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Hydroxychloroquine prevents congenital heart block recurrence in anti-Ro pregnancies
ATLANTA – Hydroxychloroquine (Plaquenil) 400 mg/day starting by pregnancy week 10 reduces recurrence of congenital heart block in infants born to women with anti-Ro antibodies, according to an open-label, prospective study presented at the annual meeting of the American College of Rheumatology.
Among antibody-positive women who had a previous pregnancy complicated by congenital heart block (CHB), the regimen reduced recurrence in a subsequent pregnancy from the expected historical rate of 18% to 7.4%, a more than 50% drop. “Given the potential benefit of hydroxychloroquine” (HCQ) and its relative safety during pregnancy, “testing all pregnancies for anti-Ro antibodies, regardless of maternal health, should be considered,” concluded investigators led by rheumatologist Peter Izmirly, MD, associate professor of medicine at New York (N.Y.) University.
About 40% of women with systemic lupus erythematosus and nearly 100% of women with Sjögren’s syndrome, as well as about 1% of women in the general population, have anti-Ro antibodies. They can be present in completely asymptomatic women, which is why the authors called for general screening. Indeed, half of the women in the trial had no or only mild, undifferentiated rheumatic symptoms. Often, “women who carry anti-Ro antibodies have no idea they have them” until they have a child with CHB and are tested, Dr. Izmirly said.
The antibodies cross the placenta and interfere with the normal development of the AV node; about 18% of infants die and most of the rest require lifelong pacing. The risk of CHB in antibody-positive women is about 2%, but once a child is born with the condition, the risk climbs to about 18% in subsequent pregnancies.
Years ago, Dr. Izmirly and his colleagues had a hunch that HCQ might help because it disrupts the toll-like receptor signaling involved in the disease process. A database review he led added weight to the idea, finding that among 257 anti-Ro positive pregnancies, the rate of CHB was 7.5% among the 40 women who happened to take HCQ, versus 21.2% among the 217 who did not. “We wanted to see if we could replicate that prospectively,” he said.
The Preventive Approach to Congenital Heart Block with Hydroxychloroquine (PATCH) trial enrolled 54 antibody positive women with a previous CHB pregnancy. They were started on 400 mg/day HCQ by gestation week 10.
There were four cases of second- or third-degree CHB among the women (7.4%, P = 0.02), all detected by fetal echocardiogram around week 20.
Nine of the women were treated with IVIG and/or dexamethasone for lupus flares or fetal heart issues other than advanced block, which confounded the results. To analyze the effect in a purely HCQ cohort, the team recruited an additional nine women not treated with any other medication during pregnancy, one of whose fetus developed third-degree heart block.
In total, 5 of 63 pregnancies (7.9%) resulted in advanced block. Among the 54 women exposed only to HCQ, the rate of second- or third-degree block was again 7.4% (4 of 54, P = .02). HCQ compliance, assessed by maternal blood levels above 200 ng/mL at least once, was 98%, and cord blood confirmed fetal exposure to HCQ.
Once detected, CHB was treated with dexamethasone or IVIG. One case progressed to cardiomyopathy, and the pregnancy was terminated. Another child required pacing after birth. Other children reverted to normal sinus rhythm but had intermittent second-degree block at age 2.
Overall, “the safety in this study was excellent,” said rheumatologist and senior investigator Jill Buyon, MD, director of the division of rheumatology at New York University.
The complications – nine births before 37 weeks, one infant small for gestational age – were not unexpected in a rheumatic population. “We were very nervous about Plaquenil cardiomyopathy” in the pregnancy that was terminated, but there was no evidence of it on histology.
The children will have ocular optical coherence tomography at age 5 to check for retinal toxicity; the 12 who have been tested so far show no obvious signs. Dr. Izmirly said he doesn’t expect to see any problems. “We are just being super cautious.”
The audience had questions about why the trial didn’t have a placebo arm. He explained that CHB is a rare event – one in 15,000 pregnancies – and it took 8 years just to adequately power the single-arm study; recruiting more than 100 additional women for a placebo-controlled trial wasn’t practical.
Also, “there was no way” women were going to be randomized to placebo when HCQ seemed so promising; 35% of the enrollees had already lost a child to CHB. “Everyone wanted the drug,” Dr. Izmirly said.
The majority of women were white, and about half met criteria for lupus and/or Sjögren’s. Anti-Ro levels remained above 1,000 EU throughout pregnancy. Women were excluded if they were taking high-dose prednisone or any dose of fluorinated corticosteroids at baseline.
The National Institutes of Health funded the work. The investigators had no relevant disclosures.
SOURCE: Izmirly P et al. Arthritis Rheumatol. 2019;71(suppl 10). Abstract 1761.
ATLANTA – Hydroxychloroquine (Plaquenil) 400 mg/day starting by pregnancy week 10 reduces recurrence of congenital heart block in infants born to women with anti-Ro antibodies, according to an open-label, prospective study presented at the annual meeting of the American College of Rheumatology.
Among antibody-positive women who had a previous pregnancy complicated by congenital heart block (CHB), the regimen reduced recurrence in a subsequent pregnancy from the expected historical rate of 18% to 7.4%, a more than 50% drop. “Given the potential benefit of hydroxychloroquine” (HCQ) and its relative safety during pregnancy, “testing all pregnancies for anti-Ro antibodies, regardless of maternal health, should be considered,” concluded investigators led by rheumatologist Peter Izmirly, MD, associate professor of medicine at New York (N.Y.) University.
About 40% of women with systemic lupus erythematosus and nearly 100% of women with Sjögren’s syndrome, as well as about 1% of women in the general population, have anti-Ro antibodies. They can be present in completely asymptomatic women, which is why the authors called for general screening. Indeed, half of the women in the trial had no or only mild, undifferentiated rheumatic symptoms. Often, “women who carry anti-Ro antibodies have no idea they have them” until they have a child with CHB and are tested, Dr. Izmirly said.
The antibodies cross the placenta and interfere with the normal development of the AV node; about 18% of infants die and most of the rest require lifelong pacing. The risk of CHB in antibody-positive women is about 2%, but once a child is born with the condition, the risk climbs to about 18% in subsequent pregnancies.
Years ago, Dr. Izmirly and his colleagues had a hunch that HCQ might help because it disrupts the toll-like receptor signaling involved in the disease process. A database review he led added weight to the idea, finding that among 257 anti-Ro positive pregnancies, the rate of CHB was 7.5% among the 40 women who happened to take HCQ, versus 21.2% among the 217 who did not. “We wanted to see if we could replicate that prospectively,” he said.
The Preventive Approach to Congenital Heart Block with Hydroxychloroquine (PATCH) trial enrolled 54 antibody positive women with a previous CHB pregnancy. They were started on 400 mg/day HCQ by gestation week 10.
There were four cases of second- or third-degree CHB among the women (7.4%, P = 0.02), all detected by fetal echocardiogram around week 20.
Nine of the women were treated with IVIG and/or dexamethasone for lupus flares or fetal heart issues other than advanced block, which confounded the results. To analyze the effect in a purely HCQ cohort, the team recruited an additional nine women not treated with any other medication during pregnancy, one of whose fetus developed third-degree heart block.
In total, 5 of 63 pregnancies (7.9%) resulted in advanced block. Among the 54 women exposed only to HCQ, the rate of second- or third-degree block was again 7.4% (4 of 54, P = .02). HCQ compliance, assessed by maternal blood levels above 200 ng/mL at least once, was 98%, and cord blood confirmed fetal exposure to HCQ.
Once detected, CHB was treated with dexamethasone or IVIG. One case progressed to cardiomyopathy, and the pregnancy was terminated. Another child required pacing after birth. Other children reverted to normal sinus rhythm but had intermittent second-degree block at age 2.
Overall, “the safety in this study was excellent,” said rheumatologist and senior investigator Jill Buyon, MD, director of the division of rheumatology at New York University.
The complications – nine births before 37 weeks, one infant small for gestational age – were not unexpected in a rheumatic population. “We were very nervous about Plaquenil cardiomyopathy” in the pregnancy that was terminated, but there was no evidence of it on histology.
The children will have ocular optical coherence tomography at age 5 to check for retinal toxicity; the 12 who have been tested so far show no obvious signs. Dr. Izmirly said he doesn’t expect to see any problems. “We are just being super cautious.”
The audience had questions about why the trial didn’t have a placebo arm. He explained that CHB is a rare event – one in 15,000 pregnancies – and it took 8 years just to adequately power the single-arm study; recruiting more than 100 additional women for a placebo-controlled trial wasn’t practical.
Also, “there was no way” women were going to be randomized to placebo when HCQ seemed so promising; 35% of the enrollees had already lost a child to CHB. “Everyone wanted the drug,” Dr. Izmirly said.
The majority of women were white, and about half met criteria for lupus and/or Sjögren’s. Anti-Ro levels remained above 1,000 EU throughout pregnancy. Women were excluded if they were taking high-dose prednisone or any dose of fluorinated corticosteroids at baseline.
The National Institutes of Health funded the work. The investigators had no relevant disclosures.
SOURCE: Izmirly P et al. Arthritis Rheumatol. 2019;71(suppl 10). Abstract 1761.
ATLANTA – Hydroxychloroquine (Plaquenil) 400 mg/day starting by pregnancy week 10 reduces recurrence of congenital heart block in infants born to women with anti-Ro antibodies, according to an open-label, prospective study presented at the annual meeting of the American College of Rheumatology.
Among antibody-positive women who had a previous pregnancy complicated by congenital heart block (CHB), the regimen reduced recurrence in a subsequent pregnancy from the expected historical rate of 18% to 7.4%, a more than 50% drop. “Given the potential benefit of hydroxychloroquine” (HCQ) and its relative safety during pregnancy, “testing all pregnancies for anti-Ro antibodies, regardless of maternal health, should be considered,” concluded investigators led by rheumatologist Peter Izmirly, MD, associate professor of medicine at New York (N.Y.) University.
About 40% of women with systemic lupus erythematosus and nearly 100% of women with Sjögren’s syndrome, as well as about 1% of women in the general population, have anti-Ro antibodies. They can be present in completely asymptomatic women, which is why the authors called for general screening. Indeed, half of the women in the trial had no or only mild, undifferentiated rheumatic symptoms. Often, “women who carry anti-Ro antibodies have no idea they have them” until they have a child with CHB and are tested, Dr. Izmirly said.
The antibodies cross the placenta and interfere with the normal development of the AV node; about 18% of infants die and most of the rest require lifelong pacing. The risk of CHB in antibody-positive women is about 2%, but once a child is born with the condition, the risk climbs to about 18% in subsequent pregnancies.
Years ago, Dr. Izmirly and his colleagues had a hunch that HCQ might help because it disrupts the toll-like receptor signaling involved in the disease process. A database review he led added weight to the idea, finding that among 257 anti-Ro positive pregnancies, the rate of CHB was 7.5% among the 40 women who happened to take HCQ, versus 21.2% among the 217 who did not. “We wanted to see if we could replicate that prospectively,” he said.
The Preventive Approach to Congenital Heart Block with Hydroxychloroquine (PATCH) trial enrolled 54 antibody positive women with a previous CHB pregnancy. They were started on 400 mg/day HCQ by gestation week 10.
There were four cases of second- or third-degree CHB among the women (7.4%, P = 0.02), all detected by fetal echocardiogram around week 20.
Nine of the women were treated with IVIG and/or dexamethasone for lupus flares or fetal heart issues other than advanced block, which confounded the results. To analyze the effect in a purely HCQ cohort, the team recruited an additional nine women not treated with any other medication during pregnancy, one of whose fetus developed third-degree heart block.
In total, 5 of 63 pregnancies (7.9%) resulted in advanced block. Among the 54 women exposed only to HCQ, the rate of second- or third-degree block was again 7.4% (4 of 54, P = .02). HCQ compliance, assessed by maternal blood levels above 200 ng/mL at least once, was 98%, and cord blood confirmed fetal exposure to HCQ.
Once detected, CHB was treated with dexamethasone or IVIG. One case progressed to cardiomyopathy, and the pregnancy was terminated. Another child required pacing after birth. Other children reverted to normal sinus rhythm but had intermittent second-degree block at age 2.
Overall, “the safety in this study was excellent,” said rheumatologist and senior investigator Jill Buyon, MD, director of the division of rheumatology at New York University.
The complications – nine births before 37 weeks, one infant small for gestational age – were not unexpected in a rheumatic population. “We were very nervous about Plaquenil cardiomyopathy” in the pregnancy that was terminated, but there was no evidence of it on histology.
The children will have ocular optical coherence tomography at age 5 to check for retinal toxicity; the 12 who have been tested so far show no obvious signs. Dr. Izmirly said he doesn’t expect to see any problems. “We are just being super cautious.”
The audience had questions about why the trial didn’t have a placebo arm. He explained that CHB is a rare event – one in 15,000 pregnancies – and it took 8 years just to adequately power the single-arm study; recruiting more than 100 additional women for a placebo-controlled trial wasn’t practical.
Also, “there was no way” women were going to be randomized to placebo when HCQ seemed so promising; 35% of the enrollees had already lost a child to CHB. “Everyone wanted the drug,” Dr. Izmirly said.
The majority of women were white, and about half met criteria for lupus and/or Sjögren’s. Anti-Ro levels remained above 1,000 EU throughout pregnancy. Women were excluded if they were taking high-dose prednisone or any dose of fluorinated corticosteroids at baseline.
The National Institutes of Health funded the work. The investigators had no relevant disclosures.
SOURCE: Izmirly P et al. Arthritis Rheumatol. 2019;71(suppl 10). Abstract 1761.
REPORTING FROM ACR 2019
Obstetrical care in crisis
For the last 25 years I have had the privilege of caring for a rural community, practicing full-scope family medicine including obstetrics with cesarean sections. I have had a deeply rewarding career, and delivering babies and watching them grow up has been one of the most gratifying parts of my work.
My concern is that, as the number of family physicians who practice maternity care has decreased, the infant and maternal mortality rate in the United States has increased, especially in rural and minority populations. Currently, 5 million women of reproductive age have no access to maternity care.
At the same time 23% of incoming family medicine residents would like to offer maternity care and are trained to do so, but few are able to find a job where this is possible.1 This is unfortunate because family physicians have the training and expertise to provide comprehensive maternity care. Although they have lower rates of cesarean section than ob-gyns, with similar outcomes, family physicians do have surgical skills, including providing cesarean sections, that are often necessary for safe delivery.2,3
In addition, family physicians have the internal medicine and behavioral health background to care for postpartum complications, as well as substance use disorders. Because they also care for children, they see postpartum women when they come in with their children for well-child checks. These visits offer an excellent opportunity to also check on the mother for postpartum depression and other signs of postpartum illness.
Centers for Disease Control and Prevention data reveal that maternal mortality can be divided into three nearly equal parts: pregnancy, delivery, and post partum. They define delivery as the week of delivery. The 48 hours post delivery accounted for only 12% of overall mortality. This means that even if women travel to metropolitan areas, they are likely to be home when they have fatal complications. The lack of trained and experienced physicians in the communities where women live increases their risks should they have complications. Most maternal fatalities occur when conditions are not recognized in a timely fashion. Some responses require procedural skills such as dilation and curettage (D&C).
As a member of the National Advisory Committee on Rural Health and Human Services, I visited several states to evaluate their rural health systems. We looked at infant mortality by county and found an enormous disparity between counties, largely caused by lack of prenatal services and obstetrical services.
These disparities between counties are getting worse. The United States is losing critical access hospitals at a rapid pace. We have lost 117 critical access hospitals in the last 10 years, with 40 in the last year alone. According to the National Rural Health Association, 4,673 additional facilities – representing more than one-third of rural hospitals in the United States – are vulnerable and could close. The reasons are multiple, but the result has been an erosion of the rural safety net, especially with regard to maternity care.
These hospital closures force women to travel farther distances for maternity care, including cesarean sections, and this contributes to increased maternal and infant mortality.5 In a study from Canada, the complication rates increased substantially as distances increased. Women are more likely to have premature deliveries, deliver on the side of the road, or end up in inappropriate facilities.
The distance from delivery is directly related to outcomes. A study from the early 1990s showed that women did better if they received maternity care from local hospitals and physicians.6 From a family medicine perspective, this makes sense because traveling to a metropolitan area means isolation from family and social networks. Stress increases because pregnant women also are often the primary caregiver of other children and the primary wage earner of the family. Although we are unsure what impact stress has on pregnancy, we do know it does have an effect on greater risk of prematurity and poor outcomes.
Obstetricians provide excellent care, but they are not a panacea. Only half of U.S. counties have adequate ob.gyn. coverage. Moreover, in many of those counties, the ob.gyns. subspecialize in gynecologic surgery and infertility, but don’t provide obstetrical care. Another challenge: ob.gyns. cannot survive financially in smaller communities; our policies must include incentives to recruit and retain them in underserved areas.
Certified nurse midwives also provide excellent care and are an invaluable member of the patient-care team, but again, they cannot be the only solution. Obstetrical emergencies do occur, and mothers need a physician trained in providing on-site medical or surgical care. They also need a hospital with adequate staff to care for emergencies.
In communities large enough to support a multispecialty group, certified medical technicians, family physicians, and ob.gyns. would ideally work alongside each other. In small communities four family physicians can provide a high level of maternity care including surgical deliveries, while supporting themselves with caring for children and elders in clinics, hospitals, and EDs.
It is unconscionable that a country as wealthy as ours would accept rates of maternal and infant mortality that rival and are often worse than developing countries. Although the reasons are many, there is no excuse. Family physicians are an essential part of reversing this trend. We need policies that enable family physicians to help resolve the shortage of maternity care for underserved communities, to address the maternal and infant mortality rate, and to provide maternity care that is part of family medicine’s full scope of practice.
Dr. Cullen is board chair of the American Academy of Family Physicians and a practicing family physician in Valdez, Alaska.
References
1. Am Board Fam Med. 2017 Jul-Aug;30(4):405-6.
2. CMAJ. 2015 Oct 27;187:1125-32.
3. J Am Board Fam Med. 2013 Jul-Aug;26(4):366-72.
4. NRHA Save Rural Hospitals Action Center. www.ruralhealthweb.org/advocate/save-rural-hospitals.
5. BMC Health Serv Res. 2011 Jun 10;11:147.
6. Am J Public Health. 1990 Jul;80(7):814-8.
For the last 25 years I have had the privilege of caring for a rural community, practicing full-scope family medicine including obstetrics with cesarean sections. I have had a deeply rewarding career, and delivering babies and watching them grow up has been one of the most gratifying parts of my work.
My concern is that, as the number of family physicians who practice maternity care has decreased, the infant and maternal mortality rate in the United States has increased, especially in rural and minority populations. Currently, 5 million women of reproductive age have no access to maternity care.
At the same time 23% of incoming family medicine residents would like to offer maternity care and are trained to do so, but few are able to find a job where this is possible.1 This is unfortunate because family physicians have the training and expertise to provide comprehensive maternity care. Although they have lower rates of cesarean section than ob-gyns, with similar outcomes, family physicians do have surgical skills, including providing cesarean sections, that are often necessary for safe delivery.2,3
In addition, family physicians have the internal medicine and behavioral health background to care for postpartum complications, as well as substance use disorders. Because they also care for children, they see postpartum women when they come in with their children for well-child checks. These visits offer an excellent opportunity to also check on the mother for postpartum depression and other signs of postpartum illness.
Centers for Disease Control and Prevention data reveal that maternal mortality can be divided into three nearly equal parts: pregnancy, delivery, and post partum. They define delivery as the week of delivery. The 48 hours post delivery accounted for only 12% of overall mortality. This means that even if women travel to metropolitan areas, they are likely to be home when they have fatal complications. The lack of trained and experienced physicians in the communities where women live increases their risks should they have complications. Most maternal fatalities occur when conditions are not recognized in a timely fashion. Some responses require procedural skills such as dilation and curettage (D&C).
