Pelin Batur, MD, FACP, NCMP, CCD

“My dear, here we must run as fast as we can, just to stay in place. And if you wish to go anywhere you must run twice as fast as that.”
—Lewis Carroll
Alice’s Adventures in Wonderland

The future of primary care internal medicine physicians is uncertain. According to a 2018 survey of internal medicine residents conducted by the American College of Physicians, only 11% were considering primary care as a career path.¹ In 1998, that number was 54%.²

See related commentary

Possible reasons are many:

• Lower pay compared with subspecialists in a pay system that rewards procedural competency over mental effort
• Work schedules less flexible than in other specialties (eg, hospital medicine practitioners may have 1 week on and 1 week off)
• Perceived lack of respect
• Increasing regulatory and record-keeping burdens
• Tyranny of 15- to 20-minute appointments (irrespective of patient complexity)
• Scope-of-practice concerns as other providers seek primary care equivalency status (eg, pharmacists, walk-in clinics, advanced practice providers, telemedicine providers).

The result is a projected shortage of primary care physicians of 21,100 to 55,200 by 2030, according to a 2019 report by the Association of American Medical Colleges,³ despite an expected growth in advanced practice providers in primary care such as nurse practitioners and physician assistants.

A practical result of this shortage will be even less patient access to primary care physicians. A 2017 national survey found that the average wait time for a new patient-physician appointment has already increased by 30% since 2014.⁴ The wait time to see a primary care physician varied between 29 days in major metropolitan areas (up 50% from 2014) and 56 days in mid-sized markets. The longest waits by market size were 109 days for new patients in Boston, MA, and 122 days for those living in Albany, NY.

What are the implications?

In this issue, Pravia and Diaz⁵ make the case that primary care providers must adapt their practices to meet the needs of younger generations by increasing their use of technology. We agree that telemedicine, wearable medical devices, and enhanced patient communication through the electronic medical record (EMR) are here to stay and should be embraced.

However, we have seen the challenges of adopting technologic advances without first making an adjustment to the volume-driven patient schedule. For such advances to be successfully integrated into a clinical practice, it is vital to be cognizant of the current challenges encountered in primary care internal medicine.

UNIQUE BURDENS ON PRIMARY CARE

In addition to the stress of addressing multiple complex medical problems within a short time, evaluating multiple medical problems often leads to increases in results to review, forms to complete, and calls to patients. Even treatment plans initiated by specialists are often deferred to primary care providers for dosing adjustments, follow-up laboratory testing, and monitoring.

Moreover, patients often seek a second opinion from their primary care provider regarding care provided by subspecialists, as they consider their primary care provider to be the doctor who knows them best. And though it can be personally gratifying to be considered a trusted partner in the patient’s care, these requests often result in additional phone calls to the office or another thing to address within a complex visit.

A large in-box can be daunting in the setting of increased EMR demands. Whether you have difficulty putting in basic orders or are an advanced user, each upgrade can make you feel like you’re using the EMR for the first time. This is a problem for all specialties, but in primary care, one is addressing a large spectrum of concerns, so there is less opportunity to use standardized templates that can help buffer the problem.

A study of primary care providers found that nearly 75% of each patient visit was spent on activities other than face-to-face patient care, including working with the EMR.⁶ Similarly, a study using in-office observations and after-hours diaries found that physicians from various specialties spend 2 hours on administrative duties for each hour that they see patients in the office, followed by an additional 1 to 2 hours of work after clinic, mostly devoted to the EMR.⁷

Clinicians using scribes to help with record-keeping duties often need to see more patients to compensate for the cost. Adding 2 to 3 patients to a daily schedule usually means adding more medical conditions to manage, with an exponential increase in testing and in-box burden.

The additional burden this coverage creates in primary care is often not well understood by those in other specialties.

Another burden unique to primary care providers is the nearly continuous publication of guidelines that are often confusing and discrepant. Because many high-impact guidelines represent expert consensus or evidence from specialist perspectives, they may not fit the primary care model or values: eg, primary care guidelines tend to place more emphasis on harms associated with screening.

Screening for breast and prostate cancers is a prime example. Both require shared decision-making based on patient preferences and values.^8,9 Detailed discussions about preventive screening can be difficult to achieve within the context of a medical visit owing to time limitations, especially if other medical conditions being addressed are equally controversial, such as blood pressure target goals. A decade ago, one could easily declare, “It’s time for your annual PSA test,” and move on to other concerns. Given the changing evidence, an informed patient is now likely to question whether this test should be done, how often it should be done, and whether a prostate examination should also be included.

The push toward population health has raised questions about the value of a preventive wellness visit, especially in healthy patients.^10,11 Arguments against the annual physical do not account for the value of these visits, which provide the opportunity to have time-intensive shared decision-making conversations and build a trusting patient-physician relationship. The value of the annual physical is not simply to do examinations for which there is limited evidence; it is a time for us to get to know our patients, to update their preventive needs (and the medical record), and to discuss which screening tests they may safely forgo to avoid unnecessary false-positives, leading to excess cost and harm.

This trusting relationship, developed over years, is likely to save both the patient and the healthcare system significant money. For example, it enables us to reassure patients that an antibiotic is not needed for their upper respiratory infection, to encourage them to try a dietary change before proceeding with computed tomography for their abdominal pain, or to discourage them from inappropriately aggressive screening tests that may result in overtesting or overdiagnosis.

Unfortunately, it is nearly impossible to accurately quantify these substantial benefits to the healthcare system and patients. And there is a real potential that recommendations against the annual physical may eventually affect future reimbursement, which would add to the time pressures of an already overburdened primary care workforce.

DO PRIMARY CARE PHYSICIANS MAKE A DIFFERENCE?

As medicine and technology evolve, patients have more ways to access care. However, the Internet also provides patients with access to more conflicting information than ever before, making it even more important for clinicians, as trusted partners in their patients’ health, to help patients navigate the waters of information and misinformation.

Studies have shown that having a primary care physician is associated with a longer life span, higher likelihood of reporting good health, and similar clinical outcomes for common conditions such as diabetes and hypertension when compared with subspecialty care, but at a lower cost and with less resource utilization.^12,13 In a study published in 2019, Basu et al¹² found that for every 10 additional primary care physicians per 100,000 population, there was an associated 51.5-day increase in life expectancy, compared with a 19.2-day increase for specialists. Cost savings also occur. Similarly, a review by the American College of Physicians¹³ found that each additional primary care physician per 10,000 population in a US state increased the state’s health quality ranking by more than 10 spots and reduced their overall spending per Medicare beneficiary. In contrast, an increase of 1 specialist per 10,000 population was linked to a 9-spot decrease in health-quality ranking and an increase in spending.

WHY CHOOSE PRIMARY CARE?

As medical students, we fell in love with internal medicine because of the complexity and intellectual challenges of working through a diagnostic dilemma. There is a certain excitement in not knowing what type of patients will show up that day.

Primary care’s focus on continuity and developing long-standing relationships with patients and their families is largely unmatched in the subspecialty field. It is satisfying to have a general knowledge of the human body, and the central vantage point with which to weigh different subspecialty recommendations. We feel such sentiments are common to those interested in primary care, but sadly, we believe these are not enough to sustain the future of primary care internal medicine.

IS THE FUTURE BRIGHT OR BLEAK?

Primary care internists must resist the call to “run twice as fast.” Instead, we need to look for ways where our unique skill sets can benefit the health of our nation while attracting students to internal medicine primary care. The following are potential areas for moving forward.

The aging of America

The US Census Bureau projects that by the year 2035, older adults will outnumber children for the first time in US history, and by the year 2060, nearly 25% of the US population will be 65 or older.¹⁴ The rise of the geriatric patient and the need for comprehensive care will create a continued demand for primary care internists. There certainly aren’t enough geriatricians to meet this need, and primary care internists are well trained to fill this gap.

The rise of the team approach

As we are learning, complex disease management benefits from a team approach. The rise of new models of care delivery such as accountable care organizations and patient-centered medical homes echo this reality. The day of a single provider “doing it all” is fading.

The focus on population health in these models has given rise to multidisciplinary teams—including physicians, nurses, advanced practice providers, social workers, and pharmacists—whose function is to help manage and improve the physical, mental, and social care of patients, often in a capitated payment system. The primary care internist can play a key role in leading these teams, and such partnerships may help lessen reliance on the current primary care hustle of 15- to 20-minute visits. In such models, it is possible that the internist will need to see each patient only once or twice a year, in a longer appointment slot, instead of 4 to 6 times per year in rushed visits. The hope is that this will encourage the relationship-building that is so important in primary care and reduce the time and volume scheduling burdens seen in the current fee-for-service system.

The joy of digging into a diagnostic dilemma has been a hallmark of internal medicine. The rise of technology should enable primary care internists to increase their diagnostic capabilities in the office without an overreliance on subspecialists.

Examples of technology that may benefit primary care are artificial intelligence with real-time diagnostic support, precision medicine, and office-based point-of-care ultrasonography.^15–17 By increasing the diagnostic power of an office-based visit, we hope that the prestige factor of primary care medicine will increase as internists incorporate such advances into their clinics—not to mention the joy of making an appropriate diagnosis in real time.

Reimbursement and the value of time

Time is a valuable commodity for primary care internists. Unfortunately, there seems to be less of it in today’s practice. Gone are the days when we could go to the doctors’ dining room to decompress, chat, and break bread with colleagues. Today, we are more likely to be found in front of our computers over lunch answering patients’ messages. Time is also a key reason that physicians express frustration with issues such as prior authorizations for medications. These tasks routinely take time away from what is valuable—the care of our patients.

The rise of innovative practice models such as direct primary care and concierge medicine can be seen as a market response to the frustrations of increasing regulatory complexity, billing hassles, and lack of time. However, some have cautioned that such models have the potential to worsen healthcare disparities because patients pay out of pocket for some or all of their care in these practices.¹⁸

Interestingly, the Centers for Medicare and Medicaid Services recently unveiled new voluntary payment models for primary care that go into effect in 2020. These models may allow for increased practice innovation. The 2 proposed options are Primary Care First (designed for small primary care practices) and Direct Contracting (aimed at larger practices). These models are designed to provide a predictable up-front payment stream (a set payment per beneficiary) to the primary care practice. Hopefully, these options will move primary care away from the current fee-for-service, multiple-patient-visit model.

The primary care model allows practices to “assume financial risk in exchange for reduced administrative burden and performance-based payments” and “introduces new, higher payments for practices that care for complex, chronically ill patients.”¹⁹ It is too soon to know the effectiveness of such models, but any reimbursement innovation should be met with cautious optimism.

In addition, the Centers for Medicare and Medicaid Services has recently moved to reduce requirements for documentation. For example, one can fully bill with a medical student note without needing to repeat visit notes.^20,21 Such changes should decrease the time needed to document the EMR and free up more time to care for patients.

A CALL TO ACTION

The national shortage of primary care providers points to the fact that this is a difficult career, and one that remains undervalued. One step we need to take is to protect the time we have with patients. It is doubtful that seeing a greater number of sicker patients each day, in addition to the responsibilities of proactive population-based care (“panel management”), will attract younger generations of physicians to fill this void, no matter what technology we adopt.

Keys to facilitating this change include understanding the value of primary care physicians, decreasing the burden of documentation, facilitating team-care options to support them, and expanding diagnostic tools available to use within primary care. If we don’t demand change, who will be there to take care of us when we grow old?

“My dear, here we must run as fast as we can, just to stay in place. And if you wish to go anywhere you must run twice as fast as that.”
—Lewis Carroll
Alice’s Adventures in Wonderland

The future of primary care internal medicine physicians is uncertain. According to a 2018 survey of internal medicine residents conducted by the American College of Physicians, only 11% were considering primary care as a career path.¹ In 1998, that number was 54%.²

See related commentary

Possible reasons are many:

• Lower pay compared with subspecialists in a pay system that rewards procedural competency over mental effort
• Work schedules less flexible than in other specialties (eg, hospital medicine practitioners may have 1 week on and 1 week off)
• Perceived lack of respect
• Increasing regulatory and record-keeping burdens
• Tyranny of 15- to 20-minute appointments (irrespective of patient complexity)
• Scope-of-practice concerns as other providers seek primary care equivalency status (eg, pharmacists, walk-in clinics, advanced practice providers, telemedicine providers).

The result is a projected shortage of primary care physicians of 21,100 to 55,200 by 2030, according to a 2019 report by the Association of American Medical Colleges,³ despite an expected growth in advanced practice providers in primary care such as nurse practitioners and physician assistants.

A practical result of this shortage will be even less patient access to primary care physicians. A 2017 national survey found that the average wait time for a new patient-physician appointment has already increased by 30% since 2014.⁴ The wait time to see a primary care physician varied between 29 days in major metropolitan areas (up 50% from 2014) and 56 days in mid-sized markets. The longest waits by market size were 109 days for new patients in Boston, MA, and 122 days for those living in Albany, NY.

What are the implications?

In this issue, Pravia and Diaz⁵ make the case that primary care providers must adapt their practices to meet the needs of younger generations by increasing their use of technology. We agree that telemedicine, wearable medical devices, and enhanced patient communication through the electronic medical record (EMR) are here to stay and should be embraced.

However, we have seen the challenges of adopting technologic advances without first making an adjustment to the volume-driven patient schedule. For such advances to be successfully integrated into a clinical practice, it is vital to be cognizant of the current challenges encountered in primary care internal medicine.

UNIQUE BURDENS ON PRIMARY CARE

In addition to the stress of addressing multiple complex medical problems within a short time, evaluating multiple medical problems often leads to increases in results to review, forms to complete, and calls to patients. Even treatment plans initiated by specialists are often deferred to primary care providers for dosing adjustments, follow-up laboratory testing, and monitoring.

Moreover, patients often seek a second opinion from their primary care provider regarding care provided by subspecialists, as they consider their primary care provider to be the doctor who knows them best. And though it can be personally gratifying to be considered a trusted partner in the patient’s care, these requests often result in additional phone calls to the office or another thing to address within a complex visit.

A large in-box can be daunting in the setting of increased EMR demands. Whether you have difficulty putting in basic orders or are an advanced user, each upgrade can make you feel like you’re using the EMR for the first time. This is a problem for all specialties, but in primary care, one is addressing a large spectrum of concerns, so there is less opportunity to use standardized templates that can help buffer the problem.

A study of primary care providers found that nearly 75% of each patient visit was spent on activities other than face-to-face patient care, including working with the EMR.⁶ Similarly, a study using in-office observations and after-hours diaries found that physicians from various specialties spend 2 hours on administrative duties for each hour that they see patients in the office, followed by an additional 1 to 2 hours of work after clinic, mostly devoted to the EMR.⁷

Clinicians using scribes to help with record-keeping duties often need to see more patients to compensate for the cost. Adding 2 to 3 patients to a daily schedule usually means adding more medical conditions to manage, with an exponential increase in testing and in-box burden.

The additional burden this coverage creates in primary care is often not well understood by those in other specialties.

Another burden unique to primary care providers is the nearly continuous publication of guidelines that are often confusing and discrepant. Because many high-impact guidelines represent expert consensus or evidence from specialist perspectives, they may not fit the primary care model or values: eg, primary care guidelines tend to place more emphasis on harms associated with screening.

Screening for breast and prostate cancers is a prime example. Both require shared decision-making based on patient preferences and values.^8,9 Detailed discussions about preventive screening can be difficult to achieve within the context of a medical visit owing to time limitations, especially if other medical conditions being addressed are equally controversial, such as blood pressure target goals. A decade ago, one could easily declare, “It’s time for your annual PSA test,” and move on to other concerns. Given the changing evidence, an informed patient is now likely to question whether this test should be done, how often it should be done, and whether a prostate examination should also be included.

The push toward population health has raised questions about the value of a preventive wellness visit, especially in healthy patients.^10,11 Arguments against the annual physical do not account for the value of these visits, which provide the opportunity to have time-intensive shared decision-making conversations and build a trusting patient-physician relationship. The value of the annual physical is not simply to do examinations for which there is limited evidence; it is a time for us to get to know our patients, to update their preventive needs (and the medical record), and to discuss which screening tests they may safely forgo to avoid unnecessary false-positives, leading to excess cost and harm.

This trusting relationship, developed over years, is likely to save both the patient and the healthcare system significant money. For example, it enables us to reassure patients that an antibiotic is not needed for their upper respiratory infection, to encourage them to try a dietary change before proceeding with computed tomography for their abdominal pain, or to discourage them from inappropriately aggressive screening tests that may result in overtesting or overdiagnosis.

Unfortunately, it is nearly impossible to accurately quantify these substantial benefits to the healthcare system and patients. And there is a real potential that recommendations against the annual physical may eventually affect future reimbursement, which would add to the time pressures of an already overburdened primary care workforce.

DO PRIMARY CARE PHYSICIANS MAKE A DIFFERENCE?

As medicine and technology evolve, patients have more ways to access care. However, the Internet also provides patients with access to more conflicting information than ever before, making it even more important for clinicians, as trusted partners in their patients’ health, to help patients navigate the waters of information and misinformation.

Studies have shown that having a primary care physician is associated with a longer life span, higher likelihood of reporting good health, and similar clinical outcomes for common conditions such as diabetes and hypertension when compared with subspecialty care, but at a lower cost and with less resource utilization.^12,13 In a study published in 2019, Basu et al¹² found that for every 10 additional primary care physicians per 100,000 population, there was an associated 51.5-day increase in life expectancy, compared with a 19.2-day increase for specialists. Cost savings also occur. Similarly, a review by the American College of Physicians¹³ found that each additional primary care physician per 10,000 population in a US state increased the state’s health quality ranking by more than 10 spots and reduced their overall spending per Medicare beneficiary. In contrast, an increase of 1 specialist per 10,000 population was linked to a 9-spot decrease in health-quality ranking and an increase in spending.

WHY CHOOSE PRIMARY CARE?

As medical students, we fell in love with internal medicine because of the complexity and intellectual challenges of working through a diagnostic dilemma. There is a certain excitement in not knowing what type of patients will show up that day.

Primary care’s focus on continuity and developing long-standing relationships with patients and their families is largely unmatched in the subspecialty field. It is satisfying to have a general knowledge of the human body, and the central vantage point with which to weigh different subspecialty recommendations. We feel such sentiments are common to those interested in primary care, but sadly, we believe these are not enough to sustain the future of primary care internal medicine.

IS THE FUTURE BRIGHT OR BLEAK?

Primary care internists must resist the call to “run twice as fast.” Instead, we need to look for ways where our unique skill sets can benefit the health of our nation while attracting students to internal medicine primary care. The following are potential areas for moving forward.

The aging of America

The US Census Bureau projects that by the year 2035, older adults will outnumber children for the first time in US history, and by the year 2060, nearly 25% of the US population will be 65 or older.¹⁴ The rise of the geriatric patient and the need for comprehensive care will create a continued demand for primary care internists. There certainly aren’t enough geriatricians to meet this need, and primary care internists are well trained to fill this gap.

The rise of the team approach

As we are learning, complex disease management benefits from a team approach. The rise of new models of care delivery such as accountable care organizations and patient-centered medical homes echo this reality. The day of a single provider “doing it all” is fading.

The focus on population health in these models has given rise to multidisciplinary teams—including physicians, nurses, advanced practice providers, social workers, and pharmacists—whose function is to help manage and improve the physical, mental, and social care of patients, often in a capitated payment system. The primary care internist can play a key role in leading these teams, and such partnerships may help lessen reliance on the current primary care hustle of 15- to 20-minute visits. In such models, it is possible that the internist will need to see each patient only once or twice a year, in a longer appointment slot, instead of 4 to 6 times per year in rushed visits. The hope is that this will encourage the relationship-building that is so important in primary care and reduce the time and volume scheduling burdens seen in the current fee-for-service system.

The joy of digging into a diagnostic dilemma has been a hallmark of internal medicine. The rise of technology should enable primary care internists to increase their diagnostic capabilities in the office without an overreliance on subspecialists.

Examples of technology that may benefit primary care are artificial intelligence with real-time diagnostic support, precision medicine, and office-based point-of-care ultrasonography.^15–17 By increasing the diagnostic power of an office-based visit, we hope that the prestige factor of primary care medicine will increase as internists incorporate such advances into their clinics—not to mention the joy of making an appropriate diagnosis in real time.

Reimbursement and the value of time

Time is a valuable commodity for primary care internists. Unfortunately, there seems to be less of it in today’s practice. Gone are the days when we could go to the doctors’ dining room to decompress, chat, and break bread with colleagues. Today, we are more likely to be found in front of our computers over lunch answering patients’ messages. Time is also a key reason that physicians express frustration with issues such as prior authorizations for medications. These tasks routinely take time away from what is valuable—the care of our patients.

The rise of innovative practice models such as direct primary care and concierge medicine can be seen as a market response to the frustrations of increasing regulatory complexity, billing hassles, and lack of time. However, some have cautioned that such models have the potential to worsen healthcare disparities because patients pay out of pocket for some or all of their care in these practices.¹⁸

Interestingly, the Centers for Medicare and Medicaid Services recently unveiled new voluntary payment models for primary care that go into effect in 2020. These models may allow for increased practice innovation. The 2 proposed options are Primary Care First (designed for small primary care practices) and Direct Contracting (aimed at larger practices). These models are designed to provide a predictable up-front payment stream (a set payment per beneficiary) to the primary care practice. Hopefully, these options will move primary care away from the current fee-for-service, multiple-patient-visit model.

The primary care model allows practices to “assume financial risk in exchange for reduced administrative burden and performance-based payments” and “introduces new, higher payments for practices that care for complex, chronically ill patients.”¹⁹ It is too soon to know the effectiveness of such models, but any reimbursement innovation should be met with cautious optimism.

In addition, the Centers for Medicare and Medicaid Services has recently moved to reduce requirements for documentation. For example, one can fully bill with a medical student note without needing to repeat visit notes.^20,21 Such changes should decrease the time needed to document the EMR and free up more time to care for patients.

A CALL TO ACTION

The national shortage of primary care providers points to the fact that this is a difficult career, and one that remains undervalued. One step we need to take is to protect the time we have with patients. It is doubtful that seeing a greater number of sicker patients each day, in addition to the responsibilities of proactive population-based care (“panel management”), will attract younger generations of physicians to fill this void, no matter what technology we adopt.

Keys to facilitating this change include understanding the value of primary care physicians, decreasing the burden of documentation, facilitating team-care options to support them, and expanding diagnostic tools available to use within primary care. If we don’t demand change, who will be there to take care of us when we grow old?

“My dear, here we must run as fast as we can, just to stay in place. And if you wish to go anywhere you must run twice as fast as that.”
—Lewis Carroll
Alice’s Adventures in Wonderland

The future of primary care internal medicine physicians is uncertain. According to a 2018 survey of internal medicine residents conducted by the American College of Physicians, only 11% were considering primary care as a career path.¹ In 1998, that number was 54%.²

See related commentary

Possible reasons are many:

• Lower pay compared with subspecialists in a pay system that rewards procedural competency over mental effort
• Work schedules less flexible than in other specialties (eg, hospital medicine practitioners may have 1 week on and 1 week off)
• Perceived lack of respect
• Increasing regulatory and record-keeping burdens
• Tyranny of 15- to 20-minute appointments (irrespective of patient complexity)
• Scope-of-practice concerns as other providers seek primary care equivalency status (eg, pharmacists, walk-in clinics, advanced practice providers, telemedicine providers).

The result is a projected shortage of primary care physicians of 21,100 to 55,200 by 2030, according to a 2019 report by the Association of American Medical Colleges,³ despite an expected growth in advanced practice providers in primary care such as nurse practitioners and physician assistants.

A practical result of this shortage will be even less patient access to primary care physicians. A 2017 national survey found that the average wait time for a new patient-physician appointment has already increased by 30% since 2014.⁴ The wait time to see a primary care physician varied between 29 days in major metropolitan areas (up 50% from 2014) and 56 days in mid-sized markets. The longest waits by market size were 109 days for new patients in Boston, MA, and 122 days for those living in Albany, NY.

What are the implications?

In this issue, Pravia and Diaz⁵ make the case that primary care providers must adapt their practices to meet the needs of younger generations by increasing their use of technology. We agree that telemedicine, wearable medical devices, and enhanced patient communication through the electronic medical record (EMR) are here to stay and should be embraced.

However, we have seen the challenges of adopting technologic advances without first making an adjustment to the volume-driven patient schedule. For such advances to be successfully integrated into a clinical practice, it is vital to be cognizant of the current challenges encountered in primary care internal medicine.

UNIQUE BURDENS ON PRIMARY CARE

In addition to the stress of addressing multiple complex medical problems within a short time, evaluating multiple medical problems often leads to increases in results to review, forms to complete, and calls to patients. Even treatment plans initiated by specialists are often deferred to primary care providers for dosing adjustments, follow-up laboratory testing, and monitoring.

Moreover, patients often seek a second opinion from their primary care provider regarding care provided by subspecialists, as they consider their primary care provider to be the doctor who knows them best. And though it can be personally gratifying to be considered a trusted partner in the patient’s care, these requests often result in additional phone calls to the office or another thing to address within a complex visit.

A large in-box can be daunting in the setting of increased EMR demands. Whether you have difficulty putting in basic orders or are an advanced user, each upgrade can make you feel like you’re using the EMR for the first time. This is a problem for all specialties, but in primary care, one is addressing a large spectrum of concerns, so there is less opportunity to use standardized templates that can help buffer the problem.

A study of primary care providers found that nearly 75% of each patient visit was spent on activities other than face-to-face patient care, including working with the EMR.⁶ Similarly, a study using in-office observations and after-hours diaries found that physicians from various specialties spend 2 hours on administrative duties for each hour that they see patients in the office, followed by an additional 1 to 2 hours of work after clinic, mostly devoted to the EMR.⁷

Clinicians using scribes to help with record-keeping duties often need to see more patients to compensate for the cost. Adding 2 to 3 patients to a daily schedule usually means adding more medical conditions to manage, with an exponential increase in testing and in-box burden.

The additional burden this coverage creates in primary care is often not well understood by those in other specialties.

Another burden unique to primary care providers is the nearly continuous publication of guidelines that are often confusing and discrepant. Because many high-impact guidelines represent expert consensus or evidence from specialist perspectives, they may not fit the primary care model or values: eg, primary care guidelines tend to place more emphasis on harms associated with screening.

Screening for breast and prostate cancers is a prime example. Both require shared decision-making based on patient preferences and values.^8,9 Detailed discussions about preventive screening can be difficult to achieve within the context of a medical visit owing to time limitations, especially if other medical conditions being addressed are equally controversial, such as blood pressure target goals. A decade ago, one could easily declare, “It’s time for your annual PSA test,” and move on to other concerns. Given the changing evidence, an informed patient is now likely to question whether this test should be done, how often it should be done, and whether a prostate examination should also be included.

The push toward population health has raised questions about the value of a preventive wellness visit, especially in healthy patients.^10,11 Arguments against the annual physical do not account for the value of these visits, which provide the opportunity to have time-intensive shared decision-making conversations and build a trusting patient-physician relationship. The value of the annual physical is not simply to do examinations for which there is limited evidence; it is a time for us to get to know our patients, to update their preventive needs (and the medical record), and to discuss which screening tests they may safely forgo to avoid unnecessary false-positives, leading to excess cost and harm.

This trusting relationship, developed over years, is likely to save both the patient and the healthcare system significant money. For example, it enables us to reassure patients that an antibiotic is not needed for their upper respiratory infection, to encourage them to try a dietary change before proceeding with computed tomography for their abdominal pain, or to discourage them from inappropriately aggressive screening tests that may result in overtesting or overdiagnosis.

Unfortunately, it is nearly impossible to accurately quantify these substantial benefits to the healthcare system and patients. And there is a real potential that recommendations against the annual physical may eventually affect future reimbursement, which would add to the time pressures of an already overburdened primary care workforce.

DO PRIMARY CARE PHYSICIANS MAKE A DIFFERENCE?

As medicine and technology evolve, patients have more ways to access care. However, the Internet also provides patients with access to more conflicting information than ever before, making it even more important for clinicians, as trusted partners in their patients’ health, to help patients navigate the waters of information and misinformation.

Studies have shown that having a primary care physician is associated with a longer life span, higher likelihood of reporting good health, and similar clinical outcomes for common conditions such as diabetes and hypertension when compared with subspecialty care, but at a lower cost and with less resource utilization.^12,13 In a study published in 2019, Basu et al¹² found that for every 10 additional primary care physicians per 100,000 population, there was an associated 51.5-day increase in life expectancy, compared with a 19.2-day increase for specialists. Cost savings also occur. Similarly, a review by the American College of Physicians¹³ found that each additional primary care physician per 10,000 population in a US state increased the state’s health quality ranking by more than 10 spots and reduced their overall spending per Medicare beneficiary. In contrast, an increase of 1 specialist per 10,000 population was linked to a 9-spot decrease in health-quality ranking and an increase in spending.

WHY CHOOSE PRIMARY CARE?

As medical students, we fell in love with internal medicine because of the complexity and intellectual challenges of working through a diagnostic dilemma. There is a certain excitement in not knowing what type of patients will show up that day.

Primary care’s focus on continuity and developing long-standing relationships with patients and their families is largely unmatched in the subspecialty field. It is satisfying to have a general knowledge of the human body, and the central vantage point with which to weigh different subspecialty recommendations. We feel such sentiments are common to those interested in primary care, but sadly, we believe these are not enough to sustain the future of primary care internal medicine.

IS THE FUTURE BRIGHT OR BLEAK?

Primary care internists must resist the call to “run twice as fast.” Instead, we need to look for ways where our unique skill sets can benefit the health of our nation while attracting students to internal medicine primary care. The following are potential areas for moving forward.

The aging of America

The US Census Bureau projects that by the year 2035, older adults will outnumber children for the first time in US history, and by the year 2060, nearly 25% of the US population will be 65 or older.¹⁴ The rise of the geriatric patient and the need for comprehensive care will create a continued demand for primary care internists. There certainly aren’t enough geriatricians to meet this need, and primary care internists are well trained to fill this gap.

The rise of the team approach

As we are learning, complex disease management benefits from a team approach. The rise of new models of care delivery such as accountable care organizations and patient-centered medical homes echo this reality. The day of a single provider “doing it all” is fading.

The focus on population health in these models has given rise to multidisciplinary teams—including physicians, nurses, advanced practice providers, social workers, and pharmacists—whose function is to help manage and improve the physical, mental, and social care of patients, often in a capitated payment system. The primary care internist can play a key role in leading these teams, and such partnerships may help lessen reliance on the current primary care hustle of 15- to 20-minute visits. In such models, it is possible that the internist will need to see each patient only once or twice a year, in a longer appointment slot, instead of 4 to 6 times per year in rushed visits. The hope is that this will encourage the relationship-building that is so important in primary care and reduce the time and volume scheduling burdens seen in the current fee-for-service system.

The joy of digging into a diagnostic dilemma has been a hallmark of internal medicine. The rise of technology should enable primary care internists to increase their diagnostic capabilities in the office without an overreliance on subspecialists.

Examples of technology that may benefit primary care are artificial intelligence with real-time diagnostic support, precision medicine, and office-based point-of-care ultrasonography.^15–17 By increasing the diagnostic power of an office-based visit, we hope that the prestige factor of primary care medicine will increase as internists incorporate such advances into their clinics—not to mention the joy of making an appropriate diagnosis in real time.

Reimbursement and the value of time

Time is a valuable commodity for primary care internists. Unfortunately, there seems to be less of it in today’s practice. Gone are the days when we could go to the doctors’ dining room to decompress, chat, and break bread with colleagues. Today, we are more likely to be found in front of our computers over lunch answering patients’ messages. Time is also a key reason that physicians express frustration with issues such as prior authorizations for medications. These tasks routinely take time away from what is valuable—the care of our patients.

The rise of innovative practice models such as direct primary care and concierge medicine can be seen as a market response to the frustrations of increasing regulatory complexity, billing hassles, and lack of time. However, some have cautioned that such models have the potential to worsen healthcare disparities because patients pay out of pocket for some or all of their care in these practices.¹⁸

Interestingly, the Centers for Medicare and Medicaid Services recently unveiled new voluntary payment models for primary care that go into effect in 2020. These models may allow for increased practice innovation. The 2 proposed options are Primary Care First (designed for small primary care practices) and Direct Contracting (aimed at larger practices). These models are designed to provide a predictable up-front payment stream (a set payment per beneficiary) to the primary care practice. Hopefully, these options will move primary care away from the current fee-for-service, multiple-patient-visit model.

The primary care model allows practices to “assume financial risk in exchange for reduced administrative burden and performance-based payments” and “introduces new, higher payments for practices that care for complex, chronically ill patients.”¹⁹ It is too soon to know the effectiveness of such models, but any reimbursement innovation should be met with cautious optimism.

In addition, the Centers for Medicare and Medicaid Services has recently moved to reduce requirements for documentation. For example, one can fully bill with a medical student note without needing to repeat visit notes.^20,21 Such changes should decrease the time needed to document the EMR and free up more time to care for patients.

A CALL TO ACTION

The national shortage of primary care providers points to the fact that this is a difficult career, and one that remains undervalued. One step we need to take is to protect the time we have with patients. It is doubtful that seeing a greater number of sicker patients each day, in addition to the responsibilities of proactive population-based care (“panel management”), will attract younger generations of physicians to fill this void, no matter what technology we adopt.

Keys to facilitating this change include understanding the value of primary care physicians, decreasing the burden of documentation, facilitating team-care options to support them, and expanding diagnostic tools available to use within primary care. If we don’t demand change, who will be there to take care of us when we grow old?

Keeping up with current evidence-based healthcare practices is key to providing good clinical care to patients. This review presents 5 vignettes that highlight key issues in women’s health: osteoporosis screening, hormonal contraceptive interactions with antibiotics, hormone replacement therapy in carriers of the BRCA1 gene mutation, risks associated with hormonal contraception, and breast cancer diagnosis using digital tomosynthesis in addition to digital mammography. Supporting articles, all published in 2017 and 2018, were selected from high-impact medical and women’s health journals.

OSTEOPOROSIS SCREENING FOR FRACTURE PREVENTION

A 60-year-old woman reports that her last menstrual period was 7 years ago. She has no history of falls or fractures, and she takes no medications. She smokes 10 cigarettes per day and drinks 3 to 4 alcoholic beverages on most days of the week. She is 5 feet 6 inches (170 cm) tall and weighs 107 lb. Should she be screened for osteoporosis?

Osteoporosis is underdiagnosed

It is estimated that, in the United States, 12.3 million individuals older than 50 will develop osteoporosis by 2020. Missed opportunities to screen high-risk individuals can lead to fractures, including fractures of the hip.¹

Updated screening recommendations

In 2018, the US Preventive Services Task Force (USPSTF) developed and published evidence-based recommendations for osteoporosis screening to help providers identify and treat osteoporosis early to prevent fractures.² Available evidence on screening and treatment in women and men were reviewed with the intention of updating the 2011 USPSTF recommendations. The review also evaluated risk assessment tools, screening intervals, and efficacy of screening and treatment in various subpopulations.

Since the 2011 recommendations, more data have become available on fracture risk assessment with or without bone mineral density measurements. In its 2018 report, the USPSTF recommends that postmenopausal women younger than 65 should undergo screening with a bone density test if their 10-year risk of major osteoporotic fracture is more than 8.4%. This is equivalent to the fracture risk of a 65-year-old white woman with no major risk factors for fracture (grade B recommendation—high certainty that the benefit is moderate, or moderate certainty that the benefit is moderate to substantial).²

Assessment of fracture risk

For postmenopausal women who are under age 65 and who have at least 1 risk factor for fracture, it is reasonable to use a clinical risk assessment tool to determine who should undergo screening with bone mineral density measurement. Risk factors associated with an increased risk of osteoporotic fractures include a parental history of hip fracture, smoking, intake of 3 or more alcoholic drinks per day, low body weight, malabsorption, rheumatoid arthritis, diabetes, and postmenopausal status (not using estrogen replacement). Medications should be carefully reviewed for those that can increase the risk of fractures, including steroids and antiestrogen treatments.

The 10-year risk of a major osteoporotic or hip fracture can be assessed using the Fractional Risk Assessment Tool (FRAX), available at www.sheffield.ac.uk/FRAX/. Other acceptable tools that perform similarly to FRAX include the Osteoporosis Risk Assessment Instrument (ORAI) (10 studies; N = 16,780), Osteoporosis Index of Risk (OSIRIS) (5 studies; N = 5,649), Osteoporosis Self-Assessment Tool (OST) (13 studies; N = 44,323), and Simple Calculated Osteoporosis Risk Estimation (SCORE) (8 studies; N = 15,362).

