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Adult separation anxiety raises suicidality risk
Separation anxiety plays a substantial role in suicidality in patients with mood and anxiety disorders, new research suggests.
Results of a study that included 500 outpatients with mood or anxiety disorders showed adult separation anxiety disorder (ASAD) was more frequent in patients with suicidal thoughts versus those who did not have the disorder. In addition, depression and separation anxiety also significantly predicted lifetime suicide risk.
“This study indicates a substantial role of separation anxiety in predicting suicidal thoughts, both as state-related symptoms ... and as longitudinal dimension symptoms,” say the investigators, led by Stefano Pini, MD, of the department of clinical and experimental medicine, section of psychiatry, University of Pisa (Italy).
“ for reducing suicide risk,” they add.
The study was published in the March/April issue of the Journal of Clinical Psychiatry.
Frequently underdiagnosed
The authors describe a “close link between suicidal behaviors and interpersonal difficulties extending beyond the traditional approach of comprehending suicide as a phenomenon mainly related to depression.”
Previous research indicates that insecure adult attachment style might be associated with a greater likelihood of suicidal thoughts and attempts, and there might be an association between individual abnormal attachment sensitivity and suicide.
“Suicidal ideation or suicide attempts may be associated with disturbances in attachment, which may lead not only to a devastating experience of losing the feeling of interdependence and closeness but also to a rejection of life itself,” the authors suggest.
ASAD may be a “key factor” in understanding the relationship between individual attachment sensitivity to separation and suicidality.
An ASAD diagnosis was traditionally reserved for children and adolescents, but DSM-5 expanded the diagnosis to include adults over 18 years of age because research had “found a later onset to be common,” spanning the life course, even in the absence of a history of separation anxiety in childhood.
“Separation anxiety is an important clinical dimension, often with roots in childhood, but likely to manifest across the lifespan,” the authors note, adding that it is “frequently underdiagnosed.”
The relationship between ASAD and suicidality has not been explored extensively, so the researchers set out to examine the association.
The study included 509 consecutively recruited adult psychiatric outpatients with mood or anxiety disorders as a principle diagnosis.
Participants completed an array of scales, including item 3 on the Hamilton Depression Rating Scale (HDRS), which measures suicidality, as well as the Mood Spectrum Self-Report (MOODS-SR), a questionnaire evaluating lifetime suicidal symptoms.
Three scales were used to measure separation anxiety disorder: The Structured Interview for Separation Anxiety Symptoms in Adulthood/Childhood (SCI-SAS-A/C); the Separation Anxiety Symptom Inventory (SASI); and the Adult Separation Anxiety Scale (ASA-27).
Waxing and waning
Of the total sample, 215 patients were diagnosed with separation anxiety disorder (mean age at onset 15 years). Of the total sample, 19.9% scored ≥ 1 on the HDRS item 3, indicating the presence of suicidality.
Patients with suicidal thoughts more frequently experienced ASAD, compared with those without suicidal thoughts (53.6% vs. 39.6%, respectively, P = .01).
“All measures of adult as well as childhood separation anxiety were significantly elevated in the group of patients with current suicidality, based on HDRS item 3,” the authors report.
Logistic regression found that ASAD, major depression, bipolar I, and bipolar II disorders all predicted suicidal thoughts.
A linear regression model found that depression (P = .001) and ASA-27 separation anxiety (P = .001) significantly predicted lifetime suicide risk, based on the MOODS-SR scale.
In addition, “mediation analysis showed that, besides a direct effect, there is also an indirect effect of depression severity on the MOODS-SR suicidality score through the ASA-27 score, indicating that separation anxiety may act as an important mediating factor in the relationship between depression and suicidality,” the authors state.
The authors observe that separation anxiety “is an important clinical dimension, often with roots in childhood, but likely to wax and wane across the lifespan and even to manifest for the first time during adulthood.”
Treatment target?
Commenting on the study for this news organization, Megan Rogers, PhD, postdoctoral research fellow, Mount Sinai Beth Israel, New York, said the findings “point to symptoms of separation anxiety as a potential indicator of suicidal ideation, and should these findings be replicated and extended through longitudinal research, it suggests that symptoms of separation anxiety may be a relevant treatment target in certain populations to mitigate suicide risk.”
Dr. Rogers, who is the student division director at the American Association of Suicidology and was not involved with the study, said she thinks that studies of suicide have focused more on “individual symptoms of separation anxiety, such as excessive worry about loved ones or distress when anticipating separation from loved ones, rather than on separation anxiety as a categorical diagnosis.”
However, the study has an important take-home message for practicing clinicians, Dr. Rogers said. “In individuals with separation anxiety disorders, particularly those with comorbid mood conditions, it may be worth conducting a more thorough assessment of suicide risk, given the possibility of elevated suicidality in these patients.”
The study was supported in part by the German Research Foundation and the Fondazione Cassa di Risparmio di la Spezia. The authors and Dr. Rogers have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Separation anxiety plays a substantial role in suicidality in patients with mood and anxiety disorders, new research suggests.
Results of a study that included 500 outpatients with mood or anxiety disorders showed adult separation anxiety disorder (ASAD) was more frequent in patients with suicidal thoughts versus those who did not have the disorder. In addition, depression and separation anxiety also significantly predicted lifetime suicide risk.
“This study indicates a substantial role of separation anxiety in predicting suicidal thoughts, both as state-related symptoms ... and as longitudinal dimension symptoms,” say the investigators, led by Stefano Pini, MD, of the department of clinical and experimental medicine, section of psychiatry, University of Pisa (Italy).
“ for reducing suicide risk,” they add.
The study was published in the March/April issue of the Journal of Clinical Psychiatry.
Frequently underdiagnosed
The authors describe a “close link between suicidal behaviors and interpersonal difficulties extending beyond the traditional approach of comprehending suicide as a phenomenon mainly related to depression.”
Previous research indicates that insecure adult attachment style might be associated with a greater likelihood of suicidal thoughts and attempts, and there might be an association between individual abnormal attachment sensitivity and suicide.
“Suicidal ideation or suicide attempts may be associated with disturbances in attachment, which may lead not only to a devastating experience of losing the feeling of interdependence and closeness but also to a rejection of life itself,” the authors suggest.
ASAD may be a “key factor” in understanding the relationship between individual attachment sensitivity to separation and suicidality.
An ASAD diagnosis was traditionally reserved for children and adolescents, but DSM-5 expanded the diagnosis to include adults over 18 years of age because research had “found a later onset to be common,” spanning the life course, even in the absence of a history of separation anxiety in childhood.
“Separation anxiety is an important clinical dimension, often with roots in childhood, but likely to manifest across the lifespan,” the authors note, adding that it is “frequently underdiagnosed.”
The relationship between ASAD and suicidality has not been explored extensively, so the researchers set out to examine the association.
The study included 509 consecutively recruited adult psychiatric outpatients with mood or anxiety disorders as a principle diagnosis.
Participants completed an array of scales, including item 3 on the Hamilton Depression Rating Scale (HDRS), which measures suicidality, as well as the Mood Spectrum Self-Report (MOODS-SR), a questionnaire evaluating lifetime suicidal symptoms.
Three scales were used to measure separation anxiety disorder: The Structured Interview for Separation Anxiety Symptoms in Adulthood/Childhood (SCI-SAS-A/C); the Separation Anxiety Symptom Inventory (SASI); and the Adult Separation Anxiety Scale (ASA-27).
Waxing and waning
Of the total sample, 215 patients were diagnosed with separation anxiety disorder (mean age at onset 15 years). Of the total sample, 19.9% scored ≥ 1 on the HDRS item 3, indicating the presence of suicidality.
Patients with suicidal thoughts more frequently experienced ASAD, compared with those without suicidal thoughts (53.6% vs. 39.6%, respectively, P = .01).
“All measures of adult as well as childhood separation anxiety were significantly elevated in the group of patients with current suicidality, based on HDRS item 3,” the authors report.
Logistic regression found that ASAD, major depression, bipolar I, and bipolar II disorders all predicted suicidal thoughts.
A linear regression model found that depression (P = .001) and ASA-27 separation anxiety (P = .001) significantly predicted lifetime suicide risk, based on the MOODS-SR scale.
In addition, “mediation analysis showed that, besides a direct effect, there is also an indirect effect of depression severity on the MOODS-SR suicidality score through the ASA-27 score, indicating that separation anxiety may act as an important mediating factor in the relationship between depression and suicidality,” the authors state.
The authors observe that separation anxiety “is an important clinical dimension, often with roots in childhood, but likely to wax and wane across the lifespan and even to manifest for the first time during adulthood.”
Treatment target?
Commenting on the study for this news organization, Megan Rogers, PhD, postdoctoral research fellow, Mount Sinai Beth Israel, New York, said the findings “point to symptoms of separation anxiety as a potential indicator of suicidal ideation, and should these findings be replicated and extended through longitudinal research, it suggests that symptoms of separation anxiety may be a relevant treatment target in certain populations to mitigate suicide risk.”
Dr. Rogers, who is the student division director at the American Association of Suicidology and was not involved with the study, said she thinks that studies of suicide have focused more on “individual symptoms of separation anxiety, such as excessive worry about loved ones or distress when anticipating separation from loved ones, rather than on separation anxiety as a categorical diagnosis.”
However, the study has an important take-home message for practicing clinicians, Dr. Rogers said. “In individuals with separation anxiety disorders, particularly those with comorbid mood conditions, it may be worth conducting a more thorough assessment of suicide risk, given the possibility of elevated suicidality in these patients.”
The study was supported in part by the German Research Foundation and the Fondazione Cassa di Risparmio di la Spezia. The authors and Dr. Rogers have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Separation anxiety plays a substantial role in suicidality in patients with mood and anxiety disorders, new research suggests.
Results of a study that included 500 outpatients with mood or anxiety disorders showed adult separation anxiety disorder (ASAD) was more frequent in patients with suicidal thoughts versus those who did not have the disorder. In addition, depression and separation anxiety also significantly predicted lifetime suicide risk.
“This study indicates a substantial role of separation anxiety in predicting suicidal thoughts, both as state-related symptoms ... and as longitudinal dimension symptoms,” say the investigators, led by Stefano Pini, MD, of the department of clinical and experimental medicine, section of psychiatry, University of Pisa (Italy).
“ for reducing suicide risk,” they add.
The study was published in the March/April issue of the Journal of Clinical Psychiatry.
Frequently underdiagnosed
The authors describe a “close link between suicidal behaviors and interpersonal difficulties extending beyond the traditional approach of comprehending suicide as a phenomenon mainly related to depression.”
Previous research indicates that insecure adult attachment style might be associated with a greater likelihood of suicidal thoughts and attempts, and there might be an association between individual abnormal attachment sensitivity and suicide.
“Suicidal ideation or suicide attempts may be associated with disturbances in attachment, which may lead not only to a devastating experience of losing the feeling of interdependence and closeness but also to a rejection of life itself,” the authors suggest.
ASAD may be a “key factor” in understanding the relationship between individual attachment sensitivity to separation and suicidality.
An ASAD diagnosis was traditionally reserved for children and adolescents, but DSM-5 expanded the diagnosis to include adults over 18 years of age because research had “found a later onset to be common,” spanning the life course, even in the absence of a history of separation anxiety in childhood.
“Separation anxiety is an important clinical dimension, often with roots in childhood, but likely to manifest across the lifespan,” the authors note, adding that it is “frequently underdiagnosed.”
The relationship between ASAD and suicidality has not been explored extensively, so the researchers set out to examine the association.
The study included 509 consecutively recruited adult psychiatric outpatients with mood or anxiety disorders as a principle diagnosis.
Participants completed an array of scales, including item 3 on the Hamilton Depression Rating Scale (HDRS), which measures suicidality, as well as the Mood Spectrum Self-Report (MOODS-SR), a questionnaire evaluating lifetime suicidal symptoms.
Three scales were used to measure separation anxiety disorder: The Structured Interview for Separation Anxiety Symptoms in Adulthood/Childhood (SCI-SAS-A/C); the Separation Anxiety Symptom Inventory (SASI); and the Adult Separation Anxiety Scale (ASA-27).
Waxing and waning
Of the total sample, 215 patients were diagnosed with separation anxiety disorder (mean age at onset 15 years). Of the total sample, 19.9% scored ≥ 1 on the HDRS item 3, indicating the presence of suicidality.
Patients with suicidal thoughts more frequently experienced ASAD, compared with those without suicidal thoughts (53.6% vs. 39.6%, respectively, P = .01).
“All measures of adult as well as childhood separation anxiety were significantly elevated in the group of patients with current suicidality, based on HDRS item 3,” the authors report.
Logistic regression found that ASAD, major depression, bipolar I, and bipolar II disorders all predicted suicidal thoughts.
A linear regression model found that depression (P = .001) and ASA-27 separation anxiety (P = .001) significantly predicted lifetime suicide risk, based on the MOODS-SR scale.
In addition, “mediation analysis showed that, besides a direct effect, there is also an indirect effect of depression severity on the MOODS-SR suicidality score through the ASA-27 score, indicating that separation anxiety may act as an important mediating factor in the relationship between depression and suicidality,” the authors state.
The authors observe that separation anxiety “is an important clinical dimension, often with roots in childhood, but likely to wax and wane across the lifespan and even to manifest for the first time during adulthood.”
Treatment target?
Commenting on the study for this news organization, Megan Rogers, PhD, postdoctoral research fellow, Mount Sinai Beth Israel, New York, said the findings “point to symptoms of separation anxiety as a potential indicator of suicidal ideation, and should these findings be replicated and extended through longitudinal research, it suggests that symptoms of separation anxiety may be a relevant treatment target in certain populations to mitigate suicide risk.”
Dr. Rogers, who is the student division director at the American Association of Suicidology and was not involved with the study, said she thinks that studies of suicide have focused more on “individual symptoms of separation anxiety, such as excessive worry about loved ones or distress when anticipating separation from loved ones, rather than on separation anxiety as a categorical diagnosis.”
However, the study has an important take-home message for practicing clinicians, Dr. Rogers said. “In individuals with separation anxiety disorders, particularly those with comorbid mood conditions, it may be worth conducting a more thorough assessment of suicide risk, given the possibility of elevated suicidality in these patients.”
The study was supported in part by the German Research Foundation and the Fondazione Cassa di Risparmio di la Spezia. The authors and Dr. Rogers have disclosed no relevant financial relationships.
A version of this article first appeared on Medscape.com.
Novel antiplatelet drug: Hope for efficacy without bleeding?
A new antiplatelet drug with a completely novel mechanism of action may hold the promise of delivering the holy grail – reducing cardiac events without increasing bleeding. That is the hope behind the new class of drugs directed against the platelet collagen glycoprotein VI (GPVI) receptor.
A phase 2 trial with the first agent in this class, known as revacept (advanceCOR), showed no increase in bleeding with the product when added to standard dual-antiplatelet therapy for patients with stable ischemic heart disease undergoing elective percutaneous coronary intervention (PCI), despite the drug’s being used at a dose that has been shown to increase platelet inhibition.
Unfortunately, there was no reduction in the primary clinical efficacy endpoint, a myocardial injury surrogate, but the authors pointed out that the overall event rate was low, and they were hopeful that future trials in a higher-risk population will show efficacy.
The ISAR PLASTER study was published online on March 31 in JAMA Cardiology.
“This new drug is targeting the collagen in the extracellular matrix of atherosclerotic plaque rather than the platelets themselves. So, in theory, this agent should not cause an increase in bleeding,” study author Steffen Massberg, DrMed, said in an interview.
Dr. Massberg explained that revacept targets the binding site for platelets on collagen that is exposed on rupture of atherosclerotic plaques and is a major trigger of platelet activation.
“In contrast to aspirin and P2Y12 inhibitors, which target all platelets, revacept only binds to sites where there is ruptured plaque. But the platelets themselves otherwise have normal function, so regular coagulation processes should be unaffected,” he commented.
“While collagen also has a role in the coagulation process, it is more involved in atherosclerotic plaque rupture, and in animal studies, revacept was effective in preventing clot formation in large arteries but only had a small effect on bleeding,” Dr. Massberg added.
In the JAMA Cardiology article, the authors further elaborated that, when collagen is exposed during atherosclerotic plaque rupture, it binds platelet GPVI, the major platelet collagen receptor.
“Glycoprotein VI in turn mediates local platelet recruitment, activation, and aggregation. Glycoprotein VI is an attractive antiplatelet target because GPVI-mediated platelet response plays a central role during myocardial infarction and stroke but is less relevant in physiological hemostasis,” they wrote.
The researchers describe revacept as a dimeric, soluble fusion protein composed of the extracellular domain of the GPVI receptor and the human Fc-fragment. It competes with endogenous platelet GPVI for binding to exposed collagen fibers and inhibits collagen-mediated platelet adhesion and aggregation selectively at the site of plaque rupture.
In addition, revacept blocks binding of von Willebrand factor to collagen and inhibits von Willebrand factor–mediated platelet activation, they reported.
“As a lesion-directed drug, revacept does not interfere with the function of circulating platelets beyond the atherosclerotic lesion,” the authors said.
In animal studies and a phase 1 clinical trial, the drug was shown to inhibit atherothrombosis but to have little effect on systemic hemostasis or bleeding.
The current ISAR-PLASTER trial is the first study of the use of the agent for patients with coronary heart disease.
For the study, 334 patients with stable ischemic heart disease undergoing elective PCI were randomly assigned to receive a single intravenous infusion of revacept 160 mg, revacept 80 mg, or placebo prior to the start of PCI in addition to standard antithrombotic therapy.
The safety endpoint was bleeding of type 2-5, per Bleeding Academic Research Consortium (BARC) criteria, at 30 days.
Results showed no significant differences in the primary efficacy endpoint (the composite of death or myocardial injury, defined as an increase in high-sensitivity cardiac troponin T [hsTnT] to at least five times the upper limit of normal within 48 hours from randomization) between the revacept and placebo groups. The primary efficacy endpoint occurred in 24.4% of the revacept 160-mg group, 25.0% of the revacept 80-mg group, and 23.3% of the placebo group.
The high dose of revacept was associated with a small but significant reduction of high-concentration collagen-induced platelet aggregation, but adenosine 5-diphosphate–induced aggregation was not affected.
Revacept did not increase bleeding. Bleeding of BARC type 2 or higher at 30 days occurred in 5.0% of the 160-mg group, 5.9% of the 80-mg group, and 8.6% of the placebo group.
Dr. Massberg pointed out that one possible explanation for the lack of difference in the efficacy outcome was that the patients enrolled in the study were at low risk.
“The rate of major adverse cardiovascular events was very low (2.5% at 30 days), and this was a low-risk population undergoing elective PCI,” he commented.
The authors also pointed out that the five-times increase in hsTnT endpoint used in the current study has little prognostic impact.
In addition, Dr. Massberg noted that, in the stable situation, myocardial injury is mostly triggered by cholesterol embolism during PCI and side-branch occlusion due to distal plaque embolization, problems that are unlikely to respond to inhibition of GPVI-collagen interaction by revacept.
He suggested that better results may be achieved in patients with acute coronary syndrome (ACS). “In ACS patients, the myocardial injury is caused by ongoing thrombotic cascades, where the collagen-platelet interaction plays a much larger role, so in theory, this drug should show a greater effect in an ACS population.”
The researchers are now planning a larger phase 3 study in that group.
“I am still optimistic. I still believe it could work,” Dr. Massberg said. “The major aim for this study was safety and dosing. There was no difference in bleeding, so safety was supported,” he added.
The ISAR-PLASTER study was funded by the German Center for Cardiovascular Research, Deutsches Herzzentrum Munchen, the Federal Ministry of Education and Research, and advanceCOR (the manufacturer of revacept). One of the coauthors of the study is a cofounder of advanceCor.
A version of this article first appeared on Medscape.com.
A new antiplatelet drug with a completely novel mechanism of action may hold the promise of delivering the holy grail – reducing cardiac events without increasing bleeding. That is the hope behind the new class of drugs directed against the platelet collagen glycoprotein VI (GPVI) receptor.
A phase 2 trial with the first agent in this class, known as revacept (advanceCOR), showed no increase in bleeding with the product when added to standard dual-antiplatelet therapy for patients with stable ischemic heart disease undergoing elective percutaneous coronary intervention (PCI), despite the drug’s being used at a dose that has been shown to increase platelet inhibition.
Unfortunately, there was no reduction in the primary clinical efficacy endpoint, a myocardial injury surrogate, but the authors pointed out that the overall event rate was low, and they were hopeful that future trials in a higher-risk population will show efficacy.
The ISAR PLASTER study was published online on March 31 in JAMA Cardiology.
“This new drug is targeting the collagen in the extracellular matrix of atherosclerotic plaque rather than the platelets themselves. So, in theory, this agent should not cause an increase in bleeding,” study author Steffen Massberg, DrMed, said in an interview.
Dr. Massberg explained that revacept targets the binding site for platelets on collagen that is exposed on rupture of atherosclerotic plaques and is a major trigger of platelet activation.
“In contrast to aspirin and P2Y12 inhibitors, which target all platelets, revacept only binds to sites where there is ruptured plaque. But the platelets themselves otherwise have normal function, so regular coagulation processes should be unaffected,” he commented.
“While collagen also has a role in the coagulation process, it is more involved in atherosclerotic plaque rupture, and in animal studies, revacept was effective in preventing clot formation in large arteries but only had a small effect on bleeding,” Dr. Massberg added.
In the JAMA Cardiology article, the authors further elaborated that, when collagen is exposed during atherosclerotic plaque rupture, it binds platelet GPVI, the major platelet collagen receptor.
“Glycoprotein VI in turn mediates local platelet recruitment, activation, and aggregation. Glycoprotein VI is an attractive antiplatelet target because GPVI-mediated platelet response plays a central role during myocardial infarction and stroke but is less relevant in physiological hemostasis,” they wrote.
The researchers describe revacept as a dimeric, soluble fusion protein composed of the extracellular domain of the GPVI receptor and the human Fc-fragment. It competes with endogenous platelet GPVI for binding to exposed collagen fibers and inhibits collagen-mediated platelet adhesion and aggregation selectively at the site of plaque rupture.
In addition, revacept blocks binding of von Willebrand factor to collagen and inhibits von Willebrand factor–mediated platelet activation, they reported.
“As a lesion-directed drug, revacept does not interfere with the function of circulating platelets beyond the atherosclerotic lesion,” the authors said.
In animal studies and a phase 1 clinical trial, the drug was shown to inhibit atherothrombosis but to have little effect on systemic hemostasis or bleeding.
The current ISAR-PLASTER trial is the first study of the use of the agent for patients with coronary heart disease.
For the study, 334 patients with stable ischemic heart disease undergoing elective PCI were randomly assigned to receive a single intravenous infusion of revacept 160 mg, revacept 80 mg, or placebo prior to the start of PCI in addition to standard antithrombotic therapy.
The safety endpoint was bleeding of type 2-5, per Bleeding Academic Research Consortium (BARC) criteria, at 30 days.
Results showed no significant differences in the primary efficacy endpoint (the composite of death or myocardial injury, defined as an increase in high-sensitivity cardiac troponin T [hsTnT] to at least five times the upper limit of normal within 48 hours from randomization) between the revacept and placebo groups. The primary efficacy endpoint occurred in 24.4% of the revacept 160-mg group, 25.0% of the revacept 80-mg group, and 23.3% of the placebo group.
The high dose of revacept was associated with a small but significant reduction of high-concentration collagen-induced platelet aggregation, but adenosine 5-diphosphate–induced aggregation was not affected.
Revacept did not increase bleeding. Bleeding of BARC type 2 or higher at 30 days occurred in 5.0% of the 160-mg group, 5.9% of the 80-mg group, and 8.6% of the placebo group.
Dr. Massberg pointed out that one possible explanation for the lack of difference in the efficacy outcome was that the patients enrolled in the study were at low risk.
“The rate of major adverse cardiovascular events was very low (2.5% at 30 days), and this was a low-risk population undergoing elective PCI,” he commented.
The authors also pointed out that the five-times increase in hsTnT endpoint used in the current study has little prognostic impact.
In addition, Dr. Massberg noted that, in the stable situation, myocardial injury is mostly triggered by cholesterol embolism during PCI and side-branch occlusion due to distal plaque embolization, problems that are unlikely to respond to inhibition of GPVI-collagen interaction by revacept.
He suggested that better results may be achieved in patients with acute coronary syndrome (ACS). “In ACS patients, the myocardial injury is caused by ongoing thrombotic cascades, where the collagen-platelet interaction plays a much larger role, so in theory, this drug should show a greater effect in an ACS population.”
The researchers are now planning a larger phase 3 study in that group.
“I am still optimistic. I still believe it could work,” Dr. Massberg said. “The major aim for this study was safety and dosing. There was no difference in bleeding, so safety was supported,” he added.
The ISAR-PLASTER study was funded by the German Center for Cardiovascular Research, Deutsches Herzzentrum Munchen, the Federal Ministry of Education and Research, and advanceCOR (the manufacturer of revacept). One of the coauthors of the study is a cofounder of advanceCor.
A version of this article first appeared on Medscape.com.
A new antiplatelet drug with a completely novel mechanism of action may hold the promise of delivering the holy grail – reducing cardiac events without increasing bleeding. That is the hope behind the new class of drugs directed against the platelet collagen glycoprotein VI (GPVI) receptor.
A phase 2 trial with the first agent in this class, known as revacept (advanceCOR), showed no increase in bleeding with the product when added to standard dual-antiplatelet therapy for patients with stable ischemic heart disease undergoing elective percutaneous coronary intervention (PCI), despite the drug’s being used at a dose that has been shown to increase platelet inhibition.
Unfortunately, there was no reduction in the primary clinical efficacy endpoint, a myocardial injury surrogate, but the authors pointed out that the overall event rate was low, and they were hopeful that future trials in a higher-risk population will show efficacy.
The ISAR PLASTER study was published online on March 31 in JAMA Cardiology.
“This new drug is targeting the collagen in the extracellular matrix of atherosclerotic plaque rather than the platelets themselves. So, in theory, this agent should not cause an increase in bleeding,” study author Steffen Massberg, DrMed, said in an interview.
Dr. Massberg explained that revacept targets the binding site for platelets on collagen that is exposed on rupture of atherosclerotic plaques and is a major trigger of platelet activation.
“In contrast to aspirin and P2Y12 inhibitors, which target all platelets, revacept only binds to sites where there is ruptured plaque. But the platelets themselves otherwise have normal function, so regular coagulation processes should be unaffected,” he commented.
“While collagen also has a role in the coagulation process, it is more involved in atherosclerotic plaque rupture, and in animal studies, revacept was effective in preventing clot formation in large arteries but only had a small effect on bleeding,” Dr. Massberg added.
In the JAMA Cardiology article, the authors further elaborated that, when collagen is exposed during atherosclerotic plaque rupture, it binds platelet GPVI, the major platelet collagen receptor.
“Glycoprotein VI in turn mediates local platelet recruitment, activation, and aggregation. Glycoprotein VI is an attractive antiplatelet target because GPVI-mediated platelet response plays a central role during myocardial infarction and stroke but is less relevant in physiological hemostasis,” they wrote.
The researchers describe revacept as a dimeric, soluble fusion protein composed of the extracellular domain of the GPVI receptor and the human Fc-fragment. It competes with endogenous platelet GPVI for binding to exposed collagen fibers and inhibits collagen-mediated platelet adhesion and aggregation selectively at the site of plaque rupture.
In addition, revacept blocks binding of von Willebrand factor to collagen and inhibits von Willebrand factor–mediated platelet activation, they reported.
“As a lesion-directed drug, revacept does not interfere with the function of circulating platelets beyond the atherosclerotic lesion,” the authors said.
In animal studies and a phase 1 clinical trial, the drug was shown to inhibit atherothrombosis but to have little effect on systemic hemostasis or bleeding.
The current ISAR-PLASTER trial is the first study of the use of the agent for patients with coronary heart disease.
For the study, 334 patients with stable ischemic heart disease undergoing elective PCI were randomly assigned to receive a single intravenous infusion of revacept 160 mg, revacept 80 mg, or placebo prior to the start of PCI in addition to standard antithrombotic therapy.
The safety endpoint was bleeding of type 2-5, per Bleeding Academic Research Consortium (BARC) criteria, at 30 days.
Results showed no significant differences in the primary efficacy endpoint (the composite of death or myocardial injury, defined as an increase in high-sensitivity cardiac troponin T [hsTnT] to at least five times the upper limit of normal within 48 hours from randomization) between the revacept and placebo groups. The primary efficacy endpoint occurred in 24.4% of the revacept 160-mg group, 25.0% of the revacept 80-mg group, and 23.3% of the placebo group.
The high dose of revacept was associated with a small but significant reduction of high-concentration collagen-induced platelet aggregation, but adenosine 5-diphosphate–induced aggregation was not affected.
Revacept did not increase bleeding. Bleeding of BARC type 2 or higher at 30 days occurred in 5.0% of the 160-mg group, 5.9% of the 80-mg group, and 8.6% of the placebo group.
Dr. Massberg pointed out that one possible explanation for the lack of difference in the efficacy outcome was that the patients enrolled in the study were at low risk.
“The rate of major adverse cardiovascular events was very low (2.5% at 30 days), and this was a low-risk population undergoing elective PCI,” he commented.
The authors also pointed out that the five-times increase in hsTnT endpoint used in the current study has little prognostic impact.
In addition, Dr. Massberg noted that, in the stable situation, myocardial injury is mostly triggered by cholesterol embolism during PCI and side-branch occlusion due to distal plaque embolization, problems that are unlikely to respond to inhibition of GPVI-collagen interaction by revacept.
