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High-calorie diet may worsen Wilson disease
A high-calorie diet may cause earlier onset of more severe Wilson disease, according to a rodent study.
If translatable to humans, the results could explain “striking phenotype-genotype discrepancies” between patients with Wilson disease, and may give reason to monitor nutrition more closely, particularly dietary levels of fat and sugar, reported lead author Claudia Einer, a PhD candidate at the German Research Center for Environmental Health in Neuherberg, Germany, and her colleagues. Their findings clarify an association between impaired copper metabolism, which defines Wilson disease, and liver steatosis, a common finding in affected patients.
“Indeed, Wilson disease often may be misdiagnosed as nonalcoholic fatty liver disease (NAFLD),” the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology. They noted that previous reports showed similar mitochondrial alterations in the livers of patients with NAFLD and those with Wilson disease. Furthermore, in a case report of two twins with Wilson disease, the twin with bulimia nervosa developed severe liver disease, whereas the other twin, who was undernourished, had mild liver disease. Considering these observations and other supportive evidence, the investigators tested this apparent relationship between a high-fat diet and liver damage in Wilson disease.
“The rationale of this study was that both enriched copper and fatty acids cause bioenergetic defects and therefore synergistically and detrimentally may coincide on hepatic mitochondria, which was found to be dramatically the case,” the investigators wrote.
The study involved homozygous Atp7b–/– rats, which mirror Wilson disease, and heterozygous Atp7b+/– rats, which served as control subjects because they lack copper accumulation. The high-calorie diet contained high fat and sugar levels to mirror “the eating habits in Western society, causing the ‘American-lifestyle-induced-obesity syndrome.’ ”
Within several weeks of starting the high-calorie diet, both control and Wilson disease rats showed higher liver triglyceride levels and visceral fat mass compared with rats on the normal diet, with liver histology also showing macrosteatosis and increased NAFLD Activity Score (NAS). Control rats maintained similar body and liver weights regardless of diet; in contrast, Wilson disease rats on the high-calorie diet showed increased liver weight, compared with Wilson disease rats on the normal diet. In addition, Wilson disease rats fed the high-calorie diet had clinical liver injury, supported by elevated aspartate aminotransferase (AST) levels and gross hepatic damage. Under the microscope, histology revealed widespread necrosis, apoptosis, inflammation, and fibrosis; findings were sufficient to constitute nonalcoholic steatohepatitis in all Wilson disease rats fed the high-calorie diet, compared with just one-third of the control rats receiving high calories. Additional testing showed that Wilson disease rats fed the high-calorie diet had disease onset 20 days sooner than did Wilson disease rats fed the normal diet.
“This is a remarkable disease acceleration,” the investigators noted, highlighting the median survival of 106 days in Wilson disease rats fed a normal diet.
Copper testing showed that Wilson disease rats fed the high-calorie diet had high serum levels of non–ceruloplasmin-bound copper, which is a sign of overt liver damage; based on histologic findings, the copper likely came from destroyed hepatocytes. Regardless of diet type, Wilson disease rats developed high levels of copper within the liver, suggesting comparable copper consumption via water sources. Regardless of genotype, the high-calorie diet led to higher mitochondrial copper levels than those of the normal diet, but Wilson disease rats showed the highest levels of copper sequestration in mitochondria, to an extreme degree.
“Importantly,” the investigators wrote, “such increased mitochondrial copper significantly correlated with a higher NAS and a progressive Histologic Activity Index score.”
Closer inspection showed that the mitochondria of Wilson disease rats were abnormal regardless of diet, but those fed the high-calorie diet had “a most severe mitochondrial phenotype,” including detached membranes and ballooned cristae.
“These structural impairments were paralleled by remarkable mitochondrial functional deficits,” the investigators reported, referring to a significant decrease in adenosine triphosphate production and an increase in mitochondrial H2O2. In response to these mitochondrial abnormalities, cholesterol-related enzymes quadrupled, most prominently for biliary excretion. The investigators summed up these hepatic events as a “toxic triad of adenosine triphosphate depletion, increased reactive oxygen species, and increased bile salts [that led] to an earlier onset of the disease and to enhanced disease progression.”
To complete the set of experiments, rats were given the copper chelator methanobactin. This treatment effectively mitigated structural and functional abnormalities in mitochondria, which drove serum levels of AST, copper, and bile salts toward normalcy. Although treatment halted overt liver damage, histology revealed that resolution was incomplete.
“We conclude that lipid accumulation in copper-burdened hepatocytes may represent a ‘second-hit’ in Wilson disease, inducing liver damage, and suggest that further research should establish whether dietary counseling of Wilson disease patients may be of therapeutic benefit,” the investigators concluded.
The study was funded by Deutsche Forschungsgemeinschaft and the WiFoMed Society. The investigators reported no conflicts of interest.
SOURCE: Einer et al. Cell Mol Gastroenterol Hepatol. 2019 Jan 11. doi: 10.1016/j.jcmgh.2018.12.005.
A high-calorie diet may cause earlier onset of more severe Wilson disease, according to a rodent study.
If translatable to humans, the results could explain “striking phenotype-genotype discrepancies” between patients with Wilson disease, and may give reason to monitor nutrition more closely, particularly dietary levels of fat and sugar, reported lead author Claudia Einer, a PhD candidate at the German Research Center for Environmental Health in Neuherberg, Germany, and her colleagues. Their findings clarify an association between impaired copper metabolism, which defines Wilson disease, and liver steatosis, a common finding in affected patients.
“Indeed, Wilson disease often may be misdiagnosed as nonalcoholic fatty liver disease (NAFLD),” the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology. They noted that previous reports showed similar mitochondrial alterations in the livers of patients with NAFLD and those with Wilson disease. Furthermore, in a case report of two twins with Wilson disease, the twin with bulimia nervosa developed severe liver disease, whereas the other twin, who was undernourished, had mild liver disease. Considering these observations and other supportive evidence, the investigators tested this apparent relationship between a high-fat diet and liver damage in Wilson disease.
“The rationale of this study was that both enriched copper and fatty acids cause bioenergetic defects and therefore synergistically and detrimentally may coincide on hepatic mitochondria, which was found to be dramatically the case,” the investigators wrote.
The study involved homozygous Atp7b–/– rats, which mirror Wilson disease, and heterozygous Atp7b+/– rats, which served as control subjects because they lack copper accumulation. The high-calorie diet contained high fat and sugar levels to mirror “the eating habits in Western society, causing the ‘American-lifestyle-induced-obesity syndrome.’ ”
Within several weeks of starting the high-calorie diet, both control and Wilson disease rats showed higher liver triglyceride levels and visceral fat mass compared with rats on the normal diet, with liver histology also showing macrosteatosis and increased NAFLD Activity Score (NAS). Control rats maintained similar body and liver weights regardless of diet; in contrast, Wilson disease rats on the high-calorie diet showed increased liver weight, compared with Wilson disease rats on the normal diet. In addition, Wilson disease rats fed the high-calorie diet had clinical liver injury, supported by elevated aspartate aminotransferase (AST) levels and gross hepatic damage. Under the microscope, histology revealed widespread necrosis, apoptosis, inflammation, and fibrosis; findings were sufficient to constitute nonalcoholic steatohepatitis in all Wilson disease rats fed the high-calorie diet, compared with just one-third of the control rats receiving high calories. Additional testing showed that Wilson disease rats fed the high-calorie diet had disease onset 20 days sooner than did Wilson disease rats fed the normal diet.
“This is a remarkable disease acceleration,” the investigators noted, highlighting the median survival of 106 days in Wilson disease rats fed a normal diet.
Copper testing showed that Wilson disease rats fed the high-calorie diet had high serum levels of non–ceruloplasmin-bound copper, which is a sign of overt liver damage; based on histologic findings, the copper likely came from destroyed hepatocytes. Regardless of diet type, Wilson disease rats developed high levels of copper within the liver, suggesting comparable copper consumption via water sources. Regardless of genotype, the high-calorie diet led to higher mitochondrial copper levels than those of the normal diet, but Wilson disease rats showed the highest levels of copper sequestration in mitochondria, to an extreme degree.
“Importantly,” the investigators wrote, “such increased mitochondrial copper significantly correlated with a higher NAS and a progressive Histologic Activity Index score.”
Closer inspection showed that the mitochondria of Wilson disease rats were abnormal regardless of diet, but those fed the high-calorie diet had “a most severe mitochondrial phenotype,” including detached membranes and ballooned cristae.
“These structural impairments were paralleled by remarkable mitochondrial functional deficits,” the investigators reported, referring to a significant decrease in adenosine triphosphate production and an increase in mitochondrial H2O2. In response to these mitochondrial abnormalities, cholesterol-related enzymes quadrupled, most prominently for biliary excretion. The investigators summed up these hepatic events as a “toxic triad of adenosine triphosphate depletion, increased reactive oxygen species, and increased bile salts [that led] to an earlier onset of the disease and to enhanced disease progression.”
To complete the set of experiments, rats were given the copper chelator methanobactin. This treatment effectively mitigated structural and functional abnormalities in mitochondria, which drove serum levels of AST, copper, and bile salts toward normalcy. Although treatment halted overt liver damage, histology revealed that resolution was incomplete.
“We conclude that lipid accumulation in copper-burdened hepatocytes may represent a ‘second-hit’ in Wilson disease, inducing liver damage, and suggest that further research should establish whether dietary counseling of Wilson disease patients may be of therapeutic benefit,” the investigators concluded.
The study was funded by Deutsche Forschungsgemeinschaft and the WiFoMed Society. The investigators reported no conflicts of interest.
SOURCE: Einer et al. Cell Mol Gastroenterol Hepatol. 2019 Jan 11. doi: 10.1016/j.jcmgh.2018.12.005.
A high-calorie diet may cause earlier onset of more severe Wilson disease, according to a rodent study.
If translatable to humans, the results could explain “striking phenotype-genotype discrepancies” between patients with Wilson disease, and may give reason to monitor nutrition more closely, particularly dietary levels of fat and sugar, reported lead author Claudia Einer, a PhD candidate at the German Research Center for Environmental Health in Neuherberg, Germany, and her colleagues. Their findings clarify an association between impaired copper metabolism, which defines Wilson disease, and liver steatosis, a common finding in affected patients.
“Indeed, Wilson disease often may be misdiagnosed as nonalcoholic fatty liver disease (NAFLD),” the investigators wrote in Cellular and Molecular Gastroenterology and Hepatology. They noted that previous reports showed similar mitochondrial alterations in the livers of patients with NAFLD and those with Wilson disease. Furthermore, in a case report of two twins with Wilson disease, the twin with bulimia nervosa developed severe liver disease, whereas the other twin, who was undernourished, had mild liver disease. Considering these observations and other supportive evidence, the investigators tested this apparent relationship between a high-fat diet and liver damage in Wilson disease.
“The rationale of this study was that both enriched copper and fatty acids cause bioenergetic defects and therefore synergistically and detrimentally may coincide on hepatic mitochondria, which was found to be dramatically the case,” the investigators wrote.
The study involved homozygous Atp7b–/– rats, which mirror Wilson disease, and heterozygous Atp7b+/– rats, which served as control subjects because they lack copper accumulation. The high-calorie diet contained high fat and sugar levels to mirror “the eating habits in Western society, causing the ‘American-lifestyle-induced-obesity syndrome.’ ”
Within several weeks of starting the high-calorie diet, both control and Wilson disease rats showed higher liver triglyceride levels and visceral fat mass compared with rats on the normal diet, with liver histology also showing macrosteatosis and increased NAFLD Activity Score (NAS). Control rats maintained similar body and liver weights regardless of diet; in contrast, Wilson disease rats on the high-calorie diet showed increased liver weight, compared with Wilson disease rats on the normal diet. In addition, Wilson disease rats fed the high-calorie diet had clinical liver injury, supported by elevated aspartate aminotransferase (AST) levels and gross hepatic damage. Under the microscope, histology revealed widespread necrosis, apoptosis, inflammation, and fibrosis; findings were sufficient to constitute nonalcoholic steatohepatitis in all Wilson disease rats fed the high-calorie diet, compared with just one-third of the control rats receiving high calories. Additional testing showed that Wilson disease rats fed the high-calorie diet had disease onset 20 days sooner than did Wilson disease rats fed the normal diet.
“This is a remarkable disease acceleration,” the investigators noted, highlighting the median survival of 106 days in Wilson disease rats fed a normal diet.
Copper testing showed that Wilson disease rats fed the high-calorie diet had high serum levels of non–ceruloplasmin-bound copper, which is a sign of overt liver damage; based on histologic findings, the copper likely came from destroyed hepatocytes. Regardless of diet type, Wilson disease rats developed high levels of copper within the liver, suggesting comparable copper consumption via water sources. Regardless of genotype, the high-calorie diet led to higher mitochondrial copper levels than those of the normal diet, but Wilson disease rats showed the highest levels of copper sequestration in mitochondria, to an extreme degree.
“Importantly,” the investigators wrote, “such increased mitochondrial copper significantly correlated with a higher NAS and a progressive Histologic Activity Index score.”
Closer inspection showed that the mitochondria of Wilson disease rats were abnormal regardless of diet, but those fed the high-calorie diet had “a most severe mitochondrial phenotype,” including detached membranes and ballooned cristae.
“These structural impairments were paralleled by remarkable mitochondrial functional deficits,” the investigators reported, referring to a significant decrease in adenosine triphosphate production and an increase in mitochondrial H2O2. In response to these mitochondrial abnormalities, cholesterol-related enzymes quadrupled, most prominently for biliary excretion. The investigators summed up these hepatic events as a “toxic triad of adenosine triphosphate depletion, increased reactive oxygen species, and increased bile salts [that led] to an earlier onset of the disease and to enhanced disease progression.”
To complete the set of experiments, rats were given the copper chelator methanobactin. This treatment effectively mitigated structural and functional abnormalities in mitochondria, which drove serum levels of AST, copper, and bile salts toward normalcy. Although treatment halted overt liver damage, histology revealed that resolution was incomplete.
“We conclude that lipid accumulation in copper-burdened hepatocytes may represent a ‘second-hit’ in Wilson disease, inducing liver damage, and suggest that further research should establish whether dietary counseling of Wilson disease patients may be of therapeutic benefit,” the investigators concluded.
The study was funded by Deutsche Forschungsgemeinschaft and the WiFoMed Society. The investigators reported no conflicts of interest.
SOURCE: Einer et al. Cell Mol Gastroenterol Hepatol. 2019 Jan 11. doi: 10.1016/j.jcmgh.2018.12.005.
FROM CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY
Glyceryl trinitrate does not improve outcomes of ischemic stroke
HONOLULU – , according to data presented at the International Stroke Conference sponsored by the American Heart Association. Results suggest that GTN causes adverse effects in patients with intracerebral hemorrhage (ICH), but this observation is not definitive, according to the researchers. Study results were published online ahead of print Feb. 6 in the Lancet.
Nitric oxide is a regulatory molecule that has vasoactive effects and promotes blood pressure reduction. Vascular levels of nitric oxide are low in stroke, which suggests that the molecule may be a target for stroke treatment. GTN, a nitric oxide donor, lowered blood pressure and improved functional outcome among patients with acute stroke in the phase 2 Rapid Intervention with GTN in Hypertensive Stroke Trial (RIGHT).
Philip Bath, MD, Stroke Association Professor of Stroke Medicine at the University of Nottingham (England), and colleagues conducted the RIGHT-2 study to evaluate the safety and efficacy of GTN when administered early after onset of suspected stroke. Paramedics randomized patients in equal groups to a GTN patch or a sham patch in the ambulance. Three more patches were administered in the hospital on the following days. Active and sham patches looked similar and had no writing on them, thus ensuring effective blinding upon administration. Investigators followed up patients by telephone at 90 days to assess the modified Rankin Scale score and markers of disability, mood, cognition, and quality of life.
Eligible participants were adults who had dialed emergency services, independently or with assistance, because of a possible stroke. They had a Face, Arm, Speech, Time (FAST) score of 2 or 3, were within 4 hours of onset, and had a systolic blood pressure greater than 120 mm Hg. Patients from nursing homes, those with hypoglycemia, those who were unconscious, and those with a witnessed seizure were excluded.
Dr. Bath and colleagues planned to enroll 850 patients from five ambulance services in 30 hospitals across the United Kingdom. Data were to be examined through an intention-to-treat analysis. During the trial, however, the investigators observed that the rate of stroke mimics was 26%, rather than the 12% that they had anticipated. To ensure the proper power for the study, the investigators increased the sample size to 1,149 patients. They also changed the planned data analysis from intention-to-treat to hierarchical analysis. Specifically, the researchers planned to perform the primary analysis in patients with stroke or TIA. If the results were positive, then they would perform a standard intention-to-treat analysis.
More than 99% of patients received the first patch. Approximately 57% of the population received the first two patches. One reason for this decrease in adherence was that many patients were discharged from the hospital with a TIA or a stroke mimic. Participants’ average age was 72. The median time from onset to randomization was 71 minutes, and the median time to treatment was 73 minutes. Participants’ mean systolic blood pressure was 162 mm Hg. Approximately 60% of the patients had a FAST score of 3. About 50% of participants had ischemic stroke, 13% had ICH, 10% had TIA, and 26% had stroke mimics.
At 1 hour after treatment initiation, systolic blood pressure decreased by 6.2 mm Hg and diastolic blood pressure decreased by 2.7 mm Hg among patients who received GTN, compared with controls. At one day, the differences were 5.2 mm Hg and 2.5 mm Hg, respectively, in treated patients, compared with controls. Blood pressure became similar between groups thereafter, “in part because of the tachyphylaxis that we know happens with GTN,” said Dr. Bath.
The researchers found no evidence of an effect of GTN on functional outcome at 90 days in participants with stroke or transient ischemic attack. The adjusted common odds ratio of poor outcome was 1.25 in the GTN group, compared with the control group (95 % confidence interval, 0.97-1.60; P = .083). “We were close to getting a negative trial,” said Dr. Bath.
Subgroup analyses revealed differences in outcome according to the time to randomization. GTN had a negative effect in patients treated within 1 hour of onset. Results were neutral, but tended to be negative, in patients treated between 1 and 2 hours of onset. Results were neutral, but tended to be positive, among patients treated at more than 2 hours after onset. There was no difference between groups in the rate of mortality.
One of the study’s limitations was its single-blind design. In addition, the trial was conducted in a single country, and the investigators changed the protocol after it was initiated. “We had a higher-than-expected [stroke] mimic rate, although I’m reassured by most experts that ... this is probably about right,” said Dr. Bath.
A potential reason for the neutral results is the negative effect that GTN had among patients with ICH, said Dr. Bath. “In that very early first hour, we are of course breaking a law that we learned in medical school, which is that the first part of hemostasis is spasm. We gave an antispasmodic: a vasodilator,” he added. “That is speculation.”
The trial was funded by the British Heart Foundation. Dr. Bath declared a modest ownership interest in Platelet Solutions and consultant or advisory board positions with Moleac, DiaMedica, Phagenesis, Nestle, and ReNeuron. The other investigators declared no conflicts of interest.
The RIGHT-2 trial shows the limitations of a prehospital enrollment model, wrote Karen C. Johnston, MD, professor of neurology at the University of Virginia in Charlottesville, and Valerie L. Durkalski-Mauldin, PhD, professor of medicine at Medical University of South Carolina in Charleston, in an editorial accompanying the RIGHT-2 trial results. The rate of nonstroke diagnoses was so high that it would have reduced the study’s power to assess the efficacy of glyceryl trinitrate (GTN), had the investigators not increased the sample size and changed the statistical analysis plan.
“Future prehospital trials need to consider the implications of enrolling, yet excluding, stroke mimics in the primary analysis,” said Dr. Johnston and Dr. Durkalski-Mauldin. Using telemedicine in the ambulance to facilitate direct contact between the stroke provider and the patient and emergency medical services provider could reduce the enrollment of patients with stroke mimics in clinical trials, they added. “Improved tools to exclude stroke mimics in the field have been difficult to develop and validate. The absence of imaging in most ambulances will continue to limit field personnel from definitively determining ischemic stroke from intracerebral hemorrhage, which will limit hyperacute trials to interventions presumed safe in both populations.”
In addition, the blood pressure reduction that GTN provided might not be clinically relevant, said Dr. Johnston and Dr. Durkalski-Mauldin. “The RIGHT-2 investigators report no difference in blood pressure at day 3 or day 4 of treatment, which might have been related to the very low adherence to study protocol by day 4.
“Regardless of these limitations, RIGHT-2 has provided high-level evidence that GTN given within 4 hours of onset does not significantly improve outcome in hyperacute patients presenting with possible stroke,” the authors concluded (Lancet. 2019 Feb 6. doi: 10.1016/
S0140-6736(19)30276-4). Dr. Johnston and Dr. Durkalski-Mauldin declared no conflicts of interest.
The RIGHT-2 trial shows the limitations of a prehospital enrollment model, wrote Karen C. Johnston, MD, professor of neurology at the University of Virginia in Charlottesville, and Valerie L. Durkalski-Mauldin, PhD, professor of medicine at Medical University of South Carolina in Charleston, in an editorial accompanying the RIGHT-2 trial results. The rate of nonstroke diagnoses was so high that it would have reduced the study’s power to assess the efficacy of glyceryl trinitrate (GTN), had the investigators not increased the sample size and changed the statistical analysis plan.
“Future prehospital trials need to consider the implications of enrolling, yet excluding, stroke mimics in the primary analysis,” said Dr. Johnston and Dr. Durkalski-Mauldin. Using telemedicine in the ambulance to facilitate direct contact between the stroke provider and the patient and emergency medical services provider could reduce the enrollment of patients with stroke mimics in clinical trials, they added. “Improved tools to exclude stroke mimics in the field have been difficult to develop and validate. The absence of imaging in most ambulances will continue to limit field personnel from definitively determining ischemic stroke from intracerebral hemorrhage, which will limit hyperacute trials to interventions presumed safe in both populations.”