As a member of the National Advisory Committee on Rural Health and Human Services, I visited several states to evaluate their rural health systems. We looked at infant mortality by county and found an enormous disparity between counties, largely caused by lack of prenatal services and obstetrical services.
These disparities between counties are getting worse. The United States is losing critical access hospitals at a rapid pace. We have lost 117 critical access hospitals in the last 10 years, with 40 in the last year alone. According to the National Rural Health Association, 4,673 additional facilities – representing more than one-third of rural hospitals in the United States – are vulnerable and could close. The reasons are multiple, but the result has been an erosion of the rural safety net, especially with regard to maternity care.
These hospital closures force women to travel farther distances for maternity care, including cesarean sections, and this contributes to increased maternal and infant mortality.5 In a study from Canada, the complication rates increased substantially as distances increased. Women are more likely to have premature deliveries, deliver on the side of the road, or end up in inappropriate facilities.
The distance from delivery is directly related to outcomes. A study from the early 1990s showed that women did better if they received maternity care from local hospitals and physicians.6 From a family medicine perspective, this makes sense because traveling to a metropolitan area means isolation from family and social networks. Stress increases because pregnant women also are often the primary caregiver of other children and the primary wage earner of the family. Although we are unsure what impact stress has on pregnancy, we do know it does have an effect on greater risk of prematurity and poor outcomes.
Obstetricians provide excellent care, but they are not a panacea. Only half of U.S. counties have adequate ob.gyn. coverage. Moreover, in many of those counties, the ob.gyns. subspecialize in gynecologic surgery and infertility, but don’t provide obstetrical care. Another challenge: ob.gyns. cannot survive financially in smaller communities; our policies must include incentives to recruit and retain them in underserved areas.
Certified nurse midwives also provide excellent care and are an invaluable member of the patient-care team, but again, they cannot be the only solution. Obstetrical emergencies do occur, and mothers need a physician trained in providing on-site medical or surgical care. They also need a hospital with adequate staff to care for emergencies.
In communities large enough to support a multispecialty group, certified medical technicians, family physicians, and ob.gyns. would ideally work alongside each other. In small communities four family physicians can provide a high level of maternity care including surgical deliveries, while supporting themselves with caring for children and elders in clinics, hospitals, and EDs.
It is unconscionable that a country as wealthy as ours would accept rates of maternal and infant mortality that rival and are often worse than developing countries. Although the reasons are many, there is no excuse. Family physicians are an essential part of reversing this trend. We need policies that enable family physicians to help resolve the shortage of maternity care for underserved communities, to address the maternal and infant mortality rate, and to provide maternity care that is part of family medicine’s full scope of practice.
Dr. Cullen is board chair of the American Academy of Family Physicians and a practicing family physician in Valdez, Alaska.
References
1. Am Board Fam Med. 2017 Jul-Aug;30(4):405-6.
2. CMAJ. 2015 Oct 27;187:1125-32.
3. J Am Board Fam Med. 2013 Jul-Aug;26(4):366-72.
4. NRHA Save Rural Hospitals Action Center. www.ruralhealthweb.org/advocate/save-rural-hospitals.
5. BMC Health Serv Res. 2011 Jun 10;11:147.
6. Am J Public Health. 1990 Jul;80(7):814-8.
For the last 25 years I have had the privilege of caring for a rural community, practicing full-scope family medicine including obstetrics with cesarean sections. I have had a deeply rewarding career, and delivering babies and watching them grow up has been one of the most gratifying parts of my work.
My concern is that, as the number of family physicians who practice maternity care has decreased, the infant and maternal mortality rate in the United States has increased, especially in rural and minority populations. Currently, 5 million women of reproductive age have no access to maternity care.
At the same time 23% of incoming family medicine residents would like to offer maternity care and are trained to do so, but few are able to find a job where this is possible.1 This is unfortunate because family physicians have the training and expertise to provide comprehensive maternity care. Although they have lower rates of cesarean section than ob-gyns, with similar outcomes, family physicians do have surgical skills, including providing cesarean sections, that are often necessary for safe delivery.2,3
In addition, family physicians have the internal medicine and behavioral health background to care for postpartum complications, as well as substance use disorders. Because they also care for children, they see postpartum women when they come in with their children for well-child checks. These visits offer an excellent opportunity to also check on the mother for postpartum depression and other signs of postpartum illness.
Centers for Disease Control and Prevention data reveal that maternal mortality can be divided into three nearly equal parts: pregnancy, delivery, and post partum. They define delivery as the week of delivery. The 48 hours post delivery accounted for only 12% of overall mortality. This means that even if women travel to metropolitan areas, they are likely to be home when they have fatal complications. The lack of trained and experienced physicians in the communities where women live increases their risks should they have complications. Most maternal fatalities occur when conditions are not recognized in a timely fashion. Some responses require procedural skills such as dilation and curettage (D&C).
As a member of the National Advisory Committee on Rural Health and Human Services, I visited several states to evaluate their rural health systems. We looked at infant mortality by county and found an enormous disparity between counties, largely caused by lack of prenatal services and obstetrical services.
These disparities between counties are getting worse. The United States is losing critical access hospitals at a rapid pace. We have lost 117 critical access hospitals in the last 10 years, with 40 in the last year alone. According to the National Rural Health Association, 4,673 additional facilities – representing more than one-third of rural hospitals in the United States – are vulnerable and could close. The reasons are multiple, but the result has been an erosion of the rural safety net, especially with regard to maternity care.
These hospital closures force women to travel farther distances for maternity care, including cesarean sections, and this contributes to increased maternal and infant mortality.5 In a study from Canada, the complication rates increased substantially as distances increased. Women are more likely to have premature deliveries, deliver on the side of the road, or end up in inappropriate facilities.
The distance from delivery is directly related to outcomes. A study from the early 1990s showed that women did better if they received maternity care from local hospitals and physicians.6 From a family medicine perspective, this makes sense because traveling to a metropolitan area means isolation from family and social networks. Stress increases because pregnant women also are often the primary caregiver of other children and the primary wage earner of the family. Although we are unsure what impact stress has on pregnancy, we do know it does have an effect on greater risk of prematurity and poor outcomes.
Obstetricians provide excellent care, but they are not a panacea. Only half of U.S. counties have adequate ob.gyn. coverage. Moreover, in many of those counties, the ob.gyns. subspecialize in gynecologic surgery and infertility, but don’t provide obstetrical care. Another challenge: ob.gyns. cannot survive financially in smaller communities; our policies must include incentives to recruit and retain them in underserved areas.
Certified nurse midwives also provide excellent care and are an invaluable member of the patient-care team, but again, they cannot be the only solution. Obstetrical emergencies do occur, and mothers need a physician trained in providing on-site medical or surgical care. They also need a hospital with adequate staff to care for emergencies.
In communities large enough to support a multispecialty group, certified medical technicians, family physicians, and ob.gyns. would ideally work alongside each other. In small communities four family physicians can provide a high level of maternity care including surgical deliveries, while supporting themselves with caring for children and elders in clinics, hospitals, and EDs.
It is unconscionable that a country as wealthy as ours would accept rates of maternal and infant mortality that rival and are often worse than developing countries. Although the reasons are many, there is no excuse. Family physicians are an essential part of reversing this trend. We need policies that enable family physicians to help resolve the shortage of maternity care for underserved communities, to address the maternal and infant mortality rate, and to provide maternity care that is part of family medicine’s full scope of practice.
Dr. Cullen is board chair of the American Academy of Family Physicians and a practicing family physician in Valdez, Alaska.
References
1. Am Board Fam Med. 2017 Jul-Aug;30(4):405-6.
2. CMAJ. 2015 Oct 27;187:1125-32.
3. J Am Board Fam Med. 2013 Jul-Aug;26(4):366-72.
4. NRHA Save Rural Hospitals Action Center. www.ruralhealthweb.org/advocate/save-rural-hospitals.
5. BMC Health Serv Res. 2011 Jun 10;11:147.
6. Am J Public Health. 1990 Jul;80(7):814-8.
Asthma exacerbation in pregnancy impacts mothers, infants
Women with asthma who suffer asthma exacerbation while pregnant are at increased risk for complications during pregnancy and delivery, and their infants are at increased risk for respiratory problems, according to data from a longitudinal study of 58,524 women with asthma.
“Asthma exacerbation during pregnancy has been found to be associated with adverse perinatal and pregnancy outcomes such as low birth weight, small for gestational age, preterm delivery, congenital malformation, preeclampsia, and perinatal mortality,” but previous studies have been small and limited to comparisons of asthmatic and nonasthmatic women, wrote Kawsari Abdullah, PhD, of Children’s Hospital of Eastern Ontario, Ottawa, and colleagues.
To determine the impact of asthma exacerbation on maternal and fetal outcomes, the researchers analyzed data from the Ontario Asthma Surveillance Information System to identify women with asthma who had at least one pregnancy resulting in a live or still birth between 2006 and 2012.
Overall, significantly more women with exacerbated asthma had preeclampsia or pregnancy-induced hypertension, compared with asthmatic women who had no exacerbations, at 5% vs. 4% and 7% vs. 5%, respectively (P less than .001), according to the study published in the European Respiratory Journal.
Adverse perinatal outcomes were significantly more likely among babies of mothers with exacerbated asthma, compared with those who had no exacerbations, including low birth weight (7% vs. 5%), small for gestational age (3% vs. 2%), preterm birth (8% vs. 7%), and congenital malformation (6% vs. 5%). All P values were less than .001, except for small for gestational age, which was P = .008.
In addition, significantly more babies of asthmatic women with exacerbated asthma during pregnancy had respiratory problems including asthma and pneumonia, compared with those of asthmatic women who had no exacerbations during pregnancy, at 38% vs. 31% and 24% vs. 22% (P less than .001 for both). The researchers found no significant interactions between maternal age and smoking and asthma exacerbations.
The findings were limited by several factors, including the lack of a validated algorithm for asthma exacerbation, which the researchers defined as five or more visits to a general practice clinician for asthma during pregnancy. Other limitations included the lack of categorizing asthma exacerbation by severity, and the inability to include the potential effects of asthma medication on maternal and fetal outcomes, Dr. Abdullah and colleagues noted.
However, the results were strengthened by the large sample size and ability to follow babies from birth until 5 years of age, they said.
“Targeting women with asthma during pregnancy and ensuring appropriate asthma management and postpartum follow-up may help to reduce the risk of pregnancy complications, adverse perinatal outcomes, and early childhood respiratory disorders,” they concluded.
This study is important because asthma is a common, potentially serious medical condition that complicates approximately 4%-8% of pregnancies, and one in three women with asthma experience an exacerbation during pregnancy, Iris Krishna, MD, a specialist in maternal/fetal medicine at Emory University, Atlanta, said in an interview.
“This study is unique in that it uses population-level data to assess the association between an asthma exacerbation during pregnancy and adverse perinatal outcomes,” Dr. Krishna said. “After adjusting for confounders, and consistent with previous studies, study findings suggest an increased risk for women with asthma who have an asthma exacerbation during pregnancy for preeclampsia [odds ratio, 1.3; P less than .001], pregnancy-induced hypertension [OR, 1.17; P less than .05], low-birth-weight infant [OR, 1.14; P less than .05], preterm birth [OR, 1.14; P less than .05], and congenital malformations [OR, 1.21; P less than .001].”
Dr. Krishna also noted the impact on early childhood outcomes. “In this study, children born to women who had an asthma exacerbation during pregnancy had a 23% higher risk of developing asthma before 5 years of age, which is consistent with previous studies. [The] investigators also reported a 12% higher risk of having pneumonia during the first 5 years of life for children born to women who had an asthma exacerbation during pregnancy.”
“Previous studies have suggested children born to mothers with uncontrolled asthma have an increased risk for respiratory infections, but this study is the first to report an association with pneumonia,” she said. This increased risk for childhood respiratory disorders warrants further study.
Consequently, “Women with asthma during pregnancy should have appropriate management to ensure good control to optimize pregnancy outcome,” Dr. Krishna emphasized. “Women who experience asthma exacerbations in pregnancy are at increased risk for preeclampsia, [pregnancy-induced hypertension], low birth weight, and preterm delivery and may require closer monitoring.”
The study was supported by the Institute for Clinical Evaluative Sciences. The researchers and Dr. Krishna had no financial conflicts to disclose.
SOURCE: Abdullah K et al. Eur Respir J. 2019 Nov 26. doi: 10.1183/13993003.01335-2019.
Women with asthma who suffer asthma exacerbation while pregnant are at increased risk for complications during pregnancy and delivery, and their infants are at increased risk for respiratory problems, according to data from a longitudinal study of 58,524 women with asthma.
“Asthma exacerbation during pregnancy has been found to be associated with adverse perinatal and pregnancy outcomes such as low birth weight, small for gestational age, preterm delivery, congenital malformation, preeclampsia, and perinatal mortality,” but previous studies have been small and limited to comparisons of asthmatic and nonasthmatic women, wrote Kawsari Abdullah, PhD, of Children’s Hospital of Eastern Ontario, Ottawa, and colleagues.
To determine the impact of asthma exacerbation on maternal and fetal outcomes, the researchers analyzed data from the Ontario Asthma Surveillance Information System to identify women with asthma who had at least one pregnancy resulting in a live or still birth between 2006 and 2012.
Overall, significantly more women with exacerbated asthma had preeclampsia or pregnancy-induced hypertension, compared with asthmatic women who had no exacerbations, at 5% vs. 4% and 7% vs. 5%, respectively (P less than .001), according to the study published in the European Respiratory Journal.
Adverse perinatal outcomes were significantly more likely among babies of mothers with exacerbated asthma, compared with those who had no exacerbations, including low birth weight (7% vs. 5%), small for gestational age (3% vs. 2%), preterm birth (8% vs. 7%), and congenital malformation (6% vs. 5%). All P values were less than .001, except for small for gestational age, which was P = .008.
In addition, significantly more babies of asthmatic women with exacerbated asthma during pregnancy had respiratory problems including asthma and pneumonia, compared with those of asthmatic women who had no exacerbations during pregnancy, at 38% vs. 31% and 24% vs. 22% (P less than .001 for both). The researchers found no significant interactions between maternal age and smoking and asthma exacerbations.
The findings were limited by several factors, including the lack of a validated algorithm for asthma exacerbation, which the researchers defined as five or more visits to a general practice clinician for asthma during pregnancy. Other limitations included the lack of categorizing asthma exacerbation by severity, and the inability to include the potential effects of asthma medication on maternal and fetal outcomes, Dr. Abdullah and colleagues noted.
However, the results were strengthened by the large sample size and ability to follow babies from birth until 5 years of age, they said.
“Targeting women with asthma during pregnancy and ensuring appropriate asthma management and postpartum follow-up may help to reduce the risk of pregnancy complications, adverse perinatal outcomes, and early childhood respiratory disorders,” they concluded.
This study is important because asthma is a common, potentially serious medical condition that complicates approximately 4%-8% of pregnancies, and one in three women with asthma experience an exacerbation during pregnancy, Iris Krishna, MD, a specialist in maternal/fetal medicine at Emory University, Atlanta, said in an interview.
“This study is unique in that it uses population-level data to assess the association between an asthma exacerbation during pregnancy and adverse perinatal outcomes,” Dr. Krishna said. “After adjusting for confounders, and consistent with previous studies, study findings suggest an increased risk for women with asthma who have an asthma exacerbation during pregnancy for preeclampsia [odds ratio, 1.3; P less than .001], pregnancy-induced hypertension [OR, 1.17; P less than .05], low-birth-weight infant [OR, 1.14; P less than .05], preterm birth [OR, 1.14; P less than .05], and congenital malformations [OR, 1.21; P less than .001].”
Dr. Krishna also noted the impact on early childhood outcomes. “In this study, children born to women who had an asthma exacerbation during pregnancy had a 23% higher risk of developing asthma before 5 years of age, which is consistent with previous studies. [The] investigators also reported a 12% higher risk of having pneumonia during the first 5 years of life for children born to women who had an asthma exacerbation during pregnancy.”
“Previous studies have suggested children born to mothers with uncontrolled asthma have an increased risk for respiratory infections, but this study is the first to report an association with pneumonia,” she said. This increased risk for childhood respiratory disorders warrants further study.
Consequently, “Women with asthma during pregnancy should have appropriate management to ensure good control to optimize pregnancy outcome,” Dr. Krishna emphasized. “Women who experience asthma exacerbations in pregnancy are at increased risk for preeclampsia, [pregnancy-induced hypertension], low birth weight, and preterm delivery and may require closer monitoring.”
The study was supported by the Institute for Clinical Evaluative Sciences. The researchers and Dr. Krishna had no financial conflicts to disclose.
SOURCE: Abdullah K et al. Eur Respir J. 2019 Nov 26. doi: 10.1183/13993003.01335-2019.
Women with asthma who suffer asthma exacerbation while pregnant are at increased risk for complications during pregnancy and delivery, and their infants are at increased risk for respiratory problems, according to data from a longitudinal study of 58,524 women with asthma.
“Asthma exacerbation during pregnancy has been found to be associated with adverse perinatal and pregnancy outcomes such as low birth weight, small for gestational age, preterm delivery, congenital malformation, preeclampsia, and perinatal mortality,” but previous studies have been small and limited to comparisons of asthmatic and nonasthmatic women, wrote Kawsari Abdullah, PhD, of Children’s Hospital of Eastern Ontario, Ottawa, and colleagues.
To determine the impact of asthma exacerbation on maternal and fetal outcomes, the researchers analyzed data from the Ontario Asthma Surveillance Information System to identify women with asthma who had at least one pregnancy resulting in a live or still birth between 2006 and 2012.
Overall, significantly more women with exacerbated asthma had preeclampsia or pregnancy-induced hypertension, compared with asthmatic women who had no exacerbations, at 5% vs. 4% and 7% vs. 5%, respectively (P less than .001), according to the study published in the European Respiratory Journal.
Adverse perinatal outcomes were significantly more likely among babies of mothers with exacerbated asthma, compared with those who had no exacerbations, including low birth weight (7% vs. 5%), small for gestational age (3% vs. 2%), preterm birth (8% vs. 7%), and congenital malformation (6% vs. 5%). All P values were less than .001, except for small for gestational age, which was P = .008.
In addition, significantly more babies of asthmatic women with exacerbated asthma during pregnancy had respiratory problems including asthma and pneumonia, compared with those of asthmatic women who had no exacerbations during pregnancy, at 38% vs. 31% and 24% vs. 22% (P less than .001 for both). The researchers found no significant interactions between maternal age and smoking and asthma exacerbations.
The findings were limited by several factors, including the lack of a validated algorithm for asthma exacerbation, which the researchers defined as five or more visits to a general practice clinician for asthma during pregnancy. Other limitations included the lack of categorizing asthma exacerbation by severity, and the inability to include the potential effects of asthma medication on maternal and fetal outcomes, Dr. Abdullah and colleagues noted.
However, the results were strengthened by the large sample size and ability to follow babies from birth until 5 years of age, they said.
“Targeting women with asthma during pregnancy and ensuring appropriate asthma management and postpartum follow-up may help to reduce the risk of pregnancy complications, adverse perinatal outcomes, and early childhood respiratory disorders,” they concluded.
This study is important because asthma is a common, potentially serious medical condition that complicates approximately 4%-8% of pregnancies, and one in three women with asthma experience an exacerbation during pregnancy, Iris Krishna, MD, a specialist in maternal/fetal medicine at Emory University, Atlanta, said in an interview.