He suggested that better results may be achieved in patients with acute coronary syndrome (ACS). “In ACS patients, the myocardial injury is caused by ongoing thrombotic cascades, where the collagen-platelet interaction plays a much larger role, so in theory, this drug should show a greater effect in an ACS population.”
The researchers are now planning a larger phase 3 study in that group.
“I am still optimistic. I still believe it could work,” Dr. Massberg said. “The major aim for this study was safety and dosing. There was no difference in bleeding, so safety was supported,” he added.
The ISAR-PLASTER study was funded by the German Center for Cardiovascular Research, Deutsches Herzzentrum Munchen, the Federal Ministry of Education and Research, and advanceCOR (the manufacturer of revacept). One of the coauthors of the study is a cofounder of advanceCor.
A version of this article first appeared on Medscape.com.
The interplay between staffing and scheduling
Top five findings from the 2020 SoHM
The biennial State of Hospital Medicine (SoHM) Report was released in fall 2020, reflecting surveys collected just as the pandemic was ramping up. Thus, a COVID Addendum of results was collected and published a few months later. What did these reports tell us about existing and developing trends in staffing and scheduling?
Here is a top five list of findings for hospital medicine programs (HMGs) serving adults only. These are just highlights; for further detail, visit the SHM website to learn more and purchase your copy. The information in the SoHM is extraordinarily helpful in planning for your group’s future staffing and scheduling needs.
5. Average group size has increased
Andrew White, MD, SFHM, associate professor of medicine at the University of Washington, Seattle, provided a deep-dive discussion on the increase of group sizes in the March 2021 issue of The Hospitalist. Group size has impacted the way a hospitalist group schedules, when reviewing correlating scheduling survey responses.
Group size can have a direct correlation to scheduling methodology. The number of employed/contracted physician hospitalists in individual groups is up about 25%. Alongside the increase in physician hospitalists is an increase in both nurse practitioners (NPs) and physician assistants (PAs) in adult hospitalist groups, with the largest growth in PAs. In fact, in 2020, the average number of NPs and PAs per hospitalist group is approaching similar numbers.
In 2020, more than half of all programs reported not having a backup call system. One could speculate that the larger group size has allowed adult hospitalist groups better ability to staff upper fluctuations in daily volume. This could have resulted in day-to-day scheduling ease and flexibility.
4. Shift-type is shifting
In scheduling adult hospitalist groups, fewer groups reported dedicated nocturnists and more groups reported dedicated day admitters.
Just above a third of all adult hospitalist programs report having dedicated day admitter shifts, and the presence of nocturnists is at a 6-year low. One speculation that could be made is that hospitalists are making more of an effort to ensure that more admissions are done during the day and not held over for nighttime. This would be consistent with the strong pressure for hospitals to decrease door-to-floor admission times. However, the presence of nocturnists increases steadily with group size. Ninety-four percent of HMGs with 30-49 physician FTEs and 98% of groups with 50 or more physician FTEs reported using dedicated nocturnists.
3. COVID-19 impacts hospitalist workflows
It’s not hard to imagine that COVID-19 has affected all hospitalist groups: adult, pediatric, and adult/pediatric groups. COVID-19 has affected all lives – at home and at work – across the world. More than 80% of all adult hospitalist groups report having implemented changes (beyond dedicated COVID-19 teams) in workflows and/or how work is allocated among its providers. And nearly 20% report that this is likely a permanent change.
2. Schedules have been disrupted by COVID-19
More than half of adult hospitalist groups report having their schedules disrupted by COVID-19. The top two disruptors are loss of staff time due to exposure quarantine, and lost provider time due to COVID-19 illness. All the while, adult hospitalist groups have been taking care of more and more hospitalized patients.
While some groups have not made any changes in scheduling due to COVID-19, many have. Nearly 60% of all groups have increased scheduling flexibility or changed their scheduling model. For about 11% of all groups, this change is likely to be permanent.
1. COVID-19 has changed scheduling methodologies – perhaps for the long-term
Three out of four adult hospitalist groups have created new COVID-19 dedicated teams each day. This has likely had one of the most impacts.
Unit-based assignment reported in the 2020 SoHM was already up from the 2018 SoHM Report (42.7% vs 36%). Now, in addition to nocturnists, day admitter, rounder roles, and unit-based assignments, hospital medicine groups must also incorporate COVID-19 teams into daily scheduling considerations. One in five groups report this change may likely be a permanent addition to the hospitalist schedule. Wow.
As we think forward to the 2022 SoHM, staffing and scheduling of adult hospital medicine group will be a key topic of the survey. How does COVID-19 change hospital medicine groups in the medium and long term? One thing is for sure – hospital medicine groups are resilient and have proven to be creative in ensuring our hospitalized patients are well cared for.
Post your thoughts and questions for your peer network on the SHM Online Community: HMX. Let’s keep the conversation going on how we can help each other create sustainable staffing and scheduling models that are continuously adapting to our peripandemic environment.
Ms. Trask is national vice president of the Hospital Medicine Service Line at Catholic Health Initiatives in Englewood, Colo.
Top five findings from the 2020 SoHM
Top five findings from the 2020 SoHM
The biennial State of Hospital Medicine (SoHM) Report was released in fall 2020, reflecting surveys collected just as the pandemic was ramping up. Thus, a COVID Addendum of results was collected and published a few months later. What did these reports tell us about existing and developing trends in staffing and scheduling?
Here is a top five list of findings for hospital medicine programs (HMGs) serving adults only. These are just highlights; for further detail, visit the SHM website to learn more and purchase your copy. The information in the SoHM is extraordinarily helpful in planning for your group’s future staffing and scheduling needs.
5. Average group size has increased
Andrew White, MD, SFHM, associate professor of medicine at the University of Washington, Seattle, provided a deep-dive discussion on the increase of group sizes in the March 2021 issue of The Hospitalist. Group size has impacted the way a hospitalist group schedules, when reviewing correlating scheduling survey responses.
Group size can have a direct correlation to scheduling methodology. The number of employed/contracted physician hospitalists in individual groups is up about 25%. Alongside the increase in physician hospitalists is an increase in both nurse practitioners (NPs) and physician assistants (PAs) in adult hospitalist groups, with the largest growth in PAs. In fact, in 2020, the average number of NPs and PAs per hospitalist group is approaching similar numbers.
In 2020, more than half of all programs reported not having a backup call system. One could speculate that the larger group size has allowed adult hospitalist groups better ability to staff upper fluctuations in daily volume. This could have resulted in day-to-day scheduling ease and flexibility.
4. Shift-type is shifting
In scheduling adult hospitalist groups, fewer groups reported dedicated nocturnists and more groups reported dedicated day admitters.
Just above a third of all adult hospitalist programs report having dedicated day admitter shifts, and the presence of nocturnists is at a 6-year low. One speculation that could be made is that hospitalists are making more of an effort to ensure that more admissions are done during the day and not held over for nighttime. This would be consistent with the strong pressure for hospitals to decrease door-to-floor admission times. However, the presence of nocturnists increases steadily with group size. Ninety-four percent of HMGs with 30-49 physician FTEs and 98% of groups with 50 or more physician FTEs reported using dedicated nocturnists.
3. COVID-19 impacts hospitalist workflows
It’s not hard to imagine that COVID-19 has affected all hospitalist groups: adult, pediatric, and adult/pediatric groups. COVID-19 has affected all lives – at home and at work – across the world. More than 80% of all adult hospitalist groups report having implemented changes (beyond dedicated COVID-19 teams) in workflows and/or how work is allocated among its providers. And nearly 20% report that this is likely a permanent change.
2. Schedules have been disrupted by COVID-19
More than half of adult hospitalist groups report having their schedules disrupted by COVID-19. The top two disruptors are loss of staff time due to exposure quarantine, and lost provider time due to COVID-19 illness. All the while, adult hospitalist groups have been taking care of more and more hospitalized patients.
While some groups have not made any changes in scheduling due to COVID-19, many have. Nearly 60% of all groups have increased scheduling flexibility or changed their scheduling model. For about 11% of all groups, this change is likely to be permanent.
1. COVID-19 has changed scheduling methodologies – perhaps for the long-term
Three out of four adult hospitalist groups have created new COVID-19 dedicated teams each day. This has likely had one of the most impacts.
Unit-based assignment reported in the 2020 SoHM was already up from the 2018 SoHM Report (42.7% vs 36%). Now, in addition to nocturnists, day admitter, rounder roles, and unit-based assignments, hospital medicine groups must also incorporate COVID-19 teams into daily scheduling considerations. One in five groups report this change may likely be a permanent addition to the hospitalist schedule. Wow.
As we think forward to the 2022 SoHM, staffing and scheduling of adult hospital medicine group will be a key topic of the survey. How does COVID-19 change hospital medicine groups in the medium and long term? One thing is for sure – hospital medicine groups are resilient and have proven to be creative in ensuring our hospitalized patients are well cared for.
Post your thoughts and questions for your peer network on the SHM Online Community: HMX. Let’s keep the conversation going on how we can help each other create sustainable staffing and scheduling models that are continuously adapting to our peripandemic environment.
Ms. Trask is national vice president of the Hospital Medicine Service Line at Catholic Health Initiatives in Englewood, Colo.
The biennial State of Hospital Medicine (SoHM) Report was released in fall 2020, reflecting surveys collected just as the pandemic was ramping up. Thus, a COVID Addendum of results was collected and published a few months later. What did these reports tell us about existing and developing trends in staffing and scheduling?
Here is a top five list of findings for hospital medicine programs (HMGs) serving adults only. These are just highlights; for further detail, visit the SHM website to learn more and purchase your copy. The information in the SoHM is extraordinarily helpful in planning for your group’s future staffing and scheduling needs.
5. Average group size has increased
Andrew White, MD, SFHM, associate professor of medicine at the University of Washington, Seattle, provided a deep-dive discussion on the increase of group sizes in the March 2021 issue of The Hospitalist. Group size has impacted the way a hospitalist group schedules, when reviewing correlating scheduling survey responses.
Group size can have a direct correlation to scheduling methodology. The number of employed/contracted physician hospitalists in individual groups is up about 25%. Alongside the increase in physician hospitalists is an increase in both nurse practitioners (NPs) and physician assistants (PAs) in adult hospitalist groups, with the largest growth in PAs. In fact, in 2020, the average number of NPs and PAs per hospitalist group is approaching similar numbers.
In 2020, more than half of all programs reported not having a backup call system. One could speculate that the larger group size has allowed adult hospitalist groups better ability to staff upper fluctuations in daily volume. This could have resulted in day-to-day scheduling ease and flexibility.
4. Shift-type is shifting
In scheduling adult hospitalist groups, fewer groups reported dedicated nocturnists and more groups reported dedicated day admitters.
Just above a third of all adult hospitalist programs report having dedicated day admitter shifts, and the presence of nocturnists is at a 6-year low. One speculation that could be made is that hospitalists are making more of an effort to ensure that more admissions are done during the day and not held over for nighttime. This would be consistent with the strong pressure for hospitals to decrease door-to-floor admission times. However, the presence of nocturnists increases steadily with group size. Ninety-four percent of HMGs with 30-49 physician FTEs and 98% of groups with 50 or more physician FTEs reported using dedicated nocturnists.
3. COVID-19 impacts hospitalist workflows
It’s not hard to imagine that COVID-19 has affected all hospitalist groups: adult, pediatric, and adult/pediatric groups. COVID-19 has affected all lives – at home and at work – across the world. More than 80% of all adult hospitalist groups report having implemented changes (beyond dedicated COVID-19 teams) in workflows and/or how work is allocated among its providers. And nearly 20% report that this is likely a permanent change.
2. Schedules have been disrupted by COVID-19
More than half of adult hospitalist groups report having their schedules disrupted by COVID-19. The top two disruptors are loss of staff time due to exposure quarantine, and lost provider time due to COVID-19 illness. All the while, adult hospitalist groups have been taking care of more and more hospitalized patients.
While some groups have not made any changes in scheduling due to COVID-19, many have. Nearly 60% of all groups have increased scheduling flexibility or changed their scheduling model. For about 11% of all groups, this change is likely to be permanent.
1. COVID-19 has changed scheduling methodologies – perhaps for the long-term
Three out of four adult hospitalist groups have created new COVID-19 dedicated teams each day. This has likely had one of the most impacts.
Unit-based assignment reported in the 2020 SoHM was already up from the 2018 SoHM Report (42.7% vs 36%). Now, in addition to nocturnists, day admitter, rounder roles, and unit-based assignments, hospital medicine groups must also incorporate COVID-19 teams into daily scheduling considerations. One in five groups report this change may likely be a permanent addition to the hospitalist schedule. Wow.
As we think forward to the 2022 SoHM, staffing and scheduling of adult hospital medicine group will be a key topic of the survey. How does COVID-19 change hospital medicine groups in the medium and long term? One thing is for sure – hospital medicine groups are resilient and have proven to be creative in ensuring our hospitalized patients are well cared for.
Post your thoughts and questions for your peer network on the SHM Online Community: HMX. Let’s keep the conversation going on how we can help each other create sustainable staffing and scheduling models that are continuously adapting to our peripandemic environment.
Ms. Trask is national vice president of the Hospital Medicine Service Line at Catholic Health Initiatives in Englewood, Colo.
Verification bias casts doubt on IgA tTG in celiac disease
Immunoglobulin A tissue transglutaminase offers a noninvasive way to detect celiac disease, but new research suggests that its sensitivity may be overestimated and that it may not be an effective screening test, at least in asymptomatic individuals. The reason comes down to verification bias, wherein a technique appears to have higher sensitivity and lower specificity because individuals who screen positive are more likely to have their disease confirmed by a follow-up small-bowel biopsy while those who screen negative are unlikely to have a follow-up biopsy that could reveal missed celiac disease.
“The issue with verification bias is that only the patients that screen positive on that index test are going to be getting the reference test, so there’s probably a good chance that if they screen positive when they go to that reference test they’ll also be positive. What you’re missing from when you’re calculating sensitivity is, what about the ones that are negative on the index test? Would they have been positive on that reference test? That’s not even coming into your calculation because they’re not getting that reference test,” said Marisa Stahl, MD, a physician and researcher at the Children’s Hospital Colorado Center of Celiac Disease in Aurora. Dr. Stahl was not involved in the meta-analysis, but commented on it in an interview.
The only way to fully correct for this bias is to conduct both IgA tissue transglutaminase (tTG) testing and small bowel biopsy on a complete or random sample of patients and compare the sensitivity and specificity of IgA tTG with the preferred method small-bowel biopsy. However, this is rarely done. Instead, when the U.S. Preventive Services Task Force concluded that evidence was insufficient for IgA tTG testing for celiac disease, it relied on a 2016 comparative effectiveness review of nine studies that estimated sensitivity at 92.6% and specificity at 97.6%. USPSTF remained noncommittal because of inadequate evidence surrounding the balance of benefit and harms of screening for celiac disease in asymptomatic individuals.
In the current meta-analysis, Isabel Hujoel, MD, of the Mayo Clinic, Rochester, Minn., and colleagues tested whether the studies used by USPSTF may have overestimated sensitivity because of verification bias. In a report in the Journal of Clinical Gastroenterology, they reviewed those same nine studies to see the potential impact of verification bias. They rated each individual study as being at high, low, or unclear risk of verification bias and found five they considered to be high risk.
To reveal the impact of small-bowel biopsy referral rates on sensitivity and specificity, the researchers reviewed a separate set of nine retrospective and prospective studies to determine the frequency of referral for both IgA tTG–positive patients (positive referral rate) and IgA tTG–negative patients (negative referral rate), which were 79.2% and 3.6%, respectively.
The researchers then used these values to recalculate the sensitivities and specificities in the five original studies considered high risk for verification bias, then pooled those adjusted values with the remaining, unadjusted values from the studies considered low or unclear risk of bias. The new overall values were 57.1% sensitivity (95% confidence interval, 35.4%-76.4%) and 99.6% specificity (95% CI, 98.4%-99.9%).
“The reported sensitivity and specificity of IgA tTG ... are substantially biased due to a lack of adjustment for verification bias. Specifically, adjusting for verification bias decreases the sensitivity of IgA tTG from 92.5% to 57.1%, with a drop in the lower limit of the 95% CI to 35.4%, and an increase in the specificity from 97.9% to 99.6%, The low estimated sensitivity of IgA tTG raises concern on the accuracy of this test and supports performing a systematic review that accounts for verification bias. ... After adjusting for verification bias, the estimated sensitivity of IgA tTG falls to the point where the serologic marker may no longer be clinically useful as a screening test,” the authors wrote.
The numbers came as a bit of a shock to Dr. Stahl because the sensitivity was so much lower than has been traditionally accepted. “But the more important concept from the paper is that the sensitivity is probably lower than what we oftentimes reference, and we should think more about the population of patients that could potentially screen negative and still have celiac disease,” she said. Although there is no literature to back this up at this time, Dr. Stahl also believes that this may be more common in adults, who have a higher incidence of seronegative Celiac disease.
The issue isn’t restricted to celiac disease. Verification bias can also affect the sensitivity and specificity values from other index screens that are followed by invasive reference tests, like occult blood and colonoscopy or hepatitis C serology and liver biopsy. “A lot of times you ethically cannot put everyone through the [more invasive] reference test, so it definitely applies to other tests we screen for in GI. When we’re quoting numbers and doing systematic reviews and meta-analyses, we should be accounting for those biases,” said Dr. Stahl.
No source of funding was disclosed. The authors declared that they have nothing to disclose. Dr. Stahl consults for Evo-Endo.
Immunoglobulin A tissue transglutaminase offers a noninvasive way to detect celiac disease, but new research suggests that its sensitivity may be overestimated and that it may not be an effective screening test, at least in asymptomatic individuals. The reason comes down to verification bias, wherein a technique appears to have higher sensitivity and lower specificity because individuals who screen positive are more likely to have their disease confirmed by a follow-up small-bowel biopsy while those who screen negative are unlikely to have a follow-up biopsy that could reveal missed celiac disease.
“The issue with verification bias is that only the patients that screen positive on that index test are going to be getting the reference test, so there’s probably a good chance that if they screen positive when they go to that reference test they’ll also be positive. What you’re missing from when you’re calculating sensitivity is, what about the ones that are negative on the index test? Would they have been positive on that reference test? That’s not even coming into your calculation because they’re not getting that reference test,” said Marisa Stahl, MD, a physician and researcher at the Children’s Hospital Colorado Center of Celiac Disease in Aurora. Dr. Stahl was not involved in the meta-analysis, but commented on it in an interview.
The only way to fully correct for this bias is to conduct both IgA tissue transglutaminase (tTG) testing and small bowel biopsy on a complete or random sample of patients and compare the sensitivity and specificity of IgA tTG with the preferred method small-bowel biopsy. However, this is rarely done. Instead, when the U.S. Preventive Services Task Force concluded that evidence was insufficient for IgA tTG testing for celiac disease, it relied on a 2016 comparative effectiveness review of nine studies that estimated sensitivity at 92.6% and specificity at 97.6%. USPSTF remained noncommittal because of inadequate evidence surrounding the balance of benefit and harms of screening for celiac disease in asymptomatic individuals.
In the current meta-analysis, Isabel Hujoel, MD, of the Mayo Clinic, Rochester, Minn., and colleagues tested whether the studies used by USPSTF may have overestimated sensitivity because of verification bias. In a report in the Journal of Clinical Gastroenterology, they reviewed those same nine studies to see the potential impact of verification bias. They rated each individual study as being at high, low, or unclear risk of verification bias and found five they considered to be high risk.
To reveal the impact of small-bowel biopsy referral rates on sensitivity and specificity, the researchers reviewed a separate set of nine retrospective and prospective studies to determine the frequency of referral for both IgA tTG–positive patients (positive referral rate) and IgA tTG–negative patients (negative referral rate), which were 79.2% and 3.6%, respectively.
The researchers then used these values to recalculate the sensitivities and specificities in the five original studies considered high risk for verification bias, then pooled those adjusted values with the remaining, unadjusted values from the studies considered low or unclear risk of bias. The new overall values were 57.1% sensitivity (95% confidence interval, 35.4%-76.4%) and 99.6% specificity (95% CI, 98.4%-99.9%).
“The reported sensitivity and specificity of IgA tTG ... are substantially biased due to a lack of adjustment for verification bias. Specifically, adjusting for verification bias decreases the sensitivity of IgA tTG from 92.5% to 57.1%, with a drop in the lower limit of the 95% CI to 35.4%, and an increase in the specificity from 97.9% to 99.6%, The low estimated sensitivity of IgA tTG raises concern on the accuracy of this test and supports performing a systematic review that accounts for verification bias. ... After adjusting for verification bias, the estimated sensitivity of IgA tTG falls to the point where the serologic marker may no longer be clinically useful as a screening test,” the authors wrote.
The numbers came as a bit of a shock to Dr. Stahl because the sensitivity was so much lower than has been traditionally accepted. “But the more important concept from the paper is that the sensitivity is probably lower than what we oftentimes reference, and we should think more about the population of patients that could potentially screen negative and still have celiac disease,” she said. Although there is no literature to back this up at this time, Dr. Stahl also believes that this may be more common in adults, who have a higher incidence of seronegative Celiac disease.
The issue isn’t restricted to celiac disease. Verification bias can also affect the sensitivity and specificity values from other index screens that are followed by invasive reference tests, like occult blood and colonoscopy or hepatitis C serology and liver biopsy. “A lot of times you ethically cannot put everyone through the [more invasive] reference test, so it definitely applies to other tests we screen for in GI. When we’re quoting numbers and doing systematic reviews and meta-analyses, we should be accounting for those biases,” said Dr. Stahl.
No source of funding was disclosed. The authors declared that they have nothing to disclose. Dr. Stahl consults for Evo-Endo.
Immunoglobulin A tissue transglutaminase offers a noninvasive way to detect celiac disease, but new research suggests that its sensitivity may be overestimated and that it may not be an effective screening test, at least in asymptomatic individuals. The reason comes down to verification bias, wherein a technique appears to have higher sensitivity and lower specificity because individuals who screen positive are more likely to have their disease confirmed by a follow-up small-bowel biopsy while those who screen negative are unlikely to have a follow-up biopsy that could reveal missed celiac disease.
“The issue with verification bias is that only the patients that screen positive on that index test are going to be getting the reference test, so there’s probably a good chance that if they screen positive when they go to that reference test they’ll also be positive. What you’re missing from when you’re calculating sensitivity is, what about the ones that are negative on the index test? Would they have been positive on that reference test? That’s not even coming into your calculation because they’re not getting that reference test,” said Marisa Stahl, MD, a physician and researcher at the Children’s Hospital Colorado Center of Celiac Disease in Aurora. Dr. Stahl was not involved in the meta-analysis, but commented on it in an interview.
The only way to fully correct for this bias is to conduct both IgA tissue transglutaminase (tTG) testing and small bowel biopsy on a complete or random sample of patients and compare the sensitivity and specificity of IgA tTG with the preferred method small-bowel biopsy. However, this is rarely done. Instead, when the U.S. Preventive Services Task Force concluded that evidence was insufficient for IgA tTG testing for celiac disease, it relied on a 2016 comparative effectiveness review of nine studies that estimated sensitivity at 92.6% and specificity at 97.6%. USPSTF remained noncommittal because of inadequate evidence surrounding the balance of benefit and harms of screening for celiac disease in asymptomatic individuals.
In the current meta-analysis, Isabel Hujoel, MD, of the Mayo Clinic, Rochester, Minn., and colleagues tested whether the studies used by USPSTF may have overestimated sensitivity because of verification bias. In a report in the Journal of Clinical Gastroenterology, they reviewed those same nine studies to see the potential impact of verification bias. They rated each individual study as being at high, low, or unclear risk of verification bias and found five they considered to be high risk.
To reveal the impact of small-bowel biopsy referral rates on sensitivity and specificity, the researchers reviewed a separate set of nine retrospective and prospective studies to determine the frequency of referral for both IgA tTG–positive patients (positive referral rate) and IgA tTG–negative patients (negative referral rate), which were 79.2% and 3.6%, respectively.
The researchers then used these values to recalculate the sensitivities and specificities in the five original studies considered high risk for verification bias, then pooled those adjusted values with the remaining, unadjusted values from the studies considered low or unclear risk of bias. The new overall values were 57.1% sensitivity (95% confidence interval, 35.4%-76.4%) and 99.6% specificity (95% CI, 98.4%-99.9%).
“The reported sensitivity and specificity of IgA tTG ... are substantially biased due to a lack of adjustment for verification bias. Specifically, adjusting for verification bias decreases the sensitivity of IgA tTG from 92.5% to 57.1%, with a drop in the lower limit of the 95% CI to 35.4%, and an increase in the specificity from 97.9% to 99.6%, The low estimated sensitivity of IgA tTG raises concern on the accuracy of this test and supports performing a systematic review that accounts for verification bias. ... After adjusting for verification bias, the estimated sensitivity of IgA tTG falls to the point where the serologic marker may no longer be clinically useful as a screening test,” the authors wrote.
The numbers came as a bit of a shock to Dr. Stahl because the sensitivity was so much lower than has been traditionally accepted. “But the more important concept from the paper is that the sensitivity is probably lower than what we oftentimes reference, and we should think more about the population of patients that could potentially screen negative and still have celiac disease,” she said. Although there is no literature to back this up at this time, Dr. Stahl also believes that this may be more common in adults, who have a higher incidence of seronegative Celiac disease.
The issue isn’t restricted to celiac disease. Verification bias can also affect the sensitivity and specificity values from other index screens that are followed by invasive reference tests, like occult blood and colonoscopy or hepatitis C serology and liver biopsy. “A lot of times you ethically cannot put everyone through the [more invasive] reference test, so it definitely applies to other tests we screen for in GI. When we’re quoting numbers and doing systematic reviews and meta-analyses, we should be accounting for those biases,” said Dr. Stahl.
No source of funding was disclosed. The authors declared that they have nothing to disclose. Dr. Stahl consults for Evo-Endo.
FROM THE JOURNAL OF CLINICAL GASTROENTEROLOGY
Optimize your treatment of endometriosis by using an FDA-approved hormonal medication
Women with endometriosis often present for medical care for one or more of the following health issues: pelvic pain, infertility, and/or an adnexal cyst (endometrioma). For women with moderate or severe pelvic pain and laparoscopically diagnosed endometriosis, hormone therapy is often necessary to achieve maximal long-term reduction in pain and optimize health. I focus on opportunities to optimize hormonal treatment of endometriosis in this editorial.
When plan A is not working, move expeditiously to plan B
Cyclic or continuous combination estrogen-progestin contraceptives are commonly prescribed to treat pelvic pain caused by endometriosis. Although endometriosis pain may initially improve with estrogen-progestin contraceptives, many women on this medication will eventually report that they have worsening pelvic pain that adversely impacts their daily activities. Surprisingly, clinicians often continue to prescribe estrogen-progestin contraceptives even after the patient reports that the treatment is not effective, and their pain continues to be bothersome.
Patients benefit when they have access to the full range of hormone treatments that have been approved by the FDA for the treatment of moderate to severe pelvic pain caused by endometriosis (TABLE). In the situation where an estrogen-progestin contraceptive is no longer effective at reducing the pelvic pain, I will often offer the patient the option of norethindrone acetate (NEA) or elagolix treatment. My experience is that stopping the estrogen-progestin contraceptive and starting NEA or elagolix will result in a significant decrease in pain symptoms and improvement in the patient’s quality of life.
Other FDA-approved options to treat pelvic pain caused by endometriosis include depot medroxyprogesterone acetate injectable suspension, depot leuprolide acetate, goserelin implant, and danazol. I do not routinely prescribe depot medroxyprogesterone acetate because some patients report new onset or worsening symptoms of depression on the medication. I prescribe depot-leuprolide acetate less often than in the past, because many patients report moderate to severe hypoestrogenic symptoms on this medication. In women taking depot-leuprolide acetate, moderate to severe vasomotor symptoms can be improved by prescribing NEA pills, but the alternative of norethindrone monotherapy is less expensive. I seldom use goserelin or danazol in my practice. The needle required to place the goserelin implant has a diameter of approximately 1.7 mm (16 gauge) or 2.1 mm (14 gauge), for the 3.6 mg and 10 mg doses, respectively. The large diameter of the needle can cause pain and bruising at the implant site. As a comparison, the progestin subdermal implant needle is approximately 2.1 mm in diameter. Danazol is associated with weight gain, and most women prefer to avoid this side effect.
Continue to: Norethindrone acetate...
Norethindrone acetate
NEA 5 mg daily is approved by the FDA to treat endometriosis.1 NEA was approved at a time when large controlled clinical trials were not routinely required for a medicine to be approved. The data to support NEA treatment of pelvic pain caused by endometriosis is based on cohort studies. In a study of 194 women, median age 21 years with moderate to severe pelvic pain and surgically proven endometriosis, the effect of NEA on pelvic pain was explored.2 The initial dose of NEA was 5 mg daily. If the patient did not achieve a reduction in pelvic pain and amenorrhea on the NEA dose of 5 mg daily, the dose was increased by 2.5 mg every 2 weeks, up to a maximum of 15 mg, until amenorrhea and/or a decrease in pelvic pain was achieved. Ninety-five percent of the women in this cohort had previously been treated with an estrogen-progestin contraceptive or a GnRH antagonist and had discontinued those medications because of inadequate control of pelvic pain or because of side effects of the medication.
