Clinical Review

Increasingly, bone health and fragility fracture prevention is one of the most important aspects of healthy aging that we, as women’s health care providers (HCPs), must be sure is part of our thought process in caring for women at midlife and beyond. Virtually all ObGyn HCPs are aware of breast health, both in terms of the clinical breast exam and imaging surveillance. The 5-year relative survival rate for “localized breast cancer” is 99%.¹ Most recent data on hip fracture, however, indicate that it is associated with a mortality in the first year of 21%!² We need to be sure that our patients understand this.

Previously, this column provided an update on osteoporosis. In 2016, I asked to change the focus to “Update on bone health” to highlight that simply relying on dual energy x-ray absorptiometry (DXA) testing of bone mass with arbitrary cutoffs for osteoporosis, osteopenia, and normal bone mass is not adequate for improving overall bone health. The addition of the FRAX fracture risk assessment tool, now widely employed, as well as the trabecular bone score (TBS), not widely employed, helps to refine the assessment of patients’ risk status. Further, issues such as sarcopenia, adequate dietary calcium and vitamin D supplementation, and fall prevention (improving balance, use of nonskid rugs in the bathroom, avoiding black ice when present, having nothing to slip on between the bed and the bathroom in the middle of the night, and so on) also are essential elements of “bone health.”

Finally, I cannot stress enough the importance of developing a good relationship with whatever facility one uses for DXA testing in order to maximize use of the reports and potential limitations. In addition, we should identify a metabolic bone specialist for referral of unusual cases or patients who require medications unlikely to be prescribed by us as ObGyns, and develop some familiarity with therapies that may be utilized.

Osteosarcopenia greatly enhances fall and fracture risk

Sepúlveda-Loyola W, Phu S, Bani Hassan E, et al. The joint occurrence of osteoporosis and sarcopenia (osteosarcopenia): definitions and characteristics. J Am Med Dir Assoc. 2020;21:220-225.

Tokeshi S, Eguchi Y, Suzuki M, et al. Relationship between skeletal muscle mass, bone mineral density, and trabecular bone score in osteoporotic vertebral compression fractures. Asian Spine J. 2020 Sep 3. doi: 10.31616/asj.2020.0045.

Kirk B, Zanker J, Duque G. Osteosarcopenia: epidemiology, diagnosis, and treatment—facts and numbers. J Cachexia Sarcopenia Muscle. 2020;11:609-618.

The topic of sarcopenia as defined by the concurrent presence of low muscle mass, physical performance, and strength has been discussed previously in this Update series.³ Now, osteosarcopenia, defined as the concomitant presence of osteoporosis or osteopenia combined with sarcopenia, seems to be an extremely important gauge of fracture risk, especially now as the population’s longevity has increased dramatically. This new syndrome is associated with higher disability and rates of fracture and falls in older people compared with either entity (the bone component or the sarcopenia component) alone.^4,5 In fact, in the 2016 ICD-10-CM, sarcopenia was finally recognized as a disease entity.

Severe sarcopenia is known to increase the risk for falls.⁶ Furthermore, evidence is increasing of cross talk between muscle and bone.⁴ The diagnostic criteria of osteopenia and osteoporosis are well established; however, absolute criteria for sarcopenia lack an international consensus.

Continue to: Assess for osteopenia/osteoporosis plus sarcopenia to determine those at greatest fracture risk...

Assess for osteopenia/osteoporosis plus sarcopenia to determine those at greatest fracture risk

Sepúlveda-Loyola and colleagues performed a cross-sectional analysis of 253 participants, of which 77% were women, average age 78, who presented for a “falls and fractures” risk assessment. T-scores were measured by DXA. In addition, the investigators measured components of sarcopenia, including physical performance (evaluated by hand grip strength, gait speed, timed up and go test, and 5-time sit to stand test) and dynamic and static balance. Falls in the previous year were self-reported, with 42% of participants having fallen once and 54%, more than once.

Results. Participants with osteosarcopenia had a statistically significant increased rate of falls of approximately threefold and an increased rate of fractures that was approximately fourfold when compared with osteopenia or osteoporosis alone.

Another important finding was that, despite the links between osteoporosis, fracture, and poor clinical outcomes, the investigators did not find differences in fracture rates in the osteopenic compared with the osteoporotic classifications. Their findings corroborated those of other studies that reported discrepancies in fractures and bone mineral density (BMD), with osteopenic older adults experiencing fracture rates similar to and in some cases greater than those diagnosed with osteoporosis.⁷

Thus, it appears that the use of T-scores that combine osteopenic and osteoporotic criteria into the osteosarcopenic category may be sufficient to capture individuals at the greatest risk of fracture.

Skeletal muscle mass plays a role in vertebral compression fractures

Tokeshi and colleagues conducted retrospective observational study to investigate the relationships between skeletal muscle mass, BMD, and TBS in individuals with osteoporotic vertebral compression fractures.

They evaluated 142 patients with an average age of 75; of these, 30% had radiographically diagnosed vertebral compression fractures (average age, 79) and 70% had no vertebral compression fractures (average age, 70). Body composition was measured using whole-body DXA; appendicular skeletal muscle mass index was determined as the sum of upper and lower extremities’ lean mass (kg/height in m² ). TBS was measured using the patented algorithm software on DXA scans for the lumbar vertebrae.

Results. The investigators found that the vertebral compression fracture group was statistically significantly older, had lower femur BMD, and had decreased leg muscle mass. The TBS was not identified as a risk factor.

Certain lifestyle factors add to risk of osteosarcopenia

In an editorial, Kirk and colleagues summarized the epidemiology, diagnosis, and treatment of osteosarcopenia. They concluded that this syndrome can be expected to grow in age-related and disease-related states as a consequence of immunosenescence coinciding with an increase in sedentary lifestyle, obesity, and fat infiltration of muscle and bone.

Increasingly, clinicians should screen for osteosarcopenia via imaging methods (DXA) to quantitate bone mass (as is currently done) and, increasingly, quantify muscle mass. In addition, assessment of muscle strength, easily done by testing grip strength, as well as functional capacity (gait speed), will become increasingly important.

Finally, the authors call for a more comprehensive geriatric assessment that includes medical history and risk factors as well as treatment (including osteoporosis drugs, where indicated), and progressive resistance and balance exercises. Nutritional recommendations, in terms of protein, vitamin D, and calcium, also are necessary. They anticipate that diagnosis and treatment of osteosarcopenia will become part of routine health care in the future.

Continue to: The denosumab discontinuation dilemma...

The denosumab discontinuation dilemma

Lyu H, Yoshida K, Zhao SS, et al. Delayed denosumab injections and fracture risk among patients with osteoporosis: a population-based cohort study. Ann Intern Med. 2020;173:516-526.

Tripto-Shkolnik L, Fund N, Rouach V, et al. Fracture incidence after denosumab discontinuation: real-world data from a large healthcare provider. Bone. 2020;130:115150.

Denosumab, marketed under the brand name Prolia, is a human monoclonal antibody that blocks the binding of RANK ligand and inhibits development and activity of osteoclast, thus decreasing bone resorption and increasing BMD. In the original pivotal clinical trial of denosumab, almost 7,900 women between the ages of 60 and 90 (average age, 73) with osteoporotic T-scores were enrolled.⁸ The women were randomly assigned to receive 60 mg of denosumab subcutaneously every 6 months or placebo for a total of 3 years. In that trial, the denosumabtreated group, relative to the placebo group, showed a statistically significant decrease in radiographic vertebral fracture, hip fracture, and nonvertebral fracture. 

An open-label extension study looked at denosumab use for a total of 10 years.⁹ That study found that denosumab treatment for up to 10 years was associated with low rates of adverse events, low fracture incidence compared with that observed during the original trial, and continued increases in BMD without plateau. Thus, denosumab appeared to be an extremely safe and effective agent for treating postmenopausal women with osteoporosis.

Denosumab cessation leads to rebound vertebral fractures

As opposed to bisphosphonates, denosumab does not incorporate into bone matrix, and bone turnover is not suppressed after cessation of its use. Reports have implied that denosumab discontinuation may lead to an increased risk of multiple vertebral fractures.¹⁰ One theory is that unlike atypical femoral fractures that seem to emerge from failure of microdamage repair in cortical bone with long-term antiresorptive treatment, denosumab rebound–associated vertebral fractures seem to originate from the synergy of rapid bone resorption and accelerated microdamage accumulation in trabecular bone triggered by the discontinuation of this highly potent reversible agent.¹¹

Post hoc analysis of the denosumab placebo-controlled trial and its extension reported that the vertebral fracture rate increased after denosumab discontinuation to the level observed in untreated patients.¹² Further, a majority of participants who did sustain vertebral fracture after discontinuing denosumab had multiple vertebral fractures, with the risk being greatest in participants who had a prior vertebral facture. This caused those authors to suggest that patients who discontinued denosumab should rapidly transition to an alternative antiresorptive treatment.

Effect of dose delays, discontinuation on vertebral fracture rate

Lyu and colleagues recently described their population-based cohort study of the United Kingdom’s Health Improvement Network primary care database between 2010 and 2019. They found that delayed administration of a subsequent denosumab dose by more than 16 weeks was associated with an increased risk for vertebral fracture compared with on-time dosing. They noted, however, that the evidence was insufficient to conclude that fracture risk at any other anatomic sites is increased with such a delay.

In a similar study, Tripto-Shkolnik and colleagues examined an Israeli database of 2.3 million members in a state-mandated health organization. They identified osteoporotic patients with at least 2 denosumab prescription dispenses and defined treatment discontinuation as a refill gap of 3 months or more. Fractures were identified by an osteoporosis registry, including fractures that occurred within 1 year from discontinuation in denosumab discontinuers as well as from the second year of treatment forward for persistent users. They identified 1,500 denosumab discontinuers (average age, 72) and 1,610 persistent users (average age also 72). At baseline, the groups were comparable in fracture history, smoking, and bone density.

In the discontinuation group, 0.8% had multiple vertebral fractures versus 0.1% in the persistent users (P = .006); the overall rate of fractures per 100 patient-years of follow-up was 3 times higher in the discontinuation group than in the persistent user group, and the rate of vertebral fractures was almost 5 times higher in the discontinuation group.

Continue to: Atypical femur fracture risk and bisphosphonate use...

Atypical femur fracture risk and bisphosphonate use

Black DM, Geiger EJ, Eastell R, et al. Atypical femur fracture risk versus fragility fracture prevention with bisphosphonates. N Engl J Med. 2020;383:743-753.

Since their introduction in the 1990s, bisphosphonates have been the mainstay of osteoporosis treatment. This category of medications inhibits osteoclast-mediated resorption and remodeling of bone. Various large, randomized, controlled trials have established the efficacy of bisphosphonates to increase BMD and decrease the risk of hip and vertebral fracture by as much as 40% to 70%.¹³

However, case reports of unusual fragility fractures in the subtrochanteric region and along the femoral diaphysis in patients treated with bisphosphonates started to appear approximately 15 years ago.¹⁴ Since then, concerns and publicity about these atypical fractures have led to substantial declines in bisphosphonate use clinically.

Bisphosphonate preventive benefits versus atypical fracture risk

Black and colleagues reviewed data on women 50 years and older who were enrolled in the Kaiser Permanente health care system in California. The total cohort included slightly more than 1 million women, of which almost 200,000 (17.9%) used bisphosphonates at any point from 2007–2017.

A total of 277 atypical femur fractures occurred. Among bisphosphonate users, there were 1.74 fractures per 10,000 patient-years. Overall, there were almost 59 fractures per 10,000 person-years. The incidence of atypical fractures was highest in women between the ages of 75 and 84 years, and the incidence diminished after age 85. Rates of atypical fractures increased as the duration of bisphosphonate use increased. In addition, rates of atypical fractures decreased with time since bisphosphonate discontinuation.

The rate of atypical fractures in women who had never received bisphosphonate therapy was 0.1 per 10,000 person-years. The number of fractures prevented for each fracture type far outweighed bisphosphonate-associated atypical fractures at all time points along the 10 years of study. In White women, for instance, at 3 years there were 541 clinical fractures prevented and 149 hip fractures prevented, while 2 bisphosphonate-associated atypical fractures occurred, all per 10,000 women.

Interestingly, in the Asian population at the same time point, 330 clinical fractures were prevented and 91 hip fractures were prevented, but 8 atypical fractures of the femur occurred, per 10,000 women. The authors further referenced an earlier Kaiser study that showed that 49% of 142 atypical femur fractures occurred in Asian patients who comprised only 10% of the study population.¹⁵

The authors concluded that the risk of atypical femur fracture increases with longer duration of bisphosphate use and rapidly decreases after bisphosphate discontinuation. Asian women have a higher risk than White women. With bisphosphonate treatment, the absolute risk of atypical femur fracture is very low compared with the reduction in the risk of hip and other fractures.

Continue to: Romosozumab increases BMD gains and improves T-scores...

Romosozumab increases BMD gains and improves T-scores

Cosman F, Lewiecki EM, Ebeling PR, et al. T-score as an indicator of fracture risk during treatment with romosozumab or alendronate in the ARCH trial. J Bone Miner Res. 2020;35:1333-1342

Romosozumab (Evenity) is a monoclonal antibody that binds and inhibits sclerostin, thus having the dual effect of increasing bone formation and decreasing bone resorption.¹⁶ It is administered for 1 year as monthly doses of 210 mg subcutaneously. Previous studies have shown that romosozumab produces large increases in lumbar spine and total hip BMD,¹⁷ reduces the risk of new vertebral and clinical fractures compared with placebo,¹⁶ and reduces the risk of vertebral, clinical, nonvertebral, and hip fractures compared with alendronate over a median treatment period of 33 months (the ARCH study).¹⁸

According to the package insert, romosozumab is indicated “for the treatment of osteoporosis in postmenopausal women at high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture; or patients who have failed or are intolerant to other available osteoporosis therapy.”

Should T-score be a therapeutic target?

Cosman and colleagues performed a post hoc analysis of the ARCH trial specifically to evaluate mean BMD and corresponding mean T-score changes (and the relationships between T-scores) after 1 year of romosozumab or alendronate therapy and subsequent fracture incidence. The study is quite detailed with much numerical data and statistical analysis.

Basically, the ARCH trial randomly assigned patients with osteoporosis to receive either monthly subcutaneous romosozumab 210 mg or weekly oral alendronate 70 mg for 12 months. After the double-blind portion of the trial, all patients received open label weekly oral alendronate 70 mg through the end of study (24 months), although they were still blinded to the initial treatment assignment. In addition, patients received daily calcium and vitamin D supplements.

The data analysis found that 1 year of romosozumab led to larger BMD gains than alendronate therapy. Also, the T-score achieved with either therapy was directly related to subsequent fracture risk. The authors thus proposed that these data support the use of the T-score as a therapeutic target for patients with osteoporosis.

It is important to note that in the original ARCH study, the participants’ average age was 71 years and approximately one-third were older than 75. The average T-score was -2.7 at both the lumbar spine and femoral neck. Approximately 20% of patients had a pre-existing vertebral fracture, and approximately 20% had a previous nonvertebral fracture.

The authors of the current study, furthermore, found that mean BMD gains after 1 year of romosozumab treatment were more than twice those seen with alendronate at the total hip, femoral neck, and lumbar spine. These BMD changes resulted in a larger proportion of patients who achieved T-scores above the osteoporosis level at each of the skeletal sites after 1 year of therapy. Fewer fractures occurred during the second year and the entire open label period among patients who had received romosozumab first compared with those who received alendronate.●

Increasingly, bone health and fragility fracture prevention is one of the most important aspects of healthy aging that we, as women’s health care providers (HCPs), must be sure is part of our thought process in caring for women at midlife and beyond. Virtually all ObGyn HCPs are aware of breast health, both in terms of the clinical breast exam and imaging surveillance. The 5-year relative survival rate for “localized breast cancer” is 99%.¹ Most recent data on hip fracture, however, indicate that it is associated with a mortality in the first year of 21%!² We need to be sure that our patients understand this.

Previously, this column provided an update on osteoporosis. In 2016, I asked to change the focus to “Update on bone health” to highlight that simply relying on dual energy x-ray absorptiometry (DXA) testing of bone mass with arbitrary cutoffs for osteoporosis, osteopenia, and normal bone mass is not adequate for improving overall bone health. The addition of the FRAX fracture risk assessment tool, now widely employed, as well as the trabecular bone score (TBS), not widely employed, helps to refine the assessment of patients’ risk status. Further, issues such as sarcopenia, adequate dietary calcium and vitamin D supplementation, and fall prevention (improving balance, use of nonskid rugs in the bathroom, avoiding black ice when present, having nothing to slip on between the bed and the bathroom in the middle of the night, and so on) also are essential elements of “bone health.”

Finally, I cannot stress enough the importance of developing a good relationship with whatever facility one uses for DXA testing in order to maximize use of the reports and potential limitations. In addition, we should identify a metabolic bone specialist for referral of unusual cases or patients who require medications unlikely to be prescribed by us as ObGyns, and develop some familiarity with therapies that may be utilized.

Osteosarcopenia greatly enhances fall and fracture risk

Sepúlveda-Loyola W, Phu S, Bani Hassan E, et al. The joint occurrence of osteoporosis and sarcopenia (osteosarcopenia): definitions and characteristics. J Am Med Dir Assoc. 2020;21:220-225.

Tokeshi S, Eguchi Y, Suzuki M, et al. Relationship between skeletal muscle mass, bone mineral density, and trabecular bone score in osteoporotic vertebral compression fractures. Asian Spine J. 2020 Sep 3. doi: 10.31616/asj.2020.0045.

Kirk B, Zanker J, Duque G. Osteosarcopenia: epidemiology, diagnosis, and treatment—facts and numbers. J Cachexia Sarcopenia Muscle. 2020;11:609-618.

The topic of sarcopenia as defined by the concurrent presence of low muscle mass, physical performance, and strength has been discussed previously in this Update series.³ Now, osteosarcopenia, defined as the concomitant presence of osteoporosis or osteopenia combined with sarcopenia, seems to be an extremely important gauge of fracture risk, especially now as the population’s longevity has increased dramatically. This new syndrome is associated with higher disability and rates of fracture and falls in older people compared with either entity (the bone component or the sarcopenia component) alone.^4,5 In fact, in the 2016 ICD-10-CM, sarcopenia was finally recognized as a disease entity.

Severe sarcopenia is known to increase the risk for falls.⁶ Furthermore, evidence is increasing of cross talk between muscle and bone.⁴ The diagnostic criteria of osteopenia and osteoporosis are well established; however, absolute criteria for sarcopenia lack an international consensus.

Continue to: Assess for osteopenia/osteoporosis plus sarcopenia to determine those at greatest fracture risk...

Assess for osteopenia/osteoporosis plus sarcopenia to determine those at greatest fracture risk

Sepúlveda-Loyola and colleagues performed a cross-sectional analysis of 253 participants, of which 77% were women, average age 78, who presented for a “falls and fractures” risk assessment. T-scores were measured by DXA. In addition, the investigators measured components of sarcopenia, including physical performance (evaluated by hand grip strength, gait speed, timed up and go test, and 5-time sit to stand test) and dynamic and static balance. Falls in the previous year were self-reported, with 42% of participants having fallen once and 54%, more than once.

Results. Participants with osteosarcopenia had a statistically significant increased rate of falls of approximately threefold and an increased rate of fractures that was approximately fourfold when compared with osteopenia or osteoporosis alone.

Another important finding was that, despite the links between osteoporosis, fracture, and poor clinical outcomes, the investigators did not find differences in fracture rates in the osteopenic compared with the osteoporotic classifications. Their findings corroborated those of other studies that reported discrepancies in fractures and bone mineral density (BMD), with osteopenic older adults experiencing fracture rates similar to and in some cases greater than those diagnosed with osteoporosis.⁷

Thus, it appears that the use of T-scores that combine osteopenic and osteoporotic criteria into the osteosarcopenic category may be sufficient to capture individuals at the greatest risk of fracture.

Skeletal muscle mass plays a role in vertebral compression fractures

Tokeshi and colleagues conducted retrospective observational study to investigate the relationships between skeletal muscle mass, BMD, and TBS in individuals with osteoporotic vertebral compression fractures.

They evaluated 142 patients with an average age of 75; of these, 30% had radiographically diagnosed vertebral compression fractures (average age, 79) and 70% had no vertebral compression fractures (average age, 70). Body composition was measured using whole-body DXA; appendicular skeletal muscle mass index was determined as the sum of upper and lower extremities’ lean mass (kg/height in m² ). TBS was measured using the patented algorithm software on DXA scans for the lumbar vertebrae.

Results. The investigators found that the vertebral compression fracture group was statistically significantly older, had lower femur BMD, and had decreased leg muscle mass. The TBS was not identified as a risk factor.

Certain lifestyle factors add to risk of osteosarcopenia

In an editorial, Kirk and colleagues summarized the epidemiology, diagnosis, and treatment of osteosarcopenia. They concluded that this syndrome can be expected to grow in age-related and disease-related states as a consequence of immunosenescence coinciding with an increase in sedentary lifestyle, obesity, and fat infiltration of muscle and bone.

Increasingly, clinicians should screen for osteosarcopenia via imaging methods (DXA) to quantitate bone mass (as is currently done) and, increasingly, quantify muscle mass. In addition, assessment of muscle strength, easily done by testing grip strength, as well as functional capacity (gait speed), will become increasingly important.

Finally, the authors call for a more comprehensive geriatric assessment that includes medical history and risk factors as well as treatment (including osteoporosis drugs, where indicated), and progressive resistance and balance exercises. Nutritional recommendations, in terms of protein, vitamin D, and calcium, also are necessary. They anticipate that diagnosis and treatment of osteosarcopenia will become part of routine health care in the future.

Continue to: The denosumab discontinuation dilemma...

The denosumab discontinuation dilemma

Lyu H, Yoshida K, Zhao SS, et al. Delayed denosumab injections and fracture risk among patients with osteoporosis: a population-based cohort study. Ann Intern Med. 2020;173:516-526.

Tripto-Shkolnik L, Fund N, Rouach V, et al. Fracture incidence after denosumab discontinuation: real-world data from a large healthcare provider. Bone. 2020;130:115150.

Denosumab, marketed under the brand name Prolia, is a human monoclonal antibody that blocks the binding of RANK ligand and inhibits development and activity of osteoclast, thus decreasing bone resorption and increasing BMD. In the original pivotal clinical trial of denosumab, almost 7,900 women between the ages of 60 and 90 (average age, 73) with osteoporotic T-scores were enrolled.⁸ The women were randomly assigned to receive 60 mg of denosumab subcutaneously every 6 months or placebo for a total of 3 years. In that trial, the denosumabtreated group, relative to the placebo group, showed a statistically significant decrease in radiographic vertebral fracture, hip fracture, and nonvertebral fracture. 

An open-label extension study looked at denosumab use for a total of 10 years.⁹ That study found that denosumab treatment for up to 10 years was associated with low rates of adverse events, low fracture incidence compared with that observed during the original trial, and continued increases in BMD without plateau. Thus, denosumab appeared to be an extremely safe and effective agent for treating postmenopausal women with osteoporosis.

Denosumab cessation leads to rebound vertebral fractures

As opposed to bisphosphonates, denosumab does not incorporate into bone matrix, and bone turnover is not suppressed after cessation of its use. Reports have implied that denosumab discontinuation may lead to an increased risk of multiple vertebral fractures.¹⁰ One theory is that unlike atypical femoral fractures that seem to emerge from failure of microdamage repair in cortical bone with long-term antiresorptive treatment, denosumab rebound–associated vertebral fractures seem to originate from the synergy of rapid bone resorption and accelerated microdamage accumulation in trabecular bone triggered by the discontinuation of this highly potent reversible agent.¹¹

Post hoc analysis of the denosumab placebo-controlled trial and its extension reported that the vertebral fracture rate increased after denosumab discontinuation to the level observed in untreated patients.¹² Further, a majority of participants who did sustain vertebral fracture after discontinuing denosumab had multiple vertebral fractures, with the risk being greatest in participants who had a prior vertebral facture. This caused those authors to suggest that patients who discontinued denosumab should rapidly transition to an alternative antiresorptive treatment.

Effect of dose delays, discontinuation on vertebral fracture rate

Lyu and colleagues recently described their population-based cohort study of the United Kingdom’s Health Improvement Network primary care database between 2010 and 2019. They found that delayed administration of a subsequent denosumab dose by more than 16 weeks was associated with an increased risk for vertebral fracture compared with on-time dosing. They noted, however, that the evidence was insufficient to conclude that fracture risk at any other anatomic sites is increased with such a delay.

In a similar study, Tripto-Shkolnik and colleagues examined an Israeli database of 2.3 million members in a state-mandated health organization. They identified osteoporotic patients with at least 2 denosumab prescription dispenses and defined treatment discontinuation as a refill gap of 3 months or more. Fractures were identified by an osteoporosis registry, including fractures that occurred within 1 year from discontinuation in denosumab discontinuers as well as from the second year of treatment forward for persistent users. They identified 1,500 denosumab discontinuers (average age, 72) and 1,610 persistent users (average age also 72). At baseline, the groups were comparable in fracture history, smoking, and bone density.

In the discontinuation group, 0.8% had multiple vertebral fractures versus 0.1% in the persistent users (P = .006); the overall rate of fractures per 100 patient-years of follow-up was 3 times higher in the discontinuation group than in the persistent user group, and the rate of vertebral fractures was almost 5 times higher in the discontinuation group.

Continue to: Atypical femur fracture risk and bisphosphonate use...

Atypical femur fracture risk and bisphosphonate use

Black DM, Geiger EJ, Eastell R, et al. Atypical femur fracture risk versus fragility fracture prevention with bisphosphonates. N Engl J Med. 2020;383:743-753.

Since their introduction in the 1990s, bisphosphonates have been the mainstay of osteoporosis treatment. This category of medications inhibits osteoclast-mediated resorption and remodeling of bone. Various large, randomized, controlled trials have established the efficacy of bisphosphonates to increase BMD and decrease the risk of hip and vertebral fracture by as much as 40% to 70%.¹³

However, case reports of unusual fragility fractures in the subtrochanteric region and along the femoral diaphysis in patients treated with bisphosphonates started to appear approximately 15 years ago.¹⁴ Since then, concerns and publicity about these atypical fractures have led to substantial declines in bisphosphonate use clinically.

Bisphosphonate preventive benefits versus atypical fracture risk

Black and colleagues reviewed data on women 50 years and older who were enrolled in the Kaiser Permanente health care system in California. The total cohort included slightly more than 1 million women, of which almost 200,000 (17.9%) used bisphosphonates at any point from 2007–2017.

A total of 277 atypical femur fractures occurred. Among bisphosphonate users, there were 1.74 fractures per 10,000 patient-years. Overall, there were almost 59 fractures per 10,000 person-years. The incidence of atypical fractures was highest in women between the ages of 75 and 84 years, and the incidence diminished after age 85. Rates of atypical fractures increased as the duration of bisphosphonate use increased. In addition, rates of atypical fractures decreased with time since bisphosphonate discontinuation.

The rate of atypical fractures in women who had never received bisphosphonate therapy was 0.1 per 10,000 person-years. The number of fractures prevented for each fracture type far outweighed bisphosphonate-associated atypical fractures at all time points along the 10 years of study. In White women, for instance, at 3 years there were 541 clinical fractures prevented and 149 hip fractures prevented, while 2 bisphosphonate-associated atypical fractures occurred, all per 10,000 women.

Interestingly, in the Asian population at the same time point, 330 clinical fractures were prevented and 91 hip fractures were prevented, but 8 atypical fractures of the femur occurred, per 10,000 women. The authors further referenced an earlier Kaiser study that showed that 49% of 142 atypical femur fractures occurred in Asian patients who comprised only 10% of the study population.¹⁵

The authors concluded that the risk of atypical femur fracture increases with longer duration of bisphosphate use and rapidly decreases after bisphosphate discontinuation. Asian women have a higher risk than White women. With bisphosphonate treatment, the absolute risk of atypical femur fracture is very low compared with the reduction in the risk of hip and other fractures.

Continue to: Romosozumab increases BMD gains and improves T-scores...

Romosozumab increases BMD gains and improves T-scores

Cosman F, Lewiecki EM, Ebeling PR, et al. T-score as an indicator of fracture risk during treatment with romosozumab or alendronate in the ARCH trial. J Bone Miner Res. 2020;35:1333-1342

Romosozumab (Evenity) is a monoclonal antibody that binds and inhibits sclerostin, thus having the dual effect of increasing bone formation and decreasing bone resorption.¹⁶ It is administered for 1 year as monthly doses of 210 mg subcutaneously. Previous studies have shown that romosozumab produces large increases in lumbar spine and total hip BMD,¹⁷ reduces the risk of new vertebral and clinical fractures compared with placebo,¹⁶ and reduces the risk of vertebral, clinical, nonvertebral, and hip fractures compared with alendronate over a median treatment period of 33 months (the ARCH study).¹⁸

According to the package insert, romosozumab is indicated “for the treatment of osteoporosis in postmenopausal women at high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture; or patients who have failed or are intolerant to other available osteoporosis therapy.”

Should T-score be a therapeutic target?

Cosman and colleagues performed a post hoc analysis of the ARCH trial specifically to evaluate mean BMD and corresponding mean T-score changes (and the relationships between T-scores) after 1 year of romosozumab or alendronate therapy and subsequent fracture incidence. The study is quite detailed with much numerical data and statistical analysis.

Basically, the ARCH trial randomly assigned patients with osteoporosis to receive either monthly subcutaneous romosozumab 210 mg or weekly oral alendronate 70 mg for 12 months. After the double-blind portion of the trial, all patients received open label weekly oral alendronate 70 mg through the end of study (24 months), although they were still blinded to the initial treatment assignment. In addition, patients received daily calcium and vitamin D supplements.

The data analysis found that 1 year of romosozumab led to larger BMD gains than alendronate therapy. Also, the T-score achieved with either therapy was directly related to subsequent fracture risk. The authors thus proposed that these data support the use of the T-score as a therapeutic target for patients with osteoporosis.

It is important to note that in the original ARCH study, the participants’ average age was 71 years and approximately one-third were older than 75. The average T-score was -2.7 at both the lumbar spine and femoral neck. Approximately 20% of patients had a pre-existing vertebral fracture, and approximately 20% had a previous nonvertebral fracture.

The authors of the current study, furthermore, found that mean BMD gains after 1 year of romosozumab treatment were more than twice those seen with alendronate at the total hip, femoral neck, and lumbar spine. These BMD changes resulted in a larger proportion of patients who achieved T-scores above the osteoporosis level at each of the skeletal sites after 1 year of therapy. Fewer fractures occurred during the second year and the entire open label period among patients who had received romosozumab first compared with those who received alendronate.●

Increasingly, bone health and fragility fracture prevention is one of the most important aspects of healthy aging that we, as women’s health care providers (HCPs), must be sure is part of our thought process in caring for women at midlife and beyond. Virtually all ObGyn HCPs are aware of breast health, both in terms of the clinical breast exam and imaging surveillance. The 5-year relative survival rate for “localized breast cancer” is 99%.¹ Most recent data on hip fracture, however, indicate that it is associated with a mortality in the first year of 21%!² We need to be sure that our patients understand this.

Previously, this column provided an update on osteoporosis. In 2016, I asked to change the focus to “Update on bone health” to highlight that simply relying on dual energy x-ray absorptiometry (DXA) testing of bone mass with arbitrary cutoffs for osteoporosis, osteopenia, and normal bone mass is not adequate for improving overall bone health. The addition of the FRAX fracture risk assessment tool, now widely employed, as well as the trabecular bone score (TBS), not widely employed, helps to refine the assessment of patients’ risk status. Further, issues such as sarcopenia, adequate dietary calcium and vitamin D supplementation, and fall prevention (improving balance, use of nonskid rugs in the bathroom, avoiding black ice when present, having nothing to slip on between the bed and the bathroom in the middle of the night, and so on) also are essential elements of “bone health.”

Finally, I cannot stress enough the importance of developing a good relationship with whatever facility one uses for DXA testing in order to maximize use of the reports and potential limitations. In addition, we should identify a metabolic bone specialist for referral of unusual cases or patients who require medications unlikely to be prescribed by us as ObGyns, and develop some familiarity with therapies that may be utilized.

Osteosarcopenia greatly enhances fall and fracture risk

Sepúlveda-Loyola W, Phu S, Bani Hassan E, et al. The joint occurrence of osteoporosis and sarcopenia (osteosarcopenia): definitions and characteristics. J Am Med Dir Assoc. 2020;21:220-225.

Tokeshi S, Eguchi Y, Suzuki M, et al. Relationship between skeletal muscle mass, bone mineral density, and trabecular bone score in osteoporotic vertebral compression fractures. Asian Spine J. 2020 Sep 3. doi: 10.31616/asj.2020.0045.

Kirk B, Zanker J, Duque G. Osteosarcopenia: epidemiology, diagnosis, and treatment—facts and numbers. J Cachexia Sarcopenia Muscle. 2020;11:609-618.

The topic of sarcopenia as defined by the concurrent presence of low muscle mass, physical performance, and strength has been discussed previously in this Update series.³ Now, osteosarcopenia, defined as the concomitant presence of osteoporosis or osteopenia combined with sarcopenia, seems to be an extremely important gauge of fracture risk, especially now as the population’s longevity has increased dramatically. This new syndrome is associated with higher disability and rates of fracture and falls in older people compared with either entity (the bone component or the sarcopenia component) alone.^4,5 In fact, in the 2016 ICD-10-CM, sarcopenia was finally recognized as a disease entity.

Severe sarcopenia is known to increase the risk for falls.⁶ Furthermore, evidence is increasing of cross talk between muscle and bone.⁴ The diagnostic criteria of osteopenia and osteoporosis are well established; however, absolute criteria for sarcopenia lack an international consensus.

Continue to: Assess for osteopenia/osteoporosis plus sarcopenia to determine those at greatest fracture risk...

Assess for osteopenia/osteoporosis plus sarcopenia to determine those at greatest fracture risk

Sepúlveda-Loyola and colleagues performed a cross-sectional analysis of 253 participants, of which 77% were women, average age 78, who presented for a “falls and fractures” risk assessment. T-scores were measured by DXA. In addition, the investigators measured components of sarcopenia, including physical performance (evaluated by hand grip strength, gait speed, timed up and go test, and 5-time sit to stand test) and dynamic and static balance. Falls in the previous year were self-reported, with 42% of participants having fallen once and 54%, more than once.

Results. Participants with osteosarcopenia had a statistically significant increased rate of falls of approximately threefold and an increased rate of fractures that was approximately fourfold when compared with osteopenia or osteoporosis alone.

Another important finding was that, despite the links between osteoporosis, fracture, and poor clinical outcomes, the investigators did not find differences in fracture rates in the osteopenic compared with the osteoporotic classifications. Their findings corroborated those of other studies that reported discrepancies in fractures and bone mineral density (BMD), with osteopenic older adults experiencing fracture rates similar to and in some cases greater than those diagnosed with osteoporosis.⁷

Thus, it appears that the use of T-scores that combine osteopenic and osteoporotic criteria into the osteosarcopenic category may be sufficient to capture individuals at the greatest risk of fracture.

Skeletal muscle mass plays a role in vertebral compression fractures

Tokeshi and colleagues conducted retrospective observational study to investigate the relationships between skeletal muscle mass, BMD, and TBS in individuals with osteoporotic vertebral compression fractures.

They evaluated 142 patients with an average age of 75; of these, 30% had radiographically diagnosed vertebral compression fractures (average age, 79) and 70% had no vertebral compression fractures (average age, 70). Body composition was measured using whole-body DXA; appendicular skeletal muscle mass index was determined as the sum of upper and lower extremities’ lean mass (kg/height in m² ). TBS was measured using the patented algorithm software on DXA scans for the lumbar vertebrae.

Results. The investigators found that the vertebral compression fracture group was statistically significantly older, had lower femur BMD, and had decreased leg muscle mass. The TBS was not identified as a risk factor.

Certain lifestyle factors add to risk of osteosarcopenia

In an editorial, Kirk and colleagues summarized the epidemiology, diagnosis, and treatment of osteosarcopenia. They concluded that this syndrome can be expected to grow in age-related and disease-related states as a consequence of immunosenescence coinciding with an increase in sedentary lifestyle, obesity, and fat infiltration of muscle and bone.

Increasingly, clinicians should screen for osteosarcopenia via imaging methods (DXA) to quantitate bone mass (as is currently done) and, increasingly, quantify muscle mass. In addition, assessment of muscle strength, easily done by testing grip strength, as well as functional capacity (gait speed), will become increasingly important.

Finally, the authors call for a more comprehensive geriatric assessment that includes medical history and risk factors as well as treatment (including osteoporosis drugs, where indicated), and progressive resistance and balance exercises. Nutritional recommendations, in terms of protein, vitamin D, and calcium, also are necessary. They anticipate that diagnosis and treatment of osteosarcopenia will become part of routine health care in the future.

Continue to: The denosumab discontinuation dilemma...

The denosumab discontinuation dilemma

Lyu H, Yoshida K, Zhao SS, et al. Delayed denosumab injections and fracture risk among patients with osteoporosis: a population-based cohort study. Ann Intern Med. 2020;173:516-526.

Tripto-Shkolnik L, Fund N, Rouach V, et al. Fracture incidence after denosumab discontinuation: real-world data from a large healthcare provider. Bone. 2020;130:115150.

Denosumab, marketed under the brand name Prolia, is a human monoclonal antibody that blocks the binding of RANK ligand and inhibits development and activity of osteoclast, thus decreasing bone resorption and increasing BMD. In the original pivotal clinical trial of denosumab, almost 7,900 women between the ages of 60 and 90 (average age, 73) with osteoporotic T-scores were enrolled.⁸ The women were randomly assigned to receive 60 mg of denosumab subcutaneously every 6 months or placebo for a total of 3 years. In that trial, the denosumabtreated group, relative to the placebo group, showed a statistically significant decrease in radiographic vertebral fracture, hip fracture, and nonvertebral fracture. 

An open-label extension study looked at denosumab use for a total of 10 years.⁹ That study found that denosumab treatment for up to 10 years was associated with low rates of adverse events, low fracture incidence compared with that observed during the original trial, and continued increases in BMD without plateau. Thus, denosumab appeared to be an extremely safe and effective agent for treating postmenopausal women with osteoporosis.

Denosumab cessation leads to rebound vertebral fractures

As opposed to bisphosphonates, denosumab does not incorporate into bone matrix, and bone turnover is not suppressed after cessation of its use. Reports have implied that denosumab discontinuation may lead to an increased risk of multiple vertebral fractures.¹⁰ One theory is that unlike atypical femoral fractures that seem to emerge from failure of microdamage repair in cortical bone with long-term antiresorptive treatment, denosumab rebound–associated vertebral fractures seem to originate from the synergy of rapid bone resorption and accelerated microdamage accumulation in trabecular bone triggered by the discontinuation of this highly potent reversible agent.¹¹

Post hoc analysis of the denosumab placebo-controlled trial and its extension reported that the vertebral fracture rate increased after denosumab discontinuation to the level observed in untreated patients.¹² Further, a majority of participants who did sustain vertebral fracture after discontinuing denosumab had multiple vertebral fractures, with the risk being greatest in participants who had a prior vertebral facture. This caused those authors to suggest that patients who discontinued denosumab should rapidly transition to an alternative antiresorptive treatment.

Effect of dose delays, discontinuation on vertebral fracture rate

Lyu and colleagues recently described their population-based cohort study of the United Kingdom’s Health Improvement Network primary care database between 2010 and 2019. They found that delayed administration of a subsequent denosumab dose by more than 16 weeks was associated with an increased risk for vertebral fracture compared with on-time dosing. They noted, however, that the evidence was insufficient to conclude that fracture risk at any other anatomic sites is increased with such a delay.

In a similar study, Tripto-Shkolnik and colleagues examined an Israeli database of 2.3 million members in a state-mandated health organization. They identified osteoporotic patients with at least 2 denosumab prescription dispenses and defined treatment discontinuation as a refill gap of 3 months or more. Fractures were identified by an osteoporosis registry, including fractures that occurred within 1 year from discontinuation in denosumab discontinuers as well as from the second year of treatment forward for persistent users. They identified 1,500 denosumab discontinuers (average age, 72) and 1,610 persistent users (average age also 72). At baseline, the groups were comparable in fracture history, smoking, and bone density.

In the discontinuation group, 0.8% had multiple vertebral fractures versus 0.1% in the persistent users (P = .006); the overall rate of fractures per 100 patient-years of follow-up was 3 times higher in the discontinuation group than in the persistent user group, and the rate of vertebral fractures was almost 5 times higher in the discontinuation group.

Continue to: Atypical femur fracture risk and bisphosphonate use...

Atypical femur fracture risk and bisphosphonate use

Black DM, Geiger EJ, Eastell R, et al. Atypical femur fracture risk versus fragility fracture prevention with bisphosphonates. N Engl J Med. 2020;383:743-753.

Since their introduction in the 1990s, bisphosphonates have been the mainstay of osteoporosis treatment. This category of medications inhibits osteoclast-mediated resorption and remodeling of bone. Various large, randomized, controlled trials have established the efficacy of bisphosphonates to increase BMD and decrease the risk of hip and vertebral fracture by as much as 40% to 70%.¹³

However, case reports of unusual fragility fractures in the subtrochanteric region and along the femoral diaphysis in patients treated with bisphosphonates started to appear approximately 15 years ago.¹⁴ Since then, concerns and publicity about these atypical fractures have led to substantial declines in bisphosphonate use clinically.

Bisphosphonate preventive benefits versus atypical fracture risk

Black and colleagues reviewed data on women 50 years and older who were enrolled in the Kaiser Permanente health care system in California. The total cohort included slightly more than 1 million women, of which almost 200,000 (17.9%) used bisphosphonates at any point from 2007–2017.

A total of 277 atypical femur fractures occurred. Among bisphosphonate users, there were 1.74 fractures per 10,000 patient-years. Overall, there were almost 59 fractures per 10,000 person-years. The incidence of atypical fractures was highest in women between the ages of 75 and 84 years, and the incidence diminished after age 85. Rates of atypical fractures increased as the duration of bisphosphonate use increased. In addition, rates of atypical fractures decreased with time since bisphosphonate discontinuation.

The rate of atypical fractures in women who had never received bisphosphonate therapy was 0.1 per 10,000 person-years. The number of fractures prevented for each fracture type far outweighed bisphosphonate-associated atypical fractures at all time points along the 10 years of study. In White women, for instance, at 3 years there were 541 clinical fractures prevented and 149 hip fractures prevented, while 2 bisphosphonate-associated atypical fractures occurred, all per 10,000 women.

Interestingly, in the Asian population at the same time point, 330 clinical fractures were prevented and 91 hip fractures were prevented, but 8 atypical fractures of the femur occurred, per 10,000 women. The authors further referenced an earlier Kaiser study that showed that 49% of 142 atypical femur fractures occurred in Asian patients who comprised only 10% of the study population.¹⁵

The authors concluded that the risk of atypical femur fracture increases with longer duration of bisphosphate use and rapidly decreases after bisphosphate discontinuation. Asian women have a higher risk than White women. With bisphosphonate treatment, the absolute risk of atypical femur fracture is very low compared with the reduction in the risk of hip and other fractures.

Continue to: Romosozumab increases BMD gains and improves T-scores...

Romosozumab increases BMD gains and improves T-scores

Cosman F, Lewiecki EM, Ebeling PR, et al. T-score as an indicator of fracture risk during treatment with romosozumab or alendronate in the ARCH trial. J Bone Miner Res. 2020;35:1333-1342

Romosozumab (Evenity) is a monoclonal antibody that binds and inhibits sclerostin, thus having the dual effect of increasing bone formation and decreasing bone resorption.¹⁶ It is administered for 1 year as monthly doses of 210 mg subcutaneously. Previous studies have shown that romosozumab produces large increases in lumbar spine and total hip BMD,¹⁷ reduces the risk of new vertebral and clinical fractures compared with placebo,¹⁶ and reduces the risk of vertebral, clinical, nonvertebral, and hip fractures compared with alendronate over a median treatment period of 33 months (the ARCH study).¹⁸

According to the package insert, romosozumab is indicated “for the treatment of osteoporosis in postmenopausal women at high risk for fracture, defined as a history of osteoporotic fracture, or multiple risk factors for fracture; or patients who have failed or are intolerant to other available osteoporosis therapy.”

