Expert Commentary

EXPERT COMMENTARY

Pregnancy management when delivery appears to be imminent at 22 to 26 weeks’ gestation—a window defined as the periviable period—is among the most challenging situations that obstetricians face. Expert guidance exists both at a national level in a shared guideline from the American College of Obstetricians and Gynecologists and the Society of Maternal Fetal Medicine and, ideally, at a local level where teams of obstetricians and neonatologists have considered in their facility what represents best care.¹ But whether national or local, such consensus is largely expert opinion based on a foundation limited by available evidence, which is almost always retrospective analysis of rare cases.

Among the most important yet often missing data points are outcomes of neonates born in the periviable period. Surveys suggest that obstetric care providers often underestimate the chance of survival following periviable delivery.² Understanding and weighing anticipated outcomes inform decision making regarding management and planned obstetric and neonatal interventions, including plans for neonatal resuscitation.

Not surprisingly, perhaps, survival of periviable neonates has been linked clearly to willingness to undertake resuscitation.³ Yet decisions are not and should not be all about survival. Patients and providers want to know about short- and long-term morbidity, especially neurologic health, among survivors. Available collections of morbidity and mortality data, however, often are limited by whether all cases are captured or just those from specialized centers with particular management approaches, which outcomes are included and how they are defined, and the inevitable reality that the outcome of death “competes” with the outcome of neurologic development (that is, those neonates who die are not at risk for later abnormal neurologic outcome).

Given the need for more and better information, the data from a recent study by Younge and colleagues is especially welcome. The investigators reported on survival and neurologic outcome among more than 4,000 births between 22 and 24 weeks’ gestation at 11 centers in the United States.

Details of the study

The authors compared outcomes among three 3-year epochs between 2000 and 2011 and reported that the rate of survival without neurodevelopmental impairment increased over this period while the rate of survival with such impairment did not change. This argues that the observed overall increase in survival over these 12 years was not simply a tradeoff for life with significant impairment.

Within that overall message, however, the details of the data are important. Survival without neurodevelopmental impairment did improve from epoch 1 to epoch 3, but just from 16% to 20% (95% confidence interval [CI], 18–23; P = .001). Most neonates in the 2008–2011 epoch died (64%; 95% CI, 61–66; P<.001) or were severely impaired (16%; 95% CI, 14–18; P = .29). This led the authors to conclude that “despite improvements over time, the incidence of death, neurodevelopmental impairment, and other adverse outcomes remains high.” Examined separately, outcomes for infants born at 22 0/7 to 22 6/7 weeks’ gestation were very limited and unchanged over the 3 epochs studied, with death rates of 97% to 98% and survival without neurodevelopmental impairment of just 1%. In my own practice I do not encourage neonatal resuscitation, cesarean delivery, or many other interventions at less than 23 weeks’ gestation.

By contrast, the study showed that at 24 0/7 to 24 6/7 weeks’ gestation in the 2008–2011 epoch, 55% of neonates survived and, overall, 32% of infants survived without evidence of neurodevelopmental impairment at 18 to 22 months of age.

Related Article:
Is expectant management a safe alternative to immediate delivery in patients with PPROM close to term?

Study strengths and weaknesses

It is important to note that the definition of neurodevelopmental impairment used in the Younge study included only what many would classify as severe impairment, and survivors in this cohort “without” neurodevelopmental impairment may still have had important neurologic and other health concerns. In addition, the study did not track outcomes of the children at school age or beyond, when other developmental issues may become evident. As well, the study data may not be generalizable, for it included births from just 11 specialized centers, albeit a consortium accounting for 4% to 5% of periviable births in the United States.

Nevertheless, in supporting findings from other US and European analyses, these new data will help inform counseling conversations in the years to come. Such conversations should consider options for resuscitation, palliative care, and, at less than 24 weeks’ gestation, pregnancy termination. In individual cases these and many other decisions will be informed by both specific clinical circumstances—estimated fetal weight, fetal sex, presence of infection, use of antenatal steroids—and, perhaps most important, individual and family values and preferences. Despite these new data, managing periviable gestations will remain a great and important challenge.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

EXPERT COMMENTARY

Pregnancy management when delivery appears to be imminent at 22 to 26 weeks’ gestation—a window defined as the periviable period—is among the most challenging situations that obstetricians face. Expert guidance exists both at a national level in a shared guideline from the American College of Obstetricians and Gynecologists and the Society of Maternal Fetal Medicine and, ideally, at a local level where teams of obstetricians and neonatologists have considered in their facility what represents best care.¹ But whether national or local, such consensus is largely expert opinion based on a foundation limited by available evidence, which is almost always retrospective analysis of rare cases.

Among the most important yet often missing data points are outcomes of neonates born in the periviable period. Surveys suggest that obstetric care providers often underestimate the chance of survival following periviable delivery.² Understanding and weighing anticipated outcomes inform decision making regarding management and planned obstetric and neonatal interventions, including plans for neonatal resuscitation.

Not surprisingly, perhaps, survival of periviable neonates has been linked clearly to willingness to undertake resuscitation.³ Yet decisions are not and should not be all about survival. Patients and providers want to know about short- and long-term morbidity, especially neurologic health, among survivors. Available collections of morbidity and mortality data, however, often are limited by whether all cases are captured or just those from specialized centers with particular management approaches, which outcomes are included and how they are defined, and the inevitable reality that the outcome of death “competes” with the outcome of neurologic development (that is, those neonates who die are not at risk for later abnormal neurologic outcome).

Given the need for more and better information, the data from a recent study by Younge and colleagues is especially welcome. The investigators reported on survival and neurologic outcome among more than 4,000 births between 22 and 24 weeks’ gestation at 11 centers in the United States.

Details of the study

The authors compared outcomes among three 3-year epochs between 2000 and 2011 and reported that the rate of survival without neurodevelopmental impairment increased over this period while the rate of survival with such impairment did not change. This argues that the observed overall increase in survival over these 12 years was not simply a tradeoff for life with significant impairment.

Within that overall message, however, the details of the data are important. Survival without neurodevelopmental impairment did improve from epoch 1 to epoch 3, but just from 16% to 20% (95% confidence interval [CI], 18–23; P = .001). Most neonates in the 2008–2011 epoch died (64%; 95% CI, 61–66; P<.001) or were severely impaired (16%; 95% CI, 14–18; P = .29). This led the authors to conclude that “despite improvements over time, the incidence of death, neurodevelopmental impairment, and other adverse outcomes remains high.” Examined separately, outcomes for infants born at 22 0/7 to 22 6/7 weeks’ gestation were very limited and unchanged over the 3 epochs studied, with death rates of 97% to 98% and survival without neurodevelopmental impairment of just 1%. In my own practice I do not encourage neonatal resuscitation, cesarean delivery, or many other interventions at less than 23 weeks’ gestation.

By contrast, the study showed that at 24 0/7 to 24 6/7 weeks’ gestation in the 2008–2011 epoch, 55% of neonates survived and, overall, 32% of infants survived without evidence of neurodevelopmental impairment at 18 to 22 months of age.

Related Article:
Is expectant management a safe alternative to immediate delivery in patients with PPROM close to term?

Study strengths and weaknesses

It is important to note that the definition of neurodevelopmental impairment used in the Younge study included only what many would classify as severe impairment, and survivors in this cohort “without” neurodevelopmental impairment may still have had important neurologic and other health concerns. In addition, the study did not track outcomes of the children at school age or beyond, when other developmental issues may become evident. As well, the study data may not be generalizable, for it included births from just 11 specialized centers, albeit a consortium accounting for 4% to 5% of periviable births in the United States.