In this large cohort, 65% of women reported significant improvement in pelvic pain, with a median pain score of 5 before treatment and 0 following NEA treatment. About 55% of the women reported no side effects. The most commonly reported side effects were weight gain (16%; mean weight gain, 3.1 kg), acne (10%), mood lability (9%), hot flashes (8%), depression (6%), scalp hair loss (4%), headache (4%), nausea (3%), and deepening of the voice (1%). (In this study women could report more than one side effect.)
In another cohort study of 52 women with pelvic pain and surgically confirmed endometriosis, NEA treatment resulted in pain relief in 94% of the women.3 Breakthrough bleeding was a common side effect, reported by 58% of participants. The investigators concluded that NEA treatment was a “cost-effective alternative with relatively mild side effects in the treatment of symptomatic endometriosis.” A conclusion which I endorse.
NEA has been reported to effectively treat ovarian endometriomas and rectovaginal endometriosis.4,5 In a cohort of 18 women who had previously had the surgical resection of an ovarian endometriosis cyst and had postoperative recurrence of pelvic pain and ovarian endometriosis, treatment was initiated with an escalating NEA regimen.4 Treatment was initiated with NEA 5 mg daily, with the dosage increased every 2 weeks by 2.5 mg until amenorrhea was established. Most women achieved amenorrhea with NEA 5 mg daily, and 89% had reduced pelvic pain. The investigators reported complete regression of the endometriosis cyst(s) in 74% of the women. In my experience, NEA does not result in complete regression of endometriosis cysts, but it does cause a reduction in cyst diameter and total volume.
In a retrospective cohort study, 61 women with pelvic pain and rectovaginal endometriosis had 5 years of treatment with NEA 2.5 mg or 5.0 mg daily.5 NEA treatment resulted in a decrease in dysmenorrhea, deep dyspareunia, and dyschezia. The most common side effects attributed to NEA treatment were weight gain (30%), vaginal bleeding (23%), decreased libido (11%), headache (9%), bloating or swelling (8%), depression (7%), and acne (5%). In women who had sequential imaging studies, NEA treatment resulted in a decrease in rectovaginal lesion volume, stable disease volume, or an increase in lesion volume in 56%, 32%, and 12% of the women, respectively. The investigators concluded that for women with rectovaginal endometriosis, NEA treatment is a low-cost option for long-term treatment.
In my practice, I do not prescribe NEA at doses greater than 5 mg daily. There are case reports that NEA at a dose of ≥10 mg daily is associated with the development of a hepatic adenoma,6 elevated liver transaminase concentration,7 and jaundice.8 If NEA 5 mg daily is not effective in controlling pelvic pain caused by endometriosis, I stop the NEA and start a GnRH analogue, most often elagolix.
NEA 5 mg is not FDA approved as a contraceptive. However, norethindrone 0.35 mg daily, also known as the “mini-pill”, is approved as a progestin-only contraceptive.9 NEA is rapidly and completely deacetylated to norethindrone, and the disposition of oral NEA is indistinguishable from that of norethindrone.1 Since norethindrone 0.35 mg daily is approved as a contraceptive, it is highly likely that NEA 5 mg has contraceptive properties if taken daily.
Continue to: Elagolix...
Elagolix
Elagolix is FDA approved for the treatment of pelvic pain caused by endometriosis. I reviewed the key studies resulting in FDA approval in the November 2018 issue of
In the Elaris Endometriosis-I study, 872 women with endometriosis and pelvic pain were randomly assigned to treatment with 1 of 2 doses of elagolix (high-dose [200 mg twice daily] and low-dose [150 mg once daily]) or placebo.11 After 3 months of therapy, a clinically meaningful reduction in dysmenorrhea pain was reported by 76%, 46%, and 20% of the women in the high-dose elagolix, low-dose elagolix, and placebo groups, respectively (P<.001 for comparisons of elagolix to placebo). After 3 months of therapy, a clinically meaningful reduction in nonmenstrual pain or decreased or stable use of rescue analgesics was reported by 55%, 50%, and 37% of the women in the high-dose elagolix, low-dose elagolix, and placebo groups, respectively (P<.01 low-dose elagolix vs placebo and P<.001 high-dose elagolix vs placebo).
Hot flashes that were severe enough to be reported as an adverse event by the study participants were reported by 42%, 24%, and 7% of the women in the high-dose elagolix, low-dose elagolix, and placebo groups. Bone density was measured at baseline and after 6 months of treatment. Lumbar bone density changes were -2.61%, -0.32%, and +0.47% and hip femoral neck bone density changes were -1.89%, -0.39%, and +0.02% in the high-dose elagolix, low-dose elagolix, and placebo groups, respectively.
Another large clinical trial of elagolix for the treatment of pelvic pain caused by endometriosis, Elaris EM-II, involving 817 women, produced results very similar to those reported in Elaris EM-I. The elagolix continuation studies, Elaris EM-III and -IV, demonstrated efficacy and safety of elagolix through 12 months of treatment.12
In my 2018 review,10 I noted that elagolix dose adjustment can be utilized to attempt to achieve maximal pain relief with minimal vasomotor symptoms. Elagolix at 200 mg twice daily produces a mean estradiol concentration of 12 pg/mL, whereas elagolix at 150 mg daily resulted in a mean estradiol concentration of 41 pg/mL.13 The estrogen threshold hypothesis posits that in women with endometriosis a stable estradiol concentration of 20 to 30 pg/mL is often associated with decreased pain and fewer vasomotor events.14 To achieve the target estradiol range of 20 to 30 pg/mL, I often initiate elagolix treatment with 200 mg twice daily. This enables a rapid onset of amenorrhea and a reduction in pelvic pain. Once amenorrhea has been achieved and a decrease in pelvic pain has occurred, I adjust the dose downward to 200 mg twice daily on even calendar days of each month and 200 mg once daily on odd calendar days each month. Some women will have continued pain relief and amenorrhea when the dose is further decreased to 200 mg once daily. If bothersome bleeding recurs and/or pain symptoms increase in severity, the dose can be increased to 200 mg twice daily or an alternating regimen of 200 mg twice daily and 200 mg once daily, every 2 days. An alternative to dose adjustment is to combine elagolix with NEA, which can reduce the severity of hot flashes and reduce bone loss caused by hypoestrogenism.15,16
Health insurers and pharmacy benefits managers may require a prior authorization before approving and dispensing elagolix. The prior authorization process can be burdensome for clinicians, consuming limited healthcare resources, contributing to burnout and frustrating patients.17 Elagolix is less expensive than depot-leuprolide acetate and nafarelin nasal spray and somewhat more expensive than a goserelin implant.18,19
Elagolix is not approved as a contraceptive. In the Elaris EM-I and -II trials women were advised to use 2 forms of contraception, although pregnancies did occur. There were 6 pregnancies among 475 women taking elagolix 150 mg daily and 2 pregnancies among 477 women taking elagolix 200 mg twice daily.20 Women taking elagolix should be advised to use a contraceptive, but not an estrogen-progestin contraceptive.
Continue to: Do not use opioids to treat chronic pelvic pain caused by endometriosis...
Do not use opioids to treat chronic pelvic pain caused by endometriosis
One of the greatest public health tragedies of our era is the opioid misuse epidemic. Hundreds of thousands of deaths have been caused by opioid misuse. The Centers for Disease Control and Prevention reported that for the 12-month period ending in May 2020, there were 81,000 opioid-related deaths, the greatest number ever reported in a 12-month period.21 Many authorities believe that in the United States opioid medications have been over-prescribed, contributing to the opioid misuse epidemic. There is little evidence that chronic pelvic pain is optimally managed by chronic treatment with an opioid.22,23 Prescribing opioids to vulnerable individuals to treat chronic pelvic pain may result in opioid dependency and adversely affect the patient’s health. It is best to pledge not to prescribe an opioid medication for a woman with chronic pelvic pain caused by endometriosis. In situations when pelvic pain is difficult to control with hormonal therapy and nonopioid pain medications, referral to a specialty pain practice may be warranted.
Post–conservative surgery hormone treatment reduces pelvic pain recurrence
In a meta-analysis of 14 studies that reported on endometriosis recurrence rates following conservative surgery, recurrence (defined as recurrent pelvic pain or an imaging study showing recurrent endometriosis) was significantly reduced with the use of hormone treatment compared with expectant management or placebo treatment.24 The postoperative relative risk of endometriosis recurrence was reduced by 83% with progestin treatment, 64% with estrogen-progestin contraceptive treatment, and 38% with GnRH analogue treatment. Overall, the number of patients that needed to be treated to prevent one endometriosis recurrence was 10, assuming a recurrence rate of 25% in the placebo treatment or expectant management groups.
For women with pelvic pain caused by endometriosis who develop a recurrence of pelvic pain while on postoperative hormone treatment, it is important for the prescribing clinician to be flexible and consider changing the hormone regimen. For example, if a postoperative patient is treated with a continuous estrogen-progestin contraceptive and develops recurrent pain, I will stop the contraceptive and initiate treatment with either NEA or elagolix.
Capitalize on opportunities to improve the medical care of women with endometriosis
Early diagnosis of endometriosis can be facilitated by recognizing that the condition is a common cause of moderate to severe dysmenorrhea. In 5 studies involving 1,187 women, the mean length of time from onset of pelvic pain symptoms to diagnosis of endometriosis was 8.6 years.25 If a woman with pelvic pain caused by endometriosis has not had sufficient pain relief with one brand of continuous estrogen-progestin contraceptive, it is best not to prescribe an alternative brand but rather to switch to a progestin-only treatment or a GnRH antagonist. If plan A is not working, move expeditiously to plan B. ●
- Aygestin [package insert]. Barr Laboratories: Pomona, NY; 2007.
- Kaser DJ, Missmer SA, Berry KF, et al. Use of norethindrone acetate alone for postoperative suppression of endometriosis symptoms. J Pediatr Adolesc Gynecol. 2012;25:105-108.
- Muneyyirci-Delale O, Karacan M. Effect of norethindrone acetate in the treatment of symptomatic endometriosis. Int J Fertil Womens Med. 1998;43:24-27.
- Muneyyirci-Delale O, Anopa J, Charles C, et al. Medical management of recurrent endometrioma with long-term norethindrone acetate. Int J Women Health. 2012;4:149-154.
- Morotti M, Venturini PL, Biscaldi E, et al. Efficacy and acceptability of long-term norethindrone acetate for the treatment of rectovaginal endometriosis. Eur J Obstet Gynecol Repro Biol. 2017;213:4-10.
- Brady PC, Missmer SA, Laufer MR. Hepatic adenomas in adolescents and young women with endometriosis treated with norethindrone acetate. J Pediatr Adolesc Gynecol. 2017;30:422-424.
- Choudhary NS, Bodh V, Chaudhari S, et al. Norethisterone related drug induced liver injury: a series of 3 cases. J Clin Exp Hepatol. 2017;7:266- 268.
- Perez-Mera RA, Shields CE. Jaundice associated with norethindrone acetate therapy. N Engl J Med. 1962;267:1137-1138.
- Camila [package insert]. Mayne Pharma Inc: Greenville, NC; 2018.
- Barbieri RL. Elagolix: a new treatment for pelvic pain caused by endometriosis. OBG Manag. 2018;30:10,12-14, 20.
- Taylor HS, Giudice LC, Lessey BA, et al. Treatment of endometriosis-associated pain with elagolix, an oral GnRH antagonist. N Engl J Med. 2017;377:28-40.
- Surrey E, Taylor HS, Giudice L, et al. Long-term outcomes of elagolix in women with endometriosis: results from two extension studies. Obstet Gynecol. 2018;132:147-160.
- Orilissa [package insert]. AbbVie Inc; North Chicago, IL; 2018.
- Barbieri RL. Hormonal treatment of endometriosis: the estrogen threshold hypothesis. Am J Obstet Gynecol. 1992;166:740-745.
- Hornstein MD, Surrey ES, Weisberg GW, et al. Leuprolide acetate depot and hormonal add-back in endometriosis: a 12-month study. Lupron Add-Back Study Group. Obstet Gynecol. 1998;91:16-24.
- Gallagher JS, Missmer SA, Hornstein MD, et al. Long-term effects of gonadotropin-releasing hormone agonists and add-back in adolescent endometriosis. J Pediatr Adolesc Gynecol. 2018;31:376- 381.
- Miller A, Shor R, Waites T, et al. Prior authorization reform for better patient care. J Am Coll Cardiol. 2018;71:1937-1939.
- Depot-leuprolide acetate. Good Rx website. https://www.goodrx.com/. Accessed January 22, 2021.
- Goserelin. Good Rx website. https://www .goodrx.com/. Accessed January 22, 2021
- Taylor HS, Giudice LC, Lessey BA, et al. Treatment of endometriosis-associated pain with elagolix, an oral GnRH antagonist. N Engl J Med. 2017;377:28-40.
- Centers for Disease Control and Prevention. Overdose deaths accelerating during COVID19. https://www.cdc.gov/media/releases/2020 /p1218-overdose-deaths-covid-19.html. Reviewed December 18, 2020. Accessed March 24, 2021.
- Till SR, As-Sanie S. 3 cases of chronic pelvic pain with nonsurgical, nonopioid therapies. OBG Manag. 2018;30:41-48.
- Steele A. Opioid use and depression in chronic pelvic pain. Obstet Gynecol Clin North Am. 2014;41:491-501.
- Zakhari A, Delpero E, McKeown S, et al. Endometriosis recurrence following post-operative hormonal suppression: a systematic review and meta-analysis. Hum Reprod Update. 2021;27:96- 107.
- Barbieri RL. Why are there delays in the diagnosis of endometriosis? OBG Manag. 2017;29:8, 10-11, 16.
Robert L. Barbieri, MD
Chair Emeritus, Department of Obstetrics and Gynecology
Interim Chief, Obstetrics
Brigham and Women’s Hospital
Kate Macy Ladd Distinguished Professor of Obstetrics,
Gynecology and Reproductive Biology
Harvard Medical School
Boston, Massachusetts
Dr. Barbieri reports no financial relationships relevant to this article.
Robert L. Barbieri, MD
Chair Emeritus, Department of Obstetrics and Gynecology
Interim Chief, Obstetrics
Brigham and Women’s Hospital
Kate Macy Ladd Distinguished Professor of Obstetrics,
Gynecology and Reproductive Biology
Harvard Medical School
Boston, Massachusetts
Dr. Barbieri reports no financial relationships relevant to this article.
Robert L. Barbieri, MD
Chair Emeritus, Department of Obstetrics and Gynecology
Interim Chief, Obstetrics
Brigham and Women’s Hospital
Kate Macy Ladd Distinguished Professor of Obstetrics,
Gynecology and Reproductive Biology
Harvard Medical School
Boston, Massachusetts
Dr. Barbieri reports no financial relationships relevant to this article.
Women with endometriosis often present for medical care for one or more of the following health issues: pelvic pain, infertility, and/or an adnexal cyst (endometrioma). For women with moderate or severe pelvic pain and laparoscopically diagnosed endometriosis, hormone therapy is often necessary to achieve maximal long-term reduction in pain and optimize health. I focus on opportunities to optimize hormonal treatment of endometriosis in this editorial.
When plan A is not working, move expeditiously to plan B
Cyclic or continuous combination estrogen-progestin contraceptives are commonly prescribed to treat pelvic pain caused by endometriosis. Although endometriosis pain may initially improve with estrogen-progestin contraceptives, many women on this medication will eventually report that they have worsening pelvic pain that adversely impacts their daily activities. Surprisingly, clinicians often continue to prescribe estrogen-progestin contraceptives even after the patient reports that the treatment is not effective, and their pain continues to be bothersome.
Patients benefit when they have access to the full range of hormone treatments that have been approved by the FDA for the treatment of moderate to severe pelvic pain caused by endometriosis (TABLE). In the situation where an estrogen-progestin contraceptive is no longer effective at reducing the pelvic pain, I will often offer the patient the option of norethindrone acetate (NEA) or elagolix treatment. My experience is that stopping the estrogen-progestin contraceptive and starting NEA or elagolix will result in a significant decrease in pain symptoms and improvement in the patient’s quality of life.
Other FDA-approved options to treat pelvic pain caused by endometriosis include depot medroxyprogesterone acetate injectable suspension, depot leuprolide acetate, goserelin implant, and danazol. I do not routinely prescribe depot medroxyprogesterone acetate because some patients report new onset or worsening symptoms of depression on the medication. I prescribe depot-leuprolide acetate less often than in the past, because many patients report moderate to severe hypoestrogenic symptoms on this medication. In women taking depot-leuprolide acetate, moderate to severe vasomotor symptoms can be improved by prescribing NEA pills, but the alternative of norethindrone monotherapy is less expensive. I seldom use goserelin or danazol in my practice. The needle required to place the goserelin implant has a diameter of approximately 1.7 mm (16 gauge) or 2.1 mm (14 gauge), for the 3.6 mg and 10 mg doses, respectively. The large diameter of the needle can cause pain and bruising at the implant site. As a comparison, the progestin subdermal implant needle is approximately 2.1 mm in diameter. Danazol is associated with weight gain, and most women prefer to avoid this side effect.
Continue to: Norethindrone acetate...
Norethindrone acetate
NEA 5 mg daily is approved by the FDA to treat endometriosis.1 NEA was approved at a time when large controlled clinical trials were not routinely required for a medicine to be approved. The data to support NEA treatment of pelvic pain caused by endometriosis is based on cohort studies. In a study of 194 women, median age 21 years with moderate to severe pelvic pain and surgically proven endometriosis, the effect of NEA on pelvic pain was explored.2 The initial dose of NEA was 5 mg daily. If the patient did not achieve a reduction in pelvic pain and amenorrhea on the NEA dose of 5 mg daily, the dose was increased by 2.5 mg every 2 weeks, up to a maximum of 15 mg, until amenorrhea and/or a decrease in pelvic pain was achieved. Ninety-five percent of the women in this cohort had previously been treated with an estrogen-progestin contraceptive or a GnRH antagonist and had discontinued those medications because of inadequate control of pelvic pain or because of side effects of the medication.
In this large cohort, 65% of women reported significant improvement in pelvic pain, with a median pain score of 5 before treatment and 0 following NEA treatment. About 55% of the women reported no side effects. The most commonly reported side effects were weight gain (16%; mean weight gain, 3.1 kg), acne (10%), mood lability (9%), hot flashes (8%), depression (6%), scalp hair loss (4%), headache (4%), nausea (3%), and deepening of the voice (1%). (In this study women could report more than one side effect.)
In another cohort study of 52 women with pelvic pain and surgically confirmed endometriosis, NEA treatment resulted in pain relief in 94% of the women.3 Breakthrough bleeding was a common side effect, reported by 58% of participants. The investigators concluded that NEA treatment was a “cost-effective alternative with relatively mild side effects in the treatment of symptomatic endometriosis.” A conclusion which I endorse.
NEA has been reported to effectively treat ovarian endometriomas and rectovaginal endometriosis.4,5 In a cohort of 18 women who had previously had the surgical resection of an ovarian endometriosis cyst and had postoperative recurrence of pelvic pain and ovarian endometriosis, treatment was initiated with an escalating NEA regimen.4 Treatment was initiated with NEA 5 mg daily, with the dosage increased every 2 weeks by 2.5 mg until amenorrhea was established. Most women achieved amenorrhea with NEA 5 mg daily, and 89% had reduced pelvic pain. The investigators reported complete regression of the endometriosis cyst(s) in 74% of the women. In my experience, NEA does not result in complete regression of endometriosis cysts, but it does cause a reduction in cyst diameter and total volume.
In a retrospective cohort study, 61 women with pelvic pain and rectovaginal endometriosis had 5 years of treatment with NEA 2.5 mg or 5.0 mg daily.5 NEA treatment resulted in a decrease in dysmenorrhea, deep dyspareunia, and dyschezia. The most common side effects attributed to NEA treatment were weight gain (30%), vaginal bleeding (23%), decreased libido (11%), headache (9%), bloating or swelling (8%), depression (7%), and acne (5%). In women who had sequential imaging studies, NEA treatment resulted in a decrease in rectovaginal lesion volume, stable disease volume, or an increase in lesion volume in 56%, 32%, and 12% of the women, respectively. The investigators concluded that for women with rectovaginal endometriosis, NEA treatment is a low-cost option for long-term treatment.
In my practice, I do not prescribe NEA at doses greater than 5 mg daily. There are case reports that NEA at a dose of ≥10 mg daily is associated with the development of a hepatic adenoma,6 elevated liver transaminase concentration,7 and jaundice.8 If NEA 5 mg daily is not effective in controlling pelvic pain caused by endometriosis, I stop the NEA and start a GnRH analogue, most often elagolix.
NEA 5 mg is not FDA approved as a contraceptive. However, norethindrone 0.35 mg daily, also known as the “mini-pill”, is approved as a progestin-only contraceptive.9 NEA is rapidly and completely deacetylated to norethindrone, and the disposition of oral NEA is indistinguishable from that of norethindrone.1 Since norethindrone 0.35 mg daily is approved as a contraceptive, it is highly likely that NEA 5 mg has contraceptive properties if taken daily.
Continue to: Elagolix...
Elagolix
Elagolix is FDA approved for the treatment of pelvic pain caused by endometriosis. I reviewed the key studies resulting in FDA approval in the November 2018 issue of
In the Elaris Endometriosis-I study, 872 women with endometriosis and pelvic pain were randomly assigned to treatment with 1 of 2 doses of elagolix (high-dose [200 mg twice daily] and low-dose [150 mg once daily]) or placebo.11 After 3 months of therapy, a clinically meaningful reduction in dysmenorrhea pain was reported by 76%, 46%, and 20% of the women in the high-dose elagolix, low-dose elagolix, and placebo groups, respectively (P<.001 for comparisons of elagolix to placebo). After 3 months of therapy, a clinically meaningful reduction in nonmenstrual pain or decreased or stable use of rescue analgesics was reported by 55%, 50%, and 37% of the women in the high-dose elagolix, low-dose elagolix, and placebo groups, respectively (P<.01 low-dose elagolix vs placebo and P<.001 high-dose elagolix vs placebo).
Hot flashes that were severe enough to be reported as an adverse event by the study participants were reported by 42%, 24%, and 7% of the women in the high-dose elagolix, low-dose elagolix, and placebo groups. Bone density was measured at baseline and after 6 months of treatment. Lumbar bone density changes were -2.61%, -0.32%, and +0.47% and hip femoral neck bone density changes were -1.89%, -0.39%, and +0.02% in the high-dose elagolix, low-dose elagolix, and placebo groups, respectively.
Another large clinical trial of elagolix for the treatment of pelvic pain caused by endometriosis, Elaris EM-II, involving 817 women, produced results very similar to those reported in Elaris EM-I. The elagolix continuation studies, Elaris EM-III and -IV, demonstrated efficacy and safety of elagolix through 12 months of treatment.12
In my 2018 review,10 I noted that elagolix dose adjustment can be utilized to attempt to achieve maximal pain relief with minimal vasomotor symptoms. Elagolix at 200 mg twice daily produces a mean estradiol concentration of 12 pg/mL, whereas elagolix at 150 mg daily resulted in a mean estradiol concentration of 41 pg/mL.13 The estrogen threshold hypothesis posits that in women with endometriosis a stable estradiol concentration of 20 to 30 pg/mL is often associated with decreased pain and fewer vasomotor events.14 To achieve the target estradiol range of 20 to 30 pg/mL, I often initiate elagolix treatment with 200 mg twice daily. This enables a rapid onset of amenorrhea and a reduction in pelvic pain. Once amenorrhea has been achieved and a decrease in pelvic pain has occurred, I adjust the dose downward to 200 mg twice daily on even calendar days of each month and 200 mg once daily on odd calendar days each month. Some women will have continued pain relief and amenorrhea when the dose is further decreased to 200 mg once daily. If bothersome bleeding recurs and/or pain symptoms increase in severity, the dose can be increased to 200 mg twice daily or an alternating regimen of 200 mg twice daily and 200 mg once daily, every 2 days. An alternative to dose adjustment is to combine elagolix with NEA, which can reduce the severity of hot flashes and reduce bone loss caused by hypoestrogenism.15,16
Health insurers and pharmacy benefits managers may require a prior authorization before approving and dispensing elagolix. The prior authorization process can be burdensome for clinicians, consuming limited healthcare resources, contributing to burnout and frustrating patients.17 Elagolix is less expensive than depot-leuprolide acetate and nafarelin nasal spray and somewhat more expensive than a goserelin implant.18,19
Elagolix is not approved as a contraceptive. In the Elaris EM-I and -II trials women were advised to use 2 forms of contraception, although pregnancies did occur. There were 6 pregnancies among 475 women taking elagolix 150 mg daily and 2 pregnancies among 477 women taking elagolix 200 mg twice daily.20 Women taking elagolix should be advised to use a contraceptive, but not an estrogen-progestin contraceptive.
Continue to: Do not use opioids to treat chronic pelvic pain caused by endometriosis...
Do not use opioids to treat chronic pelvic pain caused by endometriosis
One of the greatest public health tragedies of our era is the opioid misuse epidemic. Hundreds of thousands of deaths have been caused by opioid misuse. The Centers for Disease Control and Prevention reported that for the 12-month period ending in May 2020, there were 81,000 opioid-related deaths, the greatest number ever reported in a 12-month period.21 Many authorities believe that in the United States opioid medications have been over-prescribed, contributing to the opioid misuse epidemic. There is little evidence that chronic pelvic pain is optimally managed by chronic treatment with an opioid.22,23 Prescribing opioids to vulnerable individuals to treat chronic pelvic pain may result in opioid dependency and adversely affect the patient’s health. It is best to pledge not to prescribe an opioid medication for a woman with chronic pelvic pain caused by endometriosis. In situations when pelvic pain is difficult to control with hormonal therapy and nonopioid pain medications, referral to a specialty pain practice may be warranted.
Post–conservative surgery hormone treatment reduces pelvic pain recurrence
In a meta-analysis of 14 studies that reported on endometriosis recurrence rates following conservative surgery, recurrence (defined as recurrent pelvic pain or an imaging study showing recurrent endometriosis) was significantly reduced with the use of hormone treatment compared with expectant management or placebo treatment.24 The postoperative relative risk of endometriosis recurrence was reduced by 83% with progestin treatment, 64% with estrogen-progestin contraceptive treatment, and 38% with GnRH analogue treatment. Overall, the number of patients that needed to be treated to prevent one endometriosis recurrence was 10, assuming a recurrence rate of 25% in the placebo treatment or expectant management groups.
For women with pelvic pain caused by endometriosis who develop a recurrence of pelvic pain while on postoperative hormone treatment, it is important for the prescribing clinician to be flexible and consider changing the hormone regimen. For example, if a postoperative patient is treated with a continuous estrogen-progestin contraceptive and develops recurrent pain, I will stop the contraceptive and initiate treatment with either NEA or elagolix.
Capitalize on opportunities to improve the medical care of women with endometriosis
Early diagnosis of endometriosis can be facilitated by recognizing that the condition is a common cause of moderate to severe dysmenorrhea. In 5 studies involving 1,187 women, the mean length of time from onset of pelvic pain symptoms to diagnosis of endometriosis was 8.6 years.25 If a woman with pelvic pain caused by endometriosis has not had sufficient pain relief with one brand of continuous estrogen-progestin contraceptive, it is best not to prescribe an alternative brand but rather to switch to a progestin-only treatment or a GnRH antagonist. If plan A is not working, move expeditiously to plan B. ●
Women with endometriosis often present for medical care for one or more of the following health issues: pelvic pain, infertility, and/or an adnexal cyst (endometrioma). For women with moderate or severe pelvic pain and laparoscopically diagnosed endometriosis, hormone therapy is often necessary to achieve maximal long-term reduction in pain and optimize health. I focus on opportunities to optimize hormonal treatment of endometriosis in this editorial.
When plan A is not working, move expeditiously to plan B
Cyclic or continuous combination estrogen-progestin contraceptives are commonly prescribed to treat pelvic pain caused by endometriosis. Although endometriosis pain may initially improve with estrogen-progestin contraceptives, many women on this medication will eventually report that they have worsening pelvic pain that adversely impacts their daily activities. Surprisingly, clinicians often continue to prescribe estrogen-progestin contraceptives even after the patient reports that the treatment is not effective, and their pain continues to be bothersome.
Patients benefit when they have access to the full range of hormone treatments that have been approved by the FDA for the treatment of moderate to severe pelvic pain caused by endometriosis (TABLE). In the situation where an estrogen-progestin contraceptive is no longer effective at reducing the pelvic pain, I will often offer the patient the option of norethindrone acetate (NEA) or elagolix treatment. My experience is that stopping the estrogen-progestin contraceptive and starting NEA or elagolix will result in a significant decrease in pain symptoms and improvement in the patient’s quality of life.
Other FDA-approved options to treat pelvic pain caused by endometriosis include depot medroxyprogesterone acetate injectable suspension, depot leuprolide acetate, goserelin implant, and danazol. I do not routinely prescribe depot medroxyprogesterone acetate because some patients report new onset or worsening symptoms of depression on the medication. I prescribe depot-leuprolide acetate less often than in the past, because many patients report moderate to severe hypoestrogenic symptoms on this medication. In women taking depot-leuprolide acetate, moderate to severe vasomotor symptoms can be improved by prescribing NEA pills, but the alternative of norethindrone monotherapy is less expensive. I seldom use goserelin or danazol in my practice. The needle required to place the goserelin implant has a diameter of approximately 1.7 mm (16 gauge) or 2.1 mm (14 gauge), for the 3.6 mg and 10 mg doses, respectively. The large diameter of the needle can cause pain and bruising at the implant site. As a comparison, the progestin subdermal implant needle is approximately 2.1 mm in diameter. Danazol is associated with weight gain, and most women prefer to avoid this side effect.