In addition, the blood pressure reduction that GTN provided might not be clinically relevant, said Dr. Johnston and Dr. Durkalski-Mauldin. “The RIGHT-2 investigators report no difference in blood pressure at day 3 or day 4 of treatment, which might have been related to the very low adherence to study protocol by day 4.
“Regardless of these limitations, RIGHT-2 has provided high-level evidence that GTN given within 4 hours of onset does not significantly improve outcome in hyperacute patients presenting with possible stroke,” the authors concluded (Lancet. 2019 Feb 6. doi: 10.1016/
S0140-6736(19)30276-4). Dr. Johnston and Dr. Durkalski-Mauldin declared no conflicts of interest.
The RIGHT-2 trial shows the limitations of a prehospital enrollment model, wrote Karen C. Johnston, MD, professor of neurology at the University of Virginia in Charlottesville, and Valerie L. Durkalski-Mauldin, PhD, professor of medicine at Medical University of South Carolina in Charleston, in an editorial accompanying the RIGHT-2 trial results. The rate of nonstroke diagnoses was so high that it would have reduced the study’s power to assess the efficacy of glyceryl trinitrate (GTN), had the investigators not increased the sample size and changed the statistical analysis plan.
“Future prehospital trials need to consider the implications of enrolling, yet excluding, stroke mimics in the primary analysis,” said Dr. Johnston and Dr. Durkalski-Mauldin. Using telemedicine in the ambulance to facilitate direct contact between the stroke provider and the patient and emergency medical services provider could reduce the enrollment of patients with stroke mimics in clinical trials, they added. “Improved tools to exclude stroke mimics in the field have been difficult to develop and validate. The absence of imaging in most ambulances will continue to limit field personnel from definitively determining ischemic stroke from intracerebral hemorrhage, which will limit hyperacute trials to interventions presumed safe in both populations.”
In addition, the blood pressure reduction that GTN provided might not be clinically relevant, said Dr. Johnston and Dr. Durkalski-Mauldin. “The RIGHT-2 investigators report no difference in blood pressure at day 3 or day 4 of treatment, which might have been related to the very low adherence to study protocol by day 4.
“Regardless of these limitations, RIGHT-2 has provided high-level evidence that GTN given within 4 hours of onset does not significantly improve outcome in hyperacute patients presenting with possible stroke,” the authors concluded (Lancet. 2019 Feb 6. doi: 10.1016/
S0140-6736(19)30276-4). Dr. Johnston and Dr. Durkalski-Mauldin declared no conflicts of interest.
HONOLULU – , according to data presented at the International Stroke Conference sponsored by the American Heart Association. Results suggest that GTN causes adverse effects in patients with intracerebral hemorrhage (ICH), but this observation is not definitive, according to the researchers. Study results were published online ahead of print Feb. 6 in the Lancet.
Nitric oxide is a regulatory molecule that has vasoactive effects and promotes blood pressure reduction. Vascular levels of nitric oxide are low in stroke, which suggests that the molecule may be a target for stroke treatment. GTN, a nitric oxide donor, lowered blood pressure and improved functional outcome among patients with acute stroke in the phase 2 Rapid Intervention with GTN in Hypertensive Stroke Trial (RIGHT).
Philip Bath, MD, Stroke Association Professor of Stroke Medicine at the University of Nottingham (England), and colleagues conducted the RIGHT-2 study to evaluate the safety and efficacy of GTN when administered early after onset of suspected stroke. Paramedics randomized patients in equal groups to a GTN patch or a sham patch in the ambulance. Three more patches were administered in the hospital on the following days. Active and sham patches looked similar and had no writing on them, thus ensuring effective blinding upon administration. Investigators followed up patients by telephone at 90 days to assess the modified Rankin Scale score and markers of disability, mood, cognition, and quality of life.
Eligible participants were adults who had dialed emergency services, independently or with assistance, because of a possible stroke. They had a Face, Arm, Speech, Time (FAST) score of 2 or 3, were within 4 hours of onset, and had a systolic blood pressure greater than 120 mm Hg. Patients from nursing homes, those with hypoglycemia, those who were unconscious, and those with a witnessed seizure were excluded.
Dr. Bath and colleagues planned to enroll 850 patients from five ambulance services in 30 hospitals across the United Kingdom. Data were to be examined through an intention-to-treat analysis. During the trial, however, the investigators observed that the rate of stroke mimics was 26%, rather than the 12% that they had anticipated. To ensure the proper power for the study, the investigators increased the sample size to 1,149 patients. They also changed the planned data analysis from intention-to-treat to hierarchical analysis. Specifically, the researchers planned to perform the primary analysis in patients with stroke or TIA. If the results were positive, then they would perform a standard intention-to-treat analysis.
More than 99% of patients received the first patch. Approximately 57% of the population received the first two patches. One reason for this decrease in adherence was that many patients were discharged from the hospital with a TIA or a stroke mimic. Participants’ average age was 72. The median time from onset to randomization was 71 minutes, and the median time to treatment was 73 minutes. Participants’ mean systolic blood pressure was 162 mm Hg. Approximately 60% of the patients had a FAST score of 3. About 50% of participants had ischemic stroke, 13% had ICH, 10% had TIA, and 26% had stroke mimics.
At 1 hour after treatment initiation, systolic blood pressure decreased by 6.2 mm Hg and diastolic blood pressure decreased by 2.7 mm Hg among patients who received GTN, compared with controls. At one day, the differences were 5.2 mm Hg and 2.5 mm Hg, respectively, in treated patients, compared with controls. Blood pressure became similar between groups thereafter, “in part because of the tachyphylaxis that we know happens with GTN,” said Dr. Bath.
The researchers found no evidence of an effect of GTN on functional outcome at 90 days in participants with stroke or transient ischemic attack. The adjusted common odds ratio of poor outcome was 1.25 in the GTN group, compared with the control group (95 % confidence interval, 0.97-1.60; P = .083). “We were close to getting a negative trial,” said Dr. Bath.
Subgroup analyses revealed differences in outcome according to the time to randomization. GTN had a negative effect in patients treated within 1 hour of onset. Results were neutral, but tended to be negative, in patients treated between 1 and 2 hours of onset. Results were neutral, but tended to be positive, among patients treated at more than 2 hours after onset. There was no difference between groups in the rate of mortality.
One of the study’s limitations was its single-blind design. In addition, the trial was conducted in a single country, and the investigators changed the protocol after it was initiated. “We had a higher-than-expected [stroke] mimic rate, although I’m reassured by most experts that ... this is probably about right,” said Dr. Bath.
A potential reason for the neutral results is the negative effect that GTN had among patients with ICH, said Dr. Bath. “In that very early first hour, we are of course breaking a law that we learned in medical school, which is that the first part of hemostasis is spasm. We gave an antispasmodic: a vasodilator,” he added. “That is speculation.”
The trial was funded by the British Heart Foundation. Dr. Bath declared a modest ownership interest in Platelet Solutions and consultant or advisory board positions with Moleac, DiaMedica, Phagenesis, Nestle, and ReNeuron. The other investigators declared no conflicts of interest.
HONOLULU – , according to data presented at the International Stroke Conference sponsored by the American Heart Association. Results suggest that GTN causes adverse effects in patients with intracerebral hemorrhage (ICH), but this observation is not definitive, according to the researchers. Study results were published online ahead of print Feb. 6 in the Lancet.
Nitric oxide is a regulatory molecule that has vasoactive effects and promotes blood pressure reduction. Vascular levels of nitric oxide are low in stroke, which suggests that the molecule may be a target for stroke treatment. GTN, a nitric oxide donor, lowered blood pressure and improved functional outcome among patients with acute stroke in the phase 2 Rapid Intervention with GTN in Hypertensive Stroke Trial (RIGHT).
Philip Bath, MD, Stroke Association Professor of Stroke Medicine at the University of Nottingham (England), and colleagues conducted the RIGHT-2 study to evaluate the safety and efficacy of GTN when administered early after onset of suspected stroke. Paramedics randomized patients in equal groups to a GTN patch or a sham patch in the ambulance. Three more patches were administered in the hospital on the following days. Active and sham patches looked similar and had no writing on them, thus ensuring effective blinding upon administration. Investigators followed up patients by telephone at 90 days to assess the modified Rankin Scale score and markers of disability, mood, cognition, and quality of life.
Eligible participants were adults who had dialed emergency services, independently or with assistance, because of a possible stroke. They had a Face, Arm, Speech, Time (FAST) score of 2 or 3, were within 4 hours of onset, and had a systolic blood pressure greater than 120 mm Hg. Patients from nursing homes, those with hypoglycemia, those who were unconscious, and those with a witnessed seizure were excluded.
Dr. Bath and colleagues planned to enroll 850 patients from five ambulance services in 30 hospitals across the United Kingdom. Data were to be examined through an intention-to-treat analysis. During the trial, however, the investigators observed that the rate of stroke mimics was 26%, rather than the 12% that they had anticipated. To ensure the proper power for the study, the investigators increased the sample size to 1,149 patients. They also changed the planned data analysis from intention-to-treat to hierarchical analysis. Specifically, the researchers planned to perform the primary analysis in patients with stroke or TIA. If the results were positive, then they would perform a standard intention-to-treat analysis.
More than 99% of patients received the first patch. Approximately 57% of the population received the first two patches. One reason for this decrease in adherence was that many patients were discharged from the hospital with a TIA or a stroke mimic. Participants’ average age was 72. The median time from onset to randomization was 71 minutes, and the median time to treatment was 73 minutes. Participants’ mean systolic blood pressure was 162 mm Hg. Approximately 60% of the patients had a FAST score of 3. About 50% of participants had ischemic stroke, 13% had ICH, 10% had TIA, and 26% had stroke mimics.
At 1 hour after treatment initiation, systolic blood pressure decreased by 6.2 mm Hg and diastolic blood pressure decreased by 2.7 mm Hg among patients who received GTN, compared with controls. At one day, the differences were 5.2 mm Hg and 2.5 mm Hg, respectively, in treated patients, compared with controls. Blood pressure became similar between groups thereafter, “in part because of the tachyphylaxis that we know happens with GTN,” said Dr. Bath.
The researchers found no evidence of an effect of GTN on functional outcome at 90 days in participants with stroke or transient ischemic attack. The adjusted common odds ratio of poor outcome was 1.25 in the GTN group, compared with the control group (95 % confidence interval, 0.97-1.60; P = .083). “We were close to getting a negative trial,” said Dr. Bath.
Subgroup analyses revealed differences in outcome according to the time to randomization. GTN had a negative effect in patients treated within 1 hour of onset. Results were neutral, but tended to be negative, in patients treated between 1 and 2 hours of onset. Results were neutral, but tended to be positive, among patients treated at more than 2 hours after onset. There was no difference between groups in the rate of mortality.
One of the study’s limitations was its single-blind design. In addition, the trial was conducted in a single country, and the investigators changed the protocol after it was initiated. “We had a higher-than-expected [stroke] mimic rate, although I’m reassured by most experts that ... this is probably about right,” said Dr. Bath.
A potential reason for the neutral results is the negative effect that GTN had among patients with ICH, said Dr. Bath. “In that very early first hour, we are of course breaking a law that we learned in medical school, which is that the first part of hemostasis is spasm. We gave an antispasmodic: a vasodilator,” he added. “That is speculation.”
The trial was funded by the British Heart Foundation. Dr. Bath declared a modest ownership interest in Platelet Solutions and consultant or advisory board positions with Moleac, DiaMedica, Phagenesis, Nestle, and ReNeuron. The other investigators declared no conflicts of interest.
REPORTING FROM ISC 2019
Epicutaneous milk immunotherapy can resolve pediatric eosinophilic esophagitis
SAN FRANCISCO – Clinicians safely used epicutaneous immunotherapy to resolve eosinophilic esophagitis in children and teens secondary to milk consumption in a placebo-controlled, pilot study that included 20 patients.
Following the randomized phase of the study, all 19 patients who continued to participate began an 11-month open-label phase of epicutaneous immunotherapy to milk. At the end of this open-label phase, nine patients (47%) followed in this phase showed a substantial cut in their eosinophilic esophagitis (EoE) response to milk, with fewer than 15 eosinophils in a high-powered field, said Jonathan M. Spergel, MD, chief of the allergy section and Stuart E. Starr Chair of Pediatrics at the Children’s Hospital of Philadelphia, while presenting a poster at the annual meeting of the American Academy of Allergy, Asthma, and Immunology. An immunologic response of this sort would likely correlate with substantial clinical benefit.
“I’m happy with a 47% response,” Dr. Spergel said, adding that the responding patients “tolerate milk without symptoms, and there is really no risk” from this form of immunotherapy, which produced no serious adverse effects and caused 1 of 15 patients to stop treatment because of a treatment-related effect during the randomized phase. The most common adverse reaction was gastrointestinal symptoms, but these were just marginally more common among patients on active treatment than in control patients.
In contrast, oral immunotherapy with milk has been ineffective in children with an EoE milk reaction, and results from subcutaneous or sublingual immunotherapy for this form of milk allergy haven’t been reported, he said. The most common, current approaches to managing EoE from milk in children are either milk avoidance or treatment to reduce inflammation.
The epicutaneous approach “uses substantially lower dosing [micrograms vs. milligrams], avoids oral allergen ingestion, and may have a more advantageous adverse event profile and better adherence than other therapies,” according to a recent report that tested epicutaneous immunotherapy for peanut allergy in a phase 3 trial with 356 children (JAMA. 2019 Feb 22. doi: 10.1001/jama.2019.1113). The Viaskin Milk system tested in the current milk study involves placing a disc coated with 500 mcg of lyophilized milk protein on the skin for a gradually increasing number of hours daily until the disc is worn continuously, with daily changes of the disk. On the skin, the protein on the disk interacts with epidermal Langerhans cells to trigger desensitization.
The Milk Patch for Eosinophilic Esophagitis (SMILEE) study enrolled 20 patients at Children’s Hospital aged 4-17 years old and had milk-induced EoE, and randomized 15 to receive active epicutaneous immunotherapy to milk and 5 to receive placebo treatment. The protocol called for 9 month of epicutaneous immunotherapy without any milk exposure, followed by 2 months of continued treatment coupled with at least 240 mL of milk consumption daily. At the end of 2 months the researchers performed an esophageal biopsy on each patient to determine eosinophil density in the tissue. The study’s primary endpoint was the number of eosinophils in a high-powered field.
During the randomized phase, 8 of the 15 patients assigned to active treatment and 3 of 5 patients assigned to the placebo arm had violations of the treatment protocol, the diet protocol, or both. A per protocol analysis that focused on the seven actively treated and two placebo patients who adhered to the protocol showed a mean eosinophil count of 26 cells in patients on active treatment and 95 cells among the controls, a statistically significant difference. However, for the intention-to-treat analysis, which included all 20 enrolled patients, the primary endpoint showed no significant difference in eosinophil counts between the two study arms.
Although Dr. Spergel said that he was not aware of the developing company’s plans for further study of epicutaneous milk immunotherapy, from a scientific standpoint the next step should be a phase 2 or phase 2/3 trial for safety and efficacy. EoE was historically considered a rare disease, but a 2015 review of the condition called it “one of the most common conditions diagnosed during the assessment of feeding problems in children” (New Engl J Med. 2015 Oct 22;373[17]:1640-8).
The study was funded by DBV Technologies, which is developing the epicutaneous immunotherapy system. Dr. Spergel has been a consultant to and has received research funding from DBV Technologies.
SOURCE: Spergel JM et al. J Allergy Clin Immunol. 2019 Feb;143[2]:AB430.
SAN FRANCISCO – Clinicians safely used epicutaneous immunotherapy to resolve eosinophilic esophagitis in children and teens secondary to milk consumption in a placebo-controlled, pilot study that included 20 patients.
Following the randomized phase of the study, all 19 patients who continued to participate began an 11-month open-label phase of epicutaneous immunotherapy to milk. At the end of this open-label phase, nine patients (47%) followed in this phase showed a substantial cut in their eosinophilic esophagitis (EoE) response to milk, with fewer than 15 eosinophils in a high-powered field, said Jonathan M. Spergel, MD, chief of the allergy section and Stuart E. Starr Chair of Pediatrics at the Children’s Hospital of Philadelphia, while presenting a poster at the annual meeting of the American Academy of Allergy, Asthma, and Immunology. An immunologic response of this sort would likely correlate with substantial clinical benefit.
“I’m happy with a 47% response,” Dr. Spergel said, adding that the responding patients “tolerate milk without symptoms, and there is really no risk” from this form of immunotherapy, which produced no serious adverse effects and caused 1 of 15 patients to stop treatment because of a treatment-related effect during the randomized phase. The most common adverse reaction was gastrointestinal symptoms, but these were just marginally more common among patients on active treatment than in control patients.
In contrast, oral immunotherapy with milk has been ineffective in children with an EoE milk reaction, and results from subcutaneous or sublingual immunotherapy for this form of milk allergy haven’t been reported, he said. The most common, current approaches to managing EoE from milk in children are either milk avoidance or treatment to reduce inflammation.
The epicutaneous approach “uses substantially lower dosing [micrograms vs. milligrams], avoids oral allergen ingestion, and may have a more advantageous adverse event profile and better adherence than other therapies,” according to a recent report that tested epicutaneous immunotherapy for peanut allergy in a phase 3 trial with 356 children (JAMA. 2019 Feb 22. doi: 10.1001/jama.2019.1113). The Viaskin Milk system tested in the current milk study involves placing a disc coated with 500 mcg of lyophilized milk protein on the skin for a gradually increasing number of hours daily until the disc is worn continuously, with daily changes of the disk. On the skin, the protein on the disk interacts with epidermal Langerhans cells to trigger desensitization.
The Milk Patch for Eosinophilic Esophagitis (SMILEE) study enrolled 20 patients at Children’s Hospital aged 4-17 years old and had milk-induced EoE, and randomized 15 to receive active epicutaneous immunotherapy to milk and 5 to receive placebo treatment. The protocol called for 9 month of epicutaneous immunotherapy without any milk exposure, followed by 2 months of continued treatment coupled with at least 240 mL of milk consumption daily. At the end of 2 months the researchers performed an esophageal biopsy on each patient to determine eosinophil density in the tissue. The study’s primary endpoint was the number of eosinophils in a high-powered field.
During the randomized phase, 8 of the 15 patients assigned to active treatment and 3 of 5 patients assigned to the placebo arm had violations of the treatment protocol, the diet protocol, or both. A per protocol analysis that focused on the seven actively treated and two placebo patients who adhered to the protocol showed a mean eosinophil count of 26 cells in patients on active treatment and 95 cells among the controls, a statistically significant difference. However, for the intention-to-treat analysis, which included all 20 enrolled patients, the primary endpoint showed no significant difference in eosinophil counts between the two study arms.
Although Dr. Spergel said that he was not aware of the developing company’s plans for further study of epicutaneous milk immunotherapy, from a scientific standpoint the next step should be a phase 2 or phase 2/3 trial for safety and efficacy. EoE was historically considered a rare disease, but a 2015 review of the condition called it “one of the most common conditions diagnosed during the assessment of feeding problems in children” (New Engl J Med. 2015 Oct 22;373[17]:1640-8).
The study was funded by DBV Technologies, which is developing the epicutaneous immunotherapy system. Dr. Spergel has been a consultant to and has received research funding from DBV Technologies.
SOURCE: Spergel JM et al. J Allergy Clin Immunol. 2019 Feb;143[2]:AB430.
SAN FRANCISCO – Clinicians safely used epicutaneous immunotherapy to resolve eosinophilic esophagitis in children and teens secondary to milk consumption in a placebo-controlled, pilot study that included 20 patients.
Following the randomized phase of the study, all 19 patients who continued to participate began an 11-month open-label phase of epicutaneous immunotherapy to milk. At the end of this open-label phase, nine patients (47%) followed in this phase showed a substantial cut in their eosinophilic esophagitis (EoE) response to milk, with fewer than 15 eosinophils in a high-powered field, said Jonathan M. Spergel, MD, chief of the allergy section and Stuart E. Starr Chair of Pediatrics at the Children’s Hospital of Philadelphia, while presenting a poster at the annual meeting of the American Academy of Allergy, Asthma, and Immunology. An immunologic response of this sort would likely correlate with substantial clinical benefit.
“I’m happy with a 47% response,” Dr. Spergel said, adding that the responding patients “tolerate milk without symptoms, and there is really no risk” from this form of immunotherapy, which produced no serious adverse effects and caused 1 of 15 patients to stop treatment because of a treatment-related effect during the randomized phase. The most common adverse reaction was gastrointestinal symptoms, but these were just marginally more common among patients on active treatment than in control patients.
In contrast, oral immunotherapy with milk has been ineffective in children with an EoE milk reaction, and results from subcutaneous or sublingual immunotherapy for this form of milk allergy haven’t been reported, he said. The most common, current approaches to managing EoE from milk in children are either milk avoidance or treatment to reduce inflammation.
The epicutaneous approach “uses substantially lower dosing [micrograms vs. milligrams], avoids oral allergen ingestion, and may have a more advantageous adverse event profile and better adherence than other therapies,” according to a recent report that tested epicutaneous immunotherapy for peanut allergy in a phase 3 trial with 356 children (JAMA. 2019 Feb 22. doi: 10.1001/jama.2019.1113). The Viaskin Milk system tested in the current milk study involves placing a disc coated with 500 mcg of lyophilized milk protein on the skin for a gradually increasing number of hours daily until the disc is worn continuously, with daily changes of the disk. On the skin, the protein on the disk interacts with epidermal Langerhans cells to trigger desensitization.