Nevertheless, in supporting findings from other US and European analyses, these new data will help inform counseling conversations in the years to come. Such conversations should consider options for resuscitation, palliative care, and, at less than 24 weeks’ gestation, pregnancy termination. In individual cases these and many other decisions will be informed by both specific clinical circumstances—estimated fetal weight, fetal sex, presence of infection, use of antenatal steroids—and, perhaps most important, individual and family values and preferences. Despite these new data, managing periviable gestations will remain a great and important challenge.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

EXPERT COMMENTARY

Pregnancy management when delivery appears to be imminent at 22 to 26 weeks’ gestation—a window defined as the periviable period—is among the most challenging situations that obstetricians face. Expert guidance exists both at a national level in a shared guideline from the American College of Obstetricians and Gynecologists and the Society of Maternal Fetal Medicine and, ideally, at a local level where teams of obstetricians and neonatologists have considered in their facility what represents best care.¹ But whether national or local, such consensus is largely expert opinion based on a foundation limited by available evidence, which is almost always retrospective analysis of rare cases.

Among the most important yet often missing data points are outcomes of neonates born in the periviable period. Surveys suggest that obstetric care providers often underestimate the chance of survival following periviable delivery.² Understanding and weighing anticipated outcomes inform decision making regarding management and planned obstetric and neonatal interventions, including plans for neonatal resuscitation.

Not surprisingly, perhaps, survival of periviable neonates has been linked clearly to willingness to undertake resuscitation.³ Yet decisions are not and should not be all about survival. Patients and providers want to know about short- and long-term morbidity, especially neurologic health, among survivors. Available collections of morbidity and mortality data, however, often are limited by whether all cases are captured or just those from specialized centers with particular management approaches, which outcomes are included and how they are defined, and the inevitable reality that the outcome of death “competes” with the outcome of neurologic development (that is, those neonates who die are not at risk for later abnormal neurologic outcome).

Given the need for more and better information, the data from a recent study by Younge and colleagues is especially welcome. The investigators reported on survival and neurologic outcome among more than 4,000 births between 22 and 24 weeks’ gestation at 11 centers in the United States.

Details of the study

The authors compared outcomes among three 3-year epochs between 2000 and 2011 and reported that the rate of survival without neurodevelopmental impairment increased over this period while the rate of survival with such impairment did not change. This argues that the observed overall increase in survival over these 12 years was not simply a tradeoff for life with significant impairment.

Within that overall message, however, the details of the data are important. Survival without neurodevelopmental impairment did improve from epoch 1 to epoch 3, but just from 16% to 20% (95% confidence interval [CI], 18–23; P = .001). Most neonates in the 2008–2011 epoch died (64%; 95% CI, 61–66; P<.001) or were severely impaired (16%; 95% CI, 14–18; P = .29). This led the authors to conclude that “despite improvements over time, the incidence of death, neurodevelopmental impairment, and other adverse outcomes remains high.” Examined separately, outcomes for infants born at 22 0/7 to 22 6/7 weeks’ gestation were very limited and unchanged over the 3 epochs studied, with death rates of 97% to 98% and survival without neurodevelopmental impairment of just 1%. In my own practice I do not encourage neonatal resuscitation, cesarean delivery, or many other interventions at less than 23 weeks’ gestation.

By contrast, the study showed that at 24 0/7 to 24 6/7 weeks’ gestation in the 2008–2011 epoch, 55% of neonates survived and, overall, 32% of infants survived without evidence of neurodevelopmental impairment at 18 to 22 months of age.

Related Article:
Is expectant management a safe alternative to immediate delivery in patients with PPROM close to term?

Study strengths and weaknesses

It is important to note that the definition of neurodevelopmental impairment used in the Younge study included only what many would classify as severe impairment, and survivors in this cohort “without” neurodevelopmental impairment may still have had important neurologic and other health concerns. In addition, the study did not track outcomes of the children at school age or beyond, when other developmental issues may become evident. As well, the study data may not be generalizable, for it included births from just 11 specialized centers, albeit a consortium accounting for 4% to 5% of periviable births in the United States.

Nevertheless, in supporting findings from other US and European analyses, these new data will help inform counseling conversations in the years to come. Such conversations should consider options for resuscitation, palliative care, and, at less than 24 weeks’ gestation, pregnancy termination. In individual cases these and many other decisions will be informed by both specific clinical circumstances—estimated fetal weight, fetal sex, presence of infection, use of antenatal steroids—and, perhaps most important, individual and family values and preferences. Despite these new data, managing periviable gestations will remain a great and important challenge.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

EXPERT COMMENTARY

Care of women with pelvic floor disorders, primarily urinary incontinence and POP, involves:

• assessing the patient’s symptoms and determining how bothersome they are
• educating the patient about her condition and the options for treatment
• initiating treatment with the most conservative and least invasive therapies.

Safe treatments include PFMT and pessaries, and both can be effective. However, since approximately 25% of women experience one or more pelvic floor disorders during their life, surgical repair of these disorders is common. The lifetime risk of surgery for stress urinary incontinence (SUI) or POP is 20%,¹ and one-third of patients will undergo reoperation for the same condition. Midurethral mesh slings are the gold standard for surgical management of SUI.² Use of transvaginal mesh for primary prolapse repairs, however, is associated with challenging adverse effects, and its use should be reserved for carefully selected patients.

Data from 3 recent studies contribute to our evidence base on various treatments for pelvic floor disorders.

Details of the studies

PFMT for secondary prevention of POP. In a study conducted in the United Kingdom and New Zealand, Hagen and colleagues randomly assigned 414 women with POP, with or without symptoms, to an intervention group or a control group. The women had previously participated in a longitudinal study of postpartum pelvic floor function. Participants in the intervention group (n = 207) received 5 formal sessions of PFMT over 16 weeks, followed by Pilates-based classes focused on pelvic floor exercises; those in the control group (n = 207) received an informational leaflet about prolapse and lifestyle. The primary outcome was self-reported prolapse symptoms, assessed with the POP Symptom Score (POP-SS) at 2 years.

At study end, the mean (SD) POP-SS score in the intervention group was 3.2 (3.4), compared with a mean (SD) score of 4.2 (4.4) in the control group (adjusted mean difference, −1.01; 95% confidence interval [CI], −1.70 to −0.33; P = .004).

Investigators’ interpretation. The researchers concluded that the participants in the PFMT group had a small but significant—and clinically important—decrease in prolapse symptoms.

The PROSPECT study: Standard versus augmented surgical repair. In a multicenter trial in the United Kingdom by Glazener and associates, 1,352 women with symptomatic POP were randomly allocated to surgical repair with native tissue alone (standard repair) or to standard surgical repair augmented either with polypropylene mesh or with biological graft. The primary outcomes were participant-reported prolapse symptoms (assessed with POP-SS) and prolapse-related quality of life scores; these were measured at 1 year and at 2 years.

One year after surgery, failure rates (defined as prolapse beyond the hymen) were similar in all groups (range, 14%–18%); serious adverse events were also similar in all surgical groups (range, 6%–10%). Overall, 6% of women underwent reoperation for recurrent symptoms. Among women randomly assigned to repair with mesh, 12% to 14% experienced mesh-related adverse events; three-quarters of these women ultimately required surgical excision of the mesh.

Study takeaway. Thus, in terms of effectiveness, quality of life, and adverse effects, augmentation of a vaginal surgical repair with either mesh or graft material did not improve the outcomes of women with POP.

Adverse events after surgical procedures for pelvic floor disorders. In Scotland, Morling and colleagues performed a retrospective observational cohort study of first-time surgeries for SUI (mesh or colposuspension; 16,660 procedures) and prolapse (mesh or native tissue; 18,986 procedures).