Continue to: Norethindrone acetate...
Norethindrone acetate
NEA 5 mg daily is approved by the FDA to treat endometriosis.1 NEA was approved at a time when large controlled clinical trials were not routinely required for a medicine to be approved. The data to support NEA treatment of pelvic pain caused by endometriosis is based on cohort studies. In a study of 194 women, median age 21 years with moderate to severe pelvic pain and surgically proven endometriosis, the effect of NEA on pelvic pain was explored.2 The initial dose of NEA was 5 mg daily. If the patient did not achieve a reduction in pelvic pain and amenorrhea on the NEA dose of 5 mg daily, the dose was increased by 2.5 mg every 2 weeks, up to a maximum of 15 mg, until amenorrhea and/or a decrease in pelvic pain was achieved. Ninety-five percent of the women in this cohort had previously been treated with an estrogen-progestin contraceptive or a GnRH antagonist and had discontinued those medications because of inadequate control of pelvic pain or because of side effects of the medication.
In this large cohort, 65% of women reported significant improvement in pelvic pain, with a median pain score of 5 before treatment and 0 following NEA treatment. About 55% of the women reported no side effects. The most commonly reported side effects were weight gain (16%; mean weight gain, 3.1 kg), acne (10%), mood lability (9%), hot flashes (8%), depression (6%), scalp hair loss (4%), headache (4%), nausea (3%), and deepening of the voice (1%). (In this study women could report more than one side effect.)
In another cohort study of 52 women with pelvic pain and surgically confirmed endometriosis, NEA treatment resulted in pain relief in 94% of the women.3 Breakthrough bleeding was a common side effect, reported by 58% of participants. The investigators concluded that NEA treatment was a “cost-effective alternative with relatively mild side effects in the treatment of symptomatic endometriosis.” A conclusion which I endorse.
NEA has been reported to effectively treat ovarian endometriomas and rectovaginal endometriosis.4,5 In a cohort of 18 women who had previously had the surgical resection of an ovarian endometriosis cyst and had postoperative recurrence of pelvic pain and ovarian endometriosis, treatment was initiated with an escalating NEA regimen.4 Treatment was initiated with NEA 5 mg daily, with the dosage increased every 2 weeks by 2.5 mg until amenorrhea was established. Most women achieved amenorrhea with NEA 5 mg daily, and 89% had reduced pelvic pain. The investigators reported complete regression of the endometriosis cyst(s) in 74% of the women. In my experience, NEA does not result in complete regression of endometriosis cysts, but it does cause a reduction in cyst diameter and total volume.
In a retrospective cohort study, 61 women with pelvic pain and rectovaginal endometriosis had 5 years of treatment with NEA 2.5 mg or 5.0 mg daily.5 NEA treatment resulted in a decrease in dysmenorrhea, deep dyspareunia, and dyschezia. The most common side effects attributed to NEA treatment were weight gain (30%), vaginal bleeding (23%), decreased libido (11%), headache (9%), bloating or swelling (8%), depression (7%), and acne (5%). In women who had sequential imaging studies, NEA treatment resulted in a decrease in rectovaginal lesion volume, stable disease volume, or an increase in lesion volume in 56%, 32%, and 12% of the women, respectively. The investigators concluded that for women with rectovaginal endometriosis, NEA treatment is a low-cost option for long-term treatment.
In my practice, I do not prescribe NEA at doses greater than 5 mg daily. There are case reports that NEA at a dose of ≥10 mg daily is associated with the development of a hepatic adenoma,6 elevated liver transaminase concentration,7 and jaundice.8 If NEA 5 mg daily is not effective in controlling pelvic pain caused by endometriosis, I stop the NEA and start a GnRH analogue, most often elagolix.
NEA 5 mg is not FDA approved as a contraceptive. However, norethindrone 0.35 mg daily, also known as the “mini-pill”, is approved as a progestin-only contraceptive.9 NEA is rapidly and completely deacetylated to norethindrone, and the disposition of oral NEA is indistinguishable from that of norethindrone.1 Since norethindrone 0.35 mg daily is approved as a contraceptive, it is highly likely that NEA 5 mg has contraceptive properties if taken daily.
Continue to: Elagolix...
Elagolix
Elagolix is FDA approved for the treatment of pelvic pain caused by endometriosis. I reviewed the key studies resulting in FDA approval in the November 2018 issue of
In the Elaris Endometriosis-I study, 872 women with endometriosis and pelvic pain were randomly assigned to treatment with 1 of 2 doses of elagolix (high-dose [200 mg twice daily] and low-dose [150 mg once daily]) or placebo.11 After 3 months of therapy, a clinically meaningful reduction in dysmenorrhea pain was reported by 76%, 46%, and 20% of the women in the high-dose elagolix, low-dose elagolix, and placebo groups, respectively (P<.001 for comparisons of elagolix to placebo). After 3 months of therapy, a clinically meaningful reduction in nonmenstrual pain or decreased or stable use of rescue analgesics was reported by 55%, 50%, and 37% of the women in the high-dose elagolix, low-dose elagolix, and placebo groups, respectively (P<.01 low-dose elagolix vs placebo and P<.001 high-dose elagolix vs placebo).
Hot flashes that were severe enough to be reported as an adverse event by the study participants were reported by 42%, 24%, and 7% of the women in the high-dose elagolix, low-dose elagolix, and placebo groups. Bone density was measured at baseline and after 6 months of treatment. Lumbar bone density changes were -2.61%, -0.32%, and +0.47% and hip femoral neck bone density changes were -1.89%, -0.39%, and +0.02% in the high-dose elagolix, low-dose elagolix, and placebo groups, respectively.
Another large clinical trial of elagolix for the treatment of pelvic pain caused by endometriosis, Elaris EM-II, involving 817 women, produced results very similar to those reported in Elaris EM-I. The elagolix continuation studies, Elaris EM-III and -IV, demonstrated efficacy and safety of elagolix through 12 months of treatment.12
In my 2018 review,10 I noted that elagolix dose adjustment can be utilized to attempt to achieve maximal pain relief with minimal vasomotor symptoms. Elagolix at 200 mg twice daily produces a mean estradiol concentration of 12 pg/mL, whereas elagolix at 150 mg daily resulted in a mean estradiol concentration of 41 pg/mL.13 The estrogen threshold hypothesis posits that in women with endometriosis a stable estradiol concentration of 20 to 30 pg/mL is often associated with decreased pain and fewer vasomotor events.14 To achieve the target estradiol range of 20 to 30 pg/mL, I often initiate elagolix treatment with 200 mg twice daily. This enables a rapid onset of amenorrhea and a reduction in pelvic pain. Once amenorrhea has been achieved and a decrease in pelvic pain has occurred, I adjust the dose downward to 200 mg twice daily on even calendar days of each month and 200 mg once daily on odd calendar days each month. Some women will have continued pain relief and amenorrhea when the dose is further decreased to 200 mg once daily. If bothersome bleeding recurs and/or pain symptoms increase in severity, the dose can be increased to 200 mg twice daily or an alternating regimen of 200 mg twice daily and 200 mg once daily, every 2 days. An alternative to dose adjustment is to combine elagolix with NEA, which can reduce the severity of hot flashes and reduce bone loss caused by hypoestrogenism.15,16
Health insurers and pharmacy benefits managers may require a prior authorization before approving and dispensing elagolix. The prior authorization process can be burdensome for clinicians, consuming limited healthcare resources, contributing to burnout and frustrating patients.17 Elagolix is less expensive than depot-leuprolide acetate and nafarelin nasal spray and somewhat more expensive than a goserelin implant.18,19
Elagolix is not approved as a contraceptive. In the Elaris EM-I and -II trials women were advised to use 2 forms of contraception, although pregnancies did occur. There were 6 pregnancies among 475 women taking elagolix 150 mg daily and 2 pregnancies among 477 women taking elagolix 200 mg twice daily.20 Women taking elagolix should be advised to use a contraceptive, but not an estrogen-progestin contraceptive.
Continue to: Do not use opioids to treat chronic pelvic pain caused by endometriosis...
Do not use opioids to treat chronic pelvic pain caused by endometriosis
One of the greatest public health tragedies of our era is the opioid misuse epidemic. Hundreds of thousands of deaths have been caused by opioid misuse. The Centers for Disease Control and Prevention reported that for the 12-month period ending in May 2020, there were 81,000 opioid-related deaths, the greatest number ever reported in a 12-month period.21 Many authorities believe that in the United States opioid medications have been over-prescribed, contributing to the opioid misuse epidemic. There is little evidence that chronic pelvic pain is optimally managed by chronic treatment with an opioid.22,23 Prescribing opioids to vulnerable individuals to treat chronic pelvic pain may result in opioid dependency and adversely affect the patient’s health. It is best to pledge not to prescribe an opioid medication for a woman with chronic pelvic pain caused by endometriosis. In situations when pelvic pain is difficult to control with hormonal therapy and nonopioid pain medications, referral to a specialty pain practice may be warranted.
Post–conservative surgery hormone treatment reduces pelvic pain recurrence
In a meta-analysis of 14 studies that reported on endometriosis recurrence rates following conservative surgery, recurrence (defined as recurrent pelvic pain or an imaging study showing recurrent endometriosis) was significantly reduced with the use of hormone treatment compared with expectant management or placebo treatment.24 The postoperative relative risk of endometriosis recurrence was reduced by 83% with progestin treatment, 64% with estrogen-progestin contraceptive treatment, and 38% with GnRH analogue treatment. Overall, the number of patients that needed to be treated to prevent one endometriosis recurrence was 10, assuming a recurrence rate of 25% in the placebo treatment or expectant management groups.
For women with pelvic pain caused by endometriosis who develop a recurrence of pelvic pain while on postoperative hormone treatment, it is important for the prescribing clinician to be flexible and consider changing the hormone regimen. For example, if a postoperative patient is treated with a continuous estrogen-progestin contraceptive and develops recurrent pain, I will stop the contraceptive and initiate treatment with either NEA or elagolix.
Capitalize on opportunities to improve the medical care of women with endometriosis
Early diagnosis of endometriosis can be facilitated by recognizing that the condition is a common cause of moderate to severe dysmenorrhea. In 5 studies involving 1,187 women, the mean length of time from onset of pelvic pain symptoms to diagnosis of endometriosis was 8.6 years.25 If a woman with pelvic pain caused by endometriosis has not had sufficient pain relief with one brand of continuous estrogen-progestin contraceptive, it is best not to prescribe an alternative brand but rather to switch to a progestin-only treatment or a GnRH antagonist. If plan A is not working, move expeditiously to plan B. ●
- Aygestin [package insert]. Barr Laboratories: Pomona, NY; 2007.
- Kaser DJ, Missmer SA, Berry KF, et al. Use of norethindrone acetate alone for postoperative suppression of endometriosis symptoms. J Pediatr Adolesc Gynecol. 2012;25:105-108.
- Muneyyirci-Delale O, Karacan M. Effect of norethindrone acetate in the treatment of symptomatic endometriosis. Int J Fertil Womens Med. 1998;43:24-27.
- Muneyyirci-Delale O, Anopa J, Charles C, et al. Medical management of recurrent endometrioma with long-term norethindrone acetate. Int J Women Health. 2012;4:149-154.
- Morotti M, Venturini PL, Biscaldi E, et al. Efficacy and acceptability of long-term norethindrone acetate for the treatment of rectovaginal endometriosis. Eur J Obstet Gynecol Repro Biol. 2017;213:4-10.
- Brady PC, Missmer SA, Laufer MR. Hepatic adenomas in adolescents and young women with endometriosis treated with norethindrone acetate. J Pediatr Adolesc Gynecol. 2017;30:422-424.
- Choudhary NS, Bodh V, Chaudhari S, et al. Norethisterone related drug induced liver injury: a series of 3 cases. J Clin Exp Hepatol. 2017;7:266- 268.
- Perez-Mera RA, Shields CE. Jaundice associated with norethindrone acetate therapy. N Engl J Med. 1962;267:1137-1138.
- Camila [package insert]. Mayne Pharma Inc: Greenville, NC; 2018.
- Barbieri RL. Elagolix: a new treatment for pelvic pain caused by endometriosis. OBG Manag. 2018;30:10,12-14, 20.
- Taylor HS, Giudice LC, Lessey BA, et al. Treatment of endometriosis-associated pain with elagolix, an oral GnRH antagonist. N Engl J Med. 2017;377:28-40.
- Surrey E, Taylor HS, Giudice L, et al. Long-term outcomes of elagolix in women with endometriosis: results from two extension studies. Obstet Gynecol. 2018;132:147-160.
- Orilissa [package insert]. AbbVie Inc; North Chicago, IL; 2018.
- Barbieri RL. Hormonal treatment of endometriosis: the estrogen threshold hypothesis. Am J Obstet Gynecol. 1992;166:740-745.
- Hornstein MD, Surrey ES, Weisberg GW, et al. Leuprolide acetate depot and hormonal add-back in endometriosis: a 12-month study. Lupron Add-Back Study Group. Obstet Gynecol. 1998;91:16-24.
- Gallagher JS, Missmer SA, Hornstein MD, et al. Long-term effects of gonadotropin-releasing hormone agonists and add-back in adolescent endometriosis. J Pediatr Adolesc Gynecol. 2018;31:376- 381.
- Miller A, Shor R, Waites T, et al. Prior authorization reform for better patient care. J Am Coll Cardiol. 2018;71:1937-1939.
- Depot-leuprolide acetate. Good Rx website. https://www.goodrx.com/. Accessed January 22, 2021.
- Goserelin. Good Rx website. https://www .goodrx.com/. Accessed January 22, 2021
- Taylor HS, Giudice LC, Lessey BA, et al. Treatment of endometriosis-associated pain with elagolix, an oral GnRH antagonist. N Engl J Med. 2017;377:28-40.
- Centers for Disease Control and Prevention. Overdose deaths accelerating during COVID19. https://www.cdc.gov/media/releases/2020 /p1218-overdose-deaths-covid-19.html. Reviewed December 18, 2020. Accessed March 24, 2021.
- Till SR, As-Sanie S. 3 cases of chronic pelvic pain with nonsurgical, nonopioid therapies. OBG Manag. 2018;30:41-48.
- Steele A. Opioid use and depression in chronic pelvic pain. Obstet Gynecol Clin North Am. 2014;41:491-501.
- Zakhari A, Delpero E, McKeown S, et al. Endometriosis recurrence following post-operative hormonal suppression: a systematic review and meta-analysis. Hum Reprod Update. 2021;27:96- 107.
- Barbieri RL. Why are there delays in the diagnosis of endometriosis? OBG Manag. 2017;29:8, 10-11, 16.
- Aygestin [package insert]. Barr Laboratories: Pomona, NY; 2007.
- Kaser DJ, Missmer SA, Berry KF, et al. Use of norethindrone acetate alone for postoperative suppression of endometriosis symptoms. J Pediatr Adolesc Gynecol. 2012;25:105-108.
- Muneyyirci-Delale O, Karacan M. Effect of norethindrone acetate in the treatment of symptomatic endometriosis. Int J Fertil Womens Med. 1998;43:24-27.
- Muneyyirci-Delale O, Anopa J, Charles C, et al. Medical management of recurrent endometrioma with long-term norethindrone acetate. Int J Women Health. 2012;4:149-154.
- Morotti M, Venturini PL, Biscaldi E, et al. Efficacy and acceptability of long-term norethindrone acetate for the treatment of rectovaginal endometriosis. Eur J Obstet Gynecol Repro Biol. 2017;213:4-10.
- Brady PC, Missmer SA, Laufer MR. Hepatic adenomas in adolescents and young women with endometriosis treated with norethindrone acetate. J Pediatr Adolesc Gynecol. 2017;30:422-424.
- Choudhary NS, Bodh V, Chaudhari S, et al. Norethisterone related drug induced liver injury: a series of 3 cases. J Clin Exp Hepatol. 2017;7:266- 268.
- Perez-Mera RA, Shields CE. Jaundice associated with norethindrone acetate therapy. N Engl J Med. 1962;267:1137-1138.
- Camila [package insert]. Mayne Pharma Inc: Greenville, NC; 2018.
- Barbieri RL. Elagolix: a new treatment for pelvic pain caused by endometriosis. OBG Manag. 2018;30:10,12-14, 20.
- Taylor HS, Giudice LC, Lessey BA, et al. Treatment of endometriosis-associated pain with elagolix, an oral GnRH antagonist. N Engl J Med. 2017;377:28-40.
- Surrey E, Taylor HS, Giudice L, et al. Long-term outcomes of elagolix in women with endometriosis: results from two extension studies. Obstet Gynecol. 2018;132:147-160.
- Orilissa [package insert]. AbbVie Inc; North Chicago, IL; 2018.
- Barbieri RL. Hormonal treatment of endometriosis: the estrogen threshold hypothesis. Am J Obstet Gynecol. 1992;166:740-745.
- Hornstein MD, Surrey ES, Weisberg GW, et al. Leuprolide acetate depot and hormonal add-back in endometriosis: a 12-month study. Lupron Add-Back Study Group. Obstet Gynecol. 1998;91:16-24.
- Gallagher JS, Missmer SA, Hornstein MD, et al. Long-term effects of gonadotropin-releasing hormone agonists and add-back in adolescent endometriosis. J Pediatr Adolesc Gynecol. 2018;31:376- 381.
- Miller A, Shor R, Waites T, et al. Prior authorization reform for better patient care. J Am Coll Cardiol. 2018;71:1937-1939.
- Depot-leuprolide acetate. Good Rx website. https://www.goodrx.com/. Accessed January 22, 2021.
- Goserelin. Good Rx website. https://www .goodrx.com/. Accessed January 22, 2021
- Taylor HS, Giudice LC, Lessey BA, et al. Treatment of endometriosis-associated pain with elagolix, an oral GnRH antagonist. N Engl J Med. 2017;377:28-40.
- Centers for Disease Control and Prevention. Overdose deaths accelerating during COVID19. https://www.cdc.gov/media/releases/2020 /p1218-overdose-deaths-covid-19.html. Reviewed December 18, 2020. Accessed March 24, 2021.
- Till SR, As-Sanie S. 3 cases of chronic pelvic pain with nonsurgical, nonopioid therapies. OBG Manag. 2018;30:41-48.
- Steele A. Opioid use and depression in chronic pelvic pain. Obstet Gynecol Clin North Am. 2014;41:491-501.
- Zakhari A, Delpero E, McKeown S, et al. Endometriosis recurrence following post-operative hormonal suppression: a systematic review and meta-analysis. Hum Reprod Update. 2021;27:96- 107.
- Barbieri RL. Why are there delays in the diagnosis of endometriosis? OBG Manag. 2017;29:8, 10-11, 16.
Managing the second stage of labor: An evidence-based approach
CASE Woman in second stage with prolonged pushing
Ms. J. is an 18-year-old woman (G1P0) at 39 weeks’ gestation whose cervix is completely dilated; she has been actively pushing for 60 minutes. The estimated fetal weight is 8 lb, and electronic fetal monitoring shows a Category I fetal heart rate (FHR) tracing. The presenting part remains at 0 station and occiput transverse despite great pushing effort.
After another hour of active pushing, the FHR becomes Category II with repetitive variable decelerations. During the third hour of the second stage, Ms. J. is diagnosed with chorioamnionitis and the fetus remains at 0 station. She undergoes a primary cesarean delivery (CD) complicated by bilateral lower uterine extensions and postpartum hemorrhage. The birth weight was 4,100 g, and 5- and 10-minute Apgar scores were 4 and 8, respectively. The umbilical cord arterial pH was 7.03.
Ms. J. and her baby were discharged home on postoperative day 4.
In 2014, the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine jointly released a document, “Safe prevention of the primary cesarean delivery,” in response to the sharp rise in cesarean births from 1996 to 2011.1 It described management strategies to safely reduce the most common indications for a primary CD in nulliparous women. Specifically, it recommended that the second stage of labor—defined as the interval from complete cervical dilation through delivery of the neonate—may be prolonged, as “longer durations may be appropriate on an individualized basis (eg, with the use of epidural analgesia or with fetal malposition) as long as progress is being documented.”1
A prolonged second stage was defined as 3 hours of pushing in nulliparous women and 2 hours in multiparous women, with 1 additional hour (or longer) in those receiving epidural analgesia. Indeed, the primary CD rate decreased slightly to 21.7% in 2018, down from 21.9% in 2017.2 More recent evidence, however, has shown an increase in maternal and neonatal morbidity with prolonged second stage.3-8
Efforts to manage the second stage from an evidence-based perspective are critical to balance the desired outcome of a safe vaginal delivery against the risks of prolonged second stage and operative vaginal delivery or CD.
Perspectives on the “ideal” labor duration
It is important to consider the historical context that led to the 2014 change in recommendations for duration of the second stage.9 In 1955, Dr. Emanuel Friedman published a prospective observational study of 622 consecutive primigravid parturients at term, of which 500 were included in the analysis that led to the graphicostatistical labor curve, or the well-known “Friedman’s curve.”10 The mean duration of the second stage was 0.95 hour. The statistical maximum for “ideal labor” for the second stage was set at 2 hours, with an additional hour allotted for patients receiving epidural analgesia.
In 2010, Zhang and colleagues published contemporary labor curves using data from the Consortium on Safe Labor, a multicenter retrospective observational study of 62,415 parturients.11 Among more than 25,000 nulliparous women, the median duration (95th percentile) of the second stage in hours was 1.1 (3.6), respectively. Notably, this analysis included only women with a spontaneous vaginal delivery and normal neonatal outcome.
Prior to the publication of the “Safe prevention of primary cesarean delivery,” multiple investigations examined the relationship between the duration of the second stage and adverse maternal and neonatal outcomes, and the findings have been inconsistent.12-15
For example, Cheng and colleagues noted increased maternal complications that included postpartum hemorrhage, third- and fourth-degree perineal lacerations, and chorioamnionitis, but not neonatal morbidity, with each increasing hour within the second stage.12 By contrast, a large, population-based cohort study among low-risk women showed an increase in low 5-minute Apgar scores, admission to the neonatal intensive care unit (NICU), and composite perinatal morbidity with prolonged second stage.15 Furthermore, a secondary analysis of the Pushing Early or Pushing Late with Epidural (PEOPLE) trial showed that the chances of a vaginal delivery with a newborn without signs of asphyxia decreased significantly every hour after the first hour, and the risk of postpartum hemorrhage and intrapartum fever increased significantly after 2 hours of pushing.14
While these findings may represent the risks inherent with the intervention of operative delivery and not the duration of second stage of labor per se, one could posit that if the intervention were initiated earlier, could it prevent or at least reduce maternal and neonatal morbidity?
Continue to: Factors to assess and monitor in the second stage...
Factors to assess and monitor in the second stage
When assessing progress in the second stage of labor, consider:
- maternal factors
- fetal/neonatal factors, and
- modifiable factors.
Maternal factors that influence the second stage of labor include parity, body mass index (BMI), age, and clinical pelvimetry.11,16-19 Fetal/neonatal factors that impact the second stage include the estimated fetal weight, fetal presentation (cephalic, face, and so on), position, and station, as well as the FHR Category.20, 21 Factors that can be modified in the second stage include the effect of epidural analgesia (turning it down to reduce motor blockade while maintaining sensory pain relief so that patients feel the “urge” to push), maternal pushing position and technique, the presence of maternal support person(s), manual rotation for a fetal position that is not optimal, immediate versus delayed pushing, and prevention of perineal tears.22-32 Interestingly, epidural analgesia, parity, birth weight, and station at complete dilation predicted second stage duration but accounted for only 25% of the variability in second stage length, leaving 75% of the variance unexplained.16
A specific absolute maximum length of time spent in the second stage of labor beyond which all women should undergo operative delivery has not been identified.1 Therefore, maternal, fetal/neonatal, and modifiable factors need to be critically assessed and continually monitored to determine whether a prolonged second stage or an operative delivery is warranted to prevent or minimize adverse maternal and neonatal outcomes.
Maternal factors
Maternal age correlates directly with the length of the second stage. That is, the length of the second stage increases with increasing age.17
Multiparous women have a shorter length of the second stage, regardless of epidural analgesia, compared with nulliparous women.11 In the Consortium for Safe Labor, multiparous women had a significantly shorter median second stage compared with nulliparous women.11
In adjusted analyses, maternal obesity was associated with an increased risk for CD, with the risk of CD more than 3 times greater in women with a BMI higher than 40 kg/m2 compared with those who had a BMI less than 25 kg/m2.18 There were no significant differences in the length of the second stage of labor by BMI catgeories.19
Fetal factors
Birth weight greater than 4,000 g was associated with an increased risk for arrest of descent during the second stage.33
Persistent fetal occiput posterior or transverse position may impact the duration of the second stage. A retrospective cohort study in women who underwent a trial of manual rotation compared with expectant management during the second stage of labor with the fetus in occiput posterior or occiput transverse position found that women with manual rotation were less likely to have a CD, severe perineal laceration, postpartum hemorrhage, and chorioamnionitis. However, an increased risk of cervical laceration was associated with manual rotation.20
Regarding FHR status, FHR abnormalities occurred in 91% of second stage labor patterns, with Category II being the most common.21 The fetal status should remain reassuring to allow for continuation of the second stage.
Continue to: Epidural analgesia...
Epidural analgesia
About 60% of women receive neuraxial analgesia in the United States,22 although rates vary widely across different populations. A Cochrane review showed no difference in the duration of the second stage among women who had early versus late initiation of epidural analgesia in labor.23 Epidural analgesia has no impact on the risk of CD; however, women with epidural analgesia experienced more hypotension, motor blockade, fever, and urinary retention.24
One management practice has been to discontinue epidural analgesia to allow resumption of sensory and motor nerve function. Another Cochrane systematic review found no difference in mode of delivery or neonatal outcomes.25 Rather than discontinuing epidural analgesia, which results in a profound increase in inadequate pain relief, one may consider titrating the dose with joint patient decision-making to allow for greater motor capability while maintaining adequate analgesia.34
Immediate vs delayed pushing
The 2 most common approaches to managing the second stage were either to initiate pushing with contractions once complete dilation occurred (immediate pushing) or to allow for a rest period in which the fetus passively rotated and descended while conserving a woman’s energy for pushing efforts (delayed pushing, laboring down, or passive descent). Since the publication of “Safe prevention of primary cesarean delivery,” however, studies have shown a concerning association between maternal and neonatal complications and prolonged second stage (which may occur with delayed pushing).3-8,35 An observational study of nearly 44,000 nulliparous women without epidural analgesia found that prolonged second stage was associated with increased chorioamnionitis, third- and fourth-degree lacerations, neonatal sepsis, neonatal asphyxia, and perinatal mortality.35
A pragmatic multicenter randomized clinical trial on the optimal management of second stage of labor across the United States recently was conducted.7 More than 2,000 nulliparous women at term in spontaneous or induced labor with epidural analgesia were randomly assigned at complete dilation to immediate pushing or delayed pushing (1 hour after complete dilation). There was no difference in the rate of vaginal delivery. The rate of postpartum hemorrhage was significantly lower among women in the immediate-pushing group compared with the delayed-pushing group (2.3% vs 4.0%, respectively; relative risk [RR], 0.6; 95% confidence interval [CI], 0.3–0.9; P = .03). Furthermore, rates of chorioamnionitis were significantly lower among women in the immediate-pushing group compared with the delayed-pushing group (6.7% vs 9.1%, respectively; RR, 0.70; 95% CI, 0.66–0.90; P = .005). No significant difference occurred in the composite outcome of neonatal morbidity between the groups. However neonatal acidemia (umbilical cord arterial pH <7.1) and confirmed or suspected sepsis were significantly increased in the delayed-pushing group.
The evidence supports active pushing at the start of the second stage. Women who consider delayed pushing should be informed that delayed pushing has not been shown to increase the likelihood of vaginal birth and that it is associated with increased risks of infection, hemorrhage, and neonatal acidemia.36
Maternal pushing position and technique
Spontaneous pushing (in which women are free to follow their instincts and generally push 3 to 5 times per contraction) versus directed pushing (women are encouraged to take a deep breath at the beginning of a contraction then hold it and bear down throughout the contraction) demonstrated no clear difference in duration of the second stage, perineal laceration, episiotomy, time spent pushing, or number of women with spontaneous vaginal birth. There was no difference in 5-minute Apgar score less than 7 or admission to the NICU.26
With regard to maternal positioning during the second stage, a Cochrane systematic review found benefits for upright posture, including a very small reduction in the duration of the second stage, reduction in episiotomy rates, and reduction in assisted deliveries.37 There was an increased risk of blood loss greater than 500 mL and possibly an increased risk in second-degree tears.37 Compared with women allocated to lying down, women in the upright position during the second stage with epidural analgesia had significantly fewer spontaneous vaginal births. There was no difference in operative vaginal delivery, obstetric anal sphincter injury (OASI), infant Apgar score of less than 4 at 5 minutes, and maternal fecal incontinence at 1 year.28
Continue to: Maternal support person...