“This study is unique in that it uses population-level data to assess the association between an asthma exacerbation during pregnancy and adverse perinatal outcomes,” Dr. Krishna said. “After adjusting for confounders, and consistent with previous studies, study findings suggest an increased risk for women with asthma who have an asthma exacerbation during pregnancy for preeclampsia [odds ratio, 1.3; P less than .001], pregnancy-induced hypertension [OR, 1.17; P less than .05], low-birth-weight infant [OR, 1.14; P less than .05], preterm birth [OR, 1.14; P less than .05], and congenital malformations [OR, 1.21; P less than .001].”
Dr. Krishna also noted the impact on early childhood outcomes. “In this study, children born to women who had an asthma exacerbation during pregnancy had a 23% higher risk of developing asthma before 5 years of age, which is consistent with previous studies. [The] investigators also reported a 12% higher risk of having pneumonia during the first 5 years of life for children born to women who had an asthma exacerbation during pregnancy.”
“Previous studies have suggested children born to mothers with uncontrolled asthma have an increased risk for respiratory infections, but this study is the first to report an association with pneumonia,” she said. This increased risk for childhood respiratory disorders warrants further study.
Consequently, “Women with asthma during pregnancy should have appropriate management to ensure good control to optimize pregnancy outcome,” Dr. Krishna emphasized. “Women who experience asthma exacerbations in pregnancy are at increased risk for preeclampsia, [pregnancy-induced hypertension], low birth weight, and preterm delivery and may require closer monitoring.”
The study was supported by the Institute for Clinical Evaluative Sciences. The researchers and Dr. Krishna had no financial conflicts to disclose.
SOURCE: Abdullah K et al. Eur Respir J. 2019 Nov 26. doi: 10.1183/13993003.01335-2019.
FROM THE EUROPEAN RESPIRATORY JOURNAL
Do women with diabetes need more CVD risk reduction than men?
BUSAN, SOUTH KOREA – Whether cardiovascular disease risk reduction efforts should be more aggressive in women than men with diabetes depends on how you interpret the data.
Two experts came to different conclusions on this question during a heated, but jovial, debate last week here at the International Diabetes Federation 2019 Congress.
Endocrinologist David Simmons, MB, BChir, Western Sydney University, Campbelltown, Australia, argued that diabetes erases the well-described life expectancy advantage of 4-7 years that women experience over men in the general population.
He also highlighted the fact that the heightened risk is of particular concern in both younger women and those with prior gestational diabetes.
But Timothy Davis, BMedSc, MB, BS, DPhil, an endocrinologist and general physician at Fremantle (Australia) Hospital, countered that the data only show the diabetes-attributable excess cardiovascular risk is higher in women than men, but that the absolute risk is actually greater in men.
Moreover, he argued, at least in type 1 diabetes, there is no evidence that more aggressive cardiovascular risk factor management improves outcomes.
Yes: Diabetes eliminates female CVD protection
Dr. Simmons began by pointing out that, although on average women die at an older age than men, it has been known for over 40 years that this “female protection” is lost in insulin-treated women, particularly as a result of their increased risk for cardiovascular disease.
In a 2015 meta-analysis of 26 studies, women with type 1 diabetes were found to have about a 37% greater risk of all-cause mortality, compared with men with the condition when mortality is contrasted with that of the general population, and twice the risk of both fatal and nonfatal vascular events.
The risk appeared to be greater in women who were younger at the time of diabetes diagnosis. “This is a really important point – the time we would want to intervene,” Dr. Simmons said.
In another meta-analysis of 30 studies including 2,307,694 individuals with type 2 diabetes and 252,491 deaths, the pooled women-to-men ratio of the standardized mortality ratio for all-cause mortality was 1.14.
In those with versus without type 2 diabetes, the pooled standardized mortality ratio in women was 2.30 and in men was 1.94, both significant, compared with those without diabetes.
And in a 2006 meta-analysis of 22 studies involving individuals with type 2 diabetes, the pooled data showed a 46% excess relative risk using standardized mortality ratios in women versus men for fatal coronary artery disease.
Meanwhile, in a 2018 meta-analysis of 68 studies involving nearly 1 million adults examining differences in occlusive vascular disease, after controlling for major vascular risk factors, diabetes roughly doubled the risk for occlusive vascular mortality in men (relative risk, 2.10), but tripled it in women (3.00).
Women with diabetes aged 35-59 years had the highest relative risk for death over follow-up across all age and sex groups: They had 5.5 times the excess risk, compared with those without diabetes, while the excess risk for men of that age was 2.3-fold.
“So very clearly, it’s these young women who are most at risk, “emphasized Dr. Simmons, who is an investigator for Novo Nordisk and a speaker for Medtronic, Novo Nordisk, and Sanofi.
Are disparities because of differences in cvd risk factor management?
The question has arisen whether the female/male differences might be because of differences in cardiovascular risk factor management, Simmons noted.
A 2015 American Heart Association statement laid out the evidence for lower prescribing of statins, aspirin, beta-blockers, and ACE inhibitors in women, compared with men, Dr. Simmons said.
And some studies suggest medication adherence is lower in women than men.
In terms of medications, fenofibrate appears to produce better outcomes in women than men, but there is no evidence of gender differences in the effects of statins, ACE inhibitors, or aspirin, Simmons said.
He also outlined the results of a 2008 study of 78,254 patients with acute myocardial infarction from 420 U.S. hospitals in 2001-2006.
Women were older, had more comorbidities, less often presented with ST-elevation myocardial infarction (STEMI), and had a higher rate of unadjusted in-hospital death (8.2% vs. 5.7%; P less than .0001) than men. Of the participants, 33% of women had diabetes, compared with 28% of men.
The in-hospital mortality difference disappeared after multivariable adjustment, but women with STEMI still had higher adjusted mortality rates than men.
“The underuse of evidence-based treatments and delayed reperfusion in women represent potential opportunities for reducing sex disparities in care and outcome after acute myocardial infarction,” the authors concluded.
“It’s very clear amongst our cardiology colleagues that something needs to be done and that we need more aggressive cardiological risk reduction in women,” Dr. Simmons said.
“The AHA has already decided this. It’s already a policy. So why are we having this debate?” he wondered.
He also pointed out that women with prior gestational diabetes are an exceptionally high–risk group, with a twofold excess risk for cardiovascular disease within the first 10 years post partum.
“We need to do something about this particularly high-risk group, independent of debates about gender,” Dr. Simmons emphasized. “Clearly, women with diabetes warrant more aggressive cardiovascular risk reduction than men with diabetes, especially at those younger ages,” he concluded.
No: Confusion about relative risk within each sex and absolute risk
Dr. Davis began his counterargument by stating that estimation of absolute vascular risk is an established part of strategies to prevent cardiovascular disease, including in diabetes.
And that risk, he stressed, is actually higher in men.
“Male sex is a consistent adverse risk factor in cardiovascular disease event prediction equations in type 2 diabetes. Identifying absolute risk is important,” he said, noting risk calculators include male sex, such as the risk engine derived from the United Kingdom Prospective Diabetes Trial.
And in the Australian population-based Fremantle study, of which Dr. Davis is an author, the absolute 5-year incidence rates for all outcomes – including myocardial infarction, stroke, heart failure, lower extremity amputation, cardiovascular mortality, and all-cause mortality – were consistently higher in men versus women in the first phase, which began in the 1990s and included 1,426 individuals with diabetes (91% had type 2 diabetes).
In the ongoing second phase, which began in 2008 with 1,732 participants, overall rates of those outcomes are lower and the discrepancy between men and women has narrowed, Dr. Davis noted.
Overall, the Fremantle study data “suggest that women with type 2 diabetes do not need more aggressive cardiovascular reduction than men with type 2 diabetes because they are not at increased absolute vascular risk,” he stressed.
And in a “sensitivity analysis” of two areas in Finland, the authors concluded that the stronger effect of type 2 diabetes on the risk of congenital heart disease (CHD) in women, compared with men was in part explained by a heavier risk factor burden and a greater effect of blood pressure and atherogenic dyslipidemia in women with diabetes, he explained.
The Finnish authors wrote, “In terms of absolute risk of CHD death or a major CHD event, diabetes almost completely abolished the female protection from CHD.”
But, Dr. Davis emphasized, rates were not higher in females.
So then, “why is there the view that women with type 2 diabetes need more aggressive cardiovascular risk reduction than men with diabetes?
“It probably comes back to confusion based on absolute risk versus a comparison of relative risk within each sex,” he asserted.
ADA Standards of Medical Care 2019 don’t mention gender
Lastly, in a meta-analysis published just in July this year involving more than 5 million participants, compared with men with diabetes, women with diabetes had a 58% and 13% greater risk of CHD and all-cause mortality, respectively.
“This points to an urgent need to develop sex- and gender-specific risk assessment strategies and therapeutic interventions that target diabetes management in the context of CHD prevention,” the authors concluded.
But, Dr. Davis noted, “It is not absolute vascular risk. It’s a relative risk compared across the two genders. In the paper, there is no mention of absolute vascular risk.
“Greater CVD mortality in women with and without diabetes, versus men, doesn’t mean there’s also an absolute vascular increase in women versus men with diabetes,” he said.
Moreover, Dr. Davis pointed out that in an editorial accompanying the 2015 meta-analysis in type 1 diabetes, Simmons had actually stated that absolute mortality rates are highest in men.
“I don’t know what happened to his epidemiology knowledge in the last 4 years but it seems to have gone backwards,” he joked to his debate opponent.
And, Dr. Davis asserted, even if there were a higher risk in women with type 1 diabetes, there is no evidence that cardiovascular risk reduction measures affect endpoints in that patient population. Only about 8% of people with diabetes in statin trials had type 1 diabetes.
Indeed, he noted, in the American Diabetes Association Standards of Medical Care in Diabetes – 2019, the treatment goals for individual cardiovascular risk factors do not mention gender.
What’s more, Dr. David said, there is evidence that women are significantly less likely than men to take prescribed statins and are more likely to have an eating disorder and underdose insulin, “suggesting significant issues with compliance. ... So, trying to get more intensive risk reduction in women may be a challenge.”
“Women with diabetes do not need more aggressive cardiovascular risk reduction than men with diabetes, irrespective of type,” he concluded.
A version of this story originally appeared on medscape.com.
BUSAN, SOUTH KOREA – Whether cardiovascular disease risk reduction efforts should be more aggressive in women than men with diabetes depends on how you interpret the data.
Two experts came to different conclusions on this question during a heated, but jovial, debate last week here at the International Diabetes Federation 2019 Congress.
Endocrinologist David Simmons, MB, BChir, Western Sydney University, Campbelltown, Australia, argued that diabetes erases the well-described life expectancy advantage of 4-7 years that women experience over men in the general population.
He also highlighted the fact that the heightened risk is of particular concern in both younger women and those with prior gestational diabetes.
But Timothy Davis, BMedSc, MB, BS, DPhil, an endocrinologist and general physician at Fremantle (Australia) Hospital, countered that the data only show the diabetes-attributable excess cardiovascular risk is higher in women than men, but that the absolute risk is actually greater in men.
Moreover, he argued, at least in type 1 diabetes, there is no evidence that more aggressive cardiovascular risk factor management improves outcomes.
Yes: Diabetes eliminates female CVD protection
Dr. Simmons began by pointing out that, although on average women die at an older age than men, it has been known for over 40 years that this “female protection” is lost in insulin-treated women, particularly as a result of their increased risk for cardiovascular disease.
In a 2015 meta-analysis of 26 studies, women with type 1 diabetes were found to have about a 37% greater risk of all-cause mortality, compared with men with the condition when mortality is contrasted with that of the general population, and twice the risk of both fatal and nonfatal vascular events.
The risk appeared to be greater in women who were younger at the time of diabetes diagnosis. “This is a really important point – the time we would want to intervene,” Dr. Simmons said.
In another meta-analysis of 30 studies including 2,307,694 individuals with type 2 diabetes and 252,491 deaths, the pooled women-to-men ratio of the standardized mortality ratio for all-cause mortality was 1.14.
In those with versus without type 2 diabetes, the pooled standardized mortality ratio in women was 2.30 and in men was 1.94, both significant, compared with those without diabetes.
And in a 2006 meta-analysis of 22 studies involving individuals with type 2 diabetes, the pooled data showed a 46% excess relative risk using standardized mortality ratios in women versus men for fatal coronary artery disease.
Meanwhile, in a 2018 meta-analysis of 68 studies involving nearly 1 million adults examining differences in occlusive vascular disease, after controlling for major vascular risk factors, diabetes roughly doubled the risk for occlusive vascular mortality in men (relative risk, 2.10), but tripled it in women (3.00).
Women with diabetes aged 35-59 years had the highest relative risk for death over follow-up across all age and sex groups: They had 5.5 times the excess risk, compared with those without diabetes, while the excess risk for men of that age was 2.3-fold.
“So very clearly, it’s these young women who are most at risk, “emphasized Dr. Simmons, who is an investigator for Novo Nordisk and a speaker for Medtronic, Novo Nordisk, and Sanofi.
Are disparities because of differences in cvd risk factor management?
The question has arisen whether the female/male differences might be because of differences in cardiovascular risk factor management, Simmons noted.
A 2015 American Heart Association statement laid out the evidence for lower prescribing of statins, aspirin, beta-blockers, and ACE inhibitors in women, compared with men, Dr. Simmons said.
And some studies suggest medication adherence is lower in women than men.
In terms of medications, fenofibrate appears to produce better outcomes in women than men, but there is no evidence of gender differences in the effects of statins, ACE inhibitors, or aspirin, Simmons said.
He also outlined the results of a 2008 study of 78,254 patients with acute myocardial infarction from 420 U.S. hospitals in 2001-2006.
Women were older, had more comorbidities, less often presented with ST-elevation myocardial infarction (STEMI), and had a higher rate of unadjusted in-hospital death (8.2% vs. 5.7%; P less than .0001) than men. Of the participants, 33% of women had diabetes, compared with 28% of men.
The in-hospital mortality difference disappeared after multivariable adjustment, but women with STEMI still had higher adjusted mortality rates than men.
“The underuse of evidence-based treatments and delayed reperfusion in women represent potential opportunities for reducing sex disparities in care and outcome after acute myocardial infarction,” the authors concluded.
“It’s very clear amongst our cardiology colleagues that something needs to be done and that we need more aggressive cardiological risk reduction in women,” Dr. Simmons said.
“The AHA has already decided this. It’s already a policy. So why are we having this debate?” he wondered.
He also pointed out that women with prior gestational diabetes are an exceptionally high–risk group, with a twofold excess risk for cardiovascular disease within the first 10 years post partum.
“We need to do something about this particularly high-risk group, independent of debates about gender,” Dr. Simmons emphasized. “Clearly, women with diabetes warrant more aggressive cardiovascular risk reduction than men with diabetes, especially at those younger ages,” he concluded.
No: Confusion about relative risk within each sex and absolute risk
Dr. Davis began his counterargument by stating that estimation of absolute vascular risk is an established part of strategies to prevent cardiovascular disease, including in diabetes.
And that risk, he stressed, is actually higher in men.
“Male sex is a consistent adverse risk factor in cardiovascular disease event prediction equations in type 2 diabetes. Identifying absolute risk is important,” he said, noting risk calculators include male sex, such as the risk engine derived from the United Kingdom Prospective Diabetes Trial.
And in the Australian population-based Fremantle study, of which Dr. Davis is an author, the absolute 5-year incidence rates for all outcomes – including myocardial infarction, stroke, heart failure, lower extremity amputation, cardiovascular mortality, and all-cause mortality – were consistently higher in men versus women in the first phase, which began in the 1990s and included 1,426 individuals with diabetes (91% had type 2 diabetes).
In the ongoing second phase, which began in 2008 with 1,732 participants, overall rates of those outcomes are lower and the discrepancy between men and women has narrowed, Dr. Davis noted.
Overall, the Fremantle study data “suggest that women with type 2 diabetes do not need more aggressive cardiovascular reduction than men with type 2 diabetes because they are not at increased absolute vascular risk,” he stressed.
And in a “sensitivity analysis” of two areas in Finland, the authors concluded that the stronger effect of type 2 diabetes on the risk of congenital heart disease (CHD) in women, compared with men was in part explained by a heavier risk factor burden and a greater effect of blood pressure and atherogenic dyslipidemia in women with diabetes, he explained.
The Finnish authors wrote, “In terms of absolute risk of CHD death or a major CHD event, diabetes almost completely abolished the female protection from CHD.”
But, Dr. Davis emphasized, rates were not higher in females.
So then, “why is there the view that women with type 2 diabetes need more aggressive cardiovascular risk reduction than men with diabetes?
“It probably comes back to confusion based on absolute risk versus a comparison of relative risk within each sex,” he asserted.
ADA Standards of Medical Care 2019 don’t mention gender
Lastly, in a meta-analysis published just in July this year involving more than 5 million participants, compared with men with diabetes, women with diabetes had a 58% and 13% greater risk of CHD and all-cause mortality, respectively.
“This points to an urgent need to develop sex- and gender-specific risk assessment strategies and therapeutic interventions that target diabetes management in the context of CHD prevention,” the authors concluded.
But, Dr. Davis noted, “It is not absolute vascular risk. It’s a relative risk compared across the two genders. In the paper, there is no mention of absolute vascular risk.
“Greater CVD mortality in women with and without diabetes, versus men, doesn’t mean there’s also an absolute vascular increase in women versus men with diabetes,” he said.
Moreover, Dr. Davis pointed out that in an editorial accompanying the 2015 meta-analysis in type 1 diabetes, Simmons had actually stated that absolute mortality rates are highest in men.
“I don’t know what happened to his epidemiology knowledge in the last 4 years but it seems to have gone backwards,” he joked to his debate opponent.
And, Dr. Davis asserted, even if there were a higher risk in women with type 1 diabetes, there is no evidence that cardiovascular risk reduction measures affect endpoints in that patient population. Only about 8% of people with diabetes in statin trials had type 1 diabetes.
Indeed, he noted, in the American Diabetes Association Standards of Medical Care in Diabetes – 2019, the treatment goals for individual cardiovascular risk factors do not mention gender.
What’s more, Dr. David said, there is evidence that women are significantly less likely than men to take prescribed statins and are more likely to have an eating disorder and underdose insulin, “suggesting significant issues with compliance. ... So, trying to get more intensive risk reduction in women may be a challenge.”
“Women with diabetes do not need more aggressive cardiovascular risk reduction than men with diabetes, irrespective of type,” he concluded.
A version of this story originally appeared on medscape.com.
BUSAN, SOUTH KOREA – Whether cardiovascular disease risk reduction efforts should be more aggressive in women than men with diabetes depends on how you interpret the data.
Two experts came to different conclusions on this question during a heated, but jovial, debate last week here at the International Diabetes Federation 2019 Congress.
Endocrinologist David Simmons, MB, BChir, Western Sydney University, Campbelltown, Australia, argued that diabetes erases the well-described life expectancy advantage of 4-7 years that women experience over men in the general population.
He also highlighted the fact that the heightened risk is of particular concern in both younger women and those with prior gestational diabetes.
But Timothy Davis, BMedSc, MB, BS, DPhil, an endocrinologist and general physician at Fremantle (Australia) Hospital, countered that the data only show the diabetes-attributable excess cardiovascular risk is higher in women than men, but that the absolute risk is actually greater in men.
Moreover, he argued, at least in type 1 diabetes, there is no evidence that more aggressive cardiovascular risk factor management improves outcomes.
Yes: Diabetes eliminates female CVD protection
Dr. Simmons began by pointing out that, although on average women die at an older age than men, it has been known for over 40 years that this “female protection” is lost in insulin-treated women, particularly as a result of their increased risk for cardiovascular disease.
In a 2015 meta-analysis of 26 studies, women with type 1 diabetes were found to have about a 37% greater risk of all-cause mortality, compared with men with the condition when mortality is contrasted with that of the general population, and twice the risk of both fatal and nonfatal vascular events.