After 5 years of follow-up, women who underwent midurethral mesh sling placement or colposuspension had similar rates of repeat surgery for recurrent SUI (adjusted incidence rate ratio, 0.90; 95% CI, 0.73–1.11). Use of mesh slings was associated with fewer immediate complications (adjusted relative risk, 0.44; 95% CI, 0.36–0.55) compared with nonmesh surgery.

Among women who underwent surgery for prolapse, those who had anterior and posterior repair with mesh experienced higher late complication rates than those who underwent native tissue repair. Risk for subsequent prolapse repair was similar with mesh and native-tissue procedures.

Authors’ commentary. The researchers noted that their data support the use of mesh procedures for incontinence but additional research on longer-term outcomes would be useful. However, for prolapse repair, the study results do not decidedly favor any one vault repair procedure.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

EXPERT COMMENTARY

Care of women with pelvic floor disorders, primarily urinary incontinence and POP, involves:

• assessing the patient’s symptoms and determining how bothersome they are
• educating the patient about her condition and the options for treatment
• initiating treatment with the most conservative and least invasive therapies.

Safe treatments include PFMT and pessaries, and both can be effective. However, since approximately 25% of women experience one or more pelvic floor disorders during their life, surgical repair of these disorders is common. The lifetime risk of surgery for stress urinary incontinence (SUI) or POP is 20%,¹ and one-third of patients will undergo reoperation for the same condition. Midurethral mesh slings are the gold standard for surgical management of SUI.² Use of transvaginal mesh for primary prolapse repairs, however, is associated with challenging adverse effects, and its use should be reserved for carefully selected patients.

Data from 3 recent studies contribute to our evidence base on various treatments for pelvic floor disorders.

Details of the studies

PFMT for secondary prevention of POP. In a study conducted in the United Kingdom and New Zealand, Hagen and colleagues randomly assigned 414 women with POP, with or without symptoms, to an intervention group or a control group. The women had previously participated in a longitudinal study of postpartum pelvic floor function. Participants in the intervention group (n = 207) received 5 formal sessions of PFMT over 16 weeks, followed by Pilates-based classes focused on pelvic floor exercises; those in the control group (n = 207) received an informational leaflet about prolapse and lifestyle. The primary outcome was self-reported prolapse symptoms, assessed with the POP Symptom Score (POP-SS) at 2 years.

At study end, the mean (SD) POP-SS score in the intervention group was 3.2 (3.4), compared with a mean (SD) score of 4.2 (4.4) in the control group (adjusted mean difference, −1.01; 95% confidence interval [CI], −1.70 to −0.33; P = .004).

Investigators’ interpretation. The researchers concluded that the participants in the PFMT group had a small but significant—and clinically important—decrease in prolapse symptoms.

The PROSPECT study: Standard versus augmented surgical repair. In a multicenter trial in the United Kingdom by Glazener and associates, 1,352 women with symptomatic POP were randomly allocated to surgical repair with native tissue alone (standard repair) or to standard surgical repair augmented either with polypropylene mesh or with biological graft. The primary outcomes were participant-reported prolapse symptoms (assessed with POP-SS) and prolapse-related quality of life scores; these were measured at 1 year and at 2 years.

One year after surgery, failure rates (defined as prolapse beyond the hymen) were similar in all groups (range, 14%–18%); serious adverse events were also similar in all surgical groups (range, 6%–10%). Overall, 6% of women underwent reoperation for recurrent symptoms. Among women randomly assigned to repair with mesh, 12% to 14% experienced mesh-related adverse events; three-quarters of these women ultimately required surgical excision of the mesh.

Study takeaway. Thus, in terms of effectiveness, quality of life, and adverse effects, augmentation of a vaginal surgical repair with either mesh or graft material did not improve the outcomes of women with POP.

Adverse events after surgical procedures for pelvic floor disorders. In Scotland, Morling and colleagues performed a retrospective observational cohort study of first-time surgeries for SUI (mesh or colposuspension; 16,660 procedures) and prolapse (mesh or native tissue; 18,986 procedures).

After 5 years of follow-up, women who underwent midurethral mesh sling placement or colposuspension had similar rates of repeat surgery for recurrent SUI (adjusted incidence rate ratio, 0.90; 95% CI, 0.73–1.11). Use of mesh slings was associated with fewer immediate complications (adjusted relative risk, 0.44; 95% CI, 0.36–0.55) compared with nonmesh surgery.

Among women who underwent surgery for prolapse, those who had anterior and posterior repair with mesh experienced higher late complication rates than those who underwent native tissue repair. Risk for subsequent prolapse repair was similar with mesh and native-tissue procedures.

Authors’ commentary. The researchers noted that their data support the use of mesh procedures for incontinence but additional research on longer-term outcomes would be useful. However, for prolapse repair, the study results do not decidedly favor any one vault repair procedure.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

EXPERT COMMENTARY

Care of women with pelvic floor disorders, primarily urinary incontinence and POP, involves:

• assessing the patient’s symptoms and determining how bothersome they are
• educating the patient about her condition and the options for treatment
• initiating treatment with the most conservative and least invasive therapies.

Safe treatments include PFMT and pessaries, and both can be effective. However, since approximately 25% of women experience one or more pelvic floor disorders during their life, surgical repair of these disorders is common. The lifetime risk of surgery for stress urinary incontinence (SUI) or POP is 20%,¹ and one-third of patients will undergo reoperation for the same condition. Midurethral mesh slings are the gold standard for surgical management of SUI.² Use of transvaginal mesh for primary prolapse repairs, however, is associated with challenging adverse effects, and its use should be reserved for carefully selected patients.

Data from 3 recent studies contribute to our evidence base on various treatments for pelvic floor disorders.

Details of the studies

PFMT for secondary prevention of POP. In a study conducted in the United Kingdom and New Zealand, Hagen and colleagues randomly assigned 414 women with POP, with or without symptoms, to an intervention group or a control group. The women had previously participated in a longitudinal study of postpartum pelvic floor function. Participants in the intervention group (n = 207) received 5 formal sessions of PFMT over 16 weeks, followed by Pilates-based classes focused on pelvic floor exercises; those in the control group (n = 207) received an informational leaflet about prolapse and lifestyle. The primary outcome was self-reported prolapse symptoms, assessed with the POP Symptom Score (POP-SS) at 2 years.

At study end, the mean (SD) POP-SS score in the intervention group was 3.2 (3.4), compared with a mean (SD) score of 4.2 (4.4) in the control group (adjusted mean difference, −1.01; 95% confidence interval [CI], −1.70 to −0.33; P = .004).

Investigators’ interpretation. The researchers concluded that the participants in the PFMT group had a small but significant—and clinically important—decrease in prolapse symptoms.

The PROSPECT study: Standard versus augmented surgical repair. In a multicenter trial in the United Kingdom by Glazener and associates, 1,352 women with symptomatic POP were randomly allocated to surgical repair with native tissue alone (standard repair) or to standard surgical repair augmented either with polypropylene mesh or with biological graft. The primary outcomes were participant-reported prolapse symptoms (assessed with POP-SS) and prolapse-related quality of life scores; these were measured at 1 year and at 2 years.

One year after surgery, failure rates (defined as prolapse beyond the hymen) were similar in all groups (range, 14%–18%); serious adverse events were also similar in all surgical groups (range, 6%–10%). Overall, 6% of women underwent reoperation for recurrent symptoms. Among women randomly assigned to repair with mesh, 12% to 14% experienced mesh-related adverse events; three-quarters of these women ultimately required surgical excision of the mesh.

Study takeaway. Thus, in terms of effectiveness, quality of life, and adverse effects, augmentation of a vaginal surgical repair with either mesh or graft material did not improve the outcomes of women with POP.