Maternal support person
Continuous support during labor may improve outcomes for women and infants, including increased spontaneous vaginal birth, shorter duration of labor, and decreased cesarean birth.29 In a randomized trial of 412 healthy nulliparous women, women in labor were assigned to either a support group that received continuous support from a doula or an observed group that was monitored by an inconspicuous observer. Continuous labor support significantly reduced the rate of CDs and forceps deliveries.30,36 Indeed, during the COVID-19 pandemic, doulas have found innovative ways to continue to provide this essential support through virtual health.38
Prevention of perineal tears
Evidence suggests that warm compresses, and massage, may reduce third- and fourth-degree perineal tears.31 A meta-analysis of observational studies showed a significant reduction in the risk of OASI.32
Second stage steps: Recap
Throughout the second stage of labor, the decision to continue with expectant management or intervene with either an operative vaginal delivery or a CD is complex and requires consistent assessment and integration of multiple factors. An evidence-based approach to second stage labor management includes active pushing that is either Valsalva pushing or spontaneous, coached or uncoached, but most importantly, at the start of the second stage when a patient reaches complete dilation. Reassessment should occur at regular intervals to determine progress, after ensuring maternal and fetal well-being.
If there has been no advancement in station, an attempt at manual rotation or titration of epidural analgesia should be considered. Importantly, fetal descent with adequate pushing should be demonstrated throughout the second stage.
Additional considerations that improve outcomes include warm compresses or perineal massage to prevent third- and fourth-degree tears and the presence of a continuous support person to reduce the risk for an operative delivery.
Delivery should be expected within 2 hours for multiparous women and 3 hours for nulliparous women in the second stage. Prolonging the second stage beyond these thresholds should be individualized and occur only in the setting of assured maternal and fetal well-being.
CASE An alternative management strategy
Despite Ms. J.’s great active pushing effort for 60 minutes, the presenting part remains at 0 station and occiput transverse. Ms. J. is counseled regarding the risks and benefits of an attempt at manual rotation of the fetal head, and she wishes to proceed. The fetal position remains occiput transverse.
After another hour of active pushing, the FHR becomes Category II with repetitive variable decelerations. At this time, Ms. J. is informed that there has been no descent, and she is counseled on the risks and benefits of continued pushing versus CD. Through shared decision-making, she consents to a CD. She undergoes a primary CD without complication. The birth weight was 4,100 g, and 5- and 10-minute Apgar scores were 8 and 9, respectively. The umbilical cord arterial pH was 7.13.
Ms. J. and her baby were discharged home on postoperative day 4. ●
- American College of Obstetricians and Gynecologists; Society for Maternal-Fetal Medicine; Caughey AB, Cahill AG, Guise JM, et al. Safe prevention of the primary cesarean delivery. Am J Obstet Gynecol. 2014;210:179-193. doi:10.1016/j.ajog.2014.01.026.
- Martin JA, Hamilton BE, Osterman MJ, et al. Births: final data for 2018. Natl Vital Stat Rep. 2019;68:1-47.
- Grobman WA, Bailit J, Lai Y, et al; Eunice Kennedy Schriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Association of the duration of active pushing with obstetric outcomes. Obstet Gynecol. 2016;127:667-673. doi:10.1097/aog.0000000000001354.
- Gimovsky AC, Berghella V. Randomized controlled trial of prolonged second stage: extending the time limit vs usual guidelines. Am J Obstet Gynecol. 2016;214:361.e1-6. doi:10.1016/j.ajog.2015.12.042.
- Rosenbloom JI, Stout MJ, Tuuli MG, et al. New labor management guidelines and changes in cesarean delivery patterns. Am J Obstet Gynecol. 2017;217:689.e1-689.e8. doi:10.1016/j.ajog.2017.10.007.
- Grantz KL, Sundaram R, Ma L, et al. Reassessing the duration of the second stage of labor in relation to maternal and neonatal morbidity. Obstet Gynecol. 2018;131:345-353. doi:10.1097/aog.0000000000002431.
- Cahill AG, Srinivas SK, Tita AT, et al. Effect of immediate vs delayed pushing on rates of spontaneous vaginal delivery among nulliparous women receiving neuraxial analgesia: a randomized clinical trial. JAMA. 2018;320:1444-1454. doi:10.1001/jama.2018.13986.
- Zipori Y, Grunwald O, Ginsberg Y, et al. The impact of extending the second stage of labor to prevent primary cesarean delivery on maternal and neonatal outcomes. Am J Obstet Gynecol. 2019;220:191.e1-191.e7. doi:10.1016/j.ajog.2018.10.028.
- Leveno KJ, Nelson DB, McIntire DD. Second-stage labor: how long is too long? Am J Obstet Gynecol. 2016;214:484-489. doi:10.1016/j.ajog.2015.10.926.
- Friedman EA. Primigravid labor; a graphicostatistical analysis. Obstet Gynecol. 1955;6:567-589. doi:10.1097/00006250-195512000-00001.
- Zhang J, Landy HJ, Branch DW, et al. Contemporary patterns of spontaneous labor with normal neonatal outcomes. Obstet Gynecol. 2010;116:1281-1287. doi:10.1097/AOG.0b013e3181fdef6e.
- Cheng YW, Hopkins LM, Caughey AB. How long is too long: does a prolonged second stage of labor in nulliparous women affect maternal and neonatal outcomes? Am J Obstet Gynecol. 2004;191:933-938. doi:10.1016/j.ajog.2004.05.044.
- Rouse DJ, Weiner SJ, Bloom SL, et al. Second-stage labor duration in nulliparous women: relationship to maternal and perinatal outcomes. Am J Obstet Gynecol. 2009;201:357.e1-7. doi:10.1016/j.ajog.2009.08.003.
- Le Ray C, Audibert F, Goffinet F, et al. When to stop pushing: effects of duration of second-stage expulsion efforts on maternal and neonatal outcomes in nulliparous women with epidural analgesia. Am J Obstet Gynecol. 2009;201:361.e1-7. doi:10.1016/j.ajog.2009.08.002.
- Allen VM, Baskett TF, O’Connell CM, et al. Maternal and perinatal outcomes with increasing duration of the second stage of labor. Obstet Gynecol. 2009;113:1248-1258. doi:10.1097/AOG.0b013e3181a722d6.
- Piper JM, Bolling DR, Newton ER. The second stage of labor: factors influencing duration. Am J Obstet Gynecol. 1991;165(4 pt 1):976-979. doi:10.1016/0002-9378(91)90452-w.
- Zaki MN, Hibbard JU, Kominiarek MA. Contemporary labor patterns and maternal age. Obstet Gynecol. 2013;122:1018-1024. doi:10.1097/AOG.0b013e3182a9c92c.
- Kominiarek MA, Vanveldhuisen P, Hibbard J, et al; Consortium on Safe Labor. The maternal body mass index: a strong association with delivery route. Am J Obstet Gynecol. 2010;203:264.e1-7. doi:10.1016/j.ajog.2010.06.024.
- Kominiarek MA, Zhang J, Vanveldhuisen P, et al. Contemporary labor patterns: the impact of maternal body mass index. Am J Obstet Gynecol. 2011;205:244.e1-8. doi:10.1016/j.ajog.2011.06.014.
- Shaffer BL, Cheng YW, Vargas JE, et al. Manual rotation to reduce caesarean delivery in persistent occiput posterior or transverse position. J Matern Fetal Neonatal Med. 2011;24:65-72. doi:10.3109/14767051003710276.
- Krebs HB, Petres RE, Dunn LJ. Intrapartum fetal heart rate monitoring. V. Fetal heart rate patterns in the second stage of labor. Am J Obstet Gynecol. 1981;140:435-439. doi:10.1016/0002-9378(81)90041-7.
- Grant EN, Tao W, Craig M, et al. Neuraxial analgesia effects on labour progression: facts, fallacies, uncertainties and the future. BJOG. 2015;122:288-293. doi:10.1111/1471-0528.12966.
- Sng BL, Leong WL, Zeng Y, et al. Early versus late initiation of epidural analgesia for labour. Cochrane Database Syst Rev. 2014;(10):CD007238. doi:10.1002/14651858.CD007238.pub2.
- Anim-Somuah M, Smyth RM, Cyna AM, et al. Epidural versus non-epidural or no analgesia for pain management in labour. Cochrane Database Syst Rev. 2018;5(5):CD000331. doi:10.1002/14651858.CD000331.pub4.
- Torvaldsen S, Roberts CL, Bell JC, et al. Discontinuation of epidural analgesia late in labour for reducing the adverse delivery outcomes associated with epidural analgesia. Cochrane Database Syst Rev. 2004;(4):CD004457. doi:10.1002/14651858.CD004457.pub2.
- Lemos A, Amorim MM, Dornelas de Andrade A, et al. Pushing/bearing down methods for the second stage of labour. Cochrane Database Syst Rev. 2017;3(3):CD009124. doi:10.1002/14651858.CD009124.pub3.
- Prins M, Boxem J, Lucas C, et al. Effect of spontaneous pushing versus Valsalva pushing in the second stage of labour on mother and fetus: a systematic review of randomised trials. BJOG. 2011;118:662-670. doi:10.1111/j.1471-0528.2011 .02910.x.
- Epidural and Position Trial Collaborative Group. Upright versus lying down position in second stage of labour in nulliparous women with low dose epidural: BUMPES randomised controlled trial. BMJ. 2017;359:j4471. doi:10.1136/bmj.j4471.
- Bohren MA, Hofmeyr GJ, Sakala C, et al. Continuous support for women during childbirth. Cochrane Database Syst Rev. 2017;7(7):CD003766. doi:10.1002/14651858.CD003766.pub6.
- Kennell J, Klaus M, McGrath S, et al. Continuous emotional support during labor in a US hospital. A randomized controlled trial. JAMA. 1991;265:2197-2201.
- Aasheim V, Nilsen AB, Reinar LM, et al. Perineal techniques during the second stage of labour for reducing perineal trauma. Cochrane Database Syst Rev. 2017;6(6):CD006672. doi:10.1002/14651858.CD006672.pub3.
- Bulchandani S, Watts E, Sucharitha A, et al. Manual perineal support at the time of childbirth: a systematic review and meta-analysis. BJOG. 2015;122:1157-1165. doi:10.1111/1471-0528.13431.
- Feinstein U, Sheiner E, Levy A, et al. Risk factors for arrest of descent during the second stage of labor. Int J Gynaecol Obstet. 2002;77:7-14. doi:10.1016/s0020-7292(02)00007-3.
- Cheng YW, Caughey AB. Defining and managing normal and abnormal second stage of labor. Obstet Gynecol Clin North Am. 2017;44:547-566. doi:10.1016/j.ogc.2017.08.009.
- Laughon SK, Berghella V, Reddy UM, et al. Neonatal and maternal outcomes with prolonged second stage of labor. Obstet Gynecol. 2014;124:57-67. doi:10.1097/aog.0000000000000278.
- American College of Obstetricians and Gynecologists. ACOG committee opinion no. 766: approaches to limit intervention during labor and birth. Obstet Gynecol. 2019;133:e164-e173. doi:10.1097/aog.0000000000003074.
- Gupta JK, Sood A, Hofmeyr GJ, et al. Position in the second stage of labour for women without epidural anaesthesia. Cochrane Database Syst Rev. 2017;5(5):CD002006. doi:10.1002/14651858.CD002006.pub4.
- Castaneda AN, Searcy JJ. Practising intimate labour: birth doulas respond during COVID-19. Anthropol Action. 2021;28:21-24. https://www.berghahnjournals.com/view/ journals/aia/28/1/aia280104.xml. Accessed February 8, 2021.
Dr. Ghartey is Assistant Professor, Maternal Fetal Medicine, Department of Women’s Health, Dell Medical School/ University of Texas at Austin.
Dr. Cahill is Professor, Maternal Fetal Medicine, Department of Women’s Health, Dell Medical School/ University of Texas at Austin.
The authors report no financial relationships relevant to this article.
Dr. Ghartey is Assistant Professor, Maternal Fetal Medicine, Department of Women’s Health, Dell Medical School/ University of Texas at Austin.
Dr. Cahill is Professor, Maternal Fetal Medicine, Department of Women’s Health, Dell Medical School/ University of Texas at Austin.
The authors report no financial relationships relevant to this article.
Dr. Ghartey is Assistant Professor, Maternal Fetal Medicine, Department of Women’s Health, Dell Medical School/ University of Texas at Austin.
Dr. Cahill is Professor, Maternal Fetal Medicine, Department of Women’s Health, Dell Medical School/ University of Texas at Austin.
The authors report no financial relationships relevant to this article.
CASE Woman in second stage with prolonged pushing
Ms. J. is an 18-year-old woman (G1P0) at 39 weeks’ gestation whose cervix is completely dilated; she has been actively pushing for 60 minutes. The estimated fetal weight is 8 lb, and electronic fetal monitoring shows a Category I fetal heart rate (FHR) tracing. The presenting part remains at 0 station and occiput transverse despite great pushing effort.
After another hour of active pushing, the FHR becomes Category II with repetitive variable decelerations. During the third hour of the second stage, Ms. J. is diagnosed with chorioamnionitis and the fetus remains at 0 station. She undergoes a primary cesarean delivery (CD) complicated by bilateral lower uterine extensions and postpartum hemorrhage. The birth weight was 4,100 g, and 5- and 10-minute Apgar scores were 4 and 8, respectively. The umbilical cord arterial pH was 7.03.
Ms. J. and her baby were discharged home on postoperative day 4.
In 2014, the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine jointly released a document, “Safe prevention of the primary cesarean delivery,” in response to the sharp rise in cesarean births from 1996 to 2011.1 It described management strategies to safely reduce the most common indications for a primary CD in nulliparous women. Specifically, it recommended that the second stage of labor—defined as the interval from complete cervical dilation through delivery of the neonate—may be prolonged, as “longer durations may be appropriate on an individualized basis (eg, with the use of epidural analgesia or with fetal malposition) as long as progress is being documented.”1
A prolonged second stage was defined as 3 hours of pushing in nulliparous women and 2 hours in multiparous women, with 1 additional hour (or longer) in those receiving epidural analgesia. Indeed, the primary CD rate decreased slightly to 21.7% in 2018, down from 21.9% in 2017.2 More recent evidence, however, has shown an increase in maternal and neonatal morbidity with prolonged second stage.3-8
Efforts to manage the second stage from an evidence-based perspective are critical to balance the desired outcome of a safe vaginal delivery against the risks of prolonged second stage and operative vaginal delivery or CD.
Perspectives on the “ideal” labor duration
It is important to consider the historical context that led to the 2014 change in recommendations for duration of the second stage.9 In 1955, Dr. Emanuel Friedman published a prospective observational study of 622 consecutive primigravid parturients at term, of which 500 were included in the analysis that led to the graphicostatistical labor curve, or the well-known “Friedman’s curve.”10 The mean duration of the second stage was 0.95 hour. The statistical maximum for “ideal labor” for the second stage was set at 2 hours, with an additional hour allotted for patients receiving epidural analgesia.
In 2010, Zhang and colleagues published contemporary labor curves using data from the Consortium on Safe Labor, a multicenter retrospective observational study of 62,415 parturients.11 Among more than 25,000 nulliparous women, the median duration (95th percentile) of the second stage in hours was 1.1 (3.6), respectively. Notably, this analysis included only women with a spontaneous vaginal delivery and normal neonatal outcome.
Prior to the publication of the “Safe prevention of primary cesarean delivery,” multiple investigations examined the relationship between the duration of the second stage and adverse maternal and neonatal outcomes, and the findings have been inconsistent.12-15
For example, Cheng and colleagues noted increased maternal complications that included postpartum hemorrhage, third- and fourth-degree perineal lacerations, and chorioamnionitis, but not neonatal morbidity, with each increasing hour within the second stage.12 By contrast, a large, population-based cohort study among low-risk women showed an increase in low 5-minute Apgar scores, admission to the neonatal intensive care unit (NICU), and composite perinatal morbidity with prolonged second stage.15 Furthermore, a secondary analysis of the Pushing Early or Pushing Late with Epidural (PEOPLE) trial showed that the chances of a vaginal delivery with a newborn without signs of asphyxia decreased significantly every hour after the first hour, and the risk of postpartum hemorrhage and intrapartum fever increased significantly after 2 hours of pushing.14
While these findings may represent the risks inherent with the intervention of operative delivery and not the duration of second stage of labor per se, one could posit that if the intervention were initiated earlier, could it prevent or at least reduce maternal and neonatal morbidity?
Continue to: Factors to assess and monitor in the second stage...
Factors to assess and monitor in the second stage
When assessing progress in the second stage of labor, consider:
- maternal factors
- fetal/neonatal factors, and
- modifiable factors.
Maternal factors that influence the second stage of labor include parity, body mass index (BMI), age, and clinical pelvimetry.11,16-19 Fetal/neonatal factors that impact the second stage include the estimated fetal weight, fetal presentation (cephalic, face, and so on), position, and station, as well as the FHR Category.20, 21 Factors that can be modified in the second stage include the effect of epidural analgesia (turning it down to reduce motor blockade while maintaining sensory pain relief so that patients feel the “urge” to push), maternal pushing position and technique, the presence of maternal support person(s), manual rotation for a fetal position that is not optimal, immediate versus delayed pushing, and prevention of perineal tears.22-32 Interestingly, epidural analgesia, parity, birth weight, and station at complete dilation predicted second stage duration but accounted for only 25% of the variability in second stage length, leaving 75% of the variance unexplained.16
A specific absolute maximum length of time spent in the second stage of labor beyond which all women should undergo operative delivery has not been identified.1 Therefore, maternal, fetal/neonatal, and modifiable factors need to be critically assessed and continually monitored to determine whether a prolonged second stage or an operative delivery is warranted to prevent or minimize adverse maternal and neonatal outcomes.
Maternal factors
Maternal age correlates directly with the length of the second stage. That is, the length of the second stage increases with increasing age.17
Multiparous women have a shorter length of the second stage, regardless of epidural analgesia, compared with nulliparous women.11 In the Consortium for Safe Labor, multiparous women had a significantly shorter median second stage compared with nulliparous women.11
In adjusted analyses, maternal obesity was associated with an increased risk for CD, with the risk of CD more than 3 times greater in women with a BMI higher than 40 kg/m2 compared with those who had a BMI less than 25 kg/m2.18 There were no significant differences in the length of the second stage of labor by BMI catgeories.19
Fetal factors
Birth weight greater than 4,000 g was associated with an increased risk for arrest of descent during the second stage.33
Persistent fetal occiput posterior or transverse position may impact the duration of the second stage. A retrospective cohort study in women who underwent a trial of manual rotation compared with expectant management during the second stage of labor with the fetus in occiput posterior or occiput transverse position found that women with manual rotation were less likely to have a CD, severe perineal laceration, postpartum hemorrhage, and chorioamnionitis. However, an increased risk of cervical laceration was associated with manual rotation.20
Regarding FHR status, FHR abnormalities occurred in 91% of second stage labor patterns, with Category II being the most common.21 The fetal status should remain reassuring to allow for continuation of the second stage.
Continue to: Epidural analgesia...
Epidural analgesia
About 60% of women receive neuraxial analgesia in the United States,22 although rates vary widely across different populations. A Cochrane review showed no difference in the duration of the second stage among women who had early versus late initiation of epidural analgesia in labor.23 Epidural analgesia has no impact on the risk of CD; however, women with epidural analgesia experienced more hypotension, motor blockade, fever, and urinary retention.24
One management practice has been to discontinue epidural analgesia to allow resumption of sensory and motor nerve function. Another Cochrane systematic review found no difference in mode of delivery or neonatal outcomes.25 Rather than discontinuing epidural analgesia, which results in a profound increase in inadequate pain relief, one may consider titrating the dose with joint patient decision-making to allow for greater motor capability while maintaining adequate analgesia.34
Immediate vs delayed pushing
The 2 most common approaches to managing the second stage were either to initiate pushing with contractions once complete dilation occurred (immediate pushing) or to allow for a rest period in which the fetus passively rotated and descended while conserving a woman’s energy for pushing efforts (delayed pushing, laboring down, or passive descent). Since the publication of “Safe prevention of primary cesarean delivery,” however, studies have shown a concerning association between maternal and neonatal complications and prolonged second stage (which may occur with delayed pushing).3-8,35 An observational study of nearly 44,000 nulliparous women without epidural analgesia found that prolonged second stage was associated with increased chorioamnionitis, third- and fourth-degree lacerations, neonatal sepsis, neonatal asphyxia, and perinatal mortality.35
A pragmatic multicenter randomized clinical trial on the optimal management of second stage of labor across the United States recently was conducted.7 More than 2,000 nulliparous women at term in spontaneous or induced labor with epidural analgesia were randomly assigned at complete dilation to immediate pushing or delayed pushing (1 hour after complete dilation). There was no difference in the rate of vaginal delivery. The rate of postpartum hemorrhage was significantly lower among women in the immediate-pushing group compared with the delayed-pushing group (2.3% vs 4.0%, respectively; relative risk [RR], 0.6; 95% confidence interval [CI], 0.3–0.9; P = .03). Furthermore, rates of chorioamnionitis were significantly lower among women in the immediate-pushing group compared with the delayed-pushing group (6.7% vs 9.1%, respectively; RR, 0.70; 95% CI, 0.66–0.90; P = .005). No significant difference occurred in the composite outcome of neonatal morbidity between the groups. However neonatal acidemia (umbilical cord arterial pH <7.1) and confirmed or suspected sepsis were significantly increased in the delayed-pushing group.
The evidence supports active pushing at the start of the second stage. Women who consider delayed pushing should be informed that delayed pushing has not been shown to increase the likelihood of vaginal birth and that it is associated with increased risks of infection, hemorrhage, and neonatal acidemia.36
Maternal pushing position and technique
Spontaneous pushing (in which women are free to follow their instincts and generally push 3 to 5 times per contraction) versus directed pushing (women are encouraged to take a deep breath at the beginning of a contraction then hold it and bear down throughout the contraction) demonstrated no clear difference in duration of the second stage, perineal laceration, episiotomy, time spent pushing, or number of women with spontaneous vaginal birth. There was no difference in 5-minute Apgar score less than 7 or admission to the NICU.26
With regard to maternal positioning during the second stage, a Cochrane systematic review found benefits for upright posture, including a very small reduction in the duration of the second stage, reduction in episiotomy rates, and reduction in assisted deliveries.37 There was an increased risk of blood loss greater than 500 mL and possibly an increased risk in second-degree tears.37 Compared with women allocated to lying down, women in the upright position during the second stage with epidural analgesia had significantly fewer spontaneous vaginal births. There was no difference in operative vaginal delivery, obstetric anal sphincter injury (OASI), infant Apgar score of less than 4 at 5 minutes, and maternal fecal incontinence at 1 year.28
Continue to: Maternal support person...
Maternal support person
Continuous support during labor may improve outcomes for women and infants, including increased spontaneous vaginal birth, shorter duration of labor, and decreased cesarean birth.29 In a randomized trial of 412 healthy nulliparous women, women in labor were assigned to either a support group that received continuous support from a doula or an observed group that was monitored by an inconspicuous observer. Continuous labor support significantly reduced the rate of CDs and forceps deliveries.30,36 Indeed, during the COVID-19 pandemic, doulas have found innovative ways to continue to provide this essential support through virtual health.38
Prevention of perineal tears
Evidence suggests that warm compresses, and massage, may reduce third- and fourth-degree perineal tears.31 A meta-analysis of observational studies showed a significant reduction in the risk of OASI.32
Second stage steps: Recap
Throughout the second stage of labor, the decision to continue with expectant management or intervene with either an operative vaginal delivery or a CD is complex and requires consistent assessment and integration of multiple factors. An evidence-based approach to second stage labor management includes active pushing that is either Valsalva pushing or spontaneous, coached or uncoached, but most importantly, at the start of the second stage when a patient reaches complete dilation. Reassessment should occur at regular intervals to determine progress, after ensuring maternal and fetal well-being.
If there has been no advancement in station, an attempt at manual rotation or titration of epidural analgesia should be considered. Importantly, fetal descent with adequate pushing should be demonstrated throughout the second stage.
Additional considerations that improve outcomes include warm compresses or perineal massage to prevent third- and fourth-degree tears and the presence of a continuous support person to reduce the risk for an operative delivery.
Delivery should be expected within 2 hours for multiparous women and 3 hours for nulliparous women in the second stage. Prolonging the second stage beyond these thresholds should be individualized and occur only in the setting of assured maternal and fetal well-being.
CASE An alternative management strategy
Despite Ms. J.’s great active pushing effort for 60 minutes, the presenting part remains at 0 station and occiput transverse. Ms. J. is counseled regarding the risks and benefits of an attempt at manual rotation of the fetal head, and she wishes to proceed. The fetal position remains occiput transverse.
After another hour of active pushing, the FHR becomes Category II with repetitive variable decelerations. At this time, Ms. J. is informed that there has been no descent, and she is counseled on the risks and benefits of continued pushing versus CD. Through shared decision-making, she consents to a CD. She undergoes a primary CD without complication. The birth weight was 4,100 g, and 5- and 10-minute Apgar scores were 8 and 9, respectively. The umbilical cord arterial pH was 7.13.
Ms. J. and her baby were discharged home on postoperative day 4. ●
CASE Woman in second stage with prolonged pushing
Ms. J. is an 18-year-old woman (G1P0) at 39 weeks’ gestation whose cervix is completely dilated; she has been actively pushing for 60 minutes. The estimated fetal weight is 8 lb, and electronic fetal monitoring shows a Category I fetal heart rate (FHR) tracing. The presenting part remains at 0 station and occiput transverse despite great pushing effort.
After another hour of active pushing, the FHR becomes Category II with repetitive variable decelerations. During the third hour of the second stage, Ms. J. is diagnosed with chorioamnionitis and the fetus remains at 0 station. She undergoes a primary cesarean delivery (CD) complicated by bilateral lower uterine extensions and postpartum hemorrhage. The birth weight was 4,100 g, and 5- and 10-minute Apgar scores were 4 and 8, respectively. The umbilical cord arterial pH was 7.03.
Ms. J. and her baby were discharged home on postoperative day 4.
In 2014, the American College of Obstetricians and Gynecologists and the Society for Maternal-Fetal Medicine jointly released a document, “Safe prevention of the primary cesarean delivery,” in response to the sharp rise in cesarean births from 1996 to 2011.1 It described management strategies to safely reduce the most common indications for a primary CD in nulliparous women. Specifically, it recommended that the second stage of labor—defined as the interval from complete cervical dilation through delivery of the neonate—may be prolonged, as “longer durations may be appropriate on an individualized basis (eg, with the use of epidural analgesia or with fetal malposition) as long as progress is being documented.”1
A prolonged second stage was defined as 3 hours of pushing in nulliparous women and 2 hours in multiparous women, with 1 additional hour (or longer) in those receiving epidural analgesia. Indeed, the primary CD rate decreased slightly to 21.7% in 2018, down from 21.9% in 2017.2 More recent evidence, however, has shown an increase in maternal and neonatal morbidity with prolonged second stage.3-8
Efforts to manage the second stage from an evidence-based perspective are critical to balance the desired outcome of a safe vaginal delivery against the risks of prolonged second stage and operative vaginal delivery or CD.
Perspectives on the “ideal” labor duration
It is important to consider the historical context that led to the 2014 change in recommendations for duration of the second stage.9 In 1955, Dr. Emanuel Friedman published a prospective observational study of 622 consecutive primigravid parturients at term, of which 500 were included in the analysis that led to the graphicostatistical labor curve, or the well-known “Friedman’s curve.”10 The mean duration of the second stage was 0.95 hour. The statistical maximum for “ideal labor” for the second stage was set at 2 hours, with an additional hour allotted for patients receiving epidural analgesia.
In 2010, Zhang and colleagues published contemporary labor curves using data from the Consortium on Safe Labor, a multicenter retrospective observational study of 62,415 parturients.11 Among more than 25,000 nulliparous women, the median duration (95th percentile) of the second stage in hours was 1.1 (3.6), respectively. Notably, this analysis included only women with a spontaneous vaginal delivery and normal neonatal outcome.
Prior to the publication of the “Safe prevention of primary cesarean delivery,” multiple investigations examined the relationship between the duration of the second stage and adverse maternal and neonatal outcomes, and the findings have been inconsistent.12-15
For example, Cheng and colleagues noted increased maternal complications that included postpartum hemorrhage, third- and fourth-degree perineal lacerations, and chorioamnionitis, but not neonatal morbidity, with each increasing hour within the second stage.12 By contrast, a large, population-based cohort study among low-risk women showed an increase in low 5-minute Apgar scores, admission to the neonatal intensive care unit (NICU), and composite perinatal morbidity with prolonged second stage.15 Furthermore, a secondary analysis of the Pushing Early or Pushing Late with Epidural (PEOPLE) trial showed that the chances of a vaginal delivery with a newborn without signs of asphyxia decreased significantly every hour after the first hour, and the risk of postpartum hemorrhage and intrapartum fever increased significantly after 2 hours of pushing.14
While these findings may represent the risks inherent with the intervention of operative delivery and not the duration of second stage of labor per se, one could posit that if the intervention were initiated earlier, could it prevent or at least reduce maternal and neonatal morbidity?
Continue to: Factors to assess and monitor in the second stage...
Factors to assess and monitor in the second stage
When assessing progress in the second stage of labor, consider:
- maternal factors
- fetal/neonatal factors, and
- modifiable factors.
Maternal factors that influence the second stage of labor include parity, body mass index (BMI), age, and clinical pelvimetry.11,16-19 Fetal/neonatal factors that impact the second stage include the estimated fetal weight, fetal presentation (cephalic, face, and so on), position, and station, as well as the FHR Category.20, 21 Factors that can be modified in the second stage include the effect of epidural analgesia (turning it down to reduce motor blockade while maintaining sensory pain relief so that patients feel the “urge” to push), maternal pushing position and technique, the presence of maternal support person(s), manual rotation for a fetal position that is not optimal, immediate versus delayed pushing, and prevention of perineal tears.22-32 Interestingly, epidural analgesia, parity, birth weight, and station at complete dilation predicted second stage duration but accounted for only 25% of the variability in second stage length, leaving 75% of the variance unexplained.16
A specific absolute maximum length of time spent in the second stage of labor beyond which all women should undergo operative delivery has not been identified.1 Therefore, maternal, fetal/neonatal, and modifiable factors need to be critically assessed and continually monitored to determine whether a prolonged second stage or an operative delivery is warranted to prevent or minimize adverse maternal and neonatal outcomes.