Should T-score be a therapeutic target?

Cosman and colleagues performed a post hoc analysis of the ARCH trial specifically to evaluate mean BMD and corresponding mean T-score changes (and the relationships between T-scores) after 1 year of romosozumab or alendronate therapy and subsequent fracture incidence. The study is quite detailed with much numerical data and statistical analysis.

Basically, the ARCH trial randomly assigned patients with osteoporosis to receive either monthly subcutaneous romosozumab 210 mg or weekly oral alendronate 70 mg for 12 months. After the double-blind portion of the trial, all patients received open label weekly oral alendronate 70 mg through the end of study (24 months), although they were still blinded to the initial treatment assignment. In addition, patients received daily calcium and vitamin D supplements.

The data analysis found that 1 year of romosozumab led to larger BMD gains than alendronate therapy. Also, the T-score achieved with either therapy was directly related to subsequent fracture risk. The authors thus proposed that these data support the use of the T-score as a therapeutic target for patients with osteoporosis.

It is important to note that in the original ARCH study, the participants’ average age was 71 years and approximately one-third were older than 75. The average T-score was -2.7 at both the lumbar spine and femoral neck. Approximately 20% of patients had a pre-existing vertebral fracture, and approximately 20% had a previous nonvertebral fracture.

The authors of the current study, furthermore, found that mean BMD gains after 1 year of romosozumab treatment were more than twice those seen with alendronate at the total hip, femoral neck, and lumbar spine. These BMD changes resulted in a larger proportion of patients who achieved T-scores above the osteoporosis level at each of the skeletal sites after 1 year of therapy. Fewer fractures occurred during the second year and the entire open label period among patients who had received romosozumab first compared with those who received alendronate.●

OBG Management takes the issues of systemic and structural racism incredibly seriously--not just by talking about it but by trying to highlight areas in medicine, particularly in obstetrics and gynecology, that are barriers to progress. In this new series for OBG Management, Board Member Barbara Levy, MD, faces the issues head-on, beginning with this peer-to-peer interview with Pierre Johnson, MD, ObGyn in Chicago, Illinois. Watch for future installments in upcoming issues of OBG Management.

Finding inspiration among life’s challenges

Barbara Levy, MD: I am fortunate to have met Pierre serendipitously at a training that we were both attending and was impressed by Dr. Johnson’s life story, his passion and commitment, and his dedication—not only to his personal career but also to raising up other young men of color by trying to break down barriers that face them. His life story highlights those areas of systemic and structural problems that all of us together need to address if we are going to make any progress.

Pierre Johnson, MD: Thank you, Barbara. A little about myself: I am a board-certified ObGyn, and I specialize in minimally invasive surgery. I was born on the South side of Chicago, experiencing gang violence, drugs, and substandard, underserved schools. Long story short, I had a very rough upbringing. I had a single mom and several different issues at home. I am the oldest of 5 siblings, and life was tough.

But I knew that I wanted to do something different with my life. I saw that there was a need in my community as far as health care was concerned, in particular women’s health and childbirth. I knew early on that I wanted to be an ObGyn, and the reason had a lot to do with The Cosby Show. It was the only example of a positive, successful Black man that I saw. No one graduated from college in my family. There weren’t any models of young Black excellence around me. Saying that I wanted to be a doctor planted a seed. I was 9 when my mom became pregnant with my first sibling, and it was fascinating to me. The physiology of pregnancy, and eventually childbirth, was extremely fascinating to me; it set me off on my journey to be an ObGyn.

As I got older, things didn’t get any easier. I went to high school in one of the toughest areas on the South side of Chicago. Gang violence, and violence in and of itself, were all around me, but I was able to stay focused. I went on to Xavier University in Louisiana.

Dr. Levy: There are some important things that I learned from your book and from talking to you at our first meeting. Your mom’s ObGyn, when she was pregnant with your next youngest sibling, was also a Black ObGyn. He took some time to take you under wing?

Dr. Johnson: He did. My mom’s ObGyn was a Black man. Other than The Cosby Show, that’s the only time I saw something like that. When I spoke to him, he really took the time to answer my questions and show me that he was like me; he wasn’t just a far-off mythical person, or something that I could not obtain.

Continue to: Seeing is believing when it comes to success...

Seeing is believing when it comes to success

Dr. Levy: Do you think it was important to have a role model who wasn’t a sports star?

Dr. Johnson: If you can’t see it, you can’t achieve it. He took his time to really talk to me, and it’s the little things for kids that go a long way in their life experience. I still have a relationship with him to this day. How he handled me as a kid made me realize that this is something that I could do. That was extremely important for me.

Dr. Levy: One of the structural things I think we need to point out is that the ability to see yourself as someone successful is critical. When we see 1,000 images a day and they are all White, and they are all so different from where we are that it gets incorporated into our sense of being. I think that’s really difficult for those of us of with privilege to understand what that privilege is.

Dr. Johnson: Absolutely, and I’ll even go further. In residency, 2 White females were my classmates, and both of their parents were doctors. They had grandparents who were doctors. My mom was addicted to drugs; my father was not around. They had been talking medicine since they were 5. You have to make things equitable, but in medicine it’s really not equitable. In medicine, what we don’t realize is that there is an importance for all aspects of someone’s upbringing and environment, and it’s not just what they can regurgitate on a standardized test. If a patient can’t relate to you and tell you what is wrong with them, how can you adequately treat them?

Dr. Levy: Even if they are trying to tell me, but I can’t hear it because I don’t have the language and I don’t have the background. There are really good data to show, in fact, that Black male physicians do a better job at engaging Black men to manage their hypertension.¹ When we look at the inequities in birth outcomes for women of color, indigenous women and Black women, there’s evidence that providers who come from a similar background do a better job.

Dr. Johnson: There was the study of Black infants that just came out about them dying at a 3-time higher rate in non-Black physicians’ hands.² These things need to be recognized. They need to be discussed, and they need to be identified as issues and then, realistically, we need to start talking about solutions, not get offended by what actual statistics are saying.

Foundational inequities in education

Dr. Levy: To address some of the barriers that you faced: I know that you went to a high school that was not geared toward pushing students into professional careers. Your colleagues, however, had educations that prepared them for the standardized tests and other things that they would face academically.

Dr. Johnson: People think I am kidding when I say it, but when I went into college, I didn’t know what a periodic table was. I saw it, but I had no idea what these things meant. I didn’t have any sciences or any AP classes in high school. I did well, but grades are smoke and mirrors. The true test of medicine comes with testing. From the MCATs to the boards, every step of the way there is a standardized test.

Knowledge is something that you can obtain, but test taking is a cultivated skill that happens from a very early age. Trying to teach an adult or someone in their late teens a skill that they should have learned as a kid is difficult. For me, I did not have that, so I had to program myself. I had to learn how to fundamentally take tests as an adult, where most people understand how to do that going into college and professional school.

Dr. Levy: I was impressed with your resilience. I think all of us as human beings, if we fail a test, we take it personally and think it’s about our lack of knowledge. One of the insights that you came to was that failure on those things was not that you didn’t study hard enough. In fact, you probably studied 4 times harder than most other people. You had the knowledge. Being able to get that knowledge into a standardized structured test score was the huge challenge for you.

Dr. Johnson: That’s it. I can remember taking the MCAT, and if you looked at the step 1 book, I could regurgitate to you everything on that page. However, it’s not a test about do you know it or not. It’s an understanding of the English language and how to break things down to make things fit into particular scenarios.

Continue to: A college experience focused on growth and exposure...

Dr. Levy: I was impressed by the distinction between your experience at Xavier University where there was a lot of support and guidance and help in your premed program, and what happened to you when you hit medical school.

Dr. Johnson: Xavier University in Louisiana is the number 1 institution in the country for getting minorities into professional school. They understand that they have kids that are brilliant but underprepared, and just have not had the background to actually tackle some of these tough curriculums. I always had good grades in school. But by not being challenged, I didn’t know what I didn’t really know. So now that I was seeing biology, chemistry for the first time, and trying to tackle it; there’s a failure point. I didn’t know how to take tests, and I didn’t know how to study properly. The harder I tried, the worse things got for me.

Xavier has seen that story a multitude of times. If I went to a bigger or predominantly White university, a counselor would have told me, “Well, medicine’s maybe not for you. You can’t handle a premed curriculum.” Instead, I said, “Listen, I’m studying. I’m doing all of these things, and I’m not hacking it.” And they broke it down: “Let’s get you into study groups with kids that have had these type of AP classes before. We’ll have you watch how they study,” and everything started to click. That facilitation of how to adjust to this curriculum was a godsend. It’s the only reason I’m here. I am a prime example of being brilliant enough to be able to do it, but needing the infrastructure and a system set up.

Dr. Levy: There’s a great book by Carol Dweck called Mindset that talks about education of young kids and putting them into silos so early in life; the brilliant kids go into the AP courses and the rest are labeled as inadequate. It’s assumed in a fixed mindset based on their heredity and IQ, and not based on the fact that they have not been exposed to the right things.

Xavier was growing you into the man who could, in fact, do all of those things. I think that is one of the systemic and structural issues that we have—that fixed mindset that frames a kid who is not succeeding as therefore unable to succeed, as opposed to framing that child as not having the correct tools.

New tribulations of medical school

Dr. Johnson: Absolutely. I think what Xavier did for me is to at least let me understand what I needed to do, how to comprehend and retain information, which I never had been exposed to before. Those years were very important to establishing a foundation. When going to medical school, it was like, “There’s no more excuses. What could be the problem now?” Well, now let’s talk about taking tests—a whole different skill. Xavier focused on getting me to understand how to structure my thought process and knowledge base. In medical school I had to apply those skills (because if you can’t apply them, there’s no fit).

My second through fourth year of medical school, I was the only African-American kid in my class. I was spending 20-hour days sometimes just studying, trying to overcompensate by knowing as much as I possibly could and thinking that would propel me from the test-taking standpoint. Even though I didn’t have a lot of classmates in medical school that looked like me, I did have mentors that looked similarly, who really saw potential in me. Dr. Frederick Horvath, a nephrologist in Peoria said, “What are you doing? I want you to get out of these books, and let’s go out to lunch.”

He ended up buying me some instrumental books, really talked to me, listening to my background and understanding how driven I was as a person. He took me under his wing for the rest of medical school and said, “This is how you navigate through these spaces. Yes, you need to have a fund of knowledge to be able to take these tests, but you need to start understanding how to apply it to these questions.” I’m forever grateful to Dr. Horvath for doing that because it was a point in time where I was lost and struggling.

Continue to: Hitting a stride but facing racism head-on...

Dr. Levy: You talk about the systemic and pervasive racism that was on the wards when you hit them in fourth year. If you don’t mind sharing just a little bit of that, it would help people reading this to have a better understanding of the kinds of barriers that are out there.

Dr. Johnson: Even when I talk about it today, it bothers me.

I went to medical school in Peoria, Illinois, not far from the home of the Ku Klux Klan. At that time, once you got out of Chicago it was a very brutal place, with systemic racism throughout. I was a young Black kid going through a process that not many young Black kids from the South side of Chicago go through, and you had people who had never seen anyone like me. When I was going through my clinical rotations, I knew what I was up against. I was dressed “to the T” every day, arriving early, leaving late, trying to answer questions. I would look at the evaluations, and they would be disparaging. I would look at my counterparts, how their evaluations were, and how people would respond to them, and it would be completely different.

Surgery was the part of ObGyn that I really grew to love more than anything, even more than obstetrics. When general surgery came, I wanted to take it very seriously and learn as much as I possibly could. From the beginning, I knew there was a problem because the chief resident, an older White man, wouldn’t look me in the eye or talk to me. He would make disparaging remarks. The thing that stuck out in my mind the most was when I was in the operating room transporting patients, just like a medical student did, and he came up behind me and said, “You know, Pierre, this is where a small mind and a strong back come into play.” For me, it took me to a place where I had to corral my emotions and thoughts because I just wanted to lash out and just tell him how racist and horrible that was for him to say that to me. I explained this to the powers that be, the director of the department, and they basically blew it off to the side.

When it came down to the end of the evaluation period, I passed with flying colors. But they gave me an incomplete because of that chief resident and his remarks on my evaluations. He had 3 pages of report about me as a person and as a student. He said that he had difficulty in expressing his opinions about me because of possible cultural biases that he may have had. He put “cultural biases” in an evaluation, and they looked at that and said that was enough for me to have to remediate my time. I was required to do an extra month in Pontiac, Illinois, which is even more rural than Peoria, because of a racist person that did not give me a fair opportunity because I was Black.

Like everything else in life, it was a learning experience. It’s why I fight so hard today. It’s why I’m so passionate about equity, not only in medicine but also in all aspects of society. It shows why we have police brutality and Black men dying in the streets. It shows how this happens because there are cultural and implicit biases that play out in every part of life, and we are not honest about it. Until we are honest about it and until we say that this is happening and there is something that needs to be done to address it, it’s going to continue to happen. That is my fight.

Exposing the unspoken power struggle

Dr. Levy: I couldn’t agree more. Attributing things like that to the individual, where you talk about a White man in power and a power structure that didn’t literally physically beat you but did beat you into submission. You talk about how to succeed in medical school, and how you had to suck it up and submit to something that was incredibly unfair. You understood, you were old enough, mature enough, to understand that if you fought back, you were going to lose. The only opportunity you had was to submit to that inequity and push forward.

Dr. Johnson: When I did try to fight, the chair of the department told me that either I accept the consequences or I would not graduate from medical school and be forced to do another year. That struck a chord with me. I think that happens a lot in our society, and it needs to be exposed.

Past experiences reflected in today’s society

Dr. Levy: Can you talk about what you faced in your ObGyn residency in terms of the systemic pushback, people not taking your orders, people questioning you. I know that I have heard that a great deal, and I experienced that myself as a woman.

Dr. Johnson: We look at the things that are happening now, everything from George Floyd’s murder to Colin Kaepernick taking a knee. These things are 10 years past when I first started residency. The year before I started residency, there was a noose hanging on the capitol lawn of Springfield, Illinois’ capital city. There’s systemic racism and hatred there. When I first started on the wards of my first year of ObGyn, again, I was the very first Black resident of my program’s history. Nobody could relate to me.

I went from a year-long general surgery internship at Washington Hospital Center in Washington, DC, to ObGyn residency. In the first 2 months, there were complaints of, “He’s not answering his pages. He’s not being prompt.” I went to my program director and said, “Listen, I have never had one complaint like this. There’s a problem here. And there’s a problem when I’m on the floor: When trying to give orders to nurses, they’re not taking them. I had to tell a couple of nurses, ‘I’m Dr. Johnson. Don’t call me by my first name, especially not in front of patients.’”

My director was just not hearing me, because the entire scenario was something they had never been exposed to. Systemic racism is real, and unless you experience it, it’s very difficult to accept that it is happening. But biases happen when you are not cognizant. People are used to things a certain way. Things play out in the media that make your mind think a certain way, and you don’t even realize it. You may not even want to be that way.

Continue to: Unconscious bias is a barrier to ensuring equity...

Dr. Levy: One very important point you just made is that we as the system need to be able to recognize those unconscious things, the language that we use, the disparaging remarks, the things that put people down, as well as the things that keep people out of promotion.

There are some interesting data about both race and gender and the language that we use when we write recommendations for people, that we do things unconsciously. The big message to all of us at the end is to open our minds to where those things can occur. For myself, professionally, I keep a list of words that I use when I write recommendations. I measure myself to ensure that I am using the same language for men and women, for Black and White. I think we need to overcome the system and the structure to create real equity—not equality but equity.

It begins with being real about the issues

Dr. Johnson: It’s a bigger problem than the existence of bias and racism. I think these are systemic issues that have been cultivated over centuries that have never been addressed. The true issue is that we deny that these are problems and refuse to talk about it because it makes us uncomfortable. To truly make things more equitable, we have to push our levels of comfort to be able to talk about things in a healthy manner, be open and transparent, and to start to understand how we are thinking about certain things. When you can see it, you can start to implement changes and start to change mentalities and thought processes.

For me, people say, “You don’t look like a doctor.” I get that all the time—because I have tattoos and earrings. I wear my hair in a mohawk. The image of what success looks like has been manifested through our media and culture, and it has imprinted on our minds as to how things are supposed to be. If someone doesn’t fit those molds, we start to shun them out, or we start to exhibit biases against those things. What I am trying to do is change that thought process of what a successful or a professional person looks like. It doesn’t have a look. It is not a White or Black thing. It’s an intellect, a mindset, a way of living. You have to treat every person as an individual and take all the biases out of it and understand where they are coming from and what they have to offer to the profession.

Dr. Levy: I personally was so impressed by you when I met you. I was impressed by the tattoos and the earrings, and my initial response to them was exactly that biased, “Oh, who is this person?” I checked that at the door, listened to you, and was really impressed at your surgical skill, your knowledge, your background. I am really grateful that you have been willing to spend the time to share that with everyone.

Dr. Johnson: Thank you for this discussion.

To watch the full interview between Drs. Levy and Johnson, visit: https://www.mdedge.com/obgyn/article/228507/facing-systemic-racism-health-care-inequities-medical-education. ●

OBG Management takes the issues of systemic and structural racism incredibly seriously--not just by talking about it but by trying to highlight areas in medicine, particularly in obstetrics and gynecology, that are barriers to progress. In this new series for OBG Management, Board Member Barbara Levy, MD, faces the issues head-on, beginning with this peer-to-peer interview with Pierre Johnson, MD, ObGyn in Chicago, Illinois. Watch for future installments in upcoming issues of OBG Management.

Finding inspiration among life’s challenges

Barbara Levy, MD: I am fortunate to have met Pierre serendipitously at a training that we were both attending and was impressed by Dr. Johnson’s life story, his passion and commitment, and his dedication—not only to his personal career but also to raising up other young men of color by trying to break down barriers that face them. His life story highlights those areas of systemic and structural problems that all of us together need to address if we are going to make any progress.

Pierre Johnson, MD: Thank you, Barbara. A little about myself: I am a board-certified ObGyn, and I specialize in minimally invasive surgery. I was born on the South side of Chicago, experiencing gang violence, drugs, and substandard, underserved schools. Long story short, I had a very rough upbringing. I had a single mom and several different issues at home. I am the oldest of 5 siblings, and life was tough.

But I knew that I wanted to do something different with my life. I saw that there was a need in my community as far as health care was concerned, in particular women’s health and childbirth. I knew early on that I wanted to be an ObGyn, and the reason had a lot to do with The Cosby Show. It was the only example of a positive, successful Black man that I saw. No one graduated from college in my family. There weren’t any models of young Black excellence around me. Saying that I wanted to be a doctor planted a seed. I was 9 when my mom became pregnant with my first sibling, and it was fascinating to me. The physiology of pregnancy, and eventually childbirth, was extremely fascinating to me; it set me off on my journey to be an ObGyn.

As I got older, things didn’t get any easier. I went to high school in one of the toughest areas on the South side of Chicago. Gang violence, and violence in and of itself, were all around me, but I was able to stay focused. I went on to Xavier University in Louisiana.

Dr. Levy: There are some important things that I learned from your book and from talking to you at our first meeting. Your mom’s ObGyn, when she was pregnant with your next youngest sibling, was also a Black ObGyn. He took some time to take you under wing?

Dr. Johnson: He did. My mom’s ObGyn was a Black man. Other than The Cosby Show, that’s the only time I saw something like that. When I spoke to him, he really took the time to answer my questions and show me that he was like me; he wasn’t just a far-off mythical person, or something that I could not obtain.

Continue to: Seeing is believing when it comes to success...

Seeing is believing when it comes to success

Dr. Levy: Do you think it was important to have a role model who wasn’t a sports star?

Dr. Johnson: If you can’t see it, you can’t achieve it. He took his time to really talk to me, and it’s the little things for kids that go a long way in their life experience. I still have a relationship with him to this day. How he handled me as a kid made me realize that this is something that I could do. That was extremely important for me.

Dr. Levy: One of the structural things I think we need to point out is that the ability to see yourself as someone successful is critical. When we see 1,000 images a day and they are all White, and they are all so different from where we are that it gets incorporated into our sense of being. I think that’s really difficult for those of us of with privilege to understand what that privilege is.

Dr. Johnson: Absolutely, and I’ll even go further. In residency, 2 White females were my classmates, and both of their parents were doctors. They had grandparents who were doctors. My mom was addicted to drugs; my father was not around. They had been talking medicine since they were 5. You have to make things equitable, but in medicine it’s really not equitable. In medicine, what we don’t realize is that there is an importance for all aspects of someone’s upbringing and environment, and it’s not just what they can regurgitate on a standardized test. If a patient can’t relate to you and tell you what is wrong with them, how can you adequately treat them?

Dr. Levy: Even if they are trying to tell me, but I can’t hear it because I don’t have the language and I don’t have the background. There are really good data to show, in fact, that Black male physicians do a better job at engaging Black men to manage their hypertension.¹ When we look at the inequities in birth outcomes for women of color, indigenous women and Black women, there’s evidence that providers who come from a similar background do a better job.

Dr. Johnson: There was the study of Black infants that just came out about them dying at a 3-time higher rate in non-Black physicians’ hands.² These things need to be recognized. They need to be discussed, and they need to be identified as issues and then, realistically, we need to start talking about solutions, not get offended by what actual statistics are saying.

Foundational inequities in education

Dr. Levy: To address some of the barriers that you faced: I know that you went to a high school that was not geared toward pushing students into professional careers. Your colleagues, however, had educations that prepared them for the standardized tests and other things that they would face academically.

Dr. Johnson: People think I am kidding when I say it, but when I went into college, I didn’t know what a periodic table was. I saw it, but I had no idea what these things meant. I didn’t have any sciences or any AP classes in high school. I did well, but grades are smoke and mirrors. The true test of medicine comes with testing. From the MCATs to the boards, every step of the way there is a standardized test.

Knowledge is something that you can obtain, but test taking is a cultivated skill that happens from a very early age. Trying to teach an adult or someone in their late teens a skill that they should have learned as a kid is difficult. For me, I did not have that, so I had to program myself. I had to learn how to fundamentally take tests as an adult, where most people understand how to do that going into college and professional school.

Dr. Levy: I was impressed with your resilience. I think all of us as human beings, if we fail a test, we take it personally and think it’s about our lack of knowledge. One of the insights that you came to was that failure on those things was not that you didn’t study hard enough. In fact, you probably studied 4 times harder than most other people. You had the knowledge. Being able to get that knowledge into a standardized structured test score was the huge challenge for you.

Dr. Johnson: That’s it. I can remember taking the MCAT, and if you looked at the step 1 book, I could regurgitate to you everything on that page. However, it’s not a test about do you know it or not. It’s an understanding of the English language and how to break things down to make things fit into particular scenarios.

Continue to: A college experience focused on growth and exposure...

Dr. Levy: I was impressed by the distinction between your experience at Xavier University where there was a lot of support and guidance and help in your premed program, and what happened to you when you hit medical school.

Dr. Johnson: Xavier University in Louisiana is the number 1 institution in the country for getting minorities into professional school. They understand that they have kids that are brilliant but underprepared, and just have not had the background to actually tackle some of these tough curriculums. I always had good grades in school. But by not being challenged, I didn’t know what I didn’t really know. So now that I was seeing biology, chemistry for the first time, and trying to tackle it; there’s a failure point. I didn’t know how to take tests, and I didn’t know how to study properly. The harder I tried, the worse things got for me.

Xavier has seen that story a multitude of times. If I went to a bigger or predominantly White university, a counselor would have told me, “Well, medicine’s maybe not for you. You can’t handle a premed curriculum.” Instead, I said, “Listen, I’m studying. I’m doing all of these things, and I’m not hacking it.” And they broke it down: “Let’s get you into study groups with kids that have had these type of AP classes before. We’ll have you watch how they study,” and everything started to click. That facilitation of how to adjust to this curriculum was a godsend. It’s the only reason I’m here. I am a prime example of being brilliant enough to be able to do it, but needing the infrastructure and a system set up.

Dr. Levy: There’s a great book by Carol Dweck called Mindset that talks about education of young kids and putting them into silos so early in life; the brilliant kids go into the AP courses and the rest are labeled as inadequate. It’s assumed in a fixed mindset based on their heredity and IQ, and not based on the fact that they have not been exposed to the right things.

Xavier was growing you into the man who could, in fact, do all of those things. I think that is one of the systemic and structural issues that we have—that fixed mindset that frames a kid who is not succeeding as therefore unable to succeed, as opposed to framing that child as not having the correct tools.

New tribulations of medical school

Dr. Johnson: Absolutely. I think what Xavier did for me is to at least let me understand what I needed to do, how to comprehend and retain information, which I never had been exposed to before. Those years were very important to establishing a foundation. When going to medical school, it was like, “There’s no more excuses. What could be the problem now?” Well, now let’s talk about taking tests—a whole different skill. Xavier focused on getting me to understand how to structure my thought process and knowledge base. In medical school I had to apply those skills (because if you can’t apply them, there’s no fit).

My second through fourth year of medical school, I was the only African-American kid in my class. I was spending 20-hour days sometimes just studying, trying to overcompensate by knowing as much as I possibly could and thinking that would propel me from the test-taking standpoint. Even though I didn’t have a lot of classmates in medical school that looked like me, I did have mentors that looked similarly, who really saw potential in me. Dr. Frederick Horvath, a nephrologist in Peoria said, “What are you doing? I want you to get out of these books, and let’s go out to lunch.”

He ended up buying me some instrumental books, really talked to me, listening to my background and understanding how driven I was as a person. He took me under his wing for the rest of medical school and said, “This is how you navigate through these spaces. Yes, you need to have a fund of knowledge to be able to take these tests, but you need to start understanding how to apply it to these questions.” I’m forever grateful to Dr. Horvath for doing that because it was a point in time where I was lost and struggling.

Continue to: Hitting a stride but facing racism head-on...

Dr. Levy: You talk about the systemic and pervasive racism that was on the wards when you hit them in fourth year. If you don’t mind sharing just a little bit of that, it would help people reading this to have a better understanding of the kinds of barriers that are out there.

Dr. Johnson: Even when I talk about it today, it bothers me.

I went to medical school in Peoria, Illinois, not far from the home of the Ku Klux Klan. At that time, once you got out of Chicago it was a very brutal place, with systemic racism throughout. I was a young Black kid going through a process that not many young Black kids from the South side of Chicago go through, and you had people who had never seen anyone like me. When I was going through my clinical rotations, I knew what I was up against. I was dressed “to the T” every day, arriving early, leaving late, trying to answer questions. I would look at the evaluations, and they would be disparaging. I would look at my counterparts, how their evaluations were, and how people would respond to them, and it would be completely different.

Surgery was the part of ObGyn that I really grew to love more than anything, even more than obstetrics. When general surgery came, I wanted to take it very seriously and learn as much as I possibly could. From the beginning, I knew there was a problem because the chief resident, an older White man, wouldn’t look me in the eye or talk to me. He would make disparaging remarks. The thing that stuck out in my mind the most was when I was in the operating room transporting patients, just like a medical student did, and he came up behind me and said, “You know, Pierre, this is where a small mind and a strong back come into play.” For me, it took me to a place where I had to corral my emotions and thoughts because I just wanted to lash out and just tell him how racist and horrible that was for him to say that to me. I explained this to the powers that be, the director of the department, and they basically blew it off to the side.

When it came down to the end of the evaluation period, I passed with flying colors. But they gave me an incomplete because of that chief resident and his remarks on my evaluations. He had 3 pages of report about me as a person and as a student. He said that he had difficulty in expressing his opinions about me because of possible cultural biases that he may have had. He put “cultural biases” in an evaluation, and they looked at that and said that was enough for me to have to remediate my time. I was required to do an extra month in Pontiac, Illinois, which is even more rural than Peoria, because of a racist person that did not give me a fair opportunity because I was Black.

Like everything else in life, it was a learning experience. It’s why I fight so hard today. It’s why I’m so passionate about equity, not only in medicine but also in all aspects of society. It shows why we have police brutality and Black men dying in the streets. It shows how this happens because there are cultural and implicit biases that play out in every part of life, and we are not honest about it. Until we are honest about it and until we say that this is happening and there is something that needs to be done to address it, it’s going to continue to happen. That is my fight.

Exposing the unspoken power struggle

Dr. Levy: I couldn’t agree more. Attributing things like that to the individual, where you talk about a White man in power and a power structure that didn’t literally physically beat you but did beat you into submission. You talk about how to succeed in medical school, and how you had to suck it up and submit to something that was incredibly unfair. You understood, you were old enough, mature enough, to understand that if you fought back, you were going to lose. The only opportunity you had was to submit to that inequity and push forward.

Dr. Johnson: When I did try to fight, the chair of the department told me that either I accept the consequences or I would not graduate from medical school and be forced to do another year. That struck a chord with me. I think that happens a lot in our society, and it needs to be exposed.

Past experiences reflected in today’s society

Dr. Levy: Can you talk about what you faced in your ObGyn residency in terms of the systemic pushback, people not taking your orders, people questioning you. I know that I have heard that a great deal, and I experienced that myself as a woman.

Dr. Johnson: We look at the things that are happening now, everything from George Floyd’s murder to Colin Kaepernick taking a knee. These things are 10 years past when I first started residency. The year before I started residency, there was a noose hanging on the capitol lawn of Springfield, Illinois’ capital city. There’s systemic racism and hatred there. When I first started on the wards of my first year of ObGyn, again, I was the very first Black resident of my program’s history. Nobody could relate to me.

I went from a year-long general surgery internship at Washington Hospital Center in Washington, DC, to ObGyn residency. In the first 2 months, there were complaints of, “He’s not answering his pages. He’s not being prompt.” I went to my program director and said, “Listen, I have never had one complaint like this. There’s a problem here. And there’s a problem when I’m on the floor: When trying to give orders to nurses, they’re not taking them. I had to tell a couple of nurses, ‘I’m Dr. Johnson. Don’t call me by my first name, especially not in front of patients.’”

My director was just not hearing me, because the entire scenario was something they had never been exposed to. Systemic racism is real, and unless you experience it, it’s very difficult to accept that it is happening. But biases happen when you are not cognizant. People are used to things a certain way. Things play out in the media that make your mind think a certain way, and you don’t even realize it. You may not even want to be that way.

Continue to: Unconscious bias is a barrier to ensuring equity...

Dr. Levy: One very important point you just made is that we as the system need to be able to recognize those unconscious things, the language that we use, the disparaging remarks, the things that put people down, as well as the things that keep people out of promotion.

There are some interesting data about both race and gender and the language that we use when we write recommendations for people, that we do things unconsciously. The big message to all of us at the end is to open our minds to where those things can occur. For myself, professionally, I keep a list of words that I use when I write recommendations. I measure myself to ensure that I am using the same language for men and women, for Black and White. I think we need to overcome the system and the structure to create real equity—not equality but equity.

It begins with being real about the issues

Dr. Johnson: It’s a bigger problem than the existence of bias and racism. I think these are systemic issues that have been cultivated over centuries that have never been addressed. The true issue is that we deny that these are problems and refuse to talk about it because it makes us uncomfortable. To truly make things more equitable, we have to push our levels of comfort to be able to talk about things in a healthy manner, be open and transparent, and to start to understand how we are thinking about certain things. When you can see it, you can start to implement changes and start to change mentalities and thought processes.

For me, people say, “You don’t look like a doctor.” I get that all the time—because I have tattoos and earrings. I wear my hair in a mohawk. The image of what success looks like has been manifested through our media and culture, and it has imprinted on our minds as to how things are supposed to be. If someone doesn’t fit those molds, we start to shun them out, or we start to exhibit biases against those things. What I am trying to do is change that thought process of what a successful or a professional person looks like. It doesn’t have a look. It is not a White or Black thing. It’s an intellect, a mindset, a way of living. You have to treat every person as an individual and take all the biases out of it and understand where they are coming from and what they have to offer to the profession.

Dr. Levy: I personally was so impressed by you when I met you. I was impressed by the tattoos and the earrings, and my initial response to them was exactly that biased, “Oh, who is this person?” I checked that at the door, listened to you, and was really impressed at your surgical skill, your knowledge, your background. I am really grateful that you have been willing to spend the time to share that with everyone.

Dr. Johnson: Thank you for this discussion.

To watch the full interview between Drs. Levy and Johnson, visit: https://www.mdedge.com/obgyn/article/228507/facing-systemic-racism-health-care-inequities-medical-education. ●

OBG Management takes the issues of systemic and structural racism incredibly seriously--not just by talking about it but by trying to highlight areas in medicine, particularly in obstetrics and gynecology, that are barriers to progress. In this new series for OBG Management, Board Member Barbara Levy, MD, faces the issues head-on, beginning with this peer-to-peer interview with Pierre Johnson, MD, ObGyn in Chicago, Illinois. Watch for future installments in upcoming issues of OBG Management.

Finding inspiration among life’s challenges

Barbara Levy, MD: I am fortunate to have met Pierre serendipitously at a training that we were both attending and was impressed by Dr. Johnson’s life story, his passion and commitment, and his dedication—not only to his personal career but also to raising up other young men of color by trying to break down barriers that face them. His life story highlights those areas of systemic and structural problems that all of us together need to address if we are going to make any progress.

Pierre Johnson, MD: Thank you, Barbara. A little about myself: I am a board-certified ObGyn, and I specialize in minimally invasive surgery. I was born on the South side of Chicago, experiencing gang violence, drugs, and substandard, underserved schools. Long story short, I had a very rough upbringing. I had a single mom and several different issues at home. I am the oldest of 5 siblings, and life was tough.

But I knew that I wanted to do something different with my life. I saw that there was a need in my community as far as health care was concerned, in particular women’s health and childbirth. I knew early on that I wanted to be an ObGyn, and the reason had a lot to do with The Cosby Show. It was the only example of a positive, successful Black man that I saw. No one graduated from college in my family. There weren’t any models of young Black excellence around me. Saying that I wanted to be a doctor planted a seed. I was 9 when my mom became pregnant with my first sibling, and it was fascinating to me. The physiology of pregnancy, and eventually childbirth, was extremely fascinating to me; it set me off on my journey to be an ObGyn.

As I got older, things didn’t get any easier. I went to high school in one of the toughest areas on the South side of Chicago. Gang violence, and violence in and of itself, were all around me, but I was able to stay focused. I went on to Xavier University in Louisiana.

Dr. Levy: There are some important things that I learned from your book and from talking to you at our first meeting. Your mom’s ObGyn, when she was pregnant with your next youngest sibling, was also a Black ObGyn. He took some time to take you under wing?

Dr. Johnson: He did. My mom’s ObGyn was a Black man. Other than The Cosby Show, that’s the only time I saw something like that. When I spoke to him, he really took the time to answer my questions and show me that he was like me; he wasn’t just a far-off mythical person, or something that I could not obtain.

Continue to: Seeing is believing when it comes to success...

Seeing is believing when it comes to success

Dr. Levy: Do you think it was important to have a role model who wasn’t a sports star?

Dr. Johnson: If you can’t see it, you can’t achieve it. He took his time to really talk to me, and it’s the little things for kids that go a long way in their life experience. I still have a relationship with him to this day. How he handled me as a kid made me realize that this is something that I could do. That was extremely important for me.

Dr. Levy: One of the structural things I think we need to point out is that the ability to see yourself as someone successful is critical. When we see 1,000 images a day and they are all White, and they are all so different from where we are that it gets incorporated into our sense of being. I think that’s really difficult for those of us of with privilege to understand what that privilege is.

Dr. Johnson: Absolutely, and I’ll even go further. In residency, 2 White females were my classmates, and both of their parents were doctors. They had grandparents who were doctors. My mom was addicted to drugs; my father was not around. They had been talking medicine since they were 5. You have to make things equitable, but in medicine it’s really not equitable. In medicine, what we don’t realize is that there is an importance for all aspects of someone’s upbringing and environment, and it’s not just what they can regurgitate on a standardized test. If a patient can’t relate to you and tell you what is wrong with them, how can you adequately treat them?

Dr. Levy: Even if they are trying to tell me, but I can’t hear it because I don’t have the language and I don’t have the background. There are really good data to show, in fact, that Black male physicians do a better job at engaging Black men to manage their hypertension.¹ When we look at the inequities in birth outcomes for women of color, indigenous women and Black women, there’s evidence that providers who come from a similar background do a better job.

Dr. Johnson: There was the study of Black infants that just came out about them dying at a 3-time higher rate in non-Black physicians’ hands.² These things need to be recognized. They need to be discussed, and they need to be identified as issues and then, realistically, we need to start talking about solutions, not get offended by what actual statistics are saying.

Foundational inequities in education

Dr. Levy: To address some of the barriers that you faced: I know that you went to a high school that was not geared toward pushing students into professional careers. Your colleagues, however, had educations that prepared them for the standardized tests and other things that they would face academically.

Dr. Johnson: People think I am kidding when I say it, but when I went into college, I didn’t know what a periodic table was. I saw it, but I had no idea what these things meant. I didn’t have any sciences or any AP classes in high school. I did well, but grades are smoke and mirrors. The true test of medicine comes with testing. From the MCATs to the boards, every step of the way there is a standardized test.

Knowledge is something that you can obtain, but test taking is a cultivated skill that happens from a very early age. Trying to teach an adult or someone in their late teens a skill that they should have learned as a kid is difficult. For me, I did not have that, so I had to program myself. I had to learn how to fundamentally take tests as an adult, where most people understand how to do that going into college and professional school.

Dr. Levy: I was impressed with your resilience. I think all of us as human beings, if we fail a test, we take it personally and think it’s about our lack of knowledge. One of the insights that you came to was that failure on those things was not that you didn’t study hard enough. In fact, you probably studied 4 times harder than most other people. You had the knowledge. Being able to get that knowledge into a standardized structured test score was the huge challenge for you.

Dr. Johnson: That’s it. I can remember taking the MCAT, and if you looked at the step 1 book, I could regurgitate to you everything on that page. However, it’s not a test about do you know it or not. It’s an understanding of the English language and how to break things down to make things fit into particular scenarios.

Continue to: A college experience focused on growth and exposure...

Dr. Levy: I was impressed by the distinction between your experience at Xavier University where there was a lot of support and guidance and help in your premed program, and what happened to you when you hit medical school.

Dr. Johnson: Xavier University in Louisiana is the number 1 institution in the country for getting minorities into professional school. They understand that they have kids that are brilliant but underprepared, and just have not had the background to actually tackle some of these tough curriculums. I always had good grades in school. But by not being challenged, I didn’t know what I didn’t really know. So now that I was seeing biology, chemistry for the first time, and trying to tackle it; there’s a failure point. I didn’t know how to take tests, and I didn’t know how to study properly. The harder I tried, the worse things got for me.

Xavier has seen that story a multitude of times. If I went to a bigger or predominantly White university, a counselor would have told me, “Well, medicine’s maybe not for you. You can’t handle a premed curriculum.” Instead, I said, “Listen, I’m studying. I’m doing all of these things, and I’m not hacking it.” And they broke it down: “Let’s get you into study groups with kids that have had these type of AP classes before. We’ll have you watch how they study,” and everything started to click. That facilitation of how to adjust to this curriculum was a godsend. It’s the only reason I’m here. I am a prime example of being brilliant enough to be able to do it, but needing the infrastructure and a system set up.

Dr. Levy: There’s a great book by Carol Dweck called Mindset that talks about education of young kids and putting them into silos so early in life; the brilliant kids go into the AP courses and the rest are labeled as inadequate. It’s assumed in a fixed mindset based on their heredity and IQ, and not based on the fact that they have not been exposed to the right things.

Xavier was growing you into the man who could, in fact, do all of those things. I think that is one of the systemic and structural issues that we have—that fixed mindset that frames a kid who is not succeeding as therefore unable to succeed, as opposed to framing that child as not having the correct tools.

New tribulations of medical school

Dr. Johnson: Absolutely. I think what Xavier did for me is to at least let me understand what I needed to do, how to comprehend and retain information, which I never had been exposed to before. Those years were very important to establishing a foundation. When going to medical school, it was like, “There’s no more excuses. What could be the problem now?” Well, now let’s talk about taking tests—a whole different skill. Xavier focused on getting me to understand how to structure my thought process and knowledge base. In medical school I had to apply those skills (because if you can’t apply them, there’s no fit).

My second through fourth year of medical school, I was the only African-American kid in my class. I was spending 20-hour days sometimes just studying, trying to overcompensate by knowing as much as I possibly could and thinking that would propel me from the test-taking standpoint. Even though I didn’t have a lot of classmates in medical school that looked like me, I did have mentors that looked similarly, who really saw potential in me. Dr. Frederick Horvath, a nephrologist in Peoria said, “What are you doing? I want you to get out of these books, and let’s go out to lunch.”

He ended up buying me some instrumental books, really talked to me, listening to my background and understanding how driven I was as a person. He took me under his wing for the rest of medical school and said, “This is how you navigate through these spaces. Yes, you need to have a fund of knowledge to be able to take these tests, but you need to start understanding how to apply it to these questions.” I’m forever grateful to Dr. Horvath for doing that because it was a point in time where I was lost and struggling.

Continue to: Hitting a stride but facing racism head-on...

Dr. Levy: You talk about the systemic and pervasive racism that was on the wards when you hit them in fourth year. If you don’t mind sharing just a little bit of that, it would help people reading this to have a better understanding of the kinds of barriers that are out there.

Dr. Johnson: Even when I talk about it today, it bothers me.

I went to medical school in Peoria, Illinois, not far from the home of the Ku Klux Klan. At that time, once you got out of Chicago it was a very brutal place, with systemic racism throughout. I was a young Black kid going through a process that not many young Black kids from the South side of Chicago go through, and you had people who had never seen anyone like me. When I was going through my clinical rotations, I knew what I was up against. I was dressed “to the T” every day, arriving early, leaving late, trying to answer questions. I would look at the evaluations, and they would be disparaging. I would look at my counterparts, how their evaluations were, and how people would respond to them, and it would be completely different.

Surgery was the part of ObGyn that I really grew to love more than anything, even more than obstetrics. When general surgery came, I wanted to take it very seriously and learn as much as I possibly could. From the beginning, I knew there was a problem because the chief resident, an older White man, wouldn’t look me in the eye or talk to me. He would make disparaging remarks. The thing that stuck out in my mind the most was when I was in the operating room transporting patients, just like a medical student did, and he came up behind me and said, “You know, Pierre, this is where a small mind and a strong back come into play.” For me, it took me to a place where I had to corral my emotions and thoughts because I just wanted to lash out and just tell him how racist and horrible that was for him to say that to me. I explained this to the powers that be, the director of the department, and they basically blew it off to the side.

When it came down to the end of the evaluation period, I passed with flying colors. But they gave me an incomplete because of that chief resident and his remarks on my evaluations. He had 3 pages of report about me as a person and as a student. He said that he had difficulty in expressing his opinions about me because of possible cultural biases that he may have had. He put “cultural biases” in an evaluation, and they looked at that and said that was enough for me to have to remediate my time. I was required to do an extra month in Pontiac, Illinois, which is even more rural than Peoria, because of a racist person that did not give me a fair opportunity because I was Black.

Like everything else in life, it was a learning experience. It’s why I fight so hard today. It’s why I’m so passionate about equity, not only in medicine but also in all aspects of society. It shows why we have police brutality and Black men dying in the streets. It shows how this happens because there are cultural and implicit biases that play out in every part of life, and we are not honest about it. Until we are honest about it and until we say that this is happening and there is something that needs to be done to address it, it’s going to continue to happen. That is my fight.

Exposing the unspoken power struggle

Dr. Levy: I couldn’t agree more. Attributing things like that to the individual, where you talk about a White man in power and a power structure that didn’t literally physically beat you but did beat you into submission. You talk about how to succeed in medical school, and how you had to suck it up and submit to something that was incredibly unfair. You understood, you were old enough, mature enough, to understand that if you fought back, you were going to lose. The only opportunity you had was to submit to that inequity and push forward.