The Milk Patch for Eosinophilic Esophagitis (SMILEE) study enrolled 20 patients at Children’s Hospital aged 4-17 years old and had milk-induced EoE, and randomized 15 to receive active epicutaneous immunotherapy to milk and 5 to receive placebo treatment. The protocol called for 9 month of epicutaneous immunotherapy without any milk exposure, followed by 2 months of continued treatment coupled with at least 240 mL of milk consumption daily. At the end of 2 months the researchers performed an esophageal biopsy on each patient to determine eosinophil density in the tissue. The study’s primary endpoint was the number of eosinophils in a high-powered field.
During the randomized phase, 8 of the 15 patients assigned to active treatment and 3 of 5 patients assigned to the placebo arm had violations of the treatment protocol, the diet protocol, or both. A per protocol analysis that focused on the seven actively treated and two placebo patients who adhered to the protocol showed a mean eosinophil count of 26 cells in patients on active treatment and 95 cells among the controls, a statistically significant difference. However, for the intention-to-treat analysis, which included all 20 enrolled patients, the primary endpoint showed no significant difference in eosinophil counts between the two study arms.
Although Dr. Spergel said that he was not aware of the developing company’s plans for further study of epicutaneous milk immunotherapy, from a scientific standpoint the next step should be a phase 2 or phase 2/3 trial for safety and efficacy. EoE was historically considered a rare disease, but a 2015 review of the condition called it “one of the most common conditions diagnosed during the assessment of feeding problems in children” (New Engl J Med. 2015 Oct 22;373[17]:1640-8).
The study was funded by DBV Technologies, which is developing the epicutaneous immunotherapy system. Dr. Spergel has been a consultant to and has received research funding from DBV Technologies.
SOURCE: Spergel JM et al. J Allergy Clin Immunol. 2019 Feb;143[2]:AB430.
REPORTING FROM AAAAI 2019
Key clinical point:
Major finding: After 11 months of open-label treatment, 9 of 19 patients resolved their eosinophilic esophagitis reaction to milk.
Study details: A 2-year, single-center study of epicutaneous milk immunotherapy in 20 children with milk-induced eosinophilic esophagitis.
Disclosures: The study was funded by DBV Technologies, which is developing the epicutaneous immunotherapy system. Dr. Spergel has been a consultant to and has received research funding from DBV Technologies.
Source: Spergel JM et al. J Allergy Clin Immunol. 2019 Feb;143[2]:AB430.
Poor asthma control during pregnancy trims live birth rate
SAN FRANCISCO – and among the live births had a significantly increased rate of both preterm delivery and neonatal intensive care admissions, according to a review of insurance claims data for more than 1 million American women during 2011-2015.
On the other hand, asthma severity, which the researchers inferred based on the type and amount of treatment patients received, showed essentially no link with the live birth rate, Jennifer Yland said at the annual meeting of the American Academy of Allergy, Asthma, and Immunology.
“The findings add to the body of evidence that relate poor asthma control to an increased risk for pregnancy complications.” explained Michael X. Schatz, MD, an allergist at Kaiser Permanente of Southern California, in San Diego, and a coauthor of the study.
Results from several prior studies had shown links between asthma and an increased rate of preterm birth, “but the larger, more generalizable population is a strength of the current findings. Results from prior studies have less frequently shown a link between asthma during pregnancy and neonatal ICU admissions,” he added.“The findings strengthen the case for good asthma control during pregnancy.”
For their review, Ms. Yland and her coauthors used insurance claims data from privately-insured American women aged 12-55 years who were pregnant and had drug prescription records during the study period. The database included 996,861 women without an asthma diagnosis and 29,882 women diagnosed with asthma. The analysis excluded women diagnosed with chronic obstructive pulmonary disease at least twice during pregnancy.
To analyze the pregnancy outcomes by asthma severity Ms. Yland and her associates divided the asthma patients into five subgroups based on the drug regimens they were on during pregnancy as a surrogate marker of disease severity. This analysis showed no relationship between disease severity and live birth rate.
The researchers also ran an analysis that divided patients into the quality of their management during pregnancy – either good or poor – based on either of two markers of poor control: filling five or more prescriptions for a short-acting beta-antagonist, or at least one exacerbation episode defined as an asthma-related emergency department visit, hospitalization, or need for oral corticosteroid treatment. By these criteria 7,135 (24%) of the pregnant women with asthma were poorly controlled. The live birth rate was 74% among women without asthma, 71% among those with well-controlled asthma, and 68% among women with poorly-controlled asthma, reported Ms. Yland, a researcher at the Harvard T.H. Chan School of Public Health in Boston.
In a multivariate analysis that adjusted for demographic differences and comorbidities, women with poorly-controlled asthma had preterm delivery a statistically significant 30% more often than did women with well-controlled asthma, and the rate of neonatal ICU admissions was a significant 24% higher in women with poorly-controlled asthma, compared with women who had well-controlled asthma. However, the rates of small-for-gestational-age infants and infants with congenital malformations was not significantly different between the well-controlled and poorly-controlled subgroups.
The finding that almost a quarter of the pregnant women in the study were poorly controlled wasn’t surprising, Dr. Schatz said in an interview. In some studies as many as half the asthma patients have poor control.
The 24% rate of poor asthma control during pregnancy in the studied women is “most likely an underestimate of poor control in the general population” because the study used data from women with commercial health insurance, noted Sonia Hernandez-Diaz, MD, lead investigator for the study and professor of epidemiology at Harvard T.H. Chan School of Public Health. “More disadvantaged populations, such as pregnant women on Medicaid, tend to have worse control.”
Barriers to good asthma control during pregnancy include smoking, weight gain, undertreatment, poor adherence, and viral infection. The overall approach to managing asthma during pregnancy is the same as when women are not pregnant, although certain asthma medications have a better safety record during pregnancy. “The most reassuring data exist for albuterol and inhaled steroids, particularly budesonide and fluticasone. Reassuring data also exist for the long-acting beta agonists salmeterol and formoterol, which are combined with inhaled steroids, and for montelukast,” Dr. Schatz said.
This is the first study to assess the impact of asthma management on pregnancy outcome in such a large population. The large number of women included provided a lot of statistical power and allowed the analyses to control for several potential confounders, Ms. Yland noted in an interview. She plans to expand the analysis with Medicaid data to try to further increase the generalizability and precision of the findings.
The study was funded by GlaxoSmithKline, and a coauthor of the study is a company employee. Ms. Yland had no disclosures. Dr. Schatz has received research funding from ALK, AstraZeneca, Medimmune, GlaxoSmithKline, and Merck. Dr. Hernandez-Diaz has been a consultant to Boehringer Ingelheim, Roche, and UCB, and has received research funding from GlaxoSmithKline, Lilly, and Pfizer.
SOURCE: Yland J et al. J Allergy Clin Immunol. 2019 Feb;143[2]:AB422.
SAN FRANCISCO – and among the live births had a significantly increased rate of both preterm delivery and neonatal intensive care admissions, according to a review of insurance claims data for more than 1 million American women during 2011-2015.
On the other hand, asthma severity, which the researchers inferred based on the type and amount of treatment patients received, showed essentially no link with the live birth rate, Jennifer Yland said at the annual meeting of the American Academy of Allergy, Asthma, and Immunology.
“The findings add to the body of evidence that relate poor asthma control to an increased risk for pregnancy complications.” explained Michael X. Schatz, MD, an allergist at Kaiser Permanente of Southern California, in San Diego, and a coauthor of the study.
Results from several prior studies had shown links between asthma and an increased rate of preterm birth, “but the larger, more generalizable population is a strength of the current findings. Results from prior studies have less frequently shown a link between asthma during pregnancy and neonatal ICU admissions,” he added.“The findings strengthen the case for good asthma control during pregnancy.”
For their review, Ms. Yland and her coauthors used insurance claims data from privately-insured American women aged 12-55 years who were pregnant and had drug prescription records during the study period. The database included 996,861 women without an asthma diagnosis and 29,882 women diagnosed with asthma. The analysis excluded women diagnosed with chronic obstructive pulmonary disease at least twice during pregnancy.
To analyze the pregnancy outcomes by asthma severity Ms. Yland and her associates divided the asthma patients into five subgroups based on the drug regimens they were on during pregnancy as a surrogate marker of disease severity. This analysis showed no relationship between disease severity and live birth rate.
The researchers also ran an analysis that divided patients into the quality of their management during pregnancy – either good or poor – based on either of two markers of poor control: filling five or more prescriptions for a short-acting beta-antagonist, or at least one exacerbation episode defined as an asthma-related emergency department visit, hospitalization, or need for oral corticosteroid treatment. By these criteria 7,135 (24%) of the pregnant women with asthma were poorly controlled. The live birth rate was 74% among women without asthma, 71% among those with well-controlled asthma, and 68% among women with poorly-controlled asthma, reported Ms. Yland, a researcher at the Harvard T.H. Chan School of Public Health in Boston.
In a multivariate analysis that adjusted for demographic differences and comorbidities, women with poorly-controlled asthma had preterm delivery a statistically significant 30% more often than did women with well-controlled asthma, and the rate of neonatal ICU admissions was a significant 24% higher in women with poorly-controlled asthma, compared with women who had well-controlled asthma. However, the rates of small-for-gestational-age infants and infants with congenital malformations was not significantly different between the well-controlled and poorly-controlled subgroups.
The finding that almost a quarter of the pregnant women in the study were poorly controlled wasn’t surprising, Dr. Schatz said in an interview. In some studies as many as half the asthma patients have poor control.
The 24% rate of poor asthma control during pregnancy in the studied women is “most likely an underestimate of poor control in the general population” because the study used data from women with commercial health insurance, noted Sonia Hernandez-Diaz, MD, lead investigator for the study and professor of epidemiology at Harvard T.H. Chan School of Public Health. “More disadvantaged populations, such as pregnant women on Medicaid, tend to have worse control.”
Barriers to good asthma control during pregnancy include smoking, weight gain, undertreatment, poor adherence, and viral infection. The overall approach to managing asthma during pregnancy is the same as when women are not pregnant, although certain asthma medications have a better safety record during pregnancy. “The most reassuring data exist for albuterol and inhaled steroids, particularly budesonide and fluticasone. Reassuring data also exist for the long-acting beta agonists salmeterol and formoterol, which are combined with inhaled steroids, and for montelukast,” Dr. Schatz said.
This is the first study to assess the impact of asthma management on pregnancy outcome in such a large population. The large number of women included provided a lot of statistical power and allowed the analyses to control for several potential confounders, Ms. Yland noted in an interview. She plans to expand the analysis with Medicaid data to try to further increase the generalizability and precision of the findings.
The study was funded by GlaxoSmithKline, and a coauthor of the study is a company employee. Ms. Yland had no disclosures. Dr. Schatz has received research funding from ALK, AstraZeneca, Medimmune, GlaxoSmithKline, and Merck. Dr. Hernandez-Diaz has been a consultant to Boehringer Ingelheim, Roche, and UCB, and has received research funding from GlaxoSmithKline, Lilly, and Pfizer.
SOURCE: Yland J et al. J Allergy Clin Immunol. 2019 Feb;143[2]:AB422.
SAN FRANCISCO – and among the live births had a significantly increased rate of both preterm delivery and neonatal intensive care admissions, according to a review of insurance claims data for more than 1 million American women during 2011-2015.
On the other hand, asthma severity, which the researchers inferred based on the type and amount of treatment patients received, showed essentially no link with the live birth rate, Jennifer Yland said at the annual meeting of the American Academy of Allergy, Asthma, and Immunology.
“The findings add to the body of evidence that relate poor asthma control to an increased risk for pregnancy complications.” explained Michael X. Schatz, MD, an allergist at Kaiser Permanente of Southern California, in San Diego, and a coauthor of the study.
Results from several prior studies had shown links between asthma and an increased rate of preterm birth, “but the larger, more generalizable population is a strength of the current findings. Results from prior studies have less frequently shown a link between asthma during pregnancy and neonatal ICU admissions,” he added.“The findings strengthen the case for good asthma control during pregnancy.”
For their review, Ms. Yland and her coauthors used insurance claims data from privately-insured American women aged 12-55 years who were pregnant and had drug prescription records during the study period. The database included 996,861 women without an asthma diagnosis and 29,882 women diagnosed with asthma. The analysis excluded women diagnosed with chronic obstructive pulmonary disease at least twice during pregnancy.
To analyze the pregnancy outcomes by asthma severity Ms. Yland and her associates divided the asthma patients into five subgroups based on the drug regimens they were on during pregnancy as a surrogate marker of disease severity. This analysis showed no relationship between disease severity and live birth rate.
The researchers also ran an analysis that divided patients into the quality of their management during pregnancy – either good or poor – based on either of two markers of poor control: filling five or more prescriptions for a short-acting beta-antagonist, or at least one exacerbation episode defined as an asthma-related emergency department visit, hospitalization, or need for oral corticosteroid treatment. By these criteria 7,135 (24%) of the pregnant women with asthma were poorly controlled. The live birth rate was 74% among women without asthma, 71% among those with well-controlled asthma, and 68% among women with poorly-controlled asthma, reported Ms. Yland, a researcher at the Harvard T.H. Chan School of Public Health in Boston.
In a multivariate analysis that adjusted for demographic differences and comorbidities, women with poorly-controlled asthma had preterm delivery a statistically significant 30% more often than did women with well-controlled asthma, and the rate of neonatal ICU admissions was a significant 24% higher in women with poorly-controlled asthma, compared with women who had well-controlled asthma. However, the rates of small-for-gestational-age infants and infants with congenital malformations was not significantly different between the well-controlled and poorly-controlled subgroups.
The finding that almost a quarter of the pregnant women in the study were poorly controlled wasn’t surprising, Dr. Schatz said in an interview. In some studies as many as half the asthma patients have poor control.
The 24% rate of poor asthma control during pregnancy in the studied women is “most likely an underestimate of poor control in the general population” because the study used data from women with commercial health insurance, noted Sonia Hernandez-Diaz, MD, lead investigator for the study and professor of epidemiology at Harvard T.H. Chan School of Public Health. “More disadvantaged populations, such as pregnant women on Medicaid, tend to have worse control.”
Barriers to good asthma control during pregnancy include smoking, weight gain, undertreatment, poor adherence, and viral infection. The overall approach to managing asthma during pregnancy is the same as when women are not pregnant, although certain asthma medications have a better safety record during pregnancy. “The most reassuring data exist for albuterol and inhaled steroids, particularly budesonide and fluticasone. Reassuring data also exist for the long-acting beta agonists salmeterol and formoterol, which are combined with inhaled steroids, and for montelukast,” Dr. Schatz said.
This is the first study to assess the impact of asthma management on pregnancy outcome in such a large population. The large number of women included provided a lot of statistical power and allowed the analyses to control for several potential confounders, Ms. Yland noted in an interview. She plans to expand the analysis with Medicaid data to try to further increase the generalizability and precision of the findings.
The study was funded by GlaxoSmithKline, and a coauthor of the study is a company employee. Ms. Yland had no disclosures. Dr. Schatz has received research funding from ALK, AstraZeneca, Medimmune, GlaxoSmithKline, and Merck. Dr. Hernandez-Diaz has been a consultant to Boehringer Ingelheim, Roche, and UCB, and has received research funding from GlaxoSmithKline, Lilly, and Pfizer.
SOURCE: Yland J et al. J Allergy Clin Immunol. 2019 Feb;143[2]:AB422.
REPORTING FROM AAAAI 2019
Hospitalist scheduling: A search for balance
Survey says ...
Scheduling. Has there ever been such a simple word that is so complex? A simple Internet search of hospitalist scheduling returns thousands of possible discussions, leaving readers to conclude that the possibilities are endless and the challenges great. The answer certainly is not a one-size-fits-all approach.
Hospitalist scheduling is one of the key sections in the 2018 State of Hospital Medicine (SoHM) report; the 2018 report delves deeper into hospitalist scheduling than ever before.
For those of you who have been regular users of prior SoHM reports, you should be pleasantly surprised to find new comparative values: There are nearly 50% more pages dedicated just to scheduling!
For those readers who have never subscribed to the SoHM Report, this is your chance to study how other groups approach hospitalist schedules.
Why is hospitalist scheduling such a hot topic? For one, flexible and sustainable scheduling is an important contributor to job satisfaction. It is important for hospitalists to have a high degree of input into managing and effecting change for personal work-life balance.
As John Nelson, MD, MHM, a cofounder of the Society of Hospital Medicine, wrote recently in The Hospitalist, “an optimal schedule alone isn’t the key to preventing it [burnout], but maybe a good schedule can reduce your risk you’ll suffer from it.”
Secondly, ensuring that the hospitalist team is right sized – that is, scheduling hospitalists in the right place at the right time – is an art. Using resources, such as the 2018 SoHM report, to identify quantifiable comparisons enables hospitalist groups to continuously ensure the hospitalist schedule meets the clinical demands while optimizing the hospitalist group’s schedule.
Unfilled positions
The 2018 SoHM report features a new section on unfilled positions that may provide insight and better understanding about how your group compares to others, as it relates to properly evaluating your recruitment pipeline.
For hospital medicine groups (HMGs) serving adults only, two out of three groups have unfilled positions, and about half of pediatric-only hospitalist groups have unfilled positions. Andrew White, MD, SFHM, associate professor of medicine at the University of Washington, Seattle, provided us with a deep-dive discussion of this topic in a recent article in The Hospitalist.
If your group has historically had more unfilled positions than the respondents, it might mean your group should consider different strategies to close the gap. It may also lead to conversations about how to rethink the schedule to better meet the demands of clinical care with limited resources.
So, with all these unfilled positions, how are hospitalist groups filling the gap? Not all groups are using locum tenens to fill those unfilled positions. About a third of hospitalist groups reported leaving those gaps uncovered.
The most commonly reported tactic to fill in the gaps was voluntary extra shifts by existing hospitalists (physicians and/or nurse practioners/physician assistants). This approach is used by 70% of hospitalist groups. The second most-used tactic was “moonlighters” or PRN physicians (57.4%). Thirdly, was use of locum tenens physicians.
With these baselines, we will be able to better track and trend the industry going forward.
Scheduling methodologies
For pediatric practices, the fixed rotating block scheduling has decreased over the two survey periods (16.7% versus 6.7%).
Even though the 7-on/7-off schedule remains quite popular among adult-only HMGs, many seasoned hospitalists wonder whether this is sustainable through all seasons of life. Some hospitalists have said a 7-on/7-off schedule is like turning on and off your personal life and that it takes a day or 2 to recover from 7 consecutive 12-hour days.
On the other hand, a fixed schedule is the easiest to explain, and many new hospitalists are requesting a fixed schedule. Even so, a fixed schedule may not allow for enough flexibility to adapt the schedule to the demands of patient care.
Nonetheless, a fixed schedule remains a very popular scheduling pattern. Does this scheduling model lead to burnout? Does this scheduling model increase or decrease elasticity? The debate of flexible versus fixed schedules continues!
Results by shift type
Very simply, the length of individual shifts has not changed much in prior years. For adult-only practices, most all day and night shifts are 12 hours in length. For pediatric-only HMGs, most day shifts are about 10 hours, and most night shifts are about 13 hours.
Most evening or swing shifts for adult-only practices are about 10 hours, which is a slight decrease from 2016. Pediatric-only practices’ evening shifts are about 8 hours in length.
A new question this year is about daytime admitters. For adult hospitalist groups, over half of groups have daytime admitters. For pediatric groups, nearly three out of four groups have daytime dedicated admitters. Also, the larger the group size, the more likely it is to have a dedicated daytime admitter.
Nocturnists remain in demand! Over 80% of adult hospitalist groups have on-site hospitalists at night. About a quarter of pediatric-only practices have nocturnists.
Scheduled workload distribution
One way of scheduling patient assignments is the phenomenon of unit-based assignments, or geographic rounding. As this has become more prevalent, the SHM Practice Analysis Committee recommended adding a question about unit-based assignments to the 2018 SoHM report.
The adoption of unit-based assignments is higher in academic groups (54.3%), as well as among hospitalists employed at a “hospital, health system or integrated delivery system” (47.4%), than in other group practice models.
Just as with the presence of daytime admitters, the larger the group the more likely it has some form of unit-based assignments. Further study would be needed to determine whether there is a link between the presence of daytime admitters and successful unit-based assignments for daytime rounders.
What’s the verdict?
Hospitalist scheduling will continue to evolve. It’s a never-ending balance of what’s best for patients and what’s best for hospitalists (and likely many other key stakeholders).
Scheduling is personal. Scheduling is an art form. The biggest question in this topic area is: Has anyone figured out the ‘secret sauce’ to hospitalist scheduling? Go online to SHM’s HMX to start the discussion!
Ms. Trask is national vice president of the Hospital Medicine Service Line at Catholic Health Initiatives in Englewood, Colo. She is also a member of The Hospitalist’s editorial advisory board.
Survey says ...
Survey says ...
Scheduling. Has there ever been such a simple word that is so complex? A simple Internet search of hospitalist scheduling returns thousands of possible discussions, leaving readers to conclude that the possibilities are endless and the challenges great. The answer certainly is not a one-size-fits-all approach.
Hospitalist scheduling is one of the key sections in the 2018 State of Hospital Medicine (SoHM) report; the 2018 report delves deeper into hospitalist scheduling than ever before.
For those of you who have been regular users of prior SoHM reports, you should be pleasantly surprised to find new comparative values: There are nearly 50% more pages dedicated just to scheduling!
For those readers who have never subscribed to the SoHM Report, this is your chance to study how other groups approach hospitalist schedules.
Why is hospitalist scheduling such a hot topic? For one, flexible and sustainable scheduling is an important contributor to job satisfaction. It is important for hospitalists to have a high degree of input into managing and effecting change for personal work-life balance.