Should this patient be screened for osteoporosis?

Based on the FRAX, this patient’s 10-year risk of major osteoporosis fracture is 9.2%. She would benefit from osteoporosis screening with a bone density test.

DO ANTIBIOTICS REDUCE EFFECTIVENESS OF HORMONAL CONTRACEPTION?

A 27-year-old woman presents with a dog bite on her right hand and is started on oral antibiotics. She takes an oral contraceptive that contains 35 µg of ethinyl estradiol and 0.25 mg of norgestimate. She asks if she should use condoms while taking antibiotics.

The antibiotics rifampin and rifabutin are known inducers of the hepatic enzymes required for contraceptive steroid metabolism, whereas other antibiotics are not. Despite the lack of compelling evidence that broad-spectrum antibiotics interfere with the efficacy of hormonal contraception, most pharmacists recommend backup contraception for women who use concomitant antibiotics.³ This practice could lead to poor compliance with the contraceptive regimen, the antibiotic regimen, or both.³

Simmons et al³ conducted a systematic review of randomized and nonrandomized studies that assessed pregnancy rates, breakthrough bleeding, ovulation suppression, and hormone pharmacokinetics in women taking oral or vaginal hormonal contraceptives in combination with nonrifamycin antibiotics, including oral, intramuscular, and intravenous forms. Oral contraceptives used in the studies included a range of doses and progestins, but lowest-dose pills, such as those containing less than 30 µg ethinyl estradiol or less than 150 µg levonorgestrel, were not included.

The contraceptive formulations in this systematic review³ included oral contraceptive pills, emergency contraception pills, and the contraceptive vaginal ring. The effect of antibiotics on other nonoral contraceptives, such as the transdermal patch, injectables, and progestin implants was not studied.

Four observational studies³ evaluated pregnancy rates or hormonal contraception failure with any antibiotic use. In 2 of these 4 studies, there was no difference in pregnancy rates in women who used oral contraceptives with and without nonrifamycin antibiotics. However, ethinyl estradiol was shown to have increased clearance when administered with dirithromycin (a macrolide).³ Twenty-five of the studies reported measures of contraceptive effectiveness (ovulation) and pharmacokinetic outcomes.

There were no observed differences in ovulation suppression or breakthrough bleeding in any study that combined hormonal contraceptives with an antibiotic. Furthermore, there was no significant decrease in progestin pharmacokinetic parameters during coadministration with an antibiotic.³ Study limitations included small sample sizes and the observational nature of the data.

How would you counsel this patient?

Available evidence suggests that nonrifamycin antibiotics do not diminish the effectiveness of the vaginal contraceptive ring or an oral hormonal contraceptive that contains at least 30 µg of ethinyl estradiol or 150 µg of levonorgestrel. Current guidelines do not recommend the use of additional backup contraception, regardless of hormonal contraception dose or formulation.⁴ Likewise, the most recent guidance for dental practitioners (ie, from 2012) no longer advises women to use additional contraceptive protection when taking nonrifamycin antibiotics.⁵

In our practice, we discuss the option of additional protection when prescribing formulations with lower estrogen doses (< 30 µg), not only because of the limitations of the available data, but also because of the high rates of unintended pregnancy with typical use of combined hormonal contraceptives (9% per year, unrelated to use of antibiotics).⁴ However, if our patient would rather not use additional barrier methods, she can be reassured that concomitant nonrifamycin antibiotic use is unlikely to affect contraceptive effectiveness.

A 41-year-old healthy mother of 3 was recently found to be a carrier of the BRCA1 mutation. She is planning to undergo prophylactic bilateral salpingo-oophorectomy for ovarian cancer prevention. However, she is apprehensive about undergoing surgical menopause. Should she be started on hormone replacement therapy after oophorectomy? How would hormone replacement therapy affect her risk of breast cancer?

In females who carry the BRCA1 mutation, the cumulative risk of both ovarian and breast cancer approaches 44% (95% confidence interval [CI] 36%–53%) and 72% (95% CI 65%–79%) by age 80.⁶ Prophylactic salpingo-oophorectomy reduces the risk of breast cancer by 50% and the risk of ovarian cancer by 90%. Unfortunately, premature withdrawal of ovarian hormones has been associated with long-term adverse effects including significant vasomotor symptoms, decreased quality of life, sexual dysfunction, early mortality, bone loss, decline in mood and cognition, and poor cardiovascular outcomes.⁷ Many of these effects can be avoided or lessened with hormone replacement therapy.

Kotsopoulos et al⁸ conducted a longitudinal, prospective analysis of BRCA1 mutation carriers in a multicenter study between 1995 and 2017. The mean follow-up period was 7.6 years (range 0.4–22.1). The study assessed associations between the use of hormone replacement therapy and breast cancer risk in carriers of the BRCA1 mutation who underwent prophylactic salpingo-oophorectomy. Study participants did not have a personal history of cancer. Those with a history of prophylactic mastectomy were excluded.

Participants completed a series of questionnaires every 2 years, disclosing updates in personal medical, cancer, and reproductive history. The questionnaires also inquired about the use of hormone replacement therapy, including the type used (estrogen only, progestin only, estrogen plus progestin, other), brand name, duration of use, and dose and route of administration (pill, patch, suppository).

Of the 13,087 BRCA1 mutation carriers identified, 872 met the study criteria. Of those, 377 (43%) reported using some form of hormone replacement therapy after salpingo-oophorectomy, and 495 (57%) did not. The average duration of use was 3.9 years (range 0.5–19), with most (69%) using estrogen alone; 18% used other regimens, including estrogen plus progestin and progestin only. A small percentage of participants did not indicate which formulation they used. On average, women using hormone replacement therapy underwent prophylactic oophorectomy earlier than nonusers (age 43.0 vs 48.4; absolute difference 5.5 years, P < .001).

During follow-up, there was no significant difference noted in the proportion of women diagnosed with breast cancer between hormone replacement therapy users and nonusers (10.3 vs 10.7%; absolute difference 0.4%; P = .86). In fact, for each year of estrogen-containing hormone replacement therapy, there was an 18% reduction in breast cancer risk when oophorectomy was performed before age 45 (95% CI 0.69–0.97). The authors also noted a nonsignificant 14% trend toward an increase in breast cancer risk for each year of progestin use after oophorectomy when surgery was performed before age 45 (95% CI 0.9–1.46).

Although prophylactic hysterectomy was not recommended, the authors noted that hysterectomy would eliminate the need for progestin-containing hormone replacement therapy. For those who underwent oophorectomy after age 45, hormone replacement therapy did not increase or decrease the risk of breast cancer.⁷

A meta-analysis by Marchetti et al⁹ also supports the safety of hormone replacement therapy after risk-reducing salpingo-oophorectomy. Three studies that included 1,100 patients were analyzed (including the Kotsopoulos study⁸ noted above). There was a nonsignificant decrease in breast cancer risk in women on estrogen-only hormone replacement therapy compared with women on estrogen-plus-progestin therapy (odds ratio 0.53, 95% CI 0.25–1.15). Overall, the authors regarded hormone replacement therapy as a safe therapeutic option after prophylactic salpingo-oophorectomy in carriers of the BRCA1 and BRCA2 mutations.⁹

In a case-control study published in 2016,¹⁰ hormone replacement therapy was assessed in 432 postmenopausal BRCA1 mutation carriers with invasive breast cancer (cases) and in 432 BRCA1 mutation carriers without a history of breast cancer (controls). Results showed no difference in breast cancer risk between hormone replacement therapy users and nonusers.¹⁰

Rebbeck et al¹¹ evaluated short-term hormone replacement therapy in BRCA1 and BRCA2 gene-mutation carriers after they underwent prophylactic salpingo-oophorectomy. The results showed that hormone replacement did not affect the breast cancer risk-reduction conferred with prophylactic bilateral salpingo-oophorectomy.

Johansen et al¹² evaluated hormone replacement therapy in premenopausal women after prophylactic salpingo-oophorectomy. They studied 324 carriers of BRCA gene mutations after they underwent prophylactic salpingo-oophorectomy and a subset of 950 controls who had bilateral salpingo-oophorectomy for reasons unrelated to cancer. In both groups, hormone replacement therapy was underutilized. The authors recommended using it when clinically indicated.

Should your patient start hormone replacement therapy?

This patient is healthy, and in the absence of contraindications, systemic hormone replacement therapy after prophylactic oophorectomy could mitigate the potential adverse effects of surgically induced menopause. The patient can be reassured that estrogen-containing short-term hormone replacement therapy is unlikely to increase her breast cancer risk.

A 44-year-old woman presents to your office for an annual visit. She is sexually active but does not wish to become pregnant. She has a family history of breast cancer: her mother was diagnosed at age 53. She is interested in an oral contraceptive to prevent pregnancy and acne. However, she is nervous about being on any contraceptive that may increase her risk of breast cancer.

To date, studies assessing the effect of hormonal contraception on the risk of breast cancer have produced inconsistent results. Although most studies have shown no associated risk, a few have shown a temporary 20% to 30% increased risk of breast cancer during use.^13,14 Case-controlled studies that reported an association between hormonal contraception and breast cancer included populations taking higher-dose combination pills, which are no longer prescribed. Most studies do not evaluate specific formulations of hormonal contraception, and little is known about effects associated with intrauterine devices or progestin-only contraception.

A prospective study performed by Mørch et al¹³ followed more than 1 million reproductive-aged women for a mean of 10.9 years. The Danish Cancer Registry was used to identify cases of invasive breast cancer. Women who used hormonal contraceptives had a relative risk of breast cancer of 1.20 compared with women not on hormonal contraception (95% CI 1.14–1.26). The study suggested that those who had been on contraceptive agents for more than 5 years had an increased risk and that this risk remained for 5 years after the agents were discontinued. Conversely, no increased risk of cancer was noted in those who used hormonal contraception for less than 5 years. No notable differences were seen among various formulations.

For women using the levonorgestrel-containing intrauterine device, the relative risk of breast cancer was 1.21 (95% CI 1.11–1.33). A few cancers were noted in those who used the progestin-only implant or those using depot medroxyprogesterone acetate. While the study showed an increased relative risk of breast cancer, the absolute risk was low—13 cases per 100,000, or approximately 1 additional case of breast cancer per 7,690 per year.¹³

This study had several important limitations. The authors did not adjust for common breast cancer risk factors including age at menarche, alcohol use, or breastfeeding. Additionally, the study did not account for the use of hormonal contraception before the study period and conversely, did not account for women who may have stopped taking their contraceptive despite their prescribed duration. The frequency of mammography was not explicitly noted, which could have shifted results for women who had more aggressive screening.

It is also noteworthy that the use of high-dose systemic progestins was not associated with an increased risk, whereas the levonorgestrel intrauterine device, which contains only 1/20th the dose of a low-dose oral contraceptive pill, was associated with an increased risk. This discrepancy in risk warrants further investigation, and clinicians should be aware that this inconsistency needs validation before changing clinical practice.

In an observational cohort study,¹⁵ more than 100,000 women ages 50 to 71 were followed prospectively for 15 years to evaluate the association between hormonal contraceptive use and the risk of gynecologic and breast cancers. In this study, the duration of hormonal contraceptive use, smoking status, alcohol use, body mass index, physical activity, and family history of cancer were recorded. Long-term hormonal contraceptive use reduced ovarian and endometrial cancer risks by 40% and 34%, respectively, with no increase in breast cancer risk regardless of family history.

How would you counsel the patient?

The patient should be educated on the benefits of hormonal contraception that extend beyond pregnancy prevention, including regulation of menses, improved acne, decreased risk of endometrial and ovarian cancer, and likely reductions in colorectal cancer and overall mortality risk.^13–16 Further, after their own systematic review of the data assessing risk of breast cancer with hormonal contraception, the US Centers for Disease Control and Prevention state in their guidelines that all contraceptives may be used without limitation in those who have a family history of breast cancer.⁴ Any potential increased risk of breast cancer in women using hormonal contraception is small and would not outweigh the benefits associated with use.

One must consider the impact of an unintended pregnancy in such women, including effects on the health of the fetus and mother. Recent reports on the increasing rates of maternal death in the US (23.8 of 100,000 live births) serve as a reminder of the complications that can arise with pregnancy, especially if a mother’s health is not optimized before conception.¹⁷

The same 44-year-old patient now inquires about screening for breast cancer. She is curious about 3-dimensional mammography and whether it would be a better screening test for her.

Digital breast tomosynthesis (DBT) is a newer imaging modality that provides a 3-dimensional reconstruction of the breast using low-dose x-ray imaging. Some studies have shown that combining DBT with digital mammography may be superior to digital mammography alone in detecting cancers.¹⁸ However, digital mammography is currently the gold standard for breast cancer screening and is the only test proven to reduce mortality.^18,19

In a retrospective US study of 13 medical centers,²⁰ breast cancer detection rates increased by 41% the year after DBT was introduced, from 2.9 to 4.1 per 1,000 cases. DBT was associated with 16 fewer patients recalled for repeat imaging out of 1,000 women screened (as opposed to mammography alone). Two European studies similarly suggested an increase in cancer detection with lower recall rates.^21,22

Is 3-D mammography a better option?

In a 2-arm study by Pattacini et al,¹⁸ nearly 20,000 women ages 45 to 70 were randomized to undergo either digital mammography or digital mammography plus DBT for primary breast cancer screening. Women were enrolled over a 2-year period and were followed for 4.5 years, and the development of a primary invasive cancer was the primary end point. Recall rates, reading times, and radiation doses were also compared between the 2 groups.

Overall, the cancer detection rate was higher in the digital mammography plus DBT arm compared with digital mammography alone (8.6 vs 4.5 per 1,000). The detection rates were higher in the combined screening group among all age subgroups, with relative risks ranging from 1.83 to 2.04 (P = .93). The recall rate was 3.5% in the 2 arms, with relative risks ranging from 0.93 to 1.11 (P = .52). There was a reduction in the number of false positives seen in women undergoing digital mammography plus DBT when compared with digital mammography alone, from 30 per 1,000 to 27 per 1,000.

Detection of ductal carcinoma in situ increased in the experimental arm (relative detection 2.80, 95% CI 1.01–7.65) compared with invasive cancers. Comparing radiation, the dose was 2.3 times higher in those who underwent digital mammography plus DBT. The average reading times for digital mammography alone were 20 to 85 seconds; adding DBT added 35 to 81 seconds.¹⁹

Should you advise 3-D mammography?

The patient should be educated on the benefits of both digital mammography alone and digital mammography plus DBT. The use of digital mammography plus DBT has been supported in various studies and has been shown to increase cancer detection rates, although data are still conflicting regarding recall rates.^19,20 More studies are needed to determine its effect on breast cancer morality.

Routine use of DBT in women with or without dense breast tissue has not been recommended by organizations such as the USPSTF and the American College of Obstetricians and Gynecologists.^23,24 While there is an increased dose of radiation, it still falls below the US Food and Drug Administration limits and should not be the sole barrier to use.

Keeping up with current evidence-based healthcare practices is key to providing good clinical care to patients. This review presents 5 vignettes that highlight key issues in women’s health: osteoporosis screening, hormonal contraceptive interactions with antibiotics, hormone replacement therapy in carriers of the BRCA1 gene mutation, risks associated with hormonal contraception, and breast cancer diagnosis using digital tomosynthesis in addition to digital mammography. Supporting articles, all published in 2017 and 2018, were selected from high-impact medical and women’s health journals.

OSTEOPOROSIS SCREENING FOR FRACTURE PREVENTION

A 60-year-old woman reports that her last menstrual period was 7 years ago. She has no history of falls or fractures, and she takes no medications. She smokes 10 cigarettes per day and drinks 3 to 4 alcoholic beverages on most days of the week. She is 5 feet 6 inches (170 cm) tall and weighs 107 lb. Should she be screened for osteoporosis?

Osteoporosis is underdiagnosed

It is estimated that, in the United States, 12.3 million individuals older than 50 will develop osteoporosis by 2020. Missed opportunities to screen high-risk individuals can lead to fractures, including fractures of the hip.¹

Updated screening recommendations

In 2018, the US Preventive Services Task Force (USPSTF) developed and published evidence-based recommendations for osteoporosis screening to help providers identify and treat osteoporosis early to prevent fractures.² Available evidence on screening and treatment in women and men were reviewed with the intention of updating the 2011 USPSTF recommendations. The review also evaluated risk assessment tools, screening intervals, and efficacy of screening and treatment in various subpopulations.

Since the 2011 recommendations, more data have become available on fracture risk assessment with or without bone mineral density measurements. In its 2018 report, the USPSTF recommends that postmenopausal women younger than 65 should undergo screening with a bone density test if their 10-year risk of major osteoporotic fracture is more than 8.4%. This is equivalent to the fracture risk of a 65-year-old white woman with no major risk factors for fracture (grade B recommendation—high certainty that the benefit is moderate, or moderate certainty that the benefit is moderate to substantial).²

Assessment of fracture risk

For postmenopausal women who are under age 65 and who have at least 1 risk factor for fracture, it is reasonable to use a clinical risk assessment tool to determine who should undergo screening with bone mineral density measurement. Risk factors associated with an increased risk of osteoporotic fractures include a parental history of hip fracture, smoking, intake of 3 or more alcoholic drinks per day, low body weight, malabsorption, rheumatoid arthritis, diabetes, and postmenopausal status (not using estrogen replacement). Medications should be carefully reviewed for those that can increase the risk of fractures, including steroids and antiestrogen treatments.

The 10-year risk of a major osteoporotic or hip fracture can be assessed using the Fractional Risk Assessment Tool (FRAX), available at www.sheffield.ac.uk/FRAX/. Other acceptable tools that perform similarly to FRAX include the Osteoporosis Risk Assessment Instrument (ORAI) (10 studies; N = 16,780), Osteoporosis Index of Risk (OSIRIS) (5 studies; N = 5,649), Osteoporosis Self-Assessment Tool (OST) (13 studies; N = 44,323), and Simple Calculated Osteoporosis Risk Estimation (SCORE) (8 studies; N = 15,362).

Should this patient be screened for osteoporosis?

Based on the FRAX, this patient’s 10-year risk of major osteoporosis fracture is 9.2%. She would benefit from osteoporosis screening with a bone density test.

DO ANTIBIOTICS REDUCE EFFECTIVENESS OF HORMONAL CONTRACEPTION?

A 27-year-old woman presents with a dog bite on her right hand and is started on oral antibiotics. She takes an oral contraceptive that contains 35 µg of ethinyl estradiol and 0.25 mg of norgestimate. She asks if she should use condoms while taking antibiotics.

The antibiotics rifampin and rifabutin are known inducers of the hepatic enzymes required for contraceptive steroid metabolism, whereas other antibiotics are not. Despite the lack of compelling evidence that broad-spectrum antibiotics interfere with the efficacy of hormonal contraception, most pharmacists recommend backup contraception for women who use concomitant antibiotics.³ This practice could lead to poor compliance with the contraceptive regimen, the antibiotic regimen, or both.³

Simmons et al³ conducted a systematic review of randomized and nonrandomized studies that assessed pregnancy rates, breakthrough bleeding, ovulation suppression, and hormone pharmacokinetics in women taking oral or vaginal hormonal contraceptives in combination with nonrifamycin antibiotics, including oral, intramuscular, and intravenous forms. Oral contraceptives used in the studies included a range of doses and progestins, but lowest-dose pills, such as those containing less than 30 µg ethinyl estradiol or less than 150 µg levonorgestrel, were not included.

The contraceptive formulations in this systematic review³ included oral contraceptive pills, emergency contraception pills, and the contraceptive vaginal ring. The effect of antibiotics on other nonoral contraceptives, such as the transdermal patch, injectables, and progestin implants was not studied.

Four observational studies³ evaluated pregnancy rates or hormonal contraception failure with any antibiotic use. In 2 of these 4 studies, there was no difference in pregnancy rates in women who used oral contraceptives with and without nonrifamycin antibiotics. However, ethinyl estradiol was shown to have increased clearance when administered with dirithromycin (a macrolide).³ Twenty-five of the studies reported measures of contraceptive effectiveness (ovulation) and pharmacokinetic outcomes.

There were no observed differences in ovulation suppression or breakthrough bleeding in any study that combined hormonal contraceptives with an antibiotic. Furthermore, there was no significant decrease in progestin pharmacokinetic parameters during coadministration with an antibiotic.³ Study limitations included small sample sizes and the observational nature of the data.

How would you counsel this patient?

Available evidence suggests that nonrifamycin antibiotics do not diminish the effectiveness of the vaginal contraceptive ring or an oral hormonal contraceptive that contains at least 30 µg of ethinyl estradiol or 150 µg of levonorgestrel. Current guidelines do not recommend the use of additional backup contraception, regardless of hormonal contraception dose or formulation.⁴ Likewise, the most recent guidance for dental practitioners (ie, from 2012) no longer advises women to use additional contraceptive protection when taking nonrifamycin antibiotics.⁵

In our practice, we discuss the option of additional protection when prescribing formulations with lower estrogen doses (< 30 µg), not only because of the limitations of the available data, but also because of the high rates of unintended pregnancy with typical use of combined hormonal contraceptives (9% per year, unrelated to use of antibiotics).⁴ However, if our patient would rather not use additional barrier methods, she can be reassured that concomitant nonrifamycin antibiotic use is unlikely to affect contraceptive effectiveness.

A 41-year-old healthy mother of 3 was recently found to be a carrier of the BRCA1 mutation. She is planning to undergo prophylactic bilateral salpingo-oophorectomy for ovarian cancer prevention. However, she is apprehensive about undergoing surgical menopause. Should she be started on hormone replacement therapy after oophorectomy? How would hormone replacement therapy affect her risk of breast cancer?

In females who carry the BRCA1 mutation, the cumulative risk of both ovarian and breast cancer approaches 44% (95% confidence interval [CI] 36%–53%) and 72% (95% CI 65%–79%) by age 80.⁶ Prophylactic salpingo-oophorectomy reduces the risk of breast cancer by 50% and the risk of ovarian cancer by 90%. Unfortunately, premature withdrawal of ovarian hormones has been associated with long-term adverse effects including significant vasomotor symptoms, decreased quality of life, sexual dysfunction, early mortality, bone loss, decline in mood and cognition, and poor cardiovascular outcomes.⁷ Many of these effects can be avoided or lessened with hormone replacement therapy.

Kotsopoulos et al⁸ conducted a longitudinal, prospective analysis of BRCA1 mutation carriers in a multicenter study between 1995 and 2017. The mean follow-up period was 7.6 years (range 0.4–22.1). The study assessed associations between the use of hormone replacement therapy and breast cancer risk in carriers of the BRCA1 mutation who underwent prophylactic salpingo-oophorectomy. Study participants did not have a personal history of cancer. Those with a history of prophylactic mastectomy were excluded.

Participants completed a series of questionnaires every 2 years, disclosing updates in personal medical, cancer, and reproductive history. The questionnaires also inquired about the use of hormone replacement therapy, including the type used (estrogen only, progestin only, estrogen plus progestin, other), brand name, duration of use, and dose and route of administration (pill, patch, suppository).

Of the 13,087 BRCA1 mutation carriers identified, 872 met the study criteria. Of those, 377 (43%) reported using some form of hormone replacement therapy after salpingo-oophorectomy, and 495 (57%) did not. The average duration of use was 3.9 years (range 0.5–19), with most (69%) using estrogen alone; 18% used other regimens, including estrogen plus progestin and progestin only. A small percentage of participants did not indicate which formulation they used. On average, women using hormone replacement therapy underwent prophylactic oophorectomy earlier than nonusers (age 43.0 vs 48.4; absolute difference 5.5 years, P < .001).

During follow-up, there was no significant difference noted in the proportion of women diagnosed with breast cancer between hormone replacement therapy users and nonusers (10.3 vs 10.7%; absolute difference 0.4%; P = .86). In fact, for each year of estrogen-containing hormone replacement therapy, there was an 18% reduction in breast cancer risk when oophorectomy was performed before age 45 (95% CI 0.69–0.97). The authors also noted a nonsignificant 14% trend toward an increase in breast cancer risk for each year of progestin use after oophorectomy when surgery was performed before age 45 (95% CI 0.9–1.46).

Although prophylactic hysterectomy was not recommended, the authors noted that hysterectomy would eliminate the need for progestin-containing hormone replacement therapy. For those who underwent oophorectomy after age 45, hormone replacement therapy did not increase or decrease the risk of breast cancer.⁷

A meta-analysis by Marchetti et al⁹ also supports the safety of hormone replacement therapy after risk-reducing salpingo-oophorectomy. Three studies that included 1,100 patients were analyzed (including the Kotsopoulos study⁸ noted above). There was a nonsignificant decrease in breast cancer risk in women on estrogen-only hormone replacement therapy compared with women on estrogen-plus-progestin therapy (odds ratio 0.53, 95% CI 0.25–1.15). Overall, the authors regarded hormone replacement therapy as a safe therapeutic option after prophylactic salpingo-oophorectomy in carriers of the BRCA1 and BRCA2 mutations.⁹

In a case-control study published in 2016,¹⁰ hormone replacement therapy was assessed in 432 postmenopausal BRCA1 mutation carriers with invasive breast cancer (cases) and in 432 BRCA1 mutation carriers without a history of breast cancer (controls). Results showed no difference in breast cancer risk between hormone replacement therapy users and nonusers.¹⁰

Rebbeck et al¹¹ evaluated short-term hormone replacement therapy in BRCA1 and BRCA2 gene-mutation carriers after they underwent prophylactic salpingo-oophorectomy. The results showed that hormone replacement did not affect the breast cancer risk-reduction conferred with prophylactic bilateral salpingo-oophorectomy.

Johansen et al¹² evaluated hormone replacement therapy in premenopausal women after prophylactic salpingo-oophorectomy. They studied 324 carriers of BRCA gene mutations after they underwent prophylactic salpingo-oophorectomy and a subset of 950 controls who had bilateral salpingo-oophorectomy for reasons unrelated to cancer. In both groups, hormone replacement therapy was underutilized. The authors recommended using it when clinically indicated.

Should your patient start hormone replacement therapy?

This patient is healthy, and in the absence of contraindications, systemic hormone replacement therapy after prophylactic oophorectomy could mitigate the potential adverse effects of surgically induced menopause. The patient can be reassured that estrogen-containing short-term hormone replacement therapy is unlikely to increase her breast cancer risk.

A 44-year-old woman presents to your office for an annual visit. She is sexually active but does not wish to become pregnant. She has a family history of breast cancer: her mother was diagnosed at age 53. She is interested in an oral contraceptive to prevent pregnancy and acne. However, she is nervous about being on any contraceptive that may increase her risk of breast cancer.

To date, studies assessing the effect of hormonal contraception on the risk of breast cancer have produced inconsistent results. Although most studies have shown no associated risk, a few have shown a temporary 20% to 30% increased risk of breast cancer during use.^13,14 Case-controlled studies that reported an association between hormonal contraception and breast cancer included populations taking higher-dose combination pills, which are no longer prescribed. Most studies do not evaluate specific formulations of hormonal contraception, and little is known about effects associated with intrauterine devices or progestin-only contraception.

A prospective study performed by Mørch et al¹³ followed more than 1 million reproductive-aged women for a mean of 10.9 years. The Danish Cancer Registry was used to identify cases of invasive breast cancer. Women who used hormonal contraceptives had a relative risk of breast cancer of 1.20 compared with women not on hormonal contraception (95% CI 1.14–1.26). The study suggested that those who had been on contraceptive agents for more than 5 years had an increased risk and that this risk remained for 5 years after the agents were discontinued. Conversely, no increased risk of cancer was noted in those who used hormonal contraception for less than 5 years. No notable differences were seen among various formulations.

For women using the levonorgestrel-containing intrauterine device, the relative risk of breast cancer was 1.21 (95% CI 1.11–1.33). A few cancers were noted in those who used the progestin-only implant or those using depot medroxyprogesterone acetate. While the study showed an increased relative risk of breast cancer, the absolute risk was low—13 cases per 100,000, or approximately 1 additional case of breast cancer per 7,690 per year.¹³

This study had several important limitations. The authors did not adjust for common breast cancer risk factors including age at menarche, alcohol use, or breastfeeding. Additionally, the study did not account for the use of hormonal contraception before the study period and conversely, did not account for women who may have stopped taking their contraceptive despite their prescribed duration. The frequency of mammography was not explicitly noted, which could have shifted results for women who had more aggressive screening.

It is also noteworthy that the use of high-dose systemic progestins was not associated with an increased risk, whereas the levonorgestrel intrauterine device, which contains only 1/20th the dose of a low-dose oral contraceptive pill, was associated with an increased risk. This discrepancy in risk warrants further investigation, and clinicians should be aware that this inconsistency needs validation before changing clinical practice.

In an observational cohort study,¹⁵ more than 100,000 women ages 50 to 71 were followed prospectively for 15 years to evaluate the association between hormonal contraceptive use and the risk of gynecologic and breast cancers. In this study, the duration of hormonal contraceptive use, smoking status, alcohol use, body mass index, physical activity, and family history of cancer were recorded. Long-term hormonal contraceptive use reduced ovarian and endometrial cancer risks by 40% and 34%, respectively, with no increase in breast cancer risk regardless of family history.

How would you counsel the patient?

The patient should be educated on the benefits of hormonal contraception that extend beyond pregnancy prevention, including regulation of menses, improved acne, decreased risk of endometrial and ovarian cancer, and likely reductions in colorectal cancer and overall mortality risk.^13–16 Further, after their own systematic review of the data assessing risk of breast cancer with hormonal contraception, the US Centers for Disease Control and Prevention state in their guidelines that all contraceptives may be used without limitation in those who have a family history of breast cancer.⁴ Any potential increased risk of breast cancer in women using hormonal contraception is small and would not outweigh the benefits associated with use.

One must consider the impact of an unintended pregnancy in such women, including effects on the health of the fetus and mother. Recent reports on the increasing rates of maternal death in the US (23.8 of 100,000 live births) serve as a reminder of the complications that can arise with pregnancy, especially if a mother’s health is not optimized before conception.¹⁷

The same 44-year-old patient now inquires about screening for breast cancer. She is curious about 3-dimensional mammography and whether it would be a better screening test for her.

Digital breast tomosynthesis (DBT) is a newer imaging modality that provides a 3-dimensional reconstruction of the breast using low-dose x-ray imaging. Some studies have shown that combining DBT with digital mammography may be superior to digital mammography alone in detecting cancers.¹⁸ However, digital mammography is currently the gold standard for breast cancer screening and is the only test proven to reduce mortality.^18,19

In a retrospective US study of 13 medical centers,²⁰ breast cancer detection rates increased by 41% the year after DBT was introduced, from 2.9 to 4.1 per 1,000 cases. DBT was associated with 16 fewer patients recalled for repeat imaging out of 1,000 women screened (as opposed to mammography alone). Two European studies similarly suggested an increase in cancer detection with lower recall rates.^21,22

Is 3-D mammography a better option?

In a 2-arm study by Pattacini et al,¹⁸ nearly 20,000 women ages 45 to 70 were randomized to undergo either digital mammography or digital mammography plus DBT for primary breast cancer screening. Women were enrolled over a 2-year period and were followed for 4.5 years, and the development of a primary invasive cancer was the primary end point. Recall rates, reading times, and radiation doses were also compared between the 2 groups.

Overall, the cancer detection rate was higher in the digital mammography plus DBT arm compared with digital mammography alone (8.6 vs 4.5 per 1,000). The detection rates were higher in the combined screening group among all age subgroups, with relative risks ranging from 1.83 to 2.04 (P = .93). The recall rate was 3.5% in the 2 arms, with relative risks ranging from 0.93 to 1.11 (P = .52). There was a reduction in the number of false positives seen in women undergoing digital mammography plus DBT when compared with digital mammography alone, from 30 per 1,000 to 27 per 1,000.

Detection of ductal carcinoma in situ increased in the experimental arm (relative detection 2.80, 95% CI 1.01–7.65) compared with invasive cancers. Comparing radiation, the dose was 2.3 times higher in those who underwent digital mammography plus DBT. The average reading times for digital mammography alone were 20 to 85 seconds; adding DBT added 35 to 81 seconds.¹⁹

Should you advise 3-D mammography?

The patient should be educated on the benefits of both digital mammography alone and digital mammography plus DBT. The use of digital mammography plus DBT has been supported in various studies and has been shown to increase cancer detection rates, although data are still conflicting regarding recall rates.^19,20 More studies are needed to determine its effect on breast cancer morality.

Routine use of DBT in women with or without dense breast tissue has not been recommended by organizations such as the USPSTF and the American College of Obstetricians and Gynecologists.^23,24 While there is an increased dose of radiation, it still falls below the US Food and Drug Administration limits and should not be the sole barrier to use.

Keeping up with current evidence-based healthcare practices is key to providing good clinical care to patients. This review presents 5 vignettes that highlight key issues in women’s health: osteoporosis screening, hormonal contraceptive interactions with antibiotics, hormone replacement therapy in carriers of the BRCA1 gene mutation, risks associated with hormonal contraception, and breast cancer diagnosis using digital tomosynthesis in addition to digital mammography. Supporting articles, all published in 2017 and 2018, were selected from high-impact medical and women’s health journals.

OSTEOPOROSIS SCREENING FOR FRACTURE PREVENTION

A 60-year-old woman reports that her last menstrual period was 7 years ago. She has no history of falls or fractures, and she takes no medications. She smokes 10 cigarettes per day and drinks 3 to 4 alcoholic beverages on most days of the week. She is 5 feet 6 inches (170 cm) tall and weighs 107 lb. Should she be screened for osteoporosis?

Osteoporosis is underdiagnosed

It is estimated that, in the United States, 12.3 million individuals older than 50 will develop osteoporosis by 2020. Missed opportunities to screen high-risk individuals can lead to fractures, including fractures of the hip.¹

Updated screening recommendations

In 2018, the US Preventive Services Task Force (USPSTF) developed and published evidence-based recommendations for osteoporosis screening to help providers identify and treat osteoporosis early to prevent fractures.² Available evidence on screening and treatment in women and men were reviewed with the intention of updating the 2011 USPSTF recommendations. The review also evaluated risk assessment tools, screening intervals, and efficacy of screening and treatment in various subpopulations.

Since the 2011 recommendations, more data have become available on fracture risk assessment with or without bone mineral density measurements. In its 2018 report, the USPSTF recommends that postmenopausal women younger than 65 should undergo screening with a bone density test if their 10-year risk of major osteoporotic fracture is more than 8.4%. This is equivalent to the fracture risk of a 65-year-old white woman with no major risk factors for fracture (grade B recommendation—high certainty that the benefit is moderate, or moderate certainty that the benefit is moderate to substantial).²

Assessment of fracture risk

For postmenopausal women who are under age 65 and who have at least 1 risk factor for fracture, it is reasonable to use a clinical risk assessment tool to determine who should undergo screening with bone mineral density measurement. Risk factors associated with an increased risk of osteoporotic fractures include a parental history of hip fracture, smoking, intake of 3 or more alcoholic drinks per day, low body weight, malabsorption, rheumatoid arthritis, diabetes, and postmenopausal status (not using estrogen replacement). Medications should be carefully reviewed for those that can increase the risk of fractures, including steroids and antiestrogen treatments.

The 10-year risk of a major osteoporotic or hip fracture can be assessed using the Fractional Risk Assessment Tool (FRAX), available at www.sheffield.ac.uk/FRAX/. Other acceptable tools that perform similarly to FRAX include the Osteoporosis Risk Assessment Instrument (ORAI) (10 studies; N = 16,780), Osteoporosis Index of Risk (OSIRIS) (5 studies; N = 5,649), Osteoporosis Self-Assessment Tool (OST) (13 studies; N = 44,323), and Simple Calculated Osteoporosis Risk Estimation (SCORE) (8 studies; N = 15,362).

Should this patient be screened for osteoporosis?

Based on the FRAX, this patient’s 10-year risk of major osteoporosis fracture is 9.2%. She would benefit from osteoporosis screening with a bone density test.

DO ANTIBIOTICS REDUCE EFFECTIVENESS OF HORMONAL CONTRACEPTION?

A 27-year-old woman presents with a dog bite on her right hand and is started on oral antibiotics. She takes an oral contraceptive that contains 35 µg of ethinyl estradiol and 0.25 mg of norgestimate. She asks if she should use condoms while taking antibiotics.