Adverse events after surgical procedures for pelvic floor disorders. In Scotland, Morling and colleagues performed a retrospective observational cohort study of first-time surgeries for SUI (mesh or colposuspension; 16,660 procedures) and prolapse (mesh or native tissue; 18,986 procedures).

After 5 years of follow-up, women who underwent midurethral mesh sling placement or colposuspension had similar rates of repeat surgery for recurrent SUI (adjusted incidence rate ratio, 0.90; 95% CI, 0.73–1.11). Use of mesh slings was associated with fewer immediate complications (adjusted relative risk, 0.44; 95% CI, 0.36–0.55) compared with nonmesh surgery.

Among women who underwent surgery for prolapse, those who had anterior and posterior repair with mesh experienced higher late complication rates than those who underwent native tissue repair. Risk for subsequent prolapse repair was similar with mesh and native-tissue procedures.

Authors’ commentary. The researchers noted that their data support the use of mesh procedures for incontinence but additional research on longer-term outcomes would be useful. However, for prolapse repair, the study results do not decidedly favor any one vault repair procedure.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

Also from PAGS 2016:

• Dr. Tommaso Falcone offers Top 3 things I learned at the PAGS 2016 symposium
• Visit PAGS

Also from PAGS 2016:

• Dr. Tommaso Falcone offers Top 3 things I learned at the PAGS 2016 symposium
• Visit PAGS

Also from PAGS 2016:

• Dr. Tommaso Falcone offers Top 3 things I learned at the PAGS 2016 symposium
• Visit PAGS

The recognition that human papillomavirus (HPV) oncogenic viruses cause cervical carcinoma remains one of the most game-changing medical discoveries of the last century. Improvements in screening options for detecting cervical cancer precursors followed. We now have the ability to detect high-risk HPV subtypes in routine specimens. Finally, a highly effective vaccine was developed that targets HPV types 16 and 18, which are responsible for causing approximately 70% of all cases of cervical carcinoma.

In one of the original vaccines HPV types 6 and 11, responsible for 90% of all genital warts, were also targeted. In 2014, a 9-valent vaccine incorporating an additional 5 HPV strains (31, 33, 45, 52, and 58) was approved and is set to replace all previous vaccine versions. Together, these 7 oncogenic HPV types are responsible for approximately 90% of HPV-related cancers, including cervical, anal, oropharyngeal, vaginal, and vulvar cancer.

By vaccinating boys and girls between ages 9 and 21 (for males) and 9 and 26 (for females), we could effectively eliminate 90% of genital warts and 90% of all HPV-related cancers. So why have we not capitalized on this extraordinary discovery? In 2016, why were only 40% of teenage girls and less than 25% of teenage boys vaccinated against HPV when we are immunizing 80% to 90% of these populations with tetanus, diphtheria, and acellular pertusis (Tdap) and meningococcal vaccines?

Related article:
2016 Update on cervical disease

Barriers to HPV vaccination

When the first HPV vaccine was approved in 2006, cost was a significant factor. Many health insurance plans did not cover this “discretionary” vaccine, which was viewed as a prevention for sexually transmitted infections rather than as a valuable intervention for the prevention of cervical and other cancers. At well over $125 per dose with 3 doses required for a full series, ObGyns were reluctant to stock and provide these expensive vaccines without assurance of reimbursement. The logistics of recalling patients for their subsequent vaccine doses were challenging for offices that were not accustomed to seeing patients for preventive care activities more than once a year. In addition, the office infrastructure required to maintain the vaccine stock and manage the necessary paperwork could be daunting. Finally, the requirement that patients be observed for 15 to 30 minutes in the office after vaccine administration created efficiency and rooming problems in busy, active practices.

Over time, almost all payers covered the HPV vaccines, but the logistical issues in ObGyn practices remain. Pediatric practices, on the other hand, are ideally suited for vaccine administration. Unfortunately, our colleagues delivering preventive care to young teens have persisted in considering the HPV vaccine as an optional adjunct to routine vaccination despite the advice of the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC), which for many years has recommended the HPV vaccine for girls. In 2011, the ACIP extended the HPV vaccine recommendation to include boys beginning at ages 11 to 12.

New 2-dose HPV vaccine schedule for children <15 years

In October 2016, 10 years after the first HPV vaccine approval, the ACIP and the CDC approved a reduced, 2-dose schedule for those younger than 15.¹ The first dose can be administered simultaneously with other recommended vaccines for 11- to 12-year-olds (the meningococcal and Tdap vaccines) and the second dose, 6 or 12 months later.² The 12-month interval would allow administration, once again, of all required vaccines at the annual visit.

Pivotal immunogenicity study

The new recommendation is based on robust multinational data (52 sites in 15 countries, N = 1,518) from an open-label trial.³ Immunogenicity of 2 doses of the 9-valent HPV vaccine in girls and boys ages 9 to 14 was compared with that of a standard 3-dose regimen in adolescents and young women ages 16 to 26. Five cohorts were studied: boys 9 to 14 given 2 doses at 6-month intervals; girls 9 to 14 given 2 doses at 6-month intervals; boys and girls 9 to 14 given 2 doses at a 12-month interval; girls 9 to 14 given the standard 3-dose regimen; and girls and young women 16 to 26 receiving 3 doses over 6 months.

The authors assessed the antibody responses against each HPV subtype 1 month after the final vaccine dose. Data from 1,377 participants (90.7% of the original cohort) were analyzed. Prespecified antibody titers were set conservatively to ensure adequate immunogenicity. Noninferiority criteria had to be met for all 9 HPV types.

Trial results. The immune responses for the 9- to 14-year-olds were consistently higher than those for the 16- to 26-year-old age group regardless of the regimen—not a surprising finding since the initial trials for HPV vaccine demonstrated a greater response among younger vaccine recipients. In this trial, higher antibody responses were found for the 12-month dosing interval than for the 6-month interval, although both regimens produced an adequate response.

Immunogenicity remained at 6 months. Antibody levels were retested 6 months after the last dose of HPV vaccine in a post hoc analysis. In all groups the antibody titers declined; however, there was no difference between the 2- and 3-dose cohorts. All levels remained above a threshold required for immunogenicity.

Related article:
2015 Update on cervical disease: New ammo for HPV prevention and screening

Simplified dosing may help increase vaccination rates

What does this new dosing regimen mean for practice? It will be simpler to incorporate HPV vaccination routinely into the standard vaccine regimen for preadolescent boys and girls. In addition, counseling for HPV vaccine administration can be combined with counseling for the meningococcal vaccine and routine Tdap booster.

Notably, primary care physicians have reported perceiving HPV vaccine discussions with parents as burdensome, and they tend to discuss it last after conversations about Tdap and meningococcal vaccines.⁴ Brewer and colleagues⁵ documented a 5% increase in first HPV vaccine doses among patients in practices in which the providers were taught to “announce” the need for HPV vaccine along with other routine vaccines. There was no increase in HPV vaccine uptake among practices in which providers were taught to “discuss” HPV with parents and to address their concerns, or in control practices. Therefore, less conversation about HPV and the HPV vaccine, as distinct from any other recommended vaccines, is better.

With the new 2-dose regimen, it should be easier to convey that the HPV vaccine is another necessary, routine intervention for children’s health. We should be able to achieve 90% vaccination rates for HPV—similar to rates for Tdap.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

The recognition that human papillomavirus (HPV) oncogenic viruses cause cervical carcinoma remains one of the most game-changing medical discoveries of the last century. Improvements in screening options for detecting cervical cancer precursors followed. We now have the ability to detect high-risk HPV subtypes in routine specimens. Finally, a highly effective vaccine was developed that targets HPV types 16 and 18, which are responsible for causing approximately 70% of all cases of cervical carcinoma.