Maternal factors
Maternal age correlates directly with the length of the second stage. That is, the length of the second stage increases with increasing age.17
Multiparous women have a shorter length of the second stage, regardless of epidural analgesia, compared with nulliparous women.11 In the Consortium for Safe Labor, multiparous women had a significantly shorter median second stage compared with nulliparous women.11
In adjusted analyses, maternal obesity was associated with an increased risk for CD, with the risk of CD more than 3 times greater in women with a BMI higher than 40 kg/m2 compared with those who had a BMI less than 25 kg/m2.18 There were no significant differences in the length of the second stage of labor by BMI catgeories.19
Fetal factors
Birth weight greater than 4,000 g was associated with an increased risk for arrest of descent during the second stage.33
Persistent fetal occiput posterior or transverse position may impact the duration of the second stage. A retrospective cohort study in women who underwent a trial of manual rotation compared with expectant management during the second stage of labor with the fetus in occiput posterior or occiput transverse position found that women with manual rotation were less likely to have a CD, severe perineal laceration, postpartum hemorrhage, and chorioamnionitis. However, an increased risk of cervical laceration was associated with manual rotation.20
Regarding FHR status, FHR abnormalities occurred in 91% of second stage labor patterns, with Category II being the most common.21 The fetal status should remain reassuring to allow for continuation of the second stage.
Continue to: Epidural analgesia...
Epidural analgesia
About 60% of women receive neuraxial analgesia in the United States,22 although rates vary widely across different populations. A Cochrane review showed no difference in the duration of the second stage among women who had early versus late initiation of epidural analgesia in labor.23 Epidural analgesia has no impact on the risk of CD; however, women with epidural analgesia experienced more hypotension, motor blockade, fever, and urinary retention.24
One management practice has been to discontinue epidural analgesia to allow resumption of sensory and motor nerve function. Another Cochrane systematic review found no difference in mode of delivery or neonatal outcomes.25 Rather than discontinuing epidural analgesia, which results in a profound increase in inadequate pain relief, one may consider titrating the dose with joint patient decision-making to allow for greater motor capability while maintaining adequate analgesia.34
Immediate vs delayed pushing
The 2 most common approaches to managing the second stage were either to initiate pushing with contractions once complete dilation occurred (immediate pushing) or to allow for a rest period in which the fetus passively rotated and descended while conserving a woman’s energy for pushing efforts (delayed pushing, laboring down, or passive descent). Since the publication of “Safe prevention of primary cesarean delivery,” however, studies have shown a concerning association between maternal and neonatal complications and prolonged second stage (which may occur with delayed pushing).3-8,35 An observational study of nearly 44,000 nulliparous women without epidural analgesia found that prolonged second stage was associated with increased chorioamnionitis, third- and fourth-degree lacerations, neonatal sepsis, neonatal asphyxia, and perinatal mortality.35
A pragmatic multicenter randomized clinical trial on the optimal management of second stage of labor across the United States recently was conducted.7 More than 2,000 nulliparous women at term in spontaneous or induced labor with epidural analgesia were randomly assigned at complete dilation to immediate pushing or delayed pushing (1 hour after complete dilation). There was no difference in the rate of vaginal delivery. The rate of postpartum hemorrhage was significantly lower among women in the immediate-pushing group compared with the delayed-pushing group (2.3% vs 4.0%, respectively; relative risk [RR], 0.6; 95% confidence interval [CI], 0.3–0.9; P = .03). Furthermore, rates of chorioamnionitis were significantly lower among women in the immediate-pushing group compared with the delayed-pushing group (6.7% vs 9.1%, respectively; RR, 0.70; 95% CI, 0.66–0.90; P = .005). No significant difference occurred in the composite outcome of neonatal morbidity between the groups. However neonatal acidemia (umbilical cord arterial pH <7.1) and confirmed or suspected sepsis were significantly increased in the delayed-pushing group.
The evidence supports active pushing at the start of the second stage. Women who consider delayed pushing should be informed that delayed pushing has not been shown to increase the likelihood of vaginal birth and that it is associated with increased risks of infection, hemorrhage, and neonatal acidemia.36
Maternal pushing position and technique
Spontaneous pushing (in which women are free to follow their instincts and generally push 3 to 5 times per contraction) versus directed pushing (women are encouraged to take a deep breath at the beginning of a contraction then hold it and bear down throughout the contraction) demonstrated no clear difference in duration of the second stage, perineal laceration, episiotomy, time spent pushing, or number of women with spontaneous vaginal birth. There was no difference in 5-minute Apgar score less than 7 or admission to the NICU.26
With regard to maternal positioning during the second stage, a Cochrane systematic review found benefits for upright posture, including a very small reduction in the duration of the second stage, reduction in episiotomy rates, and reduction in assisted deliveries.37 There was an increased risk of blood loss greater than 500 mL and possibly an increased risk in second-degree tears.37 Compared with women allocated to lying down, women in the upright position during the second stage with epidural analgesia had significantly fewer spontaneous vaginal births. There was no difference in operative vaginal delivery, obstetric anal sphincter injury (OASI), infant Apgar score of less than 4 at 5 minutes, and maternal fecal incontinence at 1 year.28
Continue to: Maternal support person...
Maternal support person
Continuous support during labor may improve outcomes for women and infants, including increased spontaneous vaginal birth, shorter duration of labor, and decreased cesarean birth.29 In a randomized trial of 412 healthy nulliparous women, women in labor were assigned to either a support group that received continuous support from a doula or an observed group that was monitored by an inconspicuous observer. Continuous labor support significantly reduced the rate of CDs and forceps deliveries.30,36 Indeed, during the COVID-19 pandemic, doulas have found innovative ways to continue to provide this essential support through virtual health.38
Prevention of perineal tears
Evidence suggests that warm compresses, and massage, may reduce third- and fourth-degree perineal tears.31 A meta-analysis of observational studies showed a significant reduction in the risk of OASI.32
Second stage steps: Recap
Throughout the second stage of labor, the decision to continue with expectant management or intervene with either an operative vaginal delivery or a CD is complex and requires consistent assessment and integration of multiple factors. An evidence-based approach to second stage labor management includes active pushing that is either Valsalva pushing or spontaneous, coached or uncoached, but most importantly, at the start of the second stage when a patient reaches complete dilation. Reassessment should occur at regular intervals to determine progress, after ensuring maternal and fetal well-being.
If there has been no advancement in station, an attempt at manual rotation or titration of epidural analgesia should be considered. Importantly, fetal descent with adequate pushing should be demonstrated throughout the second stage.
Additional considerations that improve outcomes include warm compresses or perineal massage to prevent third- and fourth-degree tears and the presence of a continuous support person to reduce the risk for an operative delivery.
Delivery should be expected within 2 hours for multiparous women and 3 hours for nulliparous women in the second stage. Prolonging the second stage beyond these thresholds should be individualized and occur only in the setting of assured maternal and fetal well-being.
CASE An alternative management strategy
Despite Ms. J.’s great active pushing effort for 60 minutes, the presenting part remains at 0 station and occiput transverse. Ms. J. is counseled regarding the risks and benefits of an attempt at manual rotation of the fetal head, and she wishes to proceed. The fetal position remains occiput transverse.
After another hour of active pushing, the FHR becomes Category II with repetitive variable decelerations. At this time, Ms. J. is informed that there has been no descent, and she is counseled on the risks and benefits of continued pushing versus CD. Through shared decision-making, she consents to a CD. She undergoes a primary CD without complication. The birth weight was 4,100 g, and 5- and 10-minute Apgar scores were 8 and 9, respectively. The umbilical cord arterial pH was 7.13.
Ms. J. and her baby were discharged home on postoperative day 4. ●
- American College of Obstetricians and Gynecologists; Society for Maternal-Fetal Medicine; Caughey AB, Cahill AG, Guise JM, et al. Safe prevention of the primary cesarean delivery. Am J Obstet Gynecol. 2014;210:179-193. doi:10.1016/j.ajog.2014.01.026.
- Martin JA, Hamilton BE, Osterman MJ, et al. Births: final data for 2018. Natl Vital Stat Rep. 2019;68:1-47.
- Grobman WA, Bailit J, Lai Y, et al; Eunice Kennedy Schriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Association of the duration of active pushing with obstetric outcomes. Obstet Gynecol. 2016;127:667-673. doi:10.1097/aog.0000000000001354.
- Gimovsky AC, Berghella V. Randomized controlled trial of prolonged second stage: extending the time limit vs usual guidelines. Am J Obstet Gynecol. 2016;214:361.e1-6. doi:10.1016/j.ajog.2015.12.042.
- Rosenbloom JI, Stout MJ, Tuuli MG, et al. New labor management guidelines and changes in cesarean delivery patterns. Am J Obstet Gynecol. 2017;217:689.e1-689.e8. doi:10.1016/j.ajog.2017.10.007.
- Grantz KL, Sundaram R, Ma L, et al. Reassessing the duration of the second stage of labor in relation to maternal and neonatal morbidity. Obstet Gynecol. 2018;131:345-353. doi:10.1097/aog.0000000000002431.
- Cahill AG, Srinivas SK, Tita AT, et al. Effect of immediate vs delayed pushing on rates of spontaneous vaginal delivery among nulliparous women receiving neuraxial analgesia: a randomized clinical trial. JAMA. 2018;320:1444-1454. doi:10.1001/jama.2018.13986.
- Zipori Y, Grunwald O, Ginsberg Y, et al. The impact of extending the second stage of labor to prevent primary cesarean delivery on maternal and neonatal outcomes. Am J Obstet Gynecol. 2019;220:191.e1-191.e7. doi:10.1016/j.ajog.2018.10.028.
- Leveno KJ, Nelson DB, McIntire DD. Second-stage labor: how long is too long? Am J Obstet Gynecol. 2016;214:484-489. doi:10.1016/j.ajog.2015.10.926.
- Friedman EA. Primigravid labor; a graphicostatistical analysis. Obstet Gynecol. 1955;6:567-589. doi:10.1097/00006250-195512000-00001.
- Zhang J, Landy HJ, Branch DW, et al. Contemporary patterns of spontaneous labor with normal neonatal outcomes. Obstet Gynecol. 2010;116:1281-1287. doi:10.1097/AOG.0b013e3181fdef6e.
- Cheng YW, Hopkins LM, Caughey AB. How long is too long: does a prolonged second stage of labor in nulliparous women affect maternal and neonatal outcomes? Am J Obstet Gynecol. 2004;191:933-938. doi:10.1016/j.ajog.2004.05.044.
- Rouse DJ, Weiner SJ, Bloom SL, et al. Second-stage labor duration in nulliparous women: relationship to maternal and perinatal outcomes. Am J Obstet Gynecol. 2009;201:357.e1-7. doi:10.1016/j.ajog.2009.08.003.
- Le Ray C, Audibert F, Goffinet F, et al. When to stop pushing: effects of duration of second-stage expulsion efforts on maternal and neonatal outcomes in nulliparous women with epidural analgesia. Am J Obstet Gynecol. 2009;201:361.e1-7. doi:10.1016/j.ajog.2009.08.002.
- Allen VM, Baskett TF, O’Connell CM, et al. Maternal and perinatal outcomes with increasing duration of the second stage of labor. Obstet Gynecol. 2009;113:1248-1258. doi:10.1097/AOG.0b013e3181a722d6.
- Piper JM, Bolling DR, Newton ER. The second stage of labor: factors influencing duration. Am J Obstet Gynecol. 1991;165(4 pt 1):976-979. doi:10.1016/0002-9378(91)90452-w.
- Zaki MN, Hibbard JU, Kominiarek MA. Contemporary labor patterns and maternal age. Obstet Gynecol. 2013;122:1018-1024. doi:10.1097/AOG.0b013e3182a9c92c.
- Kominiarek MA, Vanveldhuisen P, Hibbard J, et al; Consortium on Safe Labor. The maternal body mass index: a strong association with delivery route. Am J Obstet Gynecol. 2010;203:264.e1-7. doi:10.1016/j.ajog.2010.06.024.
- Kominiarek MA, Zhang J, Vanveldhuisen P, et al. Contemporary labor patterns: the impact of maternal body mass index. Am J Obstet Gynecol. 2011;205:244.e1-8. doi:10.1016/j.ajog.2011.06.014.
- Shaffer BL, Cheng YW, Vargas JE, et al. Manual rotation to reduce caesarean delivery in persistent occiput posterior or transverse position. J Matern Fetal Neonatal Med. 2011;24:65-72. doi:10.3109/14767051003710276.
- Krebs HB, Petres RE, Dunn LJ. Intrapartum fetal heart rate monitoring. V. Fetal heart rate patterns in the second stage of labor. Am J Obstet Gynecol. 1981;140:435-439. doi:10.1016/0002-9378(81)90041-7.
- Grant EN, Tao W, Craig M, et al. Neuraxial analgesia effects on labour progression: facts, fallacies, uncertainties and the future. BJOG. 2015;122:288-293. doi:10.1111/1471-0528.12966.
- Sng BL, Leong WL, Zeng Y, et al. Early versus late initiation of epidural analgesia for labour. Cochrane Database Syst Rev. 2014;(10):CD007238. doi:10.1002/14651858.CD007238.pub2.
- Anim-Somuah M, Smyth RM, Cyna AM, et al. Epidural versus non-epidural or no analgesia for pain management in labour. Cochrane Database Syst Rev. 2018;5(5):CD000331. doi:10.1002/14651858.CD000331.pub4.
- Torvaldsen S, Roberts CL, Bell JC, et al. Discontinuation of epidural analgesia late in labour for reducing the adverse delivery outcomes associated with epidural analgesia. Cochrane Database Syst Rev. 2004;(4):CD004457. doi:10.1002/14651858.CD004457.pub2.
- Lemos A, Amorim MM, Dornelas de Andrade A, et al. Pushing/bearing down methods for the second stage of labour. Cochrane Database Syst Rev. 2017;3(3):CD009124. doi:10.1002/14651858.CD009124.pub3.
- Prins M, Boxem J, Lucas C, et al. Effect of spontaneous pushing versus Valsalva pushing in the second stage of labour on mother and fetus: a systematic review of randomised trials. BJOG. 2011;118:662-670. doi:10.1111/j.1471-0528.2011 .02910.x.
- Epidural and Position Trial Collaborative Group. Upright versus lying down position in second stage of labour in nulliparous women with low dose epidural: BUMPES randomised controlled trial. BMJ. 2017;359:j4471. doi:10.1136/bmj.j4471.
- Bohren MA, Hofmeyr GJ, Sakala C, et al. Continuous support for women during childbirth. Cochrane Database Syst Rev. 2017;7(7):CD003766. doi:10.1002/14651858.CD003766.pub6.
- Kennell J, Klaus M, McGrath S, et al. Continuous emotional support during labor in a US hospital. A randomized controlled trial. JAMA. 1991;265:2197-2201.
- Aasheim V, Nilsen AB, Reinar LM, et al. Perineal techniques during the second stage of labour for reducing perineal trauma. Cochrane Database Syst Rev. 2017;6(6):CD006672. doi:10.1002/14651858.CD006672.pub3.
- Bulchandani S, Watts E, Sucharitha A, et al. Manual perineal support at the time of childbirth: a systematic review and meta-analysis. BJOG. 2015;122:1157-1165. doi:10.1111/1471-0528.13431.
- Feinstein U, Sheiner E, Levy A, et al. Risk factors for arrest of descent during the second stage of labor. Int J Gynaecol Obstet. 2002;77:7-14. doi:10.1016/s0020-7292(02)00007-3.
- Cheng YW, Caughey AB. Defining and managing normal and abnormal second stage of labor. Obstet Gynecol Clin North Am. 2017;44:547-566. doi:10.1016/j.ogc.2017.08.009.
- Laughon SK, Berghella V, Reddy UM, et al. Neonatal and maternal outcomes with prolonged second stage of labor. Obstet Gynecol. 2014;124:57-67. doi:10.1097/aog.0000000000000278.
- American College of Obstetricians and Gynecologists. ACOG committee opinion no. 766: approaches to limit intervention during labor and birth. Obstet Gynecol. 2019;133:e164-e173. doi:10.1097/aog.0000000000003074.
- Gupta JK, Sood A, Hofmeyr GJ, et al. Position in the second stage of labour for women without epidural anaesthesia. Cochrane Database Syst Rev. 2017;5(5):CD002006. doi:10.1002/14651858.CD002006.pub4.
- Castaneda AN, Searcy JJ. Practising intimate labour: birth doulas respond during COVID-19. Anthropol Action. 2021;28:21-24. https://www.berghahnjournals.com/view/ journals/aia/28/1/aia280104.xml. Accessed February 8, 2021.
- American College of Obstetricians and Gynecologists; Society for Maternal-Fetal Medicine; Caughey AB, Cahill AG, Guise JM, et al. Safe prevention of the primary cesarean delivery. Am J Obstet Gynecol. 2014;210:179-193. doi:10.1016/j.ajog.2014.01.026.
- Martin JA, Hamilton BE, Osterman MJ, et al. Births: final data for 2018. Natl Vital Stat Rep. 2019;68:1-47.
- Grobman WA, Bailit J, Lai Y, et al; Eunice Kennedy Schriver National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network. Association of the duration of active pushing with obstetric outcomes. Obstet Gynecol. 2016;127:667-673. doi:10.1097/aog.0000000000001354.
- Gimovsky AC, Berghella V. Randomized controlled trial of prolonged second stage: extending the time limit vs usual guidelines. Am J Obstet Gynecol. 2016;214:361.e1-6. doi:10.1016/j.ajog.2015.12.042.
- Rosenbloom JI, Stout MJ, Tuuli MG, et al. New labor management guidelines and changes in cesarean delivery patterns. Am J Obstet Gynecol. 2017;217:689.e1-689.e8. doi:10.1016/j.ajog.2017.10.007.
- Grantz KL, Sundaram R, Ma L, et al. Reassessing the duration of the second stage of labor in relation to maternal and neonatal morbidity. Obstet Gynecol. 2018;131:345-353. doi:10.1097/aog.0000000000002431.
- Cahill AG, Srinivas SK, Tita AT, et al. Effect of immediate vs delayed pushing on rates of spontaneous vaginal delivery among nulliparous women receiving neuraxial analgesia: a randomized clinical trial. JAMA. 2018;320:1444-1454. doi:10.1001/jama.2018.13986.
- Zipori Y, Grunwald O, Ginsberg Y, et al. The impact of extending the second stage of labor to prevent primary cesarean delivery on maternal and neonatal outcomes. Am J Obstet Gynecol. 2019;220:191.e1-191.e7. doi:10.1016/j.ajog.2018.10.028.
- Leveno KJ, Nelson DB, McIntire DD. Second-stage labor: how long is too long? Am J Obstet Gynecol. 2016;214:484-489. doi:10.1016/j.ajog.2015.10.926.
- Friedman EA. Primigravid labor; a graphicostatistical analysis. Obstet Gynecol. 1955;6:567-589. doi:10.1097/00006250-195512000-00001.
- Zhang J, Landy HJ, Branch DW, et al. Contemporary patterns of spontaneous labor with normal neonatal outcomes. Obstet Gynecol. 2010;116:1281-1287. doi:10.1097/AOG.0b013e3181fdef6e.
- Cheng YW, Hopkins LM, Caughey AB. How long is too long: does a prolonged second stage of labor in nulliparous women affect maternal and neonatal outcomes? Am J Obstet Gynecol. 2004;191:933-938. doi:10.1016/j.ajog.2004.05.044.
- Rouse DJ, Weiner SJ, Bloom SL, et al. Second-stage labor duration in nulliparous women: relationship to maternal and perinatal outcomes. Am J Obstet Gynecol. 2009;201:357.e1-7. doi:10.1016/j.ajog.2009.08.003.
- Le Ray C, Audibert F, Goffinet F, et al. When to stop pushing: effects of duration of second-stage expulsion efforts on maternal and neonatal outcomes in nulliparous women with epidural analgesia. Am J Obstet Gynecol. 2009;201:361.e1-7. doi:10.1016/j.ajog.2009.08.002.
- Allen VM, Baskett TF, O’Connell CM, et al. Maternal and perinatal outcomes with increasing duration of the second stage of labor. Obstet Gynecol. 2009;113:1248-1258. doi:10.1097/AOG.0b013e3181a722d6.
- Piper JM, Bolling DR, Newton ER. The second stage of labor: factors influencing duration. Am J Obstet Gynecol. 1991;165(4 pt 1):976-979. doi:10.1016/0002-9378(91)90452-w.
- Zaki MN, Hibbard JU, Kominiarek MA. Contemporary labor patterns and maternal age. Obstet Gynecol. 2013;122:1018-1024. doi:10.1097/AOG.0b013e3182a9c92c.
- Kominiarek MA, Vanveldhuisen P, Hibbard J, et al; Consortium on Safe Labor. The maternal body mass index: a strong association with delivery route. Am J Obstet Gynecol. 2010;203:264.e1-7. doi:10.1016/j.ajog.2010.06.024.
- Kominiarek MA, Zhang J, Vanveldhuisen P, et al. Contemporary labor patterns: the impact of maternal body mass index. Am J Obstet Gynecol. 2011;205:244.e1-8. doi:10.1016/j.ajog.2011.06.014.
- Shaffer BL, Cheng YW, Vargas JE, et al. Manual rotation to reduce caesarean delivery in persistent occiput posterior or transverse position. J Matern Fetal Neonatal Med. 2011;24:65-72. doi:10.3109/14767051003710276.
- Krebs HB, Petres RE, Dunn LJ. Intrapartum fetal heart rate monitoring. V. Fetal heart rate patterns in the second stage of labor. Am J Obstet Gynecol. 1981;140:435-439. doi:10.1016/0002-9378(81)90041-7.
- Grant EN, Tao W, Craig M, et al. Neuraxial analgesia effects on labour progression: facts, fallacies, uncertainties and the future. BJOG. 2015;122:288-293. doi:10.1111/1471-0528.12966.
- Sng BL, Leong WL, Zeng Y, et al. Early versus late initiation of epidural analgesia for labour. Cochrane Database Syst Rev. 2014;(10):CD007238. doi:10.1002/14651858.CD007238.pub2.
- Anim-Somuah M, Smyth RM, Cyna AM, et al. Epidural versus non-epidural or no analgesia for pain management in labour. Cochrane Database Syst Rev. 2018;5(5):CD000331. doi:10.1002/14651858.CD000331.pub4.
- Torvaldsen S, Roberts CL, Bell JC, et al. Discontinuation of epidural analgesia late in labour for reducing the adverse delivery outcomes associated with epidural analgesia. Cochrane Database Syst Rev. 2004;(4):CD004457. doi:10.1002/14651858.CD004457.pub2.
- Lemos A, Amorim MM, Dornelas de Andrade A, et al. Pushing/bearing down methods for the second stage of labour. Cochrane Database Syst Rev. 2017;3(3):CD009124. doi:10.1002/14651858.CD009124.pub3.
- Prins M, Boxem J, Lucas C, et al. Effect of spontaneous pushing versus Valsalva pushing in the second stage of labour on mother and fetus: a systematic review of randomised trials. BJOG. 2011;118:662-670. doi:10.1111/j.1471-0528.2011 .02910.x.
- Epidural and Position Trial Collaborative Group. Upright versus lying down position in second stage of labour in nulliparous women with low dose epidural: BUMPES randomised controlled trial. BMJ. 2017;359:j4471. doi:10.1136/bmj.j4471.
- Bohren MA, Hofmeyr GJ, Sakala C, et al. Continuous support for women during childbirth. Cochrane Database Syst Rev. 2017;7(7):CD003766. doi:10.1002/14651858.CD003766.pub6.
- Kennell J, Klaus M, McGrath S, et al. Continuous emotional support during labor in a US hospital. A randomized controlled trial. JAMA. 1991;265:2197-2201.
- Aasheim V, Nilsen AB, Reinar LM, et al. Perineal techniques during the second stage of labour for reducing perineal trauma. Cochrane Database Syst Rev. 2017;6(6):CD006672. doi:10.1002/14651858.CD006672.pub3.
- Bulchandani S, Watts E, Sucharitha A, et al. Manual perineal support at the time of childbirth: a systematic review and meta-analysis. BJOG. 2015;122:1157-1165. doi:10.1111/1471-0528.13431.
- Feinstein U, Sheiner E, Levy A, et al. Risk factors for arrest of descent during the second stage of labor. Int J Gynaecol Obstet. 2002;77:7-14. doi:10.1016/s0020-7292(02)00007-3.
- Cheng YW, Caughey AB. Defining and managing normal and abnormal second stage of labor. Obstet Gynecol Clin North Am. 2017;44:547-566. doi:10.1016/j.ogc.2017.08.009.
- Laughon SK, Berghella V, Reddy UM, et al. Neonatal and maternal outcomes with prolonged second stage of labor. Obstet Gynecol. 2014;124:57-67. doi:10.1097/aog.0000000000000278.
- American College of Obstetricians and Gynecologists. ACOG committee opinion no. 766: approaches to limit intervention during labor and birth. Obstet Gynecol. 2019;133:e164-e173. doi:10.1097/aog.0000000000003074.
- Gupta JK, Sood A, Hofmeyr GJ, et al. Position in the second stage of labour for women without epidural anaesthesia. Cochrane Database Syst Rev. 2017;5(5):CD002006. doi:10.1002/14651858.CD002006.pub4.
- Castaneda AN, Searcy JJ. Practising intimate labour: birth doulas respond during COVID-19. Anthropol Action. 2021;28:21-24. https://www.berghahnjournals.com/view/ journals/aia/28/1/aia280104.xml. Accessed February 8, 2021.
COVID-19 apps for the ObGyn health care provider: An update
More than one year after COVID-19 was declared a worldwide pandemic by the World Health Organization on March 11, 2020, the disease continues to persist, infecting more than 110 million individuals to date globally.1 As new information emerges about the coronavirus, the literature on diagnosis and management also has grown exponentially over the last year, including specific guidance for obstetric populations. With abundant information available to health care providers, COVID-19 mobile apps have the advantage of summarizing and presenting information in an organized and easily accessible manner.2
This updated review expands on a previous article by Bogaert and Chen at the start of the COVID-19 pandemic.3 Using the same methodology, in March 2021 we searched the Apple iTunes and Google Play stores using the term “COVID.” The search yielded 230 unique applications available for download. We excluded apps that were primarily developed as geographic area-specific case trackers or personal symptom trackers (193), those that provide telemedicine services (7), and nonmedical apps or ones published in a language other than English (20).
Here, we focus on the 3 mobile apps previously discussed (CDC, My Osler, and Relief Central) and 7 additional apps (TABLE). Most summarize information on the prevention, diagnosis, and treatment of coronavirus, and several also provide information on the COVID-19 vaccine. One app (COVID-19 Resource for Midwives) is specifically designed for obstetric providers, and 4 others (CDC, COVID-19 Protocols, Medscape, and WHO Academy) contain information on specific guidance for obstetric and gynecologic patient populations.
Each app was evaluated based on a condensed version of the APPLICATIONS scoring system, APPLI (comprehensiveness, price, platform, literature used, and special features).4
We hope that these mobile apps will assist the ObGyn health care provider in continuing to care for patients during this pandemic.
- World Health Organization. WHO coronavirus (COVID-19) dashboard. https://covid19.who.int/. Accessed March 12, 2021.
2. Kondylakis H, Katehakis DG, Kouroubali A, et al. COVID-19 mobile apps: a systematic review of the literature. J Med Internet Res. 2020;22:e23170.
3. Bogaert K, Chen KT. COVID-19 apps for the ObGyn health care provider. OBG Manag. 2020; 32(5):44, 46.
4. Chyjek K, Farag S, Chen KT. Rating pregnancy wheel applications using the APPLICATIONS scoring system. Obstet Gynecol. 2015;125:1478-1483.
Dr. Lillian Chen is a first-year resident in the Department of Obstetrics, Gynecology, and Reproductive Science, Icahn School of Medicine at Mount Sinai, New York, New York.
Dr. Katherine Chen is Professor of Obstetrics, Gynecology, and Reproductive Science and Medical Education, Vice-Chair of Ob-Gyn Education for the Mount Sinai Health System, Icahn School of Medicine at Mount Sinai, New York. She is an OBG Management Contributing Editor.
Dr. Katherine Chen reports being an advisory board member and receiving royalties from UpToDate, Inc. Dr. Lillian Chen reports no financial relationships relevant to this article.
Dr. Lillian Chen is a first-year resident in the Department of Obstetrics, Gynecology, and Reproductive Science, Icahn School of Medicine at Mount Sinai, New York, New York.
Dr. Katherine Chen is Professor of Obstetrics, Gynecology, and Reproductive Science and Medical Education, Vice-Chair of Ob-Gyn Education for the Mount Sinai Health System, Icahn School of Medicine at Mount Sinai, New York. She is an OBG Management Contributing Editor.
Dr. Katherine Chen reports being an advisory board member and receiving royalties from UpToDate, Inc. Dr. Lillian Chen reports no financial relationships relevant to this article.
Dr. Lillian Chen is a first-year resident in the Department of Obstetrics, Gynecology, and Reproductive Science, Icahn School of Medicine at Mount Sinai, New York, New York.