The risk appeared to be greater in women who were younger at the time of diabetes diagnosis. “This is a really important point – the time we would want to intervene,” Dr. Simmons said.
In another meta-analysis of 30 studies including 2,307,694 individuals with type 2 diabetes and 252,491 deaths, the pooled women-to-men ratio of the standardized mortality ratio for all-cause mortality was 1.14.
In those with versus without type 2 diabetes, the pooled standardized mortality ratio in women was 2.30 and in men was 1.94, both significant, compared with those without diabetes.
And in a 2006 meta-analysis of 22 studies involving individuals with type 2 diabetes, the pooled data showed a 46% excess relative risk using standardized mortality ratios in women versus men for fatal coronary artery disease.
Meanwhile, in a 2018 meta-analysis of 68 studies involving nearly 1 million adults examining differences in occlusive vascular disease, after controlling for major vascular risk factors, diabetes roughly doubled the risk for occlusive vascular mortality in men (relative risk, 2.10), but tripled it in women (3.00).
Women with diabetes aged 35-59 years had the highest relative risk for death over follow-up across all age and sex groups: They had 5.5 times the excess risk, compared with those without diabetes, while the excess risk for men of that age was 2.3-fold.
“So very clearly, it’s these young women who are most at risk, “emphasized Dr. Simmons, who is an investigator for Novo Nordisk and a speaker for Medtronic, Novo Nordisk, and Sanofi.
Are disparities because of differences in cvd risk factor management?
The question has arisen whether the female/male differences might be because of differences in cardiovascular risk factor management, Simmons noted.
A 2015 American Heart Association statement laid out the evidence for lower prescribing of statins, aspirin, beta-blockers, and ACE inhibitors in women, compared with men, Dr. Simmons said.
And some studies suggest medication adherence is lower in women than men.
In terms of medications, fenofibrate appears to produce better outcomes in women than men, but there is no evidence of gender differences in the effects of statins, ACE inhibitors, or aspirin, Simmons said.
He also outlined the results of a 2008 study of 78,254 patients with acute myocardial infarction from 420 U.S. hospitals in 2001-2006.
Women were older, had more comorbidities, less often presented with ST-elevation myocardial infarction (STEMI), and had a higher rate of unadjusted in-hospital death (8.2% vs. 5.7%; P less than .0001) than men. Of the participants, 33% of women had diabetes, compared with 28% of men.
The in-hospital mortality difference disappeared after multivariable adjustment, but women with STEMI still had higher adjusted mortality rates than men.
“The underuse of evidence-based treatments and delayed reperfusion in women represent potential opportunities for reducing sex disparities in care and outcome after acute myocardial infarction,” the authors concluded.
“It’s very clear amongst our cardiology colleagues that something needs to be done and that we need more aggressive cardiological risk reduction in women,” Dr. Simmons said.
“The AHA has already decided this. It’s already a policy. So why are we having this debate?” he wondered.
He also pointed out that women with prior gestational diabetes are an exceptionally high–risk group, with a twofold excess risk for cardiovascular disease within the first 10 years post partum.
“We need to do something about this particularly high-risk group, independent of debates about gender,” Dr. Simmons emphasized. “Clearly, women with diabetes warrant more aggressive cardiovascular risk reduction than men with diabetes, especially at those younger ages,” he concluded.
No: Confusion about relative risk within each sex and absolute risk
Dr. Davis began his counterargument by stating that estimation of absolute vascular risk is an established part of strategies to prevent cardiovascular disease, including in diabetes.
And that risk, he stressed, is actually higher in men.
“Male sex is a consistent adverse risk factor in cardiovascular disease event prediction equations in type 2 diabetes. Identifying absolute risk is important,” he said, noting risk calculators include male sex, such as the risk engine derived from the United Kingdom Prospective Diabetes Trial.
And in the Australian population-based Fremantle study, of which Dr. Davis is an author, the absolute 5-year incidence rates for all outcomes – including myocardial infarction, stroke, heart failure, lower extremity amputation, cardiovascular mortality, and all-cause mortality – were consistently higher in men versus women in the first phase, which began in the 1990s and included 1,426 individuals with diabetes (91% had type 2 diabetes).
In the ongoing second phase, which began in 2008 with 1,732 participants, overall rates of those outcomes are lower and the discrepancy between men and women has narrowed, Dr. Davis noted.
Overall, the Fremantle study data “suggest that women with type 2 diabetes do not need more aggressive cardiovascular reduction than men with type 2 diabetes because they are not at increased absolute vascular risk,” he stressed.
And in a “sensitivity analysis” of two areas in Finland, the authors concluded that the stronger effect of type 2 diabetes on the risk of congenital heart disease (CHD) in women, compared with men was in part explained by a heavier risk factor burden and a greater effect of blood pressure and atherogenic dyslipidemia in women with diabetes, he explained.
The Finnish authors wrote, “In terms of absolute risk of CHD death or a major CHD event, diabetes almost completely abolished the female protection from CHD.”
But, Dr. Davis emphasized, rates were not higher in females.
So then, “why is there the view that women with type 2 diabetes need more aggressive cardiovascular risk reduction than men with diabetes?
“It probably comes back to confusion based on absolute risk versus a comparison of relative risk within each sex,” he asserted.
ADA Standards of Medical Care 2019 don’t mention gender
Lastly, in a meta-analysis published just in July this year involving more than 5 million participants, compared with men with diabetes, women with diabetes had a 58% and 13% greater risk of CHD and all-cause mortality, respectively.
“This points to an urgent need to develop sex- and gender-specific risk assessment strategies and therapeutic interventions that target diabetes management in the context of CHD prevention,” the authors concluded.
But, Dr. Davis noted, “It is not absolute vascular risk. It’s a relative risk compared across the two genders. In the paper, there is no mention of absolute vascular risk.
“Greater CVD mortality in women with and without diabetes, versus men, doesn’t mean there’s also an absolute vascular increase in women versus men with diabetes,” he said.
Moreover, Dr. Davis pointed out that in an editorial accompanying the 2015 meta-analysis in type 1 diabetes, Simmons had actually stated that absolute mortality rates are highest in men.
“I don’t know what happened to his epidemiology knowledge in the last 4 years but it seems to have gone backwards,” he joked to his debate opponent.
And, Dr. Davis asserted, even if there were a higher risk in women with type 1 diabetes, there is no evidence that cardiovascular risk reduction measures affect endpoints in that patient population. Only about 8% of people with diabetes in statin trials had type 1 diabetes.
Indeed, he noted, in the American Diabetes Association Standards of Medical Care in Diabetes – 2019, the treatment goals for individual cardiovascular risk factors do not mention gender.
What’s more, Dr. David said, there is evidence that women are significantly less likely than men to take prescribed statins and are more likely to have an eating disorder and underdose insulin, “suggesting significant issues with compliance. ... So, trying to get more intensive risk reduction in women may be a challenge.”
“Women with diabetes do not need more aggressive cardiovascular risk reduction than men with diabetes, irrespective of type,” he concluded.
A version of this story originally appeared on medscape.com.
Reduced kidney function linked to fractures in older women
Moderate reductions in kidney function in older women are associated with an increased short-term risk of fractures, according to a study published in Osteoporosis International.
However, the longitudinal, population-based cohort study did not find an association with fracture risk either in women older than 80 years or in those with worse kidney function.
“Since the kidneys regulate homeostasis of PTH [parathyroid hormone], phosphate, calcium, and vitamin D, any disruption in function can be expected to disturb bone remodeling and have implications for skeletal health,” wrote Linnea Malmgren, MD, and colleagues from Skåne University Hospital in Malmö, Sweden.
Previous studies have found that a large proportion of older women have reduced kidney function equivalent to a diagnosis of chronic kidney disease and that it is associated with bone loss. However, there have been few studies exploring that association in a population without a diagnosis of chronic kidney disease.
In their study, Dr. Malmgren and colleagues followed 981 women aged 75 years and 685 women aged 80 years, who underwent assessment of kidney function and bone mineral density and were followed up for fracture.
They found that women who experienced an osteoporotic fracture between the ages of 75 and 80 years had significantly lower baseline kidney function, compared with those who did not experience a fracture.
Compared with women with normal kidney function at age 75, women with intermediate kidney function (estimated glomerular filtration rate 45-59 mL/min per 1.73m2) had a significant 2.21-fold higher risk of osteoporotic fracture within 2 years, a 1.51-fold higher risk up to 5 years, and an elevated risk of hip fracture.
A similar trend was seen in women with poor kidney function (eGFR less than 45 mL/min per 1.73m2), but it was not statistically significant.
The analysis also found that kidney function at age 80 years was not significantly associated with long-term fracture risk, nor was there a significant association for 10-year fracture risk in those aged 75 years.
Reduced kidney function was also associated with a higher fracture risk even in women without osteoporosis.
“As expected, fracture risk was high among those with osteoporosis, but risk seemed to further increase in women with both osteoporosis and reduced kidney function, compared with those with osteoporosis and normal function,” the authors reported.
“These findings indicate that implications for bone health and fracture risk might occur in the very common modest reduction of kidney function in the elderly, and also possibly before a diagnosis of CKD-MBD [chronic kidney disease–mineral and bone disorder].”
The study was supported by Lund University; the Swedish Research Council; Forte, Greta and Johan Kock Foundation; A. Påhlsson Foundation; A. Osterlund Foundation; H Järnhardt Foundation; King Gustav V 80-year Fund; Thelma Zoegas Foundation; Swedish Rheumatism Foundation; Skåne University Hospital Research Fund; and the Research and Development Council of Region Skåne, Sweden. No conflicts of interest were declared.
SOURCE: Malmgren L et al. Osteoporos Int. 2019 Nov 21. doi: 10.1007/s00198-019-05152-x.
Moderate reductions in kidney function in older women are associated with an increased short-term risk of fractures, according to a study published in Osteoporosis International.
However, the longitudinal, population-based cohort study did not find an association with fracture risk either in women older than 80 years or in those with worse kidney function.
“Since the kidneys regulate homeostasis of PTH [parathyroid hormone], phosphate, calcium, and vitamin D, any disruption in function can be expected to disturb bone remodeling and have implications for skeletal health,” wrote Linnea Malmgren, MD, and colleagues from Skåne University Hospital in Malmö, Sweden.
Previous studies have found that a large proportion of older women have reduced kidney function equivalent to a diagnosis of chronic kidney disease and that it is associated with bone loss. However, there have been few studies exploring that association in a population without a diagnosis of chronic kidney disease.
In their study, Dr. Malmgren and colleagues followed 981 women aged 75 years and 685 women aged 80 years, who underwent assessment of kidney function and bone mineral density and were followed up for fracture.
They found that women who experienced an osteoporotic fracture between the ages of 75 and 80 years had significantly lower baseline kidney function, compared with those who did not experience a fracture.
Compared with women with normal kidney function at age 75, women with intermediate kidney function (estimated glomerular filtration rate 45-59 mL/min per 1.73m2) had a significant 2.21-fold higher risk of osteoporotic fracture within 2 years, a 1.51-fold higher risk up to 5 years, and an elevated risk of hip fracture.
A similar trend was seen in women with poor kidney function (eGFR less than 45 mL/min per 1.73m2), but it was not statistically significant.
The analysis also found that kidney function at age 80 years was not significantly associated with long-term fracture risk, nor was there a significant association for 10-year fracture risk in those aged 75 years.
Reduced kidney function was also associated with a higher fracture risk even in women without osteoporosis.
“As expected, fracture risk was high among those with osteoporosis, but risk seemed to further increase in women with both osteoporosis and reduced kidney function, compared with those with osteoporosis and normal function,” the authors reported.
“These findings indicate that implications for bone health and fracture risk might occur in the very common modest reduction of kidney function in the elderly, and also possibly before a diagnosis of CKD-MBD [chronic kidney disease–mineral and bone disorder].”
The study was supported by Lund University; the Swedish Research Council; Forte, Greta and Johan Kock Foundation; A. Påhlsson Foundation; A. Osterlund Foundation; H Järnhardt Foundation; King Gustav V 80-year Fund; Thelma Zoegas Foundation; Swedish Rheumatism Foundation; Skåne University Hospital Research Fund; and the Research and Development Council of Region Skåne, Sweden. No conflicts of interest were declared.
SOURCE: Malmgren L et al. Osteoporos Int. 2019 Nov 21. doi: 10.1007/s00198-019-05152-x.
Moderate reductions in kidney function in older women are associated with an increased short-term risk of fractures, according to a study published in Osteoporosis International.
However, the longitudinal, population-based cohort study did not find an association with fracture risk either in women older than 80 years or in those with worse kidney function.
“Since the kidneys regulate homeostasis of PTH [parathyroid hormone], phosphate, calcium, and vitamin D, any disruption in function can be expected to disturb bone remodeling and have implications for skeletal health,” wrote Linnea Malmgren, MD, and colleagues from Skåne University Hospital in Malmö, Sweden.
Previous studies have found that a large proportion of older women have reduced kidney function equivalent to a diagnosis of chronic kidney disease and that it is associated with bone loss. However, there have been few studies exploring that association in a population without a diagnosis of chronic kidney disease.
In their study, Dr. Malmgren and colleagues followed 981 women aged 75 years and 685 women aged 80 years, who underwent assessment of kidney function and bone mineral density and were followed up for fracture.
They found that women who experienced an osteoporotic fracture between the ages of 75 and 80 years had significantly lower baseline kidney function, compared with those who did not experience a fracture.
Compared with women with normal kidney function at age 75, women with intermediate kidney function (estimated glomerular filtration rate 45-59 mL/min per 1.73m2) had a significant 2.21-fold higher risk of osteoporotic fracture within 2 years, a 1.51-fold higher risk up to 5 years, and an elevated risk of hip fracture.
A similar trend was seen in women with poor kidney function (eGFR less than 45 mL/min per 1.73m2), but it was not statistically significant.
The analysis also found that kidney function at age 80 years was not significantly associated with long-term fracture risk, nor was there a significant association for 10-year fracture risk in those aged 75 years.
Reduced kidney function was also associated with a higher fracture risk even in women without osteoporosis.
“As expected, fracture risk was high among those with osteoporosis, but risk seemed to further increase in women with both osteoporosis and reduced kidney function, compared with those with osteoporosis and normal function,” the authors reported.
“These findings indicate that implications for bone health and fracture risk might occur in the very common modest reduction of kidney function in the elderly, and also possibly before a diagnosis of CKD-MBD [chronic kidney disease–mineral and bone disorder].”
The study was supported by Lund University; the Swedish Research Council; Forte, Greta and Johan Kock Foundation; A. Påhlsson Foundation; A. Osterlund Foundation; H Järnhardt Foundation; King Gustav V 80-year Fund; Thelma Zoegas Foundation; Swedish Rheumatism Foundation; Skåne University Hospital Research Fund; and the Research and Development Council of Region Skåne, Sweden. No conflicts of interest were declared.
SOURCE: Malmgren L et al. Osteoporos Int. 2019 Nov 21. doi: 10.1007/s00198-019-05152-x.
FROM OSTEOPOROSIS INTERNATIONAL
Consider Ovarian Cancer as a Differential Diagnosis
This year in the United States, there were an estimated 22,530 new cases of ovarian cancer and an estimated 13,980 ovarian cancer deaths.1 Ovarian cancer accounts for more deaths than any other female reproductive system cancer.2 The high mortality rate is attributed to the advanced stage of cancer at initial presentation: Women diagnosed with localized disease have an estimated 5-year survival rate of 92%, while those diagnosed with advanced disease have a 5-year survival rate of 29%.3 For this reason, early detection of ovarian cancer is paramount.
A Personal Story
I think about ovarian cancer every day, because I am a survivor of this deadly disease. In 2018, at age 53, I received the diagnosis of stage 1A high-grade serous carcinoma of the left ovary. My cancer was discovered incidentally: I presented to my health care provider with a 6-month history of metrorrhagia and a prior history of regular menstruation with dysmenorrhea controlled with ibuprofen. My family and personal history of cancer was negative, I had a normal BMI, I didn’t smoke and consumed alcohol only moderately, my lifestyle was active, and I had no chronic diseases and used no medications regularly. My clinician performed a pelvic exam and ordered sexually transmitted infection testing and blood work (complete blood count, metabolic panel, and TSH). The differential diagnosis at this point included
- Thyroid dysfunction
- Perimenopause
- Sexually transmitted infection
- Coagulation defect
- Foreign body
- Infection.
All testing yielded normal findings. At my follow-up appointment, we discussed perimenopause symptoms and agreed that I would continue monitoring the bleeding. If at a later date I wanted to pursue an ultrasound, I was instructed to call the office. It was not suggested that I schedule a follow-up office visit.
Several months later, persistent metrorrhagia prompted me to request a transvaginal ultrasound (TVU)—resulting in the discovery of a left adnexal solid mass and probable endometrial polyp. A referral to a gynecologic oncologist resulted in further imaging, which confirmed the TVU results. Surgical intervention was recommended.
One week later, I underwent robotic-assisted total laparoscopic hysterectomy, bilateral salpingo-oophorectomy, left pelvic and periaortic lymph node dissection, and omentectomy. The pathology report confirmed stage 1A high-grade serous carcinoma of the left ovary, as well as stage 1A grade 1 endometrioid adenocarcinoma of the uterus. I required 6 cycles of chemotherapy before follow-up imaging yielded negative results, with no evidence of metastatic disease.
A Call to Action
The recently updated US Preventive Services Task Force guidelines continue not to recommend annual screening with TVU and/or cancer antigen 125 (CA-125) blood testing for ovarian cancer in asymptomatic, average-risk women. A review of the evidence found no mortality benefit and high false-positive rates, which led to unnecessary surgeries and physiologic stress due to excess cancer worry.4 This (lack of) recommendation leaves the clinician in the position of not performing or ordering screening tests, except in cases in which the patient presents with symptoms or requests screening for ovarian cancer.
Yet it cannot be overstated: The clinician’s role in identifying risk factors for and recognizing symptoms of ovarian cancer is extremely important in the absence of routine screening recommendations. Risk factors include a positive family history of gynecologic, breast, or colon cancers; genetic predisposition; personal history of breast cancer; use of menopausal hormone therapy; excess body weight; smoking; and sedentary lifestyle.3 In my case, my risk for ovarian cancer was average.
Continue to: With regard to symptoms...
With regard to symptoms, most women do not report any until ovarian cancer has reached advanced stages—and even then, the symptoms are vague and nonspecific.5 They may include urinary urgency or frequency; change in bowel habit; difficulty eating or feeling full quickly; persistent back, pelvic, or abdominal pain; extreme tiredness; vaginal bleeding after menopause; increased abdominal size; or bloating on most days.5
So what can we as clinicians do? First, if I may offer a word of caution: When confronted with those vague and nonspecific symptoms, be careful not to dismiss them out of hand as a result of aging, stress, or menopause. As my case demonstrates, for example, metrorrhagia is not necessarily a benign condition for the premenopausal woman.
Furthermore, we can empower patients by educating them about ovarian cancer symptoms and risk factors, information that may promote help-seeking behaviors that aid in early detection. In my case, the continued symptom of abnormal uterine bleeding prompted me to seek further assessment, which led to the discovery of ovarian cancer. Had I not been an educated and empowered patient, I would be telling a completely different story today—most likely one that would include advanced staging. Partner with your patient to discuss available diagnostic testing options and schedule follow-up appointments to monitor presenting complaints.
We also need to partner with our oncology colleagues and researchers. A positive diagnostic test result for possible malignancy necessitates referral to a gynecologic oncologist. Treatment by specialists in high-volume hospitals results in improved ovarian cancer outcomes.6 And we should advocate for continued research to support the discovery of an efficient population screening protocol for this deadly disease.