Dr. Johnson: When I did try to fight, the chair of the department told me that either I accept the consequences or I would not graduate from medical school and be forced to do another year. That struck a chord with me. I think that happens a lot in our society, and it needs to be exposed.

Past experiences reflected in today’s society

Dr. Levy: Can you talk about what you faced in your ObGyn residency in terms of the systemic pushback, people not taking your orders, people questioning you. I know that I have heard that a great deal, and I experienced that myself as a woman.

Dr. Johnson: We look at the things that are happening now, everything from George Floyd’s murder to Colin Kaepernick taking a knee. These things are 10 years past when I first started residency. The year before I started residency, there was a noose hanging on the capitol lawn of Springfield, Illinois’ capital city. There’s systemic racism and hatred there. When I first started on the wards of my first year of ObGyn, again, I was the very first Black resident of my program’s history. Nobody could relate to me.

I went from a year-long general surgery internship at Washington Hospital Center in Washington, DC, to ObGyn residency. In the first 2 months, there were complaints of, “He’s not answering his pages. He’s not being prompt.” I went to my program director and said, “Listen, I have never had one complaint like this. There’s a problem here. And there’s a problem when I’m on the floor: When trying to give orders to nurses, they’re not taking them. I had to tell a couple of nurses, ‘I’m Dr. Johnson. Don’t call me by my first name, especially not in front of patients.’”

My director was just not hearing me, because the entire scenario was something they had never been exposed to. Systemic racism is real, and unless you experience it, it’s very difficult to accept that it is happening. But biases happen when you are not cognizant. People are used to things a certain way. Things play out in the media that make your mind think a certain way, and you don’t even realize it. You may not even want to be that way.

Continue to: Unconscious bias is a barrier to ensuring equity...

Dr. Levy: One very important point you just made is that we as the system need to be able to recognize those unconscious things, the language that we use, the disparaging remarks, the things that put people down, as well as the things that keep people out of promotion.

There are some interesting data about both race and gender and the language that we use when we write recommendations for people, that we do things unconsciously. The big message to all of us at the end is to open our minds to where those things can occur. For myself, professionally, I keep a list of words that I use when I write recommendations. I measure myself to ensure that I am using the same language for men and women, for Black and White. I think we need to overcome the system and the structure to create real equity—not equality but equity.

It begins with being real about the issues

Dr. Johnson: It’s a bigger problem than the existence of bias and racism. I think these are systemic issues that have been cultivated over centuries that have never been addressed. The true issue is that we deny that these are problems and refuse to talk about it because it makes us uncomfortable. To truly make things more equitable, we have to push our levels of comfort to be able to talk about things in a healthy manner, be open and transparent, and to start to understand how we are thinking about certain things. When you can see it, you can start to implement changes and start to change mentalities and thought processes.

For me, people say, “You don’t look like a doctor.” I get that all the time—because I have tattoos and earrings. I wear my hair in a mohawk. The image of what success looks like has been manifested through our media and culture, and it has imprinted on our minds as to how things are supposed to be. If someone doesn’t fit those molds, we start to shun them out, or we start to exhibit biases against those things. What I am trying to do is change that thought process of what a successful or a professional person looks like. It doesn’t have a look. It is not a White or Black thing. It’s an intellect, a mindset, a way of living. You have to treat every person as an individual and take all the biases out of it and understand where they are coming from and what they have to offer to the profession.

Dr. Levy: I personally was so impressed by you when I met you. I was impressed by the tattoos and the earrings, and my initial response to them was exactly that biased, “Oh, who is this person?” I checked that at the door, listened to you, and was really impressed at your surgical skill, your knowledge, your background. I am really grateful that you have been willing to spend the time to share that with everyone.

Dr. Johnson: Thank you for this discussion.

To watch the full interview between Drs. Levy and Johnson, visit: https://www.mdedge.com/obgyn/article/228507/facing-systemic-racism-health-care-inequities-medical-education. ●

Over the last 30 years, surgical correction of the common condition pelvic organ prolapse (POP) and stress urinary incontinence (SUI) has become so routine and straightforward that many gynecologists and urogynecologists choose surgery as their first choice for treating these conditions, withholding it only from the riskiest patients or from those who, for a variety of reasons, do not choose surgery. Moreover, as generalist gynecologists increasingly refer patients with POP or incontinence to their urogynecologist colleagues, they increasingly lack the skills, or have not been trained, to use conservative treatment strategies for these disorders. Thus, pessaries—devices constructed of inert plastic, silicone, or latex and placed inside the vagina to support prolapsed pelvic structures—frequently are not part of the general gynecologist’s armamentarium.

When properly selected, however, pessaries used for indicated purposes and correctly fitted are an excellent, inexpensive, low-risk, and noninvasive tool that can provide immediate relief not only of POP but also of SUI and defecatory difficulties. As an alternative to surgery, pessaries are especially valuable, because the other major nonsurgical modality for treatment of POP and incontinence—pelvic floor muscle training—often is not covered by insurance (making it expensive for patients), takes many weekly sessions to complete (which can make access challenging), and frequently is not readily available.¹

POP is very common. An estimated 15% to 30% of women in North America have some degree of prolapse, and more than 500,000 surgeries for this condition are performed in the United States each year.² Risk factors for POP include:

• vaginal childbirth, especially higher parity
• advancing age
• high body mass index (BMI)
• prior hysterectomy
• raised intra-abdominal pressure, such as from obesity, chronic cough, or heavy lifting.

In addition to the discomfort caused by the herniation of pelvic and vaginal structures, POP also is associated with urinary incontinence (73%), urinary urgency and frequency (86%), and fecal incontinence (31%).³

Moreover, according to the US Census Bureau, the number of American women aged 65 or older will double to more than 40 million by 2030.⁴ This will greatly increase the population of women at risk for POP who may be candidates for pessary use. It therefore behooves gynecologists to become familiar with the correct usage, fitting, and maintenance of this effective, nonsurgical mode of treatment for POP.

In this article, I discuss why pessaries are a good option for many patients with POP, review the types of pessaries available, and offer guidance on how to choose the right pessary for an individual patient’s needs. In addition, the box at the end of this article provides an interesting timeline of pessary history dating back to antiquity.

Next month in Part 2 of this article, I cover how to fit a pessary; device aftercare; potential complications of use; and effectiveness of pessaries for POP, SUI, preterm labor prevention, and defecatory disorders.

Continue to: Potential candidates for pessary use...

Potential candidates for pessary use

Almost all women with POP—and in many cases accompanying SUI—are potential candidates for a pessary. In fact, many urogynecologists believe that a trial of pessary usage should be the first treatment modality offered for POP.⁵ Women who cannot use a pessary include those with an extremely short vagina (<6 cm) and those who have severely eroded vaginal mucosa. In the latter situation, the mucosa can be treated with estrogen cream for several weeks and, once the tissue has healed, a pessary can be fitted.

Given that surgical repair is generally a straightforward, one-time procedure that obviates the need for long-term use of an artificial device worn internally, why might a patient or her physician opt for a pessary instead?

Some of the many reasons include:

• Many patients prefer to avoid surgery.
• Many patients are not appropriate candidates for surgery because they have significant comorbid risk factors or high BMI.
• Patients may have recurrent prolapse or incontinence and wish to avoid repeat surgery.
• Patients with SUI may have heard of the occurrence of mesh erosion and wish to avoid that possibility.
• Women who live in low-resource environments or countries where elective surgical care is relatively unavailable may not have the option of surgery.

A clinician might also recommend pessary use:

• as a diagnostic tool to attempt to assess the potential results of vaginal repair surgery
• to estimate the potential effectiveness of a midurethral sling procedure; several investigators have found this to be approximately as accurate as urodynamic testing^6,7
• as prophylaxis for pregnant women with either a history of preterm cervical dilation or a short cervix detected on ultrasonography
• for pregnant women with POP that is worsening and becoming increasingly uncomfortable
• for women with POP who wish to have more children
• for short-term use while a patient is delaying or awaiting POP surgery or to allow time for other medical issues to resolve
• for patients who wish only intermittent, temporary support while exercising or engaging in sports.

Patient acceptance may be contingent on counseling

Numerous studies show that women who choose pessaries to treat POP are generally older than women who elect surgery. Still, patient acceptance of a trial of pessary use depends much on the counseling and information she receives. Properly informed, many patients with POP will opt for a trial of pessary placement. One study showed that, of women with untreated POP, 36% preferred pessary placement to surgery.⁸ Other investigators reported that when women with symptomatic POP had the benefits of a pessary versus surgery explained to them, nearly two-thirds opted for a pessary as their mode of treatment.⁹

Exceptions to pessary use

Fortunately, there are relatively few contraindications to pessary use. These are vaginal or pelvic infection and an exposed foreign body in the vagina, such as eroded vaginal mesh. In addition, patients at risk for nonadherence with follow-up care are poor candidates, as it could lead to missing such problems as mucosal erosion, ulceration, or even (extremely rarely) fistula formation. Pessaries may be inappropriate for sexually active women who on their own are unable to remove and reinsert pessary types that do not allow for intercourse while in place (see below).

Continue to: Types of pessaries...

Types of pessaries

The numerous kinds of pessaries available fall into 3 general categories: support, space filling, and lever, and devices within each group have modifications and variations. As with most areas of prescribing and treatment in medicine, it is best to become very familiar with just a few kinds of pessaries, know their indications, and use them when appropriate.

Most pessaries are constructed of inert silicone which, unlike earlier rubber pessaries, does not absorb odor or discharge. They are easy to clean, long lasting, and are autoclavable and hypoallergenic.

Support pessaries

Support pessaries look like contraceptive diaphragms. They are easy to place and remove, are comfortable, and do an excellent job correcting moderate POP. They also can control or eliminate symptoms of SUI by the pressure they exert on the urethra and their alteration of the urethrovesicular angle.

Ring pessaries. The most commonly used type of pessary, the ring pessary,¹⁰ comes in 4 variations:

• a simple open ring
• a ring with a web of material, called a “support shield,” that fills the ring
• an open ring with a firm 2-cm “incontinence knob” attached that is positioned over the urethra
• a ring with support shield and incontinence knob.

When in position, the deepest edge of a ring pessary fits behind the cervix (or in the vaginal apex for women who have had a hysterectomy) while the front of the ring slips into place behind the pubic symphysis, just like a diaphragm. When a ring with an incontinence knob is used, the ring is rotated until the knob is directly over the urethra.

Sexual intercourse is possible with any of the ring pessaries in place. Of the various types of pessaries, the ring pessary is the easiest to insert and remove. Some women tie a piece of dental floss to the edge of the ring to make its removal even easier.

The ring pessary is available in sizes 0 (44.5 mm) to 13 (127 mm). For most women a size 3, 4, or 5 ring pessary fits well.

The Marland pessary is similar to the ring pessary with the addition of a wedge-shaped piece of material approximately 3 cm in height that arises from half of the ring. It rarely is used in the United States because most American gynecologists are unfamiliar with it, and there is little evidence that it is more effective than the ring pessary.¹¹

The Shaatz pessary is a rigid round pessary, smaller in diameter than the standard ring pessary, and similar to the Gellhorn pessary (discussed below) but without a stem. It is placed the same way one places a ring pessary but with its concave surface up against the cervix or, if there is no cervix, against the upper anterior vaginal wall. Its main benefit is that it provides firmer support than the ring pessary. This pessary is not widely used in the United States.

The Gehrung pessary looks like a flat strip of material that has been bent into the shape of a “U.” It is designed to correct severe cystoceles and rectoceles. For insertion, the edges at the open end of the pessary are squeezed together and the pessary is inserted with the closed part of the “U” facing the anterior vaginal wall. The upper edge is advanced until it rests in the anterior fornix of the vagina (or in the vaginal apex in women who have had a hysterectomy). Although it is more efficacious than some other pessaries for control of vaginal wall prolapse, its unfamiliarity to clinicians and its unusual shape result in it being used rarely.

Continue to: Space-filling pessaries...

Space-filling pessaries

Space-filling pessaries are used when more severe degrees of prolapse are present than can be managed by the ring or other support pessaries. This is especially the case when the vagina is so capacious or the introitus so lax that a standard ring pessary cannot be kept in place, resulting in frequent expulsions.

Space-filling pessaries are 3 dimensional and work by filling the vagina with a relatively large object that prevents the cervix/vaginal apex from dropping down and the vaginal walls from prolapsing. They have a special role for women who:

• are posthysterectomy and have an enterocele and/or vaginal apex prolapse
• have significant rectoceles for which support pessaries are not effective
• have a wide vaginal hiatus and thus are prone to expel support pessaries.

Space-filling pessaries do have some drawbacks compared with support pessaries. For example, they do not help in controlling SUI, and they are difficult for patients to remove on their own for cleaning. In addition, sexual intercourse is impossible with a space-filling pessary in place.

The Gellhorn pessary is the most common of the space-filling pessaries, and it is the one gynecologists and urogynecologists most often use for severe prolapse. It has a concave disc that fits up against the cervix or vaginal apex and a solid stem that points down the vagina. The stem itself is supported by the perineal body. It offers excellent support for severe uterine and vaginal wall prolapse, as long as the perineal body is intact. The stem stabilizes the disc portion of the pessary and prevents pessary expulsion. Gellhorn pessaries are available with long or short stems.

The Gellhorn is inserted into the vagina by folding the stem 90 degrees until it is in the same plane as the disc. With lubricated fingers, the patient’s perineal body is depressed and the disc of the pessary is folded and slid in. The disc is then placed up against the cervix or vaginal apex with the stem pointing down the vagina and tucked just inside the posterior edge of the introitus.

Removing the Gellhorn pessary can be problematic and is difficult for patients to do on their own. Clinicians often must use a ring forceps to grasp the stem of the pessary in order to bring it into the lower vagina, where the stem is folded up against the disc and the entire pessary removed. As with all space-filling pessaries, the Gellhorn must be taken out prior to intercourse.

The Gellhorn pessary is available in sizes that range from a disc diameter of 1.5 to 3.75 inches. Those measuring 2.5, 2.75, or 3 inches are used most commonly.

The cube pessary is a soft, dice-shaped piece of silicone with an indentation in each of its 6 sides. It is used for severe prolapse.

Squeezing the cube allows for easier insertion into the vagina; once it is at the top of the vagina, the cube expands back to its normal shape. The indentations on each side of the cube attach to the vaginal walls with moderate suction, which helps to keep the pessary in place. Because of the suction, the cube pessary can be used in cases of severe prolapse when other pessaries will not stay in place; a drawback is that the suction created by the indented sides can cause vaginal mucosal erosion.¹⁰ Ideally, the cube pessary should be removed every night for cleansing as discharge and accompanying odor can accumulate. The string attached to the cube pessary aids in its removal.

The cube pessary is available in sizes 0 to 7, with edge lengths that range from 1 to 2.25 inches.

The donut pessary, as its name suggests, has the form of a large donut. It can be compressed slightly to help with insertion. Because it occupies a large space within the vagina, it is used (like the cube pessary) for treatment of severe prolapse. The size and shape of the donut pessary, however, can make it difficult for patients to insert and take out on their own.

The donut pessary is available in sizes 0 (51 mm) to 8 (95 mm).

The inflatable pessary has the same basic shape as the donut pessary and serves the same purpose: It acts as a large semisoft object that fills the vagina to support the vaginal walls and cervix (or vaginal apex) in cases of severe prolapse. The inflatable pessary differs in that it has a valve on a stem through which air can be inserted and removed. This allows the uninflated pessary to be placed relatively easily into the vagina and then pumped full of air to the dimensions necessary to prevent vaginal, cervical, uterine, or apex prolapse. Air likewise can be removed to facilitate pessary removal.

One drawback of the inflatable pessary is that it is made of latex and thus cannot be used by anyone with a latex allergy. Also, as latex retains discharge and odors, this pessary should be removed and washed daily.

The inflatable pessary is available in sizes that range from 2 to 2.75 inches in 0.25-inch increments.

Continue to: Space-filling pessaries...

In addition to the more commonly used support and space-filling pessaries, there is a third kind that is rarely used in current practice: the lever pessaries. These pessaries—the Hodge, the Smith, and the Risser—are rectangles made of inert plastic that are folded into 3 planes to facilitate positioning in the vagina. The narrower of the 2 shorter ends of the folded rectangle is placed behind the cervix or at the vaginal apex while the other short end is placed behind the symphysis pubis.

Although sometimes used to correct POP in nonpregnant women, the lever pessary’s main purpose is to antivert a retroflexed uterus and to support the cervix and uterus in cases of prolapse during pregnancy or impending cervical incompetence.

The 3 lever pessaries differ in terms of whether the narrow ends of the pessary are straight or curved and wider or narrower.

How to choose the right pessary for your patient

If a patient’s POP or urinary incontinence symptoms would best be treated with a pessary, the next step is to select the pessary type and size best suited for that patient’s needs and the size that should be prescribed. While there is controversy among experts as to whether or not certain pessaries are better than others for different indications,¹² most gynecologists and urogynecologists who use pessaries on a regular basis agree on the following:

1. Support pessaries will meet the needs of most women with moderate POP and/or SUI. These include the ring pessary with or without the support shield and with or without an incontinence knob. A support pessary is the go-to pessary in most cases. Most women find it comfortable to wear, it is easy to put in and take out, and sexual intercourse is possible with the pessary in place.

2. The specific degree of a patient’s prolapse and/or incontinence dictates whether or not to prescribe the support shield feature or the incontinence knob with a ring pessary. The shield helps support a prolapsed cervix and uterus when they are present.^5,13 The knob is a useful feature if incontinence is a prominent symptom.

3. The Gellhorn pessary is usually the first choice for more severe prolapse. As long as there is some degree of posterior perineal support, this pessary does an excellent job of correcting even severe prolapse whether of a cervix and uterus or of vaginal walls and apex. It does require the patient to have some practice and dexterity for inserting and removing it on her own; individuals not comfortable or physically able to do so will need to have the pessary removed and cleaned by a clinician on a regular basis in the office. (Part 2 of this article will discuss pessary cleansing intervals).

4. Space-filling pessaries (such as the cube and donut) are useful when there is a severe degree of prolapse and insufficient perineal support to maintain a Gellhorn pessary. In practice, they are generally used less frequently—which is unfortunate, as they are a potentially useful solution for older women with severe prolapse who might not be candidates for surgical repair. As mentioned, both the cube and donut pessaries require more frequent removal for cleaning.

5. In unusual cases, the use of 2 pessaries simultaneously may resolve a difficult problem, such as when a pessary is the only option for treatment, the prolapse is severe, or it is impossible to find a pessary that resists being expelled from the vagina.¹⁴ A space-filling pessary in the most cephalad aspect of the vagina used in conjunction with a ring pessary with support shield below it can sometimes resolve even the worst cases of prolapse.

Continue to: Stay tuned...

Stay tuned

Part 2 of this article next month will provide more information on pessaries, including fitting, aftercare, potential complications, and effectiveness in various disorders. ●

Over the last 30 years, surgical correction of the common condition pelvic organ prolapse (POP) and stress urinary incontinence (SUI) has become so routine and straightforward that many gynecologists and urogynecologists choose surgery as their first choice for treating these conditions, withholding it only from the riskiest patients or from those who, for a variety of reasons, do not choose surgery. Moreover, as generalist gynecologists increasingly refer patients with POP or incontinence to their urogynecologist colleagues, they increasingly lack the skills, or have not been trained, to use conservative treatment strategies for these disorders. Thus, pessaries—devices constructed of inert plastic, silicone, or latex and placed inside the vagina to support prolapsed pelvic structures—frequently are not part of the general gynecologist’s armamentarium.

When properly selected, however, pessaries used for indicated purposes and correctly fitted are an excellent, inexpensive, low-risk, and noninvasive tool that can provide immediate relief not only of POP but also of SUI and defecatory difficulties. As an alternative to surgery, pessaries are especially valuable, because the other major nonsurgical modality for treatment of POP and incontinence—pelvic floor muscle training—often is not covered by insurance (making it expensive for patients), takes many weekly sessions to complete (which can make access challenging), and frequently is not readily available.¹

POP is very common. An estimated 15% to 30% of women in North America have some degree of prolapse, and more than 500,000 surgeries for this condition are performed in the United States each year.² Risk factors for POP include:

• vaginal childbirth, especially higher parity
• advancing age
• high body mass index (BMI)
• prior hysterectomy
• raised intra-abdominal pressure, such as from obesity, chronic cough, or heavy lifting.

In addition to the discomfort caused by the herniation of pelvic and vaginal structures, POP also is associated with urinary incontinence (73%), urinary urgency and frequency (86%), and fecal incontinence (31%).³

Moreover, according to the US Census Bureau, the number of American women aged 65 or older will double to more than 40 million by 2030.⁴ This will greatly increase the population of women at risk for POP who may be candidates for pessary use. It therefore behooves gynecologists to become familiar with the correct usage, fitting, and maintenance of this effective, nonsurgical mode of treatment for POP.

In this article, I discuss why pessaries are a good option for many patients with POP, review the types of pessaries available, and offer guidance on how to choose the right pessary for an individual patient’s needs. In addition, the box at the end of this article provides an interesting timeline of pessary history dating back to antiquity.

Next month in Part 2 of this article, I cover how to fit a pessary; device aftercare; potential complications of use; and effectiveness of pessaries for POP, SUI, preterm labor prevention, and defecatory disorders.

Continue to: Potential candidates for pessary use...

Potential candidates for pessary use

Almost all women with POP—and in many cases accompanying SUI—are potential candidates for a pessary. In fact, many urogynecologists believe that a trial of pessary usage should be the first treatment modality offered for POP.⁵ Women who cannot use a pessary include those with an extremely short vagina (<6 cm) and those who have severely eroded vaginal mucosa. In the latter situation, the mucosa can be treated with estrogen cream for several weeks and, once the tissue has healed, a pessary can be fitted.

Given that surgical repair is generally a straightforward, one-time procedure that obviates the need for long-term use of an artificial device worn internally, why might a patient or her physician opt for a pessary instead?

Some of the many reasons include:

• Many patients prefer to avoid surgery.
• Many patients are not appropriate candidates for surgery because they have significant comorbid risk factors or high BMI.
• Patients may have recurrent prolapse or incontinence and wish to avoid repeat surgery.
• Patients with SUI may have heard of the occurrence of mesh erosion and wish to avoid that possibility.
• Women who live in low-resource environments or countries where elective surgical care is relatively unavailable may not have the option of surgery.

A clinician might also recommend pessary use:

• as a diagnostic tool to attempt to assess the potential results of vaginal repair surgery
• to estimate the potential effectiveness of a midurethral sling procedure; several investigators have found this to be approximately as accurate as urodynamic testing^6,7
• as prophylaxis for pregnant women with either a history of preterm cervical dilation or a short cervix detected on ultrasonography
• for pregnant women with POP that is worsening and becoming increasingly uncomfortable
• for women with POP who wish to have more children
• for short-term use while a patient is delaying or awaiting POP surgery or to allow time for other medical issues to resolve
• for patients who wish only intermittent, temporary support while exercising or engaging in sports.

Patient acceptance may be contingent on counseling

Numerous studies show that women who choose pessaries to treat POP are generally older than women who elect surgery. Still, patient acceptance of a trial of pessary use depends much on the counseling and information she receives. Properly informed, many patients with POP will opt for a trial of pessary placement. One study showed that, of women with untreated POP, 36% preferred pessary placement to surgery.⁸ Other investigators reported that when women with symptomatic POP had the benefits of a pessary versus surgery explained to them, nearly two-thirds opted for a pessary as their mode of treatment.⁹

Exceptions to pessary use

Fortunately, there are relatively few contraindications to pessary use. These are vaginal or pelvic infection and an exposed foreign body in the vagina, such as eroded vaginal mesh. In addition, patients at risk for nonadherence with follow-up care are poor candidates, as it could lead to missing such problems as mucosal erosion, ulceration, or even (extremely rarely) fistula formation. Pessaries may be inappropriate for sexually active women who on their own are unable to remove and reinsert pessary types that do not allow for intercourse while in place (see below).

Continue to: Types of pessaries...

Types of pessaries

The numerous kinds of pessaries available fall into 3 general categories: support, space filling, and lever, and devices within each group have modifications and variations. As with most areas of prescribing and treatment in medicine, it is best to become very familiar with just a few kinds of pessaries, know their indications, and use them when appropriate.

Most pessaries are constructed of inert silicone which, unlike earlier rubber pessaries, does not absorb odor or discharge. They are easy to clean, long lasting, and are autoclavable and hypoallergenic.

Support pessaries

Support pessaries look like contraceptive diaphragms. They are easy to place and remove, are comfortable, and do an excellent job correcting moderate POP. They also can control or eliminate symptoms of SUI by the pressure they exert on the urethra and their alteration of the urethrovesicular angle.

Ring pessaries. The most commonly used type of pessary, the ring pessary,¹⁰ comes in 4 variations:

• a simple open ring
• a ring with a web of material, called a “support shield,” that fills the ring
• an open ring with a firm 2-cm “incontinence knob” attached that is positioned over the urethra
• a ring with support shield and incontinence knob.

When in position, the deepest edge of a ring pessary fits behind the cervix (or in the vaginal apex for women who have had a hysterectomy) while the front of the ring slips into place behind the pubic symphysis, just like a diaphragm. When a ring with an incontinence knob is used, the ring is rotated until the knob is directly over the urethra.

Sexual intercourse is possible with any of the ring pessaries in place. Of the various types of pessaries, the ring pessary is the easiest to insert and remove. Some women tie a piece of dental floss to the edge of the ring to make its removal even easier.

The ring pessary is available in sizes 0 (44.5 mm) to 13 (127 mm). For most women a size 3, 4, or 5 ring pessary fits well.

The Marland pessary is similar to the ring pessary with the addition of a wedge-shaped piece of material approximately 3 cm in height that arises from half of the ring. It rarely is used in the United States because most American gynecologists are unfamiliar with it, and there is little evidence that it is more effective than the ring pessary.¹¹

The Shaatz pessary is a rigid round pessary, smaller in diameter than the standard ring pessary, and similar to the Gellhorn pessary (discussed below) but without a stem. It is placed the same way one places a ring pessary but with its concave surface up against the cervix or, if there is no cervix, against the upper anterior vaginal wall. Its main benefit is that it provides firmer support than the ring pessary. This pessary is not widely used in the United States.

The Gehrung pessary looks like a flat strip of material that has been bent into the shape of a “U.” It is designed to correct severe cystoceles and rectoceles. For insertion, the edges at the open end of the pessary are squeezed together and the pessary is inserted with the closed part of the “U” facing the anterior vaginal wall. The upper edge is advanced until it rests in the anterior fornix of the vagina (or in the vaginal apex in women who have had a hysterectomy). Although it is more efficacious than some other pessaries for control of vaginal wall prolapse, its unfamiliarity to clinicians and its unusual shape result in it being used rarely.

Continue to: Space-filling pessaries...

Space-filling pessaries

Space-filling pessaries are used when more severe degrees of prolapse are present than can be managed by the ring or other support pessaries. This is especially the case when the vagina is so capacious or the introitus so lax that a standard ring pessary cannot be kept in place, resulting in frequent expulsions.

Space-filling pessaries are 3 dimensional and work by filling the vagina with a relatively large object that prevents the cervix/vaginal apex from dropping down and the vaginal walls from prolapsing. They have a special role for women who:

• are posthysterectomy and have an enterocele and/or vaginal apex prolapse
• have significant rectoceles for which support pessaries are not effective
• have a wide vaginal hiatus and thus are prone to expel support pessaries.

Space-filling pessaries do have some drawbacks compared with support pessaries. For example, they do not help in controlling SUI, and they are difficult for patients to remove on their own for cleaning. In addition, sexual intercourse is impossible with a space-filling pessary in place.

The Gellhorn pessary is the most common of the space-filling pessaries, and it is the one gynecologists and urogynecologists most often use for severe prolapse. It has a concave disc that fits up against the cervix or vaginal apex and a solid stem that points down the vagina. The stem itself is supported by the perineal body. It offers excellent support for severe uterine and vaginal wall prolapse, as long as the perineal body is intact. The stem stabilizes the disc portion of the pessary and prevents pessary expulsion. Gellhorn pessaries are available with long or short stems.

The Gellhorn is inserted into the vagina by folding the stem 90 degrees until it is in the same plane as the disc. With lubricated fingers, the patient’s perineal body is depressed and the disc of the pessary is folded and slid in. The disc is then placed up against the cervix or vaginal apex with the stem pointing down the vagina and tucked just inside the posterior edge of the introitus.

Removing the Gellhorn pessary can be problematic and is difficult for patients to do on their own. Clinicians often must use a ring forceps to grasp the stem of the pessary in order to bring it into the lower vagina, where the stem is folded up against the disc and the entire pessary removed. As with all space-filling pessaries, the Gellhorn must be taken out prior to intercourse.

The Gellhorn pessary is available in sizes that range from a disc diameter of 1.5 to 3.75 inches. Those measuring 2.5, 2.75, or 3 inches are used most commonly.

The cube pessary is a soft, dice-shaped piece of silicone with an indentation in each of its 6 sides. It is used for severe prolapse.

Squeezing the cube allows for easier insertion into the vagina; once it is at the top of the vagina, the cube expands back to its normal shape. The indentations on each side of the cube attach to the vaginal walls with moderate suction, which helps to keep the pessary in place. Because of the suction, the cube pessary can be used in cases of severe prolapse when other pessaries will not stay in place; a drawback is that the suction created by the indented sides can cause vaginal mucosal erosion.¹⁰ Ideally, the cube pessary should be removed every night for cleansing as discharge and accompanying odor can accumulate. The string attached to the cube pessary aids in its removal.

The cube pessary is available in sizes 0 to 7, with edge lengths that range from 1 to 2.25 inches.

The donut pessary, as its name suggests, has the form of a large donut. It can be compressed slightly to help with insertion. Because it occupies a large space within the vagina, it is used (like the cube pessary) for treatment of severe prolapse. The size and shape of the donut pessary, however, can make it difficult for patients to insert and take out on their own.

The donut pessary is available in sizes 0 (51 mm) to 8 (95 mm).

The inflatable pessary has the same basic shape as the donut pessary and serves the same purpose: It acts as a large semisoft object that fills the vagina to support the vaginal walls and cervix (or vaginal apex) in cases of severe prolapse. The inflatable pessary differs in that it has a valve on a stem through which air can be inserted and removed. This allows the uninflated pessary to be placed relatively easily into the vagina and then pumped full of air to the dimensions necessary to prevent vaginal, cervical, uterine, or apex prolapse. Air likewise can be removed to facilitate pessary removal.

One drawback of the inflatable pessary is that it is made of latex and thus cannot be used by anyone with a latex allergy. Also, as latex retains discharge and odors, this pessary should be removed and washed daily.

The inflatable pessary is available in sizes that range from 2 to 2.75 inches in 0.25-inch increments.

Continue to: Space-filling pessaries...

In addition to the more commonly used support and space-filling pessaries, there is a third kind that is rarely used in current practice: the lever pessaries. These pessaries—the Hodge, the Smith, and the Risser—are rectangles made of inert plastic that are folded into 3 planes to facilitate positioning in the vagina. The narrower of the 2 shorter ends of the folded rectangle is placed behind the cervix or at the vaginal apex while the other short end is placed behind the symphysis pubis.

Although sometimes used to correct POP in nonpregnant women, the lever pessary’s main purpose is to antivert a retroflexed uterus and to support the cervix and uterus in cases of prolapse during pregnancy or impending cervical incompetence.

The 3 lever pessaries differ in terms of whether the narrow ends of the pessary are straight or curved and wider or narrower.

How to choose the right pessary for your patient

If a patient’s POP or urinary incontinence symptoms would best be treated with a pessary, the next step is to select the pessary type and size best suited for that patient’s needs and the size that should be prescribed. While there is controversy among experts as to whether or not certain pessaries are better than others for different indications,¹² most gynecologists and urogynecologists who use pessaries on a regular basis agree on the following:

1. Support pessaries will meet the needs of most women with moderate POP and/or SUI. These include the ring pessary with or without the support shield and with or without an incontinence knob. A support pessary is the go-to pessary in most cases. Most women find it comfortable to wear, it is easy to put in and take out, and sexual intercourse is possible with the pessary in place.

2. The specific degree of a patient’s prolapse and/or incontinence dictates whether or not to prescribe the support shield feature or the incontinence knob with a ring pessary. The shield helps support a prolapsed cervix and uterus when they are present.^5,13 The knob is a useful feature if incontinence is a prominent symptom.

3. The Gellhorn pessary is usually the first choice for more severe prolapse. As long as there is some degree of posterior perineal support, this pessary does an excellent job of correcting even severe prolapse whether of a cervix and uterus or of vaginal walls and apex. It does require the patient to have some practice and dexterity for inserting and removing it on her own; individuals not comfortable or physically able to do so will need to have the pessary removed and cleaned by a clinician on a regular basis in the office. (Part 2 of this article will discuss pessary cleansing intervals).

4. Space-filling pessaries (such as the cube and donut) are useful when there is a severe degree of prolapse and insufficient perineal support to maintain a Gellhorn pessary. In practice, they are generally used less frequently—which is unfortunate, as they are a potentially useful solution for older women with severe prolapse who might not be candidates for surgical repair. As mentioned, both the cube and donut pessaries require more frequent removal for cleaning.

5. In unusual cases, the use of 2 pessaries simultaneously may resolve a difficult problem, such as when a pessary is the only option for treatment, the prolapse is severe, or it is impossible to find a pessary that resists being expelled from the vagina.¹⁴ A space-filling pessary in the most cephalad aspect of the vagina used in conjunction with a ring pessary with support shield below it can sometimes resolve even the worst cases of prolapse.

Continue to: Stay tuned...

Stay tuned

Part 2 of this article next month will provide more information on pessaries, including fitting, aftercare, potential complications, and effectiveness in various disorders. ●

Over the last 30 years, surgical correction of the common condition pelvic organ prolapse (POP) and stress urinary incontinence (SUI) has become so routine and straightforward that many gynecologists and urogynecologists choose surgery as their first choice for treating these conditions, withholding it only from the riskiest patients or from those who, for a variety of reasons, do not choose surgery. Moreover, as generalist gynecologists increasingly refer patients with POP or incontinence to their urogynecologist colleagues, they increasingly lack the skills, or have not been trained, to use conservative treatment strategies for these disorders. Thus, pessaries—devices constructed of inert plastic, silicone, or latex and placed inside the vagina to support prolapsed pelvic structures—frequently are not part of the general gynecologist’s armamentarium.

When properly selected, however, pessaries used for indicated purposes and correctly fitted are an excellent, inexpensive, low-risk, and noninvasive tool that can provide immediate relief not only of POP but also of SUI and defecatory difficulties. As an alternative to surgery, pessaries are especially valuable, because the other major nonsurgical modality for treatment of POP and incontinence—pelvic floor muscle training—often is not covered by insurance (making it expensive for patients), takes many weekly sessions to complete (which can make access challenging), and frequently is not readily available.¹

POP is very common. An estimated 15% to 30% of women in North America have some degree of prolapse, and more than 500,000 surgeries for this condition are performed in the United States each year.² Risk factors for POP include:

• vaginal childbirth, especially higher parity
• advancing age
• high body mass index (BMI)
• prior hysterectomy
• raised intra-abdominal pressure, such as from obesity, chronic cough, or heavy lifting.

In addition to the discomfort caused by the herniation of pelvic and vaginal structures, POP also is associated with urinary incontinence (73%), urinary urgency and frequency (86%), and fecal incontinence (31%).³

Moreover, according to the US Census Bureau, the number of American women aged 65 or older will double to more than 40 million by 2030.⁴ This will greatly increase the population of women at risk for POP who may be candidates for pessary use. It therefore behooves gynecologists to become familiar with the correct usage, fitting, and maintenance of this effective, nonsurgical mode of treatment for POP.

In this article, I discuss why pessaries are a good option for many patients with POP, review the types of pessaries available, and offer guidance on how to choose the right pessary for an individual patient’s needs. In addition, the box at the end of this article provides an interesting timeline of pessary history dating back to antiquity.

Next month in Part 2 of this article, I cover how to fit a pessary; device aftercare; potential complications of use; and effectiveness of pessaries for POP, SUI, preterm labor prevention, and defecatory disorders.

Continue to: Potential candidates for pessary use...

Potential candidates for pessary use

Almost all women with POP—and in many cases accompanying SUI—are potential candidates for a pessary. In fact, many urogynecologists believe that a trial of pessary usage should be the first treatment modality offered for POP.⁵ Women who cannot use a pessary include those with an extremely short vagina (<6 cm) and those who have severely eroded vaginal mucosa. In the latter situation, the mucosa can be treated with estrogen cream for several weeks and, once the tissue has healed, a pessary can be fitted.

Given that surgical repair is generally a straightforward, one-time procedure that obviates the need for long-term use of an artificial device worn internally, why might a patient or her physician opt for a pessary instead?

Some of the many reasons include:

• Many patients prefer to avoid surgery.
• Many patients are not appropriate candidates for surgery because they have significant comorbid risk factors or high BMI.
• Patients may have recurrent prolapse or incontinence and wish to avoid repeat surgery.
• Patients with SUI may have heard of the occurrence of mesh erosion and wish to avoid that possibility.
• Women who live in low-resource environments or countries where elective surgical care is relatively unavailable may not have the option of surgery.

A clinician might also recommend pessary use:

• as a diagnostic tool to attempt to assess the potential results of vaginal repair surgery
• to estimate the potential effectiveness of a midurethral sling procedure; several investigators have found this to be approximately as accurate as urodynamic testing^6,7
• as prophylaxis for pregnant women with either a history of preterm cervical dilation or a short cervix detected on ultrasonography
• for pregnant women with POP that is worsening and becoming increasingly uncomfortable
• for women with POP who wish to have more children
• for short-term use while a patient is delaying or awaiting POP surgery or to allow time for other medical issues to resolve
• for patients who wish only intermittent, temporary support while exercising or engaging in sports.

Patient acceptance may be contingent on counseling

Numerous studies show that women who choose pessaries to treat POP are generally older than women who elect surgery. Still, patient acceptance of a trial of pessary use depends much on the counseling and information she receives. Properly informed, many patients with POP will opt for a trial of pessary placement. One study showed that, of women with untreated POP, 36% preferred pessary placement to surgery.⁸ Other investigators reported that when women with symptomatic POP had the benefits of a pessary versus surgery explained to them, nearly two-thirds opted for a pessary as their mode of treatment.⁹

Exceptions to pessary use

Fortunately, there are relatively few contraindications to pessary use. These are vaginal or pelvic infection and an exposed foreign body in the vagina, such as eroded vaginal mesh. In addition, patients at risk for nonadherence with follow-up care are poor candidates, as it could lead to missing such problems as mucosal erosion, ulceration, or even (extremely rarely) fistula formation. Pessaries may be inappropriate for sexually active women who on their own are unable to remove and reinsert pessary types that do not allow for intercourse while in place (see below).

Continue to: Types of pessaries...

Types of pessaries

The numerous kinds of pessaries available fall into 3 general categories: support, space filling, and lever, and devices within each group have modifications and variations. As with most areas of prescribing and treatment in medicine, it is best to become very familiar with just a few kinds of pessaries, know their indications, and use them when appropriate.

Most pessaries are constructed of inert silicone which, unlike earlier rubber pessaries, does not absorb odor or discharge. They are easy to clean, long lasting, and are autoclavable and hypoallergenic.

Support pessaries

Support pessaries look like contraceptive diaphragms. They are easy to place and remove, are comfortable, and do an excellent job correcting moderate POP. They also can control or eliminate symptoms of SUI by the pressure they exert on the urethra and their alteration of the urethrovesicular angle.

Ring pessaries. The most commonly used type of pessary, the ring pessary,¹⁰ comes in 4 variations:

• a simple open ring
• a ring with a web of material, called a “support shield,” that fills the ring
• an open ring with a firm 2-cm “incontinence knob” attached that is positioned over the urethra
• a ring with support shield and incontinence knob.

When in position, the deepest edge of a ring pessary fits behind the cervix (or in the vaginal apex for women who have had a hysterectomy) while the front of the ring slips into place behind the pubic symphysis, just like a diaphragm. When a ring with an incontinence knob is used, the ring is rotated until the knob is directly over the urethra.

Sexual intercourse is possible with any of the ring pessaries in place. Of the various types of pessaries, the ring pessary is the easiest to insert and remove. Some women tie a piece of dental floss to the edge of the ring to make its removal even easier.

The ring pessary is available in sizes 0 (44.5 mm) to 13 (127 mm). For most women a size 3, 4, or 5 ring pessary fits well.

The Marland pessary is similar to the ring pessary with the addition of a wedge-shaped piece of material approximately 3 cm in height that arises from half of the ring. It rarely is used in the United States because most American gynecologists are unfamiliar with it, and there is little evidence that it is more effective than the ring pessary.¹¹

The Shaatz pessary is a rigid round pessary, smaller in diameter than the standard ring pessary, and similar to the Gellhorn pessary (discussed below) but without a stem. It is placed the same way one places a ring pessary but with its concave surface up against the cervix or, if there is no cervix, against the upper anterior vaginal wall. Its main benefit is that it provides firmer support than the ring pessary. This pessary is not widely used in the United States.

The Gehrung pessary looks like a flat strip of material that has been bent into the shape of a “U.” It is designed to correct severe cystoceles and rectoceles. For insertion, the edges at the open end of the pessary are squeezed together and the pessary is inserted with the closed part of the “U” facing the anterior vaginal wall. The upper edge is advanced until it rests in the anterior fornix of the vagina (or in the vaginal apex in women who have had a hysterectomy). Although it is more efficacious than some other pessaries for control of vaginal wall prolapse, its unfamiliarity to clinicians and its unusual shape result in it being used rarely.

Continue to: Space-filling pessaries...

Space-filling pessaries

Space-filling pessaries are used when more severe degrees of prolapse are present than can be managed by the ring or other support pessaries. This is especially the case when the vagina is so capacious or the introitus so lax that a standard ring pessary cannot be kept in place, resulting in frequent expulsions.

Space-filling pessaries are 3 dimensional and work by filling the vagina with a relatively large object that prevents the cervix/vaginal apex from dropping down and the vaginal walls from prolapsing. They have a special role for women who:

• are posthysterectomy and have an enterocele and/or vaginal apex prolapse
• have significant rectoceles for which support pessaries are not effective
• have a wide vaginal hiatus and thus are prone to expel support pessaries.

Space-filling pessaries do have some drawbacks compared with support pessaries. For example, they do not help in controlling SUI, and they are difficult for patients to remove on their own for cleaning. In addition, sexual intercourse is impossible with a space-filling pessary in place.

The Gellhorn pessary is the most common of the space-filling pessaries, and it is the one gynecologists and urogynecologists most often use for severe prolapse. It has a concave disc that fits up against the cervix or vaginal apex and a solid stem that points down the vagina. The stem itself is supported by the perineal body. It offers excellent support for severe uterine and vaginal wall prolapse, as long as the perineal body is intact. The stem stabilizes the disc portion of the pessary and prevents pessary expulsion. Gellhorn pessaries are available with long or short stems.

The Gellhorn is inserted into the vagina by folding the stem 90 degrees until it is in the same plane as the disc. With lubricated fingers, the patient’s perineal body is depressed and the disc of the pessary is folded and slid in. The disc is then placed up against the cervix or vaginal apex with the stem pointing down the vagina and tucked just inside the posterior edge of the introitus.

Removing the Gellhorn pessary can be problematic and is difficult for patients to do on their own. Clinicians often must use a ring forceps to grasp the stem of the pessary in order to bring it into the lower vagina, where the stem is folded up against the disc and the entire pessary removed. As with all space-filling pessaries, the Gellhorn must be taken out prior to intercourse.

The Gellhorn pessary is available in sizes that range from a disc diameter of 1.5 to 3.75 inches. Those measuring 2.5, 2.75, or 3 inches are used most commonly.

The cube pessary is a soft, dice-shaped piece of silicone with an indentation in each of its 6 sides. It is used for severe prolapse.

