is higher but endometrial cancer risk is lower. Cyclic treatment mimics the endometrium’s normal function, resulting in bleeding that may help some women feel more “normal” and aids in knowing about a pregnancy. Those wanting to avoid bleeds and use contraception can use the levonorgestrel IUD off label.
Dr. Streicher said in an interview, “Not only is it critically important to recognize [long-term consequences] in this small group of women, but the lessons learned from young women who go though menopause can absolutely be extrapolated to women who go through menopause at an appropriate time.”
Dr. McKenzie had no disclosures. Dr. Streicher has consulted for Astellas Pharma and Church & Dwight, and she owns investments in InControl Medical and Sermonix Pharmaceutical.
FROM ACOG 2021