As John Nelson, MD, MHM, a cofounder of the Society of Hospital Medicine, wrote recently in The Hospitalist, “an optimal schedule alone isn’t the key to preventing it [burnout], but maybe a good schedule can reduce your risk you’ll suffer from it.”
Secondly, ensuring that the hospitalist team is right sized – that is, scheduling hospitalists in the right place at the right time – is an art. Using resources, such as the 2018 SoHM report, to identify quantifiable comparisons enables hospitalist groups to continuously ensure the hospitalist schedule meets the clinical demands while optimizing the hospitalist group’s schedule.
Unfilled positions
The 2018 SoHM report features a new section on unfilled positions that may provide insight and better understanding about how your group compares to others, as it relates to properly evaluating your recruitment pipeline.
For hospital medicine groups (HMGs) serving adults only, two out of three groups have unfilled positions, and about half of pediatric-only hospitalist groups have unfilled positions. Andrew White, MD, SFHM, associate professor of medicine at the University of Washington, Seattle, provided us with a deep-dive discussion of this topic in a recent article in The Hospitalist.
If your group has historically had more unfilled positions than the respondents, it might mean your group should consider different strategies to close the gap. It may also lead to conversations about how to rethink the schedule to better meet the demands of clinical care with limited resources.
So, with all these unfilled positions, how are hospitalist groups filling the gap? Not all groups are using locum tenens to fill those unfilled positions. About a third of hospitalist groups reported leaving those gaps uncovered.
The most commonly reported tactic to fill in the gaps was voluntary extra shifts by existing hospitalists (physicians and/or nurse practioners/physician assistants). This approach is used by 70% of hospitalist groups. The second most-used tactic was “moonlighters” or PRN physicians (57.4%). Thirdly, was use of locum tenens physicians.
With these baselines, we will be able to better track and trend the industry going forward.
Scheduling methodologies
For pediatric practices, the fixed rotating block scheduling has decreased over the two survey periods (16.7% versus 6.7%).
Even though the 7-on/7-off schedule remains quite popular among adult-only HMGs, many seasoned hospitalists wonder whether this is sustainable through all seasons of life. Some hospitalists have said a 7-on/7-off schedule is like turning on and off your personal life and that it takes a day or 2 to recover from 7 consecutive 12-hour days.
On the other hand, a fixed schedule is the easiest to explain, and many new hospitalists are requesting a fixed schedule. Even so, a fixed schedule may not allow for enough flexibility to adapt the schedule to the demands of patient care.
Nonetheless, a fixed schedule remains a very popular scheduling pattern. Does this scheduling model lead to burnout? Does this scheduling model increase or decrease elasticity? The debate of flexible versus fixed schedules continues!
Results by shift type
Very simply, the length of individual shifts has not changed much in prior years. For adult-only practices, most all day and night shifts are 12 hours in length. For pediatric-only HMGs, most day shifts are about 10 hours, and most night shifts are about 13 hours.
Most evening or swing shifts for adult-only practices are about 10 hours, which is a slight decrease from 2016. Pediatric-only practices’ evening shifts are about 8 hours in length.
A new question this year is about daytime admitters. For adult hospitalist groups, over half of groups have daytime admitters. For pediatric groups, nearly three out of four groups have daytime dedicated admitters. Also, the larger the group size, the more likely it is to have a dedicated daytime admitter.
Nocturnists remain in demand! Over 80% of adult hospitalist groups have on-site hospitalists at night. About a quarter of pediatric-only practices have nocturnists.
Scheduled workload distribution
One way of scheduling patient assignments is the phenomenon of unit-based assignments, or geographic rounding. As this has become more prevalent, the SHM Practice Analysis Committee recommended adding a question about unit-based assignments to the 2018 SoHM report.
The adoption of unit-based assignments is higher in academic groups (54.3%), as well as among hospitalists employed at a “hospital, health system or integrated delivery system” (47.4%), than in other group practice models.
Just as with the presence of daytime admitters, the larger the group the more likely it has some form of unit-based assignments. Further study would be needed to determine whether there is a link between the presence of daytime admitters and successful unit-based assignments for daytime rounders.
What’s the verdict?
Hospitalist scheduling will continue to evolve. It’s a never-ending balance of what’s best for patients and what’s best for hospitalists (and likely many other key stakeholders).
Scheduling is personal. Scheduling is an art form. The biggest question in this topic area is: Has anyone figured out the ‘secret sauce’ to hospitalist scheduling? Go online to SHM’s HMX to start the discussion!
Ms. Trask is national vice president of the Hospital Medicine Service Line at Catholic Health Initiatives in Englewood, Colo. She is also a member of The Hospitalist’s editorial advisory board.
Scheduling. Has there ever been such a simple word that is so complex? A simple Internet search of hospitalist scheduling returns thousands of possible discussions, leaving readers to conclude that the possibilities are endless and the challenges great. The answer certainly is not a one-size-fits-all approach.
Hospitalist scheduling is one of the key sections in the 2018 State of Hospital Medicine (SoHM) report; the 2018 report delves deeper into hospitalist scheduling than ever before.
For those of you who have been regular users of prior SoHM reports, you should be pleasantly surprised to find new comparative values: There are nearly 50% more pages dedicated just to scheduling!
For those readers who have never subscribed to the SoHM Report, this is your chance to study how other groups approach hospitalist schedules.
Why is hospitalist scheduling such a hot topic? For one, flexible and sustainable scheduling is an important contributor to job satisfaction. It is important for hospitalists to have a high degree of input into managing and effecting change for personal work-life balance.
As John Nelson, MD, MHM, a cofounder of the Society of Hospital Medicine, wrote recently in The Hospitalist, “an optimal schedule alone isn’t the key to preventing it [burnout], but maybe a good schedule can reduce your risk you’ll suffer from it.”
Secondly, ensuring that the hospitalist team is right sized – that is, scheduling hospitalists in the right place at the right time – is an art. Using resources, such as the 2018 SoHM report, to identify quantifiable comparisons enables hospitalist groups to continuously ensure the hospitalist schedule meets the clinical demands while optimizing the hospitalist group’s schedule.
Unfilled positions
The 2018 SoHM report features a new section on unfilled positions that may provide insight and better understanding about how your group compares to others, as it relates to properly evaluating your recruitment pipeline.
For hospital medicine groups (HMGs) serving adults only, two out of three groups have unfilled positions, and about half of pediatric-only hospitalist groups have unfilled positions. Andrew White, MD, SFHM, associate professor of medicine at the University of Washington, Seattle, provided us with a deep-dive discussion of this topic in a recent article in The Hospitalist.
If your group has historically had more unfilled positions than the respondents, it might mean your group should consider different strategies to close the gap. It may also lead to conversations about how to rethink the schedule to better meet the demands of clinical care with limited resources.
So, with all these unfilled positions, how are hospitalist groups filling the gap? Not all groups are using locum tenens to fill those unfilled positions. About a third of hospitalist groups reported leaving those gaps uncovered.
The most commonly reported tactic to fill in the gaps was voluntary extra shifts by existing hospitalists (physicians and/or nurse practioners/physician assistants). This approach is used by 70% of hospitalist groups. The second most-used tactic was “moonlighters” or PRN physicians (57.4%). Thirdly, was use of locum tenens physicians.
With these baselines, we will be able to better track and trend the industry going forward.
Scheduling methodologies
For pediatric practices, the fixed rotating block scheduling has decreased over the two survey periods (16.7% versus 6.7%).
Even though the 7-on/7-off schedule remains quite popular among adult-only HMGs, many seasoned hospitalists wonder whether this is sustainable through all seasons of life. Some hospitalists have said a 7-on/7-off schedule is like turning on and off your personal life and that it takes a day or 2 to recover from 7 consecutive 12-hour days.
On the other hand, a fixed schedule is the easiest to explain, and many new hospitalists are requesting a fixed schedule. Even so, a fixed schedule may not allow for enough flexibility to adapt the schedule to the demands of patient care.
Nonetheless, a fixed schedule remains a very popular scheduling pattern. Does this scheduling model lead to burnout? Does this scheduling model increase or decrease elasticity? The debate of flexible versus fixed schedules continues!
Results by shift type
Very simply, the length of individual shifts has not changed much in prior years. For adult-only practices, most all day and night shifts are 12 hours in length. For pediatric-only HMGs, most day shifts are about 10 hours, and most night shifts are about 13 hours.
Most evening or swing shifts for adult-only practices are about 10 hours, which is a slight decrease from 2016. Pediatric-only practices’ evening shifts are about 8 hours in length.
A new question this year is about daytime admitters. For adult hospitalist groups, over half of groups have daytime admitters. For pediatric groups, nearly three out of four groups have daytime dedicated admitters. Also, the larger the group size, the more likely it is to have a dedicated daytime admitter.
Nocturnists remain in demand! Over 80% of adult hospitalist groups have on-site hospitalists at night. About a quarter of pediatric-only practices have nocturnists.
Scheduled workload distribution
One way of scheduling patient assignments is the phenomenon of unit-based assignments, or geographic rounding. As this has become more prevalent, the SHM Practice Analysis Committee recommended adding a question about unit-based assignments to the 2018 SoHM report.
The adoption of unit-based assignments is higher in academic groups (54.3%), as well as among hospitalists employed at a “hospital, health system or integrated delivery system” (47.4%), than in other group practice models.
Just as with the presence of daytime admitters, the larger the group the more likely it has some form of unit-based assignments. Further study would be needed to determine whether there is a link between the presence of daytime admitters and successful unit-based assignments for daytime rounders.
What’s the verdict?
Hospitalist scheduling will continue to evolve. It’s a never-ending balance of what’s best for patients and what’s best for hospitalists (and likely many other key stakeholders).
Scheduling is personal. Scheduling is an art form. The biggest question in this topic area is: Has anyone figured out the ‘secret sauce’ to hospitalist scheduling? Go online to SHM’s HMX to start the discussion!
Ms. Trask is national vice president of the Hospital Medicine Service Line at Catholic Health Initiatives in Englewood, Colo. She is also a member of The Hospitalist’s editorial advisory board.
Engraftment achieved after conditioning without radiation, alkylating agents
HOUSTON – Use of an alemtuzumab/fludarabine conditioning regimen – without any radiation or alkylating agents – was effective in patients with a systemic regenerative disease who experienced myeloid failure after allogeneic transplantation, according to an investigator.
Of the 20 patients with dyskeratosis congenita who received the regimen, 19 achieved primary engraftment within 42 days of transplant, according to Suneet Agarwal, MD, PhD, of Dana-Farber/Boston Children’s Cancer & Blood Disorders Center and Harvard Medical School, Boston.
However, these findings may have broader implications beyond this rare disease, as this is the first reported series of patients undergoing allogeneic bone marrow transplant to achieve durable myeloid engraftment without receiving alkylating agents or radiation, Dr. Agarwal said at the Transplantation & Cellular Therapy Meetings.
In a late-breaking clinical trial presentation of the results, Dr. Agarwal noted that patients in this study all had telomere disease, defined by clinical syndrome, gene mutation, or short lymphocyte telomere length. That’s because the investigators hypothesized that telomere defects would result in a “replicative disadvantage” in hematopoietic and immune cells, which would favor engraftment.
Dyskeratosis congenita is a prototypic telomere biology disorder caused by mutations that impair telomere maintenance, he said, adding that the disease has high rates of cancer, pulmonary disease, and hepatic disease.
While allogeneic transplants are curative in the disorder, outcomes after transplantation are typically poor, with high rates of bone marrow failure, he added. By eliminating radiation and alkylator exposure, the investigators hoped salvage bone marrow transplant would be more feasible, with lower risks of organ failure and secondary malignancy.
The 20 patients Dr. Agarwal reported on were aged from 30 months to 65 years. They all received alemtuzumab/fludarabine conditioning starting at day 9 before bone marrow graft, along with graft-versus-host disease (GVHD) prophylaxis through the pre- to posttransplant period. Two had matched siblings, while 18 had unrelated donors.
Of those 20 patients, 19 achieved primary engraftment at a median of 22 days after transplant, Dr. Agarwal reported. There was no acute GVHD and four cases of chronic GVHD that resolved with oral or topical steroids.
Of the 20 patients, 18 were alive at a median follow-up of 24 months, which compares favorably with historically reported cases, according to the investigator. There was one disease-related death and one treatment-related death caused by fungal infection at 3 months post transplant, he said.
These results suggest the radiation- and alkylator-free conditioning regimen is “effective,” Dr. Agarwal said, adding that exposure to those modalities is not required for myeloid engraftment in certain clinical settings.
The meeting is held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).
Dr. Agarwal reported having no conflicts of interest.
SOURCE: Agarwal S et al. TCT 2019, Abstract LBA2.
HOUSTON – Use of an alemtuzumab/fludarabine conditioning regimen – without any radiation or alkylating agents – was effective in patients with a systemic regenerative disease who experienced myeloid failure after allogeneic transplantation, according to an investigator.
Of the 20 patients with dyskeratosis congenita who received the regimen, 19 achieved primary engraftment within 42 days of transplant, according to Suneet Agarwal, MD, PhD, of Dana-Farber/Boston Children’s Cancer & Blood Disorders Center and Harvard Medical School, Boston.
However, these findings may have broader implications beyond this rare disease, as this is the first reported series of patients undergoing allogeneic bone marrow transplant to achieve durable myeloid engraftment without receiving alkylating agents or radiation, Dr. Agarwal said at the Transplantation & Cellular Therapy Meetings.
In a late-breaking clinical trial presentation of the results, Dr. Agarwal noted that patients in this study all had telomere disease, defined by clinical syndrome, gene mutation, or short lymphocyte telomere length. That’s because the investigators hypothesized that telomere defects would result in a “replicative disadvantage” in hematopoietic and immune cells, which would favor engraftment.
Dyskeratosis congenita is a prototypic telomere biology disorder caused by mutations that impair telomere maintenance, he said, adding that the disease has high rates of cancer, pulmonary disease, and hepatic disease.
While allogeneic transplants are curative in the disorder, outcomes after transplantation are typically poor, with high rates of bone marrow failure, he added. By eliminating radiation and alkylator exposure, the investigators hoped salvage bone marrow transplant would be more feasible, with lower risks of organ failure and secondary malignancy.
The 20 patients Dr. Agarwal reported on were aged from 30 months to 65 years. They all received alemtuzumab/fludarabine conditioning starting at day 9 before bone marrow graft, along with graft-versus-host disease (GVHD) prophylaxis through the pre- to posttransplant period. Two had matched siblings, while 18 had unrelated donors.
Of those 20 patients, 19 achieved primary engraftment at a median of 22 days after transplant, Dr. Agarwal reported. There was no acute GVHD and four cases of chronic GVHD that resolved with oral or topical steroids.
Of the 20 patients, 18 were alive at a median follow-up of 24 months, which compares favorably with historically reported cases, according to the investigator. There was one disease-related death and one treatment-related death caused by fungal infection at 3 months post transplant, he said.
These results suggest the radiation- and alkylator-free conditioning regimen is “effective,” Dr. Agarwal said, adding that exposure to those modalities is not required for myeloid engraftment in certain clinical settings.
The meeting is held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).
Dr. Agarwal reported having no conflicts of interest.
SOURCE: Agarwal S et al. TCT 2019, Abstract LBA2.
HOUSTON – Use of an alemtuzumab/fludarabine conditioning regimen – without any radiation or alkylating agents – was effective in patients with a systemic regenerative disease who experienced myeloid failure after allogeneic transplantation, according to an investigator.
Of the 20 patients with dyskeratosis congenita who received the regimen, 19 achieved primary engraftment within 42 days of transplant, according to Suneet Agarwal, MD, PhD, of Dana-Farber/Boston Children’s Cancer & Blood Disorders Center and Harvard Medical School, Boston.
However, these findings may have broader implications beyond this rare disease, as this is the first reported series of patients undergoing allogeneic bone marrow transplant to achieve durable myeloid engraftment without receiving alkylating agents or radiation, Dr. Agarwal said at the Transplantation & Cellular Therapy Meetings.
In a late-breaking clinical trial presentation of the results, Dr. Agarwal noted that patients in this study all had telomere disease, defined by clinical syndrome, gene mutation, or short lymphocyte telomere length. That’s because the investigators hypothesized that telomere defects would result in a “replicative disadvantage” in hematopoietic and immune cells, which would favor engraftment.
Dyskeratosis congenita is a prototypic telomere biology disorder caused by mutations that impair telomere maintenance, he said, adding that the disease has high rates of cancer, pulmonary disease, and hepatic disease.
While allogeneic transplants are curative in the disorder, outcomes after transplantation are typically poor, with high rates of bone marrow failure, he added. By eliminating radiation and alkylator exposure, the investigators hoped salvage bone marrow transplant would be more feasible, with lower risks of organ failure and secondary malignancy.
The 20 patients Dr. Agarwal reported on were aged from 30 months to 65 years. They all received alemtuzumab/fludarabine conditioning starting at day 9 before bone marrow graft, along with graft-versus-host disease (GVHD) prophylaxis through the pre- to posttransplant period. Two had matched siblings, while 18 had unrelated donors.
Of those 20 patients, 19 achieved primary engraftment at a median of 22 days after transplant, Dr. Agarwal reported. There was no acute GVHD and four cases of chronic GVHD that resolved with oral or topical steroids.
Of the 20 patients, 18 were alive at a median follow-up of 24 months, which compares favorably with historically reported cases, according to the investigator. There was one disease-related death and one treatment-related death caused by fungal infection at 3 months post transplant, he said.
These results suggest the radiation- and alkylator-free conditioning regimen is “effective,” Dr. Agarwal said, adding that exposure to those modalities is not required for myeloid engraftment in certain clinical settings.
The meeting is held by the American Society for Blood and Marrow Transplantation and the Center for International Blood and Marrow Transplant Research. At its meeting, the American Society for Blood and Marrow Transplantation announced a new name for the society: American Society for Transplantation and Cellular Therapy (ASTCT).
Dr. Agarwal reported having no conflicts of interest.
SOURCE: Agarwal S et al. TCT 2019, Abstract LBA2.
REPORTING FROM TCT 2019
Sore on head
The FP suspected that this was a skin cancer with ulceration and pigmentation. The differential diagnosis included pigmented basal cell carcinoma, melanoma, and squamous cell carcinoma. If this were a melanoma, there would appear to be areas of regression between the islands of pigmentation. The FP explained that a biopsy was needed and suggested a broad shave biopsy because this technique would provide adequate tissue to the pathologist. (See the Watch & Learn video on “Shave biopsy.”)
The FP performed the broad shave biopsy and saw some remaining pigment at the base of the initial cut. He performed a second pass with the DermaBlade and explained this in the pathology requisition. (It is acceptable to send a deeper section of tissue if it appears that there is some remaining tumor below the initial biopsy.)
The biopsy report revealed lentigo maligna melanoma, which was approximately 2 mm thick—much deeper than the clinical appearance suggested. The pathologist combined the depths from the 2 specimens to get an approximate Breslow level. In this case, the most important information was that this was >1 mm in depth, which suggested that a sentinel lymph node biopsy would be needed for prognostic information. The patient was referred to Surgical Oncology for wide excision and sentinel lymph node biopsy.
Fortunately, the nodes were negative for metastasis. The wide excision was closed with a graft that healed well over time. The patient was followed with regular skin exams and careful lymph node exams of the neck and supraclavicular areas. He now wears a hat whenever he is outdoors.
Photo courtesy of Jonathan Karnes, MD and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Karnes J, Usatine R. Squamous cell carcinoma. In: Usatine R, Smith M, Mayeaux EJ, et al. Color Atlas and Synopsis of Family Medicine. 3rd ed. New York, NY: McGraw-Hill; 2019:1103-1111.
To learn more about the newest 3rd edition of the Color Atlas and Synopsis of Family Medicine, see: https://www.amazon.com/Color-Atlas-Synopsis-Family-Medicine/dp/1259862046/
You can get the Color Atlas of Family Medicine app by clicking on this link: usatinemedia.com
The FP suspected that this was a skin cancer with ulceration and pigmentation. The differential diagnosis included pigmented basal cell carcinoma, melanoma, and squamous cell carcinoma. If this were a melanoma, there would appear to be areas of regression between the islands of pigmentation. The FP explained that a biopsy was needed and suggested a broad shave biopsy because this technique would provide adequate tissue to the pathologist. (See the Watch & Learn video on “Shave biopsy.”)
The FP performed the broad shave biopsy and saw some remaining pigment at the base of the initial cut. He performed a second pass with the DermaBlade and explained this in the pathology requisition. (It is acceptable to send a deeper section of tissue if it appears that there is some remaining tumor below the initial biopsy.)
The biopsy report revealed lentigo maligna melanoma, which was approximately 2 mm thick—much deeper than the clinical appearance suggested. The pathologist combined the depths from the 2 specimens to get an approximate Breslow level. In this case, the most important information was that this was >1 mm in depth, which suggested that a sentinel lymph node biopsy would be needed for prognostic information. The patient was referred to Surgical Oncology for wide excision and sentinel lymph node biopsy.
Fortunately, the nodes were negative for metastasis. The wide excision was closed with a graft that healed well over time. The patient was followed with regular skin exams and careful lymph node exams of the neck and supraclavicular areas. He now wears a hat whenever he is outdoors.
Photo courtesy of Jonathan Karnes, MD and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Karnes J, Usatine R. Squamous cell carcinoma. In: Usatine R, Smith M, Mayeaux EJ, et al. Color Atlas and Synopsis of Family Medicine. 3rd ed. New York, NY: McGraw-Hill; 2019:1103-1111.