The antibiotics rifampin and rifabutin are known inducers of the hepatic enzymes required for contraceptive steroid metabolism, whereas other antibiotics are not. Despite the lack of compelling evidence that broad-spectrum antibiotics interfere with the efficacy of hormonal contraception, most pharmacists recommend backup contraception for women who use concomitant antibiotics.³ This practice could lead to poor compliance with the contraceptive regimen, the antibiotic regimen, or both.³

Simmons et al³ conducted a systematic review of randomized and nonrandomized studies that assessed pregnancy rates, breakthrough bleeding, ovulation suppression, and hormone pharmacokinetics in women taking oral or vaginal hormonal contraceptives in combination with nonrifamycin antibiotics, including oral, intramuscular, and intravenous forms. Oral contraceptives used in the studies included a range of doses and progestins, but lowest-dose pills, such as those containing less than 30 µg ethinyl estradiol or less than 150 µg levonorgestrel, were not included.

The contraceptive formulations in this systematic review³ included oral contraceptive pills, emergency contraception pills, and the contraceptive vaginal ring. The effect of antibiotics on other nonoral contraceptives, such as the transdermal patch, injectables, and progestin implants was not studied.

Four observational studies³ evaluated pregnancy rates or hormonal contraception failure with any antibiotic use. In 2 of these 4 studies, there was no difference in pregnancy rates in women who used oral contraceptives with and without nonrifamycin antibiotics. However, ethinyl estradiol was shown to have increased clearance when administered with dirithromycin (a macrolide).³ Twenty-five of the studies reported measures of contraceptive effectiveness (ovulation) and pharmacokinetic outcomes.

There were no observed differences in ovulation suppression or breakthrough bleeding in any study that combined hormonal contraceptives with an antibiotic. Furthermore, there was no significant decrease in progestin pharmacokinetic parameters during coadministration with an antibiotic.³ Study limitations included small sample sizes and the observational nature of the data.

How would you counsel this patient?

Available evidence suggests that nonrifamycin antibiotics do not diminish the effectiveness of the vaginal contraceptive ring or an oral hormonal contraceptive that contains at least 30 µg of ethinyl estradiol or 150 µg of levonorgestrel. Current guidelines do not recommend the use of additional backup contraception, regardless of hormonal contraception dose or formulation.⁴ Likewise, the most recent guidance for dental practitioners (ie, from 2012) no longer advises women to use additional contraceptive protection when taking nonrifamycin antibiotics.⁵

In our practice, we discuss the option of additional protection when prescribing formulations with lower estrogen doses (< 30 µg), not only because of the limitations of the available data, but also because of the high rates of unintended pregnancy with typical use of combined hormonal contraceptives (9% per year, unrelated to use of antibiotics).⁴ However, if our patient would rather not use additional barrier methods, she can be reassured that concomitant nonrifamycin antibiotic use is unlikely to affect contraceptive effectiveness.

A 41-year-old healthy mother of 3 was recently found to be a carrier of the BRCA1 mutation. She is planning to undergo prophylactic bilateral salpingo-oophorectomy for ovarian cancer prevention. However, she is apprehensive about undergoing surgical menopause. Should she be started on hormone replacement therapy after oophorectomy? How would hormone replacement therapy affect her risk of breast cancer?

In females who carry the BRCA1 mutation, the cumulative risk of both ovarian and breast cancer approaches 44% (95% confidence interval [CI] 36%–53%) and 72% (95% CI 65%–79%) by age 80.⁶ Prophylactic salpingo-oophorectomy reduces the risk of breast cancer by 50% and the risk of ovarian cancer by 90%. Unfortunately, premature withdrawal of ovarian hormones has been associated with long-term adverse effects including significant vasomotor symptoms, decreased quality of life, sexual dysfunction, early mortality, bone loss, decline in mood and cognition, and poor cardiovascular outcomes.⁷ Many of these effects can be avoided or lessened with hormone replacement therapy.

Kotsopoulos et al⁸ conducted a longitudinal, prospective analysis of BRCA1 mutation carriers in a multicenter study between 1995 and 2017. The mean follow-up period was 7.6 years (range 0.4–22.1). The study assessed associations between the use of hormone replacement therapy and breast cancer risk in carriers of the BRCA1 mutation who underwent prophylactic salpingo-oophorectomy. Study participants did not have a personal history of cancer. Those with a history of prophylactic mastectomy were excluded.

Participants completed a series of questionnaires every 2 years, disclosing updates in personal medical, cancer, and reproductive history. The questionnaires also inquired about the use of hormone replacement therapy, including the type used (estrogen only, progestin only, estrogen plus progestin, other), brand name, duration of use, and dose and route of administration (pill, patch, suppository).

Of the 13,087 BRCA1 mutation carriers identified, 872 met the study criteria. Of those, 377 (43%) reported using some form of hormone replacement therapy after salpingo-oophorectomy, and 495 (57%) did not. The average duration of use was 3.9 years (range 0.5–19), with most (69%) using estrogen alone; 18% used other regimens, including estrogen plus progestin and progestin only. A small percentage of participants did not indicate which formulation they used. On average, women using hormone replacement therapy underwent prophylactic oophorectomy earlier than nonusers (age 43.0 vs 48.4; absolute difference 5.5 years, P < .001).

During follow-up, there was no significant difference noted in the proportion of women diagnosed with breast cancer between hormone replacement therapy users and nonusers (10.3 vs 10.7%; absolute difference 0.4%; P = .86). In fact, for each year of estrogen-containing hormone replacement therapy, there was an 18% reduction in breast cancer risk when oophorectomy was performed before age 45 (95% CI 0.69–0.97). The authors also noted a nonsignificant 14% trend toward an increase in breast cancer risk for each year of progestin use after oophorectomy when surgery was performed before age 45 (95% CI 0.9–1.46).

Although prophylactic hysterectomy was not recommended, the authors noted that hysterectomy would eliminate the need for progestin-containing hormone replacement therapy. For those who underwent oophorectomy after age 45, hormone replacement therapy did not increase or decrease the risk of breast cancer.⁷

A meta-analysis by Marchetti et al⁹ also supports the safety of hormone replacement therapy after risk-reducing salpingo-oophorectomy. Three studies that included 1,100 patients were analyzed (including the Kotsopoulos study⁸ noted above). There was a nonsignificant decrease in breast cancer risk in women on estrogen-only hormone replacement therapy compared with women on estrogen-plus-progestin therapy (odds ratio 0.53, 95% CI 0.25–1.15). Overall, the authors regarded hormone replacement therapy as a safe therapeutic option after prophylactic salpingo-oophorectomy in carriers of the BRCA1 and BRCA2 mutations.⁹

In a case-control study published in 2016,¹⁰ hormone replacement therapy was assessed in 432 postmenopausal BRCA1 mutation carriers with invasive breast cancer (cases) and in 432 BRCA1 mutation carriers without a history of breast cancer (controls). Results showed no difference in breast cancer risk between hormone replacement therapy users and nonusers.¹⁰

Rebbeck et al¹¹ evaluated short-term hormone replacement therapy in BRCA1 and BRCA2 gene-mutation carriers after they underwent prophylactic salpingo-oophorectomy. The results showed that hormone replacement did not affect the breast cancer risk-reduction conferred with prophylactic bilateral salpingo-oophorectomy.

Johansen et al¹² evaluated hormone replacement therapy in premenopausal women after prophylactic salpingo-oophorectomy. They studied 324 carriers of BRCA gene mutations after they underwent prophylactic salpingo-oophorectomy and a subset of 950 controls who had bilateral salpingo-oophorectomy for reasons unrelated to cancer. In both groups, hormone replacement therapy was underutilized. The authors recommended using it when clinically indicated.

Should your patient start hormone replacement therapy?

This patient is healthy, and in the absence of contraindications, systemic hormone replacement therapy after prophylactic oophorectomy could mitigate the potential adverse effects of surgically induced menopause. The patient can be reassured that estrogen-containing short-term hormone replacement therapy is unlikely to increase her breast cancer risk.

A 44-year-old woman presents to your office for an annual visit. She is sexually active but does not wish to become pregnant. She has a family history of breast cancer: her mother was diagnosed at age 53. She is interested in an oral contraceptive to prevent pregnancy and acne. However, she is nervous about being on any contraceptive that may increase her risk of breast cancer.

To date, studies assessing the effect of hormonal contraception on the risk of breast cancer have produced inconsistent results. Although most studies have shown no associated risk, a few have shown a temporary 20% to 30% increased risk of breast cancer during use.^13,14 Case-controlled studies that reported an association between hormonal contraception and breast cancer included populations taking higher-dose combination pills, which are no longer prescribed. Most studies do not evaluate specific formulations of hormonal contraception, and little is known about effects associated with intrauterine devices or progestin-only contraception.

A prospective study performed by Mørch et al¹³ followed more than 1 million reproductive-aged women for a mean of 10.9 years. The Danish Cancer Registry was used to identify cases of invasive breast cancer. Women who used hormonal contraceptives had a relative risk of breast cancer of 1.20 compared with women not on hormonal contraception (95% CI 1.14–1.26). The study suggested that those who had been on contraceptive agents for more than 5 years had an increased risk and that this risk remained for 5 years after the agents were discontinued. Conversely, no increased risk of cancer was noted in those who used hormonal contraception for less than 5 years. No notable differences were seen among various formulations.

For women using the levonorgestrel-containing intrauterine device, the relative risk of breast cancer was 1.21 (95% CI 1.11–1.33). A few cancers were noted in those who used the progestin-only implant or those using depot medroxyprogesterone acetate. While the study showed an increased relative risk of breast cancer, the absolute risk was low—13 cases per 100,000, or approximately 1 additional case of breast cancer per 7,690 per year.¹³

This study had several important limitations. The authors did not adjust for common breast cancer risk factors including age at menarche, alcohol use, or breastfeeding. Additionally, the study did not account for the use of hormonal contraception before the study period and conversely, did not account for women who may have stopped taking their contraceptive despite their prescribed duration. The frequency of mammography was not explicitly noted, which could have shifted results for women who had more aggressive screening.

It is also noteworthy that the use of high-dose systemic progestins was not associated with an increased risk, whereas the levonorgestrel intrauterine device, which contains only 1/20th the dose of a low-dose oral contraceptive pill, was associated with an increased risk. This discrepancy in risk warrants further investigation, and clinicians should be aware that this inconsistency needs validation before changing clinical practice.

In an observational cohort study,¹⁵ more than 100,000 women ages 50 to 71 were followed prospectively for 15 years to evaluate the association between hormonal contraceptive use and the risk of gynecologic and breast cancers. In this study, the duration of hormonal contraceptive use, smoking status, alcohol use, body mass index, physical activity, and family history of cancer were recorded. Long-term hormonal contraceptive use reduced ovarian and endometrial cancer risks by 40% and 34%, respectively, with no increase in breast cancer risk regardless of family history.

How would you counsel the patient?

The patient should be educated on the benefits of hormonal contraception that extend beyond pregnancy prevention, including regulation of menses, improved acne, decreased risk of endometrial and ovarian cancer, and likely reductions in colorectal cancer and overall mortality risk.^13–16 Further, after their own systematic review of the data assessing risk of breast cancer with hormonal contraception, the US Centers for Disease Control and Prevention state in their guidelines that all contraceptives may be used without limitation in those who have a family history of breast cancer.⁴ Any potential increased risk of breast cancer in women using hormonal contraception is small and would not outweigh the benefits associated with use.

One must consider the impact of an unintended pregnancy in such women, including effects on the health of the fetus and mother. Recent reports on the increasing rates of maternal death in the US (23.8 of 100,000 live births) serve as a reminder of the complications that can arise with pregnancy, especially if a mother’s health is not optimized before conception.¹⁷

The same 44-year-old patient now inquires about screening for breast cancer. She is curious about 3-dimensional mammography and whether it would be a better screening test for her.

Digital breast tomosynthesis (DBT) is a newer imaging modality that provides a 3-dimensional reconstruction of the breast using low-dose x-ray imaging. Some studies have shown that combining DBT with digital mammography may be superior to digital mammography alone in detecting cancers.¹⁸ However, digital mammography is currently the gold standard for breast cancer screening and is the only test proven to reduce mortality.^18,19

In a retrospective US study of 13 medical centers,²⁰ breast cancer detection rates increased by 41% the year after DBT was introduced, from 2.9 to 4.1 per 1,000 cases. DBT was associated with 16 fewer patients recalled for repeat imaging out of 1,000 women screened (as opposed to mammography alone). Two European studies similarly suggested an increase in cancer detection with lower recall rates.^21,22

Is 3-D mammography a better option?

In a 2-arm study by Pattacini et al,¹⁸ nearly 20,000 women ages 45 to 70 were randomized to undergo either digital mammography or digital mammography plus DBT for primary breast cancer screening. Women were enrolled over a 2-year period and were followed for 4.5 years, and the development of a primary invasive cancer was the primary end point. Recall rates, reading times, and radiation doses were also compared between the 2 groups.

Overall, the cancer detection rate was higher in the digital mammography plus DBT arm compared with digital mammography alone (8.6 vs 4.5 per 1,000). The detection rates were higher in the combined screening group among all age subgroups, with relative risks ranging from 1.83 to 2.04 (P = .93). The recall rate was 3.5% in the 2 arms, with relative risks ranging from 0.93 to 1.11 (P = .52). There was a reduction in the number of false positives seen in women undergoing digital mammography plus DBT when compared with digital mammography alone, from 30 per 1,000 to 27 per 1,000.

Detection of ductal carcinoma in situ increased in the experimental arm (relative detection 2.80, 95% CI 1.01–7.65) compared with invasive cancers. Comparing radiation, the dose was 2.3 times higher in those who underwent digital mammography plus DBT. The average reading times for digital mammography alone were 20 to 85 seconds; adding DBT added 35 to 81 seconds.¹⁹

Should you advise 3-D mammography?

The patient should be educated on the benefits of both digital mammography alone and digital mammography plus DBT. The use of digital mammography plus DBT has been supported in various studies and has been shown to increase cancer detection rates, although data are still conflicting regarding recall rates.^19,20 More studies are needed to determine its effect on breast cancer morality.

Routine use of DBT in women with or without dense breast tissue has not been recommended by organizations such as the USPSTF and the American College of Obstetricians and Gynecologists.^23,24 While there is an increased dose of radiation, it still falls below the US Food and Drug Administration limits and should not be the sole barrier to use.

In Reply: We would like to thank Dr. Lichtenberg for giving us the opportunity to clarify and expand on questions regarding HPV vaccine efficacy.

Our statement “HPV immunization can prevent up to 70% of cases of cervical cancer due to HPV as well as 90% of genital warts” was based on a statement by Thaxton and Waxman, ie, that immunization against HPV types 16 and 18 has the potential to prevent 70% of cancers of the cervix plus a large percentage of other lower anogenital tract cancers.¹ This was meant to describe the prevention potential of the quadrivalent vaccine. The currently available Gardasil 9 targets the HPV types that account for 90% of cervical cancers,² with projected effectiveness likely to vary based on geographic variation in HPV subtypes, ranging from 86.5% in Australia to 92% in North America.³ It is difficult to precisely calculate the effectiveness of HPV vaccination alone, given that cervical cancer prevention is twofold, with primary vaccination and secondary screening (with several notable updates to US national screening guidelines during the same time frame as vaccine development).⁴

It is true that the 29% decrease in US cervical cancer incidence rates during the years 2011–2014 compared with 2003–2006 is less than the predicted 70%.⁵ However, not all eligible US females are vaccinated; according to reports from the US Centers for Disease Control and Prevention, 49% of adolescents were appropriately immunized against HPV in 2017, an increase over the rate of only 35% in 2014.⁶ Low vaccination rates undoubtedly negatively impact any benefits from herd immunity, though the exact benefits of this population immunity are difficult to quantify.⁷

In Australia, a national school-based HPV vaccination program was initiated in 2007, making the vaccine available for free. Over 70% of girls ages 12 and 13 were vaccinated, and follow-up within the same decade showed a greater than 90% reduction in genital warts, as well as a reduction in high-grade cervical lesions.⁸ In addition, the incidence of genital warts in unvaccinated heterosexual males during the prevaccination vs the vaccination period decreased by up to 81% (a marker of herd immunity).⁹

In the US, the HPV subtypes found in the quadrivalent vaccine decreased by 71% in those ages 14 to 19, within 8 years of vaccine introduction.¹⁰ An analysis of US state cancer registries between 2009 and 2012 showed that in Michigan, the rates of high-grade, precancerous lesions declined by 37% each year for women ages 15 to 19, thought to be due to changes in screening and vaccination guidelines.¹¹ Similarly, an analysis of 9 million privately insured US females showed that the presence of high-grade precancerous lesions significantly decreased between the years 2007 and 2014 in those ages 15 to 24 (vaccinated individuals), but not in those ages 25 to 39 (unvaccinated individuals).¹² Most recently, a study of 10,206 women showed a 21.9% decrease in cervical intraepithelial neoplasia grade 2 or worse lesions due to HPV subtypes 16 or 18 in those who have received at least 1 dose of the vaccine; reduced rates in unvaccinated women were also seen, representing first evidence of herd immunity in the United States.¹³ In contrast, the rates of high-grade lesions due to nonvaccine HPV subtypes remained constant. Given that progression to cervical cancer can take 10 to 15 years or longer after HPV infection, true vaccine benefits will emerge once increased vaccination rates are achieved and after at least a decade of follow-up.

We applaud Dr. Lichtenberg’s efforts to clarify vaccine efficacy for appropriate counseling, as this is key to ensuring patient trust. Immunization fears have fueled the re-emergence of vaccine-preventable illnesses across the world. Given the wave of vaccine misinformation on the Internet, we all face patients and family members skeptical of vaccine efficacy and safety. Those requesting more information deserve an honest, informed discussion with their provider. Interestingly, however, among 955 unvaccinated women, the belief of not being at risk for HPV was the most common reason for not receiving the vaccine.¹⁴ Effective education can be achieved by focusing on the personal risks of HPV to the patient, as well as the overall favorable risk vs benefits of vaccination. Quoting an exact rate of cancer reduction is likely a less effective counseling strategy, and these efficacy estimates will change as vaccination rates and HPV prevalence within the population change over time.

In Reply: We would like to thank Dr. Lichtenberg for giving us the opportunity to clarify and expand on questions regarding HPV vaccine efficacy.

Our statement “HPV immunization can prevent up to 70% of cases of cervical cancer due to HPV as well as 90% of genital warts” was based on a statement by Thaxton and Waxman, ie, that immunization against HPV types 16 and 18 has the potential to prevent 70% of cancers of the cervix plus a large percentage of other lower anogenital tract cancers.¹ This was meant to describe the prevention potential of the quadrivalent vaccine. The currently available Gardasil 9 targets the HPV types that account for 90% of cervical cancers,² with projected effectiveness likely to vary based on geographic variation in HPV subtypes, ranging from 86.5% in Australia to 92% in North America.³ It is difficult to precisely calculate the effectiveness of HPV vaccination alone, given that cervical cancer prevention is twofold, with primary vaccination and secondary screening (with several notable updates to US national screening guidelines during the same time frame as vaccine development).⁴

It is true that the 29% decrease in US cervical cancer incidence rates during the years 2011–2014 compared with 2003–2006 is less than the predicted 70%.⁵ However, not all eligible US females are vaccinated; according to reports from the US Centers for Disease Control and Prevention, 49% of adolescents were appropriately immunized against HPV in 2017, an increase over the rate of only 35% in 2014.⁶ Low vaccination rates undoubtedly negatively impact any benefits from herd immunity, though the exact benefits of this population immunity are difficult to quantify.⁷

In Australia, a national school-based HPV vaccination program was initiated in 2007, making the vaccine available for free. Over 70% of girls ages 12 and 13 were vaccinated, and follow-up within the same decade showed a greater than 90% reduction in genital warts, as well as a reduction in high-grade cervical lesions.⁸ In addition, the incidence of genital warts in unvaccinated heterosexual males during the prevaccination vs the vaccination period decreased by up to 81% (a marker of herd immunity).⁹

In the US, the HPV subtypes found in the quadrivalent vaccine decreased by 71% in those ages 14 to 19, within 8 years of vaccine introduction.¹⁰ An analysis of US state cancer registries between 2009 and 2012 showed that in Michigan, the rates of high-grade, precancerous lesions declined by 37% each year for women ages 15 to 19, thought to be due to changes in screening and vaccination guidelines.¹¹ Similarly, an analysis of 9 million privately insured US females showed that the presence of high-grade precancerous lesions significantly decreased between the years 2007 and 2014 in those ages 15 to 24 (vaccinated individuals), but not in those ages 25 to 39 (unvaccinated individuals).¹² Most recently, a study of 10,206 women showed a 21.9% decrease in cervical intraepithelial neoplasia grade 2 or worse lesions due to HPV subtypes 16 or 18 in those who have received at least 1 dose of the vaccine; reduced rates in unvaccinated women were also seen, representing first evidence of herd immunity in the United States.¹³ In contrast, the rates of high-grade lesions due to nonvaccine HPV subtypes remained constant. Given that progression to cervical cancer can take 10 to 15 years or longer after HPV infection, true vaccine benefits will emerge once increased vaccination rates are achieved and after at least a decade of follow-up.

We applaud Dr. Lichtenberg’s efforts to clarify vaccine efficacy for appropriate counseling, as this is key to ensuring patient trust. Immunization fears have fueled the re-emergence of vaccine-preventable illnesses across the world. Given the wave of vaccine misinformation on the Internet, we all face patients and family members skeptical of vaccine efficacy and safety. Those requesting more information deserve an honest, informed discussion with their provider. Interestingly, however, among 955 unvaccinated women, the belief of not being at risk for HPV was the most common reason for not receiving the vaccine.¹⁴ Effective education can be achieved by focusing on the personal risks of HPV to the patient, as well as the overall favorable risk vs benefits of vaccination. Quoting an exact rate of cancer reduction is likely a less effective counseling strategy, and these efficacy estimates will change as vaccination rates and HPV prevalence within the population change over time.

In Reply: We would like to thank Dr. Lichtenberg for giving us the opportunity to clarify and expand on questions regarding HPV vaccine efficacy.

Our statement “HPV immunization can prevent up to 70% of cases of cervical cancer due to HPV as well as 90% of genital warts” was based on a statement by Thaxton and Waxman, ie, that immunization against HPV types 16 and 18 has the potential to prevent 70% of cancers of the cervix plus a large percentage of other lower anogenital tract cancers.¹ This was meant to describe the prevention potential of the quadrivalent vaccine. The currently available Gardasil 9 targets the HPV types that account for 90% of cervical cancers,² with projected effectiveness likely to vary based on geographic variation in HPV subtypes, ranging from 86.5% in Australia to 92% in North America.³ It is difficult to precisely calculate the effectiveness of HPV vaccination alone, given that cervical cancer prevention is twofold, with primary vaccination and secondary screening (with several notable updates to US national screening guidelines during the same time frame as vaccine development).⁴

It is true that the 29% decrease in US cervical cancer incidence rates during the years 2011–2014 compared with 2003–2006 is less than the predicted 70%.⁵ However, not all eligible US females are vaccinated; according to reports from the US Centers for Disease Control and Prevention, 49% of adolescents were appropriately immunized against HPV in 2017, an increase over the rate of only 35% in 2014.⁶ Low vaccination rates undoubtedly negatively impact any benefits from herd immunity, though the exact benefits of this population immunity are difficult to quantify.⁷

In Australia, a national school-based HPV vaccination program was initiated in 2007, making the vaccine available for free. Over 70% of girls ages 12 and 13 were vaccinated, and follow-up within the same decade showed a greater than 90% reduction in genital warts, as well as a reduction in high-grade cervical lesions.⁸ In addition, the incidence of genital warts in unvaccinated heterosexual males during the prevaccination vs the vaccination period decreased by up to 81% (a marker of herd immunity).⁹

In the US, the HPV subtypes found in the quadrivalent vaccine decreased by 71% in those ages 14 to 19, within 8 years of vaccine introduction.¹⁰ An analysis of US state cancer registries between 2009 and 2012 showed that in Michigan, the rates of high-grade, precancerous lesions declined by 37% each year for women ages 15 to 19, thought to be due to changes in screening and vaccination guidelines.¹¹ Similarly, an analysis of 9 million privately insured US females showed that the presence of high-grade precancerous lesions significantly decreased between the years 2007 and 2014 in those ages 15 to 24 (vaccinated individuals), but not in those ages 25 to 39 (unvaccinated individuals).¹² Most recently, a study of 10,206 women showed a 21.9% decrease in cervical intraepithelial neoplasia grade 2 or worse lesions due to HPV subtypes 16 or 18 in those who have received at least 1 dose of the vaccine; reduced rates in unvaccinated women were also seen, representing first evidence of herd immunity in the United States.¹³ In contrast, the rates of high-grade lesions due to nonvaccine HPV subtypes remained constant. Given that progression to cervical cancer can take 10 to 15 years or longer after HPV infection, true vaccine benefits will emerge once increased vaccination rates are achieved and after at least a decade of follow-up.

We applaud Dr. Lichtenberg’s efforts to clarify vaccine efficacy for appropriate counseling, as this is key to ensuring patient trust. Immunization fears have fueled the re-emergence of vaccine-preventable illnesses across the world. Given the wave of vaccine misinformation on the Internet, we all face patients and family members skeptical of vaccine efficacy and safety. Those requesting more information deserve an honest, informed discussion with their provider. Interestingly, however, among 955 unvaccinated women, the belief of not being at risk for HPV was the most common reason for not receiving the vaccine.¹⁴ Effective education can be achieved by focusing on the personal risks of HPV to the patient, as well as the overall favorable risk vs benefits of vaccination. Quoting an exact rate of cancer reduction is likely a less effective counseling strategy, and these efficacy estimates will change as vaccination rates and HPV prevalence within the population change over time.

About 12% of women worldwide are infected with human papillomavirus (HPV).¹ Persistent HPV infection with high-risk strains such as HPV 6, 11, 16, and 18 cause nearly all cases of cervical cancer and some anal, vaginal, penile, and oropharyngeal cancers.² An estimated 13,000 cases of invasive cervical cancer will be diagnosed this year in the United States alone.³

Up to 70% of HPV-related cervical cancer cases can be prevented with vaccination. A number of changes have been made to the vaccination schedule within the past few years—patients younger than 15 need only 2 rather than 3 doses, and the vaccine itself can be used in adults up to age 45.

Vaccination and routine cervical cancer screening are both necessary to prevent this disease³ along with effective family and patient counseling. Here, we discuss the most up-to-date HPV vaccination recommendations, current cervical cancer screening guidelines, counseling techniques that increase vaccination acceptance rates, and follow-up protocols for abnormal cervical cancer screening results.

TYPES OF HPV VACCINES

HPV immunization can prevent up to 70% of cases of cervical cancer due to HPV as well as 90% of genital warts.⁴ The US Food and Drug Administration (FDA) has approved 3 HPV vaccines:

• Gardasil 9 targets HPV types 6, 11, 16, and 18 along with 31, 33, 45, 52, 58—these cause 90% of cervical cancer cases and most cases of genital warts⁵—making it the most effective vaccine available; Gardasil 9 is the only HPV vaccine currently available in the United States
• The bivalent vaccine (Cervarix) targeted HPV 16 and 18 only, and was discontinued in the United States in 2016
• The quadrivalent HPV vaccine (Gardasil) targeted HPV 16 and 18 as well as 6 and 11, which cause most cases of genital warts; the last available doses in the United States expired in May 2017; it has been replaced by Gardasil 9.

The incidence of cervical cancer in the United States dropped 29% among 15- to 24-year-olds from 2003–2006 when HPV vaccination first started to 2011–2014.⁶

VACCINE DOSING RECOMMENDATIONS FOR PRIMARY PREVENTION

The Advisory Committee on Immunization Practices (ACIP) revised its HPV vaccine schedule in 2016, when it decreased the necessary doses from 3 to 2 for patients under age 15 and addressed the needs of special patient populations.⁷ In late 2018, the FDA approved the use of the vaccine in men and women up to age 45. However, no change in guidelines have yet been made (Table 1).

In females, the ACIP recommends starting HPV vaccination at age 11 or 12, but it can be given as early as age 9. A 2-dose schedule is recommended for the 9-valent vaccine before the patient’s 15th birthday (the second dose 6 to 12 months after the first).⁷ For females who initiate HPV vaccination between ages 15 and 45, a 3-dose schedule is necessary (at 0, 1 to 2, and 6 months).^7,8

The change to a 2-dose schedule was prompted by an evaluation of girls ages 9 to 13 randomized to receive either a 2- or 3-dose schedule. Antibody responses with a 2-dose schedule were not inferior to those of young women (ages 16 to 26) who received all 3 doses.⁹ The geometric mean titer ratios remained noninferior throughout the study period of 36 months.

However, a loss of noninferiority was noted for HPV-18 by 24 months and for HPV-6 by 36 months.⁹ Thus, further studies are needed to understand the duration of protection with a 2-dose schedule. Nevertheless, decreasing the number of doses makes it a more convenient and cost-effective option for many families.

The recommendations are the same for males except for one notable difference: in males ages 21 to 26, vaccination is not routinely recommended by the ACIP, but rather it is considered a “permissive use” recommendation: ie, the vaccine should be offered and final decisions on administration be made after individualized discussion with the patient.¹⁰ Permissive-use status also means the vaccine may not be covered by health insurance. Even though the vaccine is now available to men and women until age 45, many insurance plans do not cover it after age 26.

Children of either sex with a history of sexual abuse should receive their first vaccine dose beginning at age 9.⁷

Immunocompromised patients should follow the 3-dose schedule regardless of their sex or the age when vaccination was initiated.¹⁰

For transgender patients and for men not previously vaccinated who have sex with men, the 3-dose schedule vaccine should be given by the age of 26 (this is a routine recommendation, not a permissive one).⁸

Effective patient and family counseling is important. Even though the first HPV vaccine was approved in 2006, only 34.9% of US adolescents were fully vaccinated by 2015. This was in part because providers did not recommend it, were unfamiliar with it, or had concerns about its safety,^11,12 and in part because some parents refused it.

The physician must address any myths regarding HPV vaccination and ensure that parents and patients understand that HPV vaccine is safe and effective. Studies have shown that with high-quality recommendations (ie, the care provider strongly endorses the HPV vaccine, encourages same-day vaccination, and discusses cancer prevention), patients are 9 times more likely to start the HPV vaccination schedule and 3 times more likely to follow through with subsequent doses.¹³

Providing good family and patient education does not necessarily require spending more counseling time. A recent study showed that spending less time discussing the HPV vaccine can lead to better vaccine coverage.¹⁴ The study compared parent HPV vaccine counseling techniques and found that simply informing patients and their families that the HPV vaccine was due was associated with a higher vaccine acceptance rate than inviting conversations about it.¹⁴ When providers announced that the vaccine was due, assuming the parents were ready to vaccinate, there was a 5.4% increase in HPV vaccination coverage.¹⁴

Conversely, physicians who engaged parents in open-ended discussions about the HPV vaccine did not improve HPV vaccination coverage.¹⁴ The authors suggested that providers approach HPV vaccination as if they were counseling patients and families about the need to avoid second-hand smoke or the need to use car seats. If parents or patients resist the presumptive announcement approach, expanded counseling and shared decision-making are appropriate. This includes addressing misconceptions that parents and patients may have about the HPV vaccine. The American Cancer Society lists 8 facts to reference (Table 2).¹⁵

SECONDARY PREVENTION: CERVICAL CANCER SCREENING

Since the introduction of the Papanicolaou (Pap) test, US cervical cancer incidence rates have decreased by more than 60%.¹⁶ Because almost all cervical cancer is preventable with proper screening, all women ages 21 to 65 should be screened.

Currently, there are 3 options available for cervical cancer screening: the Pap-only test, the Pap-HPV cotest, and the high-risk HPV-only test (Table 3). The latter 2 options detect high-risk HPV genotypes.

Several organizations have screening algorithms that recommend when to use these tests, but the 3 that shape today’s standard of care in cervical cancer screening come from the American College of Obstetricians and Gynecologists (ACOG), the American Society for Colposcopy and Cervical Pathology (ASCCP), and US Preventive Services Task Force (USPSTF).^17–19

Pap-only testing is performed every 3 years to screen for cervical neoplasia that might indicate premalignancy.

Pap-HPV cotesting is performed every 5 years in women older than 30 with past normal screening. Until 2018, all 3 organizations recommended cotesting as the preferred screening algorithm for women ages 30 to 65.^17–19 Patients with a history of abnormal test results require more frequent testing as recommended by the ASCCP.¹⁸

The high-risk HPV-only test utilizes real-time polymerase chain reaction to detect HPV 16, HPV 18, and 12 other HPV genotypes. Only 2 tests are approved by the FDA as stand-alone cervical cancer screening tests—the Roche Cobas HPV test approved in 2014 and the Becton Dickinson Onclarity HPV assay approved in 2018. Other HPV tests that are used in a cotesting strategy should not be used for high-risk HPV-only testing because their performance characteristics may differ.

In 2015, the Addressing the Need for Advanced HPV Diagnostics (ATHENA) study showed that 1 round of high-risk HPV-only screening for women older than 25 was more sensitive than Pap-only or cotesting for stage 3 cervical intraepithelial neoplasia or more severe disease (after 3 years of follow-up).²⁰ Current guidelines from ASCCP¹⁸ and ACOG¹⁷ state that the high-risk HPV test can be repeated every 3 years (when used to screen by itself) if the woman is older than 25 and has had a normal test result.

If the HPV test result is positive for high-risk HPV 16 or 18 genotypes, then immediate colposcopy is indicated; women who test positive for one of the other 12 high-risk subtypes will need to undergo a Pap test to determine the appropriate follow-up (Figure 1).^18,21

In 2018, the USPSTF updated its recommendations, noting that for women age 30 to 65, Pap-only testing every 3 years, cotesting every 5 years, or high-risk HPV-only testing every 5 years are all appropriate screening strategies, with the Pap-only or high-risk HPV-only screenings being preferred.¹⁹ This is in contrast to ACOG and ASCCP recommendations for cotesting every 5 years, with alternative options of Pap-only or HPV-only testing being done every 3 years.^17,18

The USPSTF reviewed large randomized and observational studies to summarize the effectiveness of the 3 screening strategies and commissioned a decision analysis model to compare the risks, benefits, and costs of the 3 screening algorithms. The guideline statement notes both cotesting and high-risk HPV testing offer similar cancer detection rates: each prevents 1 additional cancer per 1,000 women screened as opposed to Pap-only testing.¹⁹

Also, tests that incorporate high-risk HPV screening may offer better detection of cervical adenocarcinoma (which has a worse prognosis than the more common squamous cell carcinoma type). However, both HPV-based screening strategies are more likely to require additional colposcopies for follow-up than Pap-only screening (1,630 colposcopies required for each cancer prevented with high-risk HPV alone, 1,635 with cotesting). Colposcopy is a simple office procedure that causes minimal discomfort to the patient.

The USPSTF guideline also differs in the recommended frequency of high-risk HPV-only testing; a high-risk HPV result should be repeated every 5 years if normal (as opposed to every 3 years as recommended by ACOG and ASCCP).¹⁹ The 5-year recommendation is based on analysis modeling, which suggests that performing high-risk HPV-only testing more frequently is unlikely to improve detection rates but will increase the number of screening tests and colposcopies.¹⁹

No trial has directly compared cotesting with high-risk HPV testing for more than 2 rounds of screening. The updated USPSTF recommendations are based on modeling estimates and expert opinion, which assesses cost and benefit vs harm in the long term. Also, no high-risk HPV test is currently FDA-approved for every-5-year screening when used by itself.

All 3 cervical cancer screening methods provide highly effective cancer prevention, so it is important for providers to choose the strategy that best fits their practice. The most critical aspect of screening is getting all women screened, no matter which method is used.

It is critical to remember that the screening intervals are intended for patients without symptoms. Those who have new concerns such as bleeding should have a diagnostic Pap done to evaluate their symptoms.

Follow-up of abnormal results

Regardless of the pathway chosen, appropriate follow-up of any abnormal test result is critical to the early detection of cancer. Established follow-up guidelines exist,^22,23 but accessing this information can be difficult for the busy clinician. The ASCCP has a mobile phone application that outlines the action steps corresponding to the patient’s age and results of any combination of Pap or HPV testing. The app also includes the best screening algorithms for a particular patient.²⁴

All guidelines agree that cervical cancer screening should start at age 21, regardless of HPV vaccination status or age of sexual initiation.^17,18,25 Screening can be discontinued at age 65 for women with normal screening results in the prior decade (3 consecutive negative Pap results or 2 consecutive negative cotest results).²³

For women who have had a total hysterectomy and no history of cervical neoplasia, screening should be stopped immediately after the procedure. However, several high-risk groups of women will need continued screening past the age of 65, or after a hysterectomy.