Dr. Katherine Chen is Professor of Obstetrics, Gynecology, and Reproductive Science and Medical Education, Vice-Chair of Ob-Gyn Education for the Mount Sinai Health System, Icahn School of Medicine at Mount Sinai, New York. She is an OBG Management Contributing Editor.
Dr. Katherine Chen reports being an advisory board member and receiving royalties from UpToDate, Inc. Dr. Lillian Chen reports no financial relationships relevant to this article.
More than one year after COVID-19 was declared a worldwide pandemic by the World Health Organization on March 11, 2020, the disease continues to persist, infecting more than 110 million individuals to date globally.1 As new information emerges about the coronavirus, the literature on diagnosis and management also has grown exponentially over the last year, including specific guidance for obstetric populations. With abundant information available to health care providers, COVID-19 mobile apps have the advantage of summarizing and presenting information in an organized and easily accessible manner.2
This updated review expands on a previous article by Bogaert and Chen at the start of the COVID-19 pandemic.3 Using the same methodology, in March 2021 we searched the Apple iTunes and Google Play stores using the term “COVID.” The search yielded 230 unique applications available for download. We excluded apps that were primarily developed as geographic area-specific case trackers or personal symptom trackers (193), those that provide telemedicine services (7), and nonmedical apps or ones published in a language other than English (20).
Here, we focus on the 3 mobile apps previously discussed (CDC, My Osler, and Relief Central) and 7 additional apps (TABLE). Most summarize information on the prevention, diagnosis, and treatment of coronavirus, and several also provide information on the COVID-19 vaccine. One app (COVID-19 Resource for Midwives) is specifically designed for obstetric providers, and 4 others (CDC, COVID-19 Protocols, Medscape, and WHO Academy) contain information on specific guidance for obstetric and gynecologic patient populations.
Each app was evaluated based on a condensed version of the APPLICATIONS scoring system, APPLI (comprehensiveness, price, platform, literature used, and special features).4
We hope that these mobile apps will assist the ObGyn health care provider in continuing to care for patients during this pandemic.
More than one year after COVID-19 was declared a worldwide pandemic by the World Health Organization on March 11, 2020, the disease continues to persist, infecting more than 110 million individuals to date globally.1 As new information emerges about the coronavirus, the literature on diagnosis and management also has grown exponentially over the last year, including specific guidance for obstetric populations. With abundant information available to health care providers, COVID-19 mobile apps have the advantage of summarizing and presenting information in an organized and easily accessible manner.2
This updated review expands on a previous article by Bogaert and Chen at the start of the COVID-19 pandemic.3 Using the same methodology, in March 2021 we searched the Apple iTunes and Google Play stores using the term “COVID.” The search yielded 230 unique applications available for download. We excluded apps that were primarily developed as geographic area-specific case trackers or personal symptom trackers (193), those that provide telemedicine services (7), and nonmedical apps or ones published in a language other than English (20).
Here, we focus on the 3 mobile apps previously discussed (CDC, My Osler, and Relief Central) and 7 additional apps (TABLE). Most summarize information on the prevention, diagnosis, and treatment of coronavirus, and several also provide information on the COVID-19 vaccine. One app (COVID-19 Resource for Midwives) is specifically designed for obstetric providers, and 4 others (CDC, COVID-19 Protocols, Medscape, and WHO Academy) contain information on specific guidance for obstetric and gynecologic patient populations.
Each app was evaluated based on a condensed version of the APPLICATIONS scoring system, APPLI (comprehensiveness, price, platform, literature used, and special features).4
We hope that these mobile apps will assist the ObGyn health care provider in continuing to care for patients during this pandemic.
- World Health Organization. WHO coronavirus (COVID-19) dashboard. https://covid19.who.int/. Accessed March 12, 2021.
2. Kondylakis H, Katehakis DG, Kouroubali A, et al. COVID-19 mobile apps: a systematic review of the literature. J Med Internet Res. 2020;22:e23170.
3. Bogaert K, Chen KT. COVID-19 apps for the ObGyn health care provider. OBG Manag. 2020; 32(5):44, 46.
4. Chyjek K, Farag S, Chen KT. Rating pregnancy wheel applications using the APPLICATIONS scoring system. Obstet Gynecol. 2015;125:1478-1483.
- World Health Organization. WHO coronavirus (COVID-19) dashboard. https://covid19.who.int/. Accessed March 12, 2021.
2. Kondylakis H, Katehakis DG, Kouroubali A, et al. COVID-19 mobile apps: a systematic review of the literature. J Med Internet Res. 2020;22:e23170.
3. Bogaert K, Chen KT. COVID-19 apps for the ObGyn health care provider. OBG Manag. 2020; 32(5):44, 46.
4. Chyjek K, Farag S, Chen KT. Rating pregnancy wheel applications using the APPLICATIONS scoring system. Obstet Gynecol. 2015;125:1478-1483.
Study IDs most common lingering symptoms 8 months after mild COVID
Loss of smell, loss of taste, dyspnea, and fatigue are the four most common symptoms that health care professionals in Sweden report 8 months after mild COVID-19 illness, new evidence reveals.
according to the study.
“We see that a substantial portion of health care workers suffer from long-term symptoms after mild COVID-19,” senior author Charlotte Thålin, MD, PhD, said in an interview. She added that loss of smell and taste “may seem trivial, but have a negative impact on work, social, and home life in the long run.”
The study is noteworthy not only for tracking the COVID-19-related experiences of health care workers over time, but also for what it did not find. There was no increased prevalence of cognitive issues – including memory or concentration – that others have linked to what’s often called long-haul COVID-19.
The research letter was published online April 7, 2021, in JAMA.
“Even if you are young and previously healthy, a mild COVID-19 infection may result in long-term consequences,” said Dr. Thålin, from the department of clinical sciences at Danderyd Hospital, Karolinska Institute, Stockholm.
The researchers did not observe an increased risk for long-term symptoms after asymptomatic COVID-19.
Adding to existing evidence
This research letter “adds to the growing body of literature showing that people recovering from COVID have reported a diverse array of symptoms lasting for months after initial infection,” Lekshmi Santhosh, MD, said in an interview. She is physician faculty lead at the University of California, San Francisco Post-COVID OPTIMAL Clinic.
Previous research revealed severe long-term symptoms, including heart palpitations and neurologic impairments, among people hospitalized with COVID-19. However, “there is limited data on the long-term effects after mild COVID-19, and these studies are often hampered by selection bias and without proper control groups,” Dr. Thålin said.
The absence of these more severe symptoms after mild COVID-19 is “reassuring,” she added.
The current findings are part of the ongoing COMMUNITY (COVID-19 Biomarker and Immunity) study looking at long-term immunity. Health care professionals enrolled in the research between April 15 and May 8, 2020, and have initial blood tests repeated every 4 months.
Dr. Thålin, lead author Sebastian Havervall, MD, and their colleagues compared symptom reporting between 323 hospital employees who had mild COVID-19 at least 8 months earlier with 1,072 employees who did not have COVID-19 throughout the study.
The results show that 26% of those who had COVID-19 previously had at least one moderate to severe symptom that lasted more than 2 months, compared with 9% in the control group.
The group with a history of mild COVID-19 was a median 43 years old and 83% were women. The controls were a median 47 years old and 86% were women.
“These data mirror what we have seen across long-term cohorts of patients with COVID-19 infection. Notably, mild illness among previously healthy individuals may be associated with long-term persistent symptoms,” Sarah Jolley, MD, a pulmonologist specializing in critical care at the University of Colorado Hospital in Aurora and director of the Post-COVID Clinic, said in an interview.
“In this cohort, similar to others, this seems to be more pronounced in women,” Dr. Jolley added.
Key findings on functioning
At 8 months, using a smartphone app, participants reported presence, duration, and severity of 23 predefined symptoms. Researchers used the Sheehan Disability Scale to gauge functional impairment.
A total of 11% participants reported at least one symptom that negatively affected work or social or home life at 8 months versus only 2% of the control group.
Seropositive participants were almost two times more likely to report that their long-term symptoms moderately to markedly disrupted their work life, 8% versus 4% of seronegative healthcare workers (relative risk, 1.8; 95%; confidence interval, 1.2-2.9).
Disruptions to a social life from long-term symptoms were 2.5 times more likely in the seropositive group. A total 15% of this cohort reported moderate to marked effects, compared with 6% of the seronegative group (RR, 2.5; 95% CI, 1.8-3.6).
The researchers also inquired about home life disruptions, which were reported by 12% of the seropositive health care workers and 5% of the seronegative participants (RR, 2.3; 95% CI, 1.6-3.4).
The study’s findings “tracks with a lot of the other work we’re seeing,” David Putrino, PT, PhD, director of rehabilitation innovation at Mount Sinai Health System in New York, said in an interview. He and his colleagues are responsible for managing the rehabilitation of patients with long COVID.
Interestingly, the proportion of people with persistent symptoms might be underestimated in this research, Dr. Putrino said. “Antibodies are not an entirely reliable biomarker. So what the researchers are using here is the most conservative measure of who may have had the virus.”
Potential recall bias and the subjective rating of symptoms were possible limitations of the study.
When asked to speculate why researchers did not find higher levels of cognitive dysfunction, Dr. Putrino said that self-reports are generally less reliable than measures like the Montreal Cognitive Assessment for detecting cognitive impairment.
Furthermore, unlike many of the people with long-haul COVID-19 whom he treats clinically – ones who are “really struggling” – the health care workers studied in Sweden are functioning well enough to perform their duties at the hospital, so the study population may not represent the population at large.
More research required
“More research needs to be conducted to investigate the mechanisms underlying these persistent symptoms, and several centers, including UCSF, are conducting research into why this might be,” Dr. Santhosh said.
Dr. Thålin and colleagues plan to continue following participants. “The primary aim of the COMMUNITY study is to investigate long-term immunity after COVID-19, but we will also look into possible underlying pathophysiological mechanisms behind COVID-19–related long-term symptoms,” she said.
“I hope to see that taste and smell will return,” Dr. Thålin added.
“We’re really just starting to understand the long-term effects of COVID-19,” Putrino said. “This is something we’re going to see a lot of moving forward.”
Dr. Thålin, Dr. Santhosh, Dr. Jolley, and Dr. Putrino disclosed no relevant financial relationships. The research was funded by grants from the Knut and Alice Wallenberg Foundation, Jonas and Christina af Jochnick Foundation, Leif Lundblad Family Foundation, Region Stockholm, and Erling-Persson Family Foundation.
A version of this article first appeared on Medscape.com.
Loss of smell, loss of taste, dyspnea, and fatigue are the four most common symptoms that health care professionals in Sweden report 8 months after mild COVID-19 illness, new evidence reveals.
according to the study.
“We see that a substantial portion of health care workers suffer from long-term symptoms after mild COVID-19,” senior author Charlotte Thålin, MD, PhD, said in an interview. She added that loss of smell and taste “may seem trivial, but have a negative impact on work, social, and home life in the long run.”
The study is noteworthy not only for tracking the COVID-19-related experiences of health care workers over time, but also for what it did not find. There was no increased prevalence of cognitive issues – including memory or concentration – that others have linked to what’s often called long-haul COVID-19.
The research letter was published online April 7, 2021, in JAMA.
“Even if you are young and previously healthy, a mild COVID-19 infection may result in long-term consequences,” said Dr. Thålin, from the department of clinical sciences at Danderyd Hospital, Karolinska Institute, Stockholm.
The researchers did not observe an increased risk for long-term symptoms after asymptomatic COVID-19.
Adding to existing evidence
This research letter “adds to the growing body of literature showing that people recovering from COVID have reported a diverse array of symptoms lasting for months after initial infection,” Lekshmi Santhosh, MD, said in an interview. She is physician faculty lead at the University of California, San Francisco Post-COVID OPTIMAL Clinic.
Previous research revealed severe long-term symptoms, including heart palpitations and neurologic impairments, among people hospitalized with COVID-19. However, “there is limited data on the long-term effects after mild COVID-19, and these studies are often hampered by selection bias and without proper control groups,” Dr. Thålin said.
The absence of these more severe symptoms after mild COVID-19 is “reassuring,” she added.
The current findings are part of the ongoing COMMUNITY (COVID-19 Biomarker and Immunity) study looking at long-term immunity. Health care professionals enrolled in the research between April 15 and May 8, 2020, and have initial blood tests repeated every 4 months.
Dr. Thålin, lead author Sebastian Havervall, MD, and their colleagues compared symptom reporting between 323 hospital employees who had mild COVID-19 at least 8 months earlier with 1,072 employees who did not have COVID-19 throughout the study.
The results show that 26% of those who had COVID-19 previously had at least one moderate to severe symptom that lasted more than 2 months, compared with 9% in the control group.
The group with a history of mild COVID-19 was a median 43 years old and 83% were women. The controls were a median 47 years old and 86% were women.
“These data mirror what we have seen across long-term cohorts of patients with COVID-19 infection. Notably, mild illness among previously healthy individuals may be associated with long-term persistent symptoms,” Sarah Jolley, MD, a pulmonologist specializing in critical care at the University of Colorado Hospital in Aurora and director of the Post-COVID Clinic, said in an interview.
“In this cohort, similar to others, this seems to be more pronounced in women,” Dr. Jolley added.
Key findings on functioning
At 8 months, using a smartphone app, participants reported presence, duration, and severity of 23 predefined symptoms. Researchers used the Sheehan Disability Scale to gauge functional impairment.
A total of 11% participants reported at least one symptom that negatively affected work or social or home life at 8 months versus only 2% of the control group.
Seropositive participants were almost two times more likely to report that their long-term symptoms moderately to markedly disrupted their work life, 8% versus 4% of seronegative healthcare workers (relative risk, 1.8; 95%; confidence interval, 1.2-2.9).
Disruptions to a social life from long-term symptoms were 2.5 times more likely in the seropositive group. A total 15% of this cohort reported moderate to marked effects, compared with 6% of the seronegative group (RR, 2.5; 95% CI, 1.8-3.6).
The researchers also inquired about home life disruptions, which were reported by 12% of the seropositive health care workers and 5% of the seronegative participants (RR, 2.3; 95% CI, 1.6-3.4).
The study’s findings “tracks with a lot of the other work we’re seeing,” David Putrino, PT, PhD, director of rehabilitation innovation at Mount Sinai Health System in New York, said in an interview. He and his colleagues are responsible for managing the rehabilitation of patients with long COVID.
Interestingly, the proportion of people with persistent symptoms might be underestimated in this research, Dr. Putrino said. “Antibodies are not an entirely reliable biomarker. So what the researchers are using here is the most conservative measure of who may have had the virus.”
Potential recall bias and the subjective rating of symptoms were possible limitations of the study.
When asked to speculate why researchers did not find higher levels of cognitive dysfunction, Dr. Putrino said that self-reports are generally less reliable than measures like the Montreal Cognitive Assessment for detecting cognitive impairment.
Furthermore, unlike many of the people with long-haul COVID-19 whom he treats clinically – ones who are “really struggling” – the health care workers studied in Sweden are functioning well enough to perform their duties at the hospital, so the study population may not represent the population at large.
More research required
“More research needs to be conducted to investigate the mechanisms underlying these persistent symptoms, and several centers, including UCSF, are conducting research into why this might be,” Dr. Santhosh said.
Dr. Thålin and colleagues plan to continue following participants. “The primary aim of the COMMUNITY study is to investigate long-term immunity after COVID-19, but we will also look into possible underlying pathophysiological mechanisms behind COVID-19–related long-term symptoms,” she said.
“I hope to see that taste and smell will return,” Dr. Thålin added.
“We’re really just starting to understand the long-term effects of COVID-19,” Putrino said. “This is something we’re going to see a lot of moving forward.”
Dr. Thålin, Dr. Santhosh, Dr. Jolley, and Dr. Putrino disclosed no relevant financial relationships. The research was funded by grants from the Knut and Alice Wallenberg Foundation, Jonas and Christina af Jochnick Foundation, Leif Lundblad Family Foundation, Region Stockholm, and Erling-Persson Family Foundation.
A version of this article first appeared on Medscape.com.
Loss of smell, loss of taste, dyspnea, and fatigue are the four most common symptoms that health care professionals in Sweden report 8 months after mild COVID-19 illness, new evidence reveals.
according to the study.
“We see that a substantial portion of health care workers suffer from long-term symptoms after mild COVID-19,” senior author Charlotte Thålin, MD, PhD, said in an interview. She added that loss of smell and taste “may seem trivial, but have a negative impact on work, social, and home life in the long run.”
The study is noteworthy not only for tracking the COVID-19-related experiences of health care workers over time, but also for what it did not find. There was no increased prevalence of cognitive issues – including memory or concentration – that others have linked to what’s often called long-haul COVID-19.
The research letter was published online April 7, 2021, in JAMA.
“Even if you are young and previously healthy, a mild COVID-19 infection may result in long-term consequences,” said Dr. Thålin, from the department of clinical sciences at Danderyd Hospital, Karolinska Institute, Stockholm.
The researchers did not observe an increased risk for long-term symptoms after asymptomatic COVID-19.
Adding to existing evidence
This research letter “adds to the growing body of literature showing that people recovering from COVID have reported a diverse array of symptoms lasting for months after initial infection,” Lekshmi Santhosh, MD, said in an interview. She is physician faculty lead at the University of California, San Francisco Post-COVID OPTIMAL Clinic.
Previous research revealed severe long-term symptoms, including heart palpitations and neurologic impairments, among people hospitalized with COVID-19. However, “there is limited data on the long-term effects after mild COVID-19, and these studies are often hampered by selection bias and without proper control groups,” Dr. Thålin said.
The absence of these more severe symptoms after mild COVID-19 is “reassuring,” she added.
The current findings are part of the ongoing COMMUNITY (COVID-19 Biomarker and Immunity) study looking at long-term immunity. Health care professionals enrolled in the research between April 15 and May 8, 2020, and have initial blood tests repeated every 4 months.
Dr. Thålin, lead author Sebastian Havervall, MD, and their colleagues compared symptom reporting between 323 hospital employees who had mild COVID-19 at least 8 months earlier with 1,072 employees who did not have COVID-19 throughout the study.
The results show that 26% of those who had COVID-19 previously had at least one moderate to severe symptom that lasted more than 2 months, compared with 9% in the control group.
The group with a history of mild COVID-19 was a median 43 years old and 83% were women. The controls were a median 47 years old and 86% were women.
“These data mirror what we have seen across long-term cohorts of patients with COVID-19 infection. Notably, mild illness among previously healthy individuals may be associated with long-term persistent symptoms,” Sarah Jolley, MD, a pulmonologist specializing in critical care at the University of Colorado Hospital in Aurora and director of the Post-COVID Clinic, said in an interview.
“In this cohort, similar to others, this seems to be more pronounced in women,” Dr. Jolley added.
Key findings on functioning
At 8 months, using a smartphone app, participants reported presence, duration, and severity of 23 predefined symptoms. Researchers used the Sheehan Disability Scale to gauge functional impairment.
A total of 11% participants reported at least one symptom that negatively affected work or social or home life at 8 months versus only 2% of the control group.
Seropositive participants were almost two times more likely to report that their long-term symptoms moderately to markedly disrupted their work life, 8% versus 4% of seronegative healthcare workers (relative risk, 1.8; 95%; confidence interval, 1.2-2.9).
Disruptions to a social life from long-term symptoms were 2.5 times more likely in the seropositive group. A total 15% of this cohort reported moderate to marked effects, compared with 6% of the seronegative group (RR, 2.5; 95% CI, 1.8-3.6).
The researchers also inquired about home life disruptions, which were reported by 12% of the seropositive health care workers and 5% of the seronegative participants (RR, 2.3; 95% CI, 1.6-3.4).
The study’s findings “tracks with a lot of the other work we’re seeing,” David Putrino, PT, PhD, director of rehabilitation innovation at Mount Sinai Health System in New York, said in an interview. He and his colleagues are responsible for managing the rehabilitation of patients with long COVID.
Interestingly, the proportion of people with persistent symptoms might be underestimated in this research, Dr. Putrino said. “Antibodies are not an entirely reliable biomarker. So what the researchers are using here is the most conservative measure of who may have had the virus.”
Potential recall bias and the subjective rating of symptoms were possible limitations of the study.
When asked to speculate why researchers did not find higher levels of cognitive dysfunction, Dr. Putrino said that self-reports are generally less reliable than measures like the Montreal Cognitive Assessment for detecting cognitive impairment.
Furthermore, unlike many of the people with long-haul COVID-19 whom he treats clinically – ones who are “really struggling” – the health care workers studied in Sweden are functioning well enough to perform their duties at the hospital, so the study population may not represent the population at large.
More research required
“More research needs to be conducted to investigate the mechanisms underlying these persistent symptoms, and several centers, including UCSF, are conducting research into why this might be,” Dr. Santhosh said.
Dr. Thålin and colleagues plan to continue following participants. “The primary aim of the COMMUNITY study is to investigate long-term immunity after COVID-19, but we will also look into possible underlying pathophysiological mechanisms behind COVID-19–related long-term symptoms,” she said.
“I hope to see that taste and smell will return,” Dr. Thålin added.
“We’re really just starting to understand the long-term effects of COVID-19,” Putrino said. “This is something we’re going to see a lot of moving forward.”
Dr. Thålin, Dr. Santhosh, Dr. Jolley, and Dr. Putrino disclosed no relevant financial relationships. The research was funded by grants from the Knut and Alice Wallenberg Foundation, Jonas and Christina af Jochnick Foundation, Leif Lundblad Family Foundation, Region Stockholm, and Erling-Persson Family Foundation.
A version of this article first appeared on Medscape.com.
High-Potency Topical Steroid Treatment of Multiple Keratoacanthomas Associated With Prurigo Nodularis
Practice Gap
Multiple keratoacanthomas (KAs) of the legs often are a challenge to treat, especially when these lesions appear within a field of prurigo nodules. Multiple KAs associated with prurigo nodularis is a rarer finding; more often, the condition is reported on the lower limbs of elderly women with actinically damaged skin.1,2 At times, it can be difficult to distinguish between KA and prurigo nodularis in these patients, who often report notable pruritus and might have associated eczematous dermatitis.2
Keratoacanthomas often are treated with aggressive modalities, such as Mohs micrographic surgery, excision, and electrodesiccation and curettage. Some patients are hesitant to undergo surgical treatment, however, preferring a less invasive approach. Trauma from these aggressive modalities also can be associated with recurrence of existing lesions or development of new KAs, possibly related to stimulation of a local inflammatory response and upregulation of helper T cells.2-4
Acitretin and other systemic retinoids often are considered first-line therapy for multiple KAs. Cyclosporine has been added as adjunctive treatment in cases associated with prurigo nodularis or eczematous dermatitis1,2; however, these treatments have a high rate of discontinuation because of adverse effects, including transaminitis, xerostomia, alopecia (acitretin), and renal toxicity (cyclosporine).2
Another treatment option for patients with coexisting KA and prurigo nodularis is intralesional corticosteroids, often administered in combination with systemic retinoids.3 Topical 5-fluorouracil (5-FU) has been used successfully for KA, but topical treatment options are limited if 5-FU fails. Topical imiquimod and cryotherapy are thought to be of little benefit, and the appearance of new KA within imiquimod and cryotherapy treatment fields has been reported.1,2 Topical corticosteroids have been used as an adjuvant therapy for multiple KAs associated with prurigo nodularis; however, a PubMed search of articles indexed for MEDLINE using the terms keratoacanthoma and steroid and keratoacanthoma and prurigo nodularis yielded no published reports of successful use of topical corticosteroids as monotherapy.2
The Technique
For patients who want to continue topical treatment of coexisting KA and prurigo nodularis after topical 5-FU fails, we have found success applying a high-potency topical corticosteroid to affected areas under occlusion nightly for 6 to 8 weeks. This treatment not only leads to resolution of KA but also simultaneously treats prurigo nodules that might be clinically difficult to distinguish from KA in some presentations. This regimen has been implemented in our practice with remarkable reduction of KA burden and relief of pruritus.
In a 68-year-old woman who was treated with this technique, multiple biopsies had shown KA (or well-differentiated squamous cell carcinoma that appeared clinically as KA) on the shin (Figure, A) arising amid many lesions consistent with prurigo nodules. Topical 5-FU had failed, but the patient did not want to be treated with a more invasive modality, such as excision or injection.
Instead, we treated the patient with clobetasol propionate ointment 0.05% under occlusion nightly for 6 weeks. This strategy produced resolution of both KA and prurigo nodules (Figure, B). When lesions recurred after a few months, they were successfully re-treated with topical clobetasol under occlusion in a second 6-week course.
Practical Implications
Treatment of multiple KAs associated with prurigo nodularis can present a distinct challenge. For the subset of patients who want to pursue topical treatment, options reported in the literature are limited. We have found success treating multiple KAs and associated prurigo nodules with a high-potency topical corticosteroid under occlusion, with minimal or no adverse effects. We believe that a topical corticosteroid can be implemented easily in clinical practice before a more invasive surgical or intralesional modality is considered.
- Kwiek B, Schwartz RA. Keratoacanthoma (KA): an update and review. J Am Acad Dermatol. 2016;74:1220-1233. doi:10.1016/j.jaad.2015.11.033
- Wu TP, Miller K, Cohen DE, et al. Keratoacanthomas arising in association with prurigo nodules in pruritic, actinically damaged skin. J Am Acad Dermatol. 2013;69:426-430. doi:10.1016/J.JAAD.2013.03.035
- Sanders S, Busam KJ, Halpern AC, et al. Intralesional corticosteroid treatment of multiple eruptive keratoacanthomas: case report and review of a controversial therapy. Dermatol Surg. 2002;28:954-958. doi:10.1046/j.1524-4725.2002.02069.x
- Lee S, Coutts I, Ryan A, et al. Keratoacanthoma formation after skin grafting: a brief report and pathophysiological hypothesis. Australas J Dermatol. 2017;58:E117-E119. doi:10.1111/ajd.12501
Practice Gap
Multiple keratoacanthomas (KAs) of the legs often are a challenge to treat, especially when these lesions appear within a field of prurigo nodules. Multiple KAs associated with prurigo nodularis is a rarer finding; more often, the condition is reported on the lower limbs of elderly women with actinically damaged skin.1,2 At times, it can be difficult to distinguish between KA and prurigo nodularis in these patients, who often report notable pruritus and might have associated eczematous dermatitis.2
Keratoacanthomas often are treated with aggressive modalities, such as Mohs micrographic surgery, excision, and electrodesiccation and curettage. Some patients are hesitant to undergo surgical treatment, however, preferring a less invasive approach. Trauma from these aggressive modalities also can be associated with recurrence of existing lesions or development of new KAs, possibly related to stimulation of a local inflammatory response and upregulation of helper T cells.2-4
Acitretin and other systemic retinoids often are considered first-line therapy for multiple KAs. Cyclosporine has been added as adjunctive treatment in cases associated with prurigo nodularis or eczematous dermatitis1,2; however, these treatments have a high rate of discontinuation because of adverse effects, including transaminitis, xerostomia, alopecia (acitretin), and renal toxicity (cyclosporine).2
Another treatment option for patients with coexisting KA and prurigo nodularis is intralesional corticosteroids, often administered in combination with systemic retinoids.3 Topical 5-fluorouracil (5-FU) has been used successfully for KA, but topical treatment options are limited if 5-FU fails. Topical imiquimod and cryotherapy are thought to be of little benefit, and the appearance of new KA within imiquimod and cryotherapy treatment fields has been reported.1,2 Topical corticosteroids have been used as an adjuvant therapy for multiple KAs associated with prurigo nodularis; however, a PubMed search of articles indexed for MEDLINE using the terms keratoacanthoma and steroid and keratoacanthoma and prurigo nodularis yielded no published reports of successful use of topical corticosteroids as monotherapy.2
The Technique
For patients who want to continue topical treatment of coexisting KA and prurigo nodularis after topical 5-FU fails, we have found success applying a high-potency topical corticosteroid to affected areas under occlusion nightly for 6 to 8 weeks. This treatment not only leads to resolution of KA but also simultaneously treats prurigo nodules that might be clinically difficult to distinguish from KA in some presentations. This regimen has been implemented in our practice with remarkable reduction of KA burden and relief of pruritus.
In a 68-year-old woman who was treated with this technique, multiple biopsies had shown KA (or well-differentiated squamous cell carcinoma that appeared clinically as KA) on the shin (Figure, A) arising amid many lesions consistent with prurigo nodules. Topical 5-FU had failed, but the patient did not want to be treated with a more invasive modality, such as excision or injection.
Instead, we treated the patient with clobetasol propionate ointment 0.05% under occlusion nightly for 6 weeks. This strategy produced resolution of both KA and prurigo nodules (Figure, B). When lesions recurred after a few months, they were successfully re-treated with topical clobetasol under occlusion in a second 6-week course.
Practical Implications
Treatment of multiple KAs associated with prurigo nodularis can present a distinct challenge. For the subset of patients who want to pursue topical treatment, options reported in the literature are limited. We have found success treating multiple KAs and associated prurigo nodules with a high-potency topical corticosteroid under occlusion, with minimal or no adverse effects. We believe that a topical corticosteroid can be implemented easily in clinical practice before a more invasive surgical or intralesional modality is considered.