To learn more about the newest 3rd edition of the Color Atlas and Synopsis of Family Medicine, see: https://www.amazon.com/Color-Atlas-Synopsis-Family-Medicine/dp/1259862046/
You can get the Color Atlas of Family Medicine app by clicking on this link: usatinemedia.com
The FP suspected that this was a skin cancer with ulceration and pigmentation. The differential diagnosis included pigmented basal cell carcinoma, melanoma, and squamous cell carcinoma. If this were a melanoma, there would appear to be areas of regression between the islands of pigmentation. The FP explained that a biopsy was needed and suggested a broad shave biopsy because this technique would provide adequate tissue to the pathologist. (See the Watch & Learn video on “Shave biopsy.”)
The FP performed the broad shave biopsy and saw some remaining pigment at the base of the initial cut. He performed a second pass with the DermaBlade and explained this in the pathology requisition. (It is acceptable to send a deeper section of tissue if it appears that there is some remaining tumor below the initial biopsy.)
The biopsy report revealed lentigo maligna melanoma, which was approximately 2 mm thick—much deeper than the clinical appearance suggested. The pathologist combined the depths from the 2 specimens to get an approximate Breslow level. In this case, the most important information was that this was >1 mm in depth, which suggested that a sentinel lymph node biopsy would be needed for prognostic information. The patient was referred to Surgical Oncology for wide excision and sentinel lymph node biopsy.
Fortunately, the nodes were negative for metastasis. The wide excision was closed with a graft that healed well over time. The patient was followed with regular skin exams and careful lymph node exams of the neck and supraclavicular areas. He now wears a hat whenever he is outdoors.
Photo courtesy of Jonathan Karnes, MD and text for Photo Rounds Friday courtesy of Richard P. Usatine, MD. This case was adapted from: Karnes J, Usatine R. Squamous cell carcinoma. In: Usatine R, Smith M, Mayeaux EJ, et al. Color Atlas and Synopsis of Family Medicine. 3rd ed. New York, NY: McGraw-Hill; 2019:1103-1111.
To learn more about the newest 3rd edition of the Color Atlas and Synopsis of Family Medicine, see: https://www.amazon.com/Color-Atlas-Synopsis-Family-Medicine/dp/1259862046/
You can get the Color Atlas of Family Medicine app by clicking on this link: usatinemedia.com
Analysis suggests ‘Burkitt-like lymphoma’ is a misnomer
They found that BLL-11q has a genomic and mutational profile more closely related to that of high grade B-cell lymphoma (HGBCL) or diffuse large B-cell lymphoma (DLBCL) than typical Burkitt lymphoma (BL).
The researchers also found that BLL-11q has clinical, morphologic, and phenotypic features that are “more consistent” with HGBCL or DLBCL than with typical BL.
“These observations support a reconsideration of the ‘Burkitt-like’ term for these tumors,” Blanca Gonzalez-Farre, MD, of Hospital Clínic de Barcelona, and her colleagues wrote in Haematologica.
To reach this conclusion, the researchers performed copy number analysis and sequencing of B-cell lymphoma-related genes in 11 cases of BLL-11q.
The copy number analysis revealed that seven BLL-11q cases had the typical 11q gain/loss pattern, two had an 11q terminal deletion, one had two gains and two losses, and one had an 11q23.3-q25 copy number neutral loss of heterozygosity in addition to gain.
The BLL-11q cases also had frequent gains of 5q21.3-q32 and losses of 6q12.1-q21. However, they lacked the 1q gains observed in MYC-positive BL and alterations typically observed in germinal center B-cell like (GCB) DLBCL, such as gains in 2p16.1 and 7p.
Targeted sequencing of the BLL-11q cases revealed mutations typically observed in germinal center-derived lymphomas, including mutations in BTG2, DDX3X, ETS1, EP300, GNA13, CREBBP, KMT2C, EZH2, ARID1A, KMT2D, HIST1H1D, HIST1H2BC, and TMEM30A.
However, the BLL-11q cases lacked mutations in ID3, TCF3, and CCND3, which are typically observed in BL.
“In addition to the genetic differences, our BLL-11q differed clinically, morphologically, and phenotypically from conventional BL and instead showed features more consistent with HGBCL or DLBCL,” the researchers wrote.
Specifically, the BLL-11q patients were all younger than 40 years, with a median age of 15. Most presented with localized lymphadenopathy. And all had favorable treatment outcomes, remaining alive and free of disease at a median follow-up of 30 months.
All cases had a germinal center phenotype. They did not have the typical cytological features of BL, but they did have a high proliferative index, and some cases had a starry sky pattern.
The researchers said the BLL-11q cases were better classified as HGBCL not otherwise specified (n = 8), DLBCL (n = 2), and atypical BL (n = 1).
Considering these findings together, the team concluded that a more appropriate name for BLL-11q might be “aggressive B-cell lymphoma with 11q aberration.”
This research was supported by Asociación Española Contra el Cáncer and other organizations, as well as the government of Catalonia.
SOURCE: Gonzalez-Farre B et al. Haematologica. 2019 Feb 7. doi: 10.3324/haematol.2018.207928.
They found that BLL-11q has a genomic and mutational profile more closely related to that of high grade B-cell lymphoma (HGBCL) or diffuse large B-cell lymphoma (DLBCL) than typical Burkitt lymphoma (BL).
The researchers also found that BLL-11q has clinical, morphologic, and phenotypic features that are “more consistent” with HGBCL or DLBCL than with typical BL.
“These observations support a reconsideration of the ‘Burkitt-like’ term for these tumors,” Blanca Gonzalez-Farre, MD, of Hospital Clínic de Barcelona, and her colleagues wrote in Haematologica.
To reach this conclusion, the researchers performed copy number analysis and sequencing of B-cell lymphoma-related genes in 11 cases of BLL-11q.
The copy number analysis revealed that seven BLL-11q cases had the typical 11q gain/loss pattern, two had an 11q terminal deletion, one had two gains and two losses, and one had an 11q23.3-q25 copy number neutral loss of heterozygosity in addition to gain.
The BLL-11q cases also had frequent gains of 5q21.3-q32 and losses of 6q12.1-q21. However, they lacked the 1q gains observed in MYC-positive BL and alterations typically observed in germinal center B-cell like (GCB) DLBCL, such as gains in 2p16.1 and 7p.
Targeted sequencing of the BLL-11q cases revealed mutations typically observed in germinal center-derived lymphomas, including mutations in BTG2, DDX3X, ETS1, EP300, GNA13, CREBBP, KMT2C, EZH2, ARID1A, KMT2D, HIST1H1D, HIST1H2BC, and TMEM30A.
However, the BLL-11q cases lacked mutations in ID3, TCF3, and CCND3, which are typically observed in BL.
“In addition to the genetic differences, our BLL-11q differed clinically, morphologically, and phenotypically from conventional BL and instead showed features more consistent with HGBCL or DLBCL,” the researchers wrote.
Specifically, the BLL-11q patients were all younger than 40 years, with a median age of 15. Most presented with localized lymphadenopathy. And all had favorable treatment outcomes, remaining alive and free of disease at a median follow-up of 30 months.
All cases had a germinal center phenotype. They did not have the typical cytological features of BL, but they did have a high proliferative index, and some cases had a starry sky pattern.
The researchers said the BLL-11q cases were better classified as HGBCL not otherwise specified (n = 8), DLBCL (n = 2), and atypical BL (n = 1).
Considering these findings together, the team concluded that a more appropriate name for BLL-11q might be “aggressive B-cell lymphoma with 11q aberration.”
This research was supported by Asociación Española Contra el Cáncer and other organizations, as well as the government of Catalonia.
SOURCE: Gonzalez-Farre B et al. Haematologica. 2019 Feb 7. doi: 10.3324/haematol.2018.207928.
They found that BLL-11q has a genomic and mutational profile more closely related to that of high grade B-cell lymphoma (HGBCL) or diffuse large B-cell lymphoma (DLBCL) than typical Burkitt lymphoma (BL).
The researchers also found that BLL-11q has clinical, morphologic, and phenotypic features that are “more consistent” with HGBCL or DLBCL than with typical BL.
“These observations support a reconsideration of the ‘Burkitt-like’ term for these tumors,” Blanca Gonzalez-Farre, MD, of Hospital Clínic de Barcelona, and her colleagues wrote in Haematologica.
To reach this conclusion, the researchers performed copy number analysis and sequencing of B-cell lymphoma-related genes in 11 cases of BLL-11q.
The copy number analysis revealed that seven BLL-11q cases had the typical 11q gain/loss pattern, two had an 11q terminal deletion, one had two gains and two losses, and one had an 11q23.3-q25 copy number neutral loss of heterozygosity in addition to gain.
The BLL-11q cases also had frequent gains of 5q21.3-q32 and losses of 6q12.1-q21. However, they lacked the 1q gains observed in MYC-positive BL and alterations typically observed in germinal center B-cell like (GCB) DLBCL, such as gains in 2p16.1 and 7p.
Targeted sequencing of the BLL-11q cases revealed mutations typically observed in germinal center-derived lymphomas, including mutations in BTG2, DDX3X, ETS1, EP300, GNA13, CREBBP, KMT2C, EZH2, ARID1A, KMT2D, HIST1H1D, HIST1H2BC, and TMEM30A.
However, the BLL-11q cases lacked mutations in ID3, TCF3, and CCND3, which are typically observed in BL.
“In addition to the genetic differences, our BLL-11q differed clinically, morphologically, and phenotypically from conventional BL and instead showed features more consistent with HGBCL or DLBCL,” the researchers wrote.
Specifically, the BLL-11q patients were all younger than 40 years, with a median age of 15. Most presented with localized lymphadenopathy. And all had favorable treatment outcomes, remaining alive and free of disease at a median follow-up of 30 months.
All cases had a germinal center phenotype. They did not have the typical cytological features of BL, but they did have a high proliferative index, and some cases had a starry sky pattern.
The researchers said the BLL-11q cases were better classified as HGBCL not otherwise specified (n = 8), DLBCL (n = 2), and atypical BL (n = 1).
Considering these findings together, the team concluded that a more appropriate name for BLL-11q might be “aggressive B-cell lymphoma with 11q aberration.”
This research was supported by Asociación Española Contra el Cáncer and other organizations, as well as the government of Catalonia.
SOURCE: Gonzalez-Farre B et al. Haematologica. 2019 Feb 7. doi: 10.3324/haematol.2018.207928.
REPORTING FROM HAEMATOLOGICA
A systematic approach to chronic abnormal uterine bleeding
Menstrual bleeding is considered normal when it occurs regularly (every 21-35 days), lasts 4 to 8 days, and is not associated with heavy bleeding.1 During the first few years after menarche, it is normal for girls to experience irregular menstrual cycles but, by the third year, 60% to 80% of girls have an adult pattern of menstrual bleeding.2
Menstrual flow without normal volume, duration, regularity, or frequency is considered abnormal uterine bleeding (AUB). The condition is considered acute if there is need for immediate intervention. In the absence of the need for immediate intervention, recurrent AUB is classified as chronic.3 Chronic AUB is the focus of this article.
Invaluable tool: The FIGO classification
In 2011, the
- structural causes, recalled by “PALM” (Polyps, Adenomyosis, Leiomyoma, and Malignancy/hyperplasia)
- nonstructural causes, recalled by “COEIN” (Coagulopathy, Ovulatory dysfunction, Endometrial, Iatrogenic, and Not yet classified).
The PALM–COEIN system also uses descriptive terminology (heavy bleeding, intermenstrual bleeding) to characterize the bleeding pattern.3 The American College of Obstetricians and Gynecologists has adopted this classification system and recommends that such historically used terminology as “dysfunctional uterine bleeding,” “menorrhagia,” and “metrorrhagia” be abandoned.1
The initial workup of all causes of chronic uterine bleeding begins with a history; physical examination, including pelvic exam; and laboratory testing, including a urine pregnancy test, complete blood count, and a test of thyroid-stimulating hormone (TABLE 2). The need for additional laboratory testing, imaging, or endometrial biopsy depends on the suspected cause of AUB, detailed stepwise in FIGURE 1 (women <18 years) and FIGURE 2 (≥18 years).
We first briefly review the 9 categories of AUB in the PALM–COEIN system; discuss the most common causes in more detail; and review common treatment options (TABLE 3).
CASE 1
Marsha R, a 41-year-old-woman, complains of heavy menstrual bleeding for the past year that has become worse over the past 2 months. Her menstrual cycles have occurred every 28 days and last 10 days; she uses 10 to 12 pads a day.
Continue to: Recently, Ms. R reports...
Recently, Ms. R reports, she has been bleeding continuously for 14 days, with episodes of lighter bleeding followed by heavier bleeding. She also complains of fatigue.
Bimanual examination is notable for an enlarged uterus.
How would you proceed with the workup of this patient, to determine the cause of her bleeding and tailor management accordingly?
Structural AUB: The “PALM” mnemonic
A structural cause of AUB must be considered when you encounter an abnormality on physical exam (TABLE 1).3 In obese women or other patients in whom the physical exam is difficult, historical clues—including postcoital bleeding, intermenstrual bleeding, or pelvic pain or pressure—also suggest a structural abnormality.4
Transvaginal ultrasonography (TVUS) is the initial method of evaluation when a structural abnormality is suspected.1,4 However, although TVUS is excellent at visualizing the myometrium, lesions within the uterine cavity can be missed. If intracavitary pathology, such as submucosal fibroids or endometrial polyps, is suspected, additional imaging with saline infusion sonohysterography (SIS) should be performed. If a cavitary abnormality is confirmed, hysteroscopy is indicated.1 Magnetic resonance imaging (MRI) is reserved for cases in which a uterine cavity abnormality is found on TVUS but cannot be further characterized by SIS or hysteroscopy.1
Continue to: Endometrial biopsy...
Endometrial biopsy (EMB) is indicated as part of the initial evaluation of AUB in all women >45 years and in younger women who have risk factors for endometrial cancer, including polycystic ovary syndrome (PCOS), obesity, and hereditary nonpolyposis colorectal cancer. Such biopsy is necessary in these women whether or not another condition is the cause of the AUB and regardless of findings on TVUS.1-4 Endometrial biopsy should also be performed in women with AUB that persists despite medical management. If office EMB is nondiagnostic, hysteroscopy or SIS can be used to obtain tissue samples for further evaluation.5
Polyps. An endometrial polyp is a benign growth of endometrial tissue that is covered with epithelial cells. Polyps are often diagnosed by EMB or TVUS when these techniques are performed as part of the workup for AUB.6 Endometrial polyps are found more commonly in postmenopausal women, but should be considered as a cause of AUB in premenopausal women, too, especially those with intermenstrual bleeding or postcoital bleeding (or both) that is unresponsive to medical management.7 Risk factors for polyps include older age, obesity, and treatment with tamoxifen.7 The usual treatment for symptomatic endometrial polyps is removal by operative hysteroscopy.7
Adenomyosis. Ectopic endometrial tissue in the myometrium that leads to hypertrophy of the myometrium and uterine enlargement is known as adenomyosis. The disorder is most often diagnosed in women 40 to 50 years of age, who commonly complain of heavy uterine bleeding (40%-60% of cases) and dysmenorrhea (65%).8 Although definitive diagnosis is made histologically at hysterectomy, TVUS and MRI can be useful tools to help narrow the differential diagnosis in women with unexplained AUB.
According to a systematic review,9 the sensitivity and specificity of imaging in the diagnosis of adenomyosis is 72% and 81%, respectively, for TVUS and 77% and 89%, respectively, for MRI. Needle biopsy, performed hysteroscopically or laparoscopically, is less useful because the technique has low sensitivity (reported variously as 8%-56%) in diagnosing adenomyosis.8
Treatment options for adenomyosis are medical management with agents that reduce bleeding (eg, a combination oral contraceptive [OC], nonsteroidal anti-inflammatory drugs [NSAIDs], the antifibrinolytic tranexamic acid, and, when there is no distortion of the uterine cavity, a levonorgestrel intrauterine device [LNG-IUD]); uterine artery embolization; and hysterectomy.8
Continue to: Leiomyoma
Leiomyoma. Uterine fibroids, or leiomyomas, are benign, fibromuscular solid tumors, thought to be hormone-dependent because many regress after menopause. In women of reproductive age, uterine fibroids are the most common cause of structural AUB, with a cumulative incidence of 70% to 80% among women in this age group.3,10 Fibroids are more common in African-American women, women who experienced early menarche, and women who are obese, have PCOS, or had a late first pregnancy.3-10
Many fibroids are asymptomatic, and are found incidentally on sonographic examination performed for other reasons; in one-third of affected patients, the fibroids result in heavy menstrual bleeding.10 Intermenstrual bleeding and postcoital bleeding can occur, but are not common symptoms with fibroids. Consider other causes of AUB, such as endometrial polyps, when these symptoms are present.
Treatment of fibroids is medical or surgical. Medical management is a reasonable first-line option, especially in women who have not completed childbearing and who have small (<3 cm in diameter) fibroids. Options include a combination OC, NSAIDs, tranexamic acid, and, when the uterine cavity is not distorted, an LNG-IUD.4,10,11
For women with larger fibroids, those for whom the aforementioned medical treatments are unsuccessful, and those who are seeking more definitive treatment, uterine artery embolization, myomectomy, or hysterectomy can be considered.
› Uterine artery embolization is performed by an interventional radiologist under local anesthesia and, if necessary, moderate sedation.12 After the procedure, fibroids decrease in size due to avascular necrosis, but the remainder of the myometrium is relatively unaffected because collateral blood supply develops.13,14 Patients might experience abdominal cramping for 2 or 3 days following the procedure, which can be managed with an oral NSAID.12 Approximately 90% of women treated with embolization note improvement in AUB by 3 months after the procedure.15 Uterine artery embolization is not recommended in women who have not completed childbearing.12,16,17
Continue to: Myomectomy
› Myomectomy (removal of the leiomyoma) is the surgical treatment of choice for women who want to maintain fertility. Depending on the size and location of the fibroid(s), myomectomy can be performed as an open surgical procedure, laparoscopically, or hysteroscopically. At the discretion of the surgeon, leuprolide acetate, a gonadotropin-releasing hormone agonist, can be prescribed for 3 months before myomectomy to reduce intraoperative blood loss by decreasing the vascularity of the fibroids.4,18 Reduction in bleeding is reported in 70% to 90% of patients who undergo myomectomy.19
› Hysterectomy, the definitive treatment for uterine fibroids, should be reserved for women who have completed childbearing and who have failed (or have a contraindication to) other treatment options.
Malignancy/hyperplasia. EMB should be performed when endometrial malignancy/hyperplasia is suspected. As noted, endometrial cancer should be considered as a diagnostic possibility in women >45 years, in younger women with risk factors, and in women who have failed to respond to medical treatment for other suspected causes of AUB.5
When hyperplasia without atypia is diagnosed, the LNG-IUD or oral progesterone is an acceptable treatment option; note that fewer women who have an LNG-IUD eventually require hysterectomy, compared to women who take oral hormone therapy for AUB.20 When hyperplasia with atypia is diagnosed, hysterectomy is the treatment of choice. If a woman wishes to maintain fertility, however, oral progesterone therapy can be offered.21
When the diagnosis is cancer, the patient should be referred to a gynecologic oncologist for staging and treatment. Treatment varies depending on stage, but generally requires hysterectomy including bilateral salpingo-oophorectomy, with possible chemotherapy or radiation, or both.22
Continue to: CASE 1
CASE 1
Ms. R undergoes a sonogram that reveals a 4-cm fibroid in the uterine fundus that has not distorted the uterine cavity. Although she has completed childbearing, Ms. R is not interested in a surgical procedure at this time. You recommend insertion of an LNG-IUD; she accepts your advice.
CASE 2
Claire G, 27 years old, with a body mass index of 41,* complains of irregular menses for several months. Her menstrual cycle is irregular, as is the duration of menses and amount of bleeding. She has some mild fatigue without dizziness.
The physical exam is notable for mild hirsutism, without abnormalities on pelvic examination. Lab testing reveals iron-deficiency anemia; a pregnancy test is negative.
The questions that were raised by Ms. R’s case challenge you here, too: What is the appropriate workup of Ms. G’s bleeding? Once the cause is confirmed, how should you treat her?
Nonstructural AUB: The “COEIN” mnemonic
In the absence of abnormalities on a pelvic exam, and after excluding endometrial malignancy/hyperplasia in patients with the aforementioned risk factors, a nonstructural cause of AUB should be considered (TABLE 1).3 In women 20 to 40 years of age, the primary common cause of nonstructural uterine bleeding is ovulatory dysfunction, most often caused by PCOS or anovulatory bleeding.
Continue to: For nonstructual causes of AUB...
For nonstructural causes of AUB, the recommended laboratory workup varies with the suspected diagnosis. In addition, recently pregnant women should have a quantitative assay of β human chorionic gonadotropin to evaluate for trophoblastic disease.5,23
Imaging is not usually recommended when the cause of AUB is suspected to be nonstructural. However, when PCOS is suspected, TVUS can be used to confirm the presence of polycystic ovaries.23
As noted, EMB should be performed when AUB is present in women >45 years, in patients of any age group who fail to respond to medical therapy, and in those at increased risk for endometrial cancer.
Coagulopathy. When heavy bleeding has been present since the onset of menarche, inherited bleeding disorders must be considered, the most common of which is von Willebrand disease, a disorder of platelet adhesion.24 It is estimated that just under 50% of adolescents with abnormal uterine bleeding have a coagulopathy, most often a platelet function disorder.25 Additional clues to the presence of a coagulation disorder include a family history of bleeding disorder, a personal history of bleeding problems associated with surgery, and a history of iron-deficiency anemia.26 Abnormal uterine bleeding might resolve with treatment of the underlying coagulopathy; if it does not, consider consultation with a hematologist before prescribing an NSAID or an OC.