For a woman with a history of stage 2 cervical intraepithelial neoplasia or higher grade lesions, routine screening is continued for an additional 20 years, even if she is over age 65. Pap-only testing every 3 years is acceptable, because the role of HPV testing is unclear after hysterectomy.²³ Prior guidelines suggested annual screening in these patients, so the change to every 3 years is notable. Many gynecologic oncologists will recommend that women with a history of cervical cancer continue annual screening indefinitely.

Within the first 2 to 3 years after treatment for high-grade dysplastic changes, annual follow-up is done by the gynecologic oncology team. Providers who offer follow-up during this time frame should keep in communication with the oncology team to ensure appropriate, individualized care. These recommendations are based on expert opinion, so variations in clinical practice may be seen.

Women infected with the human immunodeficiency virus can have Pap-only testing every 3 years, after a series of 3 normal annual Pap results.²⁶ But screening does not stop at age 65.^23,26 For patients who are immunosuppressed or have a history of diethylstilbestrol exposure, screening should be done annually indefinitely.²³

About 12% of women worldwide are infected with human papillomavirus (HPV).¹ Persistent HPV infection with high-risk strains such as HPV 6, 11, 16, and 18 cause nearly all cases of cervical cancer and some anal, vaginal, penile, and oropharyngeal cancers.² An estimated 13,000 cases of invasive cervical cancer will be diagnosed this year in the United States alone.³

Up to 70% of HPV-related cervical cancer cases can be prevented with vaccination. A number of changes have been made to the vaccination schedule within the past few years—patients younger than 15 need only 2 rather than 3 doses, and the vaccine itself can be used in adults up to age 45.

Vaccination and routine cervical cancer screening are both necessary to prevent this disease³ along with effective family and patient counseling. Here, we discuss the most up-to-date HPV vaccination recommendations, current cervical cancer screening guidelines, counseling techniques that increase vaccination acceptance rates, and follow-up protocols for abnormal cervical cancer screening results.

TYPES OF HPV VACCINES

HPV immunization can prevent up to 70% of cases of cervical cancer due to HPV as well as 90% of genital warts.⁴ The US Food and Drug Administration (FDA) has approved 3 HPV vaccines:

• Gardasil 9 targets HPV types 6, 11, 16, and 18 along with 31, 33, 45, 52, 58—these cause 90% of cervical cancer cases and most cases of genital warts⁵—making it the most effective vaccine available; Gardasil 9 is the only HPV vaccine currently available in the United States
• The bivalent vaccine (Cervarix) targeted HPV 16 and 18 only, and was discontinued in the United States in 2016
• The quadrivalent HPV vaccine (Gardasil) targeted HPV 16 and 18 as well as 6 and 11, which cause most cases of genital warts; the last available doses in the United States expired in May 2017; it has been replaced by Gardasil 9.

The incidence of cervical cancer in the United States dropped 29% among 15- to 24-year-olds from 2003–2006 when HPV vaccination first started to 2011–2014.⁶

VACCINE DOSING RECOMMENDATIONS FOR PRIMARY PREVENTION

The Advisory Committee on Immunization Practices (ACIP) revised its HPV vaccine schedule in 2016, when it decreased the necessary doses from 3 to 2 for patients under age 15 and addressed the needs of special patient populations.⁷ In late 2018, the FDA approved the use of the vaccine in men and women up to age 45. However, no change in guidelines have yet been made (Table 1).

In females, the ACIP recommends starting HPV vaccination at age 11 or 12, but it can be given as early as age 9. A 2-dose schedule is recommended for the 9-valent vaccine before the patient’s 15th birthday (the second dose 6 to 12 months after the first).⁷ For females who initiate HPV vaccination between ages 15 and 45, a 3-dose schedule is necessary (at 0, 1 to 2, and 6 months).^7,8

The change to a 2-dose schedule was prompted by an evaluation of girls ages 9 to 13 randomized to receive either a 2- or 3-dose schedule. Antibody responses with a 2-dose schedule were not inferior to those of young women (ages 16 to 26) who received all 3 doses.⁹ The geometric mean titer ratios remained noninferior throughout the study period of 36 months.

However, a loss of noninferiority was noted for HPV-18 by 24 months and for HPV-6 by 36 months.⁹ Thus, further studies are needed to understand the duration of protection with a 2-dose schedule. Nevertheless, decreasing the number of doses makes it a more convenient and cost-effective option for many families.

The recommendations are the same for males except for one notable difference: in males ages 21 to 26, vaccination is not routinely recommended by the ACIP, but rather it is considered a “permissive use” recommendation: ie, the vaccine should be offered and final decisions on administration be made after individualized discussion with the patient.¹⁰ Permissive-use status also means the vaccine may not be covered by health insurance. Even though the vaccine is now available to men and women until age 45, many insurance plans do not cover it after age 26.

Children of either sex with a history of sexual abuse should receive their first vaccine dose beginning at age 9.⁷

Immunocompromised patients should follow the 3-dose schedule regardless of their sex or the age when vaccination was initiated.¹⁰

For transgender patients and for men not previously vaccinated who have sex with men, the 3-dose schedule vaccine should be given by the age of 26 (this is a routine recommendation, not a permissive one).⁸

Effective patient and family counseling is important. Even though the first HPV vaccine was approved in 2006, only 34.9% of US adolescents were fully vaccinated by 2015. This was in part because providers did not recommend it, were unfamiliar with it, or had concerns about its safety,^11,12 and in part because some parents refused it.

The physician must address any myths regarding HPV vaccination and ensure that parents and patients understand that HPV vaccine is safe and effective. Studies have shown that with high-quality recommendations (ie, the care provider strongly endorses the HPV vaccine, encourages same-day vaccination, and discusses cancer prevention), patients are 9 times more likely to start the HPV vaccination schedule and 3 times more likely to follow through with subsequent doses.¹³

Providing good family and patient education does not necessarily require spending more counseling time. A recent study showed that spending less time discussing the HPV vaccine can lead to better vaccine coverage.¹⁴ The study compared parent HPV vaccine counseling techniques and found that simply informing patients and their families that the HPV vaccine was due was associated with a higher vaccine acceptance rate than inviting conversations about it.¹⁴ When providers announced that the vaccine was due, assuming the parents were ready to vaccinate, there was a 5.4% increase in HPV vaccination coverage.¹⁴

Conversely, physicians who engaged parents in open-ended discussions about the HPV vaccine did not improve HPV vaccination coverage.¹⁴ The authors suggested that providers approach HPV vaccination as if they were counseling patients and families about the need to avoid second-hand smoke or the need to use car seats. If parents or patients resist the presumptive announcement approach, expanded counseling and shared decision-making are appropriate. This includes addressing misconceptions that parents and patients may have about the HPV vaccine. The American Cancer Society lists 8 facts to reference (Table 2).¹⁵

SECONDARY PREVENTION: CERVICAL CANCER SCREENING

Since the introduction of the Papanicolaou (Pap) test, US cervical cancer incidence rates have decreased by more than 60%.¹⁶ Because almost all cervical cancer is preventable with proper screening, all women ages 21 to 65 should be screened.

Currently, there are 3 options available for cervical cancer screening: the Pap-only test, the Pap-HPV cotest, and the high-risk HPV-only test (Table 3). The latter 2 options detect high-risk HPV genotypes.

Several organizations have screening algorithms that recommend when to use these tests, but the 3 that shape today’s standard of care in cervical cancer screening come from the American College of Obstetricians and Gynecologists (ACOG), the American Society for Colposcopy and Cervical Pathology (ASCCP), and US Preventive Services Task Force (USPSTF).^17–19

Pap-only testing is performed every 3 years to screen for cervical neoplasia that might indicate premalignancy.

Pap-HPV cotesting is performed every 5 years in women older than 30 with past normal screening. Until 2018, all 3 organizations recommended cotesting as the preferred screening algorithm for women ages 30 to 65.^17–19 Patients with a history of abnormal test results require more frequent testing as recommended by the ASCCP.¹⁸

The high-risk HPV-only test utilizes real-time polymerase chain reaction to detect HPV 16, HPV 18, and 12 other HPV genotypes. Only 2 tests are approved by the FDA as stand-alone cervical cancer screening tests—the Roche Cobas HPV test approved in 2014 and the Becton Dickinson Onclarity HPV assay approved in 2018. Other HPV tests that are used in a cotesting strategy should not be used for high-risk HPV-only testing because their performance characteristics may differ.

In 2015, the Addressing the Need for Advanced HPV Diagnostics (ATHENA) study showed that 1 round of high-risk HPV-only screening for women older than 25 was more sensitive than Pap-only or cotesting for stage 3 cervical intraepithelial neoplasia or more severe disease (after 3 years of follow-up).²⁰ Current guidelines from ASCCP¹⁸ and ACOG¹⁷ state that the high-risk HPV test can be repeated every 3 years (when used to screen by itself) if the woman is older than 25 and has had a normal test result.

If the HPV test result is positive for high-risk HPV 16 or 18 genotypes, then immediate colposcopy is indicated; women who test positive for one of the other 12 high-risk subtypes will need to undergo a Pap test to determine the appropriate follow-up (Figure 1).^18,21

In 2018, the USPSTF updated its recommendations, noting that for women age 30 to 65, Pap-only testing every 3 years, cotesting every 5 years, or high-risk HPV-only testing every 5 years are all appropriate screening strategies, with the Pap-only or high-risk HPV-only screenings being preferred.¹⁹ This is in contrast to ACOG and ASCCP recommendations for cotesting every 5 years, with alternative options of Pap-only or HPV-only testing being done every 3 years.^17,18

The USPSTF reviewed large randomized and observational studies to summarize the effectiveness of the 3 screening strategies and commissioned a decision analysis model to compare the risks, benefits, and costs of the 3 screening algorithms. The guideline statement notes both cotesting and high-risk HPV testing offer similar cancer detection rates: each prevents 1 additional cancer per 1,000 women screened as opposed to Pap-only testing.¹⁹

Also, tests that incorporate high-risk HPV screening may offer better detection of cervical adenocarcinoma (which has a worse prognosis than the more common squamous cell carcinoma type). However, both HPV-based screening strategies are more likely to require additional colposcopies for follow-up than Pap-only screening (1,630 colposcopies required for each cancer prevented with high-risk HPV alone, 1,635 with cotesting). Colposcopy is a simple office procedure that causes minimal discomfort to the patient.

The USPSTF guideline also differs in the recommended frequency of high-risk HPV-only testing; a high-risk HPV result should be repeated every 5 years if normal (as opposed to every 3 years as recommended by ACOG and ASCCP).¹⁹ The 5-year recommendation is based on analysis modeling, which suggests that performing high-risk HPV-only testing more frequently is unlikely to improve detection rates but will increase the number of screening tests and colposcopies.¹⁹

No trial has directly compared cotesting with high-risk HPV testing for more than 2 rounds of screening. The updated USPSTF recommendations are based on modeling estimates and expert opinion, which assesses cost and benefit vs harm in the long term. Also, no high-risk HPV test is currently FDA-approved for every-5-year screening when used by itself.

All 3 cervical cancer screening methods provide highly effective cancer prevention, so it is important for providers to choose the strategy that best fits their practice. The most critical aspect of screening is getting all women screened, no matter which method is used.

It is critical to remember that the screening intervals are intended for patients without symptoms. Those who have new concerns such as bleeding should have a diagnostic Pap done to evaluate their symptoms.

Follow-up of abnormal results

Regardless of the pathway chosen, appropriate follow-up of any abnormal test result is critical to the early detection of cancer. Established follow-up guidelines exist,^22,23 but accessing this information can be difficult for the busy clinician. The ASCCP has a mobile phone application that outlines the action steps corresponding to the patient’s age and results of any combination of Pap or HPV testing. The app also includes the best screening algorithms for a particular patient.²⁴

All guidelines agree that cervical cancer screening should start at age 21, regardless of HPV vaccination status or age of sexual initiation.^17,18,25 Screening can be discontinued at age 65 for women with normal screening results in the prior decade (3 consecutive negative Pap results or 2 consecutive negative cotest results).²³

For women who have had a total hysterectomy and no history of cervical neoplasia, screening should be stopped immediately after the procedure. However, several high-risk groups of women will need continued screening past the age of 65, or after a hysterectomy.

For a woman with a history of stage 2 cervical intraepithelial neoplasia or higher grade lesions, routine screening is continued for an additional 20 years, even if she is over age 65. Pap-only testing every 3 years is acceptable, because the role of HPV testing is unclear after hysterectomy.²³ Prior guidelines suggested annual screening in these patients, so the change to every 3 years is notable. Many gynecologic oncologists will recommend that women with a history of cervical cancer continue annual screening indefinitely.

Within the first 2 to 3 years after treatment for high-grade dysplastic changes, annual follow-up is done by the gynecologic oncology team. Providers who offer follow-up during this time frame should keep in communication with the oncology team to ensure appropriate, individualized care. These recommendations are based on expert opinion, so variations in clinical practice may be seen.

Women infected with the human immunodeficiency virus can have Pap-only testing every 3 years, after a series of 3 normal annual Pap results.²⁶ But screening does not stop at age 65.^23,26 For patients who are immunosuppressed or have a history of diethylstilbestrol exposure, screening should be done annually indefinitely.²³

About 12% of women worldwide are infected with human papillomavirus (HPV).¹ Persistent HPV infection with high-risk strains such as HPV 6, 11, 16, and 18 cause nearly all cases of cervical cancer and some anal, vaginal, penile, and oropharyngeal cancers.² An estimated 13,000 cases of invasive cervical cancer will be diagnosed this year in the United States alone.³

Up to 70% of HPV-related cervical cancer cases can be prevented with vaccination. A number of changes have been made to the vaccination schedule within the past few years—patients younger than 15 need only 2 rather than 3 doses, and the vaccine itself can be used in adults up to age 45.

Vaccination and routine cervical cancer screening are both necessary to prevent this disease³ along with effective family and patient counseling. Here, we discuss the most up-to-date HPV vaccination recommendations, current cervical cancer screening guidelines, counseling techniques that increase vaccination acceptance rates, and follow-up protocols for abnormal cervical cancer screening results.

TYPES OF HPV VACCINES

HPV immunization can prevent up to 70% of cases of cervical cancer due to HPV as well as 90% of genital warts.⁴ The US Food and Drug Administration (FDA) has approved 3 HPV vaccines:

• Gardasil 9 targets HPV types 6, 11, 16, and 18 along with 31, 33, 45, 52, 58—these cause 90% of cervical cancer cases and most cases of genital warts⁵—making it the most effective vaccine available; Gardasil 9 is the only HPV vaccine currently available in the United States
• The bivalent vaccine (Cervarix) targeted HPV 16 and 18 only, and was discontinued in the United States in 2016
• The quadrivalent HPV vaccine (Gardasil) targeted HPV 16 and 18 as well as 6 and 11, which cause most cases of genital warts; the last available doses in the United States expired in May 2017; it has been replaced by Gardasil 9.

The incidence of cervical cancer in the United States dropped 29% among 15- to 24-year-olds from 2003–2006 when HPV vaccination first started to 2011–2014.⁶

VACCINE DOSING RECOMMENDATIONS FOR PRIMARY PREVENTION

The Advisory Committee on Immunization Practices (ACIP) revised its HPV vaccine schedule in 2016, when it decreased the necessary doses from 3 to 2 for patients under age 15 and addressed the needs of special patient populations.⁷ In late 2018, the FDA approved the use of the vaccine in men and women up to age 45. However, no change in guidelines have yet been made (Table 1).

In females, the ACIP recommends starting HPV vaccination at age 11 or 12, but it can be given as early as age 9. A 2-dose schedule is recommended for the 9-valent vaccine before the patient’s 15th birthday (the second dose 6 to 12 months after the first).⁷ For females who initiate HPV vaccination between ages 15 and 45, a 3-dose schedule is necessary (at 0, 1 to 2, and 6 months).^7,8

The change to a 2-dose schedule was prompted by an evaluation of girls ages 9 to 13 randomized to receive either a 2- or 3-dose schedule. Antibody responses with a 2-dose schedule were not inferior to those of young women (ages 16 to 26) who received all 3 doses.⁹ The geometric mean titer ratios remained noninferior throughout the study period of 36 months.

However, a loss of noninferiority was noted for HPV-18 by 24 months and for HPV-6 by 36 months.⁹ Thus, further studies are needed to understand the duration of protection with a 2-dose schedule. Nevertheless, decreasing the number of doses makes it a more convenient and cost-effective option for many families.

The recommendations are the same for males except for one notable difference: in males ages 21 to 26, vaccination is not routinely recommended by the ACIP, but rather it is considered a “permissive use” recommendation: ie, the vaccine should be offered and final decisions on administration be made after individualized discussion with the patient.¹⁰ Permissive-use status also means the vaccine may not be covered by health insurance. Even though the vaccine is now available to men and women until age 45, many insurance plans do not cover it after age 26.

Children of either sex with a history of sexual abuse should receive their first vaccine dose beginning at age 9.⁷

Immunocompromised patients should follow the 3-dose schedule regardless of their sex or the age when vaccination was initiated.¹⁰

For transgender patients and for men not previously vaccinated who have sex with men, the 3-dose schedule vaccine should be given by the age of 26 (this is a routine recommendation, not a permissive one).⁸

Effective patient and family counseling is important. Even though the first HPV vaccine was approved in 2006, only 34.9% of US adolescents were fully vaccinated by 2015. This was in part because providers did not recommend it, were unfamiliar with it, or had concerns about its safety,^11,12 and in part because some parents refused it.

The physician must address any myths regarding HPV vaccination and ensure that parents and patients understand that HPV vaccine is safe and effective. Studies have shown that with high-quality recommendations (ie, the care provider strongly endorses the HPV vaccine, encourages same-day vaccination, and discusses cancer prevention), patients are 9 times more likely to start the HPV vaccination schedule and 3 times more likely to follow through with subsequent doses.¹³

Providing good family and patient education does not necessarily require spending more counseling time. A recent study showed that spending less time discussing the HPV vaccine can lead to better vaccine coverage.¹⁴ The study compared parent HPV vaccine counseling techniques and found that simply informing patients and their families that the HPV vaccine was due was associated with a higher vaccine acceptance rate than inviting conversations about it.¹⁴ When providers announced that the vaccine was due, assuming the parents were ready to vaccinate, there was a 5.4% increase in HPV vaccination coverage.¹⁴

Conversely, physicians who engaged parents in open-ended discussions about the HPV vaccine did not improve HPV vaccination coverage.¹⁴ The authors suggested that providers approach HPV vaccination as if they were counseling patients and families about the need to avoid second-hand smoke or the need to use car seats. If parents or patients resist the presumptive announcement approach, expanded counseling and shared decision-making are appropriate. This includes addressing misconceptions that parents and patients may have about the HPV vaccine. The American Cancer Society lists 8 facts to reference (Table 2).¹⁵

SECONDARY PREVENTION: CERVICAL CANCER SCREENING

Since the introduction of the Papanicolaou (Pap) test, US cervical cancer incidence rates have decreased by more than 60%.¹⁶ Because almost all cervical cancer is preventable with proper screening, all women ages 21 to 65 should be screened.

Currently, there are 3 options available for cervical cancer screening: the Pap-only test, the Pap-HPV cotest, and the high-risk HPV-only test (Table 3). The latter 2 options detect high-risk HPV genotypes.

Several organizations have screening algorithms that recommend when to use these tests, but the 3 that shape today’s standard of care in cervical cancer screening come from the American College of Obstetricians and Gynecologists (ACOG), the American Society for Colposcopy and Cervical Pathology (ASCCP), and US Preventive Services Task Force (USPSTF).^17–19

Pap-only testing is performed every 3 years to screen for cervical neoplasia that might indicate premalignancy.

Pap-HPV cotesting is performed every 5 years in women older than 30 with past normal screening. Until 2018, all 3 organizations recommended cotesting as the preferred screening algorithm for women ages 30 to 65.^17–19 Patients with a history of abnormal test results require more frequent testing as recommended by the ASCCP.¹⁸

The high-risk HPV-only test utilizes real-time polymerase chain reaction to detect HPV 16, HPV 18, and 12 other HPV genotypes. Only 2 tests are approved by the FDA as stand-alone cervical cancer screening tests—the Roche Cobas HPV test approved in 2014 and the Becton Dickinson Onclarity HPV assay approved in 2018. Other HPV tests that are used in a cotesting strategy should not be used for high-risk HPV-only testing because their performance characteristics may differ.

In 2015, the Addressing the Need for Advanced HPV Diagnostics (ATHENA) study showed that 1 round of high-risk HPV-only screening for women older than 25 was more sensitive than Pap-only or cotesting for stage 3 cervical intraepithelial neoplasia or more severe disease (after 3 years of follow-up).²⁰ Current guidelines from ASCCP¹⁸ and ACOG¹⁷ state that the high-risk HPV test can be repeated every 3 years (when used to screen by itself) if the woman is older than 25 and has had a normal test result.

If the HPV test result is positive for high-risk HPV 16 or 18 genotypes, then immediate colposcopy is indicated; women who test positive for one of the other 12 high-risk subtypes will need to undergo a Pap test to determine the appropriate follow-up (Figure 1).^18,21

In 2018, the USPSTF updated its recommendations, noting that for women age 30 to 65, Pap-only testing every 3 years, cotesting every 5 years, or high-risk HPV-only testing every 5 years are all appropriate screening strategies, with the Pap-only or high-risk HPV-only screenings being preferred.¹⁹ This is in contrast to ACOG and ASCCP recommendations for cotesting every 5 years, with alternative options of Pap-only or HPV-only testing being done every 3 years.^17,18

The USPSTF reviewed large randomized and observational studies to summarize the effectiveness of the 3 screening strategies and commissioned a decision analysis model to compare the risks, benefits, and costs of the 3 screening algorithms. The guideline statement notes both cotesting and high-risk HPV testing offer similar cancer detection rates: each prevents 1 additional cancer per 1,000 women screened as opposed to Pap-only testing.¹⁹

Also, tests that incorporate high-risk HPV screening may offer better detection of cervical adenocarcinoma (which has a worse prognosis than the more common squamous cell carcinoma type). However, both HPV-based screening strategies are more likely to require additional colposcopies for follow-up than Pap-only screening (1,630 colposcopies required for each cancer prevented with high-risk HPV alone, 1,635 with cotesting). Colposcopy is a simple office procedure that causes minimal discomfort to the patient.

The USPSTF guideline also differs in the recommended frequency of high-risk HPV-only testing; a high-risk HPV result should be repeated every 5 years if normal (as opposed to every 3 years as recommended by ACOG and ASCCP).¹⁹ The 5-year recommendation is based on analysis modeling, which suggests that performing high-risk HPV-only testing more frequently is unlikely to improve detection rates but will increase the number of screening tests and colposcopies.¹⁹

No trial has directly compared cotesting with high-risk HPV testing for more than 2 rounds of screening. The updated USPSTF recommendations are based on modeling estimates and expert opinion, which assesses cost and benefit vs harm in the long term. Also, no high-risk HPV test is currently FDA-approved for every-5-year screening when used by itself.

All 3 cervical cancer screening methods provide highly effective cancer prevention, so it is important for providers to choose the strategy that best fits their practice. The most critical aspect of screening is getting all women screened, no matter which method is used.

It is critical to remember that the screening intervals are intended for patients without symptoms. Those who have new concerns such as bleeding should have a diagnostic Pap done to evaluate their symptoms.

Follow-up of abnormal results

Regardless of the pathway chosen, appropriate follow-up of any abnormal test result is critical to the early detection of cancer. Established follow-up guidelines exist,^22,23 but accessing this information can be difficult for the busy clinician. The ASCCP has a mobile phone application that outlines the action steps corresponding to the patient’s age and results of any combination of Pap or HPV testing. The app also includes the best screening algorithms for a particular patient.²⁴

All guidelines agree that cervical cancer screening should start at age 21, regardless of HPV vaccination status or age of sexual initiation.^17,18,25 Screening can be discontinued at age 65 for women with normal screening results in the prior decade (3 consecutive negative Pap results or 2 consecutive negative cotest results).²³

For women who have had a total hysterectomy and no history of cervical neoplasia, screening should be stopped immediately after the procedure. However, several high-risk groups of women will need continued screening past the age of 65, or after a hysterectomy.

For a woman with a history of stage 2 cervical intraepithelial neoplasia or higher grade lesions, routine screening is continued for an additional 20 years, even if she is over age 65. Pap-only testing every 3 years is acceptable, because the role of HPV testing is unclear after hysterectomy.²³ Prior guidelines suggested annual screening in these patients, so the change to every 3 years is notable. Many gynecologic oncologists will recommend that women with a history of cervical cancer continue annual screening indefinitely.

Within the first 2 to 3 years after treatment for high-grade dysplastic changes, annual follow-up is done by the gynecologic oncology team. Providers who offer follow-up during this time frame should keep in communication with the oncology team to ensure appropriate, individualized care. These recommendations are based on expert opinion, so variations in clinical practice may be seen.

Women infected with the human immunodeficiency virus can have Pap-only testing every 3 years, after a series of 3 normal annual Pap results.²⁶ But screening does not stop at age 65.^23,26 For patients who are immunosuppressed or have a history of diethylstilbestrol exposure, screening should be done annually indefinitely.²³

Women's health encompasses a variety of topics relevant to the daily practice of internists. Staying up to date with the evidence in this wide field is a challenge.

This article reviews important studies published in 2015 and early 2016 on treatment of urinary tract infections, the optimal duration of bisphosphonate use, ovarian cancer screening, the impact of oral contraceptives and lactation on mortality rates, and the risks and benefits of intrauterine contraception. We critically appraised the studies and judged that their methodology was strong and appropriate for inclusion in this review.

IBUPROFEN FOR URINARY TRACT INFECTIONS

A 36-year-old woman reports 4 days of mild to moderate dysuria, frequency, and urgency. She denies fever, nausea, or back pain. Her last urinary tract infection was 2 years ago. Office urinalysis reveals leukocyte esterase and nitrites. She has read an article about antibiotic resistance and Clostridium difficile infection and asks you if antibiotics are truly necessary. What do you recommend?

Urinary tract infections are often self-limited

Uncomplicated urinary tract infections account for 25% of antibiotic prescriptions in primary care.¹

Several small studies have suggested that many of these infections are self-limited, resolving within 3 to 14 days without antibiotics (Table 1).^2–6 A potential disadvantage of withholding treatment is slower bacterial clearance and resolution of symptoms, but reducing the number of antibiotic prescriptions may help slow antibiotic resistance.^7,8 Surveys and qualitative studies have suggested that women are concerned about the harms of antibiotic treatment and so may be willing to avoid or postpone antibiotic use.^9–11

Ibuprofen vs fosfomycin

Gágyor et al⁶ conducted a double-blind, randomized multicenter trial in 42 general practices in Germany to assess whether treating the symptoms of uncomplicated urinary tract infection with ibuprofen would reduce antibiotic use without worsening outcomes.

Of the 779 eligible women with suspected urinary tract infection, 281 declined to participate in the study, 4 did not participate for reasons not specified, 246 received a single dose of fosfomycin 3 g, and 248 were treated with ibuprofen 400 mg three times a day for 3 days. Participants scored their daily symptoms and activity impairment, and safety data were collected for adverse events and relapses up to day 28 and within 6 and 12 months. In both groups, if symptoms worsened or persisted, antibiotic therapy was initiated at the discretion of the treating physician.

Exclusion criteria included fever, “loin” (back) tenderness, pregnancy, renal disease, a previous urinary tract infection within 2 weeks, urinary catheterization, and a contraindication to nonsteroidal anti-inflammatory medications.

Results. Within 28 days of symptom onset, women in the ibuprofen group had received 81 courses of antibiotics for symptoms of urinary tract infection (plus another 13 courses for other reasons), compared with 277 courses for urinary tract infection in the fosfomycin group (plus 6 courses for other reasons), for a relative rate reduction in antibiotic use of 66.5% (95% confidence interval [CI] 58.8%–74.4%, P < .001). The women who received ibuprofen were more likely to need antibiotics after initial treatment because of refractory symptoms but were still less likely to receive antibiotics overall (Table 1).

The mean duration of symptoms was slightly shorter in the fosfomycin group (4.6 vs 5.6 days, P < .001). However, the percentage of patients who had a recurrent urinary tract infection within 2 to 4 weeks was higher in the fosfomycin-treated patients (11% vs 6% P = .049).

Although the study was not powered to show significant differences in pyelonephritis, five patients in the ibuprofen group developed pyelonephritis compared with one in the antibiotic-treated group (P = .12).

An important limitation of the study was that nonparticipants had higher symptom scores, which may mean that the results are not generalizable to women who have recurrent urinary tract infections, longer duration of symptoms, or symptoms that are more severe. The strengths of the study were that more than half of all potentially eligible women were enrolled, and baseline data were collected from nonparticipants.

Can our patient avoid antibiotics?

Given the mild nature of her symptoms, the clinician should discuss with her the risks vs benefits of delaying antibiotics, once it has been determined that she has no risk factors for severe urinary tract infection. Her symptoms are likely to resolve within 1 week even if she declines antibiotic treatment, though they may last a day longer with ibuprofen alone than if she had received antibiotics. She should watch for symptoms of pyelonephritis (eg, flank pain, fever, chills, vomiting) and should seek prompt medical care if such symptoms occur.

DISCONTINUING BISPHOSPHONATES

A 64-year-old woman has taken alendronate for her osteoporosis for 5 years. She has no history of fractures. Her original bone density scans showed a T-score of –2.6 at the spine and –1.5 at the hip. Since she started to take alendronate, there has been no further loss in bone mineral density. She is tolerating the drug well and does not take any other medications. Should she continue the bisphosphonate?

Optimal duration of therapy unknown

The risks and benefits of long-term bisphosphonate use are debated.

In the Fracture Intervention Trial (FIT),¹² women with low bone mineral density of the femoral neck were randomized to receive alendronate or placebo and were followed for 36 months. The alendronate group had significantly fewer vertebral fractures and clinical fractures overall. Then, in the FIT Long-term Extension (FLEX) study,¹³ 1,009 alendronate-treated women in the FIT study were rerandomized to receive 5 years of additional treatment or to stop treatment. Bone density in the untreated women decreased, although not to the level it was before treatment. At the end of the study, there was no difference in hip fracture rate between the two groups (3% of each group had had a hip fracture), although women in the treated group had a lower rate of clinical vertebral fracture (2% vs 5%, relative risk 0.5, 95% CI 0.2–0.8).

In addition, rare but serious risks have been associated with bisphosphonate use, specifically atypical femoral fracture and osteonecrosis of the jaw. A US Food and Drug Administration (FDA) evaluation of long-term bisphosphonate use concluded that there was evidence of an increased risk of osteonecrosis of the jaw with longer duration of use, but causality was not established. The evaluation also noted conflicting results about the association with atypical femoral fracture.¹⁴

Based on this report and focusing on the absence of nonspine benefit after 5 years, the FDA suggested that bisphosphonates may be safely discontinued in some patients without compromising therapeutic gains, but no adequate clinical trial has yet delineated how long the benefits of treatment are maintained after cessation. A periodic reevaluation of continued need was recommended.¹⁴

New recommendations from the American Society for Bone and Mineral Research

Age is the greatest risk factor for fracture.¹⁵ Therefore, deciding whether to discontinue a bisphosphonate when a woman is older, and hence at higher risk, is a challenge.

A task force of the American Society for Bone and Mineral Research (ASBMR) has developed an evidence-based guideline on managing osteoporosis in patients on long-term bisphosphonate treatment.¹⁶ The goal was to provide guidance on the duration of bisphosphonate therapy from the perspective of risk vs benefit. The authors conducted a systematic review focusing on two randomized controlled trials (FLEX¹³ and the Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly Pivotal Fracture Trial¹⁷) that provided data on long-term bisphosphonate use.

The task force recommended¹⁶ that after 5 years of oral bisphosphonates or 3 years of intravenous bisphosphonates, risk should be reassessed. In women at high fracture risk, they recommended continuing the oral bisphosphonate for 10 years or the intravenous bisphosphonate for 6 years. Factors that favored continuation of bisphosphonate therapy were as follows:

• An osteoporotic fracture before or during therapy
• A hip bone mineral density T-score ≤ –2.5
• High risk of fracture, defined as age older than 70 or 75, other strong risk factors for fracture, or a FRAX fracture risk score¹⁸ above a country-specific threshold.

(The FRAX score is based on age, sex, weight, height, previous fracture, hip fracture in a parent, current smoking, use of glucocorticoids, rheumatoid arthritis, secondary osteoporosis, alcohol use, and bone mineral density in the femoral neck. It gives an estimate of the 10-year risk of major osteoporotic fracture and hip fracture. High risk would be a 10-year risk of major osteoporotic fracture greater than 20% or a 10-year risk of hip fracture greater than 3%.)

For women at high risk, the risks of atypical femoral fracture and osteonecrosis of the jaw are outweighed by the benefit of a reduction in vertebral fracture risk. For women not at high risk of fracture, a drug holiday of 2 to 3 years can be considered after 3 to 5 years of treatment.

Although the task force recommended reassessment after 2 to 3 years of drug holiday, how best to do this is not clear. The task force did not recommend a specific approach to reassessment, so decisions about when to restart therapy after a drug holiday could potentially be informed by subsequent bone mineral density testing if it were to show persistent bone loss. Another option could be to restart bisphosphonates after a defined amount of time (eg, 3–5 years) for women who have previously experienced benefit.

The task force recommendations are in line with those of other societies, the FDA, and expert opinion.^19–23

The American Association of Clinical Endocrinologists recommends considering a drug holiday in low-risk patients after 4 to 5 years of treatment. For high-risk patients, they recommend 1 to 2 years of drug holiday after 10 years of treatment. They encourage restarting treatment if bone mineral density decreases, bone turnover markers rise, or fracture occurs.¹⁹ This is a grade C recommendation, meaning the advice is based on descriptive studies and expert opinion.

Although some clinicians restart bisphosphonates when markers of bone turnover such as NTX (N-telopeptide of type 1 collagen) rise to premenopausal levels, there is no evidence to support this strategy.²⁴

The task force recommendations are based on limited evidence that primarily comes from white postmenopausal women. Another important limitation is that the outcomes are primarily vertebral fractures. However, until additional evidence is available, these guidelines can be useful in guiding decision-making.

Should our patient continue therapy?

Our patient is relatively young and does not have any of the high-risk features noted within the task force recommendations. She has responded well to bisphosphonate treatment and so can consider a drug holiday at this time.

OVARIAN CANCER SCREENING

A 50-year-old woman requests screening for ovarian cancer. She is postmenopausal and has no personal or family history of cancer. She is concerned because a friend forwarded an e-mail stating, “Please tell all your female friends and relatives to insist on a cancer antigen (CA) 125 blood test every year as part of their annual exam. This is an inexpensive and simple blood test. Don’t take no for an answer. If I had known then what I know now, we would have caught my cancer much earlier, before it was stage III!” What should you tell the patient?

Ovarian cancer is the most deadly of female reproductive cancers, largely because in most patients the cancer has already spread beyond the ovary by the time of clinical detection. Death rates from ovarian cancer have decreased only slightly in the past 30 years.

Little benefit and considerable harm of screening

In 2011, the Prostate Lung Colorectal Ovarian (PLCO) Cancer Screening trial²⁵ randomized more than 68,000 women ages 55 to 74 from the general US population to annual screening with CA 125 testing and transvaginal ultrasonography compared with usual care. They were followed for a median of 12.4 years.

Screening did not affect stage at diagnosis (77%–78% were in stage III or IV in both the screening and usual care groups), nor did it reduce the rate of death from ovarian cancer. In addition, false-positive findings led to some harm: nearly one in three women who had a positive screening test underwent surgery. Of 3,285 women with false-positive results, 1,080 underwent surgery, and 15% of these had at least one serious complication. The trial was stopped early due to evidence of futility.