In one of the original vaccines HPV types 6 and 11, responsible for 90% of all genital warts, were also targeted. In 2014, a 9-valent vaccine incorporating an additional 5 HPV strains (31, 33, 45, 52, and 58) was approved and is set to replace all previous vaccine versions. Together, these 7 oncogenic HPV types are responsible for approximately 90% of HPV-related cancers, including cervical, anal, oropharyngeal, vaginal, and vulvar cancer.

By vaccinating boys and girls between ages 9 and 21 (for males) and 9 and 26 (for females), we could effectively eliminate 90% of genital warts and 90% of all HPV-related cancers. So why have we not capitalized on this extraordinary discovery? In 2016, why were only 40% of teenage girls and less than 25% of teenage boys vaccinated against HPV when we are immunizing 80% to 90% of these populations with tetanus, diphtheria, and acellular pertusis (Tdap) and meningococcal vaccines?

Related article:
2016 Update on cervical disease

Barriers to HPV vaccination

When the first HPV vaccine was approved in 2006, cost was a significant factor. Many health insurance plans did not cover this “discretionary” vaccine, which was viewed as a prevention for sexually transmitted infections rather than as a valuable intervention for the prevention of cervical and other cancers. At well over $125 per dose with 3 doses required for a full series, ObGyns were reluctant to stock and provide these expensive vaccines without assurance of reimbursement. The logistics of recalling patients for their subsequent vaccine doses were challenging for offices that were not accustomed to seeing patients for preventive care activities more than once a year. In addition, the office infrastructure required to maintain the vaccine stock and manage the necessary paperwork could be daunting. Finally, the requirement that patients be observed for 15 to 30 minutes in the office after vaccine administration created efficiency and rooming problems in busy, active practices.

Over time, almost all payers covered the HPV vaccines, but the logistical issues in ObGyn practices remain. Pediatric practices, on the other hand, are ideally suited for vaccine administration. Unfortunately, our colleagues delivering preventive care to young teens have persisted in considering the HPV vaccine as an optional adjunct to routine vaccination despite the advice of the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC), which for many years has recommended the HPV vaccine for girls. In 2011, the ACIP extended the HPV vaccine recommendation to include boys beginning at ages 11 to 12.

New 2-dose HPV vaccine schedule for children <15 years

In October 2016, 10 years after the first HPV vaccine approval, the ACIP and the CDC approved a reduced, 2-dose schedule for those younger than 15.¹ The first dose can be administered simultaneously with other recommended vaccines for 11- to 12-year-olds (the meningococcal and Tdap vaccines) and the second dose, 6 or 12 months later.² The 12-month interval would allow administration, once again, of all required vaccines at the annual visit.

Pivotal immunogenicity study

The new recommendation is based on robust multinational data (52 sites in 15 countries, N = 1,518) from an open-label trial.³ Immunogenicity of 2 doses of the 9-valent HPV vaccine in girls and boys ages 9 to 14 was compared with that of a standard 3-dose regimen in adolescents and young women ages 16 to 26. Five cohorts were studied: boys 9 to 14 given 2 doses at 6-month intervals; girls 9 to 14 given 2 doses at 6-month intervals; boys and girls 9 to 14 given 2 doses at a 12-month interval; girls 9 to 14 given the standard 3-dose regimen; and girls and young women 16 to 26 receiving 3 doses over 6 months.

The authors assessed the antibody responses against each HPV subtype 1 month after the final vaccine dose. Data from 1,377 participants (90.7% of the original cohort) were analyzed. Prespecified antibody titers were set conservatively to ensure adequate immunogenicity. Noninferiority criteria had to be met for all 9 HPV types.

Trial results. The immune responses for the 9- to 14-year-olds were consistently higher than those for the 16- to 26-year-old age group regardless of the regimen—not a surprising finding since the initial trials for HPV vaccine demonstrated a greater response among younger vaccine recipients. In this trial, higher antibody responses were found for the 12-month dosing interval than for the 6-month interval, although both regimens produced an adequate response.

Immunogenicity remained at 6 months. Antibody levels were retested 6 months after the last dose of HPV vaccine in a post hoc analysis. In all groups the antibody titers declined; however, there was no difference between the 2- and 3-dose cohorts. All levels remained above a threshold required for immunogenicity.

Related article:
2015 Update on cervical disease: New ammo for HPV prevention and screening

Simplified dosing may help increase vaccination rates

What does this new dosing regimen mean for practice? It will be simpler to incorporate HPV vaccination routinely into the standard vaccine regimen for preadolescent boys and girls. In addition, counseling for HPV vaccine administration can be combined with counseling for the meningococcal vaccine and routine Tdap booster.

Notably, primary care physicians have reported perceiving HPV vaccine discussions with parents as burdensome, and they tend to discuss it last after conversations about Tdap and meningococcal vaccines.⁴ Brewer and colleagues⁵ documented a 5% increase in first HPV vaccine doses among patients in practices in which the providers were taught to “announce” the need for HPV vaccine along with other routine vaccines. There was no increase in HPV vaccine uptake among practices in which providers were taught to “discuss” HPV with parents and to address their concerns, or in control practices. Therefore, less conversation about HPV and the HPV vaccine, as distinct from any other recommended vaccines, is better.

With the new 2-dose regimen, it should be easier to convey that the HPV vaccine is another necessary, routine intervention for children’s health. We should be able to achieve 90% vaccination rates for HPV—similar to rates for Tdap.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

The recognition that human papillomavirus (HPV) oncogenic viruses cause cervical carcinoma remains one of the most game-changing medical discoveries of the last century. Improvements in screening options for detecting cervical cancer precursors followed. We now have the ability to detect high-risk HPV subtypes in routine specimens. Finally, a highly effective vaccine was developed that targets HPV types 16 and 18, which are responsible for causing approximately 70% of all cases of cervical carcinoma.

In one of the original vaccines HPV types 6 and 11, responsible for 90% of all genital warts, were also targeted. In 2014, a 9-valent vaccine incorporating an additional 5 HPV strains (31, 33, 45, 52, and 58) was approved and is set to replace all previous vaccine versions. Together, these 7 oncogenic HPV types are responsible for approximately 90% of HPV-related cancers, including cervical, anal, oropharyngeal, vaginal, and vulvar cancer.

By vaccinating boys and girls between ages 9 and 21 (for males) and 9 and 26 (for females), we could effectively eliminate 90% of genital warts and 90% of all HPV-related cancers. So why have we not capitalized on this extraordinary discovery? In 2016, why were only 40% of teenage girls and less than 25% of teenage boys vaccinated against HPV when we are immunizing 80% to 90% of these populations with tetanus, diphtheria, and acellular pertusis (Tdap) and meningococcal vaccines?

Related article:
2016 Update on cervical disease

Barriers to HPV vaccination

When the first HPV vaccine was approved in 2006, cost was a significant factor. Many health insurance plans did not cover this “discretionary” vaccine, which was viewed as a prevention for sexually transmitted infections rather than as a valuable intervention for the prevention of cervical and other cancers. At well over $125 per dose with 3 doses required for a full series, ObGyns were reluctant to stock and provide these expensive vaccines without assurance of reimbursement. The logistics of recalling patients for their subsequent vaccine doses were challenging for offices that were not accustomed to seeing patients for preventive care activities more than once a year. In addition, the office infrastructure required to maintain the vaccine stock and manage the necessary paperwork could be daunting. Finally, the requirement that patients be observed for 15 to 30 minutes in the office after vaccine administration created efficiency and rooming problems in busy, active practices.

Over time, almost all payers covered the HPV vaccines, but the logistical issues in ObGyn practices remain. Pediatric practices, on the other hand, are ideally suited for vaccine administration. Unfortunately, our colleagues delivering preventive care to young teens have persisted in considering the HPV vaccine as an optional adjunct to routine vaccination despite the advice of the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC), which for many years has recommended the HPV vaccine for girls. In 2011, the ACIP extended the HPV vaccine recommendation to include boys beginning at ages 11 to 12.