Finally, and perhaps most radically, I encourage you not to take a watch-and-wait approach in these situations. Ultrasounds are inexpensive, have low mortality risk, and achieve high sensitivity and specificity in detecting and managing adnexal abnormalities.7 In my opinion, the endorsement of TVU testing in this clinical situation is a proactive, prudent, and reasonable action compared with watching and waiting, and it may result in early detection as opposed to advanced disease.
Continue to: I hope that...
I hope that sharing my personal experience with ovarian cancer will compel health care providers to consider this disease as a differential diagnosis and perform appropriate testing when average-risk patients present with nonspecific symptoms. Ultimately, our collective goal should be to increase the survival rate and reduce the suffering associated with ovarian cancer.
1. National Cancer Institute. Cancer Stat Facts: Ovarian Cancer. https://seer.cancer.gov/statfacts/html/ovary.html. Accessed December 3, 2019.
2. American Cancer Society. Key Statistics for Ovarian Cancer. Revised January 8, 2019. www.cancer.org/cancer/ovarian-cancer/about/key-statistics.html. Accessed December 3, 2019.
3. American Cancer Society. Cancer Facts & Figures 2019. www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2019/cancer-facts-and-figures-2019.pdf . Accessed December 4, 2019.
4. Grossman DC, Surry SJ, Owens DK, et al. Screening for ovarian cancer: US Preventive Services Task Force Recommendation Statement. JAMA. 2018;319(6):588-594.
5. Smits S, Boivin J, Menon U, Brain K. Influences on anticipated time to ovarian cancer symptom presentation in women at increased risk compared to population risk of ovarian cancer. BMC Cancer. 2017;17(814):1-11.
6. Pavlik EJ. Ten important considerations for ovarian cancer screening. Diagnostics. 2017;7(22):1-11.
7. Ormsby EL, Pavlik EJ, McGahan JP. Ultrasound monitoring of extant adnexal masses in the era of type 1 and type 2 ovarian cancers: lessons learned from ovarian cancer screening trials. Diagnostics. 2017;7(25):1-19.
Yvonne L. Chapman is with Kalamazoo Valley Community College in Michigan.
Yvonne L. Chapman is with Kalamazoo Valley Community College in Michigan.
Yvonne L. Chapman is with Kalamazoo Valley Community College in Michigan.
This year in the United States, there were an estimated 22,530 new cases of ovarian cancer and an estimated 13,980 ovarian cancer deaths.1 Ovarian cancer accounts for more deaths than any other female reproductive system cancer.2 The high mortality rate is attributed to the advanced stage of cancer at initial presentation: Women diagnosed with localized disease have an estimated 5-year survival rate of 92%, while those diagnosed with advanced disease have a 5-year survival rate of 29%.3 For this reason, early detection of ovarian cancer is paramount.
A Personal Story
I think about ovarian cancer every day, because I am a survivor of this deadly disease. In 2018, at age 53, I received the diagnosis of stage 1A high-grade serous carcinoma of the left ovary. My cancer was discovered incidentally: I presented to my health care provider with a 6-month history of metrorrhagia and a prior history of regular menstruation with dysmenorrhea controlled with ibuprofen. My family and personal history of cancer was negative, I had a normal BMI, I didn’t smoke and consumed alcohol only moderately, my lifestyle was active, and I had no chronic diseases and used no medications regularly. My clinician performed a pelvic exam and ordered sexually transmitted infection testing and blood work (complete blood count, metabolic panel, and TSH). The differential diagnosis at this point included
- Thyroid dysfunction
- Perimenopause
- Sexually transmitted infection
- Coagulation defect
- Foreign body
- Infection.
All testing yielded normal findings. At my follow-up appointment, we discussed perimenopause symptoms and agreed that I would continue monitoring the bleeding. If at a later date I wanted to pursue an ultrasound, I was instructed to call the office. It was not suggested that I schedule a follow-up office visit.
Several months later, persistent metrorrhagia prompted me to request a transvaginal ultrasound (TVU)—resulting in the discovery of a left adnexal solid mass and probable endometrial polyp. A referral to a gynecologic oncologist resulted in further imaging, which confirmed the TVU results. Surgical intervention was recommended.
One week later, I underwent robotic-assisted total laparoscopic hysterectomy, bilateral salpingo-oophorectomy, left pelvic and periaortic lymph node dissection, and omentectomy. The pathology report confirmed stage 1A high-grade serous carcinoma of the left ovary, as well as stage 1A grade 1 endometrioid adenocarcinoma of the uterus. I required 6 cycles of chemotherapy before follow-up imaging yielded negative results, with no evidence of metastatic disease.
A Call to Action
The recently updated US Preventive Services Task Force guidelines continue not to recommend annual screening with TVU and/or cancer antigen 125 (CA-125) blood testing for ovarian cancer in asymptomatic, average-risk women. A review of the evidence found no mortality benefit and high false-positive rates, which led to unnecessary surgeries and physiologic stress due to excess cancer worry.4 This (lack of) recommendation leaves the clinician in the position of not performing or ordering screening tests, except in cases in which the patient presents with symptoms or requests screening for ovarian cancer.
Yet it cannot be overstated: The clinician’s role in identifying risk factors for and recognizing symptoms of ovarian cancer is extremely important in the absence of routine screening recommendations. Risk factors include a positive family history of gynecologic, breast, or colon cancers; genetic predisposition; personal history of breast cancer; use of menopausal hormone therapy; excess body weight; smoking; and sedentary lifestyle.3 In my case, my risk for ovarian cancer was average.
Continue to: With regard to symptoms...
With regard to symptoms, most women do not report any until ovarian cancer has reached advanced stages—and even then, the symptoms are vague and nonspecific.5 They may include urinary urgency or frequency; change in bowel habit; difficulty eating or feeling full quickly; persistent back, pelvic, or abdominal pain; extreme tiredness; vaginal bleeding after menopause; increased abdominal size; or bloating on most days.5
So what can we as clinicians do? First, if I may offer a word of caution: When confronted with those vague and nonspecific symptoms, be careful not to dismiss them out of hand as a result of aging, stress, or menopause. As my case demonstrates, for example, metrorrhagia is not necessarily a benign condition for the premenopausal woman.
Furthermore, we can empower patients by educating them about ovarian cancer symptoms and risk factors, information that may promote help-seeking behaviors that aid in early detection. In my case, the continued symptom of abnormal uterine bleeding prompted me to seek further assessment, which led to the discovery of ovarian cancer. Had I not been an educated and empowered patient, I would be telling a completely different story today—most likely one that would include advanced staging. Partner with your patient to discuss available diagnostic testing options and schedule follow-up appointments to monitor presenting complaints.
We also need to partner with our oncology colleagues and researchers. A positive diagnostic test result for possible malignancy necessitates referral to a gynecologic oncologist. Treatment by specialists in high-volume hospitals results in improved ovarian cancer outcomes.6 And we should advocate for continued research to support the discovery of an efficient population screening protocol for this deadly disease.
Finally, and perhaps most radically, I encourage you not to take a watch-and-wait approach in these situations. Ultrasounds are inexpensive, have low mortality risk, and achieve high sensitivity and specificity in detecting and managing adnexal abnormalities.7 In my opinion, the endorsement of TVU testing in this clinical situation is a proactive, prudent, and reasonable action compared with watching and waiting, and it may result in early detection as opposed to advanced disease.
Continue to: I hope that...
I hope that sharing my personal experience with ovarian cancer will compel health care providers to consider this disease as a differential diagnosis and perform appropriate testing when average-risk patients present with nonspecific symptoms. Ultimately, our collective goal should be to increase the survival rate and reduce the suffering associated with ovarian cancer.
This year in the United States, there were an estimated 22,530 new cases of ovarian cancer and an estimated 13,980 ovarian cancer deaths.1 Ovarian cancer accounts for more deaths than any other female reproductive system cancer.2 The high mortality rate is attributed to the advanced stage of cancer at initial presentation: Women diagnosed with localized disease have an estimated 5-year survival rate of 92%, while those diagnosed with advanced disease have a 5-year survival rate of 29%.3 For this reason, early detection of ovarian cancer is paramount.
A Personal Story
I think about ovarian cancer every day, because I am a survivor of this deadly disease. In 2018, at age 53, I received the diagnosis of stage 1A high-grade serous carcinoma of the left ovary. My cancer was discovered incidentally: I presented to my health care provider with a 6-month history of metrorrhagia and a prior history of regular menstruation with dysmenorrhea controlled with ibuprofen. My family and personal history of cancer was negative, I had a normal BMI, I didn’t smoke and consumed alcohol only moderately, my lifestyle was active, and I had no chronic diseases and used no medications regularly. My clinician performed a pelvic exam and ordered sexually transmitted infection testing and blood work (complete blood count, metabolic panel, and TSH). The differential diagnosis at this point included
- Thyroid dysfunction
- Perimenopause
- Sexually transmitted infection
- Coagulation defect
- Foreign body
- Infection.
All testing yielded normal findings. At my follow-up appointment, we discussed perimenopause symptoms and agreed that I would continue monitoring the bleeding. If at a later date I wanted to pursue an ultrasound, I was instructed to call the office. It was not suggested that I schedule a follow-up office visit.
Several months later, persistent metrorrhagia prompted me to request a transvaginal ultrasound (TVU)—resulting in the discovery of a left adnexal solid mass and probable endometrial polyp. A referral to a gynecologic oncologist resulted in further imaging, which confirmed the TVU results. Surgical intervention was recommended.
One week later, I underwent robotic-assisted total laparoscopic hysterectomy, bilateral salpingo-oophorectomy, left pelvic and periaortic lymph node dissection, and omentectomy. The pathology report confirmed stage 1A high-grade serous carcinoma of the left ovary, as well as stage 1A grade 1 endometrioid adenocarcinoma of the uterus. I required 6 cycles of chemotherapy before follow-up imaging yielded negative results, with no evidence of metastatic disease.
A Call to Action
The recently updated US Preventive Services Task Force guidelines continue not to recommend annual screening with TVU and/or cancer antigen 125 (CA-125) blood testing for ovarian cancer in asymptomatic, average-risk women. A review of the evidence found no mortality benefit and high false-positive rates, which led to unnecessary surgeries and physiologic stress due to excess cancer worry.4 This (lack of) recommendation leaves the clinician in the position of not performing or ordering screening tests, except in cases in which the patient presents with symptoms or requests screening for ovarian cancer.
Yet it cannot be overstated: The clinician’s role in identifying risk factors for and recognizing symptoms of ovarian cancer is extremely important in the absence of routine screening recommendations. Risk factors include a positive family history of gynecologic, breast, or colon cancers; genetic predisposition; personal history of breast cancer; use of menopausal hormone therapy; excess body weight; smoking; and sedentary lifestyle.3 In my case, my risk for ovarian cancer was average.
Continue to: With regard to symptoms...
With regard to symptoms, most women do not report any until ovarian cancer has reached advanced stages—and even then, the symptoms are vague and nonspecific.5 They may include urinary urgency or frequency; change in bowel habit; difficulty eating or feeling full quickly; persistent back, pelvic, or abdominal pain; extreme tiredness; vaginal bleeding after menopause; increased abdominal size; or bloating on most days.5
So what can we as clinicians do? First, if I may offer a word of caution: When confronted with those vague and nonspecific symptoms, be careful not to dismiss them out of hand as a result of aging, stress, or menopause. As my case demonstrates, for example, metrorrhagia is not necessarily a benign condition for the premenopausal woman.
Furthermore, we can empower patients by educating them about ovarian cancer symptoms and risk factors, information that may promote help-seeking behaviors that aid in early detection. In my case, the continued symptom of abnormal uterine bleeding prompted me to seek further assessment, which led to the discovery of ovarian cancer. Had I not been an educated and empowered patient, I would be telling a completely different story today—most likely one that would include advanced staging. Partner with your patient to discuss available diagnostic testing options and schedule follow-up appointments to monitor presenting complaints.
We also need to partner with our oncology colleagues and researchers. A positive diagnostic test result for possible malignancy necessitates referral to a gynecologic oncologist. Treatment by specialists in high-volume hospitals results in improved ovarian cancer outcomes.6 And we should advocate for continued research to support the discovery of an efficient population screening protocol for this deadly disease.
Finally, and perhaps most radically, I encourage you not to take a watch-and-wait approach in these situations. Ultrasounds are inexpensive, have low mortality risk, and achieve high sensitivity and specificity in detecting and managing adnexal abnormalities.7 In my opinion, the endorsement of TVU testing in this clinical situation is a proactive, prudent, and reasonable action compared with watching and waiting, and it may result in early detection as opposed to advanced disease.
Continue to: I hope that...
I hope that sharing my personal experience with ovarian cancer will compel health care providers to consider this disease as a differential diagnosis and perform appropriate testing when average-risk patients present with nonspecific symptoms. Ultimately, our collective goal should be to increase the survival rate and reduce the suffering associated with ovarian cancer.
1. National Cancer Institute. Cancer Stat Facts: Ovarian Cancer. https://seer.cancer.gov/statfacts/html/ovary.html. Accessed December 3, 2019.
2. American Cancer Society. Key Statistics for Ovarian Cancer. Revised January 8, 2019. www.cancer.org/cancer/ovarian-cancer/about/key-statistics.html. Accessed December 3, 2019.
3. American Cancer Society. Cancer Facts & Figures 2019. www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2019/cancer-facts-and-figures-2019.pdf . Accessed December 4, 2019.
4. Grossman DC, Surry SJ, Owens DK, et al. Screening for ovarian cancer: US Preventive Services Task Force Recommendation Statement. JAMA. 2018;319(6):588-594.
5. Smits S, Boivin J, Menon U, Brain K. Influences on anticipated time to ovarian cancer symptom presentation in women at increased risk compared to population risk of ovarian cancer. BMC Cancer. 2017;17(814):1-11.
6. Pavlik EJ. Ten important considerations for ovarian cancer screening. Diagnostics. 2017;7(22):1-11.
7. Ormsby EL, Pavlik EJ, McGahan JP. Ultrasound monitoring of extant adnexal masses in the era of type 1 and type 2 ovarian cancers: lessons learned from ovarian cancer screening trials. Diagnostics. 2017;7(25):1-19.
1. National Cancer Institute. Cancer Stat Facts: Ovarian Cancer. https://seer.cancer.gov/statfacts/html/ovary.html. Accessed December 3, 2019.
2. American Cancer Society. Key Statistics for Ovarian Cancer. Revised January 8, 2019. www.cancer.org/cancer/ovarian-cancer/about/key-statistics.html. Accessed December 3, 2019.
3. American Cancer Society. Cancer Facts & Figures 2019. www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2019/cancer-facts-and-figures-2019.pdf . Accessed December 4, 2019.
4. Grossman DC, Surry SJ, Owens DK, et al. Screening for ovarian cancer: US Preventive Services Task Force Recommendation Statement. JAMA. 2018;319(6):588-594.
5. Smits S, Boivin J, Menon U, Brain K. Influences on anticipated time to ovarian cancer symptom presentation in women at increased risk compared to population risk of ovarian cancer. BMC Cancer. 2017;17(814):1-11.
6. Pavlik EJ. Ten important considerations for ovarian cancer screening. Diagnostics. 2017;7(22):1-11.
7. Ormsby EL, Pavlik EJ, McGahan JP. Ultrasound monitoring of extant adnexal masses in the era of type 1 and type 2 ovarian cancers: lessons learned from ovarian cancer screening trials. Diagnostics. 2017;7(25):1-19.
Was this patient's transdermal Tx making her dog sick?
THE CASE
A 56-year-old postmenopausal woman with a history of anxiety, depression, alcohol abuse, fatigue, insomnia, and mental fogginess presented to the family medicine clinic with concerns about her companion animal because of symptoms possibly associated with the patient’s medication. Of note, the patient’s physical exam was unremarkable.
The patient noticed that her 5-year-old, 4.5-lb spayed female Chihuahua dog was exhibiting peculiar behaviors, including excessive licking of the abdomen, nipples, and vulvar areas and straining with urination. The dog’s symptoms had started 1 week after the patient began using estradiol transdermal spray (Evamist) for her menopause symptoms. The patient’s menopause symptoms included hot flushes, insomnia, and mental fogginess.
The patient had been applying the estradiol transdermal spray on her inner forearm twice daily, in the morning and at bedtime. She would let the applied medication dry for approximately 2 hours before allowing her arm to come in contact with other items. She worried that some of the hormone may have wiped off onto her couch, pillows, blankets, and other surfaces. In addition, she often cradled the dog in her arms, which allowed the canine’s back to come in contact with her inner forearms. To her knowledge, the dog did not lick or ingest the medication.
The patient had taken the dog to her veterinarian. On physical exam, the veterinarian noted that the dog had nipple and vulvar enlargement but no vaginal discharge, vaginal bleeding, skin changes, or urine abnormalities.
THE (PET’S) DIAGNOSIS, THE PATIENT’S Rx
The veterinarian diagnosed the Chihuahua with vaginal hyperplasia and vulvar enlargement secondary to hyperestrogenism. The animal’s symptoms were likely caused by exposure to the owner’s hormone replacement therapy (HRT) medication—the estradiol spray. The veterinarian advised the woman to return to her family physician to discuss her use of the topical estrogen.
The patient asked her physician (SS) to change her HRT formulation. She was given a prescription for an estradiol 0.05 mg/24-hour transdermal patch to be placed on her abdomen twice weekly. After 2 weeks of using the patch therapy, the patient’s menopausal symptoms were reported to be well controlled. In addition, the companion animal’s breast and vulvar changes resolved, as did the dog’s licking behavior.
DISCUSSION
Estrogen therapy, with or without progesterone, is the most effective treatment for postmenopausal vasomotor symptoms.1 Given the concerns raised in the Women’s Health Initiative (WHI) and other clinical trials regarding hormone therapy and cardiovascular and breast cancer findings, many clinicians look to alternative, nonoral dosage forms to improve the safety profile.
Continue to: Safety of nonroal estrogen therapy
Safety of nonoral estrogen therapy. Administration of nonoral estrogen is associated with avoidance of hepatic first-pass metabolism and a resulting lower impact on hepatic proteins. Thus, data indicate a potentially lower risk for venous thromboembolic events with transdermal estrogen compared to oral estrogen.1 Since the publication of the results of the WHI trials, prescribing patterns in the United States indicate a general decline in the proportion of oral hormones, while transdermal prescription volume has remained steady, and the use of vaginal formulations has increased.2
Topical estrogen formulations. Transdermal or topical delivery of estrogen can be achieved through various formulations, including patches, gels, and a spray. While patches are simple to use, some women display hypersensitivity to the adhesive. Use of gel and spray formulations avoids exposure to adhesives, but these pose a risk of transfer of hormonal ingredients that are not covered by a patch. This risk is amplified by the relative accessibility of the product-specific application sites, which include the arms or thighs. Each manufacturer recommends careful handwashing after handling the product, a specific drying time before the user covers the site with clothing, and avoidance of contact with the application site for a prescribed period of time, usually at least 1 to 2 hours.3-6
Our patient. This case illustrates the importance of discussing the risk of medication transfer to both humans and animals when prescribing individualized hormone therapy. While the Evamist prescribing information specifically addresses the risk of unintentional medication transfer to children, it does not discuss other contact risks.6 In the literature, there have been a limited number of reports on the adverse effects from transdermal or topical human medication transfer to pets. Notably, the American Pet Products Association estimates that in the United States, approximately 90 million dogs and 94 million cats are owned as a pet in 67% of households.7
THE TAKEAWAY
Use of HRT, including transdermal or topical estrogen formulations, is common. Given the large number of companion animals in the United States, physicians should consider that all members of a patient’s household—including pets—may be subject to unintentional secondary exposure to topical estrogen formulations and that they may experience adverse effects. This presents an opportunity for patient education, which can have a larger impact on all occupants of the home.