Squeezing the cube allows for easier insertion into the vagina; once it is at the top of the vagina, the cube expands back to its normal shape. The indentations on each side of the cube attach to the vaginal walls with moderate suction, which helps to keep the pessary in place. Because of the suction, the cube pessary can be used in cases of severe prolapse when other pessaries will not stay in place; a drawback is that the suction created by the indented sides can cause vaginal mucosal erosion.¹⁰ Ideally, the cube pessary should be removed every night for cleansing as discharge and accompanying odor can accumulate. The string attached to the cube pessary aids in its removal.

The cube pessary is available in sizes 0 to 7, with edge lengths that range from 1 to 2.25 inches.

The donut pessary, as its name suggests, has the form of a large donut. It can be compressed slightly to help with insertion. Because it occupies a large space within the vagina, it is used (like the cube pessary) for treatment of severe prolapse. The size and shape of the donut pessary, however, can make it difficult for patients to insert and take out on their own.

The donut pessary is available in sizes 0 (51 mm) to 8 (95 mm).

The inflatable pessary has the same basic shape as the donut pessary and serves the same purpose: It acts as a large semisoft object that fills the vagina to support the vaginal walls and cervix (or vaginal apex) in cases of severe prolapse. The inflatable pessary differs in that it has a valve on a stem through which air can be inserted and removed. This allows the uninflated pessary to be placed relatively easily into the vagina and then pumped full of air to the dimensions necessary to prevent vaginal, cervical, uterine, or apex prolapse. Air likewise can be removed to facilitate pessary removal.

One drawback of the inflatable pessary is that it is made of latex and thus cannot be used by anyone with a latex allergy. Also, as latex retains discharge and odors, this pessary should be removed and washed daily.

The inflatable pessary is available in sizes that range from 2 to 2.75 inches in 0.25-inch increments.

Continue to: Space-filling pessaries...

In addition to the more commonly used support and space-filling pessaries, there is a third kind that is rarely used in current practice: the lever pessaries. These pessaries—the Hodge, the Smith, and the Risser—are rectangles made of inert plastic that are folded into 3 planes to facilitate positioning in the vagina. The narrower of the 2 shorter ends of the folded rectangle is placed behind the cervix or at the vaginal apex while the other short end is placed behind the symphysis pubis.

Although sometimes used to correct POP in nonpregnant women, the lever pessary’s main purpose is to antivert a retroflexed uterus and to support the cervix and uterus in cases of prolapse during pregnancy or impending cervical incompetence.

The 3 lever pessaries differ in terms of whether the narrow ends of the pessary are straight or curved and wider or narrower.

How to choose the right pessary for your patient

If a patient’s POP or urinary incontinence symptoms would best be treated with a pessary, the next step is to select the pessary type and size best suited for that patient’s needs and the size that should be prescribed. While there is controversy among experts as to whether or not certain pessaries are better than others for different indications,¹² most gynecologists and urogynecologists who use pessaries on a regular basis agree on the following:

1. Support pessaries will meet the needs of most women with moderate POP and/or SUI. These include the ring pessary with or without the support shield and with or without an incontinence knob. A support pessary is the go-to pessary in most cases. Most women find it comfortable to wear, it is easy to put in and take out, and sexual intercourse is possible with the pessary in place.

2. The specific degree of a patient’s prolapse and/or incontinence dictates whether or not to prescribe the support shield feature or the incontinence knob with a ring pessary. The shield helps support a prolapsed cervix and uterus when they are present.^5,13 The knob is a useful feature if incontinence is a prominent symptom.

3. The Gellhorn pessary is usually the first choice for more severe prolapse. As long as there is some degree of posterior perineal support, this pessary does an excellent job of correcting even severe prolapse whether of a cervix and uterus or of vaginal walls and apex. It does require the patient to have some practice and dexterity for inserting and removing it on her own; individuals not comfortable or physically able to do so will need to have the pessary removed and cleaned by a clinician on a regular basis in the office. (Part 2 of this article will discuss pessary cleansing intervals).

4. Space-filling pessaries (such as the cube and donut) are useful when there is a severe degree of prolapse and insufficient perineal support to maintain a Gellhorn pessary. In practice, they are generally used less frequently—which is unfortunate, as they are a potentially useful solution for older women with severe prolapse who might not be candidates for surgical repair. As mentioned, both the cube and donut pessaries require more frequent removal for cleaning.

5. In unusual cases, the use of 2 pessaries simultaneously may resolve a difficult problem, such as when a pessary is the only option for treatment, the prolapse is severe, or it is impossible to find a pessary that resists being expelled from the vagina.¹⁴ A space-filling pessary in the most cephalad aspect of the vagina used in conjunction with a ring pessary with support shield below it can sometimes resolve even the worst cases of prolapse.

Continue to: Stay tuned...

Stay tuned

Part 2 of this article next month will provide more information on pessaries, including fitting, aftercare, potential complications, and effectiveness in various disorders. ●

In the era of long-acting reversible contraceptives (LARCs), the pill can seem obsolete. However, it is still the second most commonly used birth control method in the United States, chosen by 19% of female contraceptive users as of 2015–2017.¹ It also has noncontraceptive benefits, so it is important that obstetrician-gynecologists are well-versed in its uses. In this article, I will focus on combined oral contraceptives (COCs; TABLE 1), reviewing the major risks, benefits, and adverse effects of COCs before focusing on recommendations for particular formulations of COCs for various patient populations.

Benefits and risks

There are numerous noncontraceptive benefits of COCs, including menstrual cycle regulation; reduced risk of ovarian, endometrial, and colorectal cancer; and treatment of menorrhagia, dysmenorrhea, acne, menstrual migraine, premenstrual syndrome and premenstrual dysphoric disorder, pelvic pain due to endometriosis, and hirsutism.

Common patient concerns

In terms of adverse effects, there are more potential unwanted effects of concern to women than there are ones validated in the literature. Accepted adverse effects include nausea, breast tenderness, and decreased libido. However, one of the most common concerns voiced during contraceptive counseling is that COCs will cause weight gain. A 2014 Cochrane review identified 49 trials studying the weight gain question.² Of those, only 4 had a placebo or nonintervention group. Of these 4, there was no significant difference in weight change between the COC-receiving group and the control group. When patients bring up their concerns, it may help to remind them that women tend to gain weight over time whether or not they are taking a COC.

Another common concern is that COCs cause mood changes. A 2016 review by Schaffir and colleagues sheds some light on this topic,³ albeit limited by the paucity of prospective studies. This review identified only 1 randomized controlled trial comparing depression incidence among women initiating a COC versus a placebo. There was no difference in the incidence of depression among the groups at 3 months. Among 4 large retrospective studies of women using COCs, the agents either had no or a beneficial effect on mood. Schaffir’s review reports that there may be greater mood adverse effects with COCs among women with underlying mood disorders.

Patients may worry that COC use will permanently impair their fertility or delay return to fertility after discontinuation. Research does indicate that return of fertility after stopping COCs often takes several months (compared with immediate fertility after discontinuing a barrier method). However, there still seem to be comparable conception rates within 12 months after discontinuing COCs as there are after discontinuing other common nonhormonal or hormonal contraceptive methods. Fertility is not impacted by the duration of COC use. In addition, return to fertility seems to be comparable after discontinuation of extended cycle or continuous COCs compared with traditional-cycle COCs.⁴

COC safety

Known major risks of COCs include venous thromboembolism (VTE). The risk of VTE is about double among COC users than among nonpregnant nonusers: 3–9 per 10,000 woman-years compared with 1–5.⁵ In a study by the US Food and Drug Administration, drospirenone-containing COCs had double the risk of VTE than other COCs. However, the position of the American College of Obstetricians and Gynecologists on this increased risk of VTE with drospirenone-containing pills is that it is “possible” and “minimal.”⁵ It is important to remember that an alternative to COC use is pregnancy, in which the VTE risk is about double that among COC users, at 5–20 per 10,000 woman-years. This risk increases further in the postpartum period, to 40–65 per 10,000 woman-years.⁵

Another known major risk of COCs is arterial embolic disease, including cerebrovascular accidents and myocardial infarctions. Women at increased risk for these complications include those with hypertension, diabetes, and/or obesity and women who are aged 35 or older and smoke. Interestingly, women with migraines with aura are at increased risk for stroke but not for myocardial infarction. These women increase their risk of stroke 2- to 4-fold if they use COCs.

Continue to: Different pills for different problems...

Different pills for different problems

With so many pills on the market, it is important for clinicians to know how to choose a particular pill for a particular patient. The following discussion assumes that the patient in question desires a COC for contraception, then offers guidance on how to choose a pill with patient-specific noncontraceptive benefits (TABLE 2).

• Introvale and Seasonique, both extended-cycle formulations
• Amethyst, which is formulated without placebo pills so that it can be used continuously
• any other COC prescribed with instructions for the patient to skip placebo pills.

An extrapolated benefit to extended-cycle or continuous COCs use for heavy menstrual bleeding is addressing anemia.

For premenstrual dysphoric disorder, the only randomized controlled trials showing improvement involve drospirenone-ethinyl estradiol pills (Yaz and Yasmin).⁷ There is also evidence that extended cyclic or continuous use of these formulations is more impactful for premenstrual dysphoric disorder than a traditional cycle.⁸

Keeping migraine avoidance and prevention in mind. Various studies have looked at the impact of different COC formulations on menstrual-related symptoms. There is evidence of greater improvement in headache, bloating, and dysmenorrhea with extended cyclic or continuous use compared with traditional cyclic use.⁶

In terms of headache, let us delve into menstrual migraine in particular. Menstrual migraines occur sometime between 2 days prior to 2 days after the first day of menses and are linked to a sharp drop in estrogen levels. COCs are contraindicated in women with menstrual migraines with aura because of the increased stroke risk. For women with menstrual migraines without aura, COCs can prevent migraines. Prevention depends on minimizing fluctuations in estrogen levels; any change in estrogen level greater than 10 µg of ethinyl estradiol may trigger an estrogen-related migraine. All currently available regimens of COCs that comprise 21 days of active pills and 7 days of placebo involve a drop of more than 10 µg. Options that involve a drop of 10 µg or less include any continuous formulation, the extended formulation LoSeasonique (levonorgestrel 0.1 mg and ethinyl estradiol 20 µg for 84 days, then ethinyl estradiol 10 µg for 7 days), and Lo Loestrin (ethinyl estradiol 10 µg and norethindrone 1 mg for 24 days, then ethinyl estradiol 10 µg for 2 days, then placebo for 2 days).⁹

What’s best for acne-prone patients? All COCs should improve acne by increasing levels of sex hormone binding globulin. However, some comparative studies have shown drospirenone-containing COCs to be the most effective for acne. This finding makes sense in light of studies demonstrating antiandrogenic effects of drospirenone.¹⁰

Managing PCOS symptoms. It seems logical, by extension, that drospirenone-containing COCs would be particularly beneficial for treating hirsutism associated with polycystic ovary syndrome (PCOS). Other low‒androgenic-potential progestins, such as a third-generation progestin (norgestimate or desogestrel), might similarly be hypothesized to be advantageous. However, there is currently insufficient evidence to recommend any one COC formulation over another for the indication of PCOS.¹¹

Ovarian cysts: Can COCs be helpful? COCs are commonly prescribed by gynecologists for patients with functional ovarian cysts. It is important to note that COCs have not been found to hasten the resolution of existing cysts, so they should not be used for this purpose.¹² Studies of early COCs, which had high doses of estrogen (on the order of 50 µg), showed lower rates of cysts among users. This effect seems to be attenuated with the lower-estrogen-dose pills that are currently available, but there still appears to be benefit. Therefore, for a patient prone to cysts who desires an oral contraceptive, a COC containing estrogen 35 µg is likely to be the most beneficial of COCs currently on the market.^13,14

Lower-dosage COCs in perimenopause may be beneficial. COCs can ameliorate perimenopausal symptoms including abnormal uterine bleeding and vasomotor symptoms. Clinicians are often hesitant to prescribe COCs for perimenopausal women because of increased risk of VTE, stroke, myocardial infarction, and breast cancer with increasing age. However, age alone is not a contraindication to any contraceptive method. An extended cyclic or continuous regimen COC may be the best choice for a perimenopausal woman in order to avoid vasomotor symptoms that occur during hormone-free intervals. In addition, given the increasing risk of adverse effects like VTE with estrogen dose, a lower estrogen formulation is advisable.¹⁵

Patients with epilepsy who are taking antiepileptic drugs (AEDs) are a special population when it comes to COCs. Certain AEDs induce hepatic enzymes involved in the metabolism and protein binding of COCs, which can result in contraceptive failure. Strong inducers are carbamazepine, oxcarbazepine, perampanel, phenobarbital, phenytoin, and primidone. Weak inducers are clobazam, eslicarbazepine, felbamate, lamotrigine, rufinamide, and topiramate. Women taking any of the above AEDs are recommended to choose a different form of contraception than a COC. However, if they are limited to COCs for some reason, a preparation containing estrogen 50 µg is recommended. It is speculated that the efficacy and adverse effects of COCs with increased hormone doses, used in combination with enzyme-inducing AEDs, should be comparable to those with standard doses when not combined with AEDs; however, this speculation is unproven.¹⁶ There are few COCs on the market with estrogen doses of 50 µg, but a couple of examples are Kelnor and Ogestrel.

Additional factors have to be considered with concurrent COC use with the AED lamotrigine since COCs increase clearance of this agent. Therefore, patients taking lamotrigine who start COCs will need an increase in lamotrigine dose. To avoid fluctuations in lamotrigine serum levels, use of a continuous COC is recommended.¹⁷

Continue to: Pill types to minimize adverse effects or risks...

For women who desire to use a COC for contraception but who are at risk for a particular complication or are bothered by a particular adverse effect, ObGyns can optimize the choice of pill (TABLE 3). For example, women who have adverse effects of nausea and/or breast tenderness may benefit from reducing the estrogen dose to 20 µg or lower.¹⁸

Considering VTE

As discussed previously, VTE is a risk with all COCs, but some pills confer greater risk than others. For one, VTE risk increases with estrogen dose. In addition, VTE risk depends on the type of progestin. Drospirenone and third-generation progestins (norgestimate, gestodene, and desogestrel) confer a higher risk of VTE than first- or second-generation progestins. For example, a pill with estradiol 30 µg and either a third-generation progestin or drospirenone has a 50% to 80% higher risk of VTE compared with a pill with estradiol 30 µg and levonorgestrel.

For patients at particularly high risk for VTE, COCs are contraindicated. For patients for whom COCs are considered medically appropriate but who are at higher risk (eg, obese women), it is wise to use a pill containing a first-generation (norethindrone) or second-generation progestin (levonorgestrel) combined with the lowest dose of estrogen that has tolerable adverse effects.¹⁹

What about hypertension concerns?

Let us turn our attention briefly to hypertension and its relation to COC use. While the American College of Cardiology and the American Heart Association redefined hypertension in 2017 using a threshold of 130/80 mm Hg, the American College of Obstetricians and Gynecologists (ACOG) considers hypertension to be 140/90 mm Hg in terms of safety of using COCs. ACOG states, “women with blood pressure below 140/90 mm Hg may use any hormonal contraceptive method.”²⁰ In women with hypertension in the range of 140‒159 mm Hg systolic or 90‒99 mm Hg diastolic, COCs are category 3 according to the US Medical Eligibility Criteria for Contraceptive Use, meaning that the risks usually outweigh the benefits. For women with blood pressures of 160/110 mm Hg or greater, COCs are category 4 (contraindicated). If a woman with mild hypertension is started on a COC, a drospirenone-containing pill may be the best choice because of its diuretic effects. While other contemporary COCs have been associated with a mild increase in blood pressure, drospirenone-containing pills have not shown this association.²¹

Continue to: At issue: Break-through bleeding, mood, and weight gain...

At issue: Break-through bleeding, mood, and weight gain

For women bothered by intermenstrual bleeding, use of a COC with a third-generation progestin may be preferable to use of one with a first- or second-generation. It may be because of decreased abnormal bleeding that COCs with third-generation progestins have lower discontinuation rates.²² In addition, COCs containing estrogen 20 µg or less are associated with more intermenstrual bleeding than those with more than 20 µg estrogen.²³ Keep in mind that it is common with any COC to have intermenstrual bleeding for the first several months.

For women with pre-existing mood disorders or who report mood changes with COCs, it appears that fluctuations in hormone levels are problematic. Consistently, there is evidence that monophasic pills are preferable to multiphasic and that extended cyclic or continuous use is preferable to traditional cyclic use for mitigating mood adverse effects. There is mixed evidence on whether a low dose of ethinyl estradiol is better for mood.³

Although it is discussed above that randomized controlled trials have not shown an association between COC use and weight gain, many women remain concerned. For these women, a drospirenone-containing COC may be the best choice. Drospirenone has antimineralocorticoid activity, so it may help prevent water retention.

A brief word about multiphasic COCs. While these pills were designed to mimic physiologic hormone fluctuations and minimize hormonal adverse effects, there is insufficient evidence to compare their effects to those of monophasic pills.²⁴ Without such evidence, there is little reason to recommend a multiphasic pill to a patient over the more straightforward monophasic formulation.

Conclusion

There are more nuances to prescribing an optimal COC for a patient than may initially come to mind. It is useful to remember that any formulation of pill may be prescribed in an extended or continuous fashion, and there are benefits for such use for premenstrual dysphoric disorder, heavy menstrual bleeding, perimenopause, and menstrual symptoms. Although there are numerous brands of COCs available, a small cadre will suffice for almost all purposes. Such a “toolbox” of pills could include a pill formatted for continuous use (Seasonique), a low estrogen pill (Loestrin), a drospirenone-containing pill (Yaz), and a pill containing a third-generation progestin and a higher dose of estrogen (Sprintec). ●

In the era of long-acting reversible contraceptives (LARCs), the pill can seem obsolete. However, it is still the second most commonly used birth control method in the United States, chosen by 19% of female contraceptive users as of 2015–2017.¹ It also has noncontraceptive benefits, so it is important that obstetrician-gynecologists are well-versed in its uses. In this article, I will focus on combined oral contraceptives (COCs; TABLE 1), reviewing the major risks, benefits, and adverse effects of COCs before focusing on recommendations for particular formulations of COCs for various patient populations.

Benefits and risks

There are numerous noncontraceptive benefits of COCs, including menstrual cycle regulation; reduced risk of ovarian, endometrial, and colorectal cancer; and treatment of menorrhagia, dysmenorrhea, acne, menstrual migraine, premenstrual syndrome and premenstrual dysphoric disorder, pelvic pain due to endometriosis, and hirsutism.

Common patient concerns

In terms of adverse effects, there are more potential unwanted effects of concern to women than there are ones validated in the literature. Accepted adverse effects include nausea, breast tenderness, and decreased libido. However, one of the most common concerns voiced during contraceptive counseling is that COCs will cause weight gain. A 2014 Cochrane review identified 49 trials studying the weight gain question.² Of those, only 4 had a placebo or nonintervention group. Of these 4, there was no significant difference in weight change between the COC-receiving group and the control group. When patients bring up their concerns, it may help to remind them that women tend to gain weight over time whether or not they are taking a COC.

Another common concern is that COCs cause mood changes. A 2016 review by Schaffir and colleagues sheds some light on this topic,³ albeit limited by the paucity of prospective studies. This review identified only 1 randomized controlled trial comparing depression incidence among women initiating a COC versus a placebo. There was no difference in the incidence of depression among the groups at 3 months. Among 4 large retrospective studies of women using COCs, the agents either had no or a beneficial effect on mood. Schaffir’s review reports that there may be greater mood adverse effects with COCs among women with underlying mood disorders.

Patients may worry that COC use will permanently impair their fertility or delay return to fertility after discontinuation. Research does indicate that return of fertility after stopping COCs often takes several months (compared with immediate fertility after discontinuing a barrier method). However, there still seem to be comparable conception rates within 12 months after discontinuing COCs as there are after discontinuing other common nonhormonal or hormonal contraceptive methods. Fertility is not impacted by the duration of COC use. In addition, return to fertility seems to be comparable after discontinuation of extended cycle or continuous COCs compared with traditional-cycle COCs.⁴

COC safety

Known major risks of COCs include venous thromboembolism (VTE). The risk of VTE is about double among COC users than among nonpregnant nonusers: 3–9 per 10,000 woman-years compared with 1–5.⁵ In a study by the US Food and Drug Administration, drospirenone-containing COCs had double the risk of VTE than other COCs. However, the position of the American College of Obstetricians and Gynecologists on this increased risk of VTE with drospirenone-containing pills is that it is “possible” and “minimal.”⁵ It is important to remember that an alternative to COC use is pregnancy, in which the VTE risk is about double that among COC users, at 5–20 per 10,000 woman-years. This risk increases further in the postpartum period, to 40–65 per 10,000 woman-years.⁵

Another known major risk of COCs is arterial embolic disease, including cerebrovascular accidents and myocardial infarctions. Women at increased risk for these complications include those with hypertension, diabetes, and/or obesity and women who are aged 35 or older and smoke. Interestingly, women with migraines with aura are at increased risk for stroke but not for myocardial infarction. These women increase their risk of stroke 2- to 4-fold if they use COCs.

Continue to: Different pills for different problems...

Different pills for different problems

With so many pills on the market, it is important for clinicians to know how to choose a particular pill for a particular patient. The following discussion assumes that the patient in question desires a COC for contraception, then offers guidance on how to choose a pill with patient-specific noncontraceptive benefits (TABLE 2).

• Introvale and Seasonique, both extended-cycle formulations
• Amethyst, which is formulated without placebo pills so that it can be used continuously
• any other COC prescribed with instructions for the patient to skip placebo pills.

An extrapolated benefit to extended-cycle or continuous COCs use for heavy menstrual bleeding is addressing anemia.

For premenstrual dysphoric disorder, the only randomized controlled trials showing improvement involve drospirenone-ethinyl estradiol pills (Yaz and Yasmin).⁷ There is also evidence that extended cyclic or continuous use of these formulations is more impactful for premenstrual dysphoric disorder than a traditional cycle.⁸

Keeping migraine avoidance and prevention in mind. Various studies have looked at the impact of different COC formulations on menstrual-related symptoms. There is evidence of greater improvement in headache, bloating, and dysmenorrhea with extended cyclic or continuous use compared with traditional cyclic use.⁶

In terms of headache, let us delve into menstrual migraine in particular. Menstrual migraines occur sometime between 2 days prior to 2 days after the first day of menses and are linked to a sharp drop in estrogen levels. COCs are contraindicated in women with menstrual migraines with aura because of the increased stroke risk. For women with menstrual migraines without aura, COCs can prevent migraines. Prevention depends on minimizing fluctuations in estrogen levels; any change in estrogen level greater than 10 µg of ethinyl estradiol may trigger an estrogen-related migraine. All currently available regimens of COCs that comprise 21 days of active pills and 7 days of placebo involve a drop of more than 10 µg. Options that involve a drop of 10 µg or less include any continuous formulation, the extended formulation LoSeasonique (levonorgestrel 0.1 mg and ethinyl estradiol 20 µg for 84 days, then ethinyl estradiol 10 µg for 7 days), and Lo Loestrin (ethinyl estradiol 10 µg and norethindrone 1 mg for 24 days, then ethinyl estradiol 10 µg for 2 days, then placebo for 2 days).⁹

What’s best for acne-prone patients? All COCs should improve acne by increasing levels of sex hormone binding globulin. However, some comparative studies have shown drospirenone-containing COCs to be the most effective for acne. This finding makes sense in light of studies demonstrating antiandrogenic effects of drospirenone.¹⁰

Managing PCOS symptoms. It seems logical, by extension, that drospirenone-containing COCs would be particularly beneficial for treating hirsutism associated with polycystic ovary syndrome (PCOS). Other low‒androgenic-potential progestins, such as a third-generation progestin (norgestimate or desogestrel), might similarly be hypothesized to be advantageous. However, there is currently insufficient evidence to recommend any one COC formulation over another for the indication of PCOS.¹¹

Ovarian cysts: Can COCs be helpful? COCs are commonly prescribed by gynecologists for patients with functional ovarian cysts. It is important to note that COCs have not been found to hasten the resolution of existing cysts, so they should not be used for this purpose.¹² Studies of early COCs, which had high doses of estrogen (on the order of 50 µg), showed lower rates of cysts among users. This effect seems to be attenuated with the lower-estrogen-dose pills that are currently available, but there still appears to be benefit. Therefore, for a patient prone to cysts who desires an oral contraceptive, a COC containing estrogen 35 µg is likely to be the most beneficial of COCs currently on the market.^13,14

Lower-dosage COCs in perimenopause may be beneficial. COCs can ameliorate perimenopausal symptoms including abnormal uterine bleeding and vasomotor symptoms. Clinicians are often hesitant to prescribe COCs for perimenopausal women because of increased risk of VTE, stroke, myocardial infarction, and breast cancer with increasing age. However, age alone is not a contraindication to any contraceptive method. An extended cyclic or continuous regimen COC may be the best choice for a perimenopausal woman in order to avoid vasomotor symptoms that occur during hormone-free intervals. In addition, given the increasing risk of adverse effects like VTE with estrogen dose, a lower estrogen formulation is advisable.¹⁵

Patients with epilepsy who are taking antiepileptic drugs (AEDs) are a special population when it comes to COCs. Certain AEDs induce hepatic enzymes involved in the metabolism and protein binding of COCs, which can result in contraceptive failure. Strong inducers are carbamazepine, oxcarbazepine, perampanel, phenobarbital, phenytoin, and primidone. Weak inducers are clobazam, eslicarbazepine, felbamate, lamotrigine, rufinamide, and topiramate. Women taking any of the above AEDs are recommended to choose a different form of contraception than a COC. However, if they are limited to COCs for some reason, a preparation containing estrogen 50 µg is recommended. It is speculated that the efficacy and adverse effects of COCs with increased hormone doses, used in combination with enzyme-inducing AEDs, should be comparable to those with standard doses when not combined with AEDs; however, this speculation is unproven.¹⁶ There are few COCs on the market with estrogen doses of 50 µg, but a couple of examples are Kelnor and Ogestrel.

Additional factors have to be considered with concurrent COC use with the AED lamotrigine since COCs increase clearance of this agent. Therefore, patients taking lamotrigine who start COCs will need an increase in lamotrigine dose. To avoid fluctuations in lamotrigine serum levels, use of a continuous COC is recommended.¹⁷

Continue to: Pill types to minimize adverse effects or risks...

For women who desire to use a COC for contraception but who are at risk for a particular complication or are bothered by a particular adverse effect, ObGyns can optimize the choice of pill (TABLE 3). For example, women who have adverse effects of nausea and/or breast tenderness may benefit from reducing the estrogen dose to 20 µg or lower.¹⁸

Considering VTE

As discussed previously, VTE is a risk with all COCs, but some pills confer greater risk than others. For one, VTE risk increases with estrogen dose. In addition, VTE risk depends on the type of progestin. Drospirenone and third-generation progestins (norgestimate, gestodene, and desogestrel) confer a higher risk of VTE than first- or second-generation progestins. For example, a pill with estradiol 30 µg and either a third-generation progestin or drospirenone has a 50% to 80% higher risk of VTE compared with a pill with estradiol 30 µg and levonorgestrel.

For patients at particularly high risk for VTE, COCs are contraindicated. For patients for whom COCs are considered medically appropriate but who are at higher risk (eg, obese women), it is wise to use a pill containing a first-generation (norethindrone) or second-generation progestin (levonorgestrel) combined with the lowest dose of estrogen that has tolerable adverse effects.¹⁹

What about hypertension concerns?

Let us turn our attention briefly to hypertension and its relation to COC use. While the American College of Cardiology and the American Heart Association redefined hypertension in 2017 using a threshold of 130/80 mm Hg, the American College of Obstetricians and Gynecologists (ACOG) considers hypertension to be 140/90 mm Hg in terms of safety of using COCs. ACOG states, “women with blood pressure below 140/90 mm Hg may use any hormonal contraceptive method.”²⁰ In women with hypertension in the range of 140‒159 mm Hg systolic or 90‒99 mm Hg diastolic, COCs are category 3 according to the US Medical Eligibility Criteria for Contraceptive Use, meaning that the risks usually outweigh the benefits. For women with blood pressures of 160/110 mm Hg or greater, COCs are category 4 (contraindicated). If a woman with mild hypertension is started on a COC, a drospirenone-containing pill may be the best choice because of its diuretic effects. While other contemporary COCs have been associated with a mild increase in blood pressure, drospirenone-containing pills have not shown this association.²¹

Continue to: At issue: Break-through bleeding, mood, and weight gain...

At issue: Break-through bleeding, mood, and weight gain

For women bothered by intermenstrual bleeding, use of a COC with a third-generation progestin may be preferable to use of one with a first- or second-generation. It may be because of decreased abnormal bleeding that COCs with third-generation progestins have lower discontinuation rates.²² In addition, COCs containing estrogen 20 µg or less are associated with more intermenstrual bleeding than those with more than 20 µg estrogen.²³ Keep in mind that it is common with any COC to have intermenstrual bleeding for the first several months.

For women with pre-existing mood disorders or who report mood changes with COCs, it appears that fluctuations in hormone levels are problematic. Consistently, there is evidence that monophasic pills are preferable to multiphasic and that extended cyclic or continuous use is preferable to traditional cyclic use for mitigating mood adverse effects. There is mixed evidence on whether a low dose of ethinyl estradiol is better for mood.³

Although it is discussed above that randomized controlled trials have not shown an association between COC use and weight gain, many women remain concerned. For these women, a drospirenone-containing COC may be the best choice. Drospirenone has antimineralocorticoid activity, so it may help prevent water retention.

A brief word about multiphasic COCs. While these pills were designed to mimic physiologic hormone fluctuations and minimize hormonal adverse effects, there is insufficient evidence to compare their effects to those of monophasic pills.²⁴ Without such evidence, there is little reason to recommend a multiphasic pill to a patient over the more straightforward monophasic formulation.

Conclusion

There are more nuances to prescribing an optimal COC for a patient than may initially come to mind. It is useful to remember that any formulation of pill may be prescribed in an extended or continuous fashion, and there are benefits for such use for premenstrual dysphoric disorder, heavy menstrual bleeding, perimenopause, and menstrual symptoms. Although there are numerous brands of COCs available, a small cadre will suffice for almost all purposes. Such a “toolbox” of pills could include a pill formatted for continuous use (Seasonique), a low estrogen pill (Loestrin), a drospirenone-containing pill (Yaz), and a pill containing a third-generation progestin and a higher dose of estrogen (Sprintec). ●

In the era of long-acting reversible contraceptives (LARCs), the pill can seem obsolete. However, it is still the second most commonly used birth control method in the United States, chosen by 19% of female contraceptive users as of 2015–2017.¹ It also has noncontraceptive benefits, so it is important that obstetrician-gynecologists are well-versed in its uses. In this article, I will focus on combined oral contraceptives (COCs; TABLE 1), reviewing the major risks, benefits, and adverse effects of COCs before focusing on recommendations for particular formulations of COCs for various patient populations.

Benefits and risks

There are numerous noncontraceptive benefits of COCs, including menstrual cycle regulation; reduced risk of ovarian, endometrial, and colorectal cancer; and treatment of menorrhagia, dysmenorrhea, acne, menstrual migraine, premenstrual syndrome and premenstrual dysphoric disorder, pelvic pain due to endometriosis, and hirsutism.

Common patient concerns

In terms of adverse effects, there are more potential unwanted effects of concern to women than there are ones validated in the literature. Accepted adverse effects include nausea, breast tenderness, and decreased libido. However, one of the most common concerns voiced during contraceptive counseling is that COCs will cause weight gain. A 2014 Cochrane review identified 49 trials studying the weight gain question.² Of those, only 4 had a placebo or nonintervention group. Of these 4, there was no significant difference in weight change between the COC-receiving group and the control group. When patients bring up their concerns, it may help to remind them that women tend to gain weight over time whether or not they are taking a COC.

Another common concern is that COCs cause mood changes. A 2016 review by Schaffir and colleagues sheds some light on this topic,³ albeit limited by the paucity of prospective studies. This review identified only 1 randomized controlled trial comparing depression incidence among women initiating a COC versus a placebo. There was no difference in the incidence of depression among the groups at 3 months. Among 4 large retrospective studies of women using COCs, the agents either had no or a beneficial effect on mood. Schaffir’s review reports that there may be greater mood adverse effects with COCs among women with underlying mood disorders.

Patients may worry that COC use will permanently impair their fertility or delay return to fertility after discontinuation. Research does indicate that return of fertility after stopping COCs often takes several months (compared with immediate fertility after discontinuing a barrier method). However, there still seem to be comparable conception rates within 12 months after discontinuing COCs as there are after discontinuing other common nonhormonal or hormonal contraceptive methods. Fertility is not impacted by the duration of COC use. In addition, return to fertility seems to be comparable after discontinuation of extended cycle or continuous COCs compared with traditional-cycle COCs.⁴

COC safety

Known major risks of COCs include venous thromboembolism (VTE). The risk of VTE is about double among COC users than among nonpregnant nonusers: 3–9 per 10,000 woman-years compared with 1–5.⁵ In a study by the US Food and Drug Administration, drospirenone-containing COCs had double the risk of VTE than other COCs. However, the position of the American College of Obstetricians and Gynecologists on this increased risk of VTE with drospirenone-containing pills is that it is “possible” and “minimal.”⁵ It is important to remember that an alternative to COC use is pregnancy, in which the VTE risk is about double that among COC users, at 5–20 per 10,000 woman-years. This risk increases further in the postpartum period, to 40–65 per 10,000 woman-years.⁵

Another known major risk of COCs is arterial embolic disease, including cerebrovascular accidents and myocardial infarctions. Women at increased risk for these complications include those with hypertension, diabetes, and/or obesity and women who are aged 35 or older and smoke. Interestingly, women with migraines with aura are at increased risk for stroke but not for myocardial infarction. These women increase their risk of stroke 2- to 4-fold if they use COCs.

Continue to: Different pills for different problems...

Different pills for different problems

With so many pills on the market, it is important for clinicians to know how to choose a particular pill for a particular patient. The following discussion assumes that the patient in question desires a COC for contraception, then offers guidance on how to choose a pill with patient-specific noncontraceptive benefits (TABLE 2).

• Introvale and Seasonique, both extended-cycle formulations
• Amethyst, which is formulated without placebo pills so that it can be used continuously
• any other COC prescribed with instructions for the patient to skip placebo pills.

An extrapolated benefit to extended-cycle or continuous COCs use for heavy menstrual bleeding is addressing anemia.

For premenstrual dysphoric disorder, the only randomized controlled trials showing improvement involve drospirenone-ethinyl estradiol pills (Yaz and Yasmin).⁷ There is also evidence that extended cyclic or continuous use of these formulations is more impactful for premenstrual dysphoric disorder than a traditional cycle.⁸

Keeping migraine avoidance and prevention in mind. Various studies have looked at the impact of different COC formulations on menstrual-related symptoms. There is evidence of greater improvement in headache, bloating, and dysmenorrhea with extended cyclic or continuous use compared with traditional cyclic use.⁶

In terms of headache, let us delve into menstrual migraine in particular. Menstrual migraines occur sometime between 2 days prior to 2 days after the first day of menses and are linked to a sharp drop in estrogen levels. COCs are contraindicated in women with menstrual migraines with aura because of the increased stroke risk. For women with menstrual migraines without aura, COCs can prevent migraines. Prevention depends on minimizing fluctuations in estrogen levels; any change in estrogen level greater than 10 µg of ethinyl estradiol may trigger an estrogen-related migraine. All currently available regimens of COCs that comprise 21 days of active pills and 7 days of placebo involve a drop of more than 10 µg. Options that involve a drop of 10 µg or less include any continuous formulation, the extended formulation LoSeasonique (levonorgestrel 0.1 mg and ethinyl estradiol 20 µg for 84 days, then ethinyl estradiol 10 µg for 7 days), and Lo Loestrin (ethinyl estradiol 10 µg and norethindrone 1 mg for 24 days, then ethinyl estradiol 10 µg for 2 days, then placebo for 2 days).⁹

What’s best for acne-prone patients? All COCs should improve acne by increasing levels of sex hormone binding globulin. However, some comparative studies have shown drospirenone-containing COCs to be the most effective for acne. This finding makes sense in light of studies demonstrating antiandrogenic effects of drospirenone.¹⁰

Managing PCOS symptoms. It seems logical, by extension, that drospirenone-containing COCs would be particularly beneficial for treating hirsutism associated with polycystic ovary syndrome (PCOS). Other low‒androgenic-potential progestins, such as a third-generation progestin (norgestimate or desogestrel), might similarly be hypothesized to be advantageous. However, there is currently insufficient evidence to recommend any one COC formulation over another for the indication of PCOS.¹¹

Ovarian cysts: Can COCs be helpful? COCs are commonly prescribed by gynecologists for patients with functional ovarian cysts. It is important to note that COCs have not been found to hasten the resolution of existing cysts, so they should not be used for this purpose.¹² Studies of early COCs, which had high doses of estrogen (on the order of 50 µg), showed lower rates of cysts among users. This effect seems to be attenuated with the lower-estrogen-dose pills that are currently available, but there still appears to be benefit. Therefore, for a patient prone to cysts who desires an oral contraceptive, a COC containing estrogen 35 µg is likely to be the most beneficial of COCs currently on the market.^13,14

Lower-dosage COCs in perimenopause may be beneficial. COCs can ameliorate perimenopausal symptoms including abnormal uterine bleeding and vasomotor symptoms. Clinicians are often hesitant to prescribe COCs for perimenopausal women because of increased risk of VTE, stroke, myocardial infarction, and breast cancer with increasing age. However, age alone is not a contraindication to any contraceptive method. An extended cyclic or continuous regimen COC may be the best choice for a perimenopausal woman in order to avoid vasomotor symptoms that occur during hormone-free intervals. In addition, given the increasing risk of adverse effects like VTE with estrogen dose, a lower estrogen formulation is advisable.¹⁵

Patients with epilepsy who are taking antiepileptic drugs (AEDs) are a special population when it comes to COCs. Certain AEDs induce hepatic enzymes involved in the metabolism and protein binding of COCs, which can result in contraceptive failure. Strong inducers are carbamazepine, oxcarbazepine, perampanel, phenobarbital, phenytoin, and primidone. Weak inducers are clobazam, eslicarbazepine, felbamate, lamotrigine, rufinamide, and topiramate. Women taking any of the above AEDs are recommended to choose a different form of contraception than a COC. However, if they are limited to COCs for some reason, a preparation containing estrogen 50 µg is recommended. It is speculated that the efficacy and adverse effects of COCs with increased hormone doses, used in combination with enzyme-inducing AEDs, should be comparable to those with standard doses when not combined with AEDs; however, this speculation is unproven.¹⁶ There are few COCs on the market with estrogen doses of 50 µg, but a couple of examples are Kelnor and Ogestrel.

Additional factors have to be considered with concurrent COC use with the AED lamotrigine since COCs increase clearance of this agent. Therefore, patients taking lamotrigine who start COCs will need an increase in lamotrigine dose. To avoid fluctuations in lamotrigine serum levels, use of a continuous COC is recommended.¹⁷

Continue to: Pill types to minimize adverse effects or risks...

For women who desire to use a COC for contraception but who are at risk for a particular complication or are bothered by a particular adverse effect, ObGyns can optimize the choice of pill (TABLE 3). For example, women who have adverse effects of nausea and/or breast tenderness may benefit from reducing the estrogen dose to 20 µg or lower.¹⁸

Considering VTE

As discussed previously, VTE is a risk with all COCs, but some pills confer greater risk than others. For one, VTE risk increases with estrogen dose. In addition, VTE risk depends on the type of progestin. Drospirenone and third-generation progestins (norgestimate, gestodene, and desogestrel) confer a higher risk of VTE than first- or second-generation progestins. For example, a pill with estradiol 30 µg and either a third-generation progestin or drospirenone has a 50% to 80% higher risk of VTE compared with a pill with estradiol 30 µg and levonorgestrel.

For patients at particularly high risk for VTE, COCs are contraindicated. For patients for whom COCs are considered medically appropriate but who are at higher risk (eg, obese women), it is wise to use a pill containing a first-generation (norethindrone) or second-generation progestin (levonorgestrel) combined with the lowest dose of estrogen that has tolerable adverse effects.¹⁹

What about hypertension concerns?

Let us turn our attention briefly to hypertension and its relation to COC use. While the American College of Cardiology and the American Heart Association redefined hypertension in 2017 using a threshold of 130/80 mm Hg, the American College of Obstetricians and Gynecologists (ACOG) considers hypertension to be 140/90 mm Hg in terms of safety of using COCs. ACOG states, “women with blood pressure below 140/90 mm Hg may use any hormonal contraceptive method.”²⁰ In women with hypertension in the range of 140‒159 mm Hg systolic or 90‒99 mm Hg diastolic, COCs are category 3 according to the US Medical Eligibility Criteria for Contraceptive Use, meaning that the risks usually outweigh the benefits. For women with blood pressures of 160/110 mm Hg or greater, COCs are category 4 (contraindicated). If a woman with mild hypertension is started on a COC, a drospirenone-containing pill may be the best choice because of its diuretic effects. While other contemporary COCs have been associated with a mild increase in blood pressure, drospirenone-containing pills have not shown this association.²¹

Continue to: At issue: Break-through bleeding, mood, and weight gain...

At issue: Break-through bleeding, mood, and weight gain

For women bothered by intermenstrual bleeding, use of a COC with a third-generation progestin may be preferable to use of one with a first- or second-generation. It may be because of decreased abnormal bleeding that COCs with third-generation progestins have lower discontinuation rates.²² In addition, COCs containing estrogen 20 µg or less are associated with more intermenstrual bleeding than those with more than 20 µg estrogen.²³ Keep in mind that it is common with any COC to have intermenstrual bleeding for the first several months.

For women with pre-existing mood disorders or who report mood changes with COCs, it appears that fluctuations in hormone levels are problematic. Consistently, there is evidence that monophasic pills are preferable to multiphasic and that extended cyclic or continuous use is preferable to traditional cyclic use for mitigating mood adverse effects. There is mixed evidence on whether a low dose of ethinyl estradiol is better for mood.³

Although it is discussed above that randomized controlled trials have not shown an association between COC use and weight gain, many women remain concerned. For these women, a drospirenone-containing COC may be the best choice. Drospirenone has antimineralocorticoid activity, so it may help prevent water retention.

A brief word about multiphasic COCs. While these pills were designed to mimic physiologic hormone fluctuations and minimize hormonal adverse effects, there is insufficient evidence to compare their effects to those of monophasic pills.²⁴ Without such evidence, there is little reason to recommend a multiphasic pill to a patient over the more straightforward monophasic formulation.

Conclusion

There are more nuances to prescribing an optimal COC for a patient than may initially come to mind. It is useful to remember that any formulation of pill may be prescribed in an extended or continuous fashion, and there are benefits for such use for premenstrual dysphoric disorder, heavy menstrual bleeding, perimenopause, and menstrual symptoms. Although there are numerous brands of COCs available, a small cadre will suffice for almost all purposes. Such a “toolbox” of pills could include a pill formatted for continuous use (Seasonique), a low estrogen pill (Loestrin), a drospirenone-containing pill (Yaz), and a pill containing a third-generation progestin and a higher dose of estrogen (Sprintec). ●

From the University of Alabama at Birmingham, Birmingham, AL.

Abstract

Objective: To review current challenges in the management of peptic ulcer disease.

Methods: Review of the literature.

Results: Peptic ulcer disease affects 5% to 10% of the population worldwide, with recent decreases in lifetime prevalence in high-income countries. Helicobacter pylori infection and nonsteroidal anti-inflammatory drug (NSAID) use are the most important drivers of peptic ulcer disease. Current management strategies for peptic ulcer disease focus on ulcer healing; management of complications such as bleeding, perforation, and obstruction; and prevention of ulcer recurrence. Proton pump inhibitors (PPIs) are the cornerstone of medical therapy for peptic ulcers, and complement testing for and treatment of H. pylori infection as well as elimination of NSAID use. Although advances have been made in the medical and endoscopic treatment of peptic ulcer disease and the management of ulcer complications, such as bleeding and obstruction, challenges remain.