New 2-dose HPV vaccine schedule for children <15 years

In October 2016, 10 years after the first HPV vaccine approval, the ACIP and the CDC approved a reduced, 2-dose schedule for those younger than 15.¹ The first dose can be administered simultaneously with other recommended vaccines for 11- to 12-year-olds (the meningococcal and Tdap vaccines) and the second dose, 6 or 12 months later.² The 12-month interval would allow administration, once again, of all required vaccines at the annual visit.

Pivotal immunogenicity study

The new recommendation is based on robust multinational data (52 sites in 15 countries, N = 1,518) from an open-label trial.³ Immunogenicity of 2 doses of the 9-valent HPV vaccine in girls and boys ages 9 to 14 was compared with that of a standard 3-dose regimen in adolescents and young women ages 16 to 26. Five cohorts were studied: boys 9 to 14 given 2 doses at 6-month intervals; girls 9 to 14 given 2 doses at 6-month intervals; boys and girls 9 to 14 given 2 doses at a 12-month interval; girls 9 to 14 given the standard 3-dose regimen; and girls and young women 16 to 26 receiving 3 doses over 6 months.

The authors assessed the antibody responses against each HPV subtype 1 month after the final vaccine dose. Data from 1,377 participants (90.7% of the original cohort) were analyzed. Prespecified antibody titers were set conservatively to ensure adequate immunogenicity. Noninferiority criteria had to be met for all 9 HPV types.

Trial results. The immune responses for the 9- to 14-year-olds were consistently higher than those for the 16- to 26-year-old age group regardless of the regimen—not a surprising finding since the initial trials for HPV vaccine demonstrated a greater response among younger vaccine recipients. In this trial, higher antibody responses were found for the 12-month dosing interval than for the 6-month interval, although both regimens produced an adequate response.

Immunogenicity remained at 6 months. Antibody levels were retested 6 months after the last dose of HPV vaccine in a post hoc analysis. In all groups the antibody titers declined; however, there was no difference between the 2- and 3-dose cohorts. All levels remained above a threshold required for immunogenicity.

Related article:
2015 Update on cervical disease: New ammo for HPV prevention and screening

Simplified dosing may help increase vaccination rates

What does this new dosing regimen mean for practice? It will be simpler to incorporate HPV vaccination routinely into the standard vaccine regimen for preadolescent boys and girls. In addition, counseling for HPV vaccine administration can be combined with counseling for the meningococcal vaccine and routine Tdap booster.

Notably, primary care physicians have reported perceiving HPV vaccine discussions with parents as burdensome, and they tend to discuss it last after conversations about Tdap and meningococcal vaccines.⁴ Brewer and colleagues⁵ documented a 5% increase in first HPV vaccine doses among patients in practices in which the providers were taught to “announce” the need for HPV vaccine along with other routine vaccines. There was no increase in HPV vaccine uptake among practices in which providers were taught to “discuss” HPV with parents and to address their concerns, or in control practices. Therefore, less conversation about HPV and the HPV vaccine, as distinct from any other recommended vaccines, is better.

With the new 2-dose regimen, it should be easier to convey that the HPV vaccine is another necessary, routine intervention for children’s health. We should be able to achieve 90% vaccination rates for HPV—similar to rates for Tdap.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

The purpose of screening mammography is to detect tumors when they are small and nonpalpable in order to prevent more advanced breast tumors in women. Overdiagnosis, which leads to unnecessary treatment, refers to screen-detected tumors that will not lead to symptoms. Overdiagnosis cannot be measured directly and, therefore, understanding this concept is problematic for both women and clinicians.

Related article:
Women’s Preventive Services Initiative Guidelines provide consensus for practicing ObGyns

Observations from other types of cancer screening put overdiagnosis in perspective

To help us grasp the overall issue of overdiagnosis, we can consider screening mammography alongside cervical cancer screening and colon cancer screening. For instance, screening with cervical cytology has reduced the incidence of and mortality from invasive cervical cancer.¹ Likewise, colonoscopy repeatedly has been found to reduce colon cancer mortality.^2,3 Decades of media messaging have emphasized the benefits of screening mammograms.⁴ However, and in contrast with cervical cytology and colonoscopy, screening mammography has not reduced the incidence of breast cancer presenting with metastatic (advanced) disease.⁵ Likewise, as the Danish authors of a recent study published in Annals of Internal Medicine point out, screening mammography has not achieved the promised reduction in breast cancer mortality.

New data from Denmark highlight overdiagnosis concerns

Jørgensen and colleagues conducted a cohort study to estimate the incidence of screen-detected tumors that would not become clinically relevant (overdiagnosis) among women aged 35 to 84 years between 1980 and 2010 in Denmark.⁶ This country offers a particularly well-suited backdrop for a study of overdiagnosis because biennial screening mammography was introduced by region beginning in the early 1990s. By 2007, one-fifth of the country’s female population aged 50 to 69 years were invited to participate. In the following years, screening became universal for Danish women in this age group.

For the study, researchers identified the size of all invasive breast cancer tumors diagnosed over the study period and then compared the incidence rates of advanced tumors (more than 20-mm in size at detection) with nonadvanced tumors in screened and unscreened Danish regions. The investigators took into account regional differences not related to screening by assessing the trends in diagnosis of advanced and nonadvanced tumors in screened and unscreened regions among women older and younger than those screened. This gave them a better estimate of the incidence of overdiagnosis.⁶

Jørgensen and colleagues found that breast cancer screening resulted in an increase in the incidence of nonadvanced tumors, but that it did not reduce the incidence of advanced tumors. They estimated that 39% of the invasive tumors found among women aged 50 to 69 were overdiagnosed.⁶

These Danish study results, that more than one-third of screen-detected tumors represent overdiagnosis, are similar to those found for studies conducted in the United States and other countries.^7,8 The lengthy follow-up after initiation of screening and the assessment of trends in unscreened women represent strengths of the study by Jørgensen and colleagues, and speak to concerns voiced by those skeptical of reported overdiagnosis incidence rates.⁹

Although breast cancer mortality is declining, the lion’s share of this decline has resulted from improvements in systemic therapy rather than from screening mammography. Widespread screening mammography has resulted in a scenario in which women are more likely to have a breast cancer that was overdiagnosed than in having earlier detection of a tumor destined to grow larger.⁵ In the future, by targeting higher-risk women, screening may result in a better benefit:risk ratio. However, and as pointed out by Otis Brawley, MD, Chief Medical and Scientific Officer of the American Cancer Society, we must acknowledge that overdiagnosis is common, the benefits of screening have been overstated, and some patients considered as “cured” from breast cancer have in fact been harmed by unneeded treatment.¹⁰

Related article:
No surprises from the USPSTF with new guidance on screening mammography

My breast cancer screening approach

As Brawley indicates, we should not abandon screening.¹⁰ I continue to recommend screening based on US Preventive Services Taskforce guidance, beginning biennial screens at age 50.¹¹ I also recognize that some women prefer earlier and more frequent screens, while others may prefer less frequent or even no screening.

The purpose of screening mammography is to detect tumors when they are small and nonpalpable in order to prevent more advanced breast tumors in women. Overdiagnosis, which leads to unnecessary treatment, refers to screen-detected tumors that will not lead to symptoms. Overdiagnosis cannot be measured directly and, therefore, understanding this concept is problematic for both women and clinicians.