CORRESPONDENCE
Shannon Scott, DO, FACOFP, Clinical Associate Professor, Arizona College of Osteopathic Medicine, 19389 North 59th Avenue, Glendale, AZ 85308; sscott1@midwestern.edu.
1. The NAMS 2017 Hormone Therapy Position Statement Advisory Panel. The 2017 hormone therapy position statement of The North American Menopause Society. Menopause. 2017;24:728-753.
2. Steinkellner AR, Denison SE, Eldridge SL, et al. A decade of postmenopausal hormone therapy prescribing in the United States: long-term effects of the Women’s Health Initiative. Menopause. 2012;19:616-621.
3. Divigel [package insert]. Bridgewater, NJ: Vertical Pharmaceuticals, LLC; 2014.
4. Elestrin [package insert]. Somerset, NJ: Meda Pharmaceuticals; 2014.
5. Estrogel [package insert]. Herndon, VA: Ascend Therapeutics; 2018.
6. Evamist [package insert]. Minneapolis, MN: Perrigo; 2017.
7. American Pet Products Association. Pet Industry Market Size & Ownership Statistics. www.americanpetproducts.org/press_industrytrends.asp. Accessed November 1, 2019.
THE CASE
A 56-year-old postmenopausal woman with a history of anxiety, depression, alcohol abuse, fatigue, insomnia, and mental fogginess presented to the family medicine clinic with concerns about her companion animal because of symptoms possibly associated with the patient’s medication. Of note, the patient’s physical exam was unremarkable.
The patient noticed that her 5-year-old, 4.5-lb spayed female Chihuahua dog was exhibiting peculiar behaviors, including excessive licking of the abdomen, nipples, and vulvar areas and straining with urination. The dog’s symptoms had started 1 week after the patient began using estradiol transdermal spray (Evamist) for her menopause symptoms. The patient’s menopause symptoms included hot flushes, insomnia, and mental fogginess.
The patient had been applying the estradiol transdermal spray on her inner forearm twice daily, in the morning and at bedtime. She would let the applied medication dry for approximately 2 hours before allowing her arm to come in contact with other items. She worried that some of the hormone may have wiped off onto her couch, pillows, blankets, and other surfaces. In addition, she often cradled the dog in her arms, which allowed the canine’s back to come in contact with her inner forearms. To her knowledge, the dog did not lick or ingest the medication.
The patient had taken the dog to her veterinarian. On physical exam, the veterinarian noted that the dog had nipple and vulvar enlargement but no vaginal discharge, vaginal bleeding, skin changes, or urine abnormalities.
THE (PET’S) DIAGNOSIS, THE PATIENT’S Rx
The veterinarian diagnosed the Chihuahua with vaginal hyperplasia and vulvar enlargement secondary to hyperestrogenism. The animal’s symptoms were likely caused by exposure to the owner’s hormone replacement therapy (HRT) medication—the estradiol spray. The veterinarian advised the woman to return to her family physician to discuss her use of the topical estrogen.
The patient asked her physician (SS) to change her HRT formulation. She was given a prescription for an estradiol 0.05 mg/24-hour transdermal patch to be placed on her abdomen twice weekly. After 2 weeks of using the patch therapy, the patient’s menopausal symptoms were reported to be well controlled. In addition, the companion animal’s breast and vulvar changes resolved, as did the dog’s licking behavior.
DISCUSSION
Estrogen therapy, with or without progesterone, is the most effective treatment for postmenopausal vasomotor symptoms.1 Given the concerns raised in the Women’s Health Initiative (WHI) and other clinical trials regarding hormone therapy and cardiovascular and breast cancer findings, many clinicians look to alternative, nonoral dosage forms to improve the safety profile.
Continue to: Safety of nonroal estrogen therapy
Safety of nonoral estrogen therapy. Administration of nonoral estrogen is associated with avoidance of hepatic first-pass metabolism and a resulting lower impact on hepatic proteins. Thus, data indicate a potentially lower risk for venous thromboembolic events with transdermal estrogen compared to oral estrogen.1 Since the publication of the results of the WHI trials, prescribing patterns in the United States indicate a general decline in the proportion of oral hormones, while transdermal prescription volume has remained steady, and the use of vaginal formulations has increased.2
Topical estrogen formulations. Transdermal or topical delivery of estrogen can be achieved through various formulations, including patches, gels, and a spray. While patches are simple to use, some women display hypersensitivity to the adhesive. Use of gel and spray formulations avoids exposure to adhesives, but these pose a risk of transfer of hormonal ingredients that are not covered by a patch. This risk is amplified by the relative accessibility of the product-specific application sites, which include the arms or thighs. Each manufacturer recommends careful handwashing after handling the product, a specific drying time before the user covers the site with clothing, and avoidance of contact with the application site for a prescribed period of time, usually at least 1 to 2 hours.3-6
Our patient. This case illustrates the importance of discussing the risk of medication transfer to both humans and animals when prescribing individualized hormone therapy. While the Evamist prescribing information specifically addresses the risk of unintentional medication transfer to children, it does not discuss other contact risks.6 In the literature, there have been a limited number of reports on the adverse effects from transdermal or topical human medication transfer to pets. Notably, the American Pet Products Association estimates that in the United States, approximately 90 million dogs and 94 million cats are owned as a pet in 67% of households.7
THE TAKEAWAY
Use of HRT, including transdermal or topical estrogen formulations, is common. Given the large number of companion animals in the United States, physicians should consider that all members of a patient’s household—including pets—may be subject to unintentional secondary exposure to topical estrogen formulations and that they may experience adverse effects. This presents an opportunity for patient education, which can have a larger impact on all occupants of the home.
CORRESPONDENCE
Shannon Scott, DO, FACOFP, Clinical Associate Professor, Arizona College of Osteopathic Medicine, 19389 North 59th Avenue, Glendale, AZ 85308; sscott1@midwestern.edu.
THE CASE
A 56-year-old postmenopausal woman with a history of anxiety, depression, alcohol abuse, fatigue, insomnia, and mental fogginess presented to the family medicine clinic with concerns about her companion animal because of symptoms possibly associated with the patient’s medication. Of note, the patient’s physical exam was unremarkable.
The patient noticed that her 5-year-old, 4.5-lb spayed female Chihuahua dog was exhibiting peculiar behaviors, including excessive licking of the abdomen, nipples, and vulvar areas and straining with urination. The dog’s symptoms had started 1 week after the patient began using estradiol transdermal spray (Evamist) for her menopause symptoms. The patient’s menopause symptoms included hot flushes, insomnia, and mental fogginess.
The patient had been applying the estradiol transdermal spray on her inner forearm twice daily, in the morning and at bedtime. She would let the applied medication dry for approximately 2 hours before allowing her arm to come in contact with other items. She worried that some of the hormone may have wiped off onto her couch, pillows, blankets, and other surfaces. In addition, she often cradled the dog in her arms, which allowed the canine’s back to come in contact with her inner forearms. To her knowledge, the dog did not lick or ingest the medication.
The patient had taken the dog to her veterinarian. On physical exam, the veterinarian noted that the dog had nipple and vulvar enlargement but no vaginal discharge, vaginal bleeding, skin changes, or urine abnormalities.
THE (PET’S) DIAGNOSIS, THE PATIENT’S Rx
The veterinarian diagnosed the Chihuahua with vaginal hyperplasia and vulvar enlargement secondary to hyperestrogenism. The animal’s symptoms were likely caused by exposure to the owner’s hormone replacement therapy (HRT) medication—the estradiol spray. The veterinarian advised the woman to return to her family physician to discuss her use of the topical estrogen.
The patient asked her physician (SS) to change her HRT formulation. She was given a prescription for an estradiol 0.05 mg/24-hour transdermal patch to be placed on her abdomen twice weekly. After 2 weeks of using the patch therapy, the patient’s menopausal symptoms were reported to be well controlled. In addition, the companion animal’s breast and vulvar changes resolved, as did the dog’s licking behavior.
DISCUSSION
Estrogen therapy, with or without progesterone, is the most effective treatment for postmenopausal vasomotor symptoms.1 Given the concerns raised in the Women’s Health Initiative (WHI) and other clinical trials regarding hormone therapy and cardiovascular and breast cancer findings, many clinicians look to alternative, nonoral dosage forms to improve the safety profile.
Continue to: Safety of nonroal estrogen therapy
Safety of nonoral estrogen therapy. Administration of nonoral estrogen is associated with avoidance of hepatic first-pass metabolism and a resulting lower impact on hepatic proteins. Thus, data indicate a potentially lower risk for venous thromboembolic events with transdermal estrogen compared to oral estrogen.1 Since the publication of the results of the WHI trials, prescribing patterns in the United States indicate a general decline in the proportion of oral hormones, while transdermal prescription volume has remained steady, and the use of vaginal formulations has increased.2
Topical estrogen formulations. Transdermal or topical delivery of estrogen can be achieved through various formulations, including patches, gels, and a spray. While patches are simple to use, some women display hypersensitivity to the adhesive. Use of gel and spray formulations avoids exposure to adhesives, but these pose a risk of transfer of hormonal ingredients that are not covered by a patch. This risk is amplified by the relative accessibility of the product-specific application sites, which include the arms or thighs. Each manufacturer recommends careful handwashing after handling the product, a specific drying time before the user covers the site with clothing, and avoidance of contact with the application site for a prescribed period of time, usually at least 1 to 2 hours.3-6
Our patient. This case illustrates the importance of discussing the risk of medication transfer to both humans and animals when prescribing individualized hormone therapy. While the Evamist prescribing information specifically addresses the risk of unintentional medication transfer to children, it does not discuss other contact risks.6 In the literature, there have been a limited number of reports on the adverse effects from transdermal or topical human medication transfer to pets. Notably, the American Pet Products Association estimates that in the United States, approximately 90 million dogs and 94 million cats are owned as a pet in 67% of households.7
THE TAKEAWAY
Use of HRT, including transdermal or topical estrogen formulations, is common. Given the large number of companion animals in the United States, physicians should consider that all members of a patient’s household—including pets—may be subject to unintentional secondary exposure to topical estrogen formulations and that they may experience adverse effects. This presents an opportunity for patient education, which can have a larger impact on all occupants of the home.
CORRESPONDENCE
Shannon Scott, DO, FACOFP, Clinical Associate Professor, Arizona College of Osteopathic Medicine, 19389 North 59th Avenue, Glendale, AZ 85308; sscott1@midwestern.edu.
1. The NAMS 2017 Hormone Therapy Position Statement Advisory Panel. The 2017 hormone therapy position statement of The North American Menopause Society. Menopause. 2017;24:728-753.
2. Steinkellner AR, Denison SE, Eldridge SL, et al. A decade of postmenopausal hormone therapy prescribing in the United States: long-term effects of the Women’s Health Initiative. Menopause. 2012;19:616-621.
3. Divigel [package insert]. Bridgewater, NJ: Vertical Pharmaceuticals, LLC; 2014.
4. Elestrin [package insert]. Somerset, NJ: Meda Pharmaceuticals; 2014.
5. Estrogel [package insert]. Herndon, VA: Ascend Therapeutics; 2018.
6. Evamist [package insert]. Minneapolis, MN: Perrigo; 2017.
7. American Pet Products Association. Pet Industry Market Size & Ownership Statistics. www.americanpetproducts.org/press_industrytrends.asp. Accessed November 1, 2019.
1. The NAMS 2017 Hormone Therapy Position Statement Advisory Panel. The 2017 hormone therapy position statement of The North American Menopause Society. Menopause. 2017;24:728-753.
2. Steinkellner AR, Denison SE, Eldridge SL, et al. A decade of postmenopausal hormone therapy prescribing in the United States: long-term effects of the Women’s Health Initiative. Menopause. 2012;19:616-621.
3. Divigel [package insert]. Bridgewater, NJ: Vertical Pharmaceuticals, LLC; 2014.
4. Elestrin [package insert]. Somerset, NJ: Meda Pharmaceuticals; 2014.
5. Estrogel [package insert]. Herndon, VA: Ascend Therapeutics; 2018.
6. Evamist [package insert]. Minneapolis, MN: Perrigo; 2017.
7. American Pet Products Association. Pet Industry Market Size & Ownership Statistics. www.americanpetproducts.org/press_industrytrends.asp. Accessed November 1, 2019.
Early pregnancy loss: Pretreat with mifepristone?
ILLUSTRATIVE CASE
Jenny is a 29-year-old G2P1001 woman who presents to your clinic for a missed period. Her last menstrual period was about 10 weeks ago. She is found to have a positive pregnancy test in the office. On examination, her uterus is nontender and consistent in size with gestation of 7 weeks. She denies any bleeding or cramping. On ultrasound, you see a gestational sac measuring 28 mm and no embryo. You confirm early pregnancy loss. Jenny is sad about this diagnosis. She does not wish to proceed with expectant management and is hopeful to avoid a surgical procedure. How do you counsel her regarding medical management?
Early pregnancy loss or first trimester miscarriage is estimated to occur in about 1 million women in the United States annually and is the most common complication of early pregnancy.2,3 Early pregnancy loss is defined as a nonviable, intrauterine pregnancy with either an empty gestational sac or a gestational sac containing an embryo or fetus without fetal heart activity within the first 12 weeks 6 days of gestation.4
Once early pregnancy loss is confirmed by ultrasound, expectant management with no intervention is an acceptable treatment option. Women generally prefer active management, either medically or with surgical evacuation.5,6 Misoprostol 800 mcg administered vaginally or orally has been the accepted medication regimen for medical management.5 However, failure rates with misoprostol have been reported to be as high as 40%, particularly among women with a closed cervical os, who then require repeat dosing of misoprostol or surgical evacuation.6
STUDY SUMMARY
Mifepristone before misoprostol improves efficacy for early pregnancy loss
The PreFaiR (Comparative Effectiveness of Pregnancy Failure Management Regimens) study was a randomized trial that took place at 3 US centers. The study was designed to assess the safety and efficacy of pretreatment with oral mifepristone prior to use of vaginal misoprostol for the medical management of early pregnancy loss.1
Three hundred women, ≥ 18 years and undergoing medical management for early pregnancy loss, were randomized to receive misoprostol 800 mcg vaginally alone or mifepristone 200 mg orally followed by misoprostol 800 mcg vaginally 24 hours later.
Inclusion and exclusion criteria. Women who showed a nonviable intrauterine pregnancy at 5 to 12 weeks’ gestation by ultrasound were eligible for the study. Exclusion criteria included incomplete or inevitable abortion, contraindications to either study drug, viable or ectopic pregnancy, hemoglobin < 9.5 g/dL, current use of anticoagulants or the presence of a clotting disorder, and pregnancy with an intrauterine device in place.
Outcomes. The primary outcome was gestational sac expulsion by the first follow-up visit and no additional interventions within 30 days of treatment. Secondary outcomes included acceptability of treatment, adverse events, and clinical characteristics associated with successful expulsion.
Continue to: Demographics
Demographics. The mean age of the study participants in both groups was ~30 years, and there was a similar percentage of participants by self-reported race and ethnicity in both groups (~44% black, ~35% white, and ~25% Hispanic). The majority of participants in both groups were at 6 to 8 weeks’ gestation and had been pregnant at least 3 times.
Results. Researchers were able to evaluate 297 women at the initial follow-up. Of the women who received mifepristone and misoprostol, 83.8% (124 of 148 women; 95% confidence interval [CI], 76.8-89.3) had complete expulsion within 1 to 3 days, compared to 67.1% (100 of 149 women; 95% CI, 59-74.6) in the misoprostol alone group. The number needed to treat with mifepristone and misoprostol to achieve complete expulsion at the first follow-up visit was 6. The percentage of patients receiving uterine aspiration was lower in the mifepristone and misoprostol group (8.8%) than in the misoprostol alone group (23.5%; relative risk = 0.37; 95% CI, 0.21-0.68). There were no significant differences in adverse events including bleeding intensity, pelvic infection, or pain.
WHAT’S NEW
A high-quality RCT demonstrates improved efficacy
Prior studies that have looked at combined mifepristone and misoprostol treatment for early pregnancy loss had heterogeneity in outcome definitions and study designs leading to variable reports of effectiveness.1,5 This is the first high-quality, randomized trial to demonstrate the safety and efficacy of oral mifepristone pretreatment prior to misoprostol vaginal administration in the medical management of early pregnancy loss.
CAVEATS
Would a placebo group—or other forms of misoprostol—change the results?
The study did not include a placebo group; however, an investigator who was blinded to the treatment group allocation determined the primary outcome, and the lack of placebo did not introduce bias related to the outcomes.
Intravaginal misoprostol was used in this study, rather than oral, rectal, buccal, or sublingual misoprostol.7 It is not clear from this study if the results of pretreatment with mifepristone would be different if misoprostol was administered via one of these other routes.
Continue to: CHALLENGES TO IMPLEMENTATION
CHALLENGES TO IMPLEMENTATION
FDA restrictions limit availability of mifepristone
The main challenge to implementation is the availability of mifepristone. Mifepristone was approved by the US Food and Drug Administration in 2000. The approval included Risk Evaluation and Mitigation Strategy (REMS) restrictions, stipulating that a health provider be specially certified for prescribing; dispensing must occur in clinics, medical offices, or hospitals; and patients must sign a patient agreement form prior to obtaining the agent.8
ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.
1. Schreiber CA, Creinin MD, Atrio J, et al. Mifepristone pretreatment for the medical management of early pregnancy loss. N Engl J Med. 2018;378:2161-2170.
2. Ventura SJ, Curtin SC, Abma JC, et al. Estimated pregnancy rates and rates of pregnancy outcomes for the United States, 1990-2008. Natl Vital Stat Rep. 2012;60:1-21.
3. The American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 200. Early pregnancy loss. Obstet Gynecol. 2018;132:e197-e207.
4. National Institute for Health and Clinical Excellence. Ectopic pregnancy and miscarriage: diagnosis and initial management. Clinical guideline 154. www.nice.org.uk/guidance/cg154/resources/guidance-ectopic-pregnancy-and-miscarriage-pdf. Published December 2012. Accessed December 5, 2019.
5. Neilson JP, Hickey M, Vazquez JC. Medical treatment for early fetal death (less than 24 weeks). Cochrane Database Syst Rev. 2006;CD002253.
6. Schreiber CA, Chavez V, Whittaker PG, et al. Treatment decisions at the time of miscarriage diagnosis. Obstet Gynecol. 2016;128:1347-1356.
7. Ngoc NT, Blum J, Westheimer E, et al. Medical treatment of missed abortion using misoprostol. Int J Gynaecol Obstet. 2004;87:138-142.
8. US Food and Drug Administration. Mifeprex (mifepristone) information. www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/mifeprex-mifepristone-information. Updated February 5, 2018. Accessed December 5, 2019.
ILLUSTRATIVE CASE
Jenny is a 29-year-old G2P1001 woman who presents to your clinic for a missed period. Her last menstrual period was about 10 weeks ago. She is found to have a positive pregnancy test in the office. On examination, her uterus is nontender and consistent in size with gestation of 7 weeks. She denies any bleeding or cramping. On ultrasound, you see a gestational sac measuring 28 mm and no embryo. You confirm early pregnancy loss. Jenny is sad about this diagnosis. She does not wish to proceed with expectant management and is hopeful to avoid a surgical procedure. How do you counsel her regarding medical management?