Conclusion: Peptic ulcer disease is a common health problem globally, with persistent challenges related to refractory ulcers, antiplatelet and anticoagulant use, and continued bleeding in the face of endoscopic therapy. These challenges should be met with PPI therapy of adequate frequency and duration, vigilant attention to and treatment of ulcer etiology, evidence-based handling of antiplatelet and anticoagulant medications, and utilization of novel endoscopic tools to obtain improved clinical outcomes.

Keywords: H. pylori; nonsteroidal anti-inflammatory drugs; NSAIDs; proton pump inhibitor; PPI; bleeding; perforation; obstruction; refractory ulcer; salvage endoscopic therapy; transcatheter angiographic embolization.

A peptic ulcer is a fibrin-covered break in the mucosa of the digestive tract extending to the submucosa that is caused by acid injury (Figure 1). Most peptic ulcers occur in the stomach or proximal duodenum, though they may also occur in the esophagus or, less frequently, in a Meckel’s diverticulum.^1,2 The estimated worldwide prevalence of peptic ulcer disease is 5% to 10%, with an annual incidence of 0.1% to 0.3%¹; both rates are declining.³ The annual incidence of peptic ulcer disease requiring medical or surgical treatment is also declining, and currently is estimated to be 0.1% to 0.2%.⁴ The lifetime prevalence of peptic ulcers has been decreasing in high-income countries since the mid-20th century due to both the widespread use of medications that suppress gastric acid secretion and the declining prevalence of Helicobacter pylori infection.^1,3

Peptic ulcer disease in most individuals results from H. pylori infection, chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, or both. A combination of H. pylori factors and host factors lead to mucosal disruption in infected individuals who develop peptic ulcers. H. pylori–specific factors include the expression of virulence factors such as CagA and VacA, which interact with the host inflammatory response to cause mucosal injury. The mucosal inflammatory response is at least partially determined by polymorphisms in the host’s cytokine genes.^1,4 NSAIDs inhibit the production of cyclooxygenase-1-derived prostaglandins, with subsequent decreases in epithelial mucous formation, bicarbonate secretion, cell proliferation, and mucosal blood flow, all of which are key elements in the maintenance of mucosal integrity.^1,5 Less common causes of peptic ulcers include gastrinoma, adenocarcinoma, idiopathic ulcers, use of sympathomimetic drugs (eg, cocaine or methamphetamine), certain anticancer agents, and bariatric surgery.^4,6

This article provides an overview of current management principles for peptic ulcer disease and discusses current challenges in peptic ulcer management, including proton pump inhibitor (PPI) therapy, refractory ulcers, handling of antiplatelet and anticoagulants during and after peptic ulcer bleeding, and ulcer bleeding that continues despite salvage endoscopic therapy.

Methods

We searched MEDLINE using the term peptic ulcer disease in combination with the terms current challenges, epidemiology, bleeding, anticoagulant, antiplatelet, PPI potency, etiology, treatment, management, and refractory. We selected publications from the past 35 years that we judged to be relevant.

Current Management

The goals of peptic ulcer disease management are ulcer healing and prevention of recurrence. The primary interventions used in the management of peptic ulcer disease are medical therapy and implementation of measures that address the underlying etiology of the disease.

Medical Therapy

Introduced in the late 1980s, PPIs are the cornerstone of medical therapy for peptic ulcer disease.⁶ These agents irreversibly inhibit the H+/K+-ATPase pump in the gastric mucosa and thereby inhibit gastric acid secretion, promoting ulcer healing. PPIs improve rates of ulcer healing compared to H2-receptor antagonists.^4,7

Underlying Causes

The underlying cause of peptic ulcer disease should be addressed, in addition to initiating medical therapy. A detailed history of NSAID use should be obtained, and patients with peptic ulcers caused by NSAIDs should be counseled to avoid them, if possible. Patients with peptic ulcer disease who require long-term use of NSAIDs should be placed on long-term PPI therapy.⁶ Any patient with peptic ulcer disease, regardless of any history of H. pylori infection or treatment, should be tested for infection. Tests that identify active infection, such as urea breath test, stool antigen assay, or mucosal biopsy–based testing, are preferred to IgG antibody testing, although the latter is acceptable in the context of peptic ulcer disease with a high pretest probability of infection.⁸ Any evidence of active infection warrants appropriate treatment to allow ulcer healing and prevent recurrence.¹H. pylori infection is most often treated with clarithromycin triple therapy or bismuth quadruple therapy for 14 days, with regimens selected based on the presence or absence of penicillin allergy, prior antibiotic exposure, and local clarithromycin resistance rates, when known.^4,8

Managing Complications

An additional aspect of care in peptic ulcer disease is managing the complications of bleeding, perforation, and gastric outlet obstruction. Acute upper gastrointestinal bleeding (GIB) is the most common complication of peptic ulcer disease, which accounts for 40% to 60% of nonvariceal acute upper GIB.^1,6 The first step in the management of acute GIB from a peptic ulcer is fluid resuscitation to ensure hemodynamic stability. If there is associated anemia with a hemoglobin level < 8 g/dL, blood transfusion should be undertaken to target a hemoglobin level > 8 g/dL. In patients with peptic ulcer disease–related acute upper GIB and comorbid cardiovascular disease, the transfusion threshold is higher, with the specific cutoff depending on clinical status, type and severity of cardiovascular disease, and degree of bleeding. Endoscopic management should generally be undertaken within 24 hours of presentation and should not be delayed in patients taking anticoagulants.⁹ Combination endoscopic treatment with through-the-scope clips plus thermocoagulation or sclerosant injection is recommended for acutely bleeding peptic ulcers with high-risk stigmata.

Pharmacologic management of patients with bleeding peptic ulcers with high-risk stigmata includes PPI therapy, with an 80 mg intravenous (IV) loading dose followed by continuous infusion of 8 mg/hr for 72 hours to reduce rebleeding and mortality. Following completion of IV therapy, oral PPI therapy should be continued twice daily for 14 days, followed by once-daily dosing thereafter.⁹Patients with peptic ulcer perforation present with sudden-onset epigastric abdominal pain and have tenderness to palpation, guarding, and rigidity on examination, often along with tachycardia and hypotension.^1,4 Computed tomography (CT) of the abdomen is 98% sensitive for identifying and localizing a perforation. Most perforations occur in the duodenum or antrum.

Management of a peptic ulcer perforation requires consultation with a surgeon to determine whether a nonoperative approach may be employed (eg, a stable patient with a contained perforation), or if surgery is indicated. The surgical approach to peptic ulcer perforation has been impacted by the clinical success of gastric acid suppression with PPIs and H. pylori eradication, but a range of surgical approaches are still used to repair perforations, from omental patch repair with peritoneal drain placement, to more extensive surgeries such as wedge resection or partial gastrectomy.⁴ Perforation carries a high mortality risk, up to 20% to 30%, and is the leading cause of death in patients with peptic ulcer disease.^1,4

Gastric outlet obstruction, a rare complication of peptic ulcer disease, results from recurrent ulcer formation and scarring. Obstruction often presents with hypovolemia and metabolic alkalosis from prolonged vomiting. CT imaging with oral contrast is often the first diagnostic test employed to demonstrate obstruction. Upper endoscopy should be performed to evaluate the appearance and degree of obstruction as well as to obtain biopsies to evaluate for a malignant etiology of the ulcer disease. Endoscopic balloon dilation has become the cornerstone of initial therapy for obstruction from peptic ulcer disease, especially in the case of ulcers due to reversible causes. Surgery is now typically reserved for cases of refractory obstruction, after repeated endoscopic balloon dilation has failed to remove the obstruction. However, because nearly all patients with gastric outlet obstruction present with malnutrition, nutritional deficiencies should be addressed prior to the patient undergoing surgical intervention. Surgical options include pyloroplasty, antrectomy, and gastrojejunostomy.⁴

Current Challenges

Rapid Metabolism of PPIs

High-dose PPI therapy is a key component of therapy for peptic ulcer healing. PPIs are metabolized by the cytochrome P450 system, which is comprised of multiple isoenzymes. CYP2C19, an isoenzyme involved in PPI metabolism, has 21 polymorphisms, which have variable effects leading to ultra-rapid, extensive, intermediate, or poor metabolism of PPIs.¹⁰ With rapid metabolism of PPIs, standard dosing can result in inadequate suppression of acid secretion. Despite this knowledge, routine testing of CYP2C19 phenotype is not recommended due to the cost of testing. Instead, inadequate ulcer healing should prompt consideration of increased PPI dosing to 80 mg orally twice daily, which may be sufficient to overcome rapid PPI metabolism.¹¹

Relative Potency of PPIs

In addition to variation in PPI metabolism, the relative potency of various PPIs has been questioned. A review of all available clinical studies of the effects of PPIs on mean 24-hour intragastric pH reported a quantitative difference in the potency of 5 PPIs, with omeprazole as the reference standard. Potencies ranged from 0.23 omeprazole equivalents for pantoprazole to 1.82 omeprazole equivalents for rabeprazole.¹² An additional study of data from 56 randomized clinical trials confirmed that PPIs vary in potency, which was measured as time that gastric pH is less than 4. A linear increase in intragastric pH time less than 4 was observed from 9 to 64 mg omeprazole equivalents; higher doses yielded no additional benefit. An increase in PPI dosing from once daily to twice daily also increased the duration of intragastric pH time less than 4 from 15 to 21 hours.¹³ Earlier modeling of the relationship between duodenal ulcer healing and antisecretory therapy showed a strong correlation of ulcer healing with the duration of acid suppression, length of therapy, and the degree of acid suppression. Additional benefit was not observed after intragastric pH rose above 3.¹⁴ Thus, as the frequency and duration of acid suppression therapy are more important than PPI potency, PPIs can be used interchangeably.^13,14

Addressing Underlying Causes

Continued NSAID Use. Refractory peptic ulcers are defined as those that do not heal despite adherence to 8 to 12 weeks of standard acid-suppression therapy. A cause of refractory peptic ulcer disease that must be considered is continued NSAID use.^1,15 In a study of patients with refractory peptic ulcers, 27% of patients continued NSAID use, as determined by eventual disclosure by the patients or platelet cyclooxygenase activity assay, despite extensive counseling to avoid NSAIDs at the time of the diagnosis of their refractory ulcer and at subsequent visits.¹⁶ Pain may make NSAID cessation difficult for some patients, while others do not realize that over-the-counter preparations they take contain NSAIDs.¹⁵

Another group of patients with continued NSAID exposure are those who require long-term NSAID therapy for control of arthritis or the management of cardiovascular conditions. If NSAID therapy cannot be discontinued, the risk of NSAID-related gastrointestinal injury can be assessed based on the presence of multiple risk factors, including age > 65 years, high-dose NSAID therapy, a history of peptic ulcer, and concurrent use of aspirin, corticosteroids, or anticoagulants. Individuals with 3 or more of the preceding risk factors or a history of a peptic ulcer with a complication, especially if recent, are considered to be at high risk of developing an NSAID-related ulcer and possible subsequent complications.¹⁷ In these individuals, NSAID therapy should be continued with agents that have the lowest risk for gastrointestinal toxicity and at the lowest possible dose. A meta-analysis comparing nonselective NSAIDs to placebo demonstrated naproxen to have the highest risk of gastrointestinal complications, including GIB, perforation, and obstruction (adjusted rate ratio, 4.2), while diclofenac demonstrated the lowest risk (adjusted rate ratio, 1.89). High-dose NSAID therapy demonstrated a 2-fold increase in risk of peptic ulcer formation as compared to low-dose therapy.¹⁸

In addition to selecting the NSAID with the least gastrointestinal toxicity at the lowest possible dose, additional strategies to prevent peptic ulcer disease and its complications in chronic NSAID users include co-administration of a PPI and substitution of a COX-2 selective NSAID for nonselective NSAIDs.^1,9 Prior double-blind, placebo-controlled, randomized, multicenter trials with patients requiring daily NSAIDs demonstrated an up to 15% absolute reduction in the risk of developing peptic ulcers over 6 months while taking esomeprazole.¹⁹

Persistent Infection. Persistent H. pylori infection, due either to initial false-negative testing or ongoing infection despite first-line therapy, is another cause of refractory peptic ulcer disease.^1,15 Because antibiotics and PPIs can reduce the number of H. pylori bacteria, use of these medications concurrent with H. pylori testing can lead to false-negative results with several testing modalities. When suspicion for H. pylori is high, 2 or more diagnostic tests may be needed to effectively rule out infection.¹⁵

When H. pylori is detected, successful eradication is becoming more difficult due to an increasing prevalence of antibiotic resistance, leading to persistent infection in many cases and maintained risk of peptic ulcer disease, despite appropriate first-line therapy.⁸ Options for salvage therapy for persistent H. pylori, as well as information on the role and best timing of susceptibility testing, are beyond the scope of this review, but are reviewed by Lanas and Chan¹ and in the American College of Gastroenterology guideline on the treatment of H. pylori infection.⁸

Other Causes. In a meta-analysis of rigorously designed studies from North America, 20% of patients experienced ulcer recurrence at 6 months, despite successful H. pylori eradication and no NSAID use.²⁰ In addition, as H. pylori prevalence is decreasing, idiopathic ulcers are increasingly being diagnosed, and such ulcers may be associated with high rates of GIB and mortality.¹ In this subset of patients with non-H. pylori, non-NSAID ulcers, increased effort is required to further evaluate the differential diagnosis for rarer causes of upper GI tract ulcer disease (Table). Certain malignancies, including adenocarcinoma and lymphoma, can cause ulcer formation and should be considered in refractory cases. Repeat biopsy at follow-up endoscopy for persistent ulcers should always be obtained to further evaluate for malignancy.^1,15 Infectious diseases other than H. pylori infection, such as tuberculosis, syphilis, cytomegalovirus, and herpes simplex virus, are also reported as etiologies of refractory ulcers, and require specific antimicrobial treatment over and above PPI monotherapy. Special attention in biopsy sampling and sample processing is often required when infectious etiologies are being considered, as specific histologic stains and cultures may be needed for identification.¹⁵

Systemic conditions, including sarcoidosis,²¹ Behçet disease,²² and polyarteritis nodosa,^15,23 can also cause refractory ulcers. Approximately 15% of patients with Crohn disease have gastroduodenal involvement, which may include ulcers of variable sizes.^1,15,24 The increased gastric acid production seen in Zollinger-Ellison syndrome commonly presents as refractory peptic ulcers in the duodenum beyond the bulb that do not heal with standard doses of PPIs.^1,15 More rare causes of acid hypersecretion leading to refractory ulcers include idiopathic gastric acid hypersecretion and retained gastric antrum syndrome after partial gastrectomy with Billroth II anastomosis.¹⁵ Smoking is a known risk factor for impaired tissue healing throughout the body, and can contribute to impaired healing of peptic ulcers through decreased prostaglandin synthesis²⁵ and reduced gastric mucosal blood flow.²⁶ Smoking should always be addressed in patients with refractory peptic ulcers, and cessation should be strongly encouraged. Other less common causes of refractory upper GI tract ulcers include radiation therapy, crack cocaine use, and mesenteric ischemia.¹⁵

Managing Antiplatelet and Anticoagulant Medications

Use of antiplatelets and anticoagulants, alone or in combination, increases the risk of peptic ulcer bleeding. In patients who continue to take aspirin after a peptic ulcer bleed, recurrent bleeding occurs in up to 300 cases per 1000 person-years. The rate of GIB associated with aspirin use ranges from 1.1% to 2.5%, depending on the dose. Prior peptic ulcer disease, age greater than 70 years, and concurrent NSAID, steroid, anticoagulant, or dual antiplatelet therapy (DAPT) use increase the risk of bleeding while on aspirin. The rate of GIB while taking a thienopyridine alone is slightly less than that when taking aspirin, ranging from 0.5% to 1.6%. Studies to date have yielded mixed estimates of the effect of DAPT on the risk of GIB. Estimates of the risk of GIB with DAPT range from an odds ratio for serious GIB of 7.4 to an absolute risk increase of only 1.3% when compared to clopidogrel alone.²⁷

Many patients are also on warfarin or a direct oral anticoagulant (DOAC). In a study from the United Kingdom, the adjusted rate ratio of GIB with warfarin alone was 1.94, and this increased to 6.48 when warfarin was used with aspirin.²⁸ The use of warfarin and DAPT, often called triple therapy, further increases the risk of GIB, with a hazard ratio of 5.0 compared to DAPT alone, and 5.38 when compared to warfarin alone. DOACs are increasingly prescribed for the treatment and prevention of thromboembolism, and by 2014 were prescribed as often as warfarin for stroke prevention in atrial fibrillation in the United States. A meta-analysis showed the risk of major GIB did not differ between DOACs and warfarin or low-molecular-weight heparin, but among DOACs factor Xa inhibitors showed a reduced risk of GIB compared with dabigatran, a direct thrombin inhibitor.²⁹

The use of antiplatelets and anticoagulants in the context of peptic ulcer bleeding is a current management challenge. Data to guide decision-making in patients on antiplatelet and/or anticoagulant therapy who experience peptic ulcer bleeding are scarce. Decision-making in this group of patients requires balancing the severity and risk of bleeding with the risk of thromboembolism.^1,27 In patients on antiplatelet therapy for primary prophylaxis of atherothrombosis who develop bleeding from a peptic ulcer, the antiplatelet should generally be held and the indication for the medication reassessed. In patients on antiplatelet therapy for secondary prevention, the agent may be immediately resumed after endoscopy if bleeding is found to be due to an ulcer with low-risk stigmata. With bleeding resulting from an ulcer with high-risk stigmata, antiplatelet agents employed for secondary prevention may be held initially, with consideration given to early reintroduction, as early as day 3 after endoscopy.¹ In patients at high risk for atherothrombotic events, including those on aspirin for secondary prophylaxis, withholding aspirin leads to a 3-fold increase in the risk of a major adverse cardiac event, with events occurring as early as 5 days after aspirin cessation in some cases.²⁷ A randomized controlled trial of continuing low-dose aspirin versus withholding it for 8 weeks in patients on aspirin for secondary prophylaxis of cardiovascular events who experienced peptic ulcer bleeding that required endoscopic therapy demonstrated lower all-cause mortality (1.3% vs 12.9%), including death from cardiovascular or cerebrovascular events, among those who continued aspirin therapy, with a small increased risk of recurrent ulcer bleeding (10.3% vs 5.4%).³⁰ Thus, it is recommended that antiplatelet therapy, when held, be resumed as early as possible when the risk of a cardiovascular or cerebrovascular event is considered to be higher than the risk of bleeding.²⁷

When patients are on DAPT for a history of drug-eluting stent placement, withholding both antiplatelet medications should be avoided, even for a brief period of time, given the risk of in-stent thrombosis. When DAPT is employed for other reasons, it should be continued, if indicated, after bleeding that is found to be due to peptic ulcers with low-risk stigmata. If bleeding is due to a peptic ulcer with high-risk stigmata at endoscopy, then aspirin monotherapy should be continued and consultation should be obtained with a cardiologist to determine optimal timing to resume the second antiplatelet agent.¹ In patients on anticoagulants, anticoagulation should be resumed once hemostasis is achieved when the risk of withholding anticoagulation is thought to be greater than the risk of rebleeding. For example, anticoagulation should be resumed early in a patient with a mechanical heart valve to prevent thrombosis.^1,27 Following upper GIB from peptic ulcer disease, patients who will require long-term aspirin, DAPT, or anticoagulation with either warfarin or DOACs should be maintained on long-term PPI therapy to reduce the risk of recurrent bleeding.^9,27

Failure of Endoscopic Therapy to Control Peptic Ulcer Bleeding

Bleeding recurs in as many as 10% to 20% of patients after initial endoscopic control of peptic ulcer bleeding.^4,31 In this context, repeat upper endoscopy for hemostasis is preferred to surgery, as it leads to less morbidity while providing long-term control of bleeding in more than 70% of cases.^31,32 Two potential endoscopic rescue therapies that may be employed are over-the-scope clips (OTSCs) and hemostatic powder.^32,33

While through-the-scope (TTS) hemostatic clips are often used during endoscopy to control active peptic ulcer bleeding, their use may be limited in large or fibrotic ulcers due to the smaller size of the clips and method of application. OTSCs have several advantages over TTS clips; notably, their larger size allows the endoscopist to achieve deeper mucosal or submucosal clip attachment via suction of the targeted tissue into the endoscopic cap (Figure 2). In a systematic review of OTSCs, successful hemostasis was achieved in 84% of 761 lesions, including 75% of lesions due to peptic ulcer disease.³⁴ Some have argued that OTSCs may be preferred as first-line therapy over epinephrine with TTS clips for hemostasis in bleeding from high-risk peptic ulcers (ie, those with visualized arterial bleeding or a visible vessel) given observed decreases in rebleeding events.³⁵

Despite the advantages of OTSCs, endoscopists should be mindful of the potential complications of OTSC use, including luminal obstruction, particularly in the duodenum, and perforation, which occurs in 0.3% to 2% of cases. Additionally, retrieval of misplaced OTSCs presents a significant challenge. Careful decision-making with consideration of the location, size, and depth of lesions is required when deciding on OTSC placement.^34,36

A newer endoscopic tool developed for refractory bleeding from peptic ulcers and other causes is hemostatic powder. Hemostatic powders accelerate the coagulation cascade, leading to shortened coagulation times and enhanced clot formation.³⁷ A recent meta-analysis showed that immediate hemostasis could be achieved in 95% of cases of bleeding, including in 96% of cases of bleeding from peptic ulcer disease.³⁸ The primary limitation of hemostatic powders is the temporary nature of hemostasis, which requires the underlying etiology of bleeding to be addressed in order to provide long-term hemostasis. In the above meta-analysis, rebleeding occurred in 17% of cases after 30 days.³⁸

Hypotension and ulcer diameter ≥ 2 cm are independent predictors of failure of endoscopic salvage therapy.³¹ When severe bleeding is not controlled with initial endoscopic therapy or bleeding recurs despite salvage endoscopic therapy, transcatheter angiographic embolization (TAE) is the treatment of choice.⁴ Systematic reviews and meta-analyses of studies that compared TAE to surgery have shown that the rate of rebleeding may be higher with TAE, but with less morbidity and either decreased or equivalent rates of mortality, with no increased need for additional interventions.^4,32 In a case series examining 5 years of experience at a single medical center in China, massive GIB from duodenal ulcers was successfully treated with TAE in 27 of 29 cases (93% clinical success rate), with no mucosal ischemic necrosis observed.³⁹

If repeated endoscopic therapy has not led to hemostasis of a bleeding peptic ulcer and TAE is not available, then surgery is the next best option. Bleeding gastric ulcers may be excised, wedge resected, or oversewn after an anterior gastrostomy. Bleeding duodenal ulcers may require use of a Kocher maneuver and linear incision of the anterior duodenum followed by ligation of the gastroduodenal artery. Fortunately, such surgical management is rarely necessary given the availability of TAE at most centers.⁴

Conclusion

Peptic ulcer disease is a common health problem globally, with persistent challenges related to refractory ulcers, antiplatelet and anticoagulant use, and continued bleeding in the face of endoscopic therapy. These challenges should be met with adequate frequency and duration of PPI therapy, vigilant attention to and treatment of ulcer etiology, evidence-based handling of antiplatelet and anticoagulant medications, and utilization of novel endoscopic tools to obtain improved clinical outcomes.

Acknowledgment: We thank Dr. Nipun Reddy from our institution for providing the endoscopic images used in this article.

Corresponding author: Adam L. Edwards, MD, MS; [email protected].

Financial disclosures: None.

From the University of Alabama at Birmingham, Birmingham, AL.

Abstract

Objective: To review current challenges in the management of peptic ulcer disease.

Methods: Review of the literature.

Results: Peptic ulcer disease affects 5% to 10% of the population worldwide, with recent decreases in lifetime prevalence in high-income countries. Helicobacter pylori infection and nonsteroidal anti-inflammatory drug (NSAID) use are the most important drivers of peptic ulcer disease. Current management strategies for peptic ulcer disease focus on ulcer healing; management of complications such as bleeding, perforation, and obstruction; and prevention of ulcer recurrence. Proton pump inhibitors (PPIs) are the cornerstone of medical therapy for peptic ulcers, and complement testing for and treatment of H. pylori infection as well as elimination of NSAID use. Although advances have been made in the medical and endoscopic treatment of peptic ulcer disease and the management of ulcer complications, such as bleeding and obstruction, challenges remain.

Conclusion: Peptic ulcer disease is a common health problem globally, with persistent challenges related to refractory ulcers, antiplatelet and anticoagulant use, and continued bleeding in the face of endoscopic therapy. These challenges should be met with PPI therapy of adequate frequency and duration, vigilant attention to and treatment of ulcer etiology, evidence-based handling of antiplatelet and anticoagulant medications, and utilization of novel endoscopic tools to obtain improved clinical outcomes.

Keywords: H. pylori; nonsteroidal anti-inflammatory drugs; NSAIDs; proton pump inhibitor; PPI; bleeding; perforation; obstruction; refractory ulcer; salvage endoscopic therapy; transcatheter angiographic embolization.

A peptic ulcer is a fibrin-covered break in the mucosa of the digestive tract extending to the submucosa that is caused by acid injury (Figure 1). Most peptic ulcers occur in the stomach or proximal duodenum, though they may also occur in the esophagus or, less frequently, in a Meckel’s diverticulum.^1,2 The estimated worldwide prevalence of peptic ulcer disease is 5% to 10%, with an annual incidence of 0.1% to 0.3%¹; both rates are declining.³ The annual incidence of peptic ulcer disease requiring medical or surgical treatment is also declining, and currently is estimated to be 0.1% to 0.2%.⁴ The lifetime prevalence of peptic ulcers has been decreasing in high-income countries since the mid-20th century due to both the widespread use of medications that suppress gastric acid secretion and the declining prevalence of Helicobacter pylori infection.^1,3

Peptic ulcer disease in most individuals results from H. pylori infection, chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, or both. A combination of H. pylori factors and host factors lead to mucosal disruption in infected individuals who develop peptic ulcers. H. pylori–specific factors include the expression of virulence factors such as CagA and VacA, which interact with the host inflammatory response to cause mucosal injury. The mucosal inflammatory response is at least partially determined by polymorphisms in the host’s cytokine genes.^1,4 NSAIDs inhibit the production of cyclooxygenase-1-derived prostaglandins, with subsequent decreases in epithelial mucous formation, bicarbonate secretion, cell proliferation, and mucosal blood flow, all of which are key elements in the maintenance of mucosal integrity.^1,5 Less common causes of peptic ulcers include gastrinoma, adenocarcinoma, idiopathic ulcers, use of sympathomimetic drugs (eg, cocaine or methamphetamine), certain anticancer agents, and bariatric surgery.^4,6

This article provides an overview of current management principles for peptic ulcer disease and discusses current challenges in peptic ulcer management, including proton pump inhibitor (PPI) therapy, refractory ulcers, handling of antiplatelet and anticoagulants during and after peptic ulcer bleeding, and ulcer bleeding that continues despite salvage endoscopic therapy.

Methods

We searched MEDLINE using the term peptic ulcer disease in combination with the terms current challenges, epidemiology, bleeding, anticoagulant, antiplatelet, PPI potency, etiology, treatment, management, and refractory. We selected publications from the past 35 years that we judged to be relevant.

Current Management

The goals of peptic ulcer disease management are ulcer healing and prevention of recurrence. The primary interventions used in the management of peptic ulcer disease are medical therapy and implementation of measures that address the underlying etiology of the disease.

Medical Therapy

Introduced in the late 1980s, PPIs are the cornerstone of medical therapy for peptic ulcer disease.⁶ These agents irreversibly inhibit the H+/K+-ATPase pump in the gastric mucosa and thereby inhibit gastric acid secretion, promoting ulcer healing. PPIs improve rates of ulcer healing compared to H2-receptor antagonists.^4,7

Underlying Causes

The underlying cause of peptic ulcer disease should be addressed, in addition to initiating medical therapy. A detailed history of NSAID use should be obtained, and patients with peptic ulcers caused by NSAIDs should be counseled to avoid them, if possible. Patients with peptic ulcer disease who require long-term use of NSAIDs should be placed on long-term PPI therapy.⁶ Any patient with peptic ulcer disease, regardless of any history of H. pylori infection or treatment, should be tested for infection. Tests that identify active infection, such as urea breath test, stool antigen assay, or mucosal biopsy–based testing, are preferred to IgG antibody testing, although the latter is acceptable in the context of peptic ulcer disease with a high pretest probability of infection.⁸ Any evidence of active infection warrants appropriate treatment to allow ulcer healing and prevent recurrence.¹H. pylori infection is most often treated with clarithromycin triple therapy or bismuth quadruple therapy for 14 days, with regimens selected based on the presence or absence of penicillin allergy, prior antibiotic exposure, and local clarithromycin resistance rates, when known.^4,8

Managing Complications

An additional aspect of care in peptic ulcer disease is managing the complications of bleeding, perforation, and gastric outlet obstruction. Acute upper gastrointestinal bleeding (GIB) is the most common complication of peptic ulcer disease, which accounts for 40% to 60% of nonvariceal acute upper GIB.^1,6 The first step in the management of acute GIB from a peptic ulcer is fluid resuscitation to ensure hemodynamic stability. If there is associated anemia with a hemoglobin level < 8 g/dL, blood transfusion should be undertaken to target a hemoglobin level > 8 g/dL. In patients with peptic ulcer disease–related acute upper GIB and comorbid cardiovascular disease, the transfusion threshold is higher, with the specific cutoff depending on clinical status, type and severity of cardiovascular disease, and degree of bleeding. Endoscopic management should generally be undertaken within 24 hours of presentation and should not be delayed in patients taking anticoagulants.⁹ Combination endoscopic treatment with through-the-scope clips plus thermocoagulation or sclerosant injection is recommended for acutely bleeding peptic ulcers with high-risk stigmata.

Pharmacologic management of patients with bleeding peptic ulcers with high-risk stigmata includes PPI therapy, with an 80 mg intravenous (IV) loading dose followed by continuous infusion of 8 mg/hr for 72 hours to reduce rebleeding and mortality. Following completion of IV therapy, oral PPI therapy should be continued twice daily for 14 days, followed by once-daily dosing thereafter.⁹Patients with peptic ulcer perforation present with sudden-onset epigastric abdominal pain and have tenderness to palpation, guarding, and rigidity on examination, often along with tachycardia and hypotension.^1,4 Computed tomography (CT) of the abdomen is 98% sensitive for identifying and localizing a perforation. Most perforations occur in the duodenum or antrum.

Management of a peptic ulcer perforation requires consultation with a surgeon to determine whether a nonoperative approach may be employed (eg, a stable patient with a contained perforation), or if surgery is indicated. The surgical approach to peptic ulcer perforation has been impacted by the clinical success of gastric acid suppression with PPIs and H. pylori eradication, but a range of surgical approaches are still used to repair perforations, from omental patch repair with peritoneal drain placement, to more extensive surgeries such as wedge resection or partial gastrectomy.⁴ Perforation carries a high mortality risk, up to 20% to 30%, and is the leading cause of death in patients with peptic ulcer disease.^1,4

Gastric outlet obstruction, a rare complication of peptic ulcer disease, results from recurrent ulcer formation and scarring. Obstruction often presents with hypovolemia and metabolic alkalosis from prolonged vomiting. CT imaging with oral contrast is often the first diagnostic test employed to demonstrate obstruction. Upper endoscopy should be performed to evaluate the appearance and degree of obstruction as well as to obtain biopsies to evaluate for a malignant etiology of the ulcer disease. Endoscopic balloon dilation has become the cornerstone of initial therapy for obstruction from peptic ulcer disease, especially in the case of ulcers due to reversible causes. Surgery is now typically reserved for cases of refractory obstruction, after repeated endoscopic balloon dilation has failed to remove the obstruction. However, because nearly all patients with gastric outlet obstruction present with malnutrition, nutritional deficiencies should be addressed prior to the patient undergoing surgical intervention. Surgical options include pyloroplasty, antrectomy, and gastrojejunostomy.⁴

Current Challenges

Rapid Metabolism of PPIs

High-dose PPI therapy is a key component of therapy for peptic ulcer healing. PPIs are metabolized by the cytochrome P450 system, which is comprised of multiple isoenzymes. CYP2C19, an isoenzyme involved in PPI metabolism, has 21 polymorphisms, which have variable effects leading to ultra-rapid, extensive, intermediate, or poor metabolism of PPIs.¹⁰ With rapid metabolism of PPIs, standard dosing can result in inadequate suppression of acid secretion. Despite this knowledge, routine testing of CYP2C19 phenotype is not recommended due to the cost of testing. Instead, inadequate ulcer healing should prompt consideration of increased PPI dosing to 80 mg orally twice daily, which may be sufficient to overcome rapid PPI metabolism.¹¹

Relative Potency of PPIs

In addition to variation in PPI metabolism, the relative potency of various PPIs has been questioned. A review of all available clinical studies of the effects of PPIs on mean 24-hour intragastric pH reported a quantitative difference in the potency of 5 PPIs, with omeprazole as the reference standard. Potencies ranged from 0.23 omeprazole equivalents for pantoprazole to 1.82 omeprazole equivalents for rabeprazole.¹² An additional study of data from 56 randomized clinical trials confirmed that PPIs vary in potency, which was measured as time that gastric pH is less than 4. A linear increase in intragastric pH time less than 4 was observed from 9 to 64 mg omeprazole equivalents; higher doses yielded no additional benefit. An increase in PPI dosing from once daily to twice daily also increased the duration of intragastric pH time less than 4 from 15 to 21 hours.¹³ Earlier modeling of the relationship between duodenal ulcer healing and antisecretory therapy showed a strong correlation of ulcer healing with the duration of acid suppression, length of therapy, and the degree of acid suppression. Additional benefit was not observed after intragastric pH rose above 3.¹⁴ Thus, as the frequency and duration of acid suppression therapy are more important than PPI potency, PPIs can be used interchangeably.^13,14

Addressing Underlying Causes

Continued NSAID Use. Refractory peptic ulcers are defined as those that do not heal despite adherence to 8 to 12 weeks of standard acid-suppression therapy. A cause of refractory peptic ulcer disease that must be considered is continued NSAID use.^1,15 In a study of patients with refractory peptic ulcers, 27% of patients continued NSAID use, as determined by eventual disclosure by the patients or platelet cyclooxygenase activity assay, despite extensive counseling to avoid NSAIDs at the time of the diagnosis of their refractory ulcer and at subsequent visits.¹⁶ Pain may make NSAID cessation difficult for some patients, while others do not realize that over-the-counter preparations they take contain NSAIDs.¹⁵

Another group of patients with continued NSAID exposure are those who require long-term NSAID therapy for control of arthritis or the management of cardiovascular conditions. If NSAID therapy cannot be discontinued, the risk of NSAID-related gastrointestinal injury can be assessed based on the presence of multiple risk factors, including age > 65 years, high-dose NSAID therapy, a history of peptic ulcer, and concurrent use of aspirin, corticosteroids, or anticoagulants. Individuals with 3 or more of the preceding risk factors or a history of a peptic ulcer with a complication, especially if recent, are considered to be at high risk of developing an NSAID-related ulcer and possible subsequent complications.¹⁷ In these individuals, NSAID therapy should be continued with agents that have the lowest risk for gastrointestinal toxicity and at the lowest possible dose. A meta-analysis comparing nonselective NSAIDs to placebo demonstrated naproxen to have the highest risk of gastrointestinal complications, including GIB, perforation, and obstruction (adjusted rate ratio, 4.2), while diclofenac demonstrated the lowest risk (adjusted rate ratio, 1.89). High-dose NSAID therapy demonstrated a 2-fold increase in risk of peptic ulcer formation as compared to low-dose therapy.¹⁸

In addition to selecting the NSAID with the least gastrointestinal toxicity at the lowest possible dose, additional strategies to prevent peptic ulcer disease and its complications in chronic NSAID users include co-administration of a PPI and substitution of a COX-2 selective NSAID for nonselective NSAIDs.^1,9 Prior double-blind, placebo-controlled, randomized, multicenter trials with patients requiring daily NSAIDs demonstrated an up to 15% absolute reduction in the risk of developing peptic ulcers over 6 months while taking esomeprazole.¹⁹

Persistent Infection. Persistent H. pylori infection, due either to initial false-negative testing or ongoing infection despite first-line therapy, is another cause of refractory peptic ulcer disease.^1,15 Because antibiotics and PPIs can reduce the number of H. pylori bacteria, use of these medications concurrent with H. pylori testing can lead to false-negative results with several testing modalities. When suspicion for H. pylori is high, 2 or more diagnostic tests may be needed to effectively rule out infection.¹⁵

When H. pylori is detected, successful eradication is becoming more difficult due to an increasing prevalence of antibiotic resistance, leading to persistent infection in many cases and maintained risk of peptic ulcer disease, despite appropriate first-line therapy.⁸ Options for salvage therapy for persistent H. pylori, as well as information on the role and best timing of susceptibility testing, are beyond the scope of this review, but are reviewed by Lanas and Chan¹ and in the American College of Gastroenterology guideline on the treatment of H. pylori infection.⁸

Other Causes. In a meta-analysis of rigorously designed studies from North America, 20% of patients experienced ulcer recurrence at 6 months, despite successful H. pylori eradication and no NSAID use.²⁰ In addition, as H. pylori prevalence is decreasing, idiopathic ulcers are increasingly being diagnosed, and such ulcers may be associated with high rates of GIB and mortality.¹ In this subset of patients with non-H. pylori, non-NSAID ulcers, increased effort is required to further evaluate the differential diagnosis for rarer causes of upper GI tract ulcer disease (Table). Certain malignancies, including adenocarcinoma and lymphoma, can cause ulcer formation and should be considered in refractory cases. Repeat biopsy at follow-up endoscopy for persistent ulcers should always be obtained to further evaluate for malignancy.^1,15 Infectious diseases other than H. pylori infection, such as tuberculosis, syphilis, cytomegalovirus, and herpes simplex virus, are also reported as etiologies of refractory ulcers, and require specific antimicrobial treatment over and above PPI monotherapy. Special attention in biopsy sampling and sample processing is often required when infectious etiologies are being considered, as specific histologic stains and cultures may be needed for identification.¹⁵

Systemic conditions, including sarcoidosis,²¹ Behçet disease,²² and polyarteritis nodosa,^15,23 can also cause refractory ulcers. Approximately 15% of patients with Crohn disease have gastroduodenal involvement, which may include ulcers of variable sizes.^1,15,24 The increased gastric acid production seen in Zollinger-Ellison syndrome commonly presents as refractory peptic ulcers in the duodenum beyond the bulb that do not heal with standard doses of PPIs.^1,15 More rare causes of acid hypersecretion leading to refractory ulcers include idiopathic gastric acid hypersecretion and retained gastric antrum syndrome after partial gastrectomy with Billroth II anastomosis.¹⁵ Smoking is a known risk factor for impaired tissue healing throughout the body, and can contribute to impaired healing of peptic ulcers through decreased prostaglandin synthesis²⁵ and reduced gastric mucosal blood flow.²⁶ Smoking should always be addressed in patients with refractory peptic ulcers, and cessation should be strongly encouraged. Other less common causes of refractory upper GI tract ulcers include radiation therapy, crack cocaine use, and mesenteric ischemia.¹⁵

Managing Antiplatelet and Anticoagulant Medications

Use of antiplatelets and anticoagulants, alone or in combination, increases the risk of peptic ulcer bleeding. In patients who continue to take aspirin after a peptic ulcer bleed, recurrent bleeding occurs in up to 300 cases per 1000 person-years. The rate of GIB associated with aspirin use ranges from 1.1% to 2.5%, depending on the dose. Prior peptic ulcer disease, age greater than 70 years, and concurrent NSAID, steroid, anticoagulant, or dual antiplatelet therapy (DAPT) use increase the risk of bleeding while on aspirin. The rate of GIB while taking a thienopyridine alone is slightly less than that when taking aspirin, ranging from 0.5% to 1.6%. Studies to date have yielded mixed estimates of the effect of DAPT on the risk of GIB. Estimates of the risk of GIB with DAPT range from an odds ratio for serious GIB of 7.4 to an absolute risk increase of only 1.3% when compared to clopidogrel alone.²⁷

Many patients are also on warfarin or a direct oral anticoagulant (DOAC). In a study from the United Kingdom, the adjusted rate ratio of GIB with warfarin alone was 1.94, and this increased to 6.48 when warfarin was used with aspirin.²⁸ The use of warfarin and DAPT, often called triple therapy, further increases the risk of GIB, with a hazard ratio of 5.0 compared to DAPT alone, and 5.38 when compared to warfarin alone. DOACs are increasingly prescribed for the treatment and prevention of thromboembolism, and by 2014 were prescribed as often as warfarin for stroke prevention in atrial fibrillation in the United States. A meta-analysis showed the risk of major GIB did not differ between DOACs and warfarin or low-molecular-weight heparin, but among DOACs factor Xa inhibitors showed a reduced risk of GIB compared with dabigatran, a direct thrombin inhibitor.²⁹

The use of antiplatelets and anticoagulants in the context of peptic ulcer bleeding is a current management challenge. Data to guide decision-making in patients on antiplatelet and/or anticoagulant therapy who experience peptic ulcer bleeding are scarce. Decision-making in this group of patients requires balancing the severity and risk of bleeding with the risk of thromboembolism.^1,27 In patients on antiplatelet therapy for primary prophylaxis of atherothrombosis who develop bleeding from a peptic ulcer, the antiplatelet should generally be held and the indication for the medication reassessed. In patients on antiplatelet therapy for secondary prevention, the agent may be immediately resumed after endoscopy if bleeding is found to be due to an ulcer with low-risk stigmata. With bleeding resulting from an ulcer with high-risk stigmata, antiplatelet agents employed for secondary prevention may be held initially, with consideration given to early reintroduction, as early as day 3 after endoscopy.¹ In patients at high risk for atherothrombotic events, including those on aspirin for secondary prophylaxis, withholding aspirin leads to a 3-fold increase in the risk of a major adverse cardiac event, with events occurring as early as 5 days after aspirin cessation in some cases.²⁷ A randomized controlled trial of continuing low-dose aspirin versus withholding it for 8 weeks in patients on aspirin for secondary prophylaxis of cardiovascular events who experienced peptic ulcer bleeding that required endoscopic therapy demonstrated lower all-cause mortality (1.3% vs 12.9%), including death from cardiovascular or cerebrovascular events, among those who continued aspirin therapy, with a small increased risk of recurrent ulcer bleeding (10.3% vs 5.4%).³⁰ Thus, it is recommended that antiplatelet therapy, when held, be resumed as early as possible when the risk of a cardiovascular or cerebrovascular event is considered to be higher than the risk of bleeding.²⁷

When patients are on DAPT for a history of drug-eluting stent placement, withholding both antiplatelet medications should be avoided, even for a brief period of time, given the risk of in-stent thrombosis. When DAPT is employed for other reasons, it should be continued, if indicated, after bleeding that is found to be due to peptic ulcers with low-risk stigmata. If bleeding is due to a peptic ulcer with high-risk stigmata at endoscopy, then aspirin monotherapy should be continued and consultation should be obtained with a cardiologist to determine optimal timing to resume the second antiplatelet agent.¹ In patients on anticoagulants, anticoagulation should be resumed once hemostasis is achieved when the risk of withholding anticoagulation is thought to be greater than the risk of rebleeding. For example, anticoagulation should be resumed early in a patient with a mechanical heart valve to prevent thrombosis.^1,27 Following upper GIB from peptic ulcer disease, patients who will require long-term aspirin, DAPT, or anticoagulation with either warfarin or DOACs should be maintained on long-term PPI therapy to reduce the risk of recurrent bleeding.^9,27

Failure of Endoscopic Therapy to Control Peptic Ulcer Bleeding

Bleeding recurs in as many as 10% to 20% of patients after initial endoscopic control of peptic ulcer bleeding.^4,31 In this context, repeat upper endoscopy for hemostasis is preferred to surgery, as it leads to less morbidity while providing long-term control of bleeding in more than 70% of cases.^31,32 Two potential endoscopic rescue therapies that may be employed are over-the-scope clips (OTSCs) and hemostatic powder.^32,33

While through-the-scope (TTS) hemostatic clips are often used during endoscopy to control active peptic ulcer bleeding, their use may be limited in large or fibrotic ulcers due to the smaller size of the clips and method of application. OTSCs have several advantages over TTS clips; notably, their larger size allows the endoscopist to achieve deeper mucosal or submucosal clip attachment via suction of the targeted tissue into the endoscopic cap (Figure 2). In a systematic review of OTSCs, successful hemostasis was achieved in 84% of 761 lesions, including 75% of lesions due to peptic ulcer disease.³⁴ Some have argued that OTSCs may be preferred as first-line therapy over epinephrine with TTS clips for hemostasis in bleeding from high-risk peptic ulcers (ie, those with visualized arterial bleeding or a visible vessel) given observed decreases in rebleeding events.³⁵

Despite the advantages of OTSCs, endoscopists should be mindful of the potential complications of OTSC use, including luminal obstruction, particularly in the duodenum, and perforation, which occurs in 0.3% to 2% of cases. Additionally, retrieval of misplaced OTSCs presents a significant challenge. Careful decision-making with consideration of the location, size, and depth of lesions is required when deciding on OTSC placement.^34,36

A newer endoscopic tool developed for refractory bleeding from peptic ulcers and other causes is hemostatic powder. Hemostatic powders accelerate the coagulation cascade, leading to shortened coagulation times and enhanced clot formation.³⁷ A recent meta-analysis showed that immediate hemostasis could be achieved in 95% of cases of bleeding, including in 96% of cases of bleeding from peptic ulcer disease.³⁸ The primary limitation of hemostatic powders is the temporary nature of hemostasis, which requires the underlying etiology of bleeding to be addressed in order to provide long-term hemostasis. In the above meta-analysis, rebleeding occurred in 17% of cases after 30 days.³⁸

Hypotension and ulcer diameter ≥ 2 cm are independent predictors of failure of endoscopic salvage therapy.³¹ When severe bleeding is not controlled with initial endoscopic therapy or bleeding recurs despite salvage endoscopic therapy, transcatheter angiographic embolization (TAE) is the treatment of choice.⁴ Systematic reviews and meta-analyses of studies that compared TAE to surgery have shown that the rate of rebleeding may be higher with TAE, but with less morbidity and either decreased or equivalent rates of mortality, with no increased need for additional interventions.^4,32 In a case series examining 5 years of experience at a single medical center in China, massive GIB from duodenal ulcers was successfully treated with TAE in 27 of 29 cases (93% clinical success rate), with no mucosal ischemic necrosis observed.³⁹

If repeated endoscopic therapy has not led to hemostasis of a bleeding peptic ulcer and TAE is not available, then surgery is the next best option. Bleeding gastric ulcers may be excised, wedge resected, or oversewn after an anterior gastrostomy. Bleeding duodenal ulcers may require use of a Kocher maneuver and linear incision of the anterior duodenum followed by ligation of the gastroduodenal artery. Fortunately, such surgical management is rarely necessary given the availability of TAE at most centers.⁴

Conclusion

Peptic ulcer disease is a common health problem globally, with persistent challenges related to refractory ulcers, antiplatelet and anticoagulant use, and continued bleeding in the face of endoscopic therapy. These challenges should be met with adequate frequency and duration of PPI therapy, vigilant attention to and treatment of ulcer etiology, evidence-based handling of antiplatelet and anticoagulant medications, and utilization of novel endoscopic tools to obtain improved clinical outcomes.