Related article:
Women’s Preventive Services Initiative Guidelines provide consensus for practicing ObGyns

Observations from other types of cancer screening put overdiagnosis in perspective

To help us grasp the overall issue of overdiagnosis, we can consider screening mammography alongside cervical cancer screening and colon cancer screening. For instance, screening with cervical cytology has reduced the incidence of and mortality from invasive cervical cancer.¹ Likewise, colonoscopy repeatedly has been found to reduce colon cancer mortality.^2,3 Decades of media messaging have emphasized the benefits of screening mammograms.⁴ However, and in contrast with cervical cytology and colonoscopy, screening mammography has not reduced the incidence of breast cancer presenting with metastatic (advanced) disease.⁵ Likewise, as the Danish authors of a recent study published in Annals of Internal Medicine point out, screening mammography has not achieved the promised reduction in breast cancer mortality.

New data from Denmark highlight overdiagnosis concerns

Jørgensen and colleagues conducted a cohort study to estimate the incidence of screen-detected tumors that would not become clinically relevant (overdiagnosis) among women aged 35 to 84 years between 1980 and 2010 in Denmark.⁶ This country offers a particularly well-suited backdrop for a study of overdiagnosis because biennial screening mammography was introduced by region beginning in the early 1990s. By 2007, one-fifth of the country’s female population aged 50 to 69 years were invited to participate. In the following years, screening became universal for Danish women in this age group.

For the study, researchers identified the size of all invasive breast cancer tumors diagnosed over the study period and then compared the incidence rates of advanced tumors (more than 20-mm in size at detection) with nonadvanced tumors in screened and unscreened Danish regions. The investigators took into account regional differences not related to screening by assessing the trends in diagnosis of advanced and nonadvanced tumors in screened and unscreened regions among women older and younger than those screened. This gave them a better estimate of the incidence of overdiagnosis.⁶

Jørgensen and colleagues found that breast cancer screening resulted in an increase in the incidence of nonadvanced tumors, but that it did not reduce the incidence of advanced tumors. They estimated that 39% of the invasive tumors found among women aged 50 to 69 were overdiagnosed.⁶

These Danish study results, that more than one-third of screen-detected tumors represent overdiagnosis, are similar to those found for studies conducted in the United States and other countries.^7,8 The lengthy follow-up after initiation of screening and the assessment of trends in unscreened women represent strengths of the study by Jørgensen and colleagues, and speak to concerns voiced by those skeptical of reported overdiagnosis incidence rates.⁹

Although breast cancer mortality is declining, the lion’s share of this decline has resulted from improvements in systemic therapy rather than from screening mammography. Widespread screening mammography has resulted in a scenario in which women are more likely to have a breast cancer that was overdiagnosed than in having earlier detection of a tumor destined to grow larger.⁵ In the future, by targeting higher-risk women, screening may result in a better benefit:risk ratio. However, and as pointed out by Otis Brawley, MD, Chief Medical and Scientific Officer of the American Cancer Society, we must acknowledge that overdiagnosis is common, the benefits of screening have been overstated, and some patients considered as “cured” from breast cancer have in fact been harmed by unneeded treatment.¹⁰

Related article:
No surprises from the USPSTF with new guidance on screening mammography

My breast cancer screening approach

As Brawley indicates, we should not abandon screening.¹⁰ I continue to recommend screening based on US Preventive Services Taskforce guidance, beginning biennial screens at age 50.¹¹ I also recognize that some women prefer earlier and more frequent screens, while others may prefer less frequent or even no screening.

The purpose of screening mammography is to detect tumors when they are small and nonpalpable in order to prevent more advanced breast tumors in women. Overdiagnosis, which leads to unnecessary treatment, refers to screen-detected tumors that will not lead to symptoms. Overdiagnosis cannot be measured directly and, therefore, understanding this concept is problematic for both women and clinicians.

Related article:
Women’s Preventive Services Initiative Guidelines provide consensus for practicing ObGyns

Observations from other types of cancer screening put overdiagnosis in perspective

To help us grasp the overall issue of overdiagnosis, we can consider screening mammography alongside cervical cancer screening and colon cancer screening. For instance, screening with cervical cytology has reduced the incidence of and mortality from invasive cervical cancer.¹ Likewise, colonoscopy repeatedly has been found to reduce colon cancer mortality.^2,3 Decades of media messaging have emphasized the benefits of screening mammograms.⁴ However, and in contrast with cervical cytology and colonoscopy, screening mammography has not reduced the incidence of breast cancer presenting with metastatic (advanced) disease.⁵ Likewise, as the Danish authors of a recent study published in Annals of Internal Medicine point out, screening mammography has not achieved the promised reduction in breast cancer mortality.

New data from Denmark highlight overdiagnosis concerns

Jørgensen and colleagues conducted a cohort study to estimate the incidence of screen-detected tumors that would not become clinically relevant (overdiagnosis) among women aged 35 to 84 years between 1980 and 2010 in Denmark.⁶ This country offers a particularly well-suited backdrop for a study of overdiagnosis because biennial screening mammography was introduced by region beginning in the early 1990s. By 2007, one-fifth of the country’s female population aged 50 to 69 years were invited to participate. In the following years, screening became universal for Danish women in this age group.

For the study, researchers identified the size of all invasive breast cancer tumors diagnosed over the study period and then compared the incidence rates of advanced tumors (more than 20-mm in size at detection) with nonadvanced tumors in screened and unscreened Danish regions. The investigators took into account regional differences not related to screening by assessing the trends in diagnosis of advanced and nonadvanced tumors in screened and unscreened regions among women older and younger than those screened. This gave them a better estimate of the incidence of overdiagnosis.⁶

Jørgensen and colleagues found that breast cancer screening resulted in an increase in the incidence of nonadvanced tumors, but that it did not reduce the incidence of advanced tumors. They estimated that 39% of the invasive tumors found among women aged 50 to 69 were overdiagnosed.⁶

These Danish study results, that more than one-third of screen-detected tumors represent overdiagnosis, are similar to those found for studies conducted in the United States and other countries.^7,8 The lengthy follow-up after initiation of screening and the assessment of trends in unscreened women represent strengths of the study by Jørgensen and colleagues, and speak to concerns voiced by those skeptical of reported overdiagnosis incidence rates.⁹

Although breast cancer mortality is declining, the lion’s share of this decline has resulted from improvements in systemic therapy rather than from screening mammography. Widespread screening mammography has resulted in a scenario in which women are more likely to have a breast cancer that was overdiagnosed than in having earlier detection of a tumor destined to grow larger.⁵ In the future, by targeting higher-risk women, screening may result in a better benefit:risk ratio. However, and as pointed out by Otis Brawley, MD, Chief Medical and Scientific Officer of the American Cancer Society, we must acknowledge that overdiagnosis is common, the benefits of screening have been overstated, and some patients considered as “cured” from breast cancer have in fact been harmed by unneeded treatment.¹⁰

Related article:
No surprises from the USPSTF with new guidance on screening mammography

My breast cancer screening approach

As Brawley indicates, we should not abandon screening.¹⁰ I continue to recommend screening based on US Preventive Services Taskforce guidance, beginning biennial screens at age 50.¹¹ I also recognize that some women prefer earlier and more frequent screens, while others may prefer less frequent or even no screening.

EXPERT COMMENTARY

Both the Centers for Disease Control and Prevention and the World Health Organization currently recommend that patients with trichomoniasis be treated with a single 2-g oral dose of metronidazole.¹ Following treatment, the reported rates of repeat infection or persistent infection range from 5% to 31%. Repeat infection rates may be even higher in HIV-infected patients.