Early pregnancy loss or first trimester miscarriage is estimated to occur in about 1 million women in the United States annually and is the most common complication of early pregnancy.2,3 Early pregnancy loss is defined as a nonviable, intrauterine pregnancy with either an empty gestational sac or a gestational sac containing an embryo or fetus without fetal heart activity within the first 12 weeks 6 days of gestation.4
Once early pregnancy loss is confirmed by ultrasound, expectant management with no intervention is an acceptable treatment option. Women generally prefer active management, either medically or with surgical evacuation.5,6 Misoprostol 800 mcg administered vaginally or orally has been the accepted medication regimen for medical management.5 However, failure rates with misoprostol have been reported to be as high as 40%, particularly among women with a closed cervical os, who then require repeat dosing of misoprostol or surgical evacuation.6
STUDY SUMMARY
Mifepristone before misoprostol improves efficacy for early pregnancy loss
The PreFaiR (Comparative Effectiveness of Pregnancy Failure Management Regimens) study was a randomized trial that took place at 3 US centers. The study was designed to assess the safety and efficacy of pretreatment with oral mifepristone prior to use of vaginal misoprostol for the medical management of early pregnancy loss.1
Three hundred women, ≥ 18 years and undergoing medical management for early pregnancy loss, were randomized to receive misoprostol 800 mcg vaginally alone or mifepristone 200 mg orally followed by misoprostol 800 mcg vaginally 24 hours later.
Inclusion and exclusion criteria. Women who showed a nonviable intrauterine pregnancy at 5 to 12 weeks’ gestation by ultrasound were eligible for the study. Exclusion criteria included incomplete or inevitable abortion, contraindications to either study drug, viable or ectopic pregnancy, hemoglobin < 9.5 g/dL, current use of anticoagulants or the presence of a clotting disorder, and pregnancy with an intrauterine device in place.
Outcomes. The primary outcome was gestational sac expulsion by the first follow-up visit and no additional interventions within 30 days of treatment. Secondary outcomes included acceptability of treatment, adverse events, and clinical characteristics associated with successful expulsion.
Continue to: Demographics
Demographics. The mean age of the study participants in both groups was ~30 years, and there was a similar percentage of participants by self-reported race and ethnicity in both groups (~44% black, ~35% white, and ~25% Hispanic). The majority of participants in both groups were at 6 to 8 weeks’ gestation and had been pregnant at least 3 times.
Results. Researchers were able to evaluate 297 women at the initial follow-up. Of the women who received mifepristone and misoprostol, 83.8% (124 of 148 women; 95% confidence interval [CI], 76.8-89.3) had complete expulsion within 1 to 3 days, compared to 67.1% (100 of 149 women; 95% CI, 59-74.6) in the misoprostol alone group. The number needed to treat with mifepristone and misoprostol to achieve complete expulsion at the first follow-up visit was 6. The percentage of patients receiving uterine aspiration was lower in the mifepristone and misoprostol group (8.8%) than in the misoprostol alone group (23.5%; relative risk = 0.37; 95% CI, 0.21-0.68). There were no significant differences in adverse events including bleeding intensity, pelvic infection, or pain.
WHAT’S NEW
A high-quality RCT demonstrates improved efficacy
Prior studies that have looked at combined mifepristone and misoprostol treatment for early pregnancy loss had heterogeneity in outcome definitions and study designs leading to variable reports of effectiveness.1,5 This is the first high-quality, randomized trial to demonstrate the safety and efficacy of oral mifepristone pretreatment prior to misoprostol vaginal administration in the medical management of early pregnancy loss.
CAVEATS
Would a placebo group—or other forms of misoprostol—change the results?
The study did not include a placebo group; however, an investigator who was blinded to the treatment group allocation determined the primary outcome, and the lack of placebo did not introduce bias related to the outcomes.
Intravaginal misoprostol was used in this study, rather than oral, rectal, buccal, or sublingual misoprostol.7 It is not clear from this study if the results of pretreatment with mifepristone would be different if misoprostol was administered via one of these other routes.
Continue to: CHALLENGES TO IMPLEMENTATION
CHALLENGES TO IMPLEMENTATION
FDA restrictions limit availability of mifepristone
The main challenge to implementation is the availability of mifepristone. Mifepristone was approved by the US Food and Drug Administration in 2000. The approval included Risk Evaluation and Mitigation Strategy (REMS) restrictions, stipulating that a health provider be specially certified for prescribing; dispensing must occur in clinics, medical offices, or hospitals; and patients must sign a patient agreement form prior to obtaining the agent.8
ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.
ILLUSTRATIVE CASE
Jenny is a 29-year-old G2P1001 woman who presents to your clinic for a missed period. Her last menstrual period was about 10 weeks ago. She is found to have a positive pregnancy test in the office. On examination, her uterus is nontender and consistent in size with gestation of 7 weeks. She denies any bleeding or cramping. On ultrasound, you see a gestational sac measuring 28 mm and no embryo. You confirm early pregnancy loss. Jenny is sad about this diagnosis. She does not wish to proceed with expectant management and is hopeful to avoid a surgical procedure. How do you counsel her regarding medical management?
Early pregnancy loss or first trimester miscarriage is estimated to occur in about 1 million women in the United States annually and is the most common complication of early pregnancy.2,3 Early pregnancy loss is defined as a nonviable, intrauterine pregnancy with either an empty gestational sac or a gestational sac containing an embryo or fetus without fetal heart activity within the first 12 weeks 6 days of gestation.4
Once early pregnancy loss is confirmed by ultrasound, expectant management with no intervention is an acceptable treatment option. Women generally prefer active management, either medically or with surgical evacuation.5,6 Misoprostol 800 mcg administered vaginally or orally has been the accepted medication regimen for medical management.5 However, failure rates with misoprostol have been reported to be as high as 40%, particularly among women with a closed cervical os, who then require repeat dosing of misoprostol or surgical evacuation.6
STUDY SUMMARY
Mifepristone before misoprostol improves efficacy for early pregnancy loss
The PreFaiR (Comparative Effectiveness of Pregnancy Failure Management Regimens) study was a randomized trial that took place at 3 US centers. The study was designed to assess the safety and efficacy of pretreatment with oral mifepristone prior to use of vaginal misoprostol for the medical management of early pregnancy loss.1
Three hundred women, ≥ 18 years and undergoing medical management for early pregnancy loss, were randomized to receive misoprostol 800 mcg vaginally alone or mifepristone 200 mg orally followed by misoprostol 800 mcg vaginally 24 hours later.
Inclusion and exclusion criteria. Women who showed a nonviable intrauterine pregnancy at 5 to 12 weeks’ gestation by ultrasound were eligible for the study. Exclusion criteria included incomplete or inevitable abortion, contraindications to either study drug, viable or ectopic pregnancy, hemoglobin < 9.5 g/dL, current use of anticoagulants or the presence of a clotting disorder, and pregnancy with an intrauterine device in place.
Outcomes. The primary outcome was gestational sac expulsion by the first follow-up visit and no additional interventions within 30 days of treatment. Secondary outcomes included acceptability of treatment, adverse events, and clinical characteristics associated with successful expulsion.
Continue to: Demographics
Demographics. The mean age of the study participants in both groups was ~30 years, and there was a similar percentage of participants by self-reported race and ethnicity in both groups (~44% black, ~35% white, and ~25% Hispanic). The majority of participants in both groups were at 6 to 8 weeks’ gestation and had been pregnant at least 3 times.
Results. Researchers were able to evaluate 297 women at the initial follow-up. Of the women who received mifepristone and misoprostol, 83.8% (124 of 148 women; 95% confidence interval [CI], 76.8-89.3) had complete expulsion within 1 to 3 days, compared to 67.1% (100 of 149 women; 95% CI, 59-74.6) in the misoprostol alone group. The number needed to treat with mifepristone and misoprostol to achieve complete expulsion at the first follow-up visit was 6. The percentage of patients receiving uterine aspiration was lower in the mifepristone and misoprostol group (8.8%) than in the misoprostol alone group (23.5%; relative risk = 0.37; 95% CI, 0.21-0.68). There were no significant differences in adverse events including bleeding intensity, pelvic infection, or pain.
WHAT’S NEW
A high-quality RCT demonstrates improved efficacy
Prior studies that have looked at combined mifepristone and misoprostol treatment for early pregnancy loss had heterogeneity in outcome definitions and study designs leading to variable reports of effectiveness.1,5 This is the first high-quality, randomized trial to demonstrate the safety and efficacy of oral mifepristone pretreatment prior to misoprostol vaginal administration in the medical management of early pregnancy loss.
CAVEATS
Would a placebo group—or other forms of misoprostol—change the results?
The study did not include a placebo group; however, an investigator who was blinded to the treatment group allocation determined the primary outcome, and the lack of placebo did not introduce bias related to the outcomes.
Intravaginal misoprostol was used in this study, rather than oral, rectal, buccal, or sublingual misoprostol.7 It is not clear from this study if the results of pretreatment with mifepristone would be different if misoprostol was administered via one of these other routes.
Continue to: CHALLENGES TO IMPLEMENTATION
CHALLENGES TO IMPLEMENTATION
FDA restrictions limit availability of mifepristone
The main challenge to implementation is the availability of mifepristone. Mifepristone was approved by the US Food and Drug Administration in 2000. The approval included Risk Evaluation and Mitigation Strategy (REMS) restrictions, stipulating that a health provider be specially certified for prescribing; dispensing must occur in clinics, medical offices, or hospitals; and patients must sign a patient agreement form prior to obtaining the agent.8
ACKNOWLEDGEMENT
The PURLs Surveillance System was supported in part by Grant Number UL1RR024999 from the National Center For Research Resources, a Clinical Translational Science Award to the University of Chicago. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Center For Research Resources or the National Institutes of Health.
1. Schreiber CA, Creinin MD, Atrio J, et al. Mifepristone pretreatment for the medical management of early pregnancy loss. N Engl J Med. 2018;378:2161-2170.
2. Ventura SJ, Curtin SC, Abma JC, et al. Estimated pregnancy rates and rates of pregnancy outcomes for the United States, 1990-2008. Natl Vital Stat Rep. 2012;60:1-21.
3. The American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 200. Early pregnancy loss. Obstet Gynecol. 2018;132:e197-e207.
4. National Institute for Health and Clinical Excellence. Ectopic pregnancy and miscarriage: diagnosis and initial management. Clinical guideline 154. www.nice.org.uk/guidance/cg154/resources/guidance-ectopic-pregnancy-and-miscarriage-pdf. Published December 2012. Accessed December 5, 2019.
5. Neilson JP, Hickey M, Vazquez JC. Medical treatment for early fetal death (less than 24 weeks). Cochrane Database Syst Rev. 2006;CD002253.
6. Schreiber CA, Chavez V, Whittaker PG, et al. Treatment decisions at the time of miscarriage diagnosis. Obstet Gynecol. 2016;128:1347-1356.
7. Ngoc NT, Blum J, Westheimer E, et al. Medical treatment of missed abortion using misoprostol. Int J Gynaecol Obstet. 2004;87:138-142.
8. US Food and Drug Administration. Mifeprex (mifepristone) information. www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/mifeprex-mifepristone-information. Updated February 5, 2018. Accessed December 5, 2019.
1. Schreiber CA, Creinin MD, Atrio J, et al. Mifepristone pretreatment for the medical management of early pregnancy loss. N Engl J Med. 2018;378:2161-2170.
2. Ventura SJ, Curtin SC, Abma JC, et al. Estimated pregnancy rates and rates of pregnancy outcomes for the United States, 1990-2008. Natl Vital Stat Rep. 2012;60:1-21.
3. The American College of Obstetricians and Gynecologists. ACOG Practice Bulletin No. 200. Early pregnancy loss. Obstet Gynecol. 2018;132:e197-e207.
4. National Institute for Health and Clinical Excellence. Ectopic pregnancy and miscarriage: diagnosis and initial management. Clinical guideline 154. www.nice.org.uk/guidance/cg154/resources/guidance-ectopic-pregnancy-and-miscarriage-pdf. Published December 2012. Accessed December 5, 2019.
5. Neilson JP, Hickey M, Vazquez JC. Medical treatment for early fetal death (less than 24 weeks). Cochrane Database Syst Rev. 2006;CD002253.
6. Schreiber CA, Chavez V, Whittaker PG, et al. Treatment decisions at the time of miscarriage diagnosis. Obstet Gynecol. 2016;128:1347-1356.
7. Ngoc NT, Blum J, Westheimer E, et al. Medical treatment of missed abortion using misoprostol. Int J Gynaecol Obstet. 2004;87:138-142.
8. US Food and Drug Administration. Mifeprex (mifepristone) information. www.fda.gov/drugs/postmarket-drug-safety-information-patients-and-providers/mifeprex-mifepristone-information. Updated February 5, 2018. Accessed December 5, 2019.
PRACTICE CHANGER
Pretreat patients with oral mifepristone prior to using vaginal misoprostol to increase the efficacy of medical management of early pregnancy loss over that with misoprostol alone.
STRENGTH OF RECOMMENDATION
B: Based on a single, well-executed, randomized controlled trial.1
Schreiber CA, Creinin MD, Atrio J, et al. Mifepristone pretreatment for the medical management of early pregnancy loss. N Engl J Med. 2018;378:2161-2170.
Bilateral mastectomy reduces second breast cancer risk, but not deaths
Bilateral mastectomy significantly decreases the risk for a second contralateral breast cancer, but does not decrease the risk of death, compared with breast-conserving therapy, results of a large retrospective study indicate.
Among 245,418 patients followed for a median of 6.7 years, the risk of death from breast cancer was similar for those who had undergone either breast-conserving therapy or bilateral mastectomy (BLM) but was 20% higher among women who had undergone unilateral mastectomy (ULM) when compared with breast-conserving therapy, reported Allison W. Kurian, MD, MSc, from Stanford (Calif.) University, and colleagues.
“Second breast cancers are rare, and their reduction should be weighed against the harms associated with BLM,” they wrote in a study published online in Cancer.
The investigators extracted data from the Surveillance, Epidemiology, and End Results program on all women diagnosed with American Joint Committee on Cancer stage 0 to stage III unilateral breast cancer in California from 1998 to 2015 who were treated with either BLM versus breast-conserving therapy, including surgery and radiation or unilateral mastectomy.
They calculated the absolute excess risk of contralateral breast cancer as the observed minus expected number of breast cancers in the general population divided by 10,000 person-years at risk.
Of 421,643 women with a first diagnosis of primary breast cancer during the study period, 245,418 met the study criteria. Of this cohort, 7,784 (3.2%) developed a contralateral second breast cancer more than 6 months after diagnosis of the first, after a median 6.7 years of follow-up.
Slightly more than half of the cohort (52.1%) had undergone breast-conserving therapy, 37.5% underwent unilateral mastectomy, and 7.6% had bilateral mastectomy. An additional 2.9% of patients were women aged 70 years and older with stage I hormone receptor–positive, HER2-negative disease who underwent breast-conserving surgery without radiation (percentages exceed 100% because of rounding).
A multivariate-adjusted model showed that, as might be expected, patients who underwent bilateral mastectomy had a 90% reduction in risk of contralateral cancer (hazard ratio, 0.10; P less than .001), compared with breast-conserving therapy. In contrast, patients who underwent unilateral mastectomy had a slight but significant increase in risk for a second contralateral breast cancer (HR, 1.07; P = .008).
The absolute excess risk for second contralateral breast cancer was 5 per 10,000 person-years with breast-conserving therapy, 13.6 per 10,000 person-years with unilateral mastectomy, and –28.6 per 10,000 person-years with bilateral mastectomy.
When they looked at risk for death, however they found that, compared with breast-conserving therapy, breast-conserving surgery alone (HR, 1.36; P = .0001) and unilateral mastectomy (HR, 1.21; P less than .001), but not bilateral mastectomy (HR, 1.03; P = .35) were significantly associated with increased risk for breast cancer death.
The authors noted that their estimates of absolute risk of second contralateral breast cancer jibe with those of earlier studies, and can help clinicians frame the discussion of the benefits versus risks for individual patients.
“What one patient might consider to be a negligible benefit of BLM, weighed against its potential harms of greater pain, recovery time, and impact on body image and employment, might appear worthwhile to another,” they wrote.
The study was funded by the National Cancer Institute, National Institutes of Health, Department of Health & Human Services, Suzanne Pride Bryan Fund for Breast Cancer Research, Jan Weimer Faculty Chair for Breast Oncology, and the BRCA Foundation. Dr. Kurian disclosed institutional research funding from Myriad Genetics.
SOURCE: Kurin AW et al. Cancer. 2019 Nov 21. doi: 10.1002/cncr.32618.
Bilateral mastectomy significantly decreases the risk for a second contralateral breast cancer, but does not decrease the risk of death, compared with breast-conserving therapy, results of a large retrospective study indicate.
Among 245,418 patients followed for a median of 6.7 years, the risk of death from breast cancer was similar for those who had undergone either breast-conserving therapy or bilateral mastectomy (BLM) but was 20% higher among women who had undergone unilateral mastectomy (ULM) when compared with breast-conserving therapy, reported Allison W. Kurian, MD, MSc, from Stanford (Calif.) University, and colleagues.
“Second breast cancers are rare, and their reduction should be weighed against the harms associated with BLM,” they wrote in a study published online in Cancer.
The investigators extracted data from the Surveillance, Epidemiology, and End Results program on all women diagnosed with American Joint Committee on Cancer stage 0 to stage III unilateral breast cancer in California from 1998 to 2015 who were treated with either BLM versus breast-conserving therapy, including surgery and radiation or unilateral mastectomy.
They calculated the absolute excess risk of contralateral breast cancer as the observed minus expected number of breast cancers in the general population divided by 10,000 person-years at risk.
Of 421,643 women with a first diagnosis of primary breast cancer during the study period, 245,418 met the study criteria. Of this cohort, 7,784 (3.2%) developed a contralateral second breast cancer more than 6 months after diagnosis of the first, after a median 6.7 years of follow-up.
Slightly more than half of the cohort (52.1%) had undergone breast-conserving therapy, 37.5% underwent unilateral mastectomy, and 7.6% had bilateral mastectomy. An additional 2.9% of patients were women aged 70 years and older with stage I hormone receptor–positive, HER2-negative disease who underwent breast-conserving surgery without radiation (percentages exceed 100% because of rounding).
A multivariate-adjusted model showed that, as might be expected, patients who underwent bilateral mastectomy had a 90% reduction in risk of contralateral cancer (hazard ratio, 0.10; P less than .001), compared with breast-conserving therapy. In contrast, patients who underwent unilateral mastectomy had a slight but significant increase in risk for a second contralateral breast cancer (HR, 1.07; P = .008).
The absolute excess risk for second contralateral breast cancer was 5 per 10,000 person-years with breast-conserving therapy, 13.6 per 10,000 person-years with unilateral mastectomy, and –28.6 per 10,000 person-years with bilateral mastectomy.
When they looked at risk for death, however they found that, compared with breast-conserving therapy, breast-conserving surgery alone (HR, 1.36; P = .0001) and unilateral mastectomy (HR, 1.21; P less than .001), but not bilateral mastectomy (HR, 1.03; P = .35) were significantly associated with increased risk for breast cancer death.
The authors noted that their estimates of absolute risk of second contralateral breast cancer jibe with those of earlier studies, and can help clinicians frame the discussion of the benefits versus risks for individual patients.
“What one patient might consider to be a negligible benefit of BLM, weighed against its potential harms of greater pain, recovery time, and impact on body image and employment, might appear worthwhile to another,” they wrote.
The study was funded by the National Cancer Institute, National Institutes of Health, Department of Health & Human Services, Suzanne Pride Bryan Fund for Breast Cancer Research, Jan Weimer Faculty Chair for Breast Oncology, and the BRCA Foundation. Dr. Kurian disclosed institutional research funding from Myriad Genetics.
SOURCE: Kurin AW et al. Cancer. 2019 Nov 21. doi: 10.1002/cncr.32618.
Bilateral mastectomy significantly decreases the risk for a second contralateral breast cancer, but does not decrease the risk of death, compared with breast-conserving therapy, results of a large retrospective study indicate.