Acknowledgment: We thank Dr. Nipun Reddy from our institution for providing the endoscopic images used in this article.

Corresponding author: Adam L. Edwards, MD, MS; [email protected].

Financial disclosures: None.

From the University of Alabama at Birmingham, Birmingham, AL.

Abstract

Objective: To review current challenges in the management of peptic ulcer disease.

Methods: Review of the literature.

Results: Peptic ulcer disease affects 5% to 10% of the population worldwide, with recent decreases in lifetime prevalence in high-income countries. Helicobacter pylori infection and nonsteroidal anti-inflammatory drug (NSAID) use are the most important drivers of peptic ulcer disease. Current management strategies for peptic ulcer disease focus on ulcer healing; management of complications such as bleeding, perforation, and obstruction; and prevention of ulcer recurrence. Proton pump inhibitors (PPIs) are the cornerstone of medical therapy for peptic ulcers, and complement testing for and treatment of H. pylori infection as well as elimination of NSAID use. Although advances have been made in the medical and endoscopic treatment of peptic ulcer disease and the management of ulcer complications, such as bleeding and obstruction, challenges remain.

Conclusion: Peptic ulcer disease is a common health problem globally, with persistent challenges related to refractory ulcers, antiplatelet and anticoagulant use, and continued bleeding in the face of endoscopic therapy. These challenges should be met with PPI therapy of adequate frequency and duration, vigilant attention to and treatment of ulcer etiology, evidence-based handling of antiplatelet and anticoagulant medications, and utilization of novel endoscopic tools to obtain improved clinical outcomes.

Keywords: H. pylori; nonsteroidal anti-inflammatory drugs; NSAIDs; proton pump inhibitor; PPI; bleeding; perforation; obstruction; refractory ulcer; salvage endoscopic therapy; transcatheter angiographic embolization.

A peptic ulcer is a fibrin-covered break in the mucosa of the digestive tract extending to the submucosa that is caused by acid injury (Figure 1). Most peptic ulcers occur in the stomach or proximal duodenum, though they may also occur in the esophagus or, less frequently, in a Meckel’s diverticulum.^1,2 The estimated worldwide prevalence of peptic ulcer disease is 5% to 10%, with an annual incidence of 0.1% to 0.3%¹; both rates are declining.³ The annual incidence of peptic ulcer disease requiring medical or surgical treatment is also declining, and currently is estimated to be 0.1% to 0.2%.⁴ The lifetime prevalence of peptic ulcers has been decreasing in high-income countries since the mid-20th century due to both the widespread use of medications that suppress gastric acid secretion and the declining prevalence of Helicobacter pylori infection.^1,3

Peptic ulcer disease in most individuals results from H. pylori infection, chronic use of nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, or both. A combination of H. pylori factors and host factors lead to mucosal disruption in infected individuals who develop peptic ulcers. H. pylori–specific factors include the expression of virulence factors such as CagA and VacA, which interact with the host inflammatory response to cause mucosal injury. The mucosal inflammatory response is at least partially determined by polymorphisms in the host’s cytokine genes.^1,4 NSAIDs inhibit the production of cyclooxygenase-1-derived prostaglandins, with subsequent decreases in epithelial mucous formation, bicarbonate secretion, cell proliferation, and mucosal blood flow, all of which are key elements in the maintenance of mucosal integrity.^1,5 Less common causes of peptic ulcers include gastrinoma, adenocarcinoma, idiopathic ulcers, use of sympathomimetic drugs (eg, cocaine or methamphetamine), certain anticancer agents, and bariatric surgery.^4,6

This article provides an overview of current management principles for peptic ulcer disease and discusses current challenges in peptic ulcer management, including proton pump inhibitor (PPI) therapy, refractory ulcers, handling of antiplatelet and anticoagulants during and after peptic ulcer bleeding, and ulcer bleeding that continues despite salvage endoscopic therapy.

Methods

We searched MEDLINE using the term peptic ulcer disease in combination with the terms current challenges, epidemiology, bleeding, anticoagulant, antiplatelet, PPI potency, etiology, treatment, management, and refractory. We selected publications from the past 35 years that we judged to be relevant.

Current Management

The goals of peptic ulcer disease management are ulcer healing and prevention of recurrence. The primary interventions used in the management of peptic ulcer disease are medical therapy and implementation of measures that address the underlying etiology of the disease.

Medical Therapy

Introduced in the late 1980s, PPIs are the cornerstone of medical therapy for peptic ulcer disease.⁶ These agents irreversibly inhibit the H+/K+-ATPase pump in the gastric mucosa and thereby inhibit gastric acid secretion, promoting ulcer healing. PPIs improve rates of ulcer healing compared to H2-receptor antagonists.^4,7

Underlying Causes

The underlying cause of peptic ulcer disease should be addressed, in addition to initiating medical therapy. A detailed history of NSAID use should be obtained, and patients with peptic ulcers caused by NSAIDs should be counseled to avoid them, if possible. Patients with peptic ulcer disease who require long-term use of NSAIDs should be placed on long-term PPI therapy.⁶ Any patient with peptic ulcer disease, regardless of any history of H. pylori infection or treatment, should be tested for infection. Tests that identify active infection, such as urea breath test, stool antigen assay, or mucosal biopsy–based testing, are preferred to IgG antibody testing, although the latter is acceptable in the context of peptic ulcer disease with a high pretest probability of infection.⁸ Any evidence of active infection warrants appropriate treatment to allow ulcer healing and prevent recurrence.¹H. pylori infection is most often treated with clarithromycin triple therapy or bismuth quadruple therapy for 14 days, with regimens selected based on the presence or absence of penicillin allergy, prior antibiotic exposure, and local clarithromycin resistance rates, when known.^4,8

Managing Complications

An additional aspect of care in peptic ulcer disease is managing the complications of bleeding, perforation, and gastric outlet obstruction. Acute upper gastrointestinal bleeding (GIB) is the most common complication of peptic ulcer disease, which accounts for 40% to 60% of nonvariceal acute upper GIB.^1,6 The first step in the management of acute GIB from a peptic ulcer is fluid resuscitation to ensure hemodynamic stability. If there is associated anemia with a hemoglobin level < 8 g/dL, blood transfusion should be undertaken to target a hemoglobin level > 8 g/dL. In patients with peptic ulcer disease–related acute upper GIB and comorbid cardiovascular disease, the transfusion threshold is higher, with the specific cutoff depending on clinical status, type and severity of cardiovascular disease, and degree of bleeding. Endoscopic management should generally be undertaken within 24 hours of presentation and should not be delayed in patients taking anticoagulants.⁹ Combination endoscopic treatment with through-the-scope clips plus thermocoagulation or sclerosant injection is recommended for acutely bleeding peptic ulcers with high-risk stigmata.

Pharmacologic management of patients with bleeding peptic ulcers with high-risk stigmata includes PPI therapy, with an 80 mg intravenous (IV) loading dose followed by continuous infusion of 8 mg/hr for 72 hours to reduce rebleeding and mortality. Following completion of IV therapy, oral PPI therapy should be continued twice daily for 14 days, followed by once-daily dosing thereafter.⁹Patients with peptic ulcer perforation present with sudden-onset epigastric abdominal pain and have tenderness to palpation, guarding, and rigidity on examination, often along with tachycardia and hypotension.^1,4 Computed tomography (CT) of the abdomen is 98% sensitive for identifying and localizing a perforation. Most perforations occur in the duodenum or antrum.

Management of a peptic ulcer perforation requires consultation with a surgeon to determine whether a nonoperative approach may be employed (eg, a stable patient with a contained perforation), or if surgery is indicated. The surgical approach to peptic ulcer perforation has been impacted by the clinical success of gastric acid suppression with PPIs and H. pylori eradication, but a range of surgical approaches are still used to repair perforations, from omental patch repair with peritoneal drain placement, to more extensive surgeries such as wedge resection or partial gastrectomy.⁴ Perforation carries a high mortality risk, up to 20% to 30%, and is the leading cause of death in patients with peptic ulcer disease.^1,4

Gastric outlet obstruction, a rare complication of peptic ulcer disease, results from recurrent ulcer formation and scarring. Obstruction often presents with hypovolemia and metabolic alkalosis from prolonged vomiting. CT imaging with oral contrast is often the first diagnostic test employed to demonstrate obstruction. Upper endoscopy should be performed to evaluate the appearance and degree of obstruction as well as to obtain biopsies to evaluate for a malignant etiology of the ulcer disease. Endoscopic balloon dilation has become the cornerstone of initial therapy for obstruction from peptic ulcer disease, especially in the case of ulcers due to reversible causes. Surgery is now typically reserved for cases of refractory obstruction, after repeated endoscopic balloon dilation has failed to remove the obstruction. However, because nearly all patients with gastric outlet obstruction present with malnutrition, nutritional deficiencies should be addressed prior to the patient undergoing surgical intervention. Surgical options include pyloroplasty, antrectomy, and gastrojejunostomy.⁴

Current Challenges

Rapid Metabolism of PPIs

High-dose PPI therapy is a key component of therapy for peptic ulcer healing. PPIs are metabolized by the cytochrome P450 system, which is comprised of multiple isoenzymes. CYP2C19, an isoenzyme involved in PPI metabolism, has 21 polymorphisms, which have variable effects leading to ultra-rapid, extensive, intermediate, or poor metabolism of PPIs.¹⁰ With rapid metabolism of PPIs, standard dosing can result in inadequate suppression of acid secretion. Despite this knowledge, routine testing of CYP2C19 phenotype is not recommended due to the cost of testing. Instead, inadequate ulcer healing should prompt consideration of increased PPI dosing to 80 mg orally twice daily, which may be sufficient to overcome rapid PPI metabolism.¹¹

Relative Potency of PPIs

In addition to variation in PPI metabolism, the relative potency of various PPIs has been questioned. A review of all available clinical studies of the effects of PPIs on mean 24-hour intragastric pH reported a quantitative difference in the potency of 5 PPIs, with omeprazole as the reference standard. Potencies ranged from 0.23 omeprazole equivalents for pantoprazole to 1.82 omeprazole equivalents for rabeprazole.¹² An additional study of data from 56 randomized clinical trials confirmed that PPIs vary in potency, which was measured as time that gastric pH is less than 4. A linear increase in intragastric pH time less than 4 was observed from 9 to 64 mg omeprazole equivalents; higher doses yielded no additional benefit. An increase in PPI dosing from once daily to twice daily also increased the duration of intragastric pH time less than 4 from 15 to 21 hours.¹³ Earlier modeling of the relationship between duodenal ulcer healing and antisecretory therapy showed a strong correlation of ulcer healing with the duration of acid suppression, length of therapy, and the degree of acid suppression. Additional benefit was not observed after intragastric pH rose above 3.¹⁴ Thus, as the frequency and duration of acid suppression therapy are more important than PPI potency, PPIs can be used interchangeably.^13,14

Addressing Underlying Causes

Continued NSAID Use. Refractory peptic ulcers are defined as those that do not heal despite adherence to 8 to 12 weeks of standard acid-suppression therapy. A cause of refractory peptic ulcer disease that must be considered is continued NSAID use.^1,15 In a study of patients with refractory peptic ulcers, 27% of patients continued NSAID use, as determined by eventual disclosure by the patients or platelet cyclooxygenase activity assay, despite extensive counseling to avoid NSAIDs at the time of the diagnosis of their refractory ulcer and at subsequent visits.¹⁶ Pain may make NSAID cessation difficult for some patients, while others do not realize that over-the-counter preparations they take contain NSAIDs.¹⁵

Another group of patients with continued NSAID exposure are those who require long-term NSAID therapy for control of arthritis or the management of cardiovascular conditions. If NSAID therapy cannot be discontinued, the risk of NSAID-related gastrointestinal injury can be assessed based on the presence of multiple risk factors, including age > 65 years, high-dose NSAID therapy, a history of peptic ulcer, and concurrent use of aspirin, corticosteroids, or anticoagulants. Individuals with 3 or more of the preceding risk factors or a history of a peptic ulcer with a complication, especially if recent, are considered to be at high risk of developing an NSAID-related ulcer and possible subsequent complications.¹⁷ In these individuals, NSAID therapy should be continued with agents that have the lowest risk for gastrointestinal toxicity and at the lowest possible dose. A meta-analysis comparing nonselective NSAIDs to placebo demonstrated naproxen to have the highest risk of gastrointestinal complications, including GIB, perforation, and obstruction (adjusted rate ratio, 4.2), while diclofenac demonstrated the lowest risk (adjusted rate ratio, 1.89). High-dose NSAID therapy demonstrated a 2-fold increase in risk of peptic ulcer formation as compared to low-dose therapy.¹⁸

In addition to selecting the NSAID with the least gastrointestinal toxicity at the lowest possible dose, additional strategies to prevent peptic ulcer disease and its complications in chronic NSAID users include co-administration of a PPI and substitution of a COX-2 selective NSAID for nonselective NSAIDs.^1,9 Prior double-blind, placebo-controlled, randomized, multicenter trials with patients requiring daily NSAIDs demonstrated an up to 15% absolute reduction in the risk of developing peptic ulcers over 6 months while taking esomeprazole.¹⁹

Persistent Infection. Persistent H. pylori infection, due either to initial false-negative testing or ongoing infection despite first-line therapy, is another cause of refractory peptic ulcer disease.^1,15 Because antibiotics and PPIs can reduce the number of H. pylori bacteria, use of these medications concurrent with H. pylori testing can lead to false-negative results with several testing modalities. When suspicion for H. pylori is high, 2 or more diagnostic tests may be needed to effectively rule out infection.¹⁵

When H. pylori is detected, successful eradication is becoming more difficult due to an increasing prevalence of antibiotic resistance, leading to persistent infection in many cases and maintained risk of peptic ulcer disease, despite appropriate first-line therapy.⁸ Options for salvage therapy for persistent H. pylori, as well as information on the role and best timing of susceptibility testing, are beyond the scope of this review, but are reviewed by Lanas and Chan¹ and in the American College of Gastroenterology guideline on the treatment of H. pylori infection.⁸

Other Causes. In a meta-analysis of rigorously designed studies from North America, 20% of patients experienced ulcer recurrence at 6 months, despite successful H. pylori eradication and no NSAID use.²⁰ In addition, as H. pylori prevalence is decreasing, idiopathic ulcers are increasingly being diagnosed, and such ulcers may be associated with high rates of GIB and mortality.¹ In this subset of patients with non-H. pylori, non-NSAID ulcers, increased effort is required to further evaluate the differential diagnosis for rarer causes of upper GI tract ulcer disease (Table). Certain malignancies, including adenocarcinoma and lymphoma, can cause ulcer formation and should be considered in refractory cases. Repeat biopsy at follow-up endoscopy for persistent ulcers should always be obtained to further evaluate for malignancy.^1,15 Infectious diseases other than H. pylori infection, such as tuberculosis, syphilis, cytomegalovirus, and herpes simplex virus, are also reported as etiologies of refractory ulcers, and require specific antimicrobial treatment over and above PPI monotherapy. Special attention in biopsy sampling and sample processing is often required when infectious etiologies are being considered, as specific histologic stains and cultures may be needed for identification.¹⁵

Systemic conditions, including sarcoidosis,²¹ Behçet disease,²² and polyarteritis nodosa,^15,23 can also cause refractory ulcers. Approximately 15% of patients with Crohn disease have gastroduodenal involvement, which may include ulcers of variable sizes.^1,15,24 The increased gastric acid production seen in Zollinger-Ellison syndrome commonly presents as refractory peptic ulcers in the duodenum beyond the bulb that do not heal with standard doses of PPIs.^1,15 More rare causes of acid hypersecretion leading to refractory ulcers include idiopathic gastric acid hypersecretion and retained gastric antrum syndrome after partial gastrectomy with Billroth II anastomosis.¹⁵ Smoking is a known risk factor for impaired tissue healing throughout the body, and can contribute to impaired healing of peptic ulcers through decreased prostaglandin synthesis²⁵ and reduced gastric mucosal blood flow.²⁶ Smoking should always be addressed in patients with refractory peptic ulcers, and cessation should be strongly encouraged. Other less common causes of refractory upper GI tract ulcers include radiation therapy, crack cocaine use, and mesenteric ischemia.¹⁵

Managing Antiplatelet and Anticoagulant Medications

Use of antiplatelets and anticoagulants, alone or in combination, increases the risk of peptic ulcer bleeding. In patients who continue to take aspirin after a peptic ulcer bleed, recurrent bleeding occurs in up to 300 cases per 1000 person-years. The rate of GIB associated with aspirin use ranges from 1.1% to 2.5%, depending on the dose. Prior peptic ulcer disease, age greater than 70 years, and concurrent NSAID, steroid, anticoagulant, or dual antiplatelet therapy (DAPT) use increase the risk of bleeding while on aspirin. The rate of GIB while taking a thienopyridine alone is slightly less than that when taking aspirin, ranging from 0.5% to 1.6%. Studies to date have yielded mixed estimates of the effect of DAPT on the risk of GIB. Estimates of the risk of GIB with DAPT range from an odds ratio for serious GIB of 7.4 to an absolute risk increase of only 1.3% when compared to clopidogrel alone.²⁷

Many patients are also on warfarin or a direct oral anticoagulant (DOAC). In a study from the United Kingdom, the adjusted rate ratio of GIB with warfarin alone was 1.94, and this increased to 6.48 when warfarin was used with aspirin.²⁸ The use of warfarin and DAPT, often called triple therapy, further increases the risk of GIB, with a hazard ratio of 5.0 compared to DAPT alone, and 5.38 when compared to warfarin alone. DOACs are increasingly prescribed for the treatment and prevention of thromboembolism, and by 2014 were prescribed as often as warfarin for stroke prevention in atrial fibrillation in the United States. A meta-analysis showed the risk of major GIB did not differ between DOACs and warfarin or low-molecular-weight heparin, but among DOACs factor Xa inhibitors showed a reduced risk of GIB compared with dabigatran, a direct thrombin inhibitor.²⁹

The use of antiplatelets and anticoagulants in the context of peptic ulcer bleeding is a current management challenge. Data to guide decision-making in patients on antiplatelet and/or anticoagulant therapy who experience peptic ulcer bleeding are scarce. Decision-making in this group of patients requires balancing the severity and risk of bleeding with the risk of thromboembolism.^1,27 In patients on antiplatelet therapy for primary prophylaxis of atherothrombosis who develop bleeding from a peptic ulcer, the antiplatelet should generally be held and the indication for the medication reassessed. In patients on antiplatelet therapy for secondary prevention, the agent may be immediately resumed after endoscopy if bleeding is found to be due to an ulcer with low-risk stigmata. With bleeding resulting from an ulcer with high-risk stigmata, antiplatelet agents employed for secondary prevention may be held initially, with consideration given to early reintroduction, as early as day 3 after endoscopy.¹ In patients at high risk for atherothrombotic events, including those on aspirin for secondary prophylaxis, withholding aspirin leads to a 3-fold increase in the risk of a major adverse cardiac event, with events occurring as early as 5 days after aspirin cessation in some cases.²⁷ A randomized controlled trial of continuing low-dose aspirin versus withholding it for 8 weeks in patients on aspirin for secondary prophylaxis of cardiovascular events who experienced peptic ulcer bleeding that required endoscopic therapy demonstrated lower all-cause mortality (1.3% vs 12.9%), including death from cardiovascular or cerebrovascular events, among those who continued aspirin therapy, with a small increased risk of recurrent ulcer bleeding (10.3% vs 5.4%).³⁰ Thus, it is recommended that antiplatelet therapy, when held, be resumed as early as possible when the risk of a cardiovascular or cerebrovascular event is considered to be higher than the risk of bleeding.²⁷

When patients are on DAPT for a history of drug-eluting stent placement, withholding both antiplatelet medications should be avoided, even for a brief period of time, given the risk of in-stent thrombosis. When DAPT is employed for other reasons, it should be continued, if indicated, after bleeding that is found to be due to peptic ulcers with low-risk stigmata. If bleeding is due to a peptic ulcer with high-risk stigmata at endoscopy, then aspirin monotherapy should be continued and consultation should be obtained with a cardiologist to determine optimal timing to resume the second antiplatelet agent.¹ In patients on anticoagulants, anticoagulation should be resumed once hemostasis is achieved when the risk of withholding anticoagulation is thought to be greater than the risk of rebleeding. For example, anticoagulation should be resumed early in a patient with a mechanical heart valve to prevent thrombosis.^1,27 Following upper GIB from peptic ulcer disease, patients who will require long-term aspirin, DAPT, or anticoagulation with either warfarin or DOACs should be maintained on long-term PPI therapy to reduce the risk of recurrent bleeding.^9,27

Failure of Endoscopic Therapy to Control Peptic Ulcer Bleeding

Bleeding recurs in as many as 10% to 20% of patients after initial endoscopic control of peptic ulcer bleeding.^4,31 In this context, repeat upper endoscopy for hemostasis is preferred to surgery, as it leads to less morbidity while providing long-term control of bleeding in more than 70% of cases.^31,32 Two potential endoscopic rescue therapies that may be employed are over-the-scope clips (OTSCs) and hemostatic powder.^32,33

While through-the-scope (TTS) hemostatic clips are often used during endoscopy to control active peptic ulcer bleeding, their use may be limited in large or fibrotic ulcers due to the smaller size of the clips and method of application. OTSCs have several advantages over TTS clips; notably, their larger size allows the endoscopist to achieve deeper mucosal or submucosal clip attachment via suction of the targeted tissue into the endoscopic cap (Figure 2). In a systematic review of OTSCs, successful hemostasis was achieved in 84% of 761 lesions, including 75% of lesions due to peptic ulcer disease.³⁴ Some have argued that OTSCs may be preferred as first-line therapy over epinephrine with TTS clips for hemostasis in bleeding from high-risk peptic ulcers (ie, those with visualized arterial bleeding or a visible vessel) given observed decreases in rebleeding events.³⁵

Despite the advantages of OTSCs, endoscopists should be mindful of the potential complications of OTSC use, including luminal obstruction, particularly in the duodenum, and perforation, which occurs in 0.3% to 2% of cases. Additionally, retrieval of misplaced OTSCs presents a significant challenge. Careful decision-making with consideration of the location, size, and depth of lesions is required when deciding on OTSC placement.^34,36

A newer endoscopic tool developed for refractory bleeding from peptic ulcers and other causes is hemostatic powder. Hemostatic powders accelerate the coagulation cascade, leading to shortened coagulation times and enhanced clot formation.³⁷ A recent meta-analysis showed that immediate hemostasis could be achieved in 95% of cases of bleeding, including in 96% of cases of bleeding from peptic ulcer disease.³⁸ The primary limitation of hemostatic powders is the temporary nature of hemostasis, which requires the underlying etiology of bleeding to be addressed in order to provide long-term hemostasis. In the above meta-analysis, rebleeding occurred in 17% of cases after 30 days.³⁸

Hypotension and ulcer diameter ≥ 2 cm are independent predictors of failure of endoscopic salvage therapy.³¹ When severe bleeding is not controlled with initial endoscopic therapy or bleeding recurs despite salvage endoscopic therapy, transcatheter angiographic embolization (TAE) is the treatment of choice.⁴ Systematic reviews and meta-analyses of studies that compared TAE to surgery have shown that the rate of rebleeding may be higher with TAE, but with less morbidity and either decreased or equivalent rates of mortality, with no increased need for additional interventions.^4,32 In a case series examining 5 years of experience at a single medical center in China, massive GIB from duodenal ulcers was successfully treated with TAE in 27 of 29 cases (93% clinical success rate), with no mucosal ischemic necrosis observed.³⁹

If repeated endoscopic therapy has not led to hemostasis of a bleeding peptic ulcer and TAE is not available, then surgery is the next best option. Bleeding gastric ulcers may be excised, wedge resected, or oversewn after an anterior gastrostomy. Bleeding duodenal ulcers may require use of a Kocher maneuver and linear incision of the anterior duodenum followed by ligation of the gastroduodenal artery. Fortunately, such surgical management is rarely necessary given the availability of TAE at most centers.⁴

Conclusion

Peptic ulcer disease is a common health problem globally, with persistent challenges related to refractory ulcers, antiplatelet and anticoagulant use, and continued bleeding in the face of endoscopic therapy. These challenges should be met with adequate frequency and duration of PPI therapy, vigilant attention to and treatment of ulcer etiology, evidence-based handling of antiplatelet and anticoagulant medications, and utilization of novel endoscopic tools to obtain improved clinical outcomes.

Acknowledgment: We thank Dr. Nipun Reddy from our institution for providing the endoscopic images used in this article.

Corresponding author: Adam L. Edwards, MD, MS; [email protected].

Financial disclosures: None.

Performing dermatologic procedures in infants, children, and teenagers presents many unique challenges. There may be unique diagnoses, different instruments, differences in skin biology, or different approaches to pain management and anesthesia; the inclusion of a third party (caregivers) in decision processes; or a need to assess maturity level or to optimize outcomes over the patient’s lifetime. The field of pediatric procedural dermatology is broad. This article reviews some of the more common procedures performed by pediatric dermatologists and some of the more common ethical and quality-of-life (QOL) considerations one might face in procedural pediatric dermatology. (The textbook Procedural Pediatric Dermatology¹ offers a thorough discussion of this topic.)

Quality of Life

More often than not, procedures are performed in pediatric dermatology to improve QOL rather than to prevent morbidity or mortality. In the case of many self-limited conditions, such as ingrown nails or pyogenic granulomas, it is clear that intervention will improve the patient’s QOL. In the case of warts and molluscum contagiosum, emotional, social, and cultural considerations play a large role in determining whether an intervention will improve QOL. Finally, some conditions, such as genodermatoses, giant congenital melanocytic nevi, and large vascular malformations, may be associated with additional systemic symptoms and may not have good treatment options for cure. In these cases, procedural interventions will result in a mixture of positive and negative QOL outcomes that can occur at the same time.

Bemmels et al² published a qualitative study that provides a good foundation for understanding the positive and negative effects of procedural interventions on children and teenagers. In their study, children and teenagers who underwent reconstructive surgery for craniofacial differences noted improved self-esteem and reduced stigmatization. However, they also experienced negative outcomes, including an addiction to attaining a perfect surgical face, missing school for treatments, difficulty adjusting to an evolving appearance, anxiety related to not knowing when treatments will end, and experiencing stigma related to undergoing surgery.² Thus, a comprehensive plan for the management of children who need ongoing procedures should include some level of psychosocial support. Two good references on supporting young patients with visible differences include CBT for Appearance Anxiety: Psychosocial Interventions for Anxiety Due to Visible Difference³ and Reaching Teens: Strength-Based, Trauma-Sensitive, Resilience-Building Communication Strategies Rooted in Positive Youth Development.⁴

Ethics

Ethical decisions in pediatric procedural dermatology differ from adult dermatology in 3 major ways: (1) the involvement of a third party (ie, parents or legal guardians), (2) the need to assess the maturity of the patient, and (3) the need to know local laws in the jurisdiction in which care is being provided. Ethical dilemmas occur when the desires of the child, parents/guardians, and dermatologist are not in alignment. In these cases, it is important to be prepared with a moral or ethical framework to guide decision-making when conflicts occur. Two great resources are the best interest standard⁵ and the publication entitled, “Informed Consent in Decision-making in Pediatric Practice,” from the American Academy of Pediatrics.⁶

In pediatrics, it often is better to conceptualize medical decision-making as a combination of informed permission and assent of the patient rather than informed consent. Informed permission describes how a parent or surrogate makes decisions for the child or adolescent and is similar to informed consent. A parent’s informed permission may be in conflict with a child’s wishes, but it is assumed that the parent is acting in the best interest of the child. Assent of the patient is the process of obtaining a minor’s agreement to undergo an intervention even though he/she may lack legal authority or decision-making capacity to provide standard informed consent. It is important to respect the child’s right to assent to interventions to the extent that their maturity level permits to develop trust with the dermatologist and medical encounters in general.

These differences emphasize an active process in which the patient, caregiver, and physician are all involved in the health care process and allow for increasing inclusion of the child as is developmentally appropriate. In the end, however, parents have the legal authority to give or withhold permission for a procedure.⁷ When this conflicts with a child’s dissent, the dermatologist will need to objectively explore the reasons for the conflict and decide if a procedure is not in the child’s best interests. If a mutual understanding cannot be reached between the dermatologist and parents, obtaining a second opinion is a good option.⁸

Common Diagnoses

The most common diagnoses unique to procedural pediatric dermatology include congenital melanocytic nevi, vascular anomalies, midline lesions, epidermal nevi, and pilomatricomas. Prior to intervening on these lesions, it is important to consider evaluating for associated diseases.

Congenital Melanocytic Nevi
Nevus Outreach has published best practices for the management of congenital melanocytic nevi.⁹ In newborns with a congenital melanocytic nevus greater than 3 cm in diameter or more than 20 satellite lesions, it is recommended that magnetic resonance imaging (MRI) of the brain and spine with and without gadolinium contrast be obtained before 6 months of age. Within the first 6 months of life, these children also should see ophthalmologists, neurologists, pediatric dermatologists, and plastic surgeons. These early referrals will help to establish a baseline for the patient and plan for possible interventions, if needed. Additionally, before 3 years of age, every child should be referred to psychology, even if he/she is asymptomatic.¹⁰

Vascular Anomalies
Prior to intervening on a vascular anomaly, it is important to accurately classify the lesion. Once the lesion is classified, an evaluation and treatment plan can be developed. The International Society for the Study of Vascular Anomalies has published a detailed classification guide that is a useful starting point in the management of vascular anomalies.¹¹ Once a diagnosis is confirmed, further evaluation may include imaging, specialty referrals, genetic testing, biopsy, or blood tests, and a pediatric dermatologist usually helps to coordinate the care of patients with complex vascular anomalies.

Midline Lesions
Certain lesions in the midline may have a higher risk for neural tube dysraphism, and imaging should be performed prior to any procedural intervention.¹² Midline cutaneous findings that are highly likely to be associated with dysraphism are lipomas, acrochordons, pseudotails, true tails, aplasia cutis congenita, congenital scars, dermoid cysts, dermoid sinuses, and infantile hemangiomas that are greater than 2.5 cm in diameter. An MRI should be performed for all high-risk lesions. Intermediate-risk lesions are atypical dimples (>5 mm in diameter or >2.5 cm from the anal verge), hemangiomas less than 2.5 cm in diameter, and hypertrichosis. An ultrasound can screen for spinal dysraphism in these cases as long as imaging is performed prior to 6 months of age. If the child is older than 6 months, an MRI should be performed. Low-risk lesions that do not require imaging are simple dimples, hyperpigmentation, hypopigmentation, melanocytic nevi, port-wine stains, and telangiectases.

Epidermal Nevi
Children with epidermal nevi should have a complete physical examination, focusing on the skeletal system, central nervous system, and eyes. There are no specifically recommended imaging studies or referrals; however, several diagnostic clues can aid in the diagnosis of an epidermal nevus syndrome¹³:

• Schimmelpenning syndrome: extensive nevus sebaceous and bowing or pain in the legs after 2 years of age

• Phacomatosis pigmentokeratotica: nevus sebaceous and nevus spilus

• Nevus comedonicus syndrome: ipsilateral cataract

• Angora hair nevus syndrome: soft white hair within the nevus

• Becker nevus syndrome: breast hypoplasia

• Proteus syndrome: cerebriform plantar changes

• PIK3CA-related overgrowth spectrum: lipomas, macrodactyly, and/or vascular malformations

• Congenital hemidysplasia with ichthyosiform erythroderma and limb defects: inflammatory epidermal nevi, lateralization, ptychotropism, and ipsilateral limb defects

• Conradi-Hünermann-Happle syndrome: scaly red epidermal nevi without hair follicles and asymmetric limb shortening

Pilomatricomas
In addition to the tent sign—an angulated shape can be appreciated by stretching the skin overlying pilomatricomas—diagnosis of pilomatricoma can be confirmed by transillumination with an otoscope. In this case, a dark shadow typically is cast distal to where the otoscope touches the skin.¹⁴ In the case of multiple lesions, the patient should be evaluated for signs of myotonic dystrophy, Turner syndrome, and Gardner syndrome.¹⁵

Common Procedures

Pulsed Dye Laser
The pulsed dye laser is the most common laser used for red-colored lesions such as port-wine stains, facial telangiectases, and superficial hemangiomas. It also can be used to treat erythematous scars, verrucae, and psoriasis. In large vascular lesions, it typically is employed at 0.45 to 10 milliseconds every 4 to 6 weeks for 10 or more treatments. Port-wine stains preferably are treated within the first few months of life to provide the most fading without the need for general anesthesia.¹⁶ On the other hand, systemic therapy with propranolol is preferred over lasers for infantile hemangiomas.¹⁷

Long-Pulsed Alexandrite Laser (755 nm)
The alexandrite laser often is used to treat deeper vascular lesions such as venous lakes and hypertrophic port-wine stains. The operator needs to be cautious, as this laser has a higher incidence of scarring at the settings used to treat vascular lesions (typically fluences around 60–85 J/cm²).¹⁸ It also may be used for hair reduction in disorders with hypertrichosis or hidradenitis suppurativa.¹⁹

Long-Pulsed Nd:YAG Laser
The long-pulsed Nd:YAG laser also can be used to treat deep vascular lesions and remove unwanted hair. Because of its low window of safety in the treatment of vascular lesions, the alexandrite laser usually is preferred. However, it is the preferred laser for treatment of unwanted hair and hidradenitis suppurativa in darker skin types. It often provides a 50% reduction in hair density after 9 treatments.²⁰

Quality-Switched Lasers
Pigment granules in melanosomes and tattoo particles are targeted with quality-switched (QS) lasers. Typically, a device will contain a combination of QS 532-nm potassium-titanyl-phosphate (KTP) lasers, QS 1064-nm Nd:YAG lasers, and QS 755-nm alexandrite lasers in 1 machine. In general, shorter wavelengths are used to treat epidermal lesions such as ephelides, lentigines, and café-au-lait macules. Longer wavelengths are used to treat deeper lesions such as nevus of Ota. A 2017 review suggested that café-au-lait macules with ragged borders (so-called coast of Maine borders) may respond well to QS lasers.²¹

Ablative Lasers
The 10,600-nm CO₂ laser and 2940-nm erbium:YAG laser can be used to debulk superficial tumors such as lymphangiomas, syringomas, angiofibromas, and xanthomas.²² These treatments have a higher risk for scarring than other lasers, so it is important to have a good understanding of desired clinical end points before using these devices.

Fractionated Lasers
Fractionated lasers can be nonablative (several devices are available in the 1410- to 1927-nm range) or ablative (CO₂ or erbium:YAG). In pediatrics, they are usually used to treat burn scars, traumatic scars, and mild to moderate acne scarring.²² The most common side effects from fractionated lasers are prolonged erythema or hyperpigmentation. In addition, it typically takes at least 3 treatments to notice improvements.

Excisions

Pediatric procedural dermatologists remove a variety of unique lesions through excision. A few tips are provided for some of the more common lesions that may be excised in children.

Accessory Tragi
Prior to excising an accessory tragus, the surgeon should consider documenting a facial nerve examination, as accessory tragi can be associated with complete or partial facial nerve dysfunction. Additionally, there usually is an underlying cartilage structure present within the tragus. The cartilage stalk also should be addressed during the excision to avoid a continued palpable deformity after excision.

Dermoid Cysts
Dermoid cysts are the most commonly diagnosed benign orbital lesion in children.²³ Exophytic periorbital lesions, which extend outside the orbital rim, can be removed through an infrabrow incision. Endophytic periorbital lesions, which are inside the orbital rim, should be removed through a crease incision. Midline lesions may have an intracranial extension and should be imaged through MRI and/or a computed tomography.²⁴ Because dermoid cysts usually are located below the orbicularis oculi muscle, the muscle should be fixed with a suture prior to closing with skin sutures.

Pilomatricomas
Typically, a linear incision is made overlying the lesion, and then the underlying tumor is removed with sharp or blunt dissection. However, if the overlying skin has been stretched thin, a lenticular excision that includes the thinned skin may improve cosmesis.

Congenital Nevi
Large congenital nevi typically are removed through staged excisions. Lower extremity lesions are best removed before 10 months of age or before walking begins to minimize wound tension. However, if the procedure is not performed in infancy, it is best to wait until walking becomes stable.²⁵ In older children, it is advisable to splint the affected lower extremity for 2 weeks to prevent dehiscence. The interval between excisions typically is 4 to 6 weeks for small lesions and 3 months for larger nevi.

Conclusion

Procedural pediatric dermatology is a broad and emerging field. As this article highlights, children are not small versions of adults and have unique biology, diseases, therapies, social situations, and ethical challenges from adults. This article provides a superficial overview of some of the more common issues faced by pediatric dermatologists and providers who perform procedures on infants, children, and teenagers. Readers who are interested in obtaining a more in-depth understanding of procedural pediatric dermatology should look at Procedural Pediatric Dermatology,¹ the first textbook to provide expert opinion and evidence-based information on procedural management of pediatric skin conditions.

Performing dermatologic procedures in infants, children, and teenagers presents many unique challenges. There may be unique diagnoses, different instruments, differences in skin biology, or different approaches to pain management and anesthesia; the inclusion of a third party (caregivers) in decision processes; or a need to assess maturity level or to optimize outcomes over the patient’s lifetime. The field of pediatric procedural dermatology is broad. This article reviews some of the more common procedures performed by pediatric dermatologists and some of the more common ethical and quality-of-life (QOL) considerations one might face in procedural pediatric dermatology. (The textbook Procedural Pediatric Dermatology¹ offers a thorough discussion of this topic.)

Quality of Life

More often than not, procedures are performed in pediatric dermatology to improve QOL rather than to prevent morbidity or mortality. In the case of many self-limited conditions, such as ingrown nails or pyogenic granulomas, it is clear that intervention will improve the patient’s QOL. In the case of warts and molluscum contagiosum, emotional, social, and cultural considerations play a large role in determining whether an intervention will improve QOL. Finally, some conditions, such as genodermatoses, giant congenital melanocytic nevi, and large vascular malformations, may be associated with additional systemic symptoms and may not have good treatment options for cure. In these cases, procedural interventions will result in a mixture of positive and negative QOL outcomes that can occur at the same time.

Bemmels et al² published a qualitative study that provides a good foundation for understanding the positive and negative effects of procedural interventions on children and teenagers. In their study, children and teenagers who underwent reconstructive surgery for craniofacial differences noted improved self-esteem and reduced stigmatization. However, they also experienced negative outcomes, including an addiction to attaining a perfect surgical face, missing school for treatments, difficulty adjusting to an evolving appearance, anxiety related to not knowing when treatments will end, and experiencing stigma related to undergoing surgery.² Thus, a comprehensive plan for the management of children who need ongoing procedures should include some level of psychosocial support. Two good references on supporting young patients with visible differences include CBT for Appearance Anxiety: Psychosocial Interventions for Anxiety Due to Visible Difference³ and Reaching Teens: Strength-Based, Trauma-Sensitive, Resilience-Building Communication Strategies Rooted in Positive Youth Development.⁴

Ethics

Ethical decisions in pediatric procedural dermatology differ from adult dermatology in 3 major ways: (1) the involvement of a third party (ie, parents or legal guardians), (2) the need to assess the maturity of the patient, and (3) the need to know local laws in the jurisdiction in which care is being provided. Ethical dilemmas occur when the desires of the child, parents/guardians, and dermatologist are not in alignment. In these cases, it is important to be prepared with a moral or ethical framework to guide decision-making when conflicts occur. Two great resources are the best interest standard⁵ and the publication entitled, “Informed Consent in Decision-making in Pediatric Practice,” from the American Academy of Pediatrics.⁶

In pediatrics, it often is better to conceptualize medical decision-making as a combination of informed permission and assent of the patient rather than informed consent. Informed permission describes how a parent or surrogate makes decisions for the child or adolescent and is similar to informed consent. A parent’s informed permission may be in conflict with a child’s wishes, but it is assumed that the parent is acting in the best interest of the child. Assent of the patient is the process of obtaining a minor’s agreement to undergo an intervention even though he/she may lack legal authority or decision-making capacity to provide standard informed consent. It is important to respect the child’s right to assent to interventions to the extent that their maturity level permits to develop trust with the dermatologist and medical encounters in general.

These differences emphasize an active process in which the patient, caregiver, and physician are all involved in the health care process and allow for increasing inclusion of the child as is developmentally appropriate. In the end, however, parents have the legal authority to give or withhold permission for a procedure.⁷ When this conflicts with a child’s dissent, the dermatologist will need to objectively explore the reasons for the conflict and decide if a procedure is not in the child’s best interests. If a mutual understanding cannot be reached between the dermatologist and parents, obtaining a second opinion is a good option.⁸

Common Diagnoses

The most common diagnoses unique to procedural pediatric dermatology include congenital melanocytic nevi, vascular anomalies, midline lesions, epidermal nevi, and pilomatricomas. Prior to intervening on these lesions, it is important to consider evaluating for associated diseases.