A new UK study also found no benefit from screening

In the PLCO study, a CA 125 result of 35 U/mL or greater was classified as abnormal. However, researchers in the United Kingdom postulated that instead of using a single cutoff for a normal or abnormal CA 125 level, it would be better to interpret the CA 125 result according to a somewhat complicated (and proprietary) algorithm called the Risk of Ovarian Cancer Algorithm (ROCA).^26,27 The ROCA takes into account a woman’s age, menopausal status, known genetic mutations (BRCA 1 or 2 or Lynch syndrome), Ashkenazi Jewish descent, and family history of ovarian or breast cancer, as well as any change in CA 125 level over time.

In a 2016 UK study,²⁶ 202,638 postmenopausal women ages 50 to 74 were randomized to no screening, annual screening with transvaginal ultrasonography, or multimodal screening with an annual CA 125 blood test interpreted with the ROCA algorithm, adding transvaginal ultrasonography as a second-line test when needed if the CA 125 level was abnormal based on the ROCA. Women with abnormal findings on multimodal screening or ultrasonography had repeat tests, and women with persistent abnormalities underwent clinical evaluation and, when appropriate, surgery.

Participants were at average risk of ovarian cancer; those with suspected familial ovarian cancer syndrome were excluded, as were those with a personal history of ovarian cancer or other active cancer.

Results. At a median follow-up of 11.1 years, the percentage of women who were diagnosed with ovarian cancer was 0.7% in the multimodal screening group, 0.6% in the screening ultrasonography group, and 0.6% in the no-screening group. Comparing either multimodal or screening ultrasonography with no screening, there was no statistically significant reduction in mortality rate over 14 years of follow-up.

Screening had significant costs and potential harms. For every ovarian or peritoneal cancer detected by screening, an additional 2 women in the multimodal screening group and 10 women in the ultrasonography group underwent needless surgery.

Strengths of this trial included its large size, allowing adequate power to detect differences in outcomes, its multicenter setting, its high compliance rate, and the low crossover rate in the no-screening group. However, the design of the study makes it difficult to anticipate the late effects of screening. Also, the patient must purchase ROCA testing online and must also pay a consultation fee. Insurance providers do not cover this test.

Should our patient proceed with ovarian cancer screening?

No. Current evidence shows no clear benefit to ovarian cancer screening for average-risk women, and we should not recommend yearly ultrasonography and CA 125 level testing, as they are likely to cause harm without providing benefit. The US Preventive Services Task Force recommends against screening for ovarian cancer.²⁸ For premenopausal women, pregnancy, hormonal contraception, and breastfeeding all significantly decrease ovarian cancer risk by suppressing ovulation.^29–31

REPRODUCTIVE FACTORS AND THE RISK OF DEATH

A 26-year-old woman comes in to discuss her contraceptive options. She has been breastfeeding since the birth of her first baby 6 months ago, and wonders how lactation and contraception may affect her long-term health.

Questions about the safety of contraceptive options are common, especially in breastfeeding mothers.

In 2010, the long-term Royal College of General Practitioners’ Oral Contraceptive Study reported that the all-cause mortality rate was actually lower in women who used oral contraceptives.³² Similarly, in 2013, an Oxford study that followed 17,032 women for over 30 years reported no association between oral contraceptives and breast cancer.³³

However, in 2014, results from the Nurses’ Health Study indicated that breast cancer rates were higher in oral contraceptive users, although reassuringly, the study found no difference in all-cause mortality rates in women who had used oral contraception.³⁴

The European Prospective Investigation Into Cancer and Nutrition

To further characterize relationships between reproductive characteristics and mortality rates, investigators analyzed data from the European Prospective Investigation Into Cancer and Nutrition,³⁵ which recruited 322,972 women from 10 countries between 1992 and 2000. Analyses were stratified by study center and participant age and were adjusted for body mass index, physical activity, education level, smoking, and menopausal status; alcohol intake was examined as a potential confounder but was excluded from final models.

Findings. Over an average 13 years of follow-up, the rate of all-cause mortality was 20% lower in parous than in nulliparous women. In parous women, the all-cause mortality rate was additionally 18% lower in those who had breastfed vs those who had never breastfed, although breastfeeding duration was not associated with mortality. Use of oral contraceptives lowered all-cause mortality by 10% among nonsmokers; in smokers, no association with all-cause mortality was seen for oral contraceptive use, as smoking is such a powerful risk factor for mortality. The primary contributor to all-cause mortality appeared to be ischemic heart disease, the incidence of which was significantly lower in parous women (by 14%) and those who breastfed (by 20%) and was not related to oral contraceptive use.³⁵

Strengths of this study included the large sample size recruited from countries across Europe, with varying rates of breastfeeding and contraceptive use. However, as with all observational studies, it remains subject to the possibility of residual confounding.

What should we tell this patient?

After congratulating her for breastfeeding, we can reassure her about the safety of all available contraceptives. According to the US Centers for Disease Control and Prevention (CDC),³⁶ after 42 days postpartum most women can use combined hormonal contraception. All other methods can be used immediately postpartum, including progestin-only pills.

As lactational amenorrhea is only effective while mothers are exclusively breastfeeding, and short interpregnancy intervals have been associated with higher rates of adverse pregnancy outcomes,³⁷ this patient will likely benefit from promptly starting a prescription contraceptive.

HIGHLY EFFECTIVE REVERSIBLE CONTRACEPTION

This same 26-year-old patient is concerned that she will not remember to take an oral contraceptive every day, and expresses interest in a more convenient method of contraception. However, she is concerned about the potential risks.

Although intrauterine contraceptives (IUCs) are typically 20 times more effective than oral contraceptives³⁸ and have been used by millions of women worldwide, rates of use in the United States have been lower than in many other countries.³⁹

A study of intrauterine contraception

To clarify the safety of IUCs, researchers followed 61,448 women who underwent IUC placement in six European countries between 2006 and 2013.⁴⁰ Most participants received an IUC containing levonorgestrel, while 30% received a copper IUC.

Findings. Overall, rates of uterine perforation were low (approximately 1 per 1,000 insertions). The most significant risk factors for perforation were breastfeeding at the time of insertion and insertion less than 36 weeks after the last delivery. None of the perforations in the study led to serious illness or injury of intra-abdominal or pelvic structures. Interestingly, women using a levonorgestrel IUC were considerably less likely to experience a contraceptive failure than those using a copper IUC.⁴¹

Strengths of this study included the prospective data collection and power to examine rare clinical outcomes. However, it was industry-funded.

The risk of pelvic infection with an IUC is so low that the CDC does not recommend prophylactic antibiotics with the insertion procedure. If women have other indications for testing for sexually transmitted disease, an IUC can be placed the same day as testing, and before results are available.⁴² If a woman is found to have a sexually transmitted disease while she has an IUC in place, she should be treated with antibiotics, and there is no need to remove the IUC.⁴³

Subdermal implants

Another highly effective contraceptive option for this patient is the progestin-only subdermal contraceptive implant (marketed in the United States as Nexplanon). Implants have been well-studied and found to have no adverse effect on lactation.⁴⁴

Learning to place a subdermal contraceptive is far easier than learning to place an IUC, but it requires a few hours of FDA-mandated in-person training. Unfortunately, relatively few clinicians have obtained this training.⁴⁵ As placing a subdermal contraceptive is like placing an intravenous line without needing to hit the vein, this procedure can easily be incorporated into a primary care practice. Training from the manufacturer is available to providers who request it.

What should we tell this patient?

An IUC is a great option for many women. When pregnancy is desired, the device is easily removed. Of the three IUCs now available in the United States, those containing 52 mg of levonorgestrel (marketed in the United States as Mirena and Liletta) are the most effective.

The only option more effective than these IUCs is subdermal contraception.⁴⁶ These reversible contraceptives are typically more effective than permanent contraceptives (ie, tubal ligation)⁴⁷ and can be removed at any time if a patient wishes to switch to another method or to become pregnant.

Pregnancy rates following attempts at “sterilization” are higher than many realize. There are a variety of approaches to “tying tubes,” some of which may not result in complete tubal occlusion. The failure rate of the laparoscopic approach, according to the US Collaborative Review of Sterilization, ranges from 7.5 per 1,000 procedures for unipolar coagulation to a high of 36.5 per 1,000 for the spring clip.⁴⁸ The relatively commonly used Filshie clip was not included in this study, but its failure rate is reported to be between 1% and 2%.

Women's health encompasses a variety of topics relevant to the daily practice of internists. Staying up to date with the evidence in this wide field is a challenge.

This article reviews important studies published in 2015 and early 2016 on treatment of urinary tract infections, the optimal duration of bisphosphonate use, ovarian cancer screening, the impact of oral contraceptives and lactation on mortality rates, and the risks and benefits of intrauterine contraception. We critically appraised the studies and judged that their methodology was strong and appropriate for inclusion in this review.

IBUPROFEN FOR URINARY TRACT INFECTIONS

A 36-year-old woman reports 4 days of mild to moderate dysuria, frequency, and urgency. She denies fever, nausea, or back pain. Her last urinary tract infection was 2 years ago. Office urinalysis reveals leukocyte esterase and nitrites. She has read an article about antibiotic resistance and Clostridium difficile infection and asks you if antibiotics are truly necessary. What do you recommend?

Urinary tract infections are often self-limited

Uncomplicated urinary tract infections account for 25% of antibiotic prescriptions in primary care.¹

Several small studies have suggested that many of these infections are self-limited, resolving within 3 to 14 days without antibiotics (Table 1).^2–6 A potential disadvantage of withholding treatment is slower bacterial clearance and resolution of symptoms, but reducing the number of antibiotic prescriptions may help slow antibiotic resistance.^7,8 Surveys and qualitative studies have suggested that women are concerned about the harms of antibiotic treatment and so may be willing to avoid or postpone antibiotic use.^9–11

Ibuprofen vs fosfomycin

Gágyor et al⁶ conducted a double-blind, randomized multicenter trial in 42 general practices in Germany to assess whether treating the symptoms of uncomplicated urinary tract infection with ibuprofen would reduce antibiotic use without worsening outcomes.

Of the 779 eligible women with suspected urinary tract infection, 281 declined to participate in the study, 4 did not participate for reasons not specified, 246 received a single dose of fosfomycin 3 g, and 248 were treated with ibuprofen 400 mg three times a day for 3 days. Participants scored their daily symptoms and activity impairment, and safety data were collected for adverse events and relapses up to day 28 and within 6 and 12 months. In both groups, if symptoms worsened or persisted, antibiotic therapy was initiated at the discretion of the treating physician.

Exclusion criteria included fever, “loin” (back) tenderness, pregnancy, renal disease, a previous urinary tract infection within 2 weeks, urinary catheterization, and a contraindication to nonsteroidal anti-inflammatory medications.

Results. Within 28 days of symptom onset, women in the ibuprofen group had received 81 courses of antibiotics for symptoms of urinary tract infection (plus another 13 courses for other reasons), compared with 277 courses for urinary tract infection in the fosfomycin group (plus 6 courses for other reasons), for a relative rate reduction in antibiotic use of 66.5% (95% confidence interval [CI] 58.8%–74.4%, P < .001). The women who received ibuprofen were more likely to need antibiotics after initial treatment because of refractory symptoms but were still less likely to receive antibiotics overall (Table 1).

The mean duration of symptoms was slightly shorter in the fosfomycin group (4.6 vs 5.6 days, P < .001). However, the percentage of patients who had a recurrent urinary tract infection within 2 to 4 weeks was higher in the fosfomycin-treated patients (11% vs 6% P = .049).

Although the study was not powered to show significant differences in pyelonephritis, five patients in the ibuprofen group developed pyelonephritis compared with one in the antibiotic-treated group (P = .12).

An important limitation of the study was that nonparticipants had higher symptom scores, which may mean that the results are not generalizable to women who have recurrent urinary tract infections, longer duration of symptoms, or symptoms that are more severe. The strengths of the study were that more than half of all potentially eligible women were enrolled, and baseline data were collected from nonparticipants.

Can our patient avoid antibiotics?

Given the mild nature of her symptoms, the clinician should discuss with her the risks vs benefits of delaying antibiotics, once it has been determined that she has no risk factors for severe urinary tract infection. Her symptoms are likely to resolve within 1 week even if she declines antibiotic treatment, though they may last a day longer with ibuprofen alone than if she had received antibiotics. She should watch for symptoms of pyelonephritis (eg, flank pain, fever, chills, vomiting) and should seek prompt medical care if such symptoms occur.

DISCONTINUING BISPHOSPHONATES

A 64-year-old woman has taken alendronate for her osteoporosis for 5 years. She has no history of fractures. Her original bone density scans showed a T-score of –2.6 at the spine and –1.5 at the hip. Since she started to take alendronate, there has been no further loss in bone mineral density. She is tolerating the drug well and does not take any other medications. Should she continue the bisphosphonate?

Optimal duration of therapy unknown

The risks and benefits of long-term bisphosphonate use are debated.

In the Fracture Intervention Trial (FIT),¹² women with low bone mineral density of the femoral neck were randomized to receive alendronate or placebo and were followed for 36 months. The alendronate group had significantly fewer vertebral fractures and clinical fractures overall. Then, in the FIT Long-term Extension (FLEX) study,¹³ 1,009 alendronate-treated women in the FIT study were rerandomized to receive 5 years of additional treatment or to stop treatment. Bone density in the untreated women decreased, although not to the level it was before treatment. At the end of the study, there was no difference in hip fracture rate between the two groups (3% of each group had had a hip fracture), although women in the treated group had a lower rate of clinical vertebral fracture (2% vs 5%, relative risk 0.5, 95% CI 0.2–0.8).

In addition, rare but serious risks have been associated with bisphosphonate use, specifically atypical femoral fracture and osteonecrosis of the jaw. A US Food and Drug Administration (FDA) evaluation of long-term bisphosphonate use concluded that there was evidence of an increased risk of osteonecrosis of the jaw with longer duration of use, but causality was not established. The evaluation also noted conflicting results about the association with atypical femoral fracture.¹⁴

Based on this report and focusing on the absence of nonspine benefit after 5 years, the FDA suggested that bisphosphonates may be safely discontinued in some patients without compromising therapeutic gains, but no adequate clinical trial has yet delineated how long the benefits of treatment are maintained after cessation. A periodic reevaluation of continued need was recommended.¹⁴

New recommendations from the American Society for Bone and Mineral Research

Age is the greatest risk factor for fracture.¹⁵ Therefore, deciding whether to discontinue a bisphosphonate when a woman is older, and hence at higher risk, is a challenge.

A task force of the American Society for Bone and Mineral Research (ASBMR) has developed an evidence-based guideline on managing osteoporosis in patients on long-term bisphosphonate treatment.¹⁶ The goal was to provide guidance on the duration of bisphosphonate therapy from the perspective of risk vs benefit. The authors conducted a systematic review focusing on two randomized controlled trials (FLEX¹³ and the Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly Pivotal Fracture Trial¹⁷) that provided data on long-term bisphosphonate use.

The task force recommended¹⁶ that after 5 years of oral bisphosphonates or 3 years of intravenous bisphosphonates, risk should be reassessed. In women at high fracture risk, they recommended continuing the oral bisphosphonate for 10 years or the intravenous bisphosphonate for 6 years. Factors that favored continuation of bisphosphonate therapy were as follows:

• An osteoporotic fracture before or during therapy
• A hip bone mineral density T-score ≤ –2.5
• High risk of fracture, defined as age older than 70 or 75, other strong risk factors for fracture, or a FRAX fracture risk score¹⁸ above a country-specific threshold.

(The FRAX score is based on age, sex, weight, height, previous fracture, hip fracture in a parent, current smoking, use of glucocorticoids, rheumatoid arthritis, secondary osteoporosis, alcohol use, and bone mineral density in the femoral neck. It gives an estimate of the 10-year risk of major osteoporotic fracture and hip fracture. High risk would be a 10-year risk of major osteoporotic fracture greater than 20% or a 10-year risk of hip fracture greater than 3%.)

For women at high risk, the risks of atypical femoral fracture and osteonecrosis of the jaw are outweighed by the benefit of a reduction in vertebral fracture risk. For women not at high risk of fracture, a drug holiday of 2 to 3 years can be considered after 3 to 5 years of treatment.

Although the task force recommended reassessment after 2 to 3 years of drug holiday, how best to do this is not clear. The task force did not recommend a specific approach to reassessment, so decisions about when to restart therapy after a drug holiday could potentially be informed by subsequent bone mineral density testing if it were to show persistent bone loss. Another option could be to restart bisphosphonates after a defined amount of time (eg, 3–5 years) for women who have previously experienced benefit.

The task force recommendations are in line with those of other societies, the FDA, and expert opinion.^19–23

The American Association of Clinical Endocrinologists recommends considering a drug holiday in low-risk patients after 4 to 5 years of treatment. For high-risk patients, they recommend 1 to 2 years of drug holiday after 10 years of treatment. They encourage restarting treatment if bone mineral density decreases, bone turnover markers rise, or fracture occurs.¹⁹ This is a grade C recommendation, meaning the advice is based on descriptive studies and expert opinion.

Although some clinicians restart bisphosphonates when markers of bone turnover such as NTX (N-telopeptide of type 1 collagen) rise to premenopausal levels, there is no evidence to support this strategy.²⁴

The task force recommendations are based on limited evidence that primarily comes from white postmenopausal women. Another important limitation is that the outcomes are primarily vertebral fractures. However, until additional evidence is available, these guidelines can be useful in guiding decision-making.

Should our patient continue therapy?

Our patient is relatively young and does not have any of the high-risk features noted within the task force recommendations. She has responded well to bisphosphonate treatment and so can consider a drug holiday at this time.

OVARIAN CANCER SCREENING

A 50-year-old woman requests screening for ovarian cancer. She is postmenopausal and has no personal or family history of cancer. She is concerned because a friend forwarded an e-mail stating, “Please tell all your female friends and relatives to insist on a cancer antigen (CA) 125 blood test every year as part of their annual exam. This is an inexpensive and simple blood test. Don’t take no for an answer. If I had known then what I know now, we would have caught my cancer much earlier, before it was stage III!” What should you tell the patient?

Ovarian cancer is the most deadly of female reproductive cancers, largely because in most patients the cancer has already spread beyond the ovary by the time of clinical detection. Death rates from ovarian cancer have decreased only slightly in the past 30 years.

Little benefit and considerable harm of screening

In 2011, the Prostate Lung Colorectal Ovarian (PLCO) Cancer Screening trial²⁵ randomized more than 68,000 women ages 55 to 74 from the general US population to annual screening with CA 125 testing and transvaginal ultrasonography compared with usual care. They were followed for a median of 12.4 years.

Screening did not affect stage at diagnosis (77%–78% were in stage III or IV in both the screening and usual care groups), nor did it reduce the rate of death from ovarian cancer. In addition, false-positive findings led to some harm: nearly one in three women who had a positive screening test underwent surgery. Of 3,285 women with false-positive results, 1,080 underwent surgery, and 15% of these had at least one serious complication. The trial was stopped early due to evidence of futility.

A new UK study also found no benefit from screening

In the PLCO study, a CA 125 result of 35 U/mL or greater was classified as abnormal. However, researchers in the United Kingdom postulated that instead of using a single cutoff for a normal or abnormal CA 125 level, it would be better to interpret the CA 125 result according to a somewhat complicated (and proprietary) algorithm called the Risk of Ovarian Cancer Algorithm (ROCA).^26,27 The ROCA takes into account a woman’s age, menopausal status, known genetic mutations (BRCA 1 or 2 or Lynch syndrome), Ashkenazi Jewish descent, and family history of ovarian or breast cancer, as well as any change in CA 125 level over time.

In a 2016 UK study,²⁶ 202,638 postmenopausal women ages 50 to 74 were randomized to no screening, annual screening with transvaginal ultrasonography, or multimodal screening with an annual CA 125 blood test interpreted with the ROCA algorithm, adding transvaginal ultrasonography as a second-line test when needed if the CA 125 level was abnormal based on the ROCA. Women with abnormal findings on multimodal screening or ultrasonography had repeat tests, and women with persistent abnormalities underwent clinical evaluation and, when appropriate, surgery.

Participants were at average risk of ovarian cancer; those with suspected familial ovarian cancer syndrome were excluded, as were those with a personal history of ovarian cancer or other active cancer.

Results. At a median follow-up of 11.1 years, the percentage of women who were diagnosed with ovarian cancer was 0.7% in the multimodal screening group, 0.6% in the screening ultrasonography group, and 0.6% in the no-screening group. Comparing either multimodal or screening ultrasonography with no screening, there was no statistically significant reduction in mortality rate over 14 years of follow-up.

Screening had significant costs and potential harms. For every ovarian or peritoneal cancer detected by screening, an additional 2 women in the multimodal screening group and 10 women in the ultrasonography group underwent needless surgery.

Strengths of this trial included its large size, allowing adequate power to detect differences in outcomes, its multicenter setting, its high compliance rate, and the low crossover rate in the no-screening group. However, the design of the study makes it difficult to anticipate the late effects of screening. Also, the patient must purchase ROCA testing online and must also pay a consultation fee. Insurance providers do not cover this test.

Should our patient proceed with ovarian cancer screening?

No. Current evidence shows no clear benefit to ovarian cancer screening for average-risk women, and we should not recommend yearly ultrasonography and CA 125 level testing, as they are likely to cause harm without providing benefit. The US Preventive Services Task Force recommends against screening for ovarian cancer.²⁸ For premenopausal women, pregnancy, hormonal contraception, and breastfeeding all significantly decrease ovarian cancer risk by suppressing ovulation.^29–31

REPRODUCTIVE FACTORS AND THE RISK OF DEATH

A 26-year-old woman comes in to discuss her contraceptive options. She has been breastfeeding since the birth of her first baby 6 months ago, and wonders how lactation and contraception may affect her long-term health.

Questions about the safety of contraceptive options are common, especially in breastfeeding mothers.

In 2010, the long-term Royal College of General Practitioners’ Oral Contraceptive Study reported that the all-cause mortality rate was actually lower in women who used oral contraceptives.³² Similarly, in 2013, an Oxford study that followed 17,032 women for over 30 years reported no association between oral contraceptives and breast cancer.³³

However, in 2014, results from the Nurses’ Health Study indicated that breast cancer rates were higher in oral contraceptive users, although reassuringly, the study found no difference in all-cause mortality rates in women who had used oral contraception.³⁴

The European Prospective Investigation Into Cancer and Nutrition

To further characterize relationships between reproductive characteristics and mortality rates, investigators analyzed data from the European Prospective Investigation Into Cancer and Nutrition,³⁵ which recruited 322,972 women from 10 countries between 1992 and 2000. Analyses were stratified by study center and participant age and were adjusted for body mass index, physical activity, education level, smoking, and menopausal status; alcohol intake was examined as a potential confounder but was excluded from final models.

Findings. Over an average 13 years of follow-up, the rate of all-cause mortality was 20% lower in parous than in nulliparous women. In parous women, the all-cause mortality rate was additionally 18% lower in those who had breastfed vs those who had never breastfed, although breastfeeding duration was not associated with mortality. Use of oral contraceptives lowered all-cause mortality by 10% among nonsmokers; in smokers, no association with all-cause mortality was seen for oral contraceptive use, as smoking is such a powerful risk factor for mortality. The primary contributor to all-cause mortality appeared to be ischemic heart disease, the incidence of which was significantly lower in parous women (by 14%) and those who breastfed (by 20%) and was not related to oral contraceptive use.³⁵

Strengths of this study included the large sample size recruited from countries across Europe, with varying rates of breastfeeding and contraceptive use. However, as with all observational studies, it remains subject to the possibility of residual confounding.

What should we tell this patient?

After congratulating her for breastfeeding, we can reassure her about the safety of all available contraceptives. According to the US Centers for Disease Control and Prevention (CDC),³⁶ after 42 days postpartum most women can use combined hormonal contraception. All other methods can be used immediately postpartum, including progestin-only pills.

As lactational amenorrhea is only effective while mothers are exclusively breastfeeding, and short interpregnancy intervals have been associated with higher rates of adverse pregnancy outcomes,³⁷ this patient will likely benefit from promptly starting a prescription contraceptive.

HIGHLY EFFECTIVE REVERSIBLE CONTRACEPTION

This same 26-year-old patient is concerned that she will not remember to take an oral contraceptive every day, and expresses interest in a more convenient method of contraception. However, she is concerned about the potential risks.

Although intrauterine contraceptives (IUCs) are typically 20 times more effective than oral contraceptives³⁸ and have been used by millions of women worldwide, rates of use in the United States have been lower than in many other countries.³⁹

A study of intrauterine contraception

To clarify the safety of IUCs, researchers followed 61,448 women who underwent IUC placement in six European countries between 2006 and 2013.⁴⁰ Most participants received an IUC containing levonorgestrel, while 30% received a copper IUC.

Findings. Overall, rates of uterine perforation were low (approximately 1 per 1,000 insertions). The most significant risk factors for perforation were breastfeeding at the time of insertion and insertion less than 36 weeks after the last delivery. None of the perforations in the study led to serious illness or injury of intra-abdominal or pelvic structures. Interestingly, women using a levonorgestrel IUC were considerably less likely to experience a contraceptive failure than those using a copper IUC.⁴¹

Strengths of this study included the prospective data collection and power to examine rare clinical outcomes. However, it was industry-funded.

The risk of pelvic infection with an IUC is so low that the CDC does not recommend prophylactic antibiotics with the insertion procedure. If women have other indications for testing for sexually transmitted disease, an IUC can be placed the same day as testing, and before results are available.⁴² If a woman is found to have a sexually transmitted disease while she has an IUC in place, she should be treated with antibiotics, and there is no need to remove the IUC.⁴³

Subdermal implants

Another highly effective contraceptive option for this patient is the progestin-only subdermal contraceptive implant (marketed in the United States as Nexplanon). Implants have been well-studied and found to have no adverse effect on lactation.⁴⁴

Learning to place a subdermal contraceptive is far easier than learning to place an IUC, but it requires a few hours of FDA-mandated in-person training. Unfortunately, relatively few clinicians have obtained this training.⁴⁵ As placing a subdermal contraceptive is like placing an intravenous line without needing to hit the vein, this procedure can easily be incorporated into a primary care practice. Training from the manufacturer is available to providers who request it.

What should we tell this patient?

An IUC is a great option for many women. When pregnancy is desired, the device is easily removed. Of the three IUCs now available in the United States, those containing 52 mg of levonorgestrel (marketed in the United States as Mirena and Liletta) are the most effective.

The only option more effective than these IUCs is subdermal contraception.⁴⁶ These reversible contraceptives are typically more effective than permanent contraceptives (ie, tubal ligation)⁴⁷ and can be removed at any time if a patient wishes to switch to another method or to become pregnant.

Pregnancy rates following attempts at “sterilization” are higher than many realize. There are a variety of approaches to “tying tubes,” some of which may not result in complete tubal occlusion. The failure rate of the laparoscopic approach, according to the US Collaborative Review of Sterilization, ranges from 7.5 per 1,000 procedures for unipolar coagulation to a high of 36.5 per 1,000 for the spring clip.⁴⁸ The relatively commonly used Filshie clip was not included in this study, but its failure rate is reported to be between 1% and 2%.

Women's health encompasses a variety of topics relevant to the daily practice of internists. Staying up to date with the evidence in this wide field is a challenge.

This article reviews important studies published in 2015 and early 2016 on treatment of urinary tract infections, the optimal duration of bisphosphonate use, ovarian cancer screening, the impact of oral contraceptives and lactation on mortality rates, and the risks and benefits of intrauterine contraception. We critically appraised the studies and judged that their methodology was strong and appropriate for inclusion in this review.

IBUPROFEN FOR URINARY TRACT INFECTIONS

A 36-year-old woman reports 4 days of mild to moderate dysuria, frequency, and urgency. She denies fever, nausea, or back pain. Her last urinary tract infection was 2 years ago. Office urinalysis reveals leukocyte esterase and nitrites. She has read an article about antibiotic resistance and Clostridium difficile infection and asks you if antibiotics are truly necessary. What do you recommend?

Urinary tract infections are often self-limited

Uncomplicated urinary tract infections account for 25% of antibiotic prescriptions in primary care.¹

Several small studies have suggested that many of these infections are self-limited, resolving within 3 to 14 days without antibiotics (Table 1).^2–6 A potential disadvantage of withholding treatment is slower bacterial clearance and resolution of symptoms, but reducing the number of antibiotic prescriptions may help slow antibiotic resistance.^7,8 Surveys and qualitative studies have suggested that women are concerned about the harms of antibiotic treatment and so may be willing to avoid or postpone antibiotic use.^9–11

Ibuprofen vs fosfomycin

Gágyor et al⁶ conducted a double-blind, randomized multicenter trial in 42 general practices in Germany to assess whether treating the symptoms of uncomplicated urinary tract infection with ibuprofen would reduce antibiotic use without worsening outcomes.

Of the 779 eligible women with suspected urinary tract infection, 281 declined to participate in the study, 4 did not participate for reasons not specified, 246 received a single dose of fosfomycin 3 g, and 248 were treated with ibuprofen 400 mg three times a day for 3 days. Participants scored their daily symptoms and activity impairment, and safety data were collected for adverse events and relapses up to day 28 and within 6 and 12 months. In both groups, if symptoms worsened or persisted, antibiotic therapy was initiated at the discretion of the treating physician.

Exclusion criteria included fever, “loin” (back) tenderness, pregnancy, renal disease, a previous urinary tract infection within 2 weeks, urinary catheterization, and a contraindication to nonsteroidal anti-inflammatory medications.

Results. Within 28 days of symptom onset, women in the ibuprofen group had received 81 courses of antibiotics for symptoms of urinary tract infection (plus another 13 courses for other reasons), compared with 277 courses for urinary tract infection in the fosfomycin group (plus 6 courses for other reasons), for a relative rate reduction in antibiotic use of 66.5% (95% confidence interval [CI] 58.8%–74.4%, P < .001). The women who received ibuprofen were more likely to need antibiotics after initial treatment because of refractory symptoms but were still less likely to receive antibiotics overall (Table 1).

The mean duration of symptoms was slightly shorter in the fosfomycin group (4.6 vs 5.6 days, P < .001). However, the percentage of patients who had a recurrent urinary tract infection within 2 to 4 weeks was higher in the fosfomycin-treated patients (11% vs 6% P = .049).

Although the study was not powered to show significant differences in pyelonephritis, five patients in the ibuprofen group developed pyelonephritis compared with one in the antibiotic-treated group (P = .12).

An important limitation of the study was that nonparticipants had higher symptom scores, which may mean that the results are not generalizable to women who have recurrent urinary tract infections, longer duration of symptoms, or symptoms that are more severe. The strengths of the study were that more than half of all potentially eligible women were enrolled, and baseline data were collected from nonparticipants.

Can our patient avoid antibiotics?

Given the mild nature of her symptoms, the clinician should discuss with her the risks vs benefits of delaying antibiotics, once it has been determined that she has no risk factors for severe urinary tract infection. Her symptoms are likely to resolve within 1 week even if she declines antibiotic treatment, though they may last a day longer with ibuprofen alone than if she had received antibiotics. She should watch for symptoms of pyelonephritis (eg, flank pain, fever, chills, vomiting) and should seek prompt medical care if such symptoms occur.

DISCONTINUING BISPHOSPHONATES

A 64-year-old woman has taken alendronate for her osteoporosis for 5 years. She has no history of fractures. Her original bone density scans showed a T-score of –2.6 at the spine and –1.5 at the hip. Since she started to take alendronate, there has been no further loss in bone mineral density. She is tolerating the drug well and does not take any other medications. Should she continue the bisphosphonate?

Optimal duration of therapy unknown

The risks and benefits of long-term bisphosphonate use are debated.

In the Fracture Intervention Trial (FIT),¹² women with low bone mineral density of the femoral neck were randomized to receive alendronate or placebo and were followed for 36 months. The alendronate group had significantly fewer vertebral fractures and clinical fractures overall. Then, in the FIT Long-term Extension (FLEX) study,¹³ 1,009 alendronate-treated women in the FIT study were rerandomized to receive 5 years of additional treatment or to stop treatment. Bone density in the untreated women decreased, although not to the level it was before treatment. At the end of the study, there was no difference in hip fracture rate between the two groups (3% of each group had had a hip fracture), although women in the treated group had a lower rate of clinical vertebral fracture (2% vs 5%, relative risk 0.5, 95% CI 0.2–0.8).

In addition, rare but serious risks have been associated with bisphosphonate use, specifically atypical femoral fracture and osteonecrosis of the jaw. A US Food and Drug Administration (FDA) evaluation of long-term bisphosphonate use concluded that there was evidence of an increased risk of osteonecrosis of the jaw with longer duration of use, but causality was not established. The evaluation also noted conflicting results about the association with atypical femoral fracture.¹⁴

Based on this report and focusing on the absence of nonspine benefit after 5 years, the FDA suggested that bisphosphonates may be safely discontinued in some patients without compromising therapeutic gains, but no adequate clinical trial has yet delineated how long the benefits of treatment are maintained after cessation. A periodic reevaluation of continued need was recommended.¹⁴

New recommendations from the American Society for Bone and Mineral Research

Age is the greatest risk factor for fracture.¹⁵ Therefore, deciding whether to discontinue a bisphosphonate when a woman is older, and hence at higher risk, is a challenge.

A task force of the American Society for Bone and Mineral Research (ASBMR) has developed an evidence-based guideline on managing osteoporosis in patients on long-term bisphosphonate treatment.¹⁶ The goal was to provide guidance on the duration of bisphosphonate therapy from the perspective of risk vs benefit. The authors conducted a systematic review focusing on two randomized controlled trials (FLEX¹³ and the Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly Pivotal Fracture Trial¹⁷) that provided data on long-term bisphosphonate use.

The task force recommended¹⁶ that after 5 years of oral bisphosphonates or 3 years of intravenous bisphosphonates, risk should be reassessed. In women at high fracture risk, they recommended continuing the oral bisphosphonate for 10 years or the intravenous bisphosphonate for 6 years. Factors that favored continuation of bisphosphonate therapy were as follows:

• An osteoporotic fracture before or during therapy
• A hip bone mineral density T-score ≤ –2.5
• High risk of fracture, defined as age older than 70 or 75, other strong risk factors for fracture, or a FRAX fracture risk score¹⁸ above a country-specific threshold.

(The FRAX score is based on age, sex, weight, height, previous fracture, hip fracture in a parent, current smoking, use of glucocorticoids, rheumatoid arthritis, secondary osteoporosis, alcohol use, and bone mineral density in the femoral neck. It gives an estimate of the 10-year risk of major osteoporotic fracture and hip fracture. High risk would be a 10-year risk of major osteoporotic fracture greater than 20% or a 10-year risk of hip fracture greater than 3%.)

For women at high risk, the risks of atypical femoral fracture and osteonecrosis of the jaw are outweighed by the benefit of a reduction in vertebral fracture risk. For women not at high risk of fracture, a drug holiday of 2 to 3 years can be considered after 3 to 5 years of treatment.

Although the task force recommended reassessment after 2 to 3 years of drug holiday, how best to do this is not clear. The task force did not recommend a specific approach to reassessment, so decisions about when to restart therapy after a drug holiday could potentially be informed by subsequent bone mineral density testing if it were to show persistent bone loss. Another option could be to restart bisphosphonates after a defined amount of time (eg, 3–5 years) for women who have previously experienced benefit.

The task force recommendations are in line with those of other societies, the FDA, and expert opinion.^19–23

The American Association of Clinical Endocrinologists recommends considering a drug holiday in low-risk patients after 4 to 5 years of treatment. For high-risk patients, they recommend 1 to 2 years of drug holiday after 10 years of treatment. They encourage restarting treatment if bone mineral density decreases, bone turnover markers rise, or fracture occurs.¹⁹ This is a grade C recommendation, meaning the advice is based on descriptive studies and expert opinion.

Although some clinicians restart bisphosphonates when markers of bone turnover such as NTX (N-telopeptide of type 1 collagen) rise to premenopausal levels, there is no evidence to support this strategy.²⁴

The task force recommendations are based on limited evidence that primarily comes from white postmenopausal women. Another important limitation is that the outcomes are primarily vertebral fractures. However, until additional evidence is available, these guidelines can be useful in guiding decision-making.

Should our patient continue therapy?

Our patient is relatively young and does not have any of the high-risk features noted within the task force recommendations. She has responded well to bisphosphonate treatment and so can consider a drug holiday at this time.

OVARIAN CANCER SCREENING

A 50-year-old woman requests screening for ovarian cancer. She is postmenopausal and has no personal or family history of cancer. She is concerned because a friend forwarded an e-mail stating, “Please tell all your female friends and relatives to insist on a cancer antigen (CA) 125 blood test every year as part of their annual exam. This is an inexpensive and simple blood test. Don’t take no for an answer. If I had known then what I know now, we would have caught my cancer much earlier, before it was stage III!” What should you tell the patient?