Among 245,418 patients followed for a median of 6.7 years, the risk of death from breast cancer was similar for those who had undergone either breast-conserving therapy or bilateral mastectomy (BLM) but was 20% higher among women who had undergone unilateral mastectomy (ULM) when compared with breast-conserving therapy, reported Allison W. Kurian, MD, MSc, from Stanford (Calif.) University, and colleagues.
“Second breast cancers are rare, and their reduction should be weighed against the harms associated with BLM,” they wrote in a study published online in Cancer.
The investigators extracted data from the Surveillance, Epidemiology, and End Results program on all women diagnosed with American Joint Committee on Cancer stage 0 to stage III unilateral breast cancer in California from 1998 to 2015 who were treated with either BLM versus breast-conserving therapy, including surgery and radiation or unilateral mastectomy.
They calculated the absolute excess risk of contralateral breast cancer as the observed minus expected number of breast cancers in the general population divided by 10,000 person-years at risk.
Of 421,643 women with a first diagnosis of primary breast cancer during the study period, 245,418 met the study criteria. Of this cohort, 7,784 (3.2%) developed a contralateral second breast cancer more than 6 months after diagnosis of the first, after a median 6.7 years of follow-up.
Slightly more than half of the cohort (52.1%) had undergone breast-conserving therapy, 37.5% underwent unilateral mastectomy, and 7.6% had bilateral mastectomy. An additional 2.9% of patients were women aged 70 years and older with stage I hormone receptor–positive, HER2-negative disease who underwent breast-conserving surgery without radiation (percentages exceed 100% because of rounding).
A multivariate-adjusted model showed that, as might be expected, patients who underwent bilateral mastectomy had a 90% reduction in risk of contralateral cancer (hazard ratio, 0.10; P less than .001), compared with breast-conserving therapy. In contrast, patients who underwent unilateral mastectomy had a slight but significant increase in risk for a second contralateral breast cancer (HR, 1.07; P = .008).
The absolute excess risk for second contralateral breast cancer was 5 per 10,000 person-years with breast-conserving therapy, 13.6 per 10,000 person-years with unilateral mastectomy, and –28.6 per 10,000 person-years with bilateral mastectomy.
When they looked at risk for death, however they found that, compared with breast-conserving therapy, breast-conserving surgery alone (HR, 1.36; P = .0001) and unilateral mastectomy (HR, 1.21; P less than .001), but not bilateral mastectomy (HR, 1.03; P = .35) were significantly associated with increased risk for breast cancer death.
The authors noted that their estimates of absolute risk of second contralateral breast cancer jibe with those of earlier studies, and can help clinicians frame the discussion of the benefits versus risks for individual patients.
“What one patient might consider to be a negligible benefit of BLM, weighed against its potential harms of greater pain, recovery time, and impact on body image and employment, might appear worthwhile to another,” they wrote.
The study was funded by the National Cancer Institute, National Institutes of Health, Department of Health & Human Services, Suzanne Pride Bryan Fund for Breast Cancer Research, Jan Weimer Faculty Chair for Breast Oncology, and the BRCA Foundation. Dr. Kurian disclosed institutional research funding from Myriad Genetics.
SOURCE: Kurin AW et al. Cancer. 2019 Nov 21. doi: 10.1002/cncr.32618.
FROM CANCER
Oral contraceptive use associated with smaller hypothalamic and pituitary volumes
CHICAGO – Women taking oral contraceptives had, on average, a hypothalamus that was 6% smaller than those who didn’t, in a small study that used magnetic resonance imaging. Pituitary volume was also smaller.
Though the sample size was relatively small, 50 women in total, it’s the only study to date that looks at the relationship between hypothalamic volume and oral contraceptive (OC) use, and the largest examining pituitary volume, according to Ke Xun (Kevin) Chen, MD, who presented the findings at the annual meeting of the Radiological Society of North America.
Using MRI, Dr. Chen and his colleagues found that hypothalamic volume was significantly smaller in women taking oral contraceptives than those who were naturally cycling (b value = –64.1; P = .006). The pituitary gland also was significantly smaller in those taking OCs (b = –92.8; P = .007).
“I was quite surprised [at the finding], because the magnitude of the effect is not small,” especially in the context of changes in volume of other brain structures, senior author Michael L. Lipton, MD, PhD, said in an interview. In Alzheimer’s disease, for example, a volume loss of 4% annually can be expected.
However, “it’s not shocking to me in a negative way at all. I can’t tell you what it means in terms of how it’s going to affect people,” since this is a cross-sectional study that only detected a correlation and can’t say anything about a causative relationship, he added. “We don’t even know that [OCs] cause this effect. ... It’s plausible that this is just a plasticity-related change that’s simply showing us the effect of the drug.
“We’re going to be much more careful to consider oral contraceptive use as a covariate in future research studies; that’s for sure,” he said.
Although OCs have been available since their 1960 Food and Drug Administration approval, and their effects in some areas of physiology and health have been well studied, there’s still not much known about how oral contraceptives affect brain function, said Dr. Lipton, professor of neuroradiology and psychiatry and behavioral sciences at Albert Einstein College of Medicine, in the Montefiore medical system, New York.
The spark for this study came from one of Dr. Lipton’s main areas of research – sex differences in susceptibility to and recovery from traumatic brain injury. “Women are more likely to exhibit changes in their brain [after injury] – and changes in their brain function – than men,” he said.
In the present study, “we went at this trying to understand the effect to which the hormone effect might be doing something in regular, healthy people that we need to consider as part of the bigger picture,” he said.
Dr. Lipton, Dr. Chen (then a radiology resident at Albert Einstein College of Medicine), and their coauthors constructed the study to look for differences in brain structure between women who were experiencing natural menstrual cycles and those who were taking exogenous hormones, to begin to learn how oral contraceptive use might modify risk and susceptibility for neurologic disease and injury.
It had already been established that global brain volume didn’t differ between naturally cycling women and those using OCs. However, some studies had shown differences in volume of some specific brain regions, and one study had shown smaller pituitary volume in OC users, according to the presentation by Dr. Chen, who is now a radiology fellow at Brigham and Women’s Hospital, Boston. Accurately measuring hypothalamic volume represents a technical challenge, and the effect of OCs on the structure’s volume hadn’t previously been studied.
Sex hormones, said Dr. Lipton, have known trophic effects on brain tissue and ovarian sex hormones cross the blood brain barrier, so the idea that there would be some plasticity in the brains of those taking OCs wasn’t completely surprising, especially since there are hormone receptors that lie within the central nervous system. However, he said he was “very surprised” by the effect size seen in the study.
The study included 21 healthy women taking combined oral contraceptives, and 29 naturally cycling women. Participants’ mean age was 23 years for the OC users, and 21 for the naturally cycling women. Body mass index and smoking history didn’t differ between groups. Women on OCs were significantly more likely to use alcohol and to drink more frequently than those not taking OCs (P = .001). Participants were included only if they were taking a combined estrogen-progestin pill; those on noncyclical contraceptives such as implants and hormone-emitting intrauterine devices were excluded, as were naturally cycling women with very long or irregular menstrual cycles.
After multivariable statistical analysis, the only two significant predictors of hypothalamic volume were total intracranial volume and OC use. For pituitary volume, body mass index and OC use remained significant.
In addition to the MRI scans, participants also completed neurobehavioral testing to assess mood and cognition. An exploratory analysis showed no correlation between hypothalamic volume and the cognitive testing battery results, which included assessments for verbal learning and memory, executive function, and working memory.
However, a moderate positive association was seen between hypothalamic volume and anger scores (r = 0.34; P = .02). The investigators found a “strong positive correlation of hypothalamic volume with depression,” said Dr. Chen (r = 0.25; P = .09).
The investigators found no menstrual cycle-related changes in hypothalamic and pituitary volume among naturally cycling women.
Hypothalamic volume was obtained using manual segmentation of the MRIs; a combined automated-manual approach was used to obtain pituitary volume. Reliability was tested by having 5 raters each assess volumes for a randomly selected subset of the scans; inter-rater reliability fell between 0.78 and 0.86, values considered to indicate “good” reliability.
In addition to the small sample size, Dr. Chen acknowledged several limitations to the study. These included the lack of accounting for details of OC use including duration, exact type of OC, and whether women were taking the placebo phase of their pill packs at the time of scanning. Additionally, women who were naturally cycling were not asked about prior history of OC use.
Also, women’s menstrual phase was estimated from the self-reported date of the last menstrual period, rather than obtained by direct measurement via serum hormone levels.
Dr. Lipton’s perspective adds a strong note of caution to avoid overinterpretation from the study. Dr. Chen and Dr. Lipton agreed, however, that OC use should be accounted for when brain structure and function are studied in female participants.
Dr. Chen, Dr. Lipton, and their coauthors reported that they had no conflicts of interest. The authors reported no outside sources of funding.
SOURCE: Chen K et al. RSNA 2019. Presentation SSM-1904.
CHICAGO – Women taking oral contraceptives had, on average, a hypothalamus that was 6% smaller than those who didn’t, in a small study that used magnetic resonance imaging. Pituitary volume was also smaller.
Though the sample size was relatively small, 50 women in total, it’s the only study to date that looks at the relationship between hypothalamic volume and oral contraceptive (OC) use, and the largest examining pituitary volume, according to Ke Xun (Kevin) Chen, MD, who presented the findings at the annual meeting of the Radiological Society of North America.
Using MRI, Dr. Chen and his colleagues found that hypothalamic volume was significantly smaller in women taking oral contraceptives than those who were naturally cycling (b value = –64.1; P = .006). The pituitary gland also was significantly smaller in those taking OCs (b = –92.8; P = .007).
“I was quite surprised [at the finding], because the magnitude of the effect is not small,” especially in the context of changes in volume of other brain structures, senior author Michael L. Lipton, MD, PhD, said in an interview. In Alzheimer’s disease, for example, a volume loss of 4% annually can be expected.
However, “it’s not shocking to me in a negative way at all. I can’t tell you what it means in terms of how it’s going to affect people,” since this is a cross-sectional study that only detected a correlation and can’t say anything about a causative relationship, he added. “We don’t even know that [OCs] cause this effect. ... It’s plausible that this is just a plasticity-related change that’s simply showing us the effect of the drug.
“We’re going to be much more careful to consider oral contraceptive use as a covariate in future research studies; that’s for sure,” he said.
Although OCs have been available since their 1960 Food and Drug Administration approval, and their effects in some areas of physiology and health have been well studied, there’s still not much known about how oral contraceptives affect brain function, said Dr. Lipton, professor of neuroradiology and psychiatry and behavioral sciences at Albert Einstein College of Medicine, in the Montefiore medical system, New York.
The spark for this study came from one of Dr. Lipton’s main areas of research – sex differences in susceptibility to and recovery from traumatic brain injury. “Women are more likely to exhibit changes in their brain [after injury] – and changes in their brain function – than men,” he said.
In the present study, “we went at this trying to understand the effect to which the hormone effect might be doing something in regular, healthy people that we need to consider as part of the bigger picture,” he said.
Dr. Lipton, Dr. Chen (then a radiology resident at Albert Einstein College of Medicine), and their coauthors constructed the study to look for differences in brain structure between women who were experiencing natural menstrual cycles and those who were taking exogenous hormones, to begin to learn how oral contraceptive use might modify risk and susceptibility for neurologic disease and injury.
It had already been established that global brain volume didn’t differ between naturally cycling women and those using OCs. However, some studies had shown differences in volume of some specific brain regions, and one study had shown smaller pituitary volume in OC users, according to the presentation by Dr. Chen, who is now a radiology fellow at Brigham and Women’s Hospital, Boston. Accurately measuring hypothalamic volume represents a technical challenge, and the effect of OCs on the structure’s volume hadn’t previously been studied.
Sex hormones, said Dr. Lipton, have known trophic effects on brain tissue and ovarian sex hormones cross the blood brain barrier, so the idea that there would be some plasticity in the brains of those taking OCs wasn’t completely surprising, especially since there are hormone receptors that lie within the central nervous system. However, he said he was “very surprised” by the effect size seen in the study.
The study included 21 healthy women taking combined oral contraceptives, and 29 naturally cycling women. Participants’ mean age was 23 years for the OC users, and 21 for the naturally cycling women. Body mass index and smoking history didn’t differ between groups. Women on OCs were significantly more likely to use alcohol and to drink more frequently than those not taking OCs (P = .001). Participants were included only if they were taking a combined estrogen-progestin pill; those on noncyclical contraceptives such as implants and hormone-emitting intrauterine devices were excluded, as were naturally cycling women with very long or irregular menstrual cycles.
After multivariable statistical analysis, the only two significant predictors of hypothalamic volume were total intracranial volume and OC use. For pituitary volume, body mass index and OC use remained significant.
In addition to the MRI scans, participants also completed neurobehavioral testing to assess mood and cognition. An exploratory analysis showed no correlation between hypothalamic volume and the cognitive testing battery results, which included assessments for verbal learning and memory, executive function, and working memory.
However, a moderate positive association was seen between hypothalamic volume and anger scores (r = 0.34; P = .02). The investigators found a “strong positive correlation of hypothalamic volume with depression,” said Dr. Chen (r = 0.25; P = .09).
The investigators found no menstrual cycle-related changes in hypothalamic and pituitary volume among naturally cycling women.
Hypothalamic volume was obtained using manual segmentation of the MRIs; a combined automated-manual approach was used to obtain pituitary volume. Reliability was tested by having 5 raters each assess volumes for a randomly selected subset of the scans; inter-rater reliability fell between 0.78 and 0.86, values considered to indicate “good” reliability.
In addition to the small sample size, Dr. Chen acknowledged several limitations to the study. These included the lack of accounting for details of OC use including duration, exact type of OC, and whether women were taking the placebo phase of their pill packs at the time of scanning. Additionally, women who were naturally cycling were not asked about prior history of OC use.
Also, women’s menstrual phase was estimated from the self-reported date of the last menstrual period, rather than obtained by direct measurement via serum hormone levels.
Dr. Lipton’s perspective adds a strong note of caution to avoid overinterpretation from the study. Dr. Chen and Dr. Lipton agreed, however, that OC use should be accounted for when brain structure and function are studied in female participants.
Dr. Chen, Dr. Lipton, and their coauthors reported that they had no conflicts of interest. The authors reported no outside sources of funding.
SOURCE: Chen K et al. RSNA 2019. Presentation SSM-1904.
CHICAGO – Women taking oral contraceptives had, on average, a hypothalamus that was 6% smaller than those who didn’t, in a small study that used magnetic resonance imaging. Pituitary volume was also smaller.
Though the sample size was relatively small, 50 women in total, it’s the only study to date that looks at the relationship between hypothalamic volume and oral contraceptive (OC) use, and the largest examining pituitary volume, according to Ke Xun (Kevin) Chen, MD, who presented the findings at the annual meeting of the Radiological Society of North America.
Using MRI, Dr. Chen and his colleagues found that hypothalamic volume was significantly smaller in women taking oral contraceptives than those who were naturally cycling (b value = –64.1; P = .006). The pituitary gland also was significantly smaller in those taking OCs (b = –92.8; P = .007).
“I was quite surprised [at the finding], because the magnitude of the effect is not small,” especially in the context of changes in volume of other brain structures, senior author Michael L. Lipton, MD, PhD, said in an interview. In Alzheimer’s disease, for example, a volume loss of 4% annually can be expected.
However, “it’s not shocking to me in a negative way at all. I can’t tell you what it means in terms of how it’s going to affect people,” since this is a cross-sectional study that only detected a correlation and can’t say anything about a causative relationship, he added. “We don’t even know that [OCs] cause this effect. ... It’s plausible that this is just a plasticity-related change that’s simply showing us the effect of the drug.
“We’re going to be much more careful to consider oral contraceptive use as a covariate in future research studies; that’s for sure,” he said.
Although OCs have been available since their 1960 Food and Drug Administration approval, and their effects in some areas of physiology and health have been well studied, there’s still not much known about how oral contraceptives affect brain function, said Dr. Lipton, professor of neuroradiology and psychiatry and behavioral sciences at Albert Einstein College of Medicine, in the Montefiore medical system, New York.
The spark for this study came from one of Dr. Lipton’s main areas of research – sex differences in susceptibility to and recovery from traumatic brain injury. “Women are more likely to exhibit changes in their brain [after injury] – and changes in their brain function – than men,” he said.
In the present study, “we went at this trying to understand the effect to which the hormone effect might be doing something in regular, healthy people that we need to consider as part of the bigger picture,” he said.
Dr. Lipton, Dr. Chen (then a radiology resident at Albert Einstein College of Medicine), and their coauthors constructed the study to look for differences in brain structure between women who were experiencing natural menstrual cycles and those who were taking exogenous hormones, to begin to learn how oral contraceptive use might modify risk and susceptibility for neurologic disease and injury.
It had already been established that global brain volume didn’t differ between naturally cycling women and those using OCs. However, some studies had shown differences in volume of some specific brain regions, and one study had shown smaller pituitary volume in OC users, according to the presentation by Dr. Chen, who is now a radiology fellow at Brigham and Women’s Hospital, Boston. Accurately measuring hypothalamic volume represents a technical challenge, and the effect of OCs on the structure’s volume hadn’t previously been studied.
Sex hormones, said Dr. Lipton, have known trophic effects on brain tissue and ovarian sex hormones cross the blood brain barrier, so the idea that there would be some plasticity in the brains of those taking OCs wasn’t completely surprising, especially since there are hormone receptors that lie within the central nervous system. However, he said he was “very surprised” by the effect size seen in the study.
The study included 21 healthy women taking combined oral contraceptives, and 29 naturally cycling women. Participants’ mean age was 23 years for the OC users, and 21 for the naturally cycling women. Body mass index and smoking history didn’t differ between groups. Women on OCs were significantly more likely to use alcohol and to drink more frequently than those not taking OCs (P = .001). Participants were included only if they were taking a combined estrogen-progestin pill; those on noncyclical contraceptives such as implants and hormone-emitting intrauterine devices were excluded, as were naturally cycling women with very long or irregular menstrual cycles.
After multivariable statistical analysis, the only two significant predictors of hypothalamic volume were total intracranial volume and OC use. For pituitary volume, body mass index and OC use remained significant.
In addition to the MRI scans, participants also completed neurobehavioral testing to assess mood and cognition. An exploratory analysis showed no correlation between hypothalamic volume and the cognitive testing battery results, which included assessments for verbal learning and memory, executive function, and working memory.
However, a moderate positive association was seen between hypothalamic volume and anger scores (r = 0.34; P = .02). The investigators found a “strong positive correlation of hypothalamic volume with depression,” said Dr. Chen (r = 0.25; P = .09).
The investigators found no menstrual cycle-related changes in hypothalamic and pituitary volume among naturally cycling women.
Hypothalamic volume was obtained using manual segmentation of the MRIs; a combined automated-manual approach was used to obtain pituitary volume. Reliability was tested by having 5 raters each assess volumes for a randomly selected subset of the scans; inter-rater reliability fell between 0.78 and 0.86, values considered to indicate “good” reliability.
In addition to the small sample size, Dr. Chen acknowledged several limitations to the study. These included the lack of accounting for details of OC use including duration, exact type of OC, and whether women were taking the placebo phase of their pill packs at the time of scanning. Additionally, women who were naturally cycling were not asked about prior history of OC use.
Also, women’s menstrual phase was estimated from the self-reported date of the last menstrual period, rather than obtained by direct measurement via serum hormone levels.
Dr. Lipton’s perspective adds a strong note of caution to avoid overinterpretation from the study. Dr. Chen and Dr. Lipton agreed, however, that OC use should be accounted for when brain structure and function are studied in female participants.
Dr. Chen, Dr. Lipton, and their coauthors reported that they had no conflicts of interest. The authors reported no outside sources of funding.
SOURCE: Chen K et al. RSNA 2019. Presentation SSM-1904.
REPORTING FROM RSNA 2019