Heavy bleeding in patients taking an anticoagulant falls into the category of coagulopathy-related AUB. No further workup is generally needed for these women.3
Continue to: Ovulatory dysfunction
Ovulatory dysfunction. Abnormal uterine bleeding caused by ovulatory dysfunction is generally due to PCOS or anovulatory bleeding. Other causes, beyond the scope of this discussion, include hypothyroidism, hyperandrogenism, female athlete triad, stress, and hyperprolactinemia.
› Polycystic ovary syndrome. A diagnosis of PCOS is made using any of several recognized criteria. The commonly used Rotterdam 2003 criteria27 require that at least 2 of the following be present to make a diagnosis of PCOS:
- oligo-ovulation or anovulation
- hyperandrogenism
- polycystic ovaries seen on ultrasonography.
In addition, women with PCOS are frequently obese, show signs of insulin resistance (diabetes, prediabetes, acanthosis nigricans), or hyperandrogenism (hirsutism, acne). Even if these latter findings are not present at diagnosis, women with PCOS are at risk for a metabolic disorder. Once a diagnosis of PCOS has been established, therefore, screening tests for diabetes and cardiac risk factors (eg, dyslipidemia) should be performed.28.29
To evaluate for hyperandrogenism, free testosterone should be measured using a high-sensitivity immunoassay in all women in whom PCOS is suspected. Because of a higher prevalence of nonclassical (ie, late-onset) congenital adrenal hyperplasia (CAH) in women of Ashkenazi Jewish (estimated prevalence, 3.7%), Hispanic (1.9%), Slavic (1.6%), and Italian (0.3%) descent, screening for CAH as a possible cause of hyperandrogenism is also recommended, by a test of a morning 17-hydroxyprogesterone level.23,29,30 (Note: The general Caucasian population has an estimated prevalence of nonclassical CAH of 0.1%.30)
Treatment of PCOS should be individualized, based on a patient’s symptoms and comorbidities. For overweight and obese women, weight loss, exercise, and metformin (1500-2000 mg/d) are the mainstays of therapy, and might reduce AUB.29,31 If these measures do not reduce AUB, other options include an OC, an LNG-IUD, and NSAIDs.
Continue to: Information on treating other PCOS-related symptoms...
Information on treating other PCOS-related symptoms (acne, hirsutism) is available from many sources29; these treatments do not typically help the patient’s AUB, however, and are therefore not addressed in this article.
› Anovulatory bleeding. In adolescence, the most common cause of AUB is anovulation resulting from immaturity of the hypothalamic–pituitary–ovarian axis. During anovulatory cycles, the imbalance of estrogen and progesterone creates a fragile endometrium, leading to unpredictable bleeding and irregular cycles. Other less common causes of AUB, such as ovarian or adrenal tumor, should be considered in adolescents who have hirsutism but do not meet the criteria for PCOS.5
When seeing an adolescent for evaluation of AUB, be aware that emotional barriers might be present that make it difficult for her to talk about menses and sexual activity. Be patient and normalize the patient’s symptoms when appropriate. Pelvic exam can be deferred, especially in adolescents who have not yet had vaginal intercourse. When AUB occurs in an adolescent and the cause is thought to be immaturity of the hypothalamic–pituitary–ovarian axis, there is no need for laboratory testing or imaging studies, other than excluding hypothyroidism and pregnancy as the cause.
Oral contraceptives, NSAIDs, tranexamic acid, and the LNG-IUD are all options for treating patients who have anovulatory bleeding4,5 (TABLE 3). An OC has a major advantage for adolescents because it alleviates other complaints related to adolescent hormonal changes, such as acne, and provides contraception when taken on a regular basis.
Alternatively, the LNG-IUD has the benefit of ease of use once inserted, while still providing the added benefit of contraception. In women who have not yet had vaginal intercourse, an intrauterine device might not be the first choice of treatment, however, and should be prescribed only after discussion with the patient. For both OCs and the LNG-IUD, myths surrounding the use of these medications must be addressed with the patient and, if she is a minor, her parents or guardian.32
Continue to: NSAIDS can be effective because...
NSAIDs can be effective because they reduce bleeding by causing vasoconstriction, but they provide the greatest benefit when started before menses, which can be difficult for a patient who has irregular cycles.
Endometrial causes of AUB should be suspected when a patient has heavy menstrual bleeding with regular menstrual cycles and no other causes can be identified. Endometrial dysfunction as the cause of AUB stems from aberrations in the biochemical pathways of endometrial hemostasis and repair, and therefore is difficult to confirm by laboratory analysis or histologic evaluation.3 Medical management focuses on alleviating heavy menstrual bleeding (TABLE 3).
Iatrogenic. The most common type of iatrogenic AUB is unscheduled bleeding, also known as breakthrough bleeding, that occurs during hormonal treatment with an OC or during the first few months after insertion of an LNG-IUD or contraceptive implant.3 In most cases, no specific treatment is required; bleeding resolves upon continued use of the contraceptive.
Not yet classified. This category is difficult to define; it was created for causes of AUB that have not yet been identified and remain unclear. For example, a condition known as chronic endometritis is under study as a possible cause of AUB, but has not been assigned to a PALM–COEIN category.3 As more data become available and understanding of pathophysiologic mechanisms lead to better definitions of disease, this and other poorly understood conditions will be moved to an appropriate category in the FIGO classification system.
CASE 2
Ms. G is given a diagnosis of PCOS, based on her history. You recommend weight loss and exercise; screen her for diabetes and dyslipidemia; and prescribe metformin.
ACKNOWLEDGMENT
Barry D. Weiss, MD, University of Arizona College of Medicine, Department of Family and Community Medicine, Tucson, assisted with the editing of this manuscript.
CORRESPONDENCE
Melody A. Jordahl-Iafrato, MD, Community Hospital East Family Medicine Residency, 10122 East 10th Street, Suite 100, Indianapolis, IN 46229; [email protected].
1. Committee on Practice Bulletins—Gynecology. American College of Obstetricians and Gynecologists Practice Bulletin Number 128, July 2012: Diagnosis of abnormal uterine bleeding in reproductive-aged women. Obstet Gynecol. 2012;120:197-206.
2. American College of Obstetricians and Gynecologists Committee Opinion No. 651: Menstruation in girls and adolescents: using the menstrual cycle as a vital sign. Obstet Gynecol. 2015;126:e143-e146.
3. Munro MG, Critchley HO, Broder MS, et al; FIGO Working Group on Menstrual Disorders. FIGO classifcation system (PALM-COEIN) for causes of abnormal uterine bleeding in nongravid women of reproductive age. Int J Gynaecol Obstet. 2011;133:3-13.
4. National Institute for Health and Care Excellence (NICE). Heavy menstrual bleeding: assessment and management [NG88]. www.nice.org.uk/guidance/ng88. Accessed February 28, 2019.
5. Committee on Practice Bulletins—Gynecology. American College of Obstetricians and Gynecologists Practice Bulletin Number 136, July 2013: Management of abnormal uterine bleeding associated with ovulatory dysfunction. Obstet Gynecol. 2013;122:176-185.
6. Hassa H, Tekin B, Senses T, et al. Are the site, diameter, and number of endometrial polyps related with symptomatology? Am J Obstet Gynecol. 2006;194:718-721.
7. Salim S, Won H, Nesbitt-Hawes E, et al. Diagnosis and management of endometrial polyps: a critical review of the literature. J Minim Invasive Gynecol. 2011;18:569-581.
8. Struble J, Reid S, Bedaiwy MA. Adenomyosis: A clinical review of a challenging gynecologic condition. J Minim Invasive Gynecol. 2016;23:164-185.
9. Champaneria R, Abedin P, Daniels J, et al. Ultrasound scan and magnetic resonance imaging for the diagnosis of adenomyosis: systematic review comparing test accuracy. Acta Obstet Gynecol Scand. 2010;89:1374-1384.
10. Bartels CB, Cayton KC, Chuong FS, et al. An evidence-based approach to the medical management of fibroids: a systematic review. Clin Obstet Gynecol. 2016;59:30-52.
11. Lethaby A, Cooke I, Rees MC. Progesterone or progestogen-releasing intrauterine systems for heavy menstrual bleeding. Cochrane Database Syst Rev. 2005;(4):CD002126.
12. Spies JB. Current role of uterine artery embolization in the management of uterine fibroids. Clin Obstet Gynecol. 2016;59:93-102.
13. Gupta JK, Sinha A, Lumsden MA, et al. Uterine artery embolization for symptomatic uterine fibroids. Cochrane Database Syst Rev. 2014;(12):CD005073.
14. Edwards RD, Moss JG, Lumsden MA, et al; Committee of the Randomized Trial of Embolization versus Surgical Treatment for Fibroids. Uterine artery embolization versus surgery for symptomatic uterine fibroids. N Engl J Med. 2007;356:360-370.
15. Pron G, Bennett J, Common A, et al; Ontario Uterine Fibroid Embolization Collaboration Group. The Ontario Uterine Fibroid Embolization Trial. Part 2. Uterine fibroid reduction and symptom relief after uterine artery embolization for fibroids. Fertil Steril. 2003;79:120-127.
16. Torre A, Fauconnier A, Kahn V, et al. Fertility after uterine artery embolization for symptomatic multiple fibroids with no other infertility factors. Eur Radiol. 2017;27:2850-2859.
17. Mara M, Maskova J, Fucikova Z, et al. Midterm clinical and first reproductive results of a randomized controlled trial comparing uterine fibroid embolization and myomectomy. Cardiovasc Intervent Radiol. 2008;31:73-85.
18. Lethaby A, Vollenhoven B, Sowter M. Pre-operative GnRH analogue therapy before hysterectomy or myomectomy for uterine fibroids. Cochrane Database Syst Rev. 2001;(2): CD000547.
19. Capmas P, Levaillant JM, Fernandez H. Surgical techniques and outcome in the management of submucous fibroids. Curr Opin Obstet Gynecol. 2013;25:332-338.
20. Abu Hashim H, Ghayaty E, El Rakhawy M. Levonorgestrel-releasing intrauterine system vs oral progestins for non-atypical endometrial hyperplasia: a systematic review and metaanalysis of randomized trials. Am J Obstet Gynecol. 2015;213:469-478.
21. Reed SD, Voigt LF, Newton KM, et al. Weiss NS. Progestin therapy of complex endometrial hyperplasia with and without atypia. Obstet Gynecol. 2009;113;655-662.
22. Morice P, Leary A, Creutzberg C, et al. Endometrial cancer. Lancet. 2016;387:1094-1108.
23. Goodman NF, Cobin RH, Futterweit W, et al; American Association of Clinical Endocrinologists (AACE); American College of Endocrinology (ACE); Androgen Excess and PCOS Society (AES). American Association of Clinical Endocrinologists, American College of Endocrinology, and Androgen Excess and PCOS Society disease state clinical review: guide to the best practices in the evaluation and treatment of polycystic ovary syndrome—part 1. Endocr Pract. 2015;21:1291-1300.
24. Shankar M, Lee CA, Sabin CA, et al. von Willebrand disease in women with menorrhagia: a systematic review. BJOG. 2004;111:734-740.
25. Seravalli V, Linari S, Peruzzi E, et al. Prevalence of hemostatic disorders in adolescents with abnormal uterine bleeding. J Pediatr Adolesc Gynecol. 2013;26:285-289.
26. Philipp CS, Faiz A, Dowling NF, et al. Development of a screening tool for identifying women with menorrhagia for hemostatic evaluation. Am J Obstet Gynecol. 2008;198:163.e1-e8.
27. The Rotterdam ESHRE/ASRM-sponsored PCOS consensus workshop group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod. 2004;19:41-47.
28. Goodman NF, Cobin RH, Futterweit W, et al; American Association of Clinical Endocrinologists (AACE); American College of Endocrinology (ACE); Androgen Excess and PCOS Society (AES). American Association of Clinical Endocrinologists, American College of Endocrinology, and Androgen Excess and PCOS Society disease state clinical review: guide to the best practices in the evaluation and treatment of polycystic ovary syndrome—part 2. Endocr Pract. 2015;21:1415-26.
29. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No 194: Polycystic ovary syndrome. Obstet Gynecol. 2018;131:e157-e171.
30. Speiser PW, Dupont B, Rubinstein P, et al. High frequency of nonclassical steroid 21-hydroxylase deficiency. Am J Hum Genet. 1985;37:650-667.
31. Naderpoor N, Shorakae S, de Courten B, et al. Metformin and lifestyle modification in polycystic ovary syndrome: systematic review and meta-analysis. Hum Reprod Update. 2015;21:560-574.
32. Kolman KB, Hadley SK, Jordahl-Iafrato MA. Long-acting reversible contraception: who, what, when, and how. J Fam Pract. 2015;64:479-484.
Menstrual bleeding is considered normal when it occurs regularly (every 21-35 days), lasts 4 to 8 days, and is not associated with heavy bleeding.1 During the first few years after menarche, it is normal for girls to experience irregular menstrual cycles but, by the third year, 60% to 80% of girls have an adult pattern of menstrual bleeding.2
Menstrual flow without normal volume, duration, regularity, or frequency is considered abnormal uterine bleeding (AUB). The condition is considered acute if there is need for immediate intervention. In the absence of the need for immediate intervention, recurrent AUB is classified as chronic.3 Chronic AUB is the focus of this article.
Invaluable tool: The FIGO classification
In 2011, the
- structural causes, recalled by “PALM” (Polyps, Adenomyosis, Leiomyoma, and Malignancy/hyperplasia)
- nonstructural causes, recalled by “COEIN” (Coagulopathy, Ovulatory dysfunction, Endometrial, Iatrogenic, and Not yet classified).
The PALM–COEIN system also uses descriptive terminology (heavy bleeding, intermenstrual bleeding) to characterize the bleeding pattern.3 The American College of Obstetricians and Gynecologists has adopted this classification system and recommends that such historically used terminology as “dysfunctional uterine bleeding,” “menorrhagia,” and “metrorrhagia” be abandoned.1
The initial workup of all causes of chronic uterine bleeding begins with a history; physical examination, including pelvic exam; and laboratory testing, including a urine pregnancy test, complete blood count, and a test of thyroid-stimulating hormone (TABLE 2). The need for additional laboratory testing, imaging, or endometrial biopsy depends on the suspected cause of AUB, detailed stepwise in FIGURE 1 (women <18 years) and FIGURE 2 (≥18 years).
We first briefly review the 9 categories of AUB in the PALM–COEIN system; discuss the most common causes in more detail; and review common treatment options (TABLE 3).
CASE 1
Marsha R, a 41-year-old-woman, complains of heavy menstrual bleeding for the past year that has become worse over the past 2 months. Her menstrual cycles have occurred every 28 days and last 10 days; she uses 10 to 12 pads a day.
Continue to: Recently, Ms. R reports...
Recently, Ms. R reports, she has been bleeding continuously for 14 days, with episodes of lighter bleeding followed by heavier bleeding. She also complains of fatigue.
Bimanual examination is notable for an enlarged uterus.
How would you proceed with the workup of this patient, to determine the cause of her bleeding and tailor management accordingly?
Structural AUB: The “PALM” mnemonic
A structural cause of AUB must be considered when you encounter an abnormality on physical exam (TABLE 1).3 In obese women or other patients in whom the physical exam is difficult, historical clues—including postcoital bleeding, intermenstrual bleeding, or pelvic pain or pressure—also suggest a structural abnormality.4
Transvaginal ultrasonography (TVUS) is the initial method of evaluation when a structural abnormality is suspected.1,4 However, although TVUS is excellent at visualizing the myometrium, lesions within the uterine cavity can be missed. If intracavitary pathology, such as submucosal fibroids or endometrial polyps, is suspected, additional imaging with saline infusion sonohysterography (SIS) should be performed. If a cavitary abnormality is confirmed, hysteroscopy is indicated.1 Magnetic resonance imaging (MRI) is reserved for cases in which a uterine cavity abnormality is found on TVUS but cannot be further characterized by SIS or hysteroscopy.1
Continue to: Endometrial biopsy...
Endometrial biopsy (EMB) is indicated as part of the initial evaluation of AUB in all women >45 years and in younger women who have risk factors for endometrial cancer, including polycystic ovary syndrome (PCOS), obesity, and hereditary nonpolyposis colorectal cancer. Such biopsy is necessary in these women whether or not another condition is the cause of the AUB and regardless of findings on TVUS.1-4 Endometrial biopsy should also be performed in women with AUB that persists despite medical management. If office EMB is nondiagnostic, hysteroscopy or SIS can be used to obtain tissue samples for further evaluation.5
Polyps. An endometrial polyp is a benign growth of endometrial tissue that is covered with epithelial cells. Polyps are often diagnosed by EMB or TVUS when these techniques are performed as part of the workup for AUB.6 Endometrial polyps are found more commonly in postmenopausal women, but should be considered as a cause of AUB in premenopausal women, too, especially those with intermenstrual bleeding or postcoital bleeding (or both) that is unresponsive to medical management.7 Risk factors for polyps include older age, obesity, and treatment with tamoxifen.7 The usual treatment for symptomatic endometrial polyps is removal by operative hysteroscopy.7
Adenomyosis. Ectopic endometrial tissue in the myometrium that leads to hypertrophy of the myometrium and uterine enlargement is known as adenomyosis. The disorder is most often diagnosed in women 40 to 50 years of age, who commonly complain of heavy uterine bleeding (40%-60% of cases) and dysmenorrhea (65%).8 Although definitive diagnosis is made histologically at hysterectomy, TVUS and MRI can be useful tools to help narrow the differential diagnosis in women with unexplained AUB.
According to a systematic review,9 the sensitivity and specificity of imaging in the diagnosis of adenomyosis is 72% and 81%, respectively, for TVUS and 77% and 89%, respectively, for MRI. Needle biopsy, performed hysteroscopically or laparoscopically, is less useful because the technique has low sensitivity (reported variously as 8%-56%) in diagnosing adenomyosis.8
Treatment options for adenomyosis are medical management with agents that reduce bleeding (eg, a combination oral contraceptive [OC], nonsteroidal anti-inflammatory drugs [NSAIDs], the antifibrinolytic tranexamic acid, and, when there is no distortion of the uterine cavity, a levonorgestrel intrauterine device [LNG-IUD]); uterine artery embolization; and hysterectomy.8
Continue to: Leiomyoma
Leiomyoma. Uterine fibroids, or leiomyomas, are benign, fibromuscular solid tumors, thought to be hormone-dependent because many regress after menopause. In women of reproductive age, uterine fibroids are the most common cause of structural AUB, with a cumulative incidence of 70% to 80% among women in this age group.3,10 Fibroids are more common in African-American women, women who experienced early menarche, and women who are obese, have PCOS, or had a late first pregnancy.3-10
Many fibroids are asymptomatic, and are found incidentally on sonographic examination performed for other reasons; in one-third of affected patients, the fibroids result in heavy menstrual bleeding.10 Intermenstrual bleeding and postcoital bleeding can occur, but are not common symptoms with fibroids. Consider other causes of AUB, such as endometrial polyps, when these symptoms are present.
Treatment of fibroids is medical or surgical. Medical management is a reasonable first-line option, especially in women who have not completed childbearing and who have small (<3 cm in diameter) fibroids. Options include a combination OC, NSAIDs, tranexamic acid, and, when the uterine cavity is not distorted, an LNG-IUD.4,10,11
For women with larger fibroids, those for whom the aforementioned medical treatments are unsuccessful, and those who are seeking more definitive treatment, uterine artery embolization, myomectomy, or hysterectomy can be considered.
› Uterine artery embolization is performed by an interventional radiologist under local anesthesia and, if necessary, moderate sedation.12 After the procedure, fibroids decrease in size due to avascular necrosis, but the remainder of the myometrium is relatively unaffected because collateral blood supply develops.13,14 Patients might experience abdominal cramping for 2 or 3 days following the procedure, which can be managed with an oral NSAID.12 Approximately 90% of women treated with embolization note improvement in AUB by 3 months after the procedure.15 Uterine artery embolization is not recommended in women who have not completed childbearing.12,16,17
Continue to: Myomectomy
› Myomectomy (removal of the leiomyoma) is the surgical treatment of choice for women who want to maintain fertility. Depending on the size and location of the fibroid(s), myomectomy can be performed as an open surgical procedure, laparoscopically, or hysteroscopically. At the discretion of the surgeon, leuprolide acetate, a gonadotropin-releasing hormone agonist, can be prescribed for 3 months before myomectomy to reduce intraoperative blood loss by decreasing the vascularity of the fibroids.4,18 Reduction in bleeding is reported in 70% to 90% of patients who undergo myomectomy.19
› Hysterectomy, the definitive treatment for uterine fibroids, should be reserved for women who have completed childbearing and who have failed (or have a contraindication to) other treatment options.
Malignancy/hyperplasia. EMB should be performed when endometrial malignancy/hyperplasia is suspected. As noted, endometrial cancer should be considered as a diagnostic possibility in women >45 years, in younger women with risk factors, and in women who have failed to respond to medical treatment for other suspected causes of AUB.5
When hyperplasia without atypia is diagnosed, the LNG-IUD or oral progesterone is an acceptable treatment option; note that fewer women who have an LNG-IUD eventually require hysterectomy, compared to women who take oral hormone therapy for AUB.20 When hyperplasia with atypia is diagnosed, hysterectomy is the treatment of choice. If a woman wishes to maintain fertility, however, oral progesterone therapy can be offered.21
When the diagnosis is cancer, the patient should be referred to a gynecologic oncologist for staging and treatment. Treatment varies depending on stage, but generally requires hysterectomy including bilateral salpingo-oophorectomy, with possible chemotherapy or radiation, or both.22
Continue to: CASE 1
CASE 1
Ms. R undergoes a sonogram that reveals a 4-cm fibroid in the uterine fundus that has not distorted the uterine cavity. Although she has completed childbearing, Ms. R is not interested in a surgical procedure at this time. You recommend insertion of an LNG-IUD; she accepts your advice.