Ovarian cancer is the most deadly of female reproductive cancers, largely because in most patients the cancer has already spread beyond the ovary by the time of clinical detection. Death rates from ovarian cancer have decreased only slightly in the past 30 years.

Little benefit and considerable harm of screening

In 2011, the Prostate Lung Colorectal Ovarian (PLCO) Cancer Screening trial²⁵ randomized more than 68,000 women ages 55 to 74 from the general US population to annual screening with CA 125 testing and transvaginal ultrasonography compared with usual care. They were followed for a median of 12.4 years.

Screening did not affect stage at diagnosis (77%–78% were in stage III or IV in both the screening and usual care groups), nor did it reduce the rate of death from ovarian cancer. In addition, false-positive findings led to some harm: nearly one in three women who had a positive screening test underwent surgery. Of 3,285 women with false-positive results, 1,080 underwent surgery, and 15% of these had at least one serious complication. The trial was stopped early due to evidence of futility.

A new UK study also found no benefit from screening

In the PLCO study, a CA 125 result of 35 U/mL or greater was classified as abnormal. However, researchers in the United Kingdom postulated that instead of using a single cutoff for a normal or abnormal CA 125 level, it would be better to interpret the CA 125 result according to a somewhat complicated (and proprietary) algorithm called the Risk of Ovarian Cancer Algorithm (ROCA).^26,27 The ROCA takes into account a woman’s age, menopausal status, known genetic mutations (BRCA 1 or 2 or Lynch syndrome), Ashkenazi Jewish descent, and family history of ovarian or breast cancer, as well as any change in CA 125 level over time.

In a 2016 UK study,²⁶ 202,638 postmenopausal women ages 50 to 74 were randomized to no screening, annual screening with transvaginal ultrasonography, or multimodal screening with an annual CA 125 blood test interpreted with the ROCA algorithm, adding transvaginal ultrasonography as a second-line test when needed if the CA 125 level was abnormal based on the ROCA. Women with abnormal findings on multimodal screening or ultrasonography had repeat tests, and women with persistent abnormalities underwent clinical evaluation and, when appropriate, surgery.

Participants were at average risk of ovarian cancer; those with suspected familial ovarian cancer syndrome were excluded, as were those with a personal history of ovarian cancer or other active cancer.

Results. At a median follow-up of 11.1 years, the percentage of women who were diagnosed with ovarian cancer was 0.7% in the multimodal screening group, 0.6% in the screening ultrasonography group, and 0.6% in the no-screening group. Comparing either multimodal or screening ultrasonography with no screening, there was no statistically significant reduction in mortality rate over 14 years of follow-up.

Screening had significant costs and potential harms. For every ovarian or peritoneal cancer detected by screening, an additional 2 women in the multimodal screening group and 10 women in the ultrasonography group underwent needless surgery.

Strengths of this trial included its large size, allowing adequate power to detect differences in outcomes, its multicenter setting, its high compliance rate, and the low crossover rate in the no-screening group. However, the design of the study makes it difficult to anticipate the late effects of screening. Also, the patient must purchase ROCA testing online and must also pay a consultation fee. Insurance providers do not cover this test.

Should our patient proceed with ovarian cancer screening?

No. Current evidence shows no clear benefit to ovarian cancer screening for average-risk women, and we should not recommend yearly ultrasonography and CA 125 level testing, as they are likely to cause harm without providing benefit. The US Preventive Services Task Force recommends against screening for ovarian cancer.²⁸ For premenopausal women, pregnancy, hormonal contraception, and breastfeeding all significantly decrease ovarian cancer risk by suppressing ovulation.^29–31

REPRODUCTIVE FACTORS AND THE RISK OF DEATH

A 26-year-old woman comes in to discuss her contraceptive options. She has been breastfeeding since the birth of her first baby 6 months ago, and wonders how lactation and contraception may affect her long-term health.

Questions about the safety of contraceptive options are common, especially in breastfeeding mothers.

In 2010, the long-term Royal College of General Practitioners’ Oral Contraceptive Study reported that the all-cause mortality rate was actually lower in women who used oral contraceptives.³² Similarly, in 2013, an Oxford study that followed 17,032 women for over 30 years reported no association between oral contraceptives and breast cancer.³³

However, in 2014, results from the Nurses’ Health Study indicated that breast cancer rates were higher in oral contraceptive users, although reassuringly, the study found no difference in all-cause mortality rates in women who had used oral contraception.³⁴

The European Prospective Investigation Into Cancer and Nutrition

To further characterize relationships between reproductive characteristics and mortality rates, investigators analyzed data from the European Prospective Investigation Into Cancer and Nutrition,³⁵ which recruited 322,972 women from 10 countries between 1992 and 2000. Analyses were stratified by study center and participant age and were adjusted for body mass index, physical activity, education level, smoking, and menopausal status; alcohol intake was examined as a potential confounder but was excluded from final models.

Findings. Over an average 13 years of follow-up, the rate of all-cause mortality was 20% lower in parous than in nulliparous women. In parous women, the all-cause mortality rate was additionally 18% lower in those who had breastfed vs those who had never breastfed, although breastfeeding duration was not associated with mortality. Use of oral contraceptives lowered all-cause mortality by 10% among nonsmokers; in smokers, no association with all-cause mortality was seen for oral contraceptive use, as smoking is such a powerful risk factor for mortality. The primary contributor to all-cause mortality appeared to be ischemic heart disease, the incidence of which was significantly lower in parous women (by 14%) and those who breastfed (by 20%) and was not related to oral contraceptive use.³⁵

Strengths of this study included the large sample size recruited from countries across Europe, with varying rates of breastfeeding and contraceptive use. However, as with all observational studies, it remains subject to the possibility of residual confounding.

What should we tell this patient?

After congratulating her for breastfeeding, we can reassure her about the safety of all available contraceptives. According to the US Centers for Disease Control and Prevention (CDC),³⁶ after 42 days postpartum most women can use combined hormonal contraception. All other methods can be used immediately postpartum, including progestin-only pills.

As lactational amenorrhea is only effective while mothers are exclusively breastfeeding, and short interpregnancy intervals have been associated with higher rates of adverse pregnancy outcomes,³⁷ this patient will likely benefit from promptly starting a prescription contraceptive.

HIGHLY EFFECTIVE REVERSIBLE CONTRACEPTION

This same 26-year-old patient is concerned that she will not remember to take an oral contraceptive every day, and expresses interest in a more convenient method of contraception. However, she is concerned about the potential risks.

Although intrauterine contraceptives (IUCs) are typically 20 times more effective than oral contraceptives³⁸ and have been used by millions of women worldwide, rates of use in the United States have been lower than in many other countries.³⁹

A study of intrauterine contraception

To clarify the safety of IUCs, researchers followed 61,448 women who underwent IUC placement in six European countries between 2006 and 2013.⁴⁰ Most participants received an IUC containing levonorgestrel, while 30% received a copper IUC.

Findings. Overall, rates of uterine perforation were low (approximately 1 per 1,000 insertions). The most significant risk factors for perforation were breastfeeding at the time of insertion and insertion less than 36 weeks after the last delivery. None of the perforations in the study led to serious illness or injury of intra-abdominal or pelvic structures. Interestingly, women using a levonorgestrel IUC were considerably less likely to experience a contraceptive failure than those using a copper IUC.⁴¹

Strengths of this study included the prospective data collection and power to examine rare clinical outcomes. However, it was industry-funded.

The risk of pelvic infection with an IUC is so low that the CDC does not recommend prophylactic antibiotics with the insertion procedure. If women have other indications for testing for sexually transmitted disease, an IUC can be placed the same day as testing, and before results are available.⁴² If a woman is found to have a sexually transmitted disease while she has an IUC in place, she should be treated with antibiotics, and there is no need to remove the IUC.⁴³

Subdermal implants

Another highly effective contraceptive option for this patient is the progestin-only subdermal contraceptive implant (marketed in the United States as Nexplanon). Implants have been well-studied and found to have no adverse effect on lactation.⁴⁴

Learning to place a subdermal contraceptive is far easier than learning to place an IUC, but it requires a few hours of FDA-mandated in-person training. Unfortunately, relatively few clinicians have obtained this training.⁴⁵ As placing a subdermal contraceptive is like placing an intravenous line without needing to hit the vein, this procedure can easily be incorporated into a primary care practice. Training from the manufacturer is available to providers who request it.

What should we tell this patient?

An IUC is a great option for many women. When pregnancy is desired, the device is easily removed. Of the three IUCs now available in the United States, those containing 52 mg of levonorgestrel (marketed in the United States as Mirena and Liletta) are the most effective.

The only option more effective than these IUCs is subdermal contraception.⁴⁶ These reversible contraceptives are typically more effective than permanent contraceptives (ie, tubal ligation)⁴⁷ and can be removed at any time if a patient wishes to switch to another method or to become pregnant.

Pregnancy rates following attempts at “sterilization” are higher than many realize. There are a variety of approaches to “tying tubes,” some of which may not result in complete tubal occlusion. The failure rate of the laparoscopic approach, according to the US Collaborative Review of Sterilization, ranges from 7.5 per 1,000 procedures for unipolar coagulation to a high of 36.5 per 1,000 for the spring clip.⁴⁸ The relatively commonly used Filshie clip was not included in this study, but its failure rate is reported to be between 1% and 2%.

In Reply: We would like to thank Dr. Thacker for her interest in our article on the clinical considerations regarding optimal duration of hormone therapy.¹ We agree that the simple answer to whether there is there a time limit for systemic menopausal hormone therapy is no, emphasizing an individualized approach to each patient. After appropriate counseling and shared decision-making, some women may elect a short duration of therapy while others prefer longer-term use.

As Dr. Thacker mentioned, Mikkola et al² performed an observational study of more than 300,000 Finnish women who discontinued hormone therapy. Data on the number of deaths in this group were gathered from a national database and compared with the expected number of deaths in the background population; 30% of the listed causes of death were confirmed by autopsy. In women who had started hormone therapy before age 60, the risk of cardiac death was elevated within the first year after stopping it (standardized mortality ratio [SMR] 1.74; 95% confidence interval [CI] 1.37–2.19), as was the risk of stroke (SMR 2.59, 95% CI 2.08–3.19). This was not true in women who started hormone therapy at age 60 and older. These findings are consistent with our contemporary understanding that for many women younger than age 60 the benefits of hormone therapy outweigh the risks.

The study had several important limitations:

• A healthy-woman bias may have contributed to the reduction in cardiovascular risk.
• No dates for the myocardial infarctions or strokes were available, and the dates hormone therapy was discontined potentially had a 3-month error.
• No data were available on important confounding factors such as smoking, body mass index, blood pressure, lipid levels, and family history.
• Hormone therapy users were compared with an age-standardized background population, which also included hormone therapy users.
• Long-term follow-up data were also perplexing: although more women than expected died of stroke or coronary heart disease within the first year of stopping hormone therapy, after 1 year, significantly fewer women died of these conditions than expected, regardless of how long they had been on hormone therapy before stopping.

These observations highlight the need for long-term, randomized, prospective controlled studies that adequately assess all long-term outcomes (cardiovascular events, mortality, cancer, fracture) in women who initiate hormone therapy before age 60 and within 10 years of menopause, including long-term follow-up after discontinuation. Though future randomized controlled trials will be beneficial to help guide women to a more balanced understanding of long-term hormone therapy and the risks of discontinuation, the current evidence supports continuing hormone therapy in women who derive a net benefit.

In Reply: We would like to thank Dr. Thacker for her interest in our article on the clinical considerations regarding optimal duration of hormone therapy.¹ We agree that the simple answer to whether there is there a time limit for systemic menopausal hormone therapy is no, emphasizing an individualized approach to each patient. After appropriate counseling and shared decision-making, some women may elect a short duration of therapy while others prefer longer-term use.

As Dr. Thacker mentioned, Mikkola et al² performed an observational study of more than 300,000 Finnish women who discontinued hormone therapy. Data on the number of deaths in this group were gathered from a national database and compared with the expected number of deaths in the background population; 30% of the listed causes of death were confirmed by autopsy. In women who had started hormone therapy before age 60, the risk of cardiac death was elevated within the first year after stopping it (standardized mortality ratio [SMR] 1.74; 95% confidence interval [CI] 1.37–2.19), as was the risk of stroke (SMR 2.59, 95% CI 2.08–3.19). This was not true in women who started hormone therapy at age 60 and older. These findings are consistent with our contemporary understanding that for many women younger than age 60 the benefits of hormone therapy outweigh the risks.

The study had several important limitations:

• A healthy-woman bias may have contributed to the reduction in cardiovascular risk.
• No dates for the myocardial infarctions or strokes were available, and the dates hormone therapy was discontined potentially had a 3-month error.
• No data were available on important confounding factors such as smoking, body mass index, blood pressure, lipid levels, and family history.
• Hormone therapy users were compared with an age-standardized background population, which also included hormone therapy users.
• Long-term follow-up data were also perplexing: although more women than expected died of stroke or coronary heart disease within the first year of stopping hormone therapy, after 1 year, significantly fewer women died of these conditions than expected, regardless of how long they had been on hormone therapy before stopping.

These observations highlight the need for long-term, randomized, prospective controlled studies that adequately assess all long-term outcomes (cardiovascular events, mortality, cancer, fracture) in women who initiate hormone therapy before age 60 and within 10 years of menopause, including long-term follow-up after discontinuation. Though future randomized controlled trials will be beneficial to help guide women to a more balanced understanding of long-term hormone therapy and the risks of discontinuation, the current evidence supports continuing hormone therapy in women who derive a net benefit.

In Reply: We would like to thank Dr. Thacker for her interest in our article on the clinical considerations regarding optimal duration of hormone therapy.¹ We agree that the simple answer to whether there is there a time limit for systemic menopausal hormone therapy is no, emphasizing an individualized approach to each patient. After appropriate counseling and shared decision-making, some women may elect a short duration of therapy while others prefer longer-term use.

As Dr. Thacker mentioned, Mikkola et al² performed an observational study of more than 300,000 Finnish women who discontinued hormone therapy. Data on the number of deaths in this group were gathered from a national database and compared with the expected number of deaths in the background population; 30% of the listed causes of death were confirmed by autopsy. In women who had started hormone therapy before age 60, the risk of cardiac death was elevated within the first year after stopping it (standardized mortality ratio [SMR] 1.74; 95% confidence interval [CI] 1.37–2.19), as was the risk of stroke (SMR 2.59, 95% CI 2.08–3.19). This was not true in women who started hormone therapy at age 60 and older. These findings are consistent with our contemporary understanding that for many women younger than age 60 the benefits of hormone therapy outweigh the risks.

The study had several important limitations:

• A healthy-woman bias may have contributed to the reduction in cardiovascular risk.
• No dates for the myocardial infarctions or strokes were available, and the dates hormone therapy was discontined potentially had a 3-month error.
• No data were available on important confounding factors such as smoking, body mass index, blood pressure, lipid levels, and family history.
• Hormone therapy users were compared with an age-standardized background population, which also included hormone therapy users.
• Long-term follow-up data were also perplexing: although more women than expected died of stroke or coronary heart disease within the first year of stopping hormone therapy, after 1 year, significantly fewer women died of these conditions than expected, regardless of how long they had been on hormone therapy before stopping.

These observations highlight the need for long-term, randomized, prospective controlled studies that adequately assess all long-term outcomes (cardiovascular events, mortality, cancer, fracture) in women who initiate hormone therapy before age 60 and within 10 years of menopause, including long-term follow-up after discontinuation. Though future randomized controlled trials will be beneficial to help guide women to a more balanced understanding of long-term hormone therapy and the risks of discontinuation, the current evidence supports continuing hormone therapy in women who derive a net benefit.

The duration of hormone therapy needs to be an individualized decision, shared between the patient and her physician and assessed annually. Quality of life, vasomotor symptoms, current age, time since menopause, hysterectomy status, personal risks (of osteoporosis, breast cancer, heart disease, stroke,  venous thromboembolism), and patient preferences need to be considered.

The North American Menopause Society (NAMS) and other organizations recommend that the lowest dose of hormone therapy be used for the shortest duration needed to manage menopausal symptoms.^1–4 However, NAMS states that extending the duration of hormone therapy may be appropriate in women who have persistent symptoms or to prevent osteoporosis if the patient cannot tolerate alternative therapies.¹

Forty-two percent of postmenopausal women continue to experience vasomotor symptoms at age 60 to 65.⁵ The median total duration of vasomotor symptoms is 7.4 years, and in black women and women with moderate or severe hot flashes the symptoms typically last 10 years.⁶ Vasomotor symptoms recur in 50% of women who discontinue hormone therapy, regardless of whether it is stopped abruptly or tapered.¹

FACTORS TO CONSIDER WHEN PRESCRIBING HORMONE THERAPY

Bone health

A statement issued in 2013 by seven medical societies said that hormone therapy is effective and appropriate for preventing osteoporosis-related fracture in at-risk women under age 60 or within 10 years of menopause.⁷

The Women’s Health Initiative,⁸ a randomized placebo-controlled trial, showed a statistically significant lower risk of vertebral and nonvertebral fracture after 3 years of use of conjugated equine estrogen with medroxyprogesterone acetate than with placebo:

• Hazard ratio 0.76, 95% confidence interval (CI) 0.69–0.83.

It also showed a mean increase of 3.7% (P < .001) in total hip bone mineral density. By the end of the trial intervention, women receiving either this combined therapy or conjugated equine estrogen alone saw a 33% overall reduction in hip fracture risk. The absolute risk reduction was 5 per 10,000 years of use.⁹

Karim et al,¹⁰ in a large observational study that followed initial hormone therapy users over 6.5 years, found that those who stopped it had a 55% greater risk of hip fracture and experienced significant bone loss as measured by bone mineral density compared with women who continued hormone therapy, and that the protective effects of hormone therapy disappeared as early as 2 years after stopping treatment.¹⁰

NAMS also recommends that women with premature menopause (before age 40) be offered and encouraged to use hormone therapy to preserve bone density and manage vasomotor symptoms until the age of natural menopause (age 51).^1,11

Cardiovascular health

Large observational studies have found that hormone therapy is associated with a 30% to 50% lower cardiovascular risk.¹² Randomized controlled trials of hormone therapy for 7 to 11 years suggest that coronary heart disease risk is modified by age and time since menopause.^13,14

The Women’s Health Initiative and other randomized controlled trials suggest a lower risk of coronary heart disease in women who begin hormone therapy before age 60 and within 10 years of the onset of menopause, but an increased risk for women over age 60 and more than 10 years since menopause. However, several of these trends have not reached statistical significance (Table 1).^13–15

The Women’s Health Initiative⁹ published its long-term follow-up results in 2013, with data on both the intervention phase (median of 7.2 years for estrogen-only therapy and 5.6 years for estrogen-progestin therapy) and the post-stopping phase (median 6.6 years for the estrogen-only group and 8.2 years for the estrogen-progestin group), with a total cumulative follow-up of 13 years. The overall 13-year cumulative absolute risk of coronary heart disease was 4 fewer events per 10,000 years of estrogen-only therapy and 3 additional events per 10,000 years of estrogen-progestin therapy. Neither result was statistically significant:

• Hazard ratio with estrogen-only use 0.94, 95% CI 0.82–1.09
• Hazard ratio with estrogen-progestin use 1.09, 95% CI 0.92–1.24.

The Danish Osteoporosis Study was the first randomized controlled trial of hormone therapy in women ages 45 through 58 who were recently menopausal (average within 7 months of menopause).¹⁵ Women assigned to hormone therapy in the form of oral estradiol with or without norethisterone (known as norethindrone in the United States) had a statistically significant lower risk of the primary composite end point of heart failure and myocardial infarction after 11 years of hormone therapy, and this finding persisted through 16 years of follow-up (Table 1).

Stroke

Overall stroke risk was significantly increased with hormone therapy in the Women’s Health Initiative trial (hazard ratio 1.32, 95% CI 1.12–1.56); however, the absolute increase in risk was small in both estrogen-alone and estrogen-progestin therapy users, 11 and 8 events, respectively, among 10,000 users. Younger women (ages 50–59) saw a nonsignificantly lower risk (2 fewer cases per 10,000 years of use).¹⁴ After 13 years of cumulative follow-up (combined intervention and follow-up phase), the risk of stroke persisted at 5 cases per 10,000 users for both arms, but only the estrogen-progestin results were statistically significant.⁹

The Danish Osteoporosis Study¹⁵ found no increased risk of stroke after 16 years of follow-up in recently menopausal women:

• Hazard ratio 0.89, 95% CI 0.48–1.65.

Venous thromboembolism

Data from both observational and randomized controlled trials demonstrate an increased risk of venous thromboembolism with oral hormone therapy, and the risk appears to be highest during the first few years of use.¹ The pooled cohort from the Women’s Health Initiative had 18 additional cases of venous thromboembolism per 10,000 women in estrogen-progestin users compared with nonusers, and 7 additional cases in those using estrogen-only therapy.

Breast health

Observational studies and randomized controlled trials have provided data on longer use of hormone therapy and breast cancer risk, but the true magnitude of this risk is unclear.

The Danish Osteoporosis Study,¹⁵ in a younger cohort of women, showed no increased risk of breast cancer after 16 years of follow-up:

• Hazard ratio 0.90, 95% CI 0.52–1.57.

The Women’s Health Initiative⁹ showed a statistically nonsignificant lower risk of breast cancer in women of all ages exposed to conjugated equine estrogen alone for 7.1 years (6 fewer cases per 10,000 women-years of use), and after 6 years of follow-up this developed statistical significance:

• Hazard ratio 0.79, 95% CI 0.65–0.97.

In contrast, those using conjugated equine estrogen plus medroxyprogesterone acetate had a statistically nonsignificant increase in the risk of new breast cancer after 3 to 5 years:

• 3-year relative risk 1.26, 95% CI 0.73–2.20
• 5-year relative risk 1.99, 95% CI 1.18–3.35
• Absolute risk 8 cases per 10,000 women-years of use.

The increased risk of breast cancer significantly declined within 3 years after stopping hormone therapy.

However, even after stopping hormone therapy, there remains a statistically small but significant increased risk of breast cancer, as demonstrated in the postintervention 13-year follow-up data on breast cancer risk and estrogen-progestin use from the Women’s Health Initiative⁹:

• Hazard ratio 1.28, 95% CI 1.11–1.48
• Absolute cumulative risk 9 cases per 10,000 women-years of use.

The Nurses’ Health Study, an observational study, prospectively followed 11,508 hysterectomized women on estrogen therapy and found that breast cancer risk increased with longer duration of use. An analysis by Chen et al¹⁶ found a trend toward increased breast cancer risk after 10 years of estrogen therapy, but this did not become statistically significant until 20 years of ongoing estrogen use. The risk of estrogen receptor-positive and progesterone receptor-positive breast cancer became statistically significant earlier, after 15 years. The relative risk associated with using estrogen for more than 15 years was 1.18, and the risk with using it for more than 20 years was 1.42.¹⁶

To put this in perspective, Chen et al¹⁷ found a similar breast cancer risk with alcohol consumption. The relative risk of invasive breast cancer was 1.15 in women who drank 3 to 6 servings of alcohol per week, 1 serving being equivalent to 4 oz of wine, which contains 11 g of alcohol.

Mortality

Studies have suggested that hormone therapy users have a lower mortality rate, even with long-term use.

A meta-analysis¹⁸ of 8 observational trials and 19 randomized controlled trials found that younger women (average age 54) on hormone therapy had a 28% lower total mortality rate compared with women not taking hormone therapy:

• Relative risk 0.72, 95% credible interval 0.62–0.82.

The Women’s Health Initiative¹⁹ suggested that the mortality rate was 30% lower in hormone therapy users younger than age 60 than in similar nonusers, though this difference did not reach statistical significance.

• Relative risk with estrogen-only therapy: 0.71, 95% CI 0.46–1.11
• Relative risk with combined estrogen-progestin therapy 0.69, 95% CI 0.44–1.07.

The Danish Osteoporosis Study,¹⁵ at 16 years of follow-up, similarly demonstrated a 34% lower mortality rate in hormone therapy users, which was not statistically significant:

• Relative risk 0.66, 95% CI 0.41–1.08.

A Cochrane review²⁰ in 2015 found that the subgroup of women who started hormone therapy before age 60 or within 10 years of menopause saw an overall benefit in terms of survival and lower risk of coronary heart disease: RR 0.70, 95% CI 0.52–0.95 (moderate-quality evidence).

TYPE OF FORMULATION

Compared with estrogen-progestin therapy, estrogen-only therapy has a more favorable risk profile in terms of coronary heart disease and breast cancer, although stroke risk remains elevated in users of conjugated equine estrogen with or without medroxyprogesterone acetate.

There is limited evidence directly comparing different formulations of hormone therapy, although they all effectively treat vasomotor symptoms.¹

Oral vs transdermal formulations

Canonico et al,²¹ in a meta-analysis of observational studies, found that oral estrogen was associated with a higher risk of venous thromboembolism than transdermal estrogen:

• Relative risk with oral estrogen 2.5, 95% CI 1.9–3.4
• Relative risk with transdermal estrogen 1.2, 95% CI 0.9–1.7.

The Estrogen and Thromboembolism Risk (ESTHER) study²² was a multicenter case-control study of women ages 45 to 70 that assessed risk of venous thromboembolism in oral vs transdermal estrogen users. Compared with women not taking hormone therapy, current users of oral estrogen had a significantly higher risk of venous thromboembolism, while transdermal estrogen users did not:

• Odds ratio with oral estrogen 4.2, 95% CI 1.5–11.6
• Odds ratio with transdermal estrogen 0.9, 95% CI 0.4–2.1.

The Kronos Early Estrogen Prevention Study (KEEPS)²³ did not support these findings. This 4-year randomized controlled trial, published in 2014, was designed to assess the risk of atherosclerosis progression with early menopause initiation of placebo vs low-dose oral hormone therapy (conjugated equine estrogen 0.45 mg daily with cyclical micronized progesterone) or transdermal hormone therapy (estradiol 50 µg/week with cyclical micronized progesterone).

In the 727 women in the study, there was one transient ischemic attack in the oral hormone therapy group, one unconfirmed stroke in the transdermal hormone therapy group, and one case of venous thromboembolism in each group, findings that were underpowered for statistical significance. Both oral and transdermal hormonal therapy had neutral effects on atherosclerosis progression, as assessed by arterial imaging. Transdermal hormone therapy was associated with improvements in markers of insulin resistance and was not associated with an increase in triglycerides, C-reactive protein, or sex hormone-binding globulin, as would be expected with transdermal circumvention of the first-pass hepatic effect.

BALANCING THE RISKS AND BENEFITS FOR THE PATIENT

The most effective treatment for vasomotor symptoms in women at any age is hormone therapy, and the benefits are more likely to outweigh risks when initiated before age 60 or within 10 years of menopause.⁷ The Women’s Health Initiative randomized study was limited to 5.6 to 7.2 years of hormone therapy (13 years of cumulative follow-up), and the Danish Osteoporosis Study was limited to 11 years of use (16 years cumulative follow-up).

The coronary heart disease outcomes for longer durations of therapy remain uncertain. There is a small but statistically significant increased risk of stroke and venous thromboembolism with oral hormone therapy, and breast cancer risk is associated with long-term estrogen-progestin use.

Patients on hormone therapy should be evaluated annually regarding the need for ongoing therapy. Persistent moderate-severe vasomotor symptoms, quality of life benefits of hormone therapy, contraindications to its use (Table 2), and patient preference need to be assessed as well as baseline risks of cardiovascular disease, breast cancer, and fracture.

Risk calculators may facilitate the shared decision-making process. Examples are:

• The American College of Cardiology/American Heart association risk calculator for cardiovascular disease²⁴ (www.cvriskcalculator.com)
• The World Health Organization Fracture Risk Assessment Tool (FRAX)²⁵
  (www.shef.ac.uk/FRAX/tool.jsp)

• The Gail model for breast cancer risk²⁶ (www.cancer.gov/bcrisktool/).
• MenoPro, a menopause decision-support algorithm and companion mobile app developed by NAMS to help direct treatment decisions based on the 10-year risk of atherosclerotic cardiovascular disease (www.menopause.org/for-professionals/-i-menopro-i-mobile-app).²⁷
  The discussion of the risks of hormone therapy with patients should incorporate the perspective of absolute risk. For example, a woman wishing to continue estrogen-progestin therapy should be told that the Women’s Health Initiative data suggest that, after 5 years of use, breast cancer risk may be increased by 8 additional cases per 10,000 users per year. According to the World Health Organization, this magnitude of risk is defined as rare (less than 1 event per 1,000 women).²⁸

A strategy of prescribing the lowest dose to achieve the desired clinical benefits is prudent and recommended.^1–3 Table 3 outlines the estrogen formulations now available in the United States, with their doses and formulations.

Unless contraindications develop (Table 2), patients may elect to continue hormone therapy if its benefits outweigh its risks. The American College of Obstetricians and Gynecologists (ACOG) 2014 practice recommendations for management of menopausal symptoms³¹ and the 2015 NAMS statement both recommend that hormone therapy not be discontinued based solely on a woman’s age.²⁹

Hormone therapy is on the Beer’s list of potentially inappropriate medications for older adults,³⁰ which remains a hurdle to its long-term use and seems to be at odds with these ACOG and NAMS statements.

Patients who choose to discontinue hormone therapy need to be monitored for persistent bothersome vasomotor symptoms, bone loss, osteoporosis, and the genitourinary syndrome of menopause (previously referred to as vulvovaginal atrophy)³¹ and offered alternative therapies if needed.

The duration of hormone therapy needs to be an individualized decision, shared between the patient and her physician and assessed annually. Quality of life, vasomotor symptoms, current age, time since menopause, hysterectomy status, personal risks (of osteoporosis, breast cancer, heart disease, stroke,  venous thromboembolism), and patient preferences need to be considered.

The North American Menopause Society (NAMS) and other organizations recommend that the lowest dose of hormone therapy be used for the shortest duration needed to manage menopausal symptoms.^1–4 However, NAMS states that extending the duration of hormone therapy may be appropriate in women who have persistent symptoms or to prevent osteoporosis if the patient cannot tolerate alternative therapies.¹

Forty-two percent of postmenopausal women continue to experience vasomotor symptoms at age 60 to 65.⁵ The median total duration of vasomotor symptoms is 7.4 years, and in black women and women with moderate or severe hot flashes the symptoms typically last 10 years.⁶ Vasomotor symptoms recur in 50% of women who discontinue hormone therapy, regardless of whether it is stopped abruptly or tapered.¹

FACTORS TO CONSIDER WHEN PRESCRIBING HORMONE THERAPY

Bone health

A statement issued in 2013 by seven medical societies said that hormone therapy is effective and appropriate for preventing osteoporosis-related fracture in at-risk women under age 60 or within 10 years of menopause.⁷

The Women’s Health Initiative,⁸ a randomized placebo-controlled trial, showed a statistically significant lower risk of vertebral and nonvertebral fracture after 3 years of use of conjugated equine estrogen with medroxyprogesterone acetate than with placebo:

• Hazard ratio 0.76, 95% confidence interval (CI) 0.69–0.83.

It also showed a mean increase of 3.7% (P < .001) in total hip bone mineral density. By the end of the trial intervention, women receiving either this combined therapy or conjugated equine estrogen alone saw a 33% overall reduction in hip fracture risk. The absolute risk reduction was 5 per 10,000 years of use.⁹

Karim et al,¹⁰ in a large observational study that followed initial hormone therapy users over 6.5 years, found that those who stopped it had a 55% greater risk of hip fracture and experienced significant bone loss as measured by bone mineral density compared with women who continued hormone therapy, and that the protective effects of hormone therapy disappeared as early as 2 years after stopping treatment.¹⁰

NAMS also recommends that women with premature menopause (before age 40) be offered and encouraged to use hormone therapy to preserve bone density and manage vasomotor symptoms until the age of natural menopause (age 51).^1,11

Cardiovascular health

Large observational studies have found that hormone therapy is associated with a 30% to 50% lower cardiovascular risk.¹² Randomized controlled trials of hormone therapy for 7 to 11 years suggest that coronary heart disease risk is modified by age and time since menopause.^13,14

The Women’s Health Initiative and other randomized controlled trials suggest a lower risk of coronary heart disease in women who begin hormone therapy before age 60 and within 10 years of the onset of menopause, but an increased risk for women over age 60 and more than 10 years since menopause. However, several of these trends have not reached statistical significance (Table 1).^13–15

The Women’s Health Initiative⁹ published its long-term follow-up results in 2013, with data on both the intervention phase (median of 7.2 years for estrogen-only therapy and 5.6 years for estrogen-progestin therapy) and the post-stopping phase (median 6.6 years for the estrogen-only group and 8.2 years for the estrogen-progestin group), with a total cumulative follow-up of 13 years. The overall 13-year cumulative absolute risk of coronary heart disease was 4 fewer events per 10,000 years of estrogen-only therapy and 3 additional events per 10,000 years of estrogen-progestin therapy. Neither result was statistically significant:

• Hazard ratio with estrogen-only use 0.94, 95% CI 0.82–1.09
• Hazard ratio with estrogen-progestin use 1.09, 95% CI 0.92–1.24.

The Danish Osteoporosis Study was the first randomized controlled trial of hormone therapy in women ages 45 through 58 who were recently menopausal (average within 7 months of menopause).¹⁵ Women assigned to hormone therapy in the form of oral estradiol with or without norethisterone (known as norethindrone in the United States) had a statistically significant lower risk of the primary composite end point of heart failure and myocardial infarction after 11 years of hormone therapy, and this finding persisted through 16 years of follow-up (Table 1).

Stroke

Overall stroke risk was significantly increased with hormone therapy in the Women’s Health Initiative trial (hazard ratio 1.32, 95% CI 1.12–1.56); however, the absolute increase in risk was small in both estrogen-alone and estrogen-progestin therapy users, 11 and 8 events, respectively, among 10,000 users. Younger women (ages 50–59) saw a nonsignificantly lower risk (2 fewer cases per 10,000 years of use).¹⁴ After 13 years of cumulative follow-up (combined intervention and follow-up phase), the risk of stroke persisted at 5 cases per 10,000 users for both arms, but only the estrogen-progestin results were statistically significant.⁹

The Danish Osteoporosis Study¹⁵ found no increased risk of stroke after 16 years of follow-up in recently menopausal women:

• Hazard ratio 0.89, 95% CI 0.48–1.65.

Venous thromboembolism

Data from both observational and randomized controlled trials demonstrate an increased risk of venous thromboembolism with oral hormone therapy, and the risk appears to be highest during the first few years of use.¹ The pooled cohort from the Women’s Health Initiative had 18 additional cases of venous thromboembolism per 10,000 women in estrogen-progestin users compared with nonusers, and 7 additional cases in those using estrogen-only therapy.

Breast health

Observational studies and randomized controlled trials have provided data on longer use of hormone therapy and breast cancer risk, but the true magnitude of this risk is unclear.

The Danish Osteoporosis Study,¹⁵ in a younger cohort of women, showed no increased risk of breast cancer after 16 years of follow-up:

• Hazard ratio 0.90, 95% CI 0.52–1.57.

The Women’s Health Initiative⁹ showed a statistically nonsignificant lower risk of breast cancer in women of all ages exposed to conjugated equine estrogen alone for 7.1 years (6 fewer cases per 10,000 women-years of use), and after 6 years of follow-up this developed statistical significance:

• Hazard ratio 0.79, 95% CI 0.65–0.97.

In contrast, those using conjugated equine estrogen plus medroxyprogesterone acetate had a statistically nonsignificant increase in the risk of new breast cancer after 3 to 5 years:

• 3-year relative risk 1.26, 95% CI 0.73–2.20
• 5-year relative risk 1.99, 95% CI 1.18–3.35
• Absolute risk 8 cases per 10,000 women-years of use.

The increased risk of breast cancer significantly declined within 3 years after stopping hormone therapy.

However, even after stopping hormone therapy, there remains a statistically small but significant increased risk of breast cancer, as demonstrated in the postintervention 13-year follow-up data on breast cancer risk and estrogen-progestin use from the Women’s Health Initiative⁹:

• Hazard ratio 1.28, 95% CI 1.11–1.48
• Absolute cumulative risk 9 cases per 10,000 women-years of use.