Congenital Melanocytic Nevi
Nevus Outreach has published best practices for the management of congenital melanocytic nevi.⁹ In newborns with a congenital melanocytic nevus greater than 3 cm in diameter or more than 20 satellite lesions, it is recommended that magnetic resonance imaging (MRI) of the brain and spine with and without gadolinium contrast be obtained before 6 months of age. Within the first 6 months of life, these children also should see ophthalmologists, neurologists, pediatric dermatologists, and plastic surgeons. These early referrals will help to establish a baseline for the patient and plan for possible interventions, if needed. Additionally, before 3 years of age, every child should be referred to psychology, even if he/she is asymptomatic.¹⁰

Vascular Anomalies
Prior to intervening on a vascular anomaly, it is important to accurately classify the lesion. Once the lesion is classified, an evaluation and treatment plan can be developed. The International Society for the Study of Vascular Anomalies has published a detailed classification guide that is a useful starting point in the management of vascular anomalies.¹¹ Once a diagnosis is confirmed, further evaluation may include imaging, specialty referrals, genetic testing, biopsy, or blood tests, and a pediatric dermatologist usually helps to coordinate the care of patients with complex vascular anomalies.

Midline Lesions
Certain lesions in the midline may have a higher risk for neural tube dysraphism, and imaging should be performed prior to any procedural intervention.¹² Midline cutaneous findings that are highly likely to be associated with dysraphism are lipomas, acrochordons, pseudotails, true tails, aplasia cutis congenita, congenital scars, dermoid cysts, dermoid sinuses, and infantile hemangiomas that are greater than 2.5 cm in diameter. An MRI should be performed for all high-risk lesions. Intermediate-risk lesions are atypical dimples (>5 mm in diameter or >2.5 cm from the anal verge), hemangiomas less than 2.5 cm in diameter, and hypertrichosis. An ultrasound can screen for spinal dysraphism in these cases as long as imaging is performed prior to 6 months of age. If the child is older than 6 months, an MRI should be performed. Low-risk lesions that do not require imaging are simple dimples, hyperpigmentation, hypopigmentation, melanocytic nevi, port-wine stains, and telangiectases.

Epidermal Nevi
Children with epidermal nevi should have a complete physical examination, focusing on the skeletal system, central nervous system, and eyes. There are no specifically recommended imaging studies or referrals; however, several diagnostic clues can aid in the diagnosis of an epidermal nevus syndrome¹³:

• Schimmelpenning syndrome: extensive nevus sebaceous and bowing or pain in the legs after 2 years of age

• Phacomatosis pigmentokeratotica: nevus sebaceous and nevus spilus

• Nevus comedonicus syndrome: ipsilateral cataract

• Angora hair nevus syndrome: soft white hair within the nevus

• Becker nevus syndrome: breast hypoplasia

• Proteus syndrome: cerebriform plantar changes

• PIK3CA-related overgrowth spectrum: lipomas, macrodactyly, and/or vascular malformations

• Congenital hemidysplasia with ichthyosiform erythroderma and limb defects: inflammatory epidermal nevi, lateralization, ptychotropism, and ipsilateral limb defects

• Conradi-Hünermann-Happle syndrome: scaly red epidermal nevi without hair follicles and asymmetric limb shortening

Pilomatricomas
In addition to the tent sign—an angulated shape can be appreciated by stretching the skin overlying pilomatricomas—diagnosis of pilomatricoma can be confirmed by transillumination with an otoscope. In this case, a dark shadow typically is cast distal to where the otoscope touches the skin.¹⁴ In the case of multiple lesions, the patient should be evaluated for signs of myotonic dystrophy, Turner syndrome, and Gardner syndrome.¹⁵

Common Procedures

Pulsed Dye Laser
The pulsed dye laser is the most common laser used for red-colored lesions such as port-wine stains, facial telangiectases, and superficial hemangiomas. It also can be used to treat erythematous scars, verrucae, and psoriasis. In large vascular lesions, it typically is employed at 0.45 to 10 milliseconds every 4 to 6 weeks for 10 or more treatments. Port-wine stains preferably are treated within the first few months of life to provide the most fading without the need for general anesthesia.¹⁶ On the other hand, systemic therapy with propranolol is preferred over lasers for infantile hemangiomas.¹⁷

Long-Pulsed Alexandrite Laser (755 nm)
The alexandrite laser often is used to treat deeper vascular lesions such as venous lakes and hypertrophic port-wine stains. The operator needs to be cautious, as this laser has a higher incidence of scarring at the settings used to treat vascular lesions (typically fluences around 60–85 J/cm²).¹⁸ It also may be used for hair reduction in disorders with hypertrichosis or hidradenitis suppurativa.¹⁹

Long-Pulsed Nd:YAG Laser
The long-pulsed Nd:YAG laser also can be used to treat deep vascular lesions and remove unwanted hair. Because of its low window of safety in the treatment of vascular lesions, the alexandrite laser usually is preferred. However, it is the preferred laser for treatment of unwanted hair and hidradenitis suppurativa in darker skin types. It often provides a 50% reduction in hair density after 9 treatments.²⁰

Quality-Switched Lasers
Pigment granules in melanosomes and tattoo particles are targeted with quality-switched (QS) lasers. Typically, a device will contain a combination of QS 532-nm potassium-titanyl-phosphate (KTP) lasers, QS 1064-nm Nd:YAG lasers, and QS 755-nm alexandrite lasers in 1 machine. In general, shorter wavelengths are used to treat epidermal lesions such as ephelides, lentigines, and café-au-lait macules. Longer wavelengths are used to treat deeper lesions such as nevus of Ota. A 2017 review suggested that café-au-lait macules with ragged borders (so-called coast of Maine borders) may respond well to QS lasers.²¹

Ablative Lasers
The 10,600-nm CO₂ laser and 2940-nm erbium:YAG laser can be used to debulk superficial tumors such as lymphangiomas, syringomas, angiofibromas, and xanthomas.²² These treatments have a higher risk for scarring than other lasers, so it is important to have a good understanding of desired clinical end points before using these devices.

Fractionated Lasers
Fractionated lasers can be nonablative (several devices are available in the 1410- to 1927-nm range) or ablative (CO₂ or erbium:YAG). In pediatrics, they are usually used to treat burn scars, traumatic scars, and mild to moderate acne scarring.²² The most common side effects from fractionated lasers are prolonged erythema or hyperpigmentation. In addition, it typically takes at least 3 treatments to notice improvements.

Excisions

Pediatric procedural dermatologists remove a variety of unique lesions through excision. A few tips are provided for some of the more common lesions that may be excised in children.

Accessory Tragi
Prior to excising an accessory tragus, the surgeon should consider documenting a facial nerve examination, as accessory tragi can be associated with complete or partial facial nerve dysfunction. Additionally, there usually is an underlying cartilage structure present within the tragus. The cartilage stalk also should be addressed during the excision to avoid a continued palpable deformity after excision.

Dermoid Cysts
Dermoid cysts are the most commonly diagnosed benign orbital lesion in children.²³ Exophytic periorbital lesions, which extend outside the orbital rim, can be removed through an infrabrow incision. Endophytic periorbital lesions, which are inside the orbital rim, should be removed through a crease incision. Midline lesions may have an intracranial extension and should be imaged through MRI and/or a computed tomography.²⁴ Because dermoid cysts usually are located below the orbicularis oculi muscle, the muscle should be fixed with a suture prior to closing with skin sutures.

Pilomatricomas
Typically, a linear incision is made overlying the lesion, and then the underlying tumor is removed with sharp or blunt dissection. However, if the overlying skin has been stretched thin, a lenticular excision that includes the thinned skin may improve cosmesis.

Congenital Nevi
Large congenital nevi typically are removed through staged excisions. Lower extremity lesions are best removed before 10 months of age or before walking begins to minimize wound tension. However, if the procedure is not performed in infancy, it is best to wait until walking becomes stable.²⁵ In older children, it is advisable to splint the affected lower extremity for 2 weeks to prevent dehiscence. The interval between excisions typically is 4 to 6 weeks for small lesions and 3 months for larger nevi.

Conclusion

Procedural pediatric dermatology is a broad and emerging field. As this article highlights, children are not small versions of adults and have unique biology, diseases, therapies, social situations, and ethical challenges from adults. This article provides a superficial overview of some of the more common issues faced by pediatric dermatologists and providers who perform procedures on infants, children, and teenagers. Readers who are interested in obtaining a more in-depth understanding of procedural pediatric dermatology should look at Procedural Pediatric Dermatology,¹ the first textbook to provide expert opinion and evidence-based information on procedural management of pediatric skin conditions.

Performing dermatologic procedures in infants, children, and teenagers presents many unique challenges. There may be unique diagnoses, different instruments, differences in skin biology, or different approaches to pain management and anesthesia; the inclusion of a third party (caregivers) in decision processes; or a need to assess maturity level or to optimize outcomes over the patient’s lifetime. The field of pediatric procedural dermatology is broad. This article reviews some of the more common procedures performed by pediatric dermatologists and some of the more common ethical and quality-of-life (QOL) considerations one might face in procedural pediatric dermatology. (The textbook Procedural Pediatric Dermatology¹ offers a thorough discussion of this topic.)

Quality of Life

More often than not, procedures are performed in pediatric dermatology to improve QOL rather than to prevent morbidity or mortality. In the case of many self-limited conditions, such as ingrown nails or pyogenic granulomas, it is clear that intervention will improve the patient’s QOL. In the case of warts and molluscum contagiosum, emotional, social, and cultural considerations play a large role in determining whether an intervention will improve QOL. Finally, some conditions, such as genodermatoses, giant congenital melanocytic nevi, and large vascular malformations, may be associated with additional systemic symptoms and may not have good treatment options for cure. In these cases, procedural interventions will result in a mixture of positive and negative QOL outcomes that can occur at the same time.

Bemmels et al² published a qualitative study that provides a good foundation for understanding the positive and negative effects of procedural interventions on children and teenagers. In their study, children and teenagers who underwent reconstructive surgery for craniofacial differences noted improved self-esteem and reduced stigmatization. However, they also experienced negative outcomes, including an addiction to attaining a perfect surgical face, missing school for treatments, difficulty adjusting to an evolving appearance, anxiety related to not knowing when treatments will end, and experiencing stigma related to undergoing surgery.² Thus, a comprehensive plan for the management of children who need ongoing procedures should include some level of psychosocial support. Two good references on supporting young patients with visible differences include CBT for Appearance Anxiety: Psychosocial Interventions for Anxiety Due to Visible Difference³ and Reaching Teens: Strength-Based, Trauma-Sensitive, Resilience-Building Communication Strategies Rooted in Positive Youth Development.⁴

Ethics

Ethical decisions in pediatric procedural dermatology differ from adult dermatology in 3 major ways: (1) the involvement of a third party (ie, parents or legal guardians), (2) the need to assess the maturity of the patient, and (3) the need to know local laws in the jurisdiction in which care is being provided. Ethical dilemmas occur when the desires of the child, parents/guardians, and dermatologist are not in alignment. In these cases, it is important to be prepared with a moral or ethical framework to guide decision-making when conflicts occur. Two great resources are the best interest standard⁵ and the publication entitled, “Informed Consent in Decision-making in Pediatric Practice,” from the American Academy of Pediatrics.⁶

In pediatrics, it often is better to conceptualize medical decision-making as a combination of informed permission and assent of the patient rather than informed consent. Informed permission describes how a parent or surrogate makes decisions for the child or adolescent and is similar to informed consent. A parent’s informed permission may be in conflict with a child’s wishes, but it is assumed that the parent is acting in the best interest of the child. Assent of the patient is the process of obtaining a minor’s agreement to undergo an intervention even though he/she may lack legal authority or decision-making capacity to provide standard informed consent. It is important to respect the child’s right to assent to interventions to the extent that their maturity level permits to develop trust with the dermatologist and medical encounters in general.

These differences emphasize an active process in which the patient, caregiver, and physician are all involved in the health care process and allow for increasing inclusion of the child as is developmentally appropriate. In the end, however, parents have the legal authority to give or withhold permission for a procedure.⁷ When this conflicts with a child’s dissent, the dermatologist will need to objectively explore the reasons for the conflict and decide if a procedure is not in the child’s best interests. If a mutual understanding cannot be reached between the dermatologist and parents, obtaining a second opinion is a good option.⁸

Common Diagnoses

The most common diagnoses unique to procedural pediatric dermatology include congenital melanocytic nevi, vascular anomalies, midline lesions, epidermal nevi, and pilomatricomas. Prior to intervening on these lesions, it is important to consider evaluating for associated diseases.

Congenital Melanocytic Nevi
Nevus Outreach has published best practices for the management of congenital melanocytic nevi.⁹ In newborns with a congenital melanocytic nevus greater than 3 cm in diameter or more than 20 satellite lesions, it is recommended that magnetic resonance imaging (MRI) of the brain and spine with and without gadolinium contrast be obtained before 6 months of age. Within the first 6 months of life, these children also should see ophthalmologists, neurologists, pediatric dermatologists, and plastic surgeons. These early referrals will help to establish a baseline for the patient and plan for possible interventions, if needed. Additionally, before 3 years of age, every child should be referred to psychology, even if he/she is asymptomatic.¹⁰

Vascular Anomalies
Prior to intervening on a vascular anomaly, it is important to accurately classify the lesion. Once the lesion is classified, an evaluation and treatment plan can be developed. The International Society for the Study of Vascular Anomalies has published a detailed classification guide that is a useful starting point in the management of vascular anomalies.¹¹ Once a diagnosis is confirmed, further evaluation may include imaging, specialty referrals, genetic testing, biopsy, or blood tests, and a pediatric dermatologist usually helps to coordinate the care of patients with complex vascular anomalies.

Midline Lesions
Certain lesions in the midline may have a higher risk for neural tube dysraphism, and imaging should be performed prior to any procedural intervention.¹² Midline cutaneous findings that are highly likely to be associated with dysraphism are lipomas, acrochordons, pseudotails, true tails, aplasia cutis congenita, congenital scars, dermoid cysts, dermoid sinuses, and infantile hemangiomas that are greater than 2.5 cm in diameter. An MRI should be performed for all high-risk lesions. Intermediate-risk lesions are atypical dimples (>5 mm in diameter or >2.5 cm from the anal verge), hemangiomas less than 2.5 cm in diameter, and hypertrichosis. An ultrasound can screen for spinal dysraphism in these cases as long as imaging is performed prior to 6 months of age. If the child is older than 6 months, an MRI should be performed. Low-risk lesions that do not require imaging are simple dimples, hyperpigmentation, hypopigmentation, melanocytic nevi, port-wine stains, and telangiectases.

Epidermal Nevi
Children with epidermal nevi should have a complete physical examination, focusing on the skeletal system, central nervous system, and eyes. There are no specifically recommended imaging studies or referrals; however, several diagnostic clues can aid in the diagnosis of an epidermal nevus syndrome¹³:

• Schimmelpenning syndrome: extensive nevus sebaceous and bowing or pain in the legs after 2 years of age

• Phacomatosis pigmentokeratotica: nevus sebaceous and nevus spilus

• Nevus comedonicus syndrome: ipsilateral cataract

• Angora hair nevus syndrome: soft white hair within the nevus

• Becker nevus syndrome: breast hypoplasia

• Proteus syndrome: cerebriform plantar changes

• PIK3CA-related overgrowth spectrum: lipomas, macrodactyly, and/or vascular malformations

• Congenital hemidysplasia with ichthyosiform erythroderma and limb defects: inflammatory epidermal nevi, lateralization, ptychotropism, and ipsilateral limb defects

• Conradi-Hünermann-Happle syndrome: scaly red epidermal nevi without hair follicles and asymmetric limb shortening

Pilomatricomas
In addition to the tent sign—an angulated shape can be appreciated by stretching the skin overlying pilomatricomas—diagnosis of pilomatricoma can be confirmed by transillumination with an otoscope. In this case, a dark shadow typically is cast distal to where the otoscope touches the skin.¹⁴ In the case of multiple lesions, the patient should be evaluated for signs of myotonic dystrophy, Turner syndrome, and Gardner syndrome.¹⁵

Common Procedures

Pulsed Dye Laser
The pulsed dye laser is the most common laser used for red-colored lesions such as port-wine stains, facial telangiectases, and superficial hemangiomas. It also can be used to treat erythematous scars, verrucae, and psoriasis. In large vascular lesions, it typically is employed at 0.45 to 10 milliseconds every 4 to 6 weeks for 10 or more treatments. Port-wine stains preferably are treated within the first few months of life to provide the most fading without the need for general anesthesia.¹⁶ On the other hand, systemic therapy with propranolol is preferred over lasers for infantile hemangiomas.¹⁷

Long-Pulsed Alexandrite Laser (755 nm)
The alexandrite laser often is used to treat deeper vascular lesions such as venous lakes and hypertrophic port-wine stains. The operator needs to be cautious, as this laser has a higher incidence of scarring at the settings used to treat vascular lesions (typically fluences around 60–85 J/cm²).¹⁸ It also may be used for hair reduction in disorders with hypertrichosis or hidradenitis suppurativa.¹⁹

Long-Pulsed Nd:YAG Laser
The long-pulsed Nd:YAG laser also can be used to treat deep vascular lesions and remove unwanted hair. Because of its low window of safety in the treatment of vascular lesions, the alexandrite laser usually is preferred. However, it is the preferred laser for treatment of unwanted hair and hidradenitis suppurativa in darker skin types. It often provides a 50% reduction in hair density after 9 treatments.²⁰

Quality-Switched Lasers
Pigment granules in melanosomes and tattoo particles are targeted with quality-switched (QS) lasers. Typically, a device will contain a combination of QS 532-nm potassium-titanyl-phosphate (KTP) lasers, QS 1064-nm Nd:YAG lasers, and QS 755-nm alexandrite lasers in 1 machine. In general, shorter wavelengths are used to treat epidermal lesions such as ephelides, lentigines, and café-au-lait macules. Longer wavelengths are used to treat deeper lesions such as nevus of Ota. A 2017 review suggested that café-au-lait macules with ragged borders (so-called coast of Maine borders) may respond well to QS lasers.²¹

Ablative Lasers
The 10,600-nm CO₂ laser and 2940-nm erbium:YAG laser can be used to debulk superficial tumors such as lymphangiomas, syringomas, angiofibromas, and xanthomas.²² These treatments have a higher risk for scarring than other lasers, so it is important to have a good understanding of desired clinical end points before using these devices.

Fractionated Lasers
Fractionated lasers can be nonablative (several devices are available in the 1410- to 1927-nm range) or ablative (CO₂ or erbium:YAG). In pediatrics, they are usually used to treat burn scars, traumatic scars, and mild to moderate acne scarring.²² The most common side effects from fractionated lasers are prolonged erythema or hyperpigmentation. In addition, it typically takes at least 3 treatments to notice improvements.

Excisions

Pediatric procedural dermatologists remove a variety of unique lesions through excision. A few tips are provided for some of the more common lesions that may be excised in children.

Accessory Tragi
Prior to excising an accessory tragus, the surgeon should consider documenting a facial nerve examination, as accessory tragi can be associated with complete or partial facial nerve dysfunction. Additionally, there usually is an underlying cartilage structure present within the tragus. The cartilage stalk also should be addressed during the excision to avoid a continued palpable deformity after excision.

Dermoid Cysts
Dermoid cysts are the most commonly diagnosed benign orbital lesion in children.²³ Exophytic periorbital lesions, which extend outside the orbital rim, can be removed through an infrabrow incision. Endophytic periorbital lesions, which are inside the orbital rim, should be removed through a crease incision. Midline lesions may have an intracranial extension and should be imaged through MRI and/or a computed tomography.²⁴ Because dermoid cysts usually are located below the orbicularis oculi muscle, the muscle should be fixed with a suture prior to closing with skin sutures.

Pilomatricomas
Typically, a linear incision is made overlying the lesion, and then the underlying tumor is removed with sharp or blunt dissection. However, if the overlying skin has been stretched thin, a lenticular excision that includes the thinned skin may improve cosmesis.

Congenital Nevi
Large congenital nevi typically are removed through staged excisions. Lower extremity lesions are best removed before 10 months of age or before walking begins to minimize wound tension. However, if the procedure is not performed in infancy, it is best to wait until walking becomes stable.²⁵ In older children, it is advisable to splint the affected lower extremity for 2 weeks to prevent dehiscence. The interval between excisions typically is 4 to 6 weeks for small lesions and 3 months for larger nevi.

Conclusion

Procedural pediatric dermatology is a broad and emerging field. As this article highlights, children are not small versions of adults and have unique biology, diseases, therapies, social situations, and ethical challenges from adults. This article provides a superficial overview of some of the more common issues faced by pediatric dermatologists and providers who perform procedures on infants, children, and teenagers. Readers who are interested in obtaining a more in-depth understanding of procedural pediatric dermatology should look at Procedural Pediatric Dermatology,¹ the first textbook to provide expert opinion and evidence-based information on procedural management of pediatric skin conditions.

In November 2019, the American Academy of Dermatology (AAD) and the National Psoriasis Foundation (NPF) released their first set of recommendations for the management of pediatric psoriasis.¹ The pediatric guidelines discuss methods of quantifying disease severity in children, triggers and comorbidities, and the efficacy and safety of various therapeutic agents. This review aims to discuss, in a condensed form, special considerations unique to the management of children with psoriasis as presented in the guidelines as well as grade A– and grade B–level treatment recommendations (Table).

Quantifying Psoriasis Severity in Children

Percentage body surface area (BSA) involvement is the most common mode of grading psoriasis severity, with less than 3% BSA involvement being considered mild, 3% to 10% BSA moderate, and more than 10% severe disease. In children, the standard method of measuring BSA is the rule of 9’s: the head and each arm make up 9% of the total BSA, each leg and the front and back of the torso respectively each make up 18%, and the genitalia make up 1%. It also is important to consider impact on quality of life, which may be remarkable in spite of limited BSA involvement. The children’s dermatology life quality index score may be utilized in combination with affected BSA to determine the burden of psoriasis in context of impact on daily life. This metric is available in both written and cartoon form, and it consists of 10 questions that include variables such as severity of itch, impact on social life, and effects on sleep. Most notably, this tool incorporates pruritus,² which generally is addressed inadequately in pediatric psoriasis.

Triggers and Comorbidities in Pediatric Patients

In children, it is important to identify and eliminate modifiable factors that may prompt psoriasis flares. Infections, particularly group A beta-hemolytic streptococcal infections, are a major trigger in neonates and infants. Other exacerbating factors in children include emotional stress, secondhand cigarette smoke, Kawasaki disease, and withdrawal from systemic corticosteroids.

Psoriatic arthritis (PsA) is a burdensome comorbidity affecting children with psoriasis. The prevalence of joint disease is 15-times greater in children with psoriasis vs those without,³ and 80% of children with PsA develop rheumatologic symptoms, which typically include oligoarticular disease and dactylitis in infants and girls and enthesitis and axial joint involvement in boys and older children, years prior to the onset of cutaneous disease.⁴ Uveitis often occurs in children with psoriasis and PsA but not in those with isolated cutaneous disease.

Compared to unaffected children, pediatric patients with psoriasis have greater prevalence of metabolic and cardiovascular risk factors during childhood, including central obesity, hypertension, hypertriglyceridemia, hypercholesterolemia, insulin resistance, atherosclerosis, arrythmia, and valvular heart disease. Family history of obesity increases the risk for early-onset development of cutaneous lesions,^5,6 and weight reduction may alleviate severity of psoriasis lesions.⁷ In the United States, many of the metabolic associations observed are particularly robust in Black and Hispanic children vs those of other races. Furthermore, the prevalence of inflammatory bowel disease is 3- to 4-times higher in children with psoriasis compared to those without.

As with other cutaneous diseases, it is important to be aware of social and mental health concerns in children with psoriasis. The majority of pediatric patients with psoriasis experience name-calling, shaming, or bullying, and many have concerns from skin shedding and malodor. Independent risk for depression after the onset of psoriasis is high. Affected older children and adolescents are at increased risk for alcohol and drug abuse as well as eating disorders.

Despite these identified comorbidities, there are no unique screening recommendations for arthritis, ophthalmologic disease, metabolic disease, cardiovascular disease, gastrointestinal tract disease, or mental health issues in children with psoriasis. Rather, these patients should be monitored according to the American Academy of Pediatrics or American Diabetes Association guidelines for all pediatric patients.^8,9 Nonetheless, educating patients and guardians about these potential issues may be warranted.

Topical Therapies

For children with mild to moderate psoriasis, topical therapies are first line. Despite being off label, topical corticosteroids are the mainstay of therapy for localized psoriatic plaques in children. Topical vitamin D analogues—calcitriol and calcipotriol/calcipotriene—are highly effective and well tolerated, and they frequently are used in combination with topical corticosteroids. Topical calcineurin inhibitors, namely tacrolimus, also are used off label but are considered first line for sensitive regions of the skin in children, including the face, genitalia, and body folds. There currently is limited evidence for supporting the use of the topical vitamin A analogue tazarotene in children with psoriasis, though some consider its off-label use effective for pediatric nail psoriasis. It also may be used as an adjunct to topical corticosteroids to minimize irritation.

Although there is no gold standard topical regimen, combination therapy with a high-potency topical steroid and topical vitamin D analogue commonly is used to minimize steroid-induced side effects. For the first 2 weeks of treatment, they each may be applied once daily or mixed together and applied twice daily. For subsequent maintenance, topical calcipotriene may be applied on weekdays and topical steroids only on weekends. Combination calcipotriol–betamethasone dipropionate also is available as cream, ointment, foam, and suspension vehicles for use on the body and scalp in children aged 12 years and older. Tacrolimus ointment 0.1% may be applied in a thin layer up to twice daily. Concurrent emollient use also is recommended with these therapies.

Health care providers should educate patients and guardians about the potential side effects of topical therapies. They also should provide explicit instructions for amount, site, frequency, and duration of application. Topical corticosteroids commonly result in burning on application and may potentially cause skin thinning and striae with overuse. Topical vitamin D analogues may result in local irritation that may be improved by concurrent emollient use, and they generally should be avoided on sensitive sites. Topical calcineurin inhibitors are associated with burning, stinging, and pruritus, and the US Food and Drug Administration has issued a black-box warning related to risk for lymphoma with their chronic intermittent use. However, it was based on rare reports of lymphoma in transplant patients taking oral calcineurin inhibitors; no clinical trials to date in humans have demonstrated an increased risk for malignancy with topical calcineurin inhibitors.¹⁰ Tazarotene should be used cautiously in females of childbearing age given its teratogenic potential.

Children younger than 7 years are especially prone to suppression of the hypothalamic-pituitary-adrenal axis from topical corticosteroid therapy and theoretically hypercalcemia and hypervitaminosis D from topical vitamin D analogues, as their high BSA-to-volume ratio increases potential for systemic absorption. Children should avoid occlusive application of topical vitamin D analogues to large areas of the skin. Monitoring of vitamin D metabolites in the serum may be considered if calcipotriene or calcipotriol application to a large BSA is warranted.

Light-Based Therapy

In children with widespread psoriasis or those refractory to topical therapy, phototherapy may be considered. Narrowband UVB (311- to 313-nm wavelength) therapy is considered a first-line form of phototherapy in pediatric psoriasis. Mineral oil or emollient pretreatment to affected areas may augment the efficacy of UV-based treatments.¹¹ Excimer laser and UVA also may be efficacious, though evidence is limited in children. Treatment is recommended to start at 3 days a week, and once improvement is seen, the frequency can be decreased to 2 days a week. Once desired clearance is achieved, maintenance therapy can be continued at even longer intervals. Adjunctive use of tar preparations may potentiate the efficacy of phototherapy, though there is a theoretical increased risk for carcinogenicity with prolonged use of coal tar. Side effects of phototherapy include erythema, blistering hyperpigmentation, and pruritus. Psoralen is contraindicated in children younger than 12 years. All forms of phototherapy are contraindicated in children with generalized erythroderma and cutaneous cancer syndromes. Other important pediatric-specific considerations include anxiety that may be provoked by UV light machines and inconvenience of frequent appointments.

Nonbiologic Systemic Therapies

Systemic therapies may be considered in children with recalcitrant, widespread, or rapidly progressing psoriasis, particularly if the disease is accompanied by severe emotional and psychological burden. These drugs, which include methotrexate, cyclosporine, and acitretin (see eTable for recommended dosing), are advantageous in that they may be combined with other therapies; however, they have potential for dangerous toxicities.

Methotrexate is the most frequently utilized systemic therapy for psoriasis worldwide in children because of its low cost, once-weekly dosing, and the substantial amount of long-term efficacy and safety data available in the pediatric population. It is slow acting initially but has excellent long-term efficacy for nearly every subtype of psoriasis. The most common side effect of methotrexate is gastrointestinal tract intolerance. Nonetheless, adverse events are rare in children without prior history, with 1 large study (N=289) reporting no adverse events in more than 90% of patients aged 9 to 14 years treated with methotrexate.¹² Current guidelines recommend monitoring for bone marrow suppression and elevated transaminase levels 4 to 6 days after initiating treatment.¹ The absolute contraindications for methotrexate are pregnancy and liver disease, and caution should be taken in children with metabolic risk factors. Adolescents must be counseled regarding the elevated risk for hepatotoxicity associated with alcohol ingestion. Methotrexate therapy also requires 1 mg folic acid supplementation 6 to 7 days a week, which decreases the risk for developing folic acid deficiency and may decrease gastrointestinal tract intolerance and hepatic side effects that may result from therapy.

Cyclosporine is an effective and well-tolerated option for rapid control of severe psoriasis in children. It is useful for various types of psoriasis but generally is reserved for more severe subtypes, such as generalized pustular psoriasis, erythrodermic psoriasis, and uncontrolled plaque psoriasis. Long-term use of cyclosporine may result in renal toxicity and hypertension, and this therapy is absolutely contraindicated in children with kidney disease or hypertension at baseline. It is strongly recommended to evaluate blood pressure every week for the first month of therapy and at every subsequent follow-up visit, which may occur at variable intervals based on the judgement of the provider. Evaluation before and during treatment with cyclosporine also should include a complete blood cell count, complete metabolic panel, and lipid panel.

Systemic retinoids have a unique advantage over methotrexate and cyclosporine in that they are not immunosuppressive and therefore are not contraindicated in children who are very young or immunosuppressed. Children receiving systemic retinoids also can receive routine live vaccines—measles-mumps-rubella, varicella zoster, and rotavirus—that are contraindicated with other systemic therapies. Acitretin is particularly effective in pediatric patients with diffuse guttate psoriasis, pustular psoriasis, and palmoplantar psoriasis. Narrowband UVB therapy has been shown to augment the effectiveness of acitretin in children, which may allow for reduced acitretin dosing. Pustular psoriasis may respond as quickly as 3 weeks after initiation, whereas it may take 2 to 3 months before improvement is noticed in plaque psoriasis. Side effects of retinoids include skin dryness, hyperlipidemia, and gastrointestinal tract upset. The most severe long-term concern is skeletal toxicity, including premature epiphyseal closure, hyperostosis, periosteal bone formation, and decreased bone mineral density.¹ Vitamin A derivatives also are known teratogens and should be avoided in females of childbearing potential. Lipids and transaminases should be monitored routinely, and screening for depression and psychiatric symptoms should be performed frequently.¹

When utilizing systemic therapies, the objective should be to control the disease, maintain stability, and ultimately taper to the lowest effective dose or transition to a topical therapy, if feasible. Although no particular systemic therapy is recommended as first line for children with psoriasis, it is important to consider comorbidities, contraindications, monitoring frequency, mode of administration (injectable therapies elicit more psychological trauma in children than oral therapies), and expense when determining the best choice.

Biologics

Biologic agents are associated with very high to total psoriatic plaque clearance rates and require infrequent dosing and monitoring. However, their use may be limited by cost and injection phobias in children as well as limited evidence for their efficacy and safety in pediatric psoriasis. Several studies have established the safety and effectiveness of biologics in children with plaque psoriasis (see eTable for recommended dosing), whereas the evidence supporting their use in treating pustular and erythrodermic variants are limited to case reports and case series. The tumor necrosis factor α (TNF-α) inhibitor etanercept has been approved for use in children aged 4 years and older, and the IL-12/IL-23 inhibitor ustekinumab is approved in children aged 6 years and older. Other TNF-α inhibitors, namely infliximab and adalimumab, commonly are utilized off label for pediatric psoriasis. The most common side effect of biologic therapies in pediatric patients is injection-site reactions.¹ Prior to initiating therapy, children must undergo tuberculosis screening either by purified protein derivative testing or IFN-γ release assay. Testing should be repeated annually in individuals taking TNF-α inhibitors, though the utility of repeat testing when taking biologics in other classes is not clear. High-risk patients also should be screened for human immunodeficiency virus and hepatitis. Follow-up frequency may range from every 3 months to annually, based on judgement of the provider. In children who develop loss of response to biologics, methotrexate can be added to the regimen to attenuate formation of efficacy-reducing antidrug antibodies.

Final Thoughts

When managing children with psoriasis, it is important for dermatologists to appropriately educate guardians and children on the disease course, as well as consider the psychological, emotional, social, and financial factors that may direct decision-making regarding optimal therapeutics. Dermatologists should consider collaboration with the child’s primary care physician and other specialists to ensure that all needs are met.

These guidelines provide a framework agreed upon by numerous experts in pediatric psoriasis, but they are limited by gaps in the research. There still is much to be learned regarding the pathophysiology of psoriasis; the risk for developing comorbidities during adulthood; and the efficacy and safety of certain therapeutics, particularly biologics, in pediatric patients with psoriasis.

In November 2019, the American Academy of Dermatology (AAD) and the National Psoriasis Foundation (NPF) released their first set of recommendations for the management of pediatric psoriasis.¹ The pediatric guidelines discuss methods of quantifying disease severity in children, triggers and comorbidities, and the efficacy and safety of various therapeutic agents. This review aims to discuss, in a condensed form, special considerations unique to the management of children with psoriasis as presented in the guidelines as well as grade A– and grade B–level treatment recommendations (Table).

Quantifying Psoriasis Severity in Children

Percentage body surface area (BSA) involvement is the most common mode of grading psoriasis severity, with less than 3% BSA involvement being considered mild, 3% to 10% BSA moderate, and more than 10% severe disease. In children, the standard method of measuring BSA is the rule of 9’s: the head and each arm make up 9% of the total BSA, each leg and the front and back of the torso respectively each make up 18%, and the genitalia make up 1%. It also is important to consider impact on quality of life, which may be remarkable in spite of limited BSA involvement. The children’s dermatology life quality index score may be utilized in combination with affected BSA to determine the burden of psoriasis in context of impact on daily life. This metric is available in both written and cartoon form, and it consists of 10 questions that include variables such as severity of itch, impact on social life, and effects on sleep. Most notably, this tool incorporates pruritus,² which generally is addressed inadequately in pediatric psoriasis.

Triggers and Comorbidities in Pediatric Patients

In children, it is important to identify and eliminate modifiable factors that may prompt psoriasis flares. Infections, particularly group A beta-hemolytic streptococcal infections, are a major trigger in neonates and infants. Other exacerbating factors in children include emotional stress, secondhand cigarette smoke, Kawasaki disease, and withdrawal from systemic corticosteroids.

Psoriatic arthritis (PsA) is a burdensome comorbidity affecting children with psoriasis. The prevalence of joint disease is 15-times greater in children with psoriasis vs those without,³ and 80% of children with PsA develop rheumatologic symptoms, which typically include oligoarticular disease and dactylitis in infants and girls and enthesitis and axial joint involvement in boys and older children, years prior to the onset of cutaneous disease.⁴ Uveitis often occurs in children with psoriasis and PsA but not in those with isolated cutaneous disease.

Compared to unaffected children, pediatric patients with psoriasis have greater prevalence of metabolic and cardiovascular risk factors during childhood, including central obesity, hypertension, hypertriglyceridemia, hypercholesterolemia, insulin resistance, atherosclerosis, arrythmia, and valvular heart disease. Family history of obesity increases the risk for early-onset development of cutaneous lesions,^5,6 and weight reduction may alleviate severity of psoriasis lesions.⁷ In the United States, many of the metabolic associations observed are particularly robust in Black and Hispanic children vs those of other races. Furthermore, the prevalence of inflammatory bowel disease is 3- to 4-times higher in children with psoriasis compared to those without.

As with other cutaneous diseases, it is important to be aware of social and mental health concerns in children with psoriasis. The majority of pediatric patients with psoriasis experience name-calling, shaming, or bullying, and many have concerns from skin shedding and malodor. Independent risk for depression after the onset of psoriasis is high. Affected older children and adolescents are at increased risk for alcohol and drug abuse as well as eating disorders.

Despite these identified comorbidities, there are no unique screening recommendations for arthritis, ophthalmologic disease, metabolic disease, cardiovascular disease, gastrointestinal tract disease, or mental health issues in children with psoriasis. Rather, these patients should be monitored according to the American Academy of Pediatrics or American Diabetes Association guidelines for all pediatric patients.^8,9 Nonetheless, educating patients and guardians about these potential issues may be warranted.

Topical Therapies

For children with mild to moderate psoriasis, topical therapies are first line. Despite being off label, topical corticosteroids are the mainstay of therapy for localized psoriatic plaques in children. Topical vitamin D analogues—calcitriol and calcipotriol/calcipotriene—are highly effective and well tolerated, and they frequently are used in combination with topical corticosteroids. Topical calcineurin inhibitors, namely tacrolimus, also are used off label but are considered first line for sensitive regions of the skin in children, including the face, genitalia, and body folds. There currently is limited evidence for supporting the use of the topical vitamin A analogue tazarotene in children with psoriasis, though some consider its off-label use effective for pediatric nail psoriasis. It also may be used as an adjunct to topical corticosteroids to minimize irritation.

Although there is no gold standard topical regimen, combination therapy with a high-potency topical steroid and topical vitamin D analogue commonly is used to minimize steroid-induced side effects. For the first 2 weeks of treatment, they each may be applied once daily or mixed together and applied twice daily. For subsequent maintenance, topical calcipotriene may be applied on weekdays and topical steroids only on weekends. Combination calcipotriol–betamethasone dipropionate also is available as cream, ointment, foam, and suspension vehicles for use on the body and scalp in children aged 12 years and older. Tacrolimus ointment 0.1% may be applied in a thin layer up to twice daily. Concurrent emollient use also is recommended with these therapies.

Health care providers should educate patients and guardians about the potential side effects of topical therapies. They also should provide explicit instructions for amount, site, frequency, and duration of application. Topical corticosteroids commonly result in burning on application and may potentially cause skin thinning and striae with overuse. Topical vitamin D analogues may result in local irritation that may be improved by concurrent emollient use, and they generally should be avoided on sensitive sites. Topical calcineurin inhibitors are associated with burning, stinging, and pruritus, and the US Food and Drug Administration has issued a black-box warning related to risk for lymphoma with their chronic intermittent use. However, it was based on rare reports of lymphoma in transplant patients taking oral calcineurin inhibitors; no clinical trials to date in humans have demonstrated an increased risk for malignancy with topical calcineurin inhibitors.¹⁰ Tazarotene should be used cautiously in females of childbearing age given its teratogenic potential.

Children younger than 7 years are especially prone to suppression of the hypothalamic-pituitary-adrenal axis from topical corticosteroid therapy and theoretically hypercalcemia and hypervitaminosis D from topical vitamin D analogues, as their high BSA-to-volume ratio increases potential for systemic absorption. Children should avoid occlusive application of topical vitamin D analogues to large areas of the skin. Monitoring of vitamin D metabolites in the serum may be considered if calcipotriene or calcipotriol application to a large BSA is warranted.

Light-Based Therapy

In children with widespread psoriasis or those refractory to topical therapy, phototherapy may be considered. Narrowband UVB (311- to 313-nm wavelength) therapy is considered a first-line form of phototherapy in pediatric psoriasis. Mineral oil or emollient pretreatment to affected areas may augment the efficacy of UV-based treatments.¹¹ Excimer laser and UVA also may be efficacious, though evidence is limited in children. Treatment is recommended to start at 3 days a week, and once improvement is seen, the frequency can be decreased to 2 days a week. Once desired clearance is achieved, maintenance therapy can be continued at even longer intervals. Adjunctive use of tar preparations may potentiate the efficacy of phototherapy, though there is a theoretical increased risk for carcinogenicity with prolonged use of coal tar. Side effects of phototherapy include erythema, blistering hyperpigmentation, and pruritus. Psoralen is contraindicated in children younger than 12 years. All forms of phototherapy are contraindicated in children with generalized erythroderma and cutaneous cancer syndromes. Other important pediatric-specific considerations include anxiety that may be provoked by UV light machines and inconvenience of frequent appointments.

Nonbiologic Systemic Therapies

Systemic therapies may be considered in children with recalcitrant, widespread, or rapidly progressing psoriasis, particularly if the disease is accompanied by severe emotional and psychological burden. These drugs, which include methotrexate, cyclosporine, and acitretin (see eTable for recommended dosing), are advantageous in that they may be combined with other therapies; however, they have potential for dangerous toxicities.

Methotrexate is the most frequently utilized systemic therapy for psoriasis worldwide in children because of its low cost, once-weekly dosing, and the substantial amount of long-term efficacy and safety data available in the pediatric population. It is slow acting initially but has excellent long-term efficacy for nearly every subtype of psoriasis. The most common side effect of methotrexate is gastrointestinal tract intolerance. Nonetheless, adverse events are rare in children without prior history, with 1 large study (N=289) reporting no adverse events in more than 90% of patients aged 9 to 14 years treated with methotrexate.¹² Current guidelines recommend monitoring for bone marrow suppression and elevated transaminase levels 4 to 6 days after initiating treatment.¹ The absolute contraindications for methotrexate are pregnancy and liver disease, and caution should be taken in children with metabolic risk factors. Adolescents must be counseled regarding the elevated risk for hepatotoxicity associated with alcohol ingestion. Methotrexate therapy also requires 1 mg folic acid supplementation 6 to 7 days a week, which decreases the risk for developing folic acid deficiency and may decrease gastrointestinal tract intolerance and hepatic side effects that may result from therapy.

Cyclosporine is an effective and well-tolerated option for rapid control of severe psoriasis in children. It is useful for various types of psoriasis but generally is reserved for more severe subtypes, such as generalized pustular psoriasis, erythrodermic psoriasis, and uncontrolled plaque psoriasis. Long-term use of cyclosporine may result in renal toxicity and hypertension, and this therapy is absolutely contraindicated in children with kidney disease or hypertension at baseline. It is strongly recommended to evaluate blood pressure every week for the first month of therapy and at every subsequent follow-up visit, which may occur at variable intervals based on the judgement of the provider. Evaluation before and during treatment with cyclosporine also should include a complete blood cell count, complete metabolic panel, and lipid panel.

Systemic retinoids have a unique advantage over methotrexate and cyclosporine in that they are not immunosuppressive and therefore are not contraindicated in children who are very young or immunosuppressed. Children receiving systemic retinoids also can receive routine live vaccines—measles-mumps-rubella, varicella zoster, and rotavirus—that are contraindicated with other systemic therapies. Acitretin is particularly effective in pediatric patients with diffuse guttate psoriasis, pustular psoriasis, and palmoplantar psoriasis. Narrowband UVB therapy has been shown to augment the effectiveness of acitretin in children, which may allow for reduced acitretin dosing. Pustular psoriasis may respond as quickly as 3 weeks after initiation, whereas it may take 2 to 3 months before improvement is noticed in plaque psoriasis. Side effects of retinoids include skin dryness, hyperlipidemia, and gastrointestinal tract upset. The most severe long-term concern is skeletal toxicity, including premature epiphyseal closure, hyperostosis, periosteal bone formation, and decreased bone mineral density.¹ Vitamin A derivatives also are known teratogens and should be avoided in females of childbearing potential. Lipids and transaminases should be monitored routinely, and screening for depression and psychiatric symptoms should be performed frequently.¹

When utilizing systemic therapies, the objective should be to control the disease, maintain stability, and ultimately taper to the lowest effective dose or transition to a topical therapy, if feasible. Although no particular systemic therapy is recommended as first line for children with psoriasis, it is important to consider comorbidities, contraindications, monitoring frequency, mode of administration (injectable therapies elicit more psychological trauma in children than oral therapies), and expense when determining the best choice.

Biologics

Biologic agents are associated with very high to total psoriatic plaque clearance rates and require infrequent dosing and monitoring. However, their use may be limited by cost and injection phobias in children as well as limited evidence for their efficacy and safety in pediatric psoriasis. Several studies have established the safety and effectiveness of biologics in children with plaque psoriasis (see eTable for recommended dosing), whereas the evidence supporting their use in treating pustular and erythrodermic variants are limited to case reports and case series. The tumor necrosis factor α (TNF-α) inhibitor etanercept has been approved for use in children aged 4 years and older, and the IL-12/IL-23 inhibitor ustekinumab is approved in children aged 6 years and older. Other TNF-α inhibitors, namely infliximab and adalimumab, commonly are utilized off label for pediatric psoriasis. The most common side effect of biologic therapies in pediatric patients is injection-site reactions.¹ Prior to initiating therapy, children must undergo tuberculosis screening either by purified protein derivative testing or IFN-γ release assay. Testing should be repeated annually in individuals taking TNF-α inhibitors, though the utility of repeat testing when taking biologics in other classes is not clear. High-risk patients also should be screened for human immunodeficiency virus and hepatitis. Follow-up frequency may range from every 3 months to annually, based on judgement of the provider. In children who develop loss of response to biologics, methotrexate can be added to the regimen to attenuate formation of efficacy-reducing antidrug antibodies.

Final Thoughts

When managing children with psoriasis, it is important for dermatologists to appropriately educate guardians and children on the disease course, as well as consider the psychological, emotional, social, and financial factors that may direct decision-making regarding optimal therapeutics. Dermatologists should consider collaboration with the child’s primary care physician and other specialists to ensure that all needs are met.

These guidelines provide a framework agreed upon by numerous experts in pediatric psoriasis, but they are limited by gaps in the research. There still is much to be learned regarding the pathophysiology of psoriasis; the risk for developing comorbidities during adulthood; and the efficacy and safety of certain therapeutics, particularly biologics, in pediatric patients with psoriasis.

In November 2019, the American Academy of Dermatology (AAD) and the National Psoriasis Foundation (NPF) released their first set of recommendations for the management of pediatric psoriasis.¹ The pediatric guidelines discuss methods of quantifying disease severity in children, triggers and comorbidities, and the efficacy and safety of various therapeutic agents. This review aims to discuss, in a condensed form, special considerations unique to the management of children with psoriasis as presented in the guidelines as well as grade A– and grade B–level treatment recommendations (Table).

Quantifying Psoriasis Severity in Children

Percentage body surface area (BSA) involvement is the most common mode of grading psoriasis severity, with less than 3% BSA involvement being considered mild, 3% to 10% BSA moderate, and more than 10% severe disease. In children, the standard method of measuring BSA is the rule of 9’s: the head and each arm make up 9% of the total BSA, each leg and the front and back of the torso respectively each make up 18%, and the genitalia make up 1%. It also is important to consider impact on quality of life, which may be remarkable in spite of limited BSA involvement. The children’s dermatology life quality index score may be utilized in combination with affected BSA to determine the burden of psoriasis in context of impact on daily life. This metric is available in both written and cartoon form, and it consists of 10 questions that include variables such as severity of itch, impact on social life, and effects on sleep. Most notably, this tool incorporates pruritus,² which generally is addressed inadequately in pediatric psoriasis.

Triggers and Comorbidities in Pediatric Patients

In children, it is important to identify and eliminate modifiable factors that may prompt psoriasis flares. Infections, particularly group A beta-hemolytic streptococcal infections, are a major trigger in neonates and infants. Other exacerbating factors in children include emotional stress, secondhand cigarette smoke, Kawasaki disease, and withdrawal from systemic corticosteroids.

Psoriatic arthritis (PsA) is a burdensome comorbidity affecting children with psoriasis. The prevalence of joint disease is 15-times greater in children with psoriasis vs those without,³ and 80% of children with PsA develop rheumatologic symptoms, which typically include oligoarticular disease and dactylitis in infants and girls and enthesitis and axial joint involvement in boys and older children, years prior to the onset of cutaneous disease.⁴ Uveitis often occurs in children with psoriasis and PsA but not in those with isolated cutaneous disease.

Compared to unaffected children, pediatric patients with psoriasis have greater prevalence of metabolic and cardiovascular risk factors during childhood, including central obesity, hypertension, hypertriglyceridemia, hypercholesterolemia, insulin resistance, atherosclerosis, arrythmia, and valvular heart disease. Family history of obesity increases the risk for early-onset development of cutaneous lesions,^5,6 and weight reduction may alleviate severity of psoriasis lesions.⁷ In the United States, many of the metabolic associations observed are particularly robust in Black and Hispanic children vs those of other races. Furthermore, the prevalence of inflammatory bowel disease is 3- to 4-times higher in children with psoriasis compared to those without.

As with other cutaneous diseases, it is important to be aware of social and mental health concerns in children with psoriasis. The majority of pediatric patients with psoriasis experience name-calling, shaming, or bullying, and many have concerns from skin shedding and malodor. Independent risk for depression after the onset of psoriasis is high. Affected older children and adolescents are at increased risk for alcohol and drug abuse as well as eating disorders.

Despite these identified comorbidities, there are no unique screening recommendations for arthritis, ophthalmologic disease, metabolic disease, cardiovascular disease, gastrointestinal tract disease, or mental health issues in children with psoriasis. Rather, these patients should be monitored according to the American Academy of Pediatrics or American Diabetes Association guidelines for all pediatric patients.^8,9 Nonetheless, educating patients and guardians about these potential issues may be warranted.

Topical Therapies

For children with mild to moderate psoriasis, topical therapies are first line. Despite being off label, topical corticosteroids are the mainstay of therapy for localized psoriatic plaques in children. Topical vitamin D analogues—calcitriol and calcipotriol/calcipotriene—are highly effective and well tolerated, and they frequently are used in combination with topical corticosteroids. Topical calcineurin inhibitors, namely tacrolimus, also are used off label but are considered first line for sensitive regions of the skin in children, including the face, genitalia, and body folds. There currently is limited evidence for supporting the use of the topical vitamin A analogue tazarotene in children with psoriasis, though some consider its off-label use effective for pediatric nail psoriasis. It also may be used as an adjunct to topical corticosteroids to minimize irritation.

Although there is no gold standard topical regimen, combination therapy with a high-potency topical steroid and topical vitamin D analogue commonly is used to minimize steroid-induced side effects. For the first 2 weeks of treatment, they each may be applied once daily or mixed together and applied twice daily. For subsequent maintenance, topical calcipotriene may be applied on weekdays and topical steroids only on weekends. Combination calcipotriol–betamethasone dipropionate also is available as cream, ointment, foam, and suspension vehicles for use on the body and scalp in children aged 12 years and older. Tacrolimus ointment 0.1% may be applied in a thin layer up to twice daily. Concurrent emollient use also is recommended with these therapies.

Health care providers should educate patients and guardians about the potential side effects of topical therapies. They also should provide explicit instructions for amount, site, frequency, and duration of application. Topical corticosteroids commonly result in burning on application and may potentially cause skin thinning and striae with overuse. Topical vitamin D analogues may result in local irritation that may be improved by concurrent emollient use, and they generally should be avoided on sensitive sites. Topical calcineurin inhibitors are associated with burning, stinging, and pruritus, and the US Food and Drug Administration has issued a black-box warning related to risk for lymphoma with their chronic intermittent use. However, it was based on rare reports of lymphoma in transplant patients taking oral calcineurin inhibitors; no clinical trials to date in humans have demonstrated an increased risk for malignancy with topical calcineurin inhibitors.¹⁰ Tazarotene should be used cautiously in females of childbearing age given its teratogenic potential.

Children younger than 7 years are especially prone to suppression of the hypothalamic-pituitary-adrenal axis from topical corticosteroid therapy and theoretically hypercalcemia and hypervitaminosis D from topical vitamin D analogues, as their high BSA-to-volume ratio increases potential for systemic absorption. Children should avoid occlusive application of topical vitamin D analogues to large areas of the skin. Monitoring of vitamin D metabolites in the serum may be considered if calcipotriene or calcipotriol application to a large BSA is warranted.

Light-Based Therapy

In children with widespread psoriasis or those refractory to topical therapy, phototherapy may be considered. Narrowband UVB (311- to 313-nm wavelength) therapy is considered a first-line form of phototherapy in pediatric psoriasis. Mineral oil or emollient pretreatment to affected areas may augment the efficacy of UV-based treatments.¹¹ Excimer laser and UVA also may be efficacious, though evidence is limited in children. Treatment is recommended to start at 3 days a week, and once improvement is seen, the frequency can be decreased to 2 days a week. Once desired clearance is achieved, maintenance therapy can be continued at even longer intervals. Adjunctive use of tar preparations may potentiate the efficacy of phototherapy, though there is a theoretical increased risk for carcinogenicity with prolonged use of coal tar. Side effects of phototherapy include erythema, blistering hyperpigmentation, and pruritus. Psoralen is contraindicated in children younger than 12 years. All forms of phototherapy are contraindicated in children with generalized erythroderma and cutaneous cancer syndromes. Other important pediatric-specific considerations include anxiety that may be provoked by UV light machines and inconvenience of frequent appointments.

Nonbiologic Systemic Therapies

Systemic therapies may be considered in children with recalcitrant, widespread, or rapidly progressing psoriasis, particularly if the disease is accompanied by severe emotional and psychological burden. These drugs, which include methotrexate, cyclosporine, and acitretin (see eTable for recommended dosing), are advantageous in that they may be combined with other therapies; however, they have potential for dangerous toxicities.

Methotrexate is the most frequently utilized systemic therapy for psoriasis worldwide in children because of its low cost, once-weekly dosing, and the substantial amount of long-term efficacy and safety data available in the pediatric population. It is slow acting initially but has excellent long-term efficacy for nearly every subtype of psoriasis. The most common side effect of methotrexate is gastrointestinal tract intolerance. Nonetheless, adverse events are rare in children without prior history, with 1 large study (N=289) reporting no adverse events in more than 90% of patients aged 9 to 14 years treated with methotrexate.¹² Current guidelines recommend monitoring for bone marrow suppression and elevated transaminase levels 4 to 6 days after initiating treatment.¹ The absolute contraindications for methotrexate are pregnancy and liver disease, and caution should be taken in children with metabolic risk factors. Adolescents must be counseled regarding the elevated risk for hepatotoxicity associated with alcohol ingestion. Methotrexate therapy also requires 1 mg folic acid supplementation 6 to 7 days a week, which decreases the risk for developing folic acid deficiency and may decrease gastrointestinal tract intolerance and hepatic side effects that may result from therapy.

Cyclosporine is an effective and well-tolerated option for rapid control of severe psoriasis in children. It is useful for various types of psoriasis but generally is reserved for more severe subtypes, such as generalized pustular psoriasis, erythrodermic psoriasis, and uncontrolled plaque psoriasis. Long-term use of cyclosporine may result in renal toxicity and hypertension, and this therapy is absolutely contraindicated in children with kidney disease or hypertension at baseline. It is strongly recommended to evaluate blood pressure every week for the first month of therapy and at every subsequent follow-up visit, which may occur at variable intervals based on the judgement of the provider. Evaluation before and during treatment with cyclosporine also should include a complete blood cell count, complete metabolic panel, and lipid panel.

Systemic retinoids have a unique advantage over methotrexate and cyclosporine in that they are not immunosuppressive and therefore are not contraindicated in children who are very young or immunosuppressed. Children receiving systemic retinoids also can receive routine live vaccines—measles-mumps-rubella, varicella zoster, and rotavirus—that are contraindicated with other systemic therapies. Acitretin is particularly effective in pediatric patients with diffuse guttate psoriasis, pustular psoriasis, and palmoplantar psoriasis. Narrowband UVB therapy has been shown to augment the effectiveness of acitretin in children, which may allow for reduced acitretin dosing. Pustular psoriasis may respond as quickly as 3 weeks after initiation, whereas it may take 2 to 3 months before improvement is noticed in plaque psoriasis. Side effects of retinoids include skin dryness, hyperlipidemia, and gastrointestinal tract upset. The most severe long-term concern is skeletal toxicity, including premature epiphyseal closure, hyperostosis, periosteal bone formation, and decreased bone mineral density.¹ Vitamin A derivatives also are known teratogens and should be avoided in females of childbearing potential. Lipids and transaminases should be monitored routinely, and screening for depression and psychiatric symptoms should be performed frequently.¹

When utilizing systemic therapies, the objective should be to control the disease, maintain stability, and ultimately taper to the lowest effective dose or transition to a topical therapy, if feasible. Although no particular systemic therapy is recommended as first line for children with psoriasis, it is important to consider comorbidities, contraindications, monitoring frequency, mode of administration (injectable therapies elicit more psychological trauma in children than oral therapies), and expense when determining the best choice.

Biologics

Biologic agents are associated with very high to total psoriatic plaque clearance rates and require infrequent dosing and monitoring. However, their use may be limited by cost and injection phobias in children as well as limited evidence for their efficacy and safety in pediatric psoriasis. Several studies have established the safety and effectiveness of biologics in children with plaque psoriasis (see eTable for recommended dosing), whereas the evidence supporting their use in treating pustular and erythrodermic variants are limited to case reports and case series. The tumor necrosis factor α (TNF-α) inhibitor etanercept has been approved for use in children aged 4 years and older, and the IL-12/IL-23 inhibitor ustekinumab is approved in children aged 6 years and older. Other TNF-α inhibitors, namely infliximab and adalimumab, commonly are utilized off label for pediatric psoriasis. The most common side effect of biologic therapies in pediatric patients is injection-site reactions.¹ Prior to initiating therapy, children must undergo tuberculosis screening either by purified protein derivative testing or IFN-γ release assay. Testing should be repeated annually in individuals taking TNF-α inhibitors, though the utility of repeat testing when taking biologics in other classes is not clear. High-risk patients also should be screened for human immunodeficiency virus and hepatitis. Follow-up frequency may range from every 3 months to annually, based on judgement of the provider. In children who develop loss of response to biologics, methotrexate can be added to the regimen to attenuate formation of efficacy-reducing antidrug antibodies.

Final Thoughts

When managing children with psoriasis, it is important for dermatologists to appropriately educate guardians and children on the disease course, as well as consider the psychological, emotional, social, and financial factors that may direct decision-making regarding optimal therapeutics. Dermatologists should consider collaboration with the child’s primary care physician and other specialists to ensure that all needs are met.

These guidelines provide a framework agreed upon by numerous experts in pediatric psoriasis, but they are limited by gaps in the research. There still is much to be learned regarding the pathophysiology of psoriasis; the risk for developing comorbidities during adulthood; and the efficacy and safety of certain therapeutics, particularly biologics, in pediatric patients with psoriasis.

CASE Pregnant woman with positive Treponema pallidum antibody test

A 30-year-old primigravida at 10 weeks and 4 days of gestation by her last menstrual period presents to your office for her initial prenatal visit. She expresses no concerns. You order the standard set of laboratory tests, including a sexually transmitted infection (STI) screening panel. Consistent with your institution’s use of the reverse algorithm for syphilis screening, you obtain a Treponema pallidum antibody test, which reflexes to the rapid plasma reagin (RPR) test. Three days later, you receive a notification that this patient’s T pallidum antibody result was positive, followed by negative RPR test results. The follow-up T pallidum particle agglutination (TP-PA) test also was negative. Given these findings, you consider:

• What is the correct interpretation of the patient’s sequence of test results?
• Is she infected, and does she require treatment?

Meet our perpetrator

Syphilis has plagued society since the late 15th century, although its causative agent, the spirochete T pallidum, was not recognized until 1905.^1,2T pallidum bacteria are transmitted via sexual contact, as well as through vertical transmission during pregnancy or delivery. Infection with syphilis is reported in 50% to 60% of sexual partners after a single exposure to an infected individual with early syphilis, and the mean incubation period is 21 days.³T pallidum can cross the placenta and infect a fetus as early as the sixth week of gestation.³ Congenital syphilis infections occur in the neonates of 50% to 80% of women with untreated primary, secondary, or early latent syphilis infections; maternal syphilis is associated with a 21% increased risk of stillbirth, a 6% increased risk of preterm delivery, and a 9% increased risk of neonatal death.^4,5 Additionally, syphilis infection is associated with a high risk of HIV infection, as well as coinfection with other STIs.¹

Given the highly infective nature of T pallidum, as well as the severity of the potential consequences of infection for both mothers and babies, primary prevention, education of at-risk populations, and early recognition of clinical features of syphilis infection are of utmost importance in preventing morbidity and mortality. In this article, we review the epidemiology and extensive clinical manifestations of syphilis, as well as current screening recommendations and treatment for pregnant women.

The extent of the problem today

Although US rates of syphilis have ebbed and flowed for the past several decades, the current incidence has grown exponentially in recent years, with the number of cases reported to the Centers for Disease Control and Prevention (CDC) increasing by 71% from 2014 to 2018.⁶ During this time period, reported cases of primary and secondary syphilis in women more than doubled (172.7% and 165.4%, respectively) according to CDC data, accompanied by a parallel rise in reported cases of congenital syphilis in both live and stillborn infants.⁶ In 2018, the CDC reported a national rate of congenital syphilis of 33.1 cases per 100,000 live births, a 39.7% rise compared with data from 2017.⁶

Those most at risk. Risk factors for syphilis infection include age younger than 30 years, low socioeconomic status, substance abuse, HIV infection, concurrent STIs, and high-risk sexual activity (sex with multiple high-risk partners).³ Additionally, reported rates of primary and secondary syphilis infections, as well as congenital syphilis infections, are more elevated among women who identify as Black, American Indian/Alaska Native, and/or Hispanic.⁶ Congenital infections in the United States are correlated with a lack of prenatal care, which has been similarly linked with racial and socioeconomic disparities, as well as with untreated mental health and substance use disorders and recent immigration to the United States.^5,7

Continue to: The many phases of syphilis...

The many phases of syphilis

The characteristic lesion of primary syphilis is a chancre, which is a painless, ulcerative lesion with raised borders and a clean, indurated base appearing at the site of spirochete entry (FIGURE 1). Chancres most commonly appear in the genital area, with the most frequent sites in females being within the vaginal canal or on the cervix. Primary chancres tend to heal spontaneously within 3 to 6 weeks, even without treatment, and frequently are accompanied by painless inguinal lymphadenopathy. Given that the most common chancre sites are not immediately apparent, primary infections in women often go undetected.³ In fact, it is essential for clinicians to recognize that, in our routine practice, most patients with syphilis will not be symptomatic at all, and the diagnosis will only be made by serologic screening.

Following resolution of the primary phase, the patient may enter the secondary stage of T pallidum infection. During this stage, spirochetes may disseminate throughout the bloodstream to infect all major organ systems. The principal manifestations of secondary syphilis include a diffuse maculopapular rash that begins on the trunk and proximal extremities and spreads to include the palms and soles (FIGURE 2); mucosal lesions, such as mucous patches and condyloma lata (FIGURE 3); nonscarring alopecia; periostitis; generalized lymphadenopathy; and, in some cases, hepatitis or nephritis.^1,3

Untreated, about 40% of patients will progress to the tertiary stage of syphilis, which is characterized by gummas affecting the skin and mucous membranes (FIGURE 4) and cardiovascular manifestations including arterial aneurysms and aortic insufficiency.³

Neurologic manifestations of syphilis may arise during any of the above stages, though the most characteristic manifestations tend to appear decades after the primary infection. Early neurosyphilis may present as meningitis, with or without concomitant ocular syphilis (uveitis, retinitis) and/or as otic syphilis (hearing loss, persistent tinnitus).^1,5 Patients with late (tertiary) neurosyphilis tend to exhibit meningovascular symptoms similar to stroke (aphasia, hemiplegia, seizures) and/or parenchymal effects such as general paresis. Tabes dorsalis (manifestations of which include urinary and rectal incontinence, lightning pains, and ataxia) is a late-onset manifestation.^1,3

Congenital syphilis can be subdivided into an early and late stage. The first stage, in which clinical findings occur within the first 2 years of life, commonly features a desquamating rash, hepatomegaly, and rhinitis. Anemia, thrombocytopenia, periostitis, and osteomyelitis also have been documented.⁵ Of note, two-thirds of infants are asymptomatic at birth and may not develop such clinical manifestations for 3 to 8 weeks.³ If untreated, early congenital infection may progress to late manifestations, such as Hutchinson teeth, mulberry molars, interstitial keratitis, deafness, saddle nose, saber shins, and such neurologic abnormalities as developmental delay and general paresis.³

Continue to: Prenatal screening and diagnosis...

Prenatal screening and diagnosis

Current recommendations issued by the CDC and the American College of Obstetricians and Gynecologists state that all pregnant women should be screened for syphilis infection at their first presentation to care, with repeat screening between 28 and 32 weeks of gestation and at birth, for women living in areas with a high prevalence of syphilis and/or with any of the aforementioned risk factors.^3,5 Given that providers may be unfamiliar with the prevalence of syphilis in their area, and that patients may acquire or develop an infection later on in their pregnancy, researchers have begun to investigate the feasibility of universal third-trimester screening. While the cost-effectiveness of such a protocol is disputed, recent studies suggest that it may result in a substantial decrease in adverse maternal and fetal outcomes.^8,9

Diagnostic tests

The traditional algorithm for the diagnosis of syphilis infection begins with a nontreponemal screening test, such as the RPR or the Venereal Disease Research Laboratory test. If positive, these screening tests are followed by a confirmatory treponemal test, such as the fluorescent treponemal antibody (FTA) test or the TP-PA (FIGURE 5).

The “reverse” screening algorithm begins with the FTA and, if positive, reflexes to the RPR. A reactive RPR indicates an active infection, and the patient should be treated. A negative RPR should be followed by the TP-PA to rule out a false-positive immunoglobulin G test. If the TP-PA test result is positive, the diagnosis of syphilis is confirmed (FIGURE 6). It is crucial to understand, however, that treponemal antibodies will remain positive for a patient’s lifetime, and someone who may have been treated for syphilis in the past also will screen positive. Once 2 treponemal tests are positive, physicians should take a careful history to assess prior infection risk and treatment status. A negative TP-PA excludes a diagnosis of syphilis.

Advantages of the reverse screening algorithm. Nontreponemal tests are inexpensive and easy to perform, and titers allow for identification of a baseline to evaluate response to treatment.¹¹ However, given the fluctuation of RPR sensitivity (depending on stage of disease and a decreased ability to detect primary and latent stages of syphilis), there has been a resurgence of interest in the reverse algorithm.¹¹ While reverse screening has been found to incur higher costs, and may result in overtreatment and increased stress due to false-positive results,¹² there is evidence to suggest that this algorithm is more sensitive for primary and latent infections.^8,11,13-15

Given the rise in prevalence of syphilis infections in the United States over the past decade, and therefore a higher pretest probability of syphilis in the population, we favor the reverse screening algorithm in obstetrics, particularly given the risks of adverse maternal and fetal outcomes.

Treating syphilis in pregnancy

Parenteral benzathine penicillin G is the only currently recommended medication for the treatment of syphilis in pregnancy. This drug is effective in treating maternal infection and in preventing fetal infections, as well as in treating established fetal infections.^3,5 Regimens differ depending on the stage of syphilis infection (TABLE). Treatment for presumed early syphilis is recommended for women who have had sexual contact with a partner diagnosed with primary, secondary, or early latent syphilis within 3 months of their current pregnancy.⁵ Any patient with diagnosed syphilis who demonstrates clinical signs of neurologic involvement should undergo lumbar puncture to assess for evidence of neurosyphilis.³ CDC guidelines recommend that patients who report an allergy to penicillin undergo desensitization therapy in a controlled setting, as other antibiotics that have been investigated in the treatment of syphilis are either not appropriate due to teratogenicity or due to suboptimal fetal treatment.^3,5

Syphilotherapy may lead to the Jarisch-Herxheimer reaction, which is an acute systemic reaction to inflammatory cytokines produced in response to lipopolysaccharide released by dying spirochetes.⁵ This reaction is characterized by fever, chills, myalgia, headache, hypotension, and worsening of cutaneous lesions. Preterm labor and delivery and fetal heart rate tracing abnormalities also have been documented in pregnant women experiencing this reaction, particularly during the second half of pregnancy.¹⁶ Prior to the start of treatment, a detailed sonographic assessment should be performed to assess the fetus for signs of early syphilis, including hepatomegaly, elevated peak systolic velocity of the middle cerebral artery (indicative of fetal anemia), polyhydramnios, placentomegaly, or hydrops.^5,7

CASE Resolved

The combination of the patient’s test results—positive FTA, negative RPR, and negative TP-PA—suggest a false-positive treponemal assay. This sequence of tests excludes a diagnosis of syphilis; therefore, no treatment is necessary. Depending on the prevalence of syphilis in the patient’s geographic location, as well as her sexual history, rescreening between 28 and 32 weeks may be warranted. ●

CASE Pregnant woman with positive Treponema pallidum antibody test

A 30-year-old primigravida at 10 weeks and 4 days of gestation by her last menstrual period presents to your office for her initial prenatal visit. She expresses no concerns. You order the standard set of laboratory tests, including a sexually transmitted infection (STI) screening panel. Consistent with your institution’s use of the reverse algorithm for syphilis screening, you obtain a Treponema pallidum antibody test, which reflexes to the rapid plasma reagin (RPR) test. Three days later, you receive a notification that this patient’s T pallidum antibody result was positive, followed by negative RPR test results. The follow-up T pallidum particle agglutination (TP-PA) test also was negative. Given these findings, you consider:

• What is the correct interpretation of the patient’s sequence of test results?
• Is she infected, and does she require treatment?

Meet our perpetrator

Syphilis has plagued society since the late 15th century, although its causative agent, the spirochete T pallidum, was not recognized until 1905.^1,2T pallidum bacteria are transmitted via sexual contact, as well as through vertical transmission during pregnancy or delivery. Infection with syphilis is reported in 50% to 60% of sexual partners after a single exposure to an infected individual with early syphilis, and the mean incubation period is 21 days.³T pallidum can cross the placenta and infect a fetus as early as the sixth week of gestation.³ Congenital syphilis infections occur in the neonates of 50% to 80% of women with untreated primary, secondary, or early latent syphilis infections; maternal syphilis is associated with a 21% increased risk of stillbirth, a 6% increased risk of preterm delivery, and a 9% increased risk of neonatal death.^4,5 Additionally, syphilis infection is associated with a high risk of HIV infection, as well as coinfection with other STIs.¹

Given the highly infective nature of T pallidum, as well as the severity of the potential consequences of infection for both mothers and babies, primary prevention, education of at-risk populations, and early recognition of clinical features of syphilis infection are of utmost importance in preventing morbidity and mortality. In this article, we review the epidemiology and extensive clinical manifestations of syphilis, as well as current screening recommendations and treatment for pregnant women.

The extent of the problem today

Although US rates of syphilis have ebbed and flowed for the past several decades, the current incidence has grown exponentially in recent years, with the number of cases reported to the Centers for Disease Control and Prevention (CDC) increasing by 71% from 2014 to 2018.⁶ During this time period, reported cases of primary and secondary syphilis in women more than doubled (172.7% and 165.4%, respectively) according to CDC data, accompanied by a parallel rise in reported cases of congenital syphilis in both live and stillborn infants.⁶ In 2018, the CDC reported a national rate of congenital syphilis of 33.1 cases per 100,000 live births, a 39.7% rise compared with data from 2017.⁶

Those most at risk. Risk factors for syphilis infection include age younger than 30 years, low socioeconomic status, substance abuse, HIV infection, concurrent STIs, and high-risk sexual activity (sex with multiple high-risk partners).³ Additionally, reported rates of primary and secondary syphilis infections, as well as congenital syphilis infections, are more elevated among women who identify as Black, American Indian/Alaska Native, and/or Hispanic.⁶ Congenital infections in the United States are correlated with a lack of prenatal care, which has been similarly linked with racial and socioeconomic disparities, as well as with untreated mental health and substance use disorders and recent immigration to the United States.^5,7

Continue to: The many phases of syphilis...

The many phases of syphilis

The characteristic lesion of primary syphilis is a chancre, which is a painless, ulcerative lesion with raised borders and a clean, indurated base appearing at the site of spirochete entry (FIGURE 1). Chancres most commonly appear in the genital area, with the most frequent sites in females being within the vaginal canal or on the cervix. Primary chancres tend to heal spontaneously within 3 to 6 weeks, even without treatment, and frequently are accompanied by painless inguinal lymphadenopathy. Given that the most common chancre sites are not immediately apparent, primary infections in women often go undetected.³ In fact, it is essential for clinicians to recognize that, in our routine practice, most patients with syphilis will not be symptomatic at all, and the diagnosis will only be made by serologic screening.

Following resolution of the primary phase, the patient may enter the secondary stage of T pallidum infection. During this stage, spirochetes may disseminate throughout the bloodstream to infect all major organ systems. The principal manifestations of secondary syphilis include a diffuse maculopapular rash that begins on the trunk and proximal extremities and spreads to include the palms and soles (FIGURE 2); mucosal lesions, such as mucous patches and condyloma lata (FIGURE 3); nonscarring alopecia; periostitis; generalized lymphadenopathy; and, in some cases, hepatitis or nephritis.^1,3

Untreated, about 40% of patients will progress to the tertiary stage of syphilis, which is characterized by gummas affecting the skin and mucous membranes (FIGURE 4) and cardiovascular manifestations including arterial aneurysms and aortic insufficiency.³

Neurologic manifestations of syphilis may arise during any of the above stages, though the most characteristic manifestations tend to appear decades after the primary infection. Early neurosyphilis may present as meningitis, with or without concomitant ocular syphilis (uveitis, retinitis) and/or as otic syphilis (hearing loss, persistent tinnitus).^1,5 Patients with late (tertiary) neurosyphilis tend to exhibit meningovascular symptoms similar to stroke (aphasia, hemiplegia, seizures) and/or parenchymal effects such as general paresis. Tabes dorsalis (manifestations of which include urinary and rectal incontinence, lightning pains, and ataxia) is a late-onset manifestation.^1,3

Congenital syphilis can be subdivided into an early and late stage. The first stage, in which clinical findings occur within the first 2 years of life, commonly features a desquamating rash, hepatomegaly, and rhinitis. Anemia, thrombocytopenia, periostitis, and osteomyelitis also have been documented.⁵ Of note, two-thirds of infants are asymptomatic at birth and may not develop such clinical manifestations for 3 to 8 weeks.³ If untreated, early congenital infection may progress to late manifestations, such as Hutchinson teeth, mulberry molars, interstitial keratitis, deafness, saddle nose, saber shins, and such neurologic abnormalities as developmental delay and general paresis.³

Continue to: Prenatal screening and diagnosis...

Prenatal screening and diagnosis

Current recommendations issued by the CDC and the American College of Obstetricians and Gynecologists state that all pregnant women should be screened for syphilis infection at their first presentation to care, with repeat screening between 28 and 32 weeks of gestation and at birth, for women living in areas with a high prevalence of syphilis and/or with any of the aforementioned risk factors.^3,5 Given that providers may be unfamiliar with the prevalence of syphilis in their area, and that patients may acquire or develop an infection later on in their pregnancy, researchers have begun to investigate the feasibility of universal third-trimester screening. While the cost-effectiveness of such a protocol is disputed, recent studies suggest that it may result in a substantial decrease in adverse maternal and fetal outcomes.^8,9

Diagnostic tests

The traditional algorithm for the diagnosis of syphilis infection begins with a nontreponemal screening test, such as the RPR or the Venereal Disease Research Laboratory test. If positive, these screening tests are followed by a confirmatory treponemal test, such as the fluorescent treponemal antibody (FTA) test or the TP-PA (FIGURE 5).

The “reverse” screening algorithm begins with the FTA and, if positive, reflexes to the RPR. A reactive RPR indicates an active infection, and the patient should be treated. A negative RPR should be followed by the TP-PA to rule out a false-positive immunoglobulin G test. If the TP-PA test result is positive, the diagnosis of syphilis is confirmed (FIGURE 6). It is crucial to understand, however, that treponemal antibodies will remain positive for a patient’s lifetime, and someone who may have been treated for syphilis in the past also will screen positive. Once 2 treponemal tests are positive, physicians should take a careful history to assess prior infection risk and treatment status. A negative TP-PA excludes a diagnosis of syphilis.

Advantages of the reverse screening algorithm. Nontreponemal tests are inexpensive and easy to perform, and titers allow for identification of a baseline to evaluate response to treatment.¹¹ However, given the fluctuation of RPR sensitivity (depending on stage of disease and a decreased ability to detect primary and latent stages of syphilis), there has been a resurgence of interest in the reverse algorithm.¹¹ While reverse screening has been found to incur higher costs, and may result in overtreatment and increased stress due to false-positive results,¹² there is evidence to suggest that this algorithm is more sensitive for primary and latent infections.^8,11,13-15

Given the rise in prevalence of syphilis infections in the United States over the past decade, and therefore a higher pretest probability of syphilis in the population, we favor the reverse screening algorithm in obstetrics, particularly given the risks of adverse maternal and fetal outcomes.

Treating syphilis in pregnancy

Parenteral benzathine penicillin G is the only currently recommended medication for the treatment of syphilis in pregnancy. This drug is effective in treating maternal infection and in preventing fetal infections, as well as in treating established fetal infections.^3,5 Regimens differ depending on the stage of syphilis infection (TABLE). Treatment for presumed early syphilis is recommended for women who have had sexual contact with a partner diagnosed with primary, secondary, or early latent syphilis within 3 months of their current pregnancy.⁵ Any patient with diagnosed syphilis who demonstrates clinical signs of neurologic involvement should undergo lumbar puncture to assess for evidence of neurosyphilis.³ CDC guidelines recommend that patients who report an allergy to penicillin undergo desensitization therapy in a controlled setting, as other antibiotics that have been investigated in the treatment of syphilis are either not appropriate due to teratogenicity or due to suboptimal fetal treatment.^3,5

Syphilotherapy may lead to the Jarisch-Herxheimer reaction, which is an acute systemic reaction to inflammatory cytokines produced in response to lipopolysaccharide released by dying spirochetes.⁵ This reaction is characterized by fever, chills, myalgia, headache, hypotension, and worsening of cutaneous lesions. Preterm labor and delivery and fetal heart rate tracing abnormalities also have been documented in pregnant women experiencing this reaction, particularly during the second half of pregnancy.¹⁶ Prior to the start of treatment, a detailed sonographic assessment should be performed to assess the fetus for signs of early syphilis, including hepatomegaly, elevated peak systolic velocity of the middle cerebral artery (indicative of fetal anemia), polyhydramnios, placentomegaly, or hydrops.^5,7

CASE Resolved

The combination of the patient’s test results—positive FTA, negative RPR, and negative TP-PA—suggest a false-positive treponemal assay. This sequence of tests excludes a diagnosis of syphilis; therefore, no treatment is necessary. Depending on the prevalence of syphilis in the patient’s geographic location, as well as her sexual history, rescreening between 28 and 32 weeks may be warranted. ●

CASE Pregnant woman with positive Treponema pallidum antibody test

A 30-year-old primigravida at 10 weeks and 4 days of gestation by her last menstrual period presents to your office for her initial prenatal visit. She expresses no concerns. You order the standard set of laboratory tests, including a sexually transmitted infection (STI) screening panel. Consistent with your institution’s use of the reverse algorithm for syphilis screening, you obtain a Treponema pallidum antibody test, which reflexes to the rapid plasma reagin (RPR) test. Three days later, you receive a notification that this patient’s T pallidum antibody result was positive, followed by negative RPR test results. The follow-up T pallidum particle agglutination (TP-PA) test also was negative. Given these findings, you consider:

• What is the correct interpretation of the patient’s sequence of test results?
• Is she infected, and does she require treatment?

Meet our perpetrator

Syphilis has plagued society since the late 15th century, although its causative agent, the spirochete T pallidum, was not recognized until 1905.^1,2T pallidum bacteria are transmitted via sexual contact, as well as through vertical transmission during pregnancy or delivery. Infection with syphilis is reported in 50% to 60% of sexual partners after a single exposure to an infected individual with early syphilis, and the mean incubation period is 21 days.³T pallidum can cross the placenta and infect a fetus as early as the sixth week of gestation.³ Congenital syphilis infections occur in the neonates of 50% to 80% of women with untreated primary, secondary, or early latent syphilis infections; maternal syphilis is associated with a 21% increased risk of stillbirth, a 6% increased risk of preterm delivery, and a 9% increased risk of neonatal death.^4,5 Additionally, syphilis infection is associated with a high risk of HIV infection, as well as coinfection with other STIs.¹

Given the highly infective nature of T pallidum, as well as the severity of the potential consequences of infection for both mothers and babies, primary prevention, education of at-risk populations, and early recognition of clinical features of syphilis infection are of utmost importance in preventing morbidity and mortality. In this article, we review the epidemiology and extensive clinical manifestations of syphilis, as well as current screening recommendations and treatment for pregnant women.

The extent of the problem today

Although US rates of syphilis have ebbed and flowed for the past several decades, the current incidence has grown exponentially in recent years, with the number of cases reported to the Centers for Disease Control and Prevention (CDC) increasing by 71% from 2014 to 2018.⁶ During this time period, reported cases of primary and secondary syphilis in women more than doubled (172.7% and 165.4%, respectively) according to CDC data, accompanied by a parallel rise in reported cases of congenital syphilis in both live and stillborn infants.⁶ In 2018, the CDC reported a national rate of congenital syphilis of 33.1 cases per 100,000 live births, a 39.7% rise compared with data from 2017.⁶

Those most at risk. Risk factors for syphilis infection include age younger than 30 years, low socioeconomic status, substance abuse, HIV infection, concurrent STIs, and high-risk sexual activity (sex with multiple high-risk partners).³ Additionally, reported rates of primary and secondary syphilis infections, as well as congenital syphilis infections, are more elevated among women who identify as Black, American Indian/Alaska Native, and/or Hispanic.⁶ Congenital infections in the United States are correlated with a lack of prenatal care, which has been similarly linked with racial and socioeconomic disparities, as well as with untreated mental health and substance use disorders and recent immigration to the United States.^5,7

Continue to: The many phases of syphilis...

The many phases of syphilis

The characteristic lesion of primary syphilis is a chancre, which is a painless, ulcerative lesion with raised borders and a clean, indurated base appearing at the site of spirochete entry (FIGURE 1). Chancres most commonly appear in the genital area, with the most frequent sites in females being within the vaginal canal or on the cervix. Primary chancres tend to heal spontaneously within 3 to 6 weeks, even without treatment, and frequently are accompanied by painless inguinal lymphadenopathy. Given that the most common chancre sites are not immediately apparent, primary infections in women often go undetected.³ In fact, it is essential for clinicians to recognize that, in our routine practice, most patients with syphilis will not be symptomatic at all, and the diagnosis will only be made by serologic screening.

Following resolution of the primary phase, the patient may enter the secondary stage of T pallidum infection. During this stage, spirochetes may disseminate throughout the bloodstream to infect all major organ systems. The principal manifestations of secondary syphilis include a diffuse maculopapular rash that begins on the trunk and proximal extremities and spreads to include the palms and soles (FIGURE 2); mucosal lesions, such as mucous patches and condyloma lata (FIGURE 3); nonscarring alopecia; periostitis; generalized lymphadenopathy; and, in some cases, hepatitis or nephritis.^1,3

Untreated, about 40% of patients will progress to the tertiary stage of syphilis, which is characterized by gummas affecting the skin and mucous membranes (FIGURE 4) and cardiovascular manifestations including arterial aneurysms and aortic insufficiency.³

Neurologic manifestations of syphilis may arise during any of the above stages, though the most characteristic manifestations tend to appear decades after the primary infection. Early neurosyphilis may present as meningitis, with or without concomitant ocular syphilis (uveitis, retinitis) and/or as otic syphilis (hearing loss, persistent tinnitus).^1,5 Patients with late (tertiary) neurosyphilis tend to exhibit meningovascular symptoms similar to stroke (aphasia, hemiplegia, seizures) and/or parenchymal effects such as general paresis. Tabes dorsalis (manifestations of which include urinary and rectal incontinence, lightning pains, and ataxia) is a late-onset manifestation.^1,3

Congenital syphilis can be subdivided into an early and late stage. The first stage, in which clinical findings occur within the first 2 years of life, commonly features a desquamating rash, hepatomegaly, and rhinitis. Anemia, thrombocytopenia, periostitis, and osteomyelitis also have been documented.⁵ Of note, two-thirds of infants are asymptomatic at birth and may not develop such clinical manifestations for 3 to 8 weeks.³ If untreated, early congenital infection may progress to late manifestations, such as Hutchinson teeth, mulberry molars, interstitial keratitis, deafness, saddle nose, saber shins, and such neurologic abnormalities as developmental delay and general paresis.³

Continue to: Prenatal screening and diagnosis...

Prenatal screening and diagnosis

Current recommendations issued by the CDC and the American College of Obstetricians and Gynecologists state that all pregnant women should be screened for syphilis infection at their first presentation to care, with repeat screening between 28 and 32 weeks of gestation and at birth, for women living in areas with a high prevalence of syphilis and/or with any of the aforementioned risk factors.^3,5 Given that providers may be unfamiliar with the prevalence of syphilis in their area, and that patients may acquire or develop an infection later on in their pregnancy, researchers have begun to investigate the feasibility of universal third-trimester screening. While the cost-effectiveness of such a protocol is disputed, recent studies suggest that it may result in a substantial decrease in adverse maternal and fetal outcomes.^8,9

Diagnostic tests

The traditional algorithm for the diagnosis of syphilis infection begins with a nontreponemal screening test, such as the RPR or the Venereal Disease Research Laboratory test. If positive, these screening tests are followed by a confirmatory treponemal test, such as the fluorescent treponemal antibody (FTA) test or the TP-PA (FIGURE 5).

The “reverse” screening algorithm begins with the FTA and, if positive, reflexes to the RPR. A reactive RPR indicates an active infection, and the patient should be treated. A negative RPR should be followed by the TP-PA to rule out a false-positive immunoglobulin G test. If the TP-PA test result is positive, the diagnosis of syphilis is confirmed (FIGURE 6). It is crucial to understand, however, that treponemal antibodies will remain positive for a patient’s lifetime, and someone who may have been treated for syphilis in the past also will screen positive. Once 2 treponemal tests are positive, physicians should take a careful history to assess prior infection risk and treatment status. A negative TP-PA excludes a diagnosis of syphilis.

Advantages of the reverse screening algorithm. Nontreponemal tests are inexpensive and easy to perform, and titers allow for identification of a baseline to evaluate response to treatment.¹¹ However, given the fluctuation of RPR sensitivity (depending on stage of disease and a decreased ability to detect primary and latent stages of syphilis), there has been a resurgence of interest in the reverse algorithm.¹¹ While reverse screening has been found to incur higher costs, and may result in overtreatment and increased stress due to false-positive results,¹² there is evidence to suggest that this algorithm is more sensitive for primary and latent infections.^8,11,13-15

Given the rise in prevalence of syphilis infections in the United States over the past decade, and therefore a higher pretest probability of syphilis in the population, we favor the reverse screening algorithm in obstetrics, particularly given the risks of adverse maternal and fetal outcomes.

Treating syphilis in pregnancy

Parenteral benzathine penicillin G is the only currently recommended medication for the treatment of syphilis in pregnancy. This drug is effective in treating maternal infection and in preventing fetal infections, as well as in treating established fetal infections.^3,5 Regimens differ depending on the stage of syphilis infection (TABLE). Treatment for presumed early syphilis is recommended for women who have had sexual contact with a partner diagnosed with primary, secondary, or early latent syphilis within 3 months of their current pregnancy.⁵ Any patient with diagnosed syphilis who demonstrates clinical signs of neurologic involvement should undergo lumbar puncture to assess for evidence of neurosyphilis.³ CDC guidelines recommend that patients who report an allergy to penicillin undergo desensitization therapy in a controlled setting, as other antibiotics that have been investigated in the treatment of syphilis are either not appropriate due to teratogenicity or due to suboptimal fetal treatment.^3,5

Syphilotherapy