CASE 2
Claire G, 27 years old, with a body mass index of 41,* complains of irregular menses for several months. Her menstrual cycle is irregular, as is the duration of menses and amount of bleeding. She has some mild fatigue without dizziness.
The physical exam is notable for mild hirsutism, without abnormalities on pelvic examination. Lab testing reveals iron-deficiency anemia; a pregnancy test is negative.
The questions that were raised by Ms. R’s case challenge you here, too: What is the appropriate workup of Ms. G’s bleeding? Once the cause is confirmed, how should you treat her?
Nonstructural AUB: The “COEIN” mnemonic
In the absence of abnormalities on a pelvic exam, and after excluding endometrial malignancy/hyperplasia in patients with the aforementioned risk factors, a nonstructural cause of AUB should be considered (TABLE 1).3 In women 20 to 40 years of age, the primary common cause of nonstructural uterine bleeding is ovulatory dysfunction, most often caused by PCOS or anovulatory bleeding.
Continue to: For nonstructual causes of AUB...
For nonstructural causes of AUB, the recommended laboratory workup varies with the suspected diagnosis. In addition, recently pregnant women should have a quantitative assay of β human chorionic gonadotropin to evaluate for trophoblastic disease.5,23
Imaging is not usually recommended when the cause of AUB is suspected to be nonstructural. However, when PCOS is suspected, TVUS can be used to confirm the presence of polycystic ovaries.23
As noted, EMB should be performed when AUB is present in women >45 years, in patients of any age group who fail to respond to medical therapy, and in those at increased risk for endometrial cancer.
Coagulopathy. When heavy bleeding has been present since the onset of menarche, inherited bleeding disorders must be considered, the most common of which is von Willebrand disease, a disorder of platelet adhesion.24 It is estimated that just under 50% of adolescents with abnormal uterine bleeding have a coagulopathy, most often a platelet function disorder.25 Additional clues to the presence of a coagulation disorder include a family history of bleeding disorder, a personal history of bleeding problems associated with surgery, and a history of iron-deficiency anemia.26 Abnormal uterine bleeding might resolve with treatment of the underlying coagulopathy; if it does not, consider consultation with a hematologist before prescribing an NSAID or an OC.
Heavy bleeding in patients taking an anticoagulant falls into the category of coagulopathy-related AUB. No further workup is generally needed for these women.3
Continue to: Ovulatory dysfunction
Ovulatory dysfunction. Abnormal uterine bleeding caused by ovulatory dysfunction is generally due to PCOS or anovulatory bleeding. Other causes, beyond the scope of this discussion, include hypothyroidism, hyperandrogenism, female athlete triad, stress, and hyperprolactinemia.
› Polycystic ovary syndrome. A diagnosis of PCOS is made using any of several recognized criteria. The commonly used Rotterdam 2003 criteria27 require that at least 2 of the following be present to make a diagnosis of PCOS:
- oligo-ovulation or anovulation
- hyperandrogenism
- polycystic ovaries seen on ultrasonography.
In addition, women with PCOS are frequently obese, show signs of insulin resistance (diabetes, prediabetes, acanthosis nigricans), or hyperandrogenism (hirsutism, acne). Even if these latter findings are not present at diagnosis, women with PCOS are at risk for a metabolic disorder. Once a diagnosis of PCOS has been established, therefore, screening tests for diabetes and cardiac risk factors (eg, dyslipidemia) should be performed.28.29
To evaluate for hyperandrogenism, free testosterone should be measured using a high-sensitivity immunoassay in all women in whom PCOS is suspected. Because of a higher prevalence of nonclassical (ie, late-onset) congenital adrenal hyperplasia (CAH) in women of Ashkenazi Jewish (estimated prevalence, 3.7%), Hispanic (1.9%), Slavic (1.6%), and Italian (0.3%) descent, screening for CAH as a possible cause of hyperandrogenism is also recommended, by a test of a morning 17-hydroxyprogesterone level.23,29,30 (Note: The general Caucasian population has an estimated prevalence of nonclassical CAH of 0.1%.30)
Treatment of PCOS should be individualized, based on a patient’s symptoms and comorbidities. For overweight and obese women, weight loss, exercise, and metformin (1500-2000 mg/d) are the mainstays of therapy, and might reduce AUB.29,31 If these measures do not reduce AUB, other options include an OC, an LNG-IUD, and NSAIDs.
Continue to: Information on treating other PCOS-related symptoms...
Information on treating other PCOS-related symptoms (acne, hirsutism) is available from many sources29; these treatments do not typically help the patient’s AUB, however, and are therefore not addressed in this article.
› Anovulatory bleeding. In adolescence, the most common cause of AUB is anovulation resulting from immaturity of the hypothalamic–pituitary–ovarian axis. During anovulatory cycles, the imbalance of estrogen and progesterone creates a fragile endometrium, leading to unpredictable bleeding and irregular cycles. Other less common causes of AUB, such as ovarian or adrenal tumor, should be considered in adolescents who have hirsutism but do not meet the criteria for PCOS.5
When seeing an adolescent for evaluation of AUB, be aware that emotional barriers might be present that make it difficult for her to talk about menses and sexual activity. Be patient and normalize the patient’s symptoms when appropriate. Pelvic exam can be deferred, especially in adolescents who have not yet had vaginal intercourse. When AUB occurs in an adolescent and the cause is thought to be immaturity of the hypothalamic–pituitary–ovarian axis, there is no need for laboratory testing or imaging studies, other than excluding hypothyroidism and pregnancy as the cause.
Oral contraceptives, NSAIDs, tranexamic acid, and the LNG-IUD are all options for treating patients who have anovulatory bleeding4,5 (TABLE 3). An OC has a major advantage for adolescents because it alleviates other complaints related to adolescent hormonal changes, such as acne, and provides contraception when taken on a regular basis.
Alternatively, the LNG-IUD has the benefit of ease of use once inserted, while still providing the added benefit of contraception. In women who have not yet had vaginal intercourse, an intrauterine device might not be the first choice of treatment, however, and should be prescribed only after discussion with the patient. For both OCs and the LNG-IUD, myths surrounding the use of these medications must be addressed with the patient and, if she is a minor, her parents or guardian.32
Continue to: NSAIDS can be effective because...
NSAIDs can be effective because they reduce bleeding by causing vasoconstriction, but they provide the greatest benefit when started before menses, which can be difficult for a patient who has irregular cycles.
Endometrial causes of AUB should be suspected when a patient has heavy menstrual bleeding with regular menstrual cycles and no other causes can be identified. Endometrial dysfunction as the cause of AUB stems from aberrations in the biochemical pathways of endometrial hemostasis and repair, and therefore is difficult to confirm by laboratory analysis or histologic evaluation.3 Medical management focuses on alleviating heavy menstrual bleeding (TABLE 3).
Iatrogenic. The most common type of iatrogenic AUB is unscheduled bleeding, also known as breakthrough bleeding, that occurs during hormonal treatment with an OC or during the first few months after insertion of an LNG-IUD or contraceptive implant.3 In most cases, no specific treatment is required; bleeding resolves upon continued use of the contraceptive.
Not yet classified. This category is difficult to define; it was created for causes of AUB that have not yet been identified and remain unclear. For example, a condition known as chronic endometritis is under study as a possible cause of AUB, but has not been assigned to a PALM–COEIN category.3 As more data become available and understanding of pathophysiologic mechanisms lead to better definitions of disease, this and other poorly understood conditions will be moved to an appropriate category in the FIGO classification system.
CASE 2
Ms. G is given a diagnosis of PCOS, based on her history. You recommend weight loss and exercise; screen her for diabetes and dyslipidemia; and prescribe metformin.
ACKNOWLEDGMENT
Barry D. Weiss, MD, University of Arizona College of Medicine, Department of Family and Community Medicine, Tucson, assisted with the editing of this manuscript.
CORRESPONDENCE
Melody A. Jordahl-Iafrato, MD, Community Hospital East Family Medicine Residency, 10122 East 10th Street, Suite 100, Indianapolis, IN 46229; [email protected].
Menstrual bleeding is considered normal when it occurs regularly (every 21-35 days), lasts 4 to 8 days, and is not associated with heavy bleeding.1 During the first few years after menarche, it is normal for girls to experience irregular menstrual cycles but, by the third year, 60% to 80% of girls have an adult pattern of menstrual bleeding.2
Menstrual flow without normal volume, duration, regularity, or frequency is considered abnormal uterine bleeding (AUB). The condition is considered acute if there is need for immediate intervention. In the absence of the need for immediate intervention, recurrent AUB is classified as chronic.3 Chronic AUB is the focus of this article.
Invaluable tool: The FIGO classification
In 2011, the
- structural causes, recalled by “PALM” (Polyps, Adenomyosis, Leiomyoma, and Malignancy/hyperplasia)
- nonstructural causes, recalled by “COEIN” (Coagulopathy, Ovulatory dysfunction, Endometrial, Iatrogenic, and Not yet classified).
The PALM–COEIN system also uses descriptive terminology (heavy bleeding, intermenstrual bleeding) to characterize the bleeding pattern.3 The American College of Obstetricians and Gynecologists has adopted this classification system and recommends that such historically used terminology as “dysfunctional uterine bleeding,” “menorrhagia,” and “metrorrhagia” be abandoned.1
The initial workup of all causes of chronic uterine bleeding begins with a history; physical examination, including pelvic exam; and laboratory testing, including a urine pregnancy test, complete blood count, and a test of thyroid-stimulating hormone (TABLE 2). The need for additional laboratory testing, imaging, or endometrial biopsy depends on the suspected cause of AUB, detailed stepwise in FIGURE 1 (women <18 years) and FIGURE 2 (≥18 years).
We first briefly review the 9 categories of AUB in the PALM–COEIN system; discuss the most common causes in more detail; and review common treatment options (TABLE 3).
CASE 1
Marsha R, a 41-year-old-woman, complains of heavy menstrual bleeding for the past year that has become worse over the past 2 months. Her menstrual cycles have occurred every 28 days and last 10 days; she uses 10 to 12 pads a day.
Continue to: Recently, Ms. R reports...
Recently, Ms. R reports, she has been bleeding continuously for 14 days, with episodes of lighter bleeding followed by heavier bleeding. She also complains of fatigue.
Bimanual examination is notable for an enlarged uterus.
How would you proceed with the workup of this patient, to determine the cause of her bleeding and tailor management accordingly?
Structural AUB: The “PALM” mnemonic
A structural cause of AUB must be considered when you encounter an abnormality on physical exam (TABLE 1).3 In obese women or other patients in whom the physical exam is difficult, historical clues—including postcoital bleeding, intermenstrual bleeding, or pelvic pain or pressure—also suggest a structural abnormality.4
Transvaginal ultrasonography (TVUS) is the initial method of evaluation when a structural abnormality is suspected.1,4 However, although TVUS is excellent at visualizing the myometrium, lesions within the uterine cavity can be missed. If intracavitary pathology, such as submucosal fibroids or endometrial polyps, is suspected, additional imaging with saline infusion sonohysterography (SIS) should be performed. If a cavitary abnormality is confirmed, hysteroscopy is indicated.1 Magnetic resonance imaging (MRI) is reserved for cases in which a uterine cavity abnormality is found on TVUS but cannot be further characterized by SIS or hysteroscopy.1
Continue to: Endometrial biopsy...
Endometrial biopsy (EMB) is indicated as part of the initial evaluation of AUB in all women >45 years and in younger women who have risk factors for endometrial cancer, including polycystic ovary syndrome (PCOS), obesity, and hereditary nonpolyposis colorectal cancer. Such biopsy is necessary in these women whether or not another condition is the cause of the AUB and regardless of findings on TVUS.1-4 Endometrial biopsy should also be performed in women with AUB that persists despite medical management. If office EMB is nondiagnostic, hysteroscopy or SIS can be used to obtain tissue samples for further evaluation.5
Polyps. An endometrial polyp is a benign growth of endometrial tissue that is covered with epithelial cells. Polyps are often diagnosed by EMB or TVUS when these techniques are performed as part of the workup for AUB.6 Endometrial polyps are found more commonly in postmenopausal women, but should be considered as a cause of AUB in premenopausal women, too, especially those with intermenstrual bleeding or postcoital bleeding (or both) that is unresponsive to medical management.7 Risk factors for polyps include older age, obesity, and treatment with tamoxifen.7 The usual treatment for symptomatic endometrial polyps is removal by operative hysteroscopy.7
Adenomyosis. Ectopic endometrial tissue in the myometrium that leads to hypertrophy of the myometrium and uterine enlargement is known as adenomyosis. The disorder is most often diagnosed in women 40 to 50 years of age, who commonly complain of heavy uterine bleeding (40%-60% of cases) and dysmenorrhea (65%).8 Although definitive diagnosis is made histologically at hysterectomy, TVUS and MRI can be useful tools to help narrow the differential diagnosis in women with unexplained AUB.
According to a systematic review,9 the sensitivity and specificity of imaging in the diagnosis of adenomyosis is 72% and 81%, respectively, for TVUS and 77% and 89%, respectively, for MRI. Needle biopsy, performed hysteroscopically or laparoscopically, is less useful because the technique has low sensitivity (reported variously as 8%-56%) in diagnosing adenomyosis.8
Treatment options for adenomyosis are medical management with agents that reduce bleeding (eg, a combination oral contraceptive [OC], nonsteroidal anti-inflammatory drugs [NSAIDs], the antifibrinolytic tranexamic acid, and, when there is no distortion of the uterine cavity, a levonorgestrel intrauterine device [LNG-IUD]); uterine artery embolization; and hysterectomy.8
Continue to: Leiomyoma
Leiomyoma. Uterine fibroids, or leiomyomas, are benign, fibromuscular solid tumors, thought to be hormone-dependent because many regress after menopause. In women of reproductive age, uterine fibroids are the most common cause of structural AUB, with a cumulative incidence of 70% to 80% among women in this age group.3,10 Fibroids are more common in African-American women, women who experienced early menarche, and women who are obese, have PCOS, or had a late first pregnancy.3-10
Many fibroids are asymptomatic, and are found incidentally on sonographic examination performed for other reasons; in one-third of affected patients, the fibroids result in heavy menstrual bleeding.10 Intermenstrual bleeding and postcoital bleeding can occur, but are not common symptoms with fibroids. Consider other causes of AUB, such as endometrial polyps, when these symptoms are present.
Treatment of fibroids is medical or surgical. Medical management is a reasonable first-line option, especially in women who have not completed childbearing and who have small (<3 cm in diameter) fibroids. Options include a combination OC, NSAIDs, tranexamic acid, and, when the uterine cavity is not distorted, an LNG-IUD.4,10,11
For women with larger fibroids, those for whom the aforementioned medical treatments are unsuccessful, and those who are seeking more definitive treatment, uterine artery embolization, myomectomy, or hysterectomy can be considered.
› Uterine artery embolization is performed by an interventional radiologist under local anesthesia and, if necessary, moderate sedation.12 After the procedure, fibroids decrease in size due to avascular necrosis, but the remainder of the myometrium is relatively unaffected because collateral blood supply develops.13,14 Patients might experience abdominal cramping for 2 or 3 days following the procedure, which can be managed with an oral NSAID.12 Approximately 90% of women treated with embolization note improvement in AUB by 3 months after the procedure.15 Uterine artery embolization is not recommended in women who have not completed childbearing.12,16,17
Continue to: Myomectomy
› Myomectomy (removal of the leiomyoma) is the surgical treatment of choice for women who want to maintain fertility. Depending on the size and location of the fibroid(s), myomectomy can be performed as an open surgical procedure, laparoscopically, or hysteroscopically. At the discretion of the surgeon, leuprolide acetate, a gonadotropin-releasing hormone agonist, can be prescribed for 3 months before myomectomy to reduce intraoperative blood loss by decreasing the vascularity of the fibroids.4,18 Reduction in bleeding is reported in 70% to 90% of patients who undergo myomectomy.19
› Hysterectomy, the definitive treatment for uterine fibroids, should be reserved for women who have completed childbearing and who have failed (or have a contraindication to) other treatment options.
Malignancy/hyperplasia. EMB should be performed when endometrial malignancy/hyperplasia is suspected. As noted, endometrial cancer should be considered as a diagnostic possibility in women >45 years, in younger women with risk factors, and in women who have failed to respond to medical treatment for other suspected causes of AUB.5
When hyperplasia without atypia is diagnosed, the LNG-IUD or oral progesterone is an acceptable treatment option; note that fewer women who have an LNG-IUD eventually require hysterectomy, compared to women who take oral hormone therapy for AUB.20 When hyperplasia with atypia is diagnosed, hysterectomy is the treatment of choice. If a woman wishes to maintain fertility, however, oral progesterone therapy can be offered.21
When the diagnosis is cancer, the patient should be referred to a gynecologic oncologist for staging and treatment. Treatment varies depending on stage, but generally requires hysterectomy including bilateral salpingo-oophorectomy, with possible chemotherapy or radiation, or both.22
Continue to: CASE 1
CASE 1
Ms. R undergoes a sonogram that reveals a 4-cm fibroid in the uterine fundus that has not distorted the uterine cavity. Although she has completed childbearing, Ms. R is not interested in a surgical procedure at this time. You recommend insertion of an LNG-IUD; she accepts your advice.
CASE 2
Claire G, 27 years old, with a body mass index of 41,* complains of irregular menses for several months. Her menstrual cycle is irregular, as is the duration of menses and amount of bleeding. She has some mild fatigue without dizziness.
The physical exam is notable for mild hirsutism, without abnormalities on pelvic examination. Lab testing reveals iron-deficiency anemia; a pregnancy test is negative.
The questions that were raised by Ms. R’s case challenge you here, too: What is the appropriate workup of Ms. G’s bleeding? Once the cause is confirmed, how should you treat her?
Nonstructural AUB: The “COEIN” mnemonic
In the absence of abnormalities on a pelvic exam, and after excluding endometrial malignancy/hyperplasia in patients with the aforementioned risk factors, a nonstructural cause of AUB should be considered (TABLE 1).3 In women 20 to 40 years of age, the primary common cause of nonstructural uterine bleeding is ovulatory dysfunction, most often caused by PCOS or anovulatory bleeding.
Continue to: For nonstructual causes of AUB...
For nonstructural causes of AUB, the recommended laboratory workup varies with the suspected diagnosis. In addition, recently pregnant women should have a quantitative assay of β human chorionic gonadotropin to evaluate for trophoblastic disease.5,23
Imaging is not usually recommended when the cause of AUB is suspected to be nonstructural. However, when PCOS is suspected, TVUS can be used to confirm the presence of polycystic ovaries.23
As noted, EMB should be performed when AUB is present in women >45 years, in patients of any age group who fail to respond to medical therapy, and in those at increased risk for endometrial cancer.
Coagulopathy. When heavy bleeding has been present since the onset of menarche, inherited bleeding disorders must be considered, the most common of which is von Willebrand disease, a disorder of platelet adhesion.24 It is estimated that just under 50% of adolescents with abnormal uterine bleeding have a coagulopathy, most often a platelet function disorder.25 Additional clues to the presence of a coagulation disorder include a family history of bleeding disorder, a personal history of bleeding problems associated with surgery, and a history of iron-deficiency anemia.26 Abnormal uterine bleeding might resolve with treatment of the underlying coagulopathy; if it does not, consider consultation with a hematologist before prescribing an NSAID or an OC.
Heavy bleeding in patients taking an anticoagulant falls into the category of coagulopathy-related AUB. No further workup is generally needed for these women.3
Continue to: Ovulatory dysfunction
Ovulatory dysfunction. Abnormal uterine bleeding caused by ovulatory dysfunction is generally due to PCOS or anovulatory bleeding. Other causes, beyond the scope of this discussion, include hypothyroidism, hyperandrogenism, female athlete triad, stress, and hyperprolactinemia.
› Polycystic ovary syndrome. A diagnosis of PCOS is made using any of several recognized criteria. The commonly used Rotterdam 2003 criteria27 require that at least 2 of the following be present to make a diagnosis of PCOS:
- oligo-ovulation or anovulation
- hyperandrogenism
- polycystic ovaries seen on ultrasonography.
In addition, women with PCOS are frequently obese, show signs of insulin resistance (diabetes, prediabetes, acanthosis nigricans), or hyperandrogenism (hirsutism, acne). Even if these latter findings are not present at diagnosis, women with PCOS are at risk for a metabolic disorder. Once a diagnosis of PCOS has been established, therefore, screening tests for diabetes and cardiac risk factors (eg, dyslipidemia) should be performed.28.29
To evaluate for hyperandrogenism, free testosterone should be measured using a high-sensitivity immunoassay in all women in whom PCOS is suspected. Because of a higher prevalence of nonclassical (ie, late-onset) congenital adrenal hyperplasia (CAH) in women of Ashkenazi Jewish (estimated prevalence, 3.7%), Hispanic (1.9%), Slavic (1.6%), and Italian (0.3%) descent, screening for CAH as a possible cause of hyperandrogenism is also recommended, by a test of a morning 17-hydroxyprogesterone level.23,29,30 (Note: The general Caucasian population has an estimated prevalence of nonclassical CAH of 0.1%.30)
Treatment of PCOS should be individualized, based on a patient’s symptoms and comorbidities. For overweight and obese women, weight loss, exercise, and metformin (1500-2000 mg/d) are the mainstays of therapy, and might reduce AUB.29,31 If these measures do not reduce AUB, other options include an OC, an LNG-IUD, and NSAIDs.
Continue to: Information on treating other PCOS-related symptoms...
Information on treating other PCOS-related symptoms (acne, hirsutism) is available from many sources29; these treatments do not typically help the patient’s AUB, however, and are therefore not addressed in this article.