The Nurses’ Health Study, an observational study, prospectively followed 11,508 hysterectomized women on estrogen therapy and found that breast cancer risk increased with longer duration of use. An analysis by Chen et al¹⁶ found a trend toward increased breast cancer risk after 10 years of estrogen therapy, but this did not become statistically significant until 20 years of ongoing estrogen use. The risk of estrogen receptor-positive and progesterone receptor-positive breast cancer became statistically significant earlier, after 15 years. The relative risk associated with using estrogen for more than 15 years was 1.18, and the risk with using it for more than 20 years was 1.42.¹⁶

To put this in perspective, Chen et al¹⁷ found a similar breast cancer risk with alcohol consumption. The relative risk of invasive breast cancer was 1.15 in women who drank 3 to 6 servings of alcohol per week, 1 serving being equivalent to 4 oz of wine, which contains 11 g of alcohol.

Mortality

Studies have suggested that hormone therapy users have a lower mortality rate, even with long-term use.

A meta-analysis¹⁸ of 8 observational trials and 19 randomized controlled trials found that younger women (average age 54) on hormone therapy had a 28% lower total mortality rate compared with women not taking hormone therapy:

• Relative risk 0.72, 95% credible interval 0.62–0.82.

The Women’s Health Initiative¹⁹ suggested that the mortality rate was 30% lower in hormone therapy users younger than age 60 than in similar nonusers, though this difference did not reach statistical significance.

• Relative risk with estrogen-only therapy: 0.71, 95% CI 0.46–1.11
• Relative risk with combined estrogen-progestin therapy 0.69, 95% CI 0.44–1.07.

The Danish Osteoporosis Study,¹⁵ at 16 years of follow-up, similarly demonstrated a 34% lower mortality rate in hormone therapy users, which was not statistically significant:

• Relative risk 0.66, 95% CI 0.41–1.08.

A Cochrane review²⁰ in 2015 found that the subgroup of women who started hormone therapy before age 60 or within 10 years of menopause saw an overall benefit in terms of survival and lower risk of coronary heart disease: RR 0.70, 95% CI 0.52–0.95 (moderate-quality evidence).

TYPE OF FORMULATION

Compared with estrogen-progestin therapy, estrogen-only therapy has a more favorable risk profile in terms of coronary heart disease and breast cancer, although stroke risk remains elevated in users of conjugated equine estrogen with or without medroxyprogesterone acetate.

There is limited evidence directly comparing different formulations of hormone therapy, although they all effectively treat vasomotor symptoms.¹

Oral vs transdermal formulations

Canonico et al,²¹ in a meta-analysis of observational studies, found that oral estrogen was associated with a higher risk of venous thromboembolism than transdermal estrogen:

• Relative risk with oral estrogen 2.5, 95% CI 1.9–3.4
• Relative risk with transdermal estrogen 1.2, 95% CI 0.9–1.7.

The Estrogen and Thromboembolism Risk (ESTHER) study²² was a multicenter case-control study of women ages 45 to 70 that assessed risk of venous thromboembolism in oral vs transdermal estrogen users. Compared with women not taking hormone therapy, current users of oral estrogen had a significantly higher risk of venous thromboembolism, while transdermal estrogen users did not:

• Odds ratio with oral estrogen 4.2, 95% CI 1.5–11.6
• Odds ratio with transdermal estrogen 0.9, 95% CI 0.4–2.1.

The Kronos Early Estrogen Prevention Study (KEEPS)²³ did not support these findings. This 4-year randomized controlled trial, published in 2014, was designed to assess the risk of atherosclerosis progression with early menopause initiation of placebo vs low-dose oral hormone therapy (conjugated equine estrogen 0.45 mg daily with cyclical micronized progesterone) or transdermal hormone therapy (estradiol 50 µg/week with cyclical micronized progesterone).

In the 727 women in the study, there was one transient ischemic attack in the oral hormone therapy group, one unconfirmed stroke in the transdermal hormone therapy group, and one case of venous thromboembolism in each group, findings that were underpowered for statistical significance. Both oral and transdermal hormonal therapy had neutral effects on atherosclerosis progression, as assessed by arterial imaging. Transdermal hormone therapy was associated with improvements in markers of insulin resistance and was not associated with an increase in triglycerides, C-reactive protein, or sex hormone-binding globulin, as would be expected with transdermal circumvention of the first-pass hepatic effect.

BALANCING THE RISKS AND BENEFITS FOR THE PATIENT

The most effective treatment for vasomotor symptoms in women at any age is hormone therapy, and the benefits are more likely to outweigh risks when initiated before age 60 or within 10 years of menopause.⁷ The Women’s Health Initiative randomized study was limited to 5.6 to 7.2 years of hormone therapy (13 years of cumulative follow-up), and the Danish Osteoporosis Study was limited to 11 years of use (16 years cumulative follow-up).

The coronary heart disease outcomes for longer durations of therapy remain uncertain. There is a small but statistically significant increased risk of stroke and venous thromboembolism with oral hormone therapy, and breast cancer risk is associated with long-term estrogen-progestin use.

Patients on hormone therapy should be evaluated annually regarding the need for ongoing therapy. Persistent moderate-severe vasomotor symptoms, quality of life benefits of hormone therapy, contraindications to its use (Table 2), and patient preference need to be assessed as well as baseline risks of cardiovascular disease, breast cancer, and fracture.

Risk calculators may facilitate the shared decision-making process. Examples are:

• The American College of Cardiology/American Heart association risk calculator for cardiovascular disease²⁴ (www.cvriskcalculator.com)
• The World Health Organization Fracture Risk Assessment Tool (FRAX)²⁵
  (www.shef.ac.uk/FRAX/tool.jsp)

• The Gail model for breast cancer risk²⁶ (www.cancer.gov/bcrisktool/).
• MenoPro, a menopause decision-support algorithm and companion mobile app developed by NAMS to help direct treatment decisions based on the 10-year risk of atherosclerotic cardiovascular disease (www.menopause.org/for-professionals/-i-menopro-i-mobile-app).²⁷
  The discussion of the risks of hormone therapy with patients should incorporate the perspective of absolute risk. For example, a woman wishing to continue estrogen-progestin therapy should be told that the Women’s Health Initiative data suggest that, after 5 years of use, breast cancer risk may be increased by 8 additional cases per 10,000 users per year. According to the World Health Organization, this magnitude of risk is defined as rare (less than 1 event per 1,000 women).²⁸

A strategy of prescribing the lowest dose to achieve the desired clinical benefits is prudent and recommended.^1–3 Table 3 outlines the estrogen formulations now available in the United States, with their doses and formulations.

Unless contraindications develop (Table 2), patients may elect to continue hormone therapy if its benefits outweigh its risks. The American College of Obstetricians and Gynecologists (ACOG) 2014 practice recommendations for management of menopausal symptoms³¹ and the 2015 NAMS statement both recommend that hormone therapy not be discontinued based solely on a woman’s age.²⁹

Hormone therapy is on the Beer’s list of potentially inappropriate medications for older adults,³⁰ which remains a hurdle to its long-term use and seems to be at odds with these ACOG and NAMS statements.

Patients who choose to discontinue hormone therapy need to be monitored for persistent bothersome vasomotor symptoms, bone loss, osteoporosis, and the genitourinary syndrome of menopause (previously referred to as vulvovaginal atrophy)³¹ and offered alternative therapies if needed.

The duration of hormone therapy needs to be an individualized decision, shared between the patient and her physician and assessed annually. Quality of life, vasomotor symptoms, current age, time since menopause, hysterectomy status, personal risks (of osteoporosis, breast cancer, heart disease, stroke,  venous thromboembolism), and patient preferences need to be considered.

The North American Menopause Society (NAMS) and other organizations recommend that the lowest dose of hormone therapy be used for the shortest duration needed to manage menopausal symptoms.^1–4 However, NAMS states that extending the duration of hormone therapy may be appropriate in women who have persistent symptoms or to prevent osteoporosis if the patient cannot tolerate alternative therapies.¹

Forty-two percent of postmenopausal women continue to experience vasomotor symptoms at age 60 to 65.⁵ The median total duration of vasomotor symptoms is 7.4 years, and in black women and women with moderate or severe hot flashes the symptoms typically last 10 years.⁶ Vasomotor symptoms recur in 50% of women who discontinue hormone therapy, regardless of whether it is stopped abruptly or tapered.¹

FACTORS TO CONSIDER WHEN PRESCRIBING HORMONE THERAPY

Bone health

A statement issued in 2013 by seven medical societies said that hormone therapy is effective and appropriate for preventing osteoporosis-related fracture in at-risk women under age 60 or within 10 years of menopause.⁷

The Women’s Health Initiative,⁸ a randomized placebo-controlled trial, showed a statistically significant lower risk of vertebral and nonvertebral fracture after 3 years of use of conjugated equine estrogen with medroxyprogesterone acetate than with placebo:

• Hazard ratio 0.76, 95% confidence interval (CI) 0.69–0.83.

It also showed a mean increase of 3.7% (P < .001) in total hip bone mineral density. By the end of the trial intervention, women receiving either this combined therapy or conjugated equine estrogen alone saw a 33% overall reduction in hip fracture risk. The absolute risk reduction was 5 per 10,000 years of use.⁹

Karim et al,¹⁰ in a large observational study that followed initial hormone therapy users over 6.5 years, found that those who stopped it had a 55% greater risk of hip fracture and experienced significant bone loss as measured by bone mineral density compared with women who continued hormone therapy, and that the protective effects of hormone therapy disappeared as early as 2 years after stopping treatment.¹⁰

NAMS also recommends that women with premature menopause (before age 40) be offered and encouraged to use hormone therapy to preserve bone density and manage vasomotor symptoms until the age of natural menopause (age 51).^1,11

Cardiovascular health

Large observational studies have found that hormone therapy is associated with a 30% to 50% lower cardiovascular risk.¹² Randomized controlled trials of hormone therapy for 7 to 11 years suggest that coronary heart disease risk is modified by age and time since menopause.^13,14

The Women’s Health Initiative and other randomized controlled trials suggest a lower risk of coronary heart disease in women who begin hormone therapy before age 60 and within 10 years of the onset of menopause, but an increased risk for women over age 60 and more than 10 years since menopause. However, several of these trends have not reached statistical significance (Table 1).^13–15

The Women’s Health Initiative⁹ published its long-term follow-up results in 2013, with data on both the intervention phase (median of 7.2 years for estrogen-only therapy and 5.6 years for estrogen-progestin therapy) and the post-stopping phase (median 6.6 years for the estrogen-only group and 8.2 years for the estrogen-progestin group), with a total cumulative follow-up of 13 years. The overall 13-year cumulative absolute risk of coronary heart disease was 4 fewer events per 10,000 years of estrogen-only therapy and 3 additional events per 10,000 years of estrogen-progestin therapy. Neither result was statistically significant:

• Hazard ratio with estrogen-only use 0.94, 95% CI 0.82–1.09
• Hazard ratio with estrogen-progestin use 1.09, 95% CI 0.92–1.24.

The Danish Osteoporosis Study was the first randomized controlled trial of hormone therapy in women ages 45 through 58 who were recently menopausal (average within 7 months of menopause).¹⁵ Women assigned to hormone therapy in the form of oral estradiol with or without norethisterone (known as norethindrone in the United States) had a statistically significant lower risk of the primary composite end point of heart failure and myocardial infarction after 11 years of hormone therapy, and this finding persisted through 16 years of follow-up (Table 1).

Stroke

Overall stroke risk was significantly increased with hormone therapy in the Women’s Health Initiative trial (hazard ratio 1.32, 95% CI 1.12–1.56); however, the absolute increase in risk was small in both estrogen-alone and estrogen-progestin therapy users, 11 and 8 events, respectively, among 10,000 users. Younger women (ages 50–59) saw a nonsignificantly lower risk (2 fewer cases per 10,000 years of use).¹⁴ After 13 years of cumulative follow-up (combined intervention and follow-up phase), the risk of stroke persisted at 5 cases per 10,000 users for both arms, but only the estrogen-progestin results were statistically significant.⁹

The Danish Osteoporosis Study¹⁵ found no increased risk of stroke after 16 years of follow-up in recently menopausal women:

• Hazard ratio 0.89, 95% CI 0.48–1.65.

Venous thromboembolism

Data from both observational and randomized controlled trials demonstrate an increased risk of venous thromboembolism with oral hormone therapy, and the risk appears to be highest during the first few years of use.¹ The pooled cohort from the Women’s Health Initiative had 18 additional cases of venous thromboembolism per 10,000 women in estrogen-progestin users compared with nonusers, and 7 additional cases in those using estrogen-only therapy.

Breast health

Observational studies and randomized controlled trials have provided data on longer use of hormone therapy and breast cancer risk, but the true magnitude of this risk is unclear.

The Danish Osteoporosis Study,¹⁵ in a younger cohort of women, showed no increased risk of breast cancer after 16 years of follow-up:

• Hazard ratio 0.90, 95% CI 0.52–1.57.

The Women’s Health Initiative⁹ showed a statistically nonsignificant lower risk of breast cancer in women of all ages exposed to conjugated equine estrogen alone for 7.1 years (6 fewer cases per 10,000 women-years of use), and after 6 years of follow-up this developed statistical significance:

• Hazard ratio 0.79, 95% CI 0.65–0.97.

In contrast, those using conjugated equine estrogen plus medroxyprogesterone acetate had a statistically nonsignificant increase in the risk of new breast cancer after 3 to 5 years:

• 3-year relative risk 1.26, 95% CI 0.73–2.20
• 5-year relative risk 1.99, 95% CI 1.18–3.35
• Absolute risk 8 cases per 10,000 women-years of use.

The increased risk of breast cancer significantly declined within 3 years after stopping hormone therapy.

However, even after stopping hormone therapy, there remains a statistically small but significant increased risk of breast cancer, as demonstrated in the postintervention 13-year follow-up data on breast cancer risk and estrogen-progestin use from the Women’s Health Initiative⁹:

• Hazard ratio 1.28, 95% CI 1.11–1.48
• Absolute cumulative risk 9 cases per 10,000 women-years of use.

The Nurses’ Health Study, an observational study, prospectively followed 11,508 hysterectomized women on estrogen therapy and found that breast cancer risk increased with longer duration of use. An analysis by Chen et al¹⁶ found a trend toward increased breast cancer risk after 10 years of estrogen therapy, but this did not become statistically significant until 20 years of ongoing estrogen use. The risk of estrogen receptor-positive and progesterone receptor-positive breast cancer became statistically significant earlier, after 15 years. The relative risk associated with using estrogen for more than 15 years was 1.18, and the risk with using it for more than 20 years was 1.42.¹⁶

To put this in perspective, Chen et al¹⁷ found a similar breast cancer risk with alcohol consumption. The relative risk of invasive breast cancer was 1.15 in women who drank 3 to 6 servings of alcohol per week, 1 serving being equivalent to 4 oz of wine, which contains 11 g of alcohol.

Mortality

Studies have suggested that hormone therapy users have a lower mortality rate, even with long-term use.

A meta-analysis¹⁸ of 8 observational trials and 19 randomized controlled trials found that younger women (average age 54) on hormone therapy had a 28% lower total mortality rate compared with women not taking hormone therapy:

• Relative risk 0.72, 95% credible interval 0.62–0.82.

The Women’s Health Initiative¹⁹ suggested that the mortality rate was 30% lower in hormone therapy users younger than age 60 than in similar nonusers, though this difference did not reach statistical significance.

• Relative risk with estrogen-only therapy: 0.71, 95% CI 0.46–1.11
• Relative risk with combined estrogen-progestin therapy 0.69, 95% CI 0.44–1.07.

The Danish Osteoporosis Study,¹⁵ at 16 years of follow-up, similarly demonstrated a 34% lower mortality rate in hormone therapy users, which was not statistically significant:

• Relative risk 0.66, 95% CI 0.41–1.08.

A Cochrane review²⁰ in 2015 found that the subgroup of women who started hormone therapy before age 60 or within 10 years of menopause saw an overall benefit in terms of survival and lower risk of coronary heart disease: RR 0.70, 95% CI 0.52–0.95 (moderate-quality evidence).

TYPE OF FORMULATION

Compared with estrogen-progestin therapy, estrogen-only therapy has a more favorable risk profile in terms of coronary heart disease and breast cancer, although stroke risk remains elevated in users of conjugated equine estrogen with or without medroxyprogesterone acetate.

There is limited evidence directly comparing different formulations of hormone therapy, although they all effectively treat vasomotor symptoms.¹

Oral vs transdermal formulations

Canonico et al,²¹ in a meta-analysis of observational studies, found that oral estrogen was associated with a higher risk of venous thromboembolism than transdermal estrogen:

• Relative risk with oral estrogen 2.5, 95% CI 1.9–3.4
• Relative risk with transdermal estrogen 1.2, 95% CI 0.9–1.7.

The Estrogen and Thromboembolism Risk (ESTHER) study²² was a multicenter case-control study of women ages 45 to 70 that assessed risk of venous thromboembolism in oral vs transdermal estrogen users. Compared with women not taking hormone therapy, current users of oral estrogen had a significantly higher risk of venous thromboembolism, while transdermal estrogen users did not:

• Odds ratio with oral estrogen 4.2, 95% CI 1.5–11.6
• Odds ratio with transdermal estrogen 0.9, 95% CI 0.4–2.1.

The Kronos Early Estrogen Prevention Study (KEEPS)²³ did not support these findings. This 4-year randomized controlled trial, published in 2014, was designed to assess the risk of atherosclerosis progression with early menopause initiation of placebo vs low-dose oral hormone therapy (conjugated equine estrogen 0.45 mg daily with cyclical micronized progesterone) or transdermal hormone therapy (estradiol 50 µg/week with cyclical micronized progesterone).

In the 727 women in the study, there was one transient ischemic attack in the oral hormone therapy group, one unconfirmed stroke in the transdermal hormone therapy group, and one case of venous thromboembolism in each group, findings that were underpowered for statistical significance. Both oral and transdermal hormonal therapy had neutral effects on atherosclerosis progression, as assessed by arterial imaging. Transdermal hormone therapy was associated with improvements in markers of insulin resistance and was not associated with an increase in triglycerides, C-reactive protein, or sex hormone-binding globulin, as would be expected with transdermal circumvention of the first-pass hepatic effect.

BALANCING THE RISKS AND BENEFITS FOR THE PATIENT

The most effective treatment for vasomotor symptoms in women at any age is hormone therapy, and the benefits are more likely to outweigh risks when initiated before age 60 or within 10 years of menopause.⁷ The Women’s Health Initiative randomized study was limited to 5.6 to 7.2 years of hormone therapy (13 years of cumulative follow-up), and the Danish Osteoporosis Study was limited to 11 years of use (16 years cumulative follow-up).

The coronary heart disease outcomes for longer durations of therapy remain uncertain. There is a small but statistically significant increased risk of stroke and venous thromboembolism with oral hormone therapy, and breast cancer risk is associated with long-term estrogen-progestin use.

Patients on hormone therapy should be evaluated annually regarding the need for ongoing therapy. Persistent moderate-severe vasomotor symptoms, quality of life benefits of hormone therapy, contraindications to its use (Table 2), and patient preference need to be assessed as well as baseline risks of cardiovascular disease, breast cancer, and fracture.

Risk calculators may facilitate the shared decision-making process. Examples are:

• The American College of Cardiology/American Heart association risk calculator for cardiovascular disease²⁴ (www.cvriskcalculator.com)
• The World Health Organization Fracture Risk Assessment Tool (FRAX)²⁵
  (www.shef.ac.uk/FRAX/tool.jsp)

• The Gail model for breast cancer risk²⁶ (www.cancer.gov/bcrisktool/).
• MenoPro, a menopause decision-support algorithm and companion mobile app developed by NAMS to help direct treatment decisions based on the 10-year risk of atherosclerotic cardiovascular disease (www.menopause.org/for-professionals/-i-menopro-i-mobile-app).²⁷
  The discussion of the risks of hormone therapy with patients should incorporate the perspective of absolute risk. For example, a woman wishing to continue estrogen-progestin therapy should be told that the Women’s Health Initiative data suggest that, after 5 years of use, breast cancer risk may be increased by 8 additional cases per 10,000 users per year. According to the World Health Organization, this magnitude of risk is defined as rare (less than 1 event per 1,000 women).²⁸

A strategy of prescribing the lowest dose to achieve the desired clinical benefits is prudent and recommended.^1–3 Table 3 outlines the estrogen formulations now available in the United States, with their doses and formulations.

Unless contraindications develop (Table 2), patients may elect to continue hormone therapy if its benefits outweigh its risks. The American College of Obstetricians and Gynecologists (ACOG) 2014 practice recommendations for management of menopausal symptoms³¹ and the 2015 NAMS statement both recommend that hormone therapy not be discontinued based solely on a woman’s age.²⁹

Hormone therapy is on the Beer’s list of potentially inappropriate medications for older adults,³⁰ which remains a hurdle to its long-term use and seems to be at odds with these ACOG and NAMS statements.

Patients who choose to discontinue hormone therapy need to be monitored for persistent bothersome vasomotor symptoms, bone loss, osteoporosis, and the genitourinary syndrome of menopause (previously referred to as vulvovaginal atrophy)³¹ and offered alternative therapies if needed.

It is no secret that about half of all pregnancies in the United States are unintended, and that teens have the highest rate of unplanned pregnancy. What’s not so well known is that women in their 40s have the second highest rate.¹

Optimal use of contraception throughout perimenopause is crucial, but finding the right method of birth control for this patient population can be a bit of a balancing act. Long-acting reversible contraceptives (LARCs), such as an intrauterine device or progestin-only implant, are preferred first-line contraceptive options when preventing pregnancy is the primary goal, given their increased efficacy and limited number of contraindications.^2,3 However, women experiencing perimenopausal symptoms often need a combination hormonal contraceptive (CHC)—typically an estrogen-containing pill, a patch, or a vaginal ring—for relief of vasomotor symptoms and cycle control.

Women in their 40s should have access to a full array of options to help improve adherence. However, physicians may be reluctant to prescribe estrogen-containing products for patients who often have a more complex medical history than their younger counterparts, including increased risks for breast cancer, cardiovascular disease, and venous thromboembolism (VTE).

With this in mind, the Centers for Disease Control and Prevention (CDC) has identified medical conditions that may affect the use of the various types of contraceptives by perimenopausal women and issued evidence-based recommendations on the appropriateness of each method using a one-to-4 rating system (TABLE 1).² To help you address the contraceptive needs of such patients, we review the key risk factors, CDC guidelines, and optimal choices in the 4 case studies that follow.

CASE 1 › Sara G: VTE risk 

Sara G, a healthy 45-year-old, recently started dating again following her divorce. She wants to avoid pregnancy. She has no personal or family history of clotting disorders and does not smoke. However, she is obese (body mass index [BMI]=32 kg/m²), and her job as a visiting nurse requires her to spend most of the day in her car. Ms. G also has acne and wants an estrogen-containing contraceptive to help treat it.

If Ms. G were your patient, what would you offer her?

The risk for VTE increases substantially for women older than 40 years. In a recent cohort study, those ages 45 to 49 faced approximately twice the risk of women ages 25 to 29. However, the absolute risk for the older women was still low (4.7-5.3 per 10,000 woman-years).⁴ What’s more, the risk of VTE from the use of a CHC is substantially less than the risk associated with pregnancy and the postpartum period (TABLE 2).⁵

Obesity increases the risk. Women like Ms. G who are obese (BMI >30) have an increased risk for VTE associated with CHCs, but the CDC rates them as a Category 2 risk, even for obese women in their 40s—a determination that the advantages outweigh the risks.²

Progestin choice and estrogen dose matter. Combination oral contraceptives (COCs) that contain certain third-generation progestins (gestodene and desogestrel) may be more thrombophilic than those containing first- or second-generation progestins (TABLE 3).⁶ The relative risk (RR) for VTE with third-generation vs second-generation progestins is 1.3 (95% confidence interval [CI], 1.0-1.8).⁷ Formulations containing higher doses of estrogen are also more likely to be associated with VTE.⁷

Drospirenone is a newer progestin. Found in several COCs, drospirenone has antimineralocorticoid properties that help to minimize bloating and fluid retention but may also lead to a hypercoagulable state.⁵ Numerous studies have investigated the association between drospirenone and VTE risk, with conflicting results.⁸ Most recently, a large international prospective observational study involving more than 85,000 women showed no increased risk for VTE among women taking COCs with drospirenone compared with pills that do not contain this progestin.⁹

Non-oral CHCs, including the vaginal ring and the patch, offer the convenience of weekly or monthly use while providing similar benefits to COCs. Some fear that the continuous exposure to hormones associated with these methods may increase the risk for VTE, but evidence is mixed.

A large (N=1.6 million) Danish registry study published in 2012 demonstrated a 2-fold increased risk of VTE among vaginal ring users vs women taking COCs.⁴ But a multinational prospective cohort study of more than 33,000 women found no increased VTE risk in ring users,10 and a recent US database study involving more than 800,000 women reported nonsignificant VTE risk estimates for both the ring (RR=1.09; 95% CI, 0.55-2.16) and the patch (RR=1.35; 95% CI, 0.90-2.02) compared with COCs.¹¹

THE BOTTOM LINE For Ms. G, the benefits of contraception likely outweigh any small increase in her absolute risk for VTE. To minimize her risk, however, select a pill that contains a low dose (20-35 mcg) of ethinyl estradiol (EE) combined with a progestin that has not been associated with an increased VTE risk. Because of their mechanism of action, most COCs will improve acne, regardless of the progestin in the formulation.^12-14

CASE 2 › Stephanie T: CV risk

Stephanie T, 47, is in need of contraception and treatment for severe hot flashes. She has no significant past medical history, but she is obese (BMI =36), her blood pressure (BP) is 130/80 mm Hg, and her most recent labs reveal a fasting glucose of 115 and a hemoglobin A1c of 6.1%. Ms. T is concerned about arterial thromboembolic disease because of her family history: Her father had a myocardial infarction (MI) at age 56 and a maternal aunt had a stroke when she was 65.

What evidence should you consider?

Baseline arterial thromboembolic events are considerably more rare in premenopausal women than VTEs (13.2 MIs vs 24.2 thrombotic strokes per 100,000 woman-years).¹⁵ Thus, a small increased RR from a CHC is unlikely to have a significant clinical impact.

Some third-generation progestins appear to be more thrombophilic than firs tor second-generation progestins.

A systemic review and meta-analysis of studies between 1995 and 2012 showed that the odds ratio (OR) of ischemic stroke in users of COCs vs nonusers was 1.9 (95% CI, 1.24–2.91).¹⁶ This study included very few estrogen formulations with <35 mcg EE, however; even so, no increased risk of MI was found (OR=1.34; 95% CI, 0.87–2.08).¹⁶ A 15-year retrospective cohort study of 1.6 million Danish women showed that lowering the dose of EE to 20 mcg (from 30-40 mcg) significantly reduced the risk of arterial events.¹⁵ It is unclear whether the vaginal ring is associated with an increased RR of stroke compared with COCs because studies have had mixed results.^10,15 There is no compelling evidence to suggest a difference in the risk of arterial events based on the type of progestin used in the COC.¹⁵

Hypertension is a key consideration. It is important to remember that perimenopausal women may have comorbid conditions that increase their risk of arterial thromboembolic events. CHCs should be used with caution in women with hypertension, even if BP is adequately controlled—a Category 3 recommendation from the CDC. In such patients, LARC or a progestin-only pill is preferred unless there is a compelling reason to use a CHC, such as acne, vasomotor symptoms, or hirsutism.²

CHCs are contraindicated for women with a BP ≥160/100 mm Hg and/or any manifestation of vascular disease (Category 4).² Although progestin-only methods are often preferred for women with established vascular disease, depot medroxyprogesterone acetate (DMPA) is an exception (Category 3).² DMPA is not a first-line choice for such patients because of its potential to cause weight gain and worsening lipids, glucose, and insulin metabolism. Women with hypertriglyceridemia should have follow-up testing of lipid levels after initiation of hormonal contraception, especially if it contains estrogen.

Diabetes is not an absolute contraindication. Many women with diabetes can safely use CHCs (Category 2). The exceptions: those who have vascular disease, nephropathy, retinopathy, or neuropathy (Category 4) or have had diabetes for >20 years and therefore have the potential for undiagnosed vascular disease.² Generally, the use of insulin should not affect decisions regarding CHCs, and patients can be reassured that the hormones will not worsen their diabetes control.

When caring for women who have multiple risk factors for cardiovascular disease, it is important to exercise clinical judgment regarding the appropriateness of CHCs (Categories 3 and 4). Progestin-only methods have a more favorable risk profile for women at the highest risk and may provide ample relief of perimenopausal symptoms.²

THE BOTTOM LINE Ms. T may benefit from a CHC due to her severe hot flashes. She should be encouraged to adopt healthy lifestyle changes, including diet and exercise, to decrease her risk of arterial thromboembolism and VTE, but she has no contraindications to the use of a CHC at this time.

CASE 3 › Leslie C: Bone health

Leslie C, age 45, is happy with the contraceptive he has used for the past 3 years—DMPA injections every 3 months. She has no perimenopausal symptoms. However, her mother had an osteoporotic hip fracture at age 70 and Ms. C is concerned about the long-term use of DMPA.

Should Ms. C be worried?

Because of DMPA’s association with bone loss, the US Food and Drug Administration issued a black box warning in 2004 recommending that this method be used for more than 2 years only by women for whom other birth control methods are deemed inappropriate.¹⁷

Bone loss associated with longer-term use of DMPA is a greater concern for perimenopausal women because they have fewer years to recover the bone mineral density after discontinuing the contraceptive.

The bone loss may be reversed. Evidence suggests that the bone loss is reversible, however, and the American College of Obstetricians and Gynecologists has stated that a potential fracture risk need not limit a woman’s use of DMPA to 2 years.¹⁸ A retrospective cohort review of 312,295 women in the United Kingdom did not find evidence of an increased risk of fracture with long-term use of DMPA.¹⁹ It is important to note, however, that because of declining estrogen levels, perimenopausal women have fewer years than their younger counterparts to recover bone density upon discontinuation of DMPA.^20,21

THE BOTTOM LINE Because Ms. C has no perimenopausal symptoms, she may do well with LARC, which—like DMPA —would free her of the need to remember to take, apply, or insert a contraceptive regularly. It may help to point out that LARCs provide superior contraceptive efficacy compared with DMPA injections (99% vs 94%).³ Nonetheless, she and other women in their 40s who need ongoing contraception should not be discouraged from using DMPA if that is their preference.

CASE 4 › Alissa B: Breast cancer risk

Alissa B, 49, has polycystic ovaries and wonders if it is safe for her to continue her COC. She has been happy with the treatment for years because it gives her relief from hot flashes and regulates her cycles. Her 46-year-old sister was recently diagnosed with invasive breast cancer, however, and Ms. B is afraid that the hormones she takes put her at increased risk.

Should you recommend another method?

Breast cancer is an important concern for many women as they age. Although Ms. B’s family history increases her risk for developing breast cancer, a systematic review indicates that COCs do not add to this risk.²²

Weak association between family history and OC use. The review included 10 observational studies and one meta-analysis that investigated the association between COC use and breast cancer in women with a family history of the disease. Only 2 fair-quality studies showed an association, one of which included women who had begun taking the pill before 1975, when formulations typically contained higher doses of estrogen than present-day preparations.²²

The lower doses of estrogen in today’s combination oral contraceptives do not appear to significantly increase the risk of breast cancer.

Data from a recently published meta-analysis also indicate that there is no increased risk for breast cancer from COCs among women with BRCA 1 or BRCA 2 mutations. The summary RR for breast cancer in such patients was 1.13 (95% CI, 0.88-1.45), but OC users had a lower risk for ovarian cancer (summary RR=0.50; 95% CI, 0.33-0.75).²³ Additionally, investigators found no association between specific currently used COC formulations and breast cancer.²⁴

THE BOTTOM LINE Based on an independent review of the evidence, the CDC has given a family history of breast cancer a Category 1 rating. Thus, Ms. B can be reassured that she may safely continue taking her COC, which is unlikely to increase her breast cancer risk.

CORRESPONDENCE
Pelin Batur, MD, NCMP, CCD, Cleveland Clinic Independence Family Health Center, 5001 Rockside Road, IN30, Cleveland, OH 44131; baturp@ccf.org.

It is no secret that about half of all pregnancies in the United States are unintended, and that teens have the highest rate of unplanned pregnancy. What’s not so well known is that women in their 40s have the second highest rate.¹

Optimal use of contraception throughout perimenopause is crucial, but finding the right method of birth control for this patient population can be a bit of a balancing act. Long-acting reversible contraceptives (LARCs), such as an intrauterine device or progestin-only implant, are preferred first-line contraceptive options when preventing pregnancy is the primary goal, given their increased efficacy and limited number of contraindications.^2,3 However, women experiencing perimenopausal symptoms often need a combination hormonal contraceptive (CHC)—typically an estrogen-containing pill, a patch, or a vaginal ring—for relief of vasomotor symptoms and cycle control.

Women in their 40s should have access to a full array of options to help improve adherence. However, physicians may be reluctant to prescribe estrogen-containing products for patients who often have a more complex medical history than their younger counterparts, including increased risks for breast cancer, cardiovascular disease, and venous thromboembolism (VTE).

With this in mind, the Centers for Disease Control and Prevention (CDC) has identified medical conditions that may affect the use of the various types of contraceptives by perimenopausal women and issued evidence-based recommendations on the appropriateness of each method using a one-to-4 rating system (TABLE 1).² To help you address the contraceptive needs of such patients, we review the key risk factors, CDC guidelines, and optimal choices in the 4 case studies that follow.

CASE 1 › Sara G: VTE risk 

Sara G, a healthy 45-year-old, recently started dating again following her divorce. She wants to avoid pregnancy. She has no personal or family history of clotting disorders and does not smoke. However, she is obese (body mass index [BMI]=32 kg/m²), and her job as a visiting nurse requires her to spend most of the day in her car. Ms. G also has acne and wants an estrogen-containing contraceptive to help treat it.

If Ms. G were your patient, what would you offer her?

The risk for VTE increases substantially for women older than 40 years. In a recent cohort study, those ages 45 to 49 faced approximately twice the risk of women ages 25 to 29. However, the absolute risk for the older women was still low (4.7-5.3 per 10,000 woman-years).⁴ What’s more, the risk of VTE from the use of a CHC is substantially less than the risk associated with pregnancy and the postpartum period (TABLE 2).⁵

Obesity increases the risk. Women like Ms. G who are obese (BMI >30) have an increased risk for VTE associated with CHCs, but the CDC rates them as a Category 2 risk, even for obese women in their 40s—a determination that the advantages outweigh the risks.²

Progestin choice and estrogen dose matter. Combination oral contraceptives (COCs) that contain certain third-generation progestins (gestodene and desogestrel) may be more thrombophilic than those containing first- or second-generation progestins (TABLE 3).⁶ The relative risk (RR) for VTE with third-generation vs second-generation progestins is 1.3 (95% confidence interval [CI], 1.0-1.8).⁷ Formulations containing higher doses of estrogen are also more likely to be associated with VTE.⁷

Drospirenone is a newer progestin. Found in several COCs, drospirenone has antimineralocorticoid properties that help to minimize bloating and fluid retention but may also lead to a hypercoagulable state.⁵ Numerous studies have investigated the association between drospirenone and VTE risk, with conflicting results.⁸ Most recently, a large international prospective observational study involving more than 85,000 women showed no increased risk for VTE among women taking COCs with drospirenone compared with pills that do not contain this progestin.⁹

Non-oral CHCs, including the vaginal ring and the patch, offer the convenience of weekly or monthly use while providing similar benefits to COCs. Some fear that the continuous exposure to hormones associated with these methods may increase the risk for VTE, but evidence is mixed.

A large (N=1.6 million) Danish registry study published in 2012 demonstrated a 2-fold increased risk of VTE among vaginal ring users vs women taking COCs.⁴ But a multinational prospective cohort study of more than 33,000 women found no increased VTE risk in ring users,10 and a recent US database study involving more than 800,000 women reported nonsignificant VTE risk estimates for both the ring (RR=1.09; 95% CI, 0.55-2.16) and the patch (RR=1.35; 95% CI, 0.90-2.02) compared with COCs.¹¹

THE BOTTOM LINE For Ms. G, the benefits of contraception likely outweigh any small increase in her absolute risk for VTE. To minimize her risk, however, select a pill that contains a low dose (20-35 mcg) of ethinyl estradiol (EE) combined with a progestin that has not been associated with an increased VTE risk. Because of their mechanism of action, most COCs will improve acne, regardless of the progestin in the formulation.^12-14

CASE 2 › Stephanie T: CV risk

Stephanie T, 47, is in need of contraception and treatment for severe hot flashes. She has no significant past medical history, but she is obese (BMI =36), her blood pressure (BP) is 130/80 mm Hg, and her most recent labs reveal a fasting glucose of 115 and a hemoglobin A1c of 6.1%. Ms. T is concerned about arterial thromboembolic disease because of her family history: Her father had a myocardial infarction (MI) at age 56 and a maternal aunt had a stroke when she was 65.