Repeat infections presumably result from a failure to treat the patient’s sexual partner(s) or from the patient’s exposure to a new partner. Persistent infections, however, may be the result of inadequate primary therapy, even though inherent resistance of the organism to metronidazole is quite rare. To date, no single study has shown that single-dose therapy is inferior to multidose therapy, but most of these studies lack sufficient power to completely exclude the possibility of a type-2 statistical error.² To compare single-dose with multidose therapy for trichomoniasis in a more systematic manner, Howe and Kissinger conducted a meta-analysis, which was recently published in Sexually Transmitted Diseases.

Related article:
2016 Update on infectious disease

Details of the study

The investigators conducted a comprehensive literature search using Embase, Medline, and ClinicalTrials.gov; 6 articles were included in the final results, 4 of which were randomized controlled trials. Approximately 1,300 participants were included in the 6 trials. All of the patients in the single-dose treatment arms received a 2-g oral dose of metronidazole. In the multidose treatment arms for 2 studies the participants received metronidazole 250 mg orally 3 times daily for 7 days, and for 2 studies the dose was 200 mg 3 times daily for 7 days. The fifth study employed a 500-mg oral dose of metronidazole twice daily for 7 days. The final study used a 400-mg oral dose twice daily for 5 days. The key study end point was treatment failure.

Howe and Kissinger demonstrated that women who received the single 2-g dose were 1.87 times (95% CI, 1.23−2.82; P<.01) more likely to experience a treatment failure compared with women who received a multidose regimen. When the one study that focused only on HIV-infected women was excluded from analysis, the results were similar. The relative risk of treatment failure was 1.80 (95% CI, 1.07−3.02; P<.03).

Related article:
Preventing infection after cesarean delivery: Evidence-based guidance

Study limitations

The results of this meta-analysis are interesting and provocative. However, the analysis has several important limitations. Five of the 6 studies were published many years ago (1971, 1972, 1979, 1980, and 1982). The most recent study was published in 2010. The investigators used 4 different multidose regimens, with metronidazole doses ranging from 200 mg to 500 mg and duration of therapy ranging from 5 to 7 days. Four of the six investigations used saline microscopy as the definitive diagnostic test of treatment failure. Compared with culture or DNA testing, microscopy is not as accurate. Moreover, the timing of retesting varied in the studies, and some apparent treatment failures actually may have been due to reinfection. In addition, the studies did not consistently track the adequacy of treatment of the sexual partner.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

EXPERT COMMENTARY

Both the Centers for Disease Control and Prevention and the World Health Organization currently recommend that patients with trichomoniasis be treated with a single 2-g oral dose of metronidazole.¹ Following treatment, the reported rates of repeat infection or persistent infection range from 5% to 31%. Repeat infection rates may be even higher in HIV-infected patients.

Repeat infections presumably result from a failure to treat the patient’s sexual partner(s) or from the patient’s exposure to a new partner. Persistent infections, however, may be the result of inadequate primary therapy, even though inherent resistance of the organism to metronidazole is quite rare. To date, no single study has shown that single-dose therapy is inferior to multidose therapy, but most of these studies lack sufficient power to completely exclude the possibility of a type-2 statistical error.² To compare single-dose with multidose therapy for trichomoniasis in a more systematic manner, Howe and Kissinger conducted a meta-analysis, which was recently published in Sexually Transmitted Diseases.

Related article:
2016 Update on infectious disease

Details of the study

The investigators conducted a comprehensive literature search using Embase, Medline, and ClinicalTrials.gov; 6 articles were included in the final results, 4 of which were randomized controlled trials. Approximately 1,300 participants were included in the 6 trials. All of the patients in the single-dose treatment arms received a 2-g oral dose of metronidazole. In the multidose treatment arms for 2 studies the participants received metronidazole 250 mg orally 3 times daily for 7 days, and for 2 studies the dose was 200 mg 3 times daily for 7 days. The fifth study employed a 500-mg oral dose of metronidazole twice daily for 7 days. The final study used a 400-mg oral dose twice daily for 5 days. The key study end point was treatment failure.

Howe and Kissinger demonstrated that women who received the single 2-g dose were 1.87 times (95% CI, 1.23−2.82; P<.01) more likely to experience a treatment failure compared with women who received a multidose regimen. When the one study that focused only on HIV-infected women was excluded from analysis, the results were similar. The relative risk of treatment failure was 1.80 (95% CI, 1.07−3.02; P<.03).

Related article:
Preventing infection after cesarean delivery: Evidence-based guidance

Study limitations

The results of this meta-analysis are interesting and provocative. However, the analysis has several important limitations. Five of the 6 studies were published many years ago (1971, 1972, 1979, 1980, and 1982). The most recent study was published in 2010. The investigators used 4 different multidose regimens, with metronidazole doses ranging from 200 mg to 500 mg and duration of therapy ranging from 5 to 7 days. Four of the six investigations used saline microscopy as the definitive diagnostic test of treatment failure. Compared with culture or DNA testing, microscopy is not as accurate. Moreover, the timing of retesting varied in the studies, and some apparent treatment failures actually may have been due to reinfection. In addition, the studies did not consistently track the adequacy of treatment of the sexual partner.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.

EXPERT COMMENTARY

Both the Centers for Disease Control and Prevention and the World Health Organization currently recommend that patients with trichomoniasis be treated with a single 2-g oral dose of metronidazole.¹ Following treatment, the reported rates of repeat infection or persistent infection range from 5% to 31%. Repeat infection rates may be even higher in HIV-infected patients.

Repeat infections presumably result from a failure to treat the patient’s sexual partner(s) or from the patient’s exposure to a new partner. Persistent infections, however, may be the result of inadequate primary therapy, even though inherent resistance of the organism to metronidazole is quite rare. To date, no single study has shown that single-dose therapy is inferior to multidose therapy, but most of these studies lack sufficient power to completely exclude the possibility of a type-2 statistical error.² To compare single-dose with multidose therapy for trichomoniasis in a more systematic manner, Howe and Kissinger conducted a meta-analysis, which was recently published in Sexually Transmitted Diseases.

Related article:
2016 Update on infectious disease

Details of the study

The investigators conducted a comprehensive literature search using Embase, Medline, and ClinicalTrials.gov; 6 articles were included in the final results, 4 of which were randomized controlled trials. Approximately 1,300 participants were included in the 6 trials. All of the patients in the single-dose treatment arms received a 2-g oral dose of metronidazole. In the multidose treatment arms for 2 studies the participants received metronidazole 250 mg orally 3 times daily for 7 days, and for 2 studies the dose was 200 mg 3 times daily for 7 days. The fifth study employed a 500-mg oral dose of metronidazole twice daily for 7 days. The final study used a 400-mg oral dose twice daily for 5 days. The key study end point was treatment failure.

Howe and Kissinger demonstrated that women who received the single 2-g dose were 1.87 times (95% CI, 1.23−2.82; P<.01) more likely to experience a treatment failure compared with women who received a multidose regimen. When the one study that focused only on HIV-infected women was excluded from analysis, the results were similar. The relative risk of treatment failure was 1.80 (95% CI, 1.07−3.02; P<.03).

Related article:
Preventing infection after cesarean delivery: Evidence-based guidance

Study limitations

The results of this meta-analysis are interesting and provocative. However, the analysis has several important limitations. Five of the 6 studies were published many years ago (1971, 1972, 1979, 1980, and 1982). The most recent study was published in 2010. The investigators used 4 different multidose regimens, with metronidazole doses ranging from 200 mg to 500 mg and duration of therapy ranging from 5 to 7 days. Four of the six investigations used saline microscopy as the definitive diagnostic test of treatment failure. Compared with culture or DNA testing, microscopy is not as accurate. Moreover, the timing of retesting varied in the studies, and some apparent treatment failures actually may have been due to reinfection. In addition, the studies did not consistently track the adequacy of treatment of the sexual partner.

Share your thoughts! Send your Letter to the Editor to [email protected]. Please include your name and the city and state in which you practice.