› Anovulatory bleeding. In adolescence, the most common cause of AUB is anovulation resulting from immaturity of the hypothalamic–pituitary–ovarian axis. During anovulatory cycles, the imbalance of estrogen and progesterone creates a fragile endometrium, leading to unpredictable bleeding and irregular cycles. Other less common causes of AUB, such as ovarian or adrenal tumor, should be considered in adolescents who have hirsutism but do not meet the criteria for PCOS.5
When seeing an adolescent for evaluation of AUB, be aware that emotional barriers might be present that make it difficult for her to talk about menses and sexual activity. Be patient and normalize the patient’s symptoms when appropriate. Pelvic exam can be deferred, especially in adolescents who have not yet had vaginal intercourse. When AUB occurs in an adolescent and the cause is thought to be immaturity of the hypothalamic–pituitary–ovarian axis, there is no need for laboratory testing or imaging studies, other than excluding hypothyroidism and pregnancy as the cause.
Oral contraceptives, NSAIDs, tranexamic acid, and the LNG-IUD are all options for treating patients who have anovulatory bleeding4,5 (TABLE 3). An OC has a major advantage for adolescents because it alleviates other complaints related to adolescent hormonal changes, such as acne, and provides contraception when taken on a regular basis.
Alternatively, the LNG-IUD has the benefit of ease of use once inserted, while still providing the added benefit of contraception. In women who have not yet had vaginal intercourse, an intrauterine device might not be the first choice of treatment, however, and should be prescribed only after discussion with the patient. For both OCs and the LNG-IUD, myths surrounding the use of these medications must be addressed with the patient and, if she is a minor, her parents or guardian.32
Continue to: NSAIDS can be effective because...
NSAIDs can be effective because they reduce bleeding by causing vasoconstriction, but they provide the greatest benefit when started before menses, which can be difficult for a patient who has irregular cycles.
Endometrial causes of AUB should be suspected when a patient has heavy menstrual bleeding with regular menstrual cycles and no other causes can be identified. Endometrial dysfunction as the cause of AUB stems from aberrations in the biochemical pathways of endometrial hemostasis and repair, and therefore is difficult to confirm by laboratory analysis or histologic evaluation.3 Medical management focuses on alleviating heavy menstrual bleeding (TABLE 3).
Iatrogenic. The most common type of iatrogenic AUB is unscheduled bleeding, also known as breakthrough bleeding, that occurs during hormonal treatment with an OC or during the first few months after insertion of an LNG-IUD or contraceptive implant.3 In most cases, no specific treatment is required; bleeding resolves upon continued use of the contraceptive.
Not yet classified. This category is difficult to define; it was created for causes of AUB that have not yet been identified and remain unclear. For example, a condition known as chronic endometritis is under study as a possible cause of AUB, but has not been assigned to a PALM–COEIN category.3 As more data become available and understanding of pathophysiologic mechanisms lead to better definitions of disease, this and other poorly understood conditions will be moved to an appropriate category in the FIGO classification system.
CASE 2
Ms. G is given a diagnosis of PCOS, based on her history. You recommend weight loss and exercise; screen her for diabetes and dyslipidemia; and prescribe metformin.
ACKNOWLEDGMENT
Barry D. Weiss, MD, University of Arizona College of Medicine, Department of Family and Community Medicine, Tucson, assisted with the editing of this manuscript.
CORRESPONDENCE
Melody A. Jordahl-Iafrato, MD, Community Hospital East Family Medicine Residency, 10122 East 10th Street, Suite 100, Indianapolis, IN 46229; [email protected].
1. Committee on Practice Bulletins—Gynecology. American College of Obstetricians and Gynecologists Practice Bulletin Number 128, July 2012: Diagnosis of abnormal uterine bleeding in reproductive-aged women. Obstet Gynecol. 2012;120:197-206.
2. American College of Obstetricians and Gynecologists Committee Opinion No. 651: Menstruation in girls and adolescents: using the menstrual cycle as a vital sign. Obstet Gynecol. 2015;126:e143-e146.
3. Munro MG, Critchley HO, Broder MS, et al; FIGO Working Group on Menstrual Disorders. FIGO classifcation system (PALM-COEIN) for causes of abnormal uterine bleeding in nongravid women of reproductive age. Int J Gynaecol Obstet. 2011;133:3-13.
4. National Institute for Health and Care Excellence (NICE). Heavy menstrual bleeding: assessment and management [NG88]. www.nice.org.uk/guidance/ng88. Accessed February 28, 2019.
5. Committee on Practice Bulletins—Gynecology. American College of Obstetricians and Gynecologists Practice Bulletin Number 136, July 2013: Management of abnormal uterine bleeding associated with ovulatory dysfunction. Obstet Gynecol. 2013;122:176-185.
6. Hassa H, Tekin B, Senses T, et al. Are the site, diameter, and number of endometrial polyps related with symptomatology? Am J Obstet Gynecol. 2006;194:718-721.
7. Salim S, Won H, Nesbitt-Hawes E, et al. Diagnosis and management of endometrial polyps: a critical review of the literature. J Minim Invasive Gynecol. 2011;18:569-581.
8. Struble J, Reid S, Bedaiwy MA. Adenomyosis: A clinical review of a challenging gynecologic condition. J Minim Invasive Gynecol. 2016;23:164-185.
9. Champaneria R, Abedin P, Daniels J, et al. Ultrasound scan and magnetic resonance imaging for the diagnosis of adenomyosis: systematic review comparing test accuracy. Acta Obstet Gynecol Scand. 2010;89:1374-1384.
10. Bartels CB, Cayton KC, Chuong FS, et al. An evidence-based approach to the medical management of fibroids: a systematic review. Clin Obstet Gynecol. 2016;59:30-52.
11. Lethaby A, Cooke I, Rees MC. Progesterone or progestogen-releasing intrauterine systems for heavy menstrual bleeding. Cochrane Database Syst Rev. 2005;(4):CD002126.
12. Spies JB. Current role of uterine artery embolization in the management of uterine fibroids. Clin Obstet Gynecol. 2016;59:93-102.
13. Gupta JK, Sinha A, Lumsden MA, et al. Uterine artery embolization for symptomatic uterine fibroids. Cochrane Database Syst Rev. 2014;(12):CD005073.
14. Edwards RD, Moss JG, Lumsden MA, et al; Committee of the Randomized Trial of Embolization versus Surgical Treatment for Fibroids. Uterine artery embolization versus surgery for symptomatic uterine fibroids. N Engl J Med. 2007;356:360-370.
15. Pron G, Bennett J, Common A, et al; Ontario Uterine Fibroid Embolization Collaboration Group. The Ontario Uterine Fibroid Embolization Trial. Part 2. Uterine fibroid reduction and symptom relief after uterine artery embolization for fibroids. Fertil Steril. 2003;79:120-127.
16. Torre A, Fauconnier A, Kahn V, et al. Fertility after uterine artery embolization for symptomatic multiple fibroids with no other infertility factors. Eur Radiol. 2017;27:2850-2859.
17. Mara M, Maskova J, Fucikova Z, et al. Midterm clinical and first reproductive results of a randomized controlled trial comparing uterine fibroid embolization and myomectomy. Cardiovasc Intervent Radiol. 2008;31:73-85.
18. Lethaby A, Vollenhoven B, Sowter M. Pre-operative GnRH analogue therapy before hysterectomy or myomectomy for uterine fibroids. Cochrane Database Syst Rev. 2001;(2): CD000547.
19. Capmas P, Levaillant JM, Fernandez H. Surgical techniques and outcome in the management of submucous fibroids. Curr Opin Obstet Gynecol. 2013;25:332-338.
20. Abu Hashim H, Ghayaty E, El Rakhawy M. Levonorgestrel-releasing intrauterine system vs oral progestins for non-atypical endometrial hyperplasia: a systematic review and metaanalysis of randomized trials. Am J Obstet Gynecol. 2015;213:469-478.
21. Reed SD, Voigt LF, Newton KM, et al. Weiss NS. Progestin therapy of complex endometrial hyperplasia with and without atypia. Obstet Gynecol. 2009;113;655-662.
22. Morice P, Leary A, Creutzberg C, et al. Endometrial cancer. Lancet. 2016;387:1094-1108.
23. Goodman NF, Cobin RH, Futterweit W, et al; American Association of Clinical Endocrinologists (AACE); American College of Endocrinology (ACE); Androgen Excess and PCOS Society (AES). American Association of Clinical Endocrinologists, American College of Endocrinology, and Androgen Excess and PCOS Society disease state clinical review: guide to the best practices in the evaluation and treatment of polycystic ovary syndrome—part 1. Endocr Pract. 2015;21:1291-1300.
24. Shankar M, Lee CA, Sabin CA, et al. von Willebrand disease in women with menorrhagia: a systematic review. BJOG. 2004;111:734-740.
25. Seravalli V, Linari S, Peruzzi E, et al. Prevalence of hemostatic disorders in adolescents with abnormal uterine bleeding. J Pediatr Adolesc Gynecol. 2013;26:285-289.
26. Philipp CS, Faiz A, Dowling NF, et al. Development of a screening tool for identifying women with menorrhagia for hemostatic evaluation. Am J Obstet Gynecol. 2008;198:163.e1-e8.
27. The Rotterdam ESHRE/ASRM-sponsored PCOS consensus workshop group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod. 2004;19:41-47.
28. Goodman NF, Cobin RH, Futterweit W, et al; American Association of Clinical Endocrinologists (AACE); American College of Endocrinology (ACE); Androgen Excess and PCOS Society (AES). American Association of Clinical Endocrinologists, American College of Endocrinology, and Androgen Excess and PCOS Society disease state clinical review: guide to the best practices in the evaluation and treatment of polycystic ovary syndrome—part 2. Endocr Pract. 2015;21:1415-26.
29. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No 194: Polycystic ovary syndrome. Obstet Gynecol. 2018;131:e157-e171.
30. Speiser PW, Dupont B, Rubinstein P, et al. High frequency of nonclassical steroid 21-hydroxylase deficiency. Am J Hum Genet. 1985;37:650-667.
31. Naderpoor N, Shorakae S, de Courten B, et al. Metformin and lifestyle modification in polycystic ovary syndrome: systematic review and meta-analysis. Hum Reprod Update. 2015;21:560-574.
32. Kolman KB, Hadley SK, Jordahl-Iafrato MA. Long-acting reversible contraception: who, what, when, and how. J Fam Pract. 2015;64:479-484.
1. Committee on Practice Bulletins—Gynecology. American College of Obstetricians and Gynecologists Practice Bulletin Number 128, July 2012: Diagnosis of abnormal uterine bleeding in reproductive-aged women. Obstet Gynecol. 2012;120:197-206.
2. American College of Obstetricians and Gynecologists Committee Opinion No. 651: Menstruation in girls and adolescents: using the menstrual cycle as a vital sign. Obstet Gynecol. 2015;126:e143-e146.
3. Munro MG, Critchley HO, Broder MS, et al; FIGO Working Group on Menstrual Disorders. FIGO classifcation system (PALM-COEIN) for causes of abnormal uterine bleeding in nongravid women of reproductive age. Int J Gynaecol Obstet. 2011;133:3-13.
4. National Institute for Health and Care Excellence (NICE). Heavy menstrual bleeding: assessment and management [NG88]. www.nice.org.uk/guidance/ng88. Accessed February 28, 2019.
5. Committee on Practice Bulletins—Gynecology. American College of Obstetricians and Gynecologists Practice Bulletin Number 136, July 2013: Management of abnormal uterine bleeding associated with ovulatory dysfunction. Obstet Gynecol. 2013;122:176-185.
6. Hassa H, Tekin B, Senses T, et al. Are the site, diameter, and number of endometrial polyps related with symptomatology? Am J Obstet Gynecol. 2006;194:718-721.
7. Salim S, Won H, Nesbitt-Hawes E, et al. Diagnosis and management of endometrial polyps: a critical review of the literature. J Minim Invasive Gynecol. 2011;18:569-581.
8. Struble J, Reid S, Bedaiwy MA. Adenomyosis: A clinical review of a challenging gynecologic condition. J Minim Invasive Gynecol. 2016;23:164-185.
9. Champaneria R, Abedin P, Daniels J, et al. Ultrasound scan and magnetic resonance imaging for the diagnosis of adenomyosis: systematic review comparing test accuracy. Acta Obstet Gynecol Scand. 2010;89:1374-1384.
10. Bartels CB, Cayton KC, Chuong FS, et al. An evidence-based approach to the medical management of fibroids: a systematic review. Clin Obstet Gynecol. 2016;59:30-52.
11. Lethaby A, Cooke I, Rees MC. Progesterone or progestogen-releasing intrauterine systems for heavy menstrual bleeding. Cochrane Database Syst Rev. 2005;(4):CD002126.
12. Spies JB. Current role of uterine artery embolization in the management of uterine fibroids. Clin Obstet Gynecol. 2016;59:93-102.
13. Gupta JK, Sinha A, Lumsden MA, et al. Uterine artery embolization for symptomatic uterine fibroids. Cochrane Database Syst Rev. 2014;(12):CD005073.
14. Edwards RD, Moss JG, Lumsden MA, et al; Committee of the Randomized Trial of Embolization versus Surgical Treatment for Fibroids. Uterine artery embolization versus surgery for symptomatic uterine fibroids. N Engl J Med. 2007;356:360-370.
15. Pron G, Bennett J, Common A, et al; Ontario Uterine Fibroid Embolization Collaboration Group. The Ontario Uterine Fibroid Embolization Trial. Part 2. Uterine fibroid reduction and symptom relief after uterine artery embolization for fibroids. Fertil Steril. 2003;79:120-127.
16. Torre A, Fauconnier A, Kahn V, et al. Fertility after uterine artery embolization for symptomatic multiple fibroids with no other infertility factors. Eur Radiol. 2017;27:2850-2859.
17. Mara M, Maskova J, Fucikova Z, et al. Midterm clinical and first reproductive results of a randomized controlled trial comparing uterine fibroid embolization and myomectomy. Cardiovasc Intervent Radiol. 2008;31:73-85.
18. Lethaby A, Vollenhoven B, Sowter M. Pre-operative GnRH analogue therapy before hysterectomy or myomectomy for uterine fibroids. Cochrane Database Syst Rev. 2001;(2): CD000547.
19. Capmas P, Levaillant JM, Fernandez H. Surgical techniques and outcome in the management of submucous fibroids. Curr Opin Obstet Gynecol. 2013;25:332-338.
20. Abu Hashim H, Ghayaty E, El Rakhawy M. Levonorgestrel-releasing intrauterine system vs oral progestins for non-atypical endometrial hyperplasia: a systematic review and metaanalysis of randomized trials. Am J Obstet Gynecol. 2015;213:469-478.
21. Reed SD, Voigt LF, Newton KM, et al. Weiss NS. Progestin therapy of complex endometrial hyperplasia with and without atypia. Obstet Gynecol. 2009;113;655-662.
22. Morice P, Leary A, Creutzberg C, et al. Endometrial cancer. Lancet. 2016;387:1094-1108.
23. Goodman NF, Cobin RH, Futterweit W, et al; American Association of Clinical Endocrinologists (AACE); American College of Endocrinology (ACE); Androgen Excess and PCOS Society (AES). American Association of Clinical Endocrinologists, American College of Endocrinology, and Androgen Excess and PCOS Society disease state clinical review: guide to the best practices in the evaluation and treatment of polycystic ovary syndrome—part 1. Endocr Pract. 2015;21:1291-1300.
24. Shankar M, Lee CA, Sabin CA, et al. von Willebrand disease in women with menorrhagia: a systematic review. BJOG. 2004;111:734-740.
25. Seravalli V, Linari S, Peruzzi E, et al. Prevalence of hemostatic disorders in adolescents with abnormal uterine bleeding. J Pediatr Adolesc Gynecol. 2013;26:285-289.
26. Philipp CS, Faiz A, Dowling NF, et al. Development of a screening tool for identifying women with menorrhagia for hemostatic evaluation. Am J Obstet Gynecol. 2008;198:163.e1-e8.
27. The Rotterdam ESHRE/ASRM-sponsored PCOS consensus workshop group. Revised 2003 consensus on diagnostic criteria and long-term health risks related to polycystic ovary syndrome (PCOS). Hum Reprod. 2004;19:41-47.
28. Goodman NF, Cobin RH, Futterweit W, et al; American Association of Clinical Endocrinologists (AACE); American College of Endocrinology (ACE); Androgen Excess and PCOS Society (AES). American Association of Clinical Endocrinologists, American College of Endocrinology, and Androgen Excess and PCOS Society disease state clinical review: guide to the best practices in the evaluation and treatment of polycystic ovary syndrome—part 2. Endocr Pract. 2015;21:1415-26.
29. American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No 194: Polycystic ovary syndrome. Obstet Gynecol. 2018;131:e157-e171.
30. Speiser PW, Dupont B, Rubinstein P, et al. High frequency of nonclassical steroid 21-hydroxylase deficiency. Am J Hum Genet. 1985;37:650-667.
31. Naderpoor N, Shorakae S, de Courten B, et al. Metformin and lifestyle modification in polycystic ovary syndrome: systematic review and meta-analysis. Hum Reprod Update. 2015;21:560-574.
32. Kolman KB, Hadley SK, Jordahl-Iafrato MA. Long-acting reversible contraception: who, what, when, and how. J Fam Pract. 2015;64:479-484.
PRACTICE RECOMMENDATIONS
› Perform endometrial biopsy on all women who have abnormal uterine bleeding and risk factors for endometrial cancer and on all women ≥45 years, regardless of risk. C
› Initiate a workup for a coagulation disorder in women who are close to the onset of menarche and have a history of heavy menstrual bleeding. C
› Promote lifestyle changes and weight loss as primary treatments for polycystic ovary syndrome. B
Strength of recommendation (SOR)
A Good-quality patient-oriented evidence
B Inconsistent or limited-quality patient-oriented evidence
C Consensus, usual practice, opinion, disease-oriented evidence, case series
Severe maternal morbidity increasing in California
The according to a study covering almost 8.3 million births in California.
Changes in severe maternal morbidity (SMM) prevalence from 1997 to 2014 were fairly consistent by race/ethnicity, although increases for black (179%), Asian/Pacific Islander (175%), and Hispanic (173%) women were somewhat larger than for whites (163%), Stephanie A. Leonard, PhD, of Stanford (Calif.) University, and her associates reported in Annals of Epidemiology.
Differences between races/ethnicities over the entire study period were seen for SMM with and without transfusion-only cases. Individual-level factors such as cesarean birth, comorbidities, and anemia “contribute to, but do not fully explain, these disparities. Additionally, changes in the characteristics of pregnant women – including increases in comorbidities – have not affected racial/ethnic differences in severe maternal morbidity over time,” the investigators wrote.
The cohort study used data for 8,252,025 live births with birth certificates that were previously linked to delivery discharge records. SMM was measured using the Severe Maternity Morbidity Index. Because “blood transfusion is the only qualifying indicator for approximately half of SMM cases … we also studied a subset of SMM that excluded those cases for which the only indication was a blood transfusion,” they noted.
SOURCE: Leonard SA et al. Ann Epidemiol. 2019 Feb 28. doi: 10.1016/j.annepidem.2019.02.007.
The according to a study covering almost 8.3 million births in California.
Changes in severe maternal morbidity (SMM) prevalence from 1997 to 2014 were fairly consistent by race/ethnicity, although increases for black (179%), Asian/Pacific Islander (175%), and Hispanic (173%) women were somewhat larger than for whites (163%), Stephanie A. Leonard, PhD, of Stanford (Calif.) University, and her associates reported in Annals of Epidemiology.
Differences between races/ethnicities over the entire study period were seen for SMM with and without transfusion-only cases. Individual-level factors such as cesarean birth, comorbidities, and anemia “contribute to, but do not fully explain, these disparities. Additionally, changes in the characteristics of pregnant women – including increases in comorbidities – have not affected racial/ethnic differences in severe maternal morbidity over time,” the investigators wrote.
The cohort study used data for 8,252,025 live births with birth certificates that were previously linked to delivery discharge records. SMM was measured using the Severe Maternity Morbidity Index. Because “blood transfusion is the only qualifying indicator for approximately half of SMM cases … we also studied a subset of SMM that excluded those cases for which the only indication was a blood transfusion,” they noted.
SOURCE: Leonard SA et al. Ann Epidemiol. 2019 Feb 28. doi: 10.1016/j.annepidem.2019.02.007.
The according to a study covering almost 8.3 million births in California.
Changes in severe maternal morbidity (SMM) prevalence from 1997 to 2014 were fairly consistent by race/ethnicity, although increases for black (179%), Asian/Pacific Islander (175%), and Hispanic (173%) women were somewhat larger than for whites (163%), Stephanie A. Leonard, PhD, of Stanford (Calif.) University, and her associates reported in Annals of Epidemiology.
Differences between races/ethnicities over the entire study period were seen for SMM with and without transfusion-only cases. Individual-level factors such as cesarean birth, comorbidities, and anemia “contribute to, but do not fully explain, these disparities. Additionally, changes in the characteristics of pregnant women – including increases in comorbidities – have not affected racial/ethnic differences in severe maternal morbidity over time,” the investigators wrote.
The cohort study used data for 8,252,025 live births with birth certificates that were previously linked to delivery discharge records. SMM was measured using the Severe Maternity Morbidity Index. Because “blood transfusion is the only qualifying indicator for approximately half of SMM cases … we also studied a subset of SMM that excluded those cases for which the only indication was a blood transfusion,” they noted.
SOURCE: Leonard SA et al. Ann Epidemiol. 2019 Feb 28. doi: 10.1016/j.annepidem.2019.02.007.
FROM ANNALS OF EPIDEMIOLOGY