What evidence should you consider?

Baseline arterial thromboembolic events are considerably more rare in premenopausal women than VTEs (13.2 MIs vs 24.2 thrombotic strokes per 100,000 woman-years).¹⁵ Thus, a small increased RR from a CHC is unlikely to have a significant clinical impact.

Some third-generation progestins appear to be more thrombophilic than firs tor second-generation progestins.

A systemic review and meta-analysis of studies between 1995 and 2012 showed that the odds ratio (OR) of ischemic stroke in users of COCs vs nonusers was 1.9 (95% CI, 1.24–2.91).¹⁶ This study included very few estrogen formulations with <35 mcg EE, however; even so, no increased risk of MI was found (OR=1.34; 95% CI, 0.87–2.08).¹⁶ A 15-year retrospective cohort study of 1.6 million Danish women showed that lowering the dose of EE to 20 mcg (from 30-40 mcg) significantly reduced the risk of arterial events.¹⁵ It is unclear whether the vaginal ring is associated with an increased RR of stroke compared with COCs because studies have had mixed results.^10,15 There is no compelling evidence to suggest a difference in the risk of arterial events based on the type of progestin used in the COC.¹⁵

Hypertension is a key consideration. It is important to remember that perimenopausal women may have comorbid conditions that increase their risk of arterial thromboembolic events. CHCs should be used with caution in women with hypertension, even if BP is adequately controlled—a Category 3 recommendation from the CDC. In such patients, LARC or a progestin-only pill is preferred unless there is a compelling reason to use a CHC, such as acne, vasomotor symptoms, or hirsutism.²

CHCs are contraindicated for women with a BP ≥160/100 mm Hg and/or any manifestation of vascular disease (Category 4).² Although progestin-only methods are often preferred for women with established vascular disease, depot medroxyprogesterone acetate (DMPA) is an exception (Category 3).² DMPA is not a first-line choice for such patients because of its potential to cause weight gain and worsening lipids, glucose, and insulin metabolism. Women with hypertriglyceridemia should have follow-up testing of lipid levels after initiation of hormonal contraception, especially if it contains estrogen.

Diabetes is not an absolute contraindication. Many women with diabetes can safely use CHCs (Category 2). The exceptions: those who have vascular disease, nephropathy, retinopathy, or neuropathy (Category 4) or have had diabetes for >20 years and therefore have the potential for undiagnosed vascular disease.² Generally, the use of insulin should not affect decisions regarding CHCs, and patients can be reassured that the hormones will not worsen their diabetes control.

When caring for women who have multiple risk factors for cardiovascular disease, it is important to exercise clinical judgment regarding the appropriateness of CHCs (Categories 3 and 4). Progestin-only methods have a more favorable risk profile for women at the highest risk and may provide ample relief of perimenopausal symptoms.²

THE BOTTOM LINE Ms. T may benefit from a CHC due to her severe hot flashes. She should be encouraged to adopt healthy lifestyle changes, including diet and exercise, to decrease her risk of arterial thromboembolism and VTE, but she has no contraindications to the use of a CHC at this time.

CASE 3 › Leslie C: Bone health

Leslie C, age 45, is happy with the contraceptive he has used for the past 3 years—DMPA injections every 3 months. She has no perimenopausal symptoms. However, her mother had an osteoporotic hip fracture at age 70 and Ms. C is concerned about the long-term use of DMPA.

Should Ms. C be worried?

Because of DMPA’s association with bone loss, the US Food and Drug Administration issued a black box warning in 2004 recommending that this method be used for more than 2 years only by women for whom other birth control methods are deemed inappropriate.¹⁷

Bone loss associated with longer-term use of DMPA is a greater concern for perimenopausal women because they have fewer years to recover the bone mineral density after discontinuing the contraceptive.

The bone loss may be reversed. Evidence suggests that the bone loss is reversible, however, and the American College of Obstetricians and Gynecologists has stated that a potential fracture risk need not limit a woman’s use of DMPA to 2 years.¹⁸ A retrospective cohort review of 312,295 women in the United Kingdom did not find evidence of an increased risk of fracture with long-term use of DMPA.¹⁹ It is important to note, however, that because of declining estrogen levels, perimenopausal women have fewer years than their younger counterparts to recover bone density upon discontinuation of DMPA.^20,21

THE BOTTOM LINE Because Ms. C has no perimenopausal symptoms, she may do well with LARC, which—like DMPA —would free her of the need to remember to take, apply, or insert a contraceptive regularly. It may help to point out that LARCs provide superior contraceptive efficacy compared with DMPA injections (99% vs 94%).³ Nonetheless, she and other women in their 40s who need ongoing contraception should not be discouraged from using DMPA if that is their preference.

CASE 4 › Alissa B: Breast cancer risk

Alissa B, 49, has polycystic ovaries and wonders if it is safe for her to continue her COC. She has been happy with the treatment for years because it gives her relief from hot flashes and regulates her cycles. Her 46-year-old sister was recently diagnosed with invasive breast cancer, however, and Ms. B is afraid that the hormones she takes put her at increased risk.

Should you recommend another method?

Breast cancer is an important concern for many women as they age. Although Ms. B’s family history increases her risk for developing breast cancer, a systematic review indicates that COCs do not add to this risk.²²

Weak association between family history and OC use. The review included 10 observational studies and one meta-analysis that investigated the association between COC use and breast cancer in women with a family history of the disease. Only 2 fair-quality studies showed an association, one of which included women who had begun taking the pill before 1975, when formulations typically contained higher doses of estrogen than present-day preparations.²²

The lower doses of estrogen in today’s combination oral contraceptives do not appear to significantly increase the risk of breast cancer.

Data from a recently published meta-analysis also indicate that there is no increased risk for breast cancer from COCs among women with BRCA 1 or BRCA 2 mutations. The summary RR for breast cancer in such patients was 1.13 (95% CI, 0.88-1.45), but OC users had a lower risk for ovarian cancer (summary RR=0.50; 95% CI, 0.33-0.75).²³ Additionally, investigators found no association between specific currently used COC formulations and breast cancer.²⁴

THE BOTTOM LINE Based on an independent review of the evidence, the CDC has given a family history of breast cancer a Category 1 rating. Thus, Ms. B can be reassured that she may safely continue taking her COC, which is unlikely to increase her breast cancer risk.

CORRESPONDENCE
Pelin Batur, MD, NCMP, CCD, Cleveland Clinic Independence Family Health Center, 5001 Rockside Road, IN30, Cleveland, OH 44131; baturp@ccf.org.

It is no secret that about half of all pregnancies in the United States are unintended, and that teens have the highest rate of unplanned pregnancy. What’s not so well known is that women in their 40s have the second highest rate.¹

Optimal use of contraception throughout perimenopause is crucial, but finding the right method of birth control for this patient population can be a bit of a balancing act. Long-acting reversible contraceptives (LARCs), such as an intrauterine device or progestin-only implant, are preferred first-line contraceptive options when preventing pregnancy is the primary goal, given their increased efficacy and limited number of contraindications.^2,3 However, women experiencing perimenopausal symptoms often need a combination hormonal contraceptive (CHC)—typically an estrogen-containing pill, a patch, or a vaginal ring—for relief of vasomotor symptoms and cycle control.

Women in their 40s should have access to a full array of options to help improve adherence. However, physicians may be reluctant to prescribe estrogen-containing products for patients who often have a more complex medical history than their younger counterparts, including increased risks for breast cancer, cardiovascular disease, and venous thromboembolism (VTE).

With this in mind, the Centers for Disease Control and Prevention (CDC) has identified medical conditions that may affect the use of the various types of contraceptives by perimenopausal women and issued evidence-based recommendations on the appropriateness of each method using a one-to-4 rating system (TABLE 1).² To help you address the contraceptive needs of such patients, we review the key risk factors, CDC guidelines, and optimal choices in the 4 case studies that follow.

CASE 1 › Sara G: VTE risk 

Sara G, a healthy 45-year-old, recently started dating again following her divorce. She wants to avoid pregnancy. She has no personal or family history of clotting disorders and does not smoke. However, she is obese (body mass index [BMI]=32 kg/m²), and her job as a visiting nurse requires her to spend most of the day in her car. Ms. G also has acne and wants an estrogen-containing contraceptive to help treat it.

If Ms. G were your patient, what would you offer her?

The risk for VTE increases substantially for women older than 40 years. In a recent cohort study, those ages 45 to 49 faced approximately twice the risk of women ages 25 to 29. However, the absolute risk for the older women was still low (4.7-5.3 per 10,000 woman-years).⁴ What’s more, the risk of VTE from the use of a CHC is substantially less than the risk associated with pregnancy and the postpartum period (TABLE 2).⁵

Obesity increases the risk. Women like Ms. G who are obese (BMI >30) have an increased risk for VTE associated with CHCs, but the CDC rates them as a Category 2 risk, even for obese women in their 40s—a determination that the advantages outweigh the risks.²

Progestin choice and estrogen dose matter. Combination oral contraceptives (COCs) that contain certain third-generation progestins (gestodene and desogestrel) may be more thrombophilic than those containing first- or second-generation progestins (TABLE 3).⁶ The relative risk (RR) for VTE with third-generation vs second-generation progestins is 1.3 (95% confidence interval [CI], 1.0-1.8).⁷ Formulations containing higher doses of estrogen are also more likely to be associated with VTE.⁷

Drospirenone is a newer progestin. Found in several COCs, drospirenone has antimineralocorticoid properties that help to minimize bloating and fluid retention but may also lead to a hypercoagulable state.⁵ Numerous studies have investigated the association between drospirenone and VTE risk, with conflicting results.⁸ Most recently, a large international prospective observational study involving more than 85,000 women showed no increased risk for VTE among women taking COCs with drospirenone compared with pills that do not contain this progestin.⁹

Non-oral CHCs, including the vaginal ring and the patch, offer the convenience of weekly or monthly use while providing similar benefits to COCs. Some fear that the continuous exposure to hormones associated with these methods may increase the risk for VTE, but evidence is mixed.

A large (N=1.6 million) Danish registry study published in 2012 demonstrated a 2-fold increased risk of VTE among vaginal ring users vs women taking COCs.⁴ But a multinational prospective cohort study of more than 33,000 women found no increased VTE risk in ring users,10 and a recent US database study involving more than 800,000 women reported nonsignificant VTE risk estimates for both the ring (RR=1.09; 95% CI, 0.55-2.16) and the patch (RR=1.35; 95% CI, 0.90-2.02) compared with COCs.¹¹

THE BOTTOM LINE For Ms. G, the benefits of contraception likely outweigh any small increase in her absolute risk for VTE. To minimize her risk, however, select a pill that contains a low dose (20-35 mcg) of ethinyl estradiol (EE) combined with a progestin that has not been associated with an increased VTE risk. Because of their mechanism of action, most COCs will improve acne, regardless of the progestin in the formulation.^12-14

CASE 2 › Stephanie T: CV risk

Stephanie T, 47, is in need of contraception and treatment for severe hot flashes. She has no significant past medical history, but she is obese (BMI =36), her blood pressure (BP) is 130/80 mm Hg, and her most recent labs reveal a fasting glucose of 115 and a hemoglobin A1c of 6.1%. Ms. T is concerned about arterial thromboembolic disease because of her family history: Her father had a myocardial infarction (MI) at age 56 and a maternal aunt had a stroke when she was 65.

What evidence should you consider?

Baseline arterial thromboembolic events are considerably more rare in premenopausal women than VTEs (13.2 MIs vs 24.2 thrombotic strokes per 100,000 woman-years).¹⁵ Thus, a small increased RR from a CHC is unlikely to have a significant clinical impact.

Some third-generation progestins appear to be more thrombophilic than firs tor second-generation progestins.

A systemic review and meta-analysis of studies between 1995 and 2012 showed that the odds ratio (OR) of ischemic stroke in users of COCs vs nonusers was 1.9 (95% CI, 1.24–2.91).¹⁶ This study included very few estrogen formulations with <35 mcg EE, however; even so, no increased risk of MI was found (OR=1.34; 95% CI, 0.87–2.08).¹⁶ A 15-year retrospective cohort study of 1.6 million Danish women showed that lowering the dose of EE to 20 mcg (from 30-40 mcg) significantly reduced the risk of arterial events.¹⁵ It is unclear whether the vaginal ring is associated with an increased RR of stroke compared with COCs because studies have had mixed results.^10,15 There is no compelling evidence to suggest a difference in the risk of arterial events based on the type of progestin used in the COC.¹⁵

Hypertension is a key consideration. It is important to remember that perimenopausal women may have comorbid conditions that increase their risk of arterial thromboembolic events. CHCs should be used with caution in women with hypertension, even if BP is adequately controlled—a Category 3 recommendation from the CDC. In such patients, LARC or a progestin-only pill is preferred unless there is a compelling reason to use a CHC, such as acne, vasomotor symptoms, or hirsutism.²

CHCs are contraindicated for women with a BP ≥160/100 mm Hg and/or any manifestation of vascular disease (Category 4).² Although progestin-only methods are often preferred for women with established vascular disease, depot medroxyprogesterone acetate (DMPA) is an exception (Category 3).² DMPA is not a first-line choice for such patients because of its potential to cause weight gain and worsening lipids, glucose, and insulin metabolism. Women with hypertriglyceridemia should have follow-up testing of lipid levels after initiation of hormonal contraception, especially if it contains estrogen.

Diabetes is not an absolute contraindication. Many women with diabetes can safely use CHCs (Category 2). The exceptions: those who have vascular disease, nephropathy, retinopathy, or neuropathy (Category 4) or have had diabetes for >20 years and therefore have the potential for undiagnosed vascular disease.² Generally, the use of insulin should not affect decisions regarding CHCs, and patients can be reassured that the hormones will not worsen their diabetes control.

When caring for women who have multiple risk factors for cardiovascular disease, it is important to exercise clinical judgment regarding the appropriateness of CHCs (Categories 3 and 4). Progestin-only methods have a more favorable risk profile for women at the highest risk and may provide ample relief of perimenopausal symptoms.²

THE BOTTOM LINE Ms. T may benefit from a CHC due to her severe hot flashes. She should be encouraged to adopt healthy lifestyle changes, including diet and exercise, to decrease her risk of arterial thromboembolism and VTE, but she has no contraindications to the use of a CHC at this time.

CASE 3 › Leslie C: Bone health

Leslie C, age 45, is happy with the contraceptive he has used for the past 3 years—DMPA injections every 3 months. She has no perimenopausal symptoms. However, her mother had an osteoporotic hip fracture at age 70 and Ms. C is concerned about the long-term use of DMPA.

Should Ms. C be worried?

Because of DMPA’s association with bone loss, the US Food and Drug Administration issued a black box warning in 2004 recommending that this method be used for more than 2 years only by women for whom other birth control methods are deemed inappropriate.¹⁷

Bone loss associated with longer-term use of DMPA is a greater concern for perimenopausal women because they have fewer years to recover the bone mineral density after discontinuing the contraceptive.

The bone loss may be reversed. Evidence suggests that the bone loss is reversible, however, and the American College of Obstetricians and Gynecologists has stated that a potential fracture risk need not limit a woman’s use of DMPA to 2 years.¹⁸ A retrospective cohort review of 312,295 women in the United Kingdom did not find evidence of an increased risk of fracture with long-term use of DMPA.¹⁹ It is important to note, however, that because of declining estrogen levels, perimenopausal women have fewer years than their younger counterparts to recover bone density upon discontinuation of DMPA.^20,21

THE BOTTOM LINE Because Ms. C has no perimenopausal symptoms, she may do well with LARC, which—like DMPA —would free her of the need to remember to take, apply, or insert a contraceptive regularly. It may help to point out that LARCs provide superior contraceptive efficacy compared with DMPA injections (99% vs 94%).³ Nonetheless, she and other women in their 40s who need ongoing contraception should not be discouraged from using DMPA if that is their preference.

CASE 4 › Alissa B: Breast cancer risk

Alissa B, 49, has polycystic ovaries and wonders if it is safe for her to continue her COC. She has been happy with the treatment for years because it gives her relief from hot flashes and regulates her cycles. Her 46-year-old sister was recently diagnosed with invasive breast cancer, however, and Ms. B is afraid that the hormones she takes put her at increased risk.

Should you recommend another method?

Breast cancer is an important concern for many women as they age. Although Ms. B’s family history increases her risk for developing breast cancer, a systematic review indicates that COCs do not add to this risk.²²

Weak association between family history and OC use. The review included 10 observational studies and one meta-analysis that investigated the association between COC use and breast cancer in women with a family history of the disease. Only 2 fair-quality studies showed an association, one of which included women who had begun taking the pill before 1975, when formulations typically contained higher doses of estrogen than present-day preparations.²²

The lower doses of estrogen in today’s combination oral contraceptives do not appear to significantly increase the risk of breast cancer.

Data from a recently published meta-analysis also indicate that there is no increased risk for breast cancer from COCs among women with BRCA 1 or BRCA 2 mutations. The summary RR for breast cancer in such patients was 1.13 (95% CI, 0.88-1.45), but OC users had a lower risk for ovarian cancer (summary RR=0.50; 95% CI, 0.33-0.75).²³ Additionally, investigators found no association between specific currently used COC formulations and breast cancer.²⁴

THE BOTTOM LINE Based on an independent review of the evidence, the CDC has given a family history of breast cancer a Category 1 rating. Thus, Ms. B can be reassured that she may safely continue taking her COC, which is unlikely to increase her breast cancer risk.

CORRESPONDENCE
Pelin Batur, MD, NCMP, CCD, Cleveland Clinic Independence Family Health Center, 5001 Rockside Road, IN30, Cleveland, OH 44131; baturp@ccf.org.

No. According to 2013 guidelines of the US Centers for Disease Control and Prevention (CDC),¹ there is little evidence of benefit for many of the tests commonly mandated by healthcare providers before prescribing hormonal contraception (pill, ring, patch). These tests include breast and pelvic examinations, screening for cervical and sexually transmitted infections, laboratory testing, and mammography.

Only a medical history and blood pressure measurement are needed before prescribing estrogen-containing contraceptives. Patients who have elevated blood pressure but have not been previously diagnosed with hypertension should be preferentially offered other forms of contraception to avoid an additional risk of stroke or myocardial infarction, such as progestin-only products and intrauterine devices (IUDs). Women with blood pressures between 140/90 and 160/100 mm Hg may use estrogen-containing contraceptives only if other options are not appropriate. The CDC guidelines further state that if a patient is unable to come to the office for blood pressure assessment, then a community reading reported by the patient may be used to guide decision-making.

IS A PELVIC EXAMINATION NEEDED?

A pelvic examination (cervical inspection and bimanual examination) will not affect decisions related to prescribing contraceptives, except when prescribing female barrier methods (diaphragm, cervical cap) or IUDs.

Based on a systematic review of the literature between 1946 and 2014, the American College of Physicians now recommends against a screening pelvic examination in asymptomatic, nonpregnant, adult women when a Papanicolaou test is not otherwise indicated.²

The American College of Obstetricians and Gynecologists (ACOG) acknowledges that no current scientific evidence supports or refutes the need for an annual pelvic examination for an asymptomatic, low-risk patient. But ACOG supports pelvic examinations as a way to establish open communication with patients about sexual health and reproduction.³ ACOG also recommends an annual health visit for all women. Whether or not a pelvic examination is performed, women should be counseled annually about birth control and offered contraception.

Patients should also be encouraged to keep their preventive care up-to-date, including cervical cancer screening with a Papanicolaou test or a human papillomavirus test (or both) at appropriate intervals, especially if the patient has cervical abnormalities requiring follow-up. However, falling behind on preventive care should not be a barrier to obtaining contraception.

IMPROVING ADHERENCE, DECREASING UNINTENDED PREGNANCY

One goal of the CDC’s 2013 guidelines was to remove unnecessary barriers to women’s access to contraceptives. In the United States, half of all pregnancies are unintended, and almost half of unintended pregnancies lead to abortion.⁴ Only half of women who have had an abortion used any contraceptive method within the last month.⁵ This suggests high levels of unprotected and underprotected sex.

For most patients, several national societies now recommend long-acting reversible contraceptive (LARC) methods, which include IUDs and progestin-only arm implants, because they have lower failure rates in a real-world setting.^1,6,7 LARC methods offer the advantage of the patient’s not having to remember to take, apply, or insert the contraceptive (ie, they are worry-free), and of not having to rely on a yearly appointment for refills.

Emergency contraception taken orally should be offered without an office visit

The Contraceptive CHOICE Project⁸ was a large prospective cohort study that assessed the impact of offering contraception free of charge in St. Louis, Missouri. Most of the 9,256 women who participated selected a LARC method.⁸ Those taking combined hormonal contraceptives (ie, birth control pill, patch, or ring) had a higher contraceptive failure rate than those using LARC methods (4.55 vs 0.27 per 100 participant-years; hazard ratio after adjustment for age, education, and unintended pregnancy history, 21.8; 95% confidence interval 13.7–34.9). The rate of unintended pregnancy in those under age 21 using combined hormonal contraceptives was almost twice as high as in older participants. Subsequent analyses showed that the abortion rates in the St. Louis region decreased to less than a quarter of the national average after the start of this project.⁹

Given that the failure rate with combined hormonal contraceptives averages 9% per year,¹ it is of the utmost importance that providers not limit access to patients’ prescriptions by requesting unnecessary visits and tests. If oral contraception is selected, women who are dispensed a full year’s supply of pill packs are more likely to continue with their contraceptive in the long term.¹⁰

THE PATIENT WITH A COMPLEX MEDICAL HISTORY

Limiting a woman’s contraceptive choices can increase her odds of experiencing an unintended pregnancy, which is associated with a far greater risk of adverse events than any contraceptive.¹¹ Thus, the CDC developed separate guidelines in 2010 to help determine all available options for the patient with medical comorbidities and with a concerning family history (ie, breast cancer, venous thromboembolism).¹² It can be helpful to consult the 2010 CDC medical eligibility criteria before offering contraception to these patients. Compared with the 2013 guidelines, which provide practical advice on how to use each contraceptive, the 2010 guidelines give guidance on when it is appropriate to prescribe each contraceptive—eg, which contraceptives are preferred based on a patient’s risk factors, medical history, and medication use. In addition to a two-page color summary chart of the 2010 medical eligibility criteria on the CDC website (https://www.cdc.gov/reproductivehealth/unintendedpregnancy/pdf/legal_summary-chart_english_final_tag508.pdf), a free mobile app is also available to guide decision-making.¹³

Pregnancy should be ruled out before initiating any contraceptive. This can be done through a detailed history. The six-item checklist in Table 1 has a 99.8% negative predictive value, so healthcare providers may be confident that a woman is not pregnant if pregnancy is excluded based on this history.¹⁴ A pregnancy test is needed in those who test positive on the checklist if they wish to start a LARC method such as an IUD or a progestin-only arm implant. However, because the test has a high false-positive rate, initiation of shorter-acting methods such as combined hormonal contraceptives should not be delayed on the basis of a positive checklist screen alone.¹

Emergency contraception taken orally should be offered without an office visit, as its short duration of use allows women with traditional contraindications to hormonal contraceptives to safely use this birth control method.^1,12 Because all emergency contraceptives must be used within 5 days of intercourse (the earlier the better), unnecessary office visits delay access and effectiveness.

Although a levonorgestrel-based emergency contraceptive is available over the counter, ulipristal acetate is more effective, especially in women who are overweight.¹⁵ A copper IUD placed within 5 days of intercourse is the most effective form of emergency contraception¹⁵ but requires an office visit. This method is an option for most women but should be strongly considered for women at highest risk of pregnancy (previous unintended pregnancy, intercourse at midcycle, obesity).

In summary, most women may safely begin their hormonal contraceptive with a detailed medical history alone, without additional office visits, examinations, or screening tests.

No. According to 2013 guidelines of the US Centers for Disease Control and Prevention (CDC),¹ there is little evidence of benefit for many of the tests commonly mandated by healthcare providers before prescribing hormonal contraception (pill, ring, patch). These tests include breast and pelvic examinations, screening for cervical and sexually transmitted infections, laboratory testing, and mammography.

Only a medical history and blood pressure measurement are needed before prescribing estrogen-containing contraceptives. Patients who have elevated blood pressure but have not been previously diagnosed with hypertension should be preferentially offered other forms of contraception to avoid an additional risk of stroke or myocardial infarction, such as progestin-only products and intrauterine devices (IUDs). Women with blood pressures between 140/90 and 160/100 mm Hg may use estrogen-containing contraceptives only if other options are not appropriate. The CDC guidelines further state that if a patient is unable to come to the office for blood pressure assessment, then a community reading reported by the patient may be used to guide decision-making.

IS A PELVIC EXAMINATION NEEDED?

A pelvic examination (cervical inspection and bimanual examination) will not affect decisions related to prescribing contraceptives, except when prescribing female barrier methods (diaphragm, cervical cap) or IUDs.

Based on a systematic review of the literature between 1946 and 2014, the American College of Physicians now recommends against a screening pelvic examination in asymptomatic, nonpregnant, adult women when a Papanicolaou test is not otherwise indicated.²

The American College of Obstetricians and Gynecologists (ACOG) acknowledges that no current scientific evidence supports or refutes the need for an annual pelvic examination for an asymptomatic, low-risk patient. But ACOG supports pelvic examinations as a way to establish open communication with patients about sexual health and reproduction.³ ACOG also recommends an annual health visit for all women. Whether or not a pelvic examination is performed, women should be counseled annually about birth control and offered contraception.

Patients should also be encouraged to keep their preventive care up-to-date, including cervical cancer screening with a Papanicolaou test or a human papillomavirus test (or both) at appropriate intervals, especially if the patient has cervical abnormalities requiring follow-up. However, falling behind on preventive care should not be a barrier to obtaining contraception.

IMPROVING ADHERENCE, DECREASING UNINTENDED PREGNANCY

One goal of the CDC’s 2013 guidelines was to remove unnecessary barriers to women’s access to contraceptives. In the United States, half of all pregnancies are unintended, and almost half of unintended pregnancies lead to abortion.⁴ Only half of women who have had an abortion used any contraceptive method within the last month.⁵ This suggests high levels of unprotected and underprotected sex.

For most patients, several national societies now recommend long-acting reversible contraceptive (LARC) methods, which include IUDs and progestin-only arm implants, because they have lower failure rates in a real-world setting.^1,6,7 LARC methods offer the advantage of the patient’s not having to remember to take, apply, or insert the contraceptive (ie, they are worry-free), and of not having to rely on a yearly appointment for refills.

Emergency contraception taken orally should be offered without an office visit

The Contraceptive CHOICE Project⁸ was a large prospective cohort study that assessed the impact of offering contraception free of charge in St. Louis, Missouri. Most of the 9,256 women who participated selected a LARC method.⁸ Those taking combined hormonal contraceptives (ie, birth control pill, patch, or ring) had a higher contraceptive failure rate than those using LARC methods (4.55 vs 0.27 per 100 participant-years; hazard ratio after adjustment for age, education, and unintended pregnancy history, 21.8; 95% confidence interval 13.7–34.9). The rate of unintended pregnancy in those under age 21 using combined hormonal contraceptives was almost twice as high as in older participants. Subsequent analyses showed that the abortion rates in the St. Louis region decreased to less than a quarter of the national average after the start of this project.⁹

Given that the failure rate with combined hormonal contraceptives averages 9% per year,¹ it is of the utmost importance that providers not limit access to patients’ prescriptions by requesting unnecessary visits and tests. If oral contraception is selected, women who are dispensed a full year’s supply of pill packs are more likely to continue with their contraceptive in the long term.¹⁰

THE PATIENT WITH A COMPLEX MEDICAL HISTORY

Limiting a woman’s contraceptive choices can increase her odds of experiencing an unintended pregnancy, which is associated with a far greater risk of adverse events than any contraceptive.¹¹ Thus, the CDC developed separate guidelines in 2010 to help determine all available options for the patient with medical comorbidities and with a concerning family history (ie, breast cancer, venous thromboembolism).¹² It can be helpful to consult the 2010 CDC medical eligibility criteria before offering contraception to these patients. Compared with the 2013 guidelines, which provide practical advice on how to use each contraceptive, the 2010 guidelines give guidance on when it is appropriate to prescribe each contraceptive—eg, which contraceptives are preferred based on a patient’s risk factors, medical history, and medication use. In addition to a two-page color summary chart of the 2010 medical eligibility criteria on the CDC website (https://www.cdc.gov/reproductivehealth/unintendedpregnancy/pdf/legal_summary-chart_english_final_tag508.pdf), a free mobile app is also available to guide decision-making.¹³

Pregnancy should be ruled out before initiating any contraceptive. This can be done through a detailed history. The six-item checklist in Table 1 has a 99.8% negative predictive value, so healthcare providers may be confident that a woman is not pregnant if pregnancy is excluded based on this history.¹⁴ A pregnancy test is needed in those who test positive on the checklist if they wish to start a LARC method such as an IUD or a progestin-only arm implant. However, because the test has a high false-positive rate, initiation of shorter-acting methods such as combined hormonal contraceptives should not be delayed on the basis of a positive checklist screen alone.¹

Emergency contraception taken orally should be offered without an office visit, as its short duration of use allows women with traditional contraindications to hormonal contraceptives to safely use this birth control method.^1,12 Because all emergency contraceptives must be used within 5 days of intercourse (the earlier the better), unnecessary office visits delay access and effectiveness.

Although a levonorgestrel-based emergency contraceptive is available over the counter, ulipristal acetate is more effective, especially in women who are overweight.¹⁵ A copper IUD placed within 5 days of intercourse is the most effective form of emergency contraception¹⁵ but requires an office visit. This method is an option for most women but should be strongly considered for women at highest risk of pregnancy (previous unintended pregnancy, intercourse at midcycle, obesity).

In summary, most women may safely begin their hormonal contraceptive with a detailed medical history alone, without additional office visits, examinations, or screening tests.

No. According to 2013 guidelines of the US Centers for Disease Control and Prevention (CDC),¹ there is little evidence of benefit for many of the tests commonly mandated by healthcare providers before prescribing hormonal contraception (pill, ring, patch). These tests include breast and pelvic examinations, screening for cervical and sexually transmitted infections, laboratory testing, and mammography.

Only a medical history and blood pressure measurement are needed before prescribing estrogen-containing contraceptives. Patients who have elevated blood pressure but have not been previously diagnosed with hypertension should be preferentially offered other forms of contraception to avoid an additional risk of stroke or myocardial infarction, such as progestin-only products and intrauterine devices (IUDs). Women with blood pressures between 140/90 and 160/100 mm Hg may use estrogen-containing contraceptives only if other options are not appropriate. The CDC guidelines further state that if a patient is unable to come to the office for blood pressure assessment, then a community reading reported by the patient may be used to guide decision-making.

IS A PELVIC EXAMINATION NEEDED?

A pelvic examination (cervical inspection and bimanual examination) will not affect decisions related to prescribing contraceptives, except when prescribing female barrier methods (diaphragm, cervical cap) or IUDs.

Based on a systematic review of the literature between 1946 and 2014, the American College of Physicians now recommends against a screening pelvic examination in asymptomatic, nonpregnant, adult women when a Papanicolaou test is not otherwise indicated.²

The American College of Obstetricians and Gynecologists (ACOG) acknowledges that no current scientific evidence supports or refutes the need for an annual pelvic examination for an asymptomatic, low-risk patient. But ACOG supports pelvic examinations as a way to establish open communication with patients about sexual health and reproduction.³ ACOG also recommends an annual health visit for all women. Whether or not a pelvic examination is performed, women should be counseled annually about birth control and offered contraception.

Patients should also be encouraged to keep their preventive care up-to-date, including cervical cancer screening with a Papanicolaou test or a human papillomavirus test (or both) at appropriate intervals, especially if the patient has cervical abnormalities requiring follow-up. However, falling behind on preventive care should not be a barrier to obtaining contraception.

IMPROVING ADHERENCE, DECREASING UNINTENDED PREGNANCY

One goal of the CDC’s 2013 guidelines was to remove unnecessary barriers to women’s access to contraceptives. In the United States, half of all pregnancies are unintended, and almost half of unintended pregnancies lead to abortion.⁴ Only half of women who have had an abortion used any contraceptive method within the last month.⁵ This suggests high levels of unprotected and underprotected sex.

For most patients, several national societies now recommend long-acting reversible contraceptive (LARC) methods, which include IUDs and progestin-only arm implants, because they have lower failure rates in a real-world setting.^1,6,7 LARC methods offer the advantage of the patient’s not having to remember to take, apply, or insert the contraceptive (ie, they are worry-free), and of not having to rely on a yearly appointment for refills.

Emergency contraception taken orally should be offered without an office visit

The Contraceptive CHOICE Project⁸ was a large prospective cohort study that assessed the impact of offering contraception free of charge in St. Louis, Missouri. Most of the 9,256 women who participated selected a LARC method.⁸ Those taking combined hormonal contraceptives (ie, birth control pill, patch, or ring) had a higher contraceptive failure rate than those using LARC methods (4.55 vs 0.27 per 100 participant-years; hazard ratio after adjustment for age, education, and unintended pregnancy history, 21.8; 95% confidence interval 13.7–34.9). The rate of unintended pregnancy in those under age 21 using combined hormonal contraceptives was almost twice as high as in older participants. Subsequent analyses showed that the abortion rates in the St. Louis region decreased to less than a quarter of the national average after the start of this project.⁹

Given that the failure rate with combined hormonal contraceptives averages 9% per year,¹ it is of the utmost importance that providers not limit access to patients’ prescriptions by requesting unnecessary visits and tests. If oral contraception is selected, women who are dispensed a full year’s supply of pill packs are more likely to continue with their contraceptive in the long term.¹⁰

THE PATIENT WITH A COMPLEX MEDICAL HISTORY

Limiting a woman’s contraceptive choices can increase her odds of experiencing an unintended pregnancy, which is associated with a far greater risk of adverse events than any contraceptive.¹¹ Thus, the CDC developed separate guidelines in 2010 to help determine all available options for the patient with medical comorbidities and with a concerning family history (ie, breast cancer, venous thromboembolism).¹² It can be helpful to consult the 2010 CDC medical eligibility criteria before offering contraception to these patients. Compared with the 2013 guidelines, which provide practical advice on how to use each contraceptive, the 2010 guidelines give guidance on when it is appropriate to prescribe each contraceptive—eg, which contraceptives are preferred based on a patient’s risk factors, medical history, and medication use. In addition to a two-page color summary chart of the 2010 medical eligibility criteria on the CDC website (https://www.cdc.gov/reproductivehealth/unintendedpregnancy/pdf/legal_summary-chart_english_final_tag508.pdf), a free mobile app is also available to guide decision-making.¹³

Pregnancy should be ruled out before initiating any contraceptive. This can be done through a detailed history. The six-item checklist in Table 1 has a 99.8% negative predictive value, so healthcare providers may be confident that a woman is not pregnant if pregnancy is excluded based on this history.¹⁴ A pregnancy test is needed in those who test positive on the checklist if they wish to start a LARC method such as an IUD or a progestin-only arm implant. However, because the test has a high false-positive rate, initiation of shorter-acting methods such as combined hormonal contraceptives should not be delayed on the basis of a positive checklist screen alone.¹

Emergency contraception taken orally should be offered without an office visit, as its short duration of use allows women with traditional contraindications to hormonal contraceptives to safely use this birth control method.^1,12 Because all emergency contraceptives must be used within 5 days of intercourse (the earlier the better), unnecessary office visits delay access and effectiveness.

Although a levonorgestrel-based emergency contraceptive is available over the counter, ulipristal acetate is more effective, especially in women who are overweight.¹⁵ A copper IUD placed within 5 days of intercourse is the most effective form of emergency contraception¹⁵ but requires an office visit. This method is an option for most women but should be strongly considered for women at highest risk of pregnancy (previous unintended pregnancy, intercourse at midcycle, obesity).

In summary, most women may safely begin their hormonal contraceptive with a detailed medical history alone, without additional office visits, examinations, or screening tests.