Practice Gap
Multiple keratoacanthomas (KAs) of the legs often are a challenge to treat, especially when these lesions appear within a field of prurigo nodules. Multiple KAs associated with prurigo nodularis is a rarer finding; more often, the condition is reported on the lower limbs of elderly women with actinically damaged skin.1,2 At times, it can be difficult to distinguish between KA and prurigo nodularis in these patients, who often report notable pruritus and might have associated eczematous dermatitis.2
Keratoacanthomas often are treated with aggressive modalities, such as Mohs micrographic surgery, excision, and electrodesiccation and curettage. Some patients are hesitant to undergo surgical treatment, however, preferring a less invasive approach. Trauma from these aggressive modalities also can be associated with recurrence of existing lesions or development of new KAs, possibly related to stimulation of a local inflammatory response and upregulation of helper T cells.2-4
Acitretin and other systemic retinoids often are considered first-line therapy for multiple KAs. Cyclosporine has been added as adjunctive treatment in cases associated with prurigo nodularis or eczematous dermatitis1,2; however, these treatments have a high rate of discontinuation because of adverse effects, including transaminitis, xerostomia, alopecia (acitretin), and renal toxicity (cyclosporine).2
Another treatment option for patients with coexisting KA and prurigo nodularis is intralesional corticosteroids, often administered in combination with systemic retinoids.3 Topical 5-fluorouracil (5-FU) has been used successfully for KA, but topical treatment options are limited if 5-FU fails. Topical imiquimod and cryotherapy are thought to be of little benefit, and the appearance of new KA within imiquimod and cryotherapy treatment fields has been reported.1,2 Topical corticosteroids have been used as an adjuvant therapy for multiple KAs associated with prurigo nodularis; however, a PubMed search of articles indexed for MEDLINE using the terms keratoacanthoma and steroid and keratoacanthoma and prurigo nodularis yielded no published reports of successful use of topical corticosteroids as monotherapy.2
The Technique
For patients who want to continue topical treatment of coexisting KA and prurigo nodularis after topical 5-FU fails, we have found success applying a high-potency topical corticosteroid to affected areas under occlusion nightly for 6 to 8 weeks. This treatment not only leads to resolution of KA but also simultaneously treats prurigo nodules that might be clinically difficult to distinguish from KA in some presentations. This regimen has been implemented in our practice with remarkable reduction of KA burden and relief of pruritus.
In a 68-year-old woman who was treated with this technique, multiple biopsies had shown KA (or well-differentiated squamous cell carcinoma that appeared clinically as KA) on the shin (Figure, A) arising amid many lesions consistent with prurigo nodules. Topical 5-FU had failed, but the patient did not want to be treated with a more invasive modality, such as excision or injection.
Instead, we treated the patient with clobetasol propionate ointment 0.05% under occlusion nightly for 6 weeks. This strategy produced resolution of both KA and prurigo nodules (Figure, B). When lesions recurred after a few months, they were successfully re-treated with topical clobetasol under occlusion in a second 6-week course.
Practical Implications
Treatment of multiple KAs associated with prurigo nodularis can present a distinct challenge. For the subset of patients who want to pursue topical treatment, options reported in the literature are limited. We have found success treating multiple KAs and associated prurigo nodules with a high-potency topical corticosteroid under occlusion, with minimal or no adverse effects. We believe that a topical corticosteroid can be implemented easily in clinical practice before a more invasive surgical or intralesional modality is considered.
- Kwiek B, Schwartz RA. Keratoacanthoma (KA): an update and review. J Am Acad Dermatol. 2016;74:1220-1233. doi:10.1016/j.jaad.2015.11.033
- Wu TP, Miller K, Cohen DE, et al. Keratoacanthomas arising in association with prurigo nodules in pruritic, actinically damaged skin. J Am Acad Dermatol. 2013;69:426-430. doi:10.1016/J.JAAD.2013.03.035
- Sanders S, Busam KJ, Halpern AC, et al. Intralesional corticosteroid treatment of multiple eruptive keratoacanthomas: case report and review of a controversial therapy. Dermatol Surg. 2002;28:954-958. doi:10.1046/j.1524-4725.2002.02069.x
- Lee S, Coutts I, Ryan A, et al. Keratoacanthoma formation after skin grafting: a brief report and pathophysiological hypothesis. Australas J Dermatol. 2017;58:E117-E119. doi:10.1111/ajd.12501
- Kwiek B, Schwartz RA. Keratoacanthoma (KA): an update and review. J Am Acad Dermatol. 2016;74:1220-1233. doi:10.1016/j.jaad.2015.11.033
- Wu TP, Miller K, Cohen DE, et al. Keratoacanthomas arising in association with prurigo nodules in pruritic, actinically damaged skin. J Am Acad Dermatol. 2013;69:426-430. doi:10.1016/J.JAAD.2013.03.035
- Sanders S, Busam KJ, Halpern AC, et al. Intralesional corticosteroid treatment of multiple eruptive keratoacanthomas: case report and review of a controversial therapy. Dermatol Surg. 2002;28:954-958. doi:10.1046/j.1524-4725.2002.02069.x
- Lee S, Coutts I, Ryan A, et al. Keratoacanthoma formation after skin grafting: a brief report and pathophysiological hypothesis. Australas J Dermatol. 2017;58:E117-E119. doi:10.1111/ajd.12501
Gynecologic and Obstetric Implications of Darier Disease: A Dermatologist’s Perspective
Darier disease (DD)(also known as dyskeratosis follicularis) is a rare, autosomal-dominant genodermatosis characterized by greasy, rough, keratotic papules; typical nail abnormalities; mucosal changes; and characteristic dyskeratotic acantholysis that is called corps ronds and grains on histopathologic analysis. Darier disease is caused by mutations of the ATP2A2 gene on chromosome 12q23-24.1,2
Because of the autosomal-dominant pattern of inheritance in DD, if either parent is affected by DD, approximately 50% of their offspring will have the disorder. Therefore, couples need to be offered genetic counseling at a preconception visit or early in pregnancy. Although penetrance of DD is complete, spontaneous mutations are frequent and expressivity is variable1; prenatal diagnosis, though available since the 1980s, is therefore unreliable in DD, given the considerable variation in phenotypic expressivity. Differing phenotypes underscore the importance of proper counseling by the treating dermatologist or other provider. Females with a mild or nearly undetectable phenotype can give birth to a child with severe disease.
Lack of clear understanding about the variable phenotypic expressivity of DD can cause considerable anger, anxiety, guilt, psychological trauma, and fear in parents, should their child later develop a severe phenotype. They may feel that they were not properly prepared for the outcome. The physician-parent or physician-patient relationship can be negatively impacted if ongoing counseling is inadequate.
Clinically, DD presents in early adolescence (age range, 6–20 years) in most patients, which means that the disease and female reproductive years are contemporaneous. However, gynecologic and obstetric issues and complications of DD rarely have been addressed.3 Oromucosal involvement in DD is reported in 13% to 50% of cases, yet vaginal and cervical mucosal involvement rarely has been described,4,5 likely due to underreporting. Therefore, in this rare disease, it is important to address these aspects so that the patients are provided with appropriate management options.
Implications for Cervical Screening and Papanicolaou Tests
Cytopathologic findings of a Papanicolaou test taken from a patient with DD can lead to erroneous diagnosis of a low-grade squamous intraepithelial lesion due to cervical involvement by the disease process; therefore, correct interpretation of a smear may be inappropriate and erroneous. The cytopathologist needs to be informed of the patient’s diagnosis of DD in advance for appropriate reporting.5,6
Obstetric Implications
Fertility is normal in DD patients, and pregnancy usually has a normal course; however, exacerbation and remission of disease have been reported. de la Rosa Carrillo7 reported a case of vegetating DD during pregnancy. He described it as an exacerbation with concurrent bacterial infection and bilateral external otitis.7 Spouge et al8 reported a case of a 58-year-old woman who was the mother of 4 DD patients. She experienced an exacerbation of DD during all 6 pregnancies but improved immediately postpartum.8 Espy et al9 evaluated 8 cases of women with DD and described spontaneous improvement of the disorder during pregnancy (1 case) or while taking an oral contraceptive (3 cases).
Prenatal Counseling
Women with DD should be encouraged to talk to their dermatologist, obstetrician, or other provider of prenatal care regarding plans for pregnancy, labor, and delivery, as these events might be affected by the disorder. During pregnancy, careful monitoring and self-care remain essential. Simple measures to reduce the impact of irritants on DD during pregnancy include keeping the skin cool, using a soothing moisturizer, applying photoprotection, and using sunscreen. Treatment with systemic retinoids must be avoided if pregnancy is planned.
Warty plaques and papules of DD can involve flexures (groin, vulva, and perineum), with resultant malodor and pruritus10 as well as the potential for (drug resistant) secondary infection (eg, Staphylococcus aureus, group B Streptococcus, viruses [eg, Kaposi varicelliform eruption]). Skin swabs should be taken for culture and susceptibility testing, and infection should be treated at the earliest sign.
Management Concerns During Pregnancy and Delivery
Because the benefits of treating DD might outweigh risk in certain cases, thorough discussion with the patient about options is recommended, including the following concerns:
• Because mucocutaneous elasticity of the birth canal, including the vulva, perineum, and groin, is essential for nontraumatic vaginal delivery, it might be necessary to schedule an elective cesarean delivery in DD patients in whom these regions are involved.11
• In females with lower abdominal lesions, using a Pfannenstiel-Kerr incision for cesarean delivery might be problematic.11
• A single case report has described successful anesthetic management of labor, delivery, and postpartum care in a DD patient.12 Involvement of the skin of the back might preclude safe administration of regional anesthesia; however, because DD lesions are considered noninfectious, the authors operatively administered a subarachnoid block at the L3-L4 interspace through a lesion-free area. Postpartum, the patient was observed in the intensive care unit. She and the baby remained stable; she did not develop infectious complications, including a central nervous system infection.12
•Mucosal involvement is relatively rare in DD and has not been reported to compromise airway management.8
Postnatal Considerations
Breastfeeding might have to be stopped early or withheld altogether if there is widespread involvement of the skin of the breast or the nipple.11 Darier disease has been associated with neuropsychiatric manifestations, including major depression (30%), suicide attempts (13%), suicidal thoughts (31%), cyclothymia, bipolar disorder (4%), and epilepsy (3%).13,14 Therefore, patients should be screened for postpartum psychiatric manifestations at an early follow-up visit.
Final Thoughts
Although the etiology of DD is well known, the gynelogic and obstretric implications of this genodermatosis have rarely been described. This brief commentary is an attempt to provide the important information to a practicing dermatologist for appropriate management of female DD patients.
- Bale SJ, Toro JR. Genetic basis of Darier-White disease: bad pumps cause bumps. J Cutan Med Surg. 2000;4:103-106. doi:10.1177/120347540000400212
- Kansal NK, Hazarika N, Rao S. Familial case of Darier disease with guttate leukoderma: a case series from India. Indian Dermatol Online J. 2018;9:62-63. doi:10.4103/idoj.IDOJ_52_17
- Lynch PJ. Vulvar dermatoses: the eczematous diseases. In: Black M, Ambros-Rudolph CM, Edwards L, Lynch P, eds. Obstetric and Gynecologic Dermatology. 3rd ed. Mosby-Elsevier; 2008:192-194.
- Adam AE. Ectopic Darier’s disease of the cervix: an extraordinary cause of an abnormal smear. Cytopathology. 1996;7:414-421. doi:10.1111/j.1365-2303.1996.tb00547.x
- Suárez-Peñaranda JM, Antúnez JR, Del Rio E, et al. Vaginal involvement in a woman with Darier’s disease: a case report. Acta Cytol. 2005;49:530-532. doi:10.1159/000326200
- Boon ME. Dr. Darier’s lesson: it can be advantageous to the patient to ignore evident cytonuclear changes. Acta Cytol. 2005;49:469-470. doi:10.1159/000326189
- de la Rosa Carrillo D. Vegetating Darier’s disease during pregnancy. Acta Derm Venereol. 2006;86:259-260. doi:10.2340/00015555-0066
- Spouge JD, Trott JR, Chesko G. Darier-White’s disease: a cause of white lesions of the mucosa. report of four cases. Oral Surg Oral Med Oral Pathol. 1966;21:441-457. doi:10.1016/0030-4220(66)90401-4
- Espy PD, Stone S, Jolly HW Jr. Hormonal dependency in Darier disease. Cutis. 1976;17:315-320.
- De D, Kanwar AJ, Saikia UN. Uncommon flexural presentation of Darier disease. J Cutan Med Surg. 2008;12:249-252. doi:10.2310/7750.2008.07035
- Quinlivan JA, O'Halloran LC. Darier’s disease and pregnancy. Dermatol Aspects. 2013;1:1-3. doi:10.7243/2053-5309-1-1
- Sharma R, Singh BP, Das SN. Anesthetic management of cesarean section in a parturient with Darier’s disease. Acta Anaesthesiol Taiwan. 2010;48:158-159. doi:10.1016/S1875-4597(10)60051-3
- Gordon-Smith K, Jones LA, Burge SM, et al. The neuropsychiatric phenotype in Darier disease. Br J Dermatol. 2010;163:515-522. doi:10.1111/j.1365-2133.2010.09834.x
- Dodiuk-Gad RP, Cohen-Barak E, Khayat M, et al. Darier disease in Israel: combined evaluation of genetic and neuropsychiatric aspects. Br J Dermatol. 2016;174:562-568. doi:10.1111/bjd.14220
Darier disease (DD)(also known as dyskeratosis follicularis) is a rare, autosomal-dominant genodermatosis characterized by greasy, rough, keratotic papules; typical nail abnormalities; mucosal changes; and characteristic dyskeratotic acantholysis that is called corps ronds and grains on histopathologic analysis. Darier disease is caused by mutations of the ATP2A2 gene on chromosome 12q23-24.1,2
Because of the autosomal-dominant pattern of inheritance in DD, if either parent is affected by DD, approximately 50% of their offspring will have the disorder. Therefore, couples need to be offered genetic counseling at a preconception visit or early in pregnancy. Although penetrance of DD is complete, spontaneous mutations are frequent and expressivity is variable1; prenatal diagnosis, though available since the 1980s, is therefore unreliable in DD, given the considerable variation in phenotypic expressivity. Differing phenotypes underscore the importance of proper counseling by the treating dermatologist or other provider. Females with a mild or nearly undetectable phenotype can give birth to a child with severe disease.
Lack of clear understanding about the variable phenotypic expressivity of DD can cause considerable anger, anxiety, guilt, psychological trauma, and fear in parents, should their child later develop a severe phenotype. They may feel that they were not properly prepared for the outcome. The physician-parent or physician-patient relationship can be negatively impacted if ongoing counseling is inadequate.
Clinically, DD presents in early adolescence (age range, 6–20 years) in most patients, which means that the disease and female reproductive years are contemporaneous. However, gynecologic and obstetric issues and complications of DD rarely have been addressed.3 Oromucosal involvement in DD is reported in 13% to 50% of cases, yet vaginal and cervical mucosal involvement rarely has been described,4,5 likely due to underreporting. Therefore, in this rare disease, it is important to address these aspects so that the patients are provided with appropriate management options.
Implications for Cervical Screening and Papanicolaou Tests
Cytopathologic findings of a Papanicolaou test taken from a patient with DD can lead to erroneous diagnosis of a low-grade squamous intraepithelial lesion due to cervical involvement by the disease process; therefore, correct interpretation of a smear may be inappropriate and erroneous. The cytopathologist needs to be informed of the patient’s diagnosis of DD in advance for appropriate reporting.5,6
Obstetric Implications
Fertility is normal in DD patients, and pregnancy usually has a normal course; however, exacerbation and remission of disease have been reported. de la Rosa Carrillo7 reported a case of vegetating DD during pregnancy. He described it as an exacerbation with concurrent bacterial infection and bilateral external otitis.7 Spouge et al8 reported a case of a 58-year-old woman who was the mother of 4 DD patients. She experienced an exacerbation of DD during all 6 pregnancies but improved immediately postpartum.8 Espy et al9 evaluated 8 cases of women with DD and described spontaneous improvement of the disorder during pregnancy (1 case) or while taking an oral contraceptive (3 cases).
Prenatal Counseling
Women with DD should be encouraged to talk to their dermatologist, obstetrician, or other provider of prenatal care regarding plans for pregnancy, labor, and delivery, as these events might be affected by the disorder. During pregnancy, careful monitoring and self-care remain essential. Simple measures to reduce the impact of irritants on DD during pregnancy include keeping the skin cool, using a soothing moisturizer, applying photoprotection, and using sunscreen. Treatment with systemic retinoids must be avoided if pregnancy is planned.
Warty plaques and papules of DD can involve flexures (groin, vulva, and perineum), with resultant malodor and pruritus10 as well as the potential for (drug resistant) secondary infection (eg, Staphylococcus aureus, group B Streptococcus, viruses [eg, Kaposi varicelliform eruption]). Skin swabs should be taken for culture and susceptibility testing, and infection should be treated at the earliest sign.
Management Concerns During Pregnancy and Delivery
Because the benefits of treating DD might outweigh risk in certain cases, thorough discussion with the patient about options is recommended, including the following concerns:
• Because mucocutaneous elasticity of the birth canal, including the vulva, perineum, and groin, is essential for nontraumatic vaginal delivery, it might be necessary to schedule an elective cesarean delivery in DD patients in whom these regions are involved.11
• In females with lower abdominal lesions, using a Pfannenstiel-Kerr incision for cesarean delivery might be problematic.11
• A single case report has described successful anesthetic management of labor, delivery, and postpartum care in a DD patient.12 Involvement of the skin of the back might preclude safe administration of regional anesthesia; however, because DD lesions are considered noninfectious, the authors operatively administered a subarachnoid block at the L3-L4 interspace through a lesion-free area. Postpartum, the patient was observed in the intensive care unit. She and the baby remained stable; she did not develop infectious complications, including a central nervous system infection.12
•Mucosal involvement is relatively rare in DD and has not been reported to compromise airway management.8
Postnatal Considerations
Breastfeeding might have to be stopped early or withheld altogether if there is widespread involvement of the skin of the breast or the nipple.11 Darier disease has been associated with neuropsychiatric manifestations, including major depression (30%), suicide attempts (13%), suicidal thoughts (31%), cyclothymia, bipolar disorder (4%), and epilepsy (3%).13,14 Therefore, patients should be screened for postpartum psychiatric manifestations at an early follow-up visit.
Final Thoughts
Although the etiology of DD is well known, the gynelogic and obstretric implications of this genodermatosis have rarely been described. This brief commentary is an attempt to provide the important information to a practicing dermatologist for appropriate management of female DD patients.
Darier disease (DD)(also known as dyskeratosis follicularis) is a rare, autosomal-dominant genodermatosis characterized by greasy, rough, keratotic papules; typical nail abnormalities; mucosal changes; and characteristic dyskeratotic acantholysis that is called corps ronds and grains on histopathologic analysis. Darier disease is caused by mutations of the ATP2A2 gene on chromosome 12q23-24.1,2
Because of the autosomal-dominant pattern of inheritance in DD, if either parent is affected by DD, approximately 50% of their offspring will have the disorder. Therefore, couples need to be offered genetic counseling at a preconception visit or early in pregnancy. Although penetrance of DD is complete, spontaneous mutations are frequent and expressivity is variable1; prenatal diagnosis, though available since the 1980s, is therefore unreliable in DD, given the considerable variation in phenotypic expressivity. Differing phenotypes underscore the importance of proper counseling by the treating dermatologist or other provider. Females with a mild or nearly undetectable phenotype can give birth to a child with severe disease.
Lack of clear understanding about the variable phenotypic expressivity of DD can cause considerable anger, anxiety, guilt, psychological trauma, and fear in parents, should their child later develop a severe phenotype. They may feel that they were not properly prepared for the outcome. The physician-parent or physician-patient relationship can be negatively impacted if ongoing counseling is inadequate.
Clinically, DD presents in early adolescence (age range, 6–20 years) in most patients, which means that the disease and female reproductive years are contemporaneous. However, gynecologic and obstetric issues and complications of DD rarely have been addressed.3 Oromucosal involvement in DD is reported in 13% to 50% of cases, yet vaginal and cervical mucosal involvement rarely has been described,4,5 likely due to underreporting. Therefore, in this rare disease, it is important to address these aspects so that the patients are provided with appropriate management options.
Implications for Cervical Screening and Papanicolaou Tests
Cytopathologic findings of a Papanicolaou test taken from a patient with DD can lead to erroneous diagnosis of a low-grade squamous intraepithelial lesion due to cervical involvement by the disease process; therefore, correct interpretation of a smear may be inappropriate and erroneous. The cytopathologist needs to be informed of the patient’s diagnosis of DD in advance for appropriate reporting.5,6
Obstetric Implications
Fertility is normal in DD patients, and pregnancy usually has a normal course; however, exacerbation and remission of disease have been reported. de la Rosa Carrillo7 reported a case of vegetating DD during pregnancy. He described it as an exacerbation with concurrent bacterial infection and bilateral external otitis.7 Spouge et al8 reported a case of a 58-year-old woman who was the mother of 4 DD patients. She experienced an exacerbation of DD during all 6 pregnancies but improved immediately postpartum.8 Espy et al9 evaluated 8 cases of women with DD and described spontaneous improvement of the disorder during pregnancy (1 case) or while taking an oral contraceptive (3 cases).
Prenatal Counseling
Women with DD should be encouraged to talk to their dermatologist, obstetrician, or other provider of prenatal care regarding plans for pregnancy, labor, and delivery, as these events might be affected by the disorder. During pregnancy, careful monitoring and self-care remain essential. Simple measures to reduce the impact of irritants on DD during pregnancy include keeping the skin cool, using a soothing moisturizer, applying photoprotection, and using sunscreen. Treatment with systemic retinoids must be avoided if pregnancy is planned.
Warty plaques and papules of DD can involve flexures (groin, vulva, and perineum), with resultant malodor and pruritus10 as well as the potential for (drug resistant) secondary infection (eg, Staphylococcus aureus, group B Streptococcus, viruses [eg, Kaposi varicelliform eruption]). Skin swabs should be taken for culture and susceptibility testing, and infection should be treated at the earliest sign.
Management Concerns During Pregnancy and Delivery
Because the benefits of treating DD might outweigh risk in certain cases, thorough discussion with the patient about options is recommended, including the following concerns:
• Because mucocutaneous elasticity of the birth canal, including the vulva, perineum, and groin, is essential for nontraumatic vaginal delivery, it might be necessary to schedule an elective cesarean delivery in DD patients in whom these regions are involved.11
• In females with lower abdominal lesions, using a Pfannenstiel-Kerr incision for cesarean delivery might be problematic.11
• A single case report has described successful anesthetic management of labor, delivery, and postpartum care in a DD patient.12 Involvement of the skin of the back might preclude safe administration of regional anesthesia; however, because DD lesions are considered noninfectious, the authors operatively administered a subarachnoid block at the L3-L4 interspace through a lesion-free area. Postpartum, the patient was observed in the intensive care unit. She and the baby remained stable; she did not develop infectious complications, including a central nervous system infection.12
•Mucosal involvement is relatively rare in DD and has not been reported to compromise airway management.8
Postnatal Considerations
Breastfeeding might have to be stopped early or withheld altogether if there is widespread involvement of the skin of the breast or the nipple.11 Darier disease has been associated with neuropsychiatric manifestations, including major depression (30%), suicide attempts (13%), suicidal thoughts (31%), cyclothymia, bipolar disorder (4%), and epilepsy (3%).13,14 Therefore, patients should be screened for postpartum psychiatric manifestations at an early follow-up visit.
Final Thoughts
Although the etiology of DD is well known, the gynelogic and obstretric implications of this genodermatosis have rarely been described. This brief commentary is an attempt to provide the important information to a practicing dermatologist for appropriate management of female DD patients.
- Bale SJ, Toro JR. Genetic basis of Darier-White disease: bad pumps cause bumps. J Cutan Med Surg. 2000;4:103-106. doi:10.1177/120347540000400212
- Kansal NK, Hazarika N, Rao S. Familial case of Darier disease with guttate leukoderma: a case series from India. Indian Dermatol Online J. 2018;9:62-63. doi:10.4103/idoj.IDOJ_52_17
- Lynch PJ. Vulvar dermatoses: the eczematous diseases. In: Black M, Ambros-Rudolph CM, Edwards L, Lynch P, eds. Obstetric and Gynecologic Dermatology. 3rd ed. Mosby-Elsevier; 2008:192-194.
- Adam AE. Ectopic Darier’s disease of the cervix: an extraordinary cause of an abnormal smear. Cytopathology. 1996;7:414-421. doi:10.1111/j.1365-2303.1996.tb00547.x
- Suárez-Peñaranda JM, Antúnez JR, Del Rio E, et al. Vaginal involvement in a woman with Darier’s disease: a case report. Acta Cytol. 2005;49:530-532. doi:10.1159/000326200
- Boon ME. Dr. Darier’s lesson: it can be advantageous to the patient to ignore evident cytonuclear changes. Acta Cytol. 2005;49:469-470. doi:10.1159/000326189
- de la Rosa Carrillo D. Vegetating Darier’s disease during pregnancy. Acta Derm Venereol. 2006;86:259-260. doi:10.2340/00015555-0066
- Spouge JD, Trott JR, Chesko G. Darier-White’s disease: a cause of white lesions of the mucosa. report of four cases. Oral Surg Oral Med Oral Pathol. 1966;21:441-457. doi:10.1016/0030-4220(66)90401-4
- Espy PD, Stone S, Jolly HW Jr. Hormonal dependency in Darier disease. Cutis. 1976;17:315-320.
- De D, Kanwar AJ, Saikia UN. Uncommon flexural presentation of Darier disease. J Cutan Med Surg. 2008;12:249-252. doi:10.2310/7750.2008.07035
- Quinlivan JA, O'Halloran LC. Darier’s disease and pregnancy. Dermatol Aspects. 2013;1:1-3. doi:10.7243/2053-5309-1-1
- Sharma R, Singh BP, Das SN. Anesthetic management of cesarean section in a parturient with Darier’s disease. Acta Anaesthesiol Taiwan. 2010;48:158-159. doi:10.1016/S1875-4597(10)60051-3
- Gordon-Smith K, Jones LA, Burge SM, et al. The neuropsychiatric phenotype in Darier disease. Br J Dermatol. 2010;163:515-522. doi:10.1111/j.1365-2133.2010.09834.x
- Dodiuk-Gad RP, Cohen-Barak E, Khayat M, et al. Darier disease in Israel: combined evaluation of genetic and neuropsychiatric aspects. Br J Dermatol. 2016;174:562-568. doi:10.1111/bjd.14220
- Bale SJ, Toro JR. Genetic basis of Darier-White disease: bad pumps cause bumps. J Cutan Med Surg. 2000;4:103-106. doi:10.1177/120347540000400212
- Kansal NK, Hazarika N, Rao S. Familial case of Darier disease with guttate leukoderma: a case series from India. Indian Dermatol Online J. 2018;9:62-63. doi:10.4103/idoj.IDOJ_52_17
- Lynch PJ. Vulvar dermatoses: the eczematous diseases. In: Black M, Ambros-Rudolph CM, Edwards L, Lynch P, eds. Obstetric and Gynecologic Dermatology. 3rd ed. Mosby-Elsevier; 2008:192-194.
- Adam AE. Ectopic Darier’s disease of the cervix: an extraordinary cause of an abnormal smear. Cytopathology. 1996;7:414-421. doi:10.1111/j.1365-2303.1996.tb00547.x
- Suárez-Peñaranda JM, Antúnez JR, Del Rio E, et al. Vaginal involvement in a woman with Darier’s disease: a case report. Acta Cytol. 2005;49:530-532. doi:10.1159/000326200
- Boon ME. Dr. Darier’s lesson: it can be advantageous to the patient to ignore evident cytonuclear changes. Acta Cytol. 2005;49:469-470. doi:10.1159/000326189
- de la Rosa Carrillo D. Vegetating Darier’s disease during pregnancy. Acta Derm Venereol. 2006;86:259-260. doi:10.2340/00015555-0066
- Spouge JD, Trott JR, Chesko G. Darier-White’s disease: a cause of white lesions of the mucosa. report of four cases. Oral Surg Oral Med Oral Pathol. 1966;21:441-457. doi:10.1016/0030-4220(66)90401-4
- Espy PD, Stone S, Jolly HW Jr. Hormonal dependency in Darier disease. Cutis. 1976;17:315-320.
- De D, Kanwar AJ, Saikia UN. Uncommon flexural presentation of Darier disease. J Cutan Med Surg. 2008;12:249-252. doi:10.2310/7750.2008.07035
- Quinlivan JA, O'Halloran LC. Darier’s disease and pregnancy. Dermatol Aspects. 2013;1:1-3. doi:10.7243/2053-5309-1-1
- Sharma R, Singh BP, Das SN. Anesthetic management of cesarean section in a parturient with Darier’s disease. Acta Anaesthesiol Taiwan. 2010;48:158-159. doi:10.1016/S1875-4597(10)60051-3
- Gordon-Smith K, Jones LA, Burge SM, et al. The neuropsychiatric phenotype in Darier disease. Br J Dermatol. 2010;163:515-522. doi:10.1111/j.1365-2133.2010.09834.x
- Dodiuk-Gad RP, Cohen-Barak E, Khayat M, et al. Darier disease in Israel: combined evaluation of genetic and neuropsychiatric aspects. Br J Dermatol. 2016;174:562-568. doi:10.1111/bjd.14220
Practice Points
- Because Darier disease (DD) manifests during reproductive years, systemic retinoids should be used carefully in female patients.
- For a Papanicolaou test to be properly interpreted in a patient with DD, the cytopathologist must be informed of the DD diagnosis.
- Darier disease may be exacerbated or relieved during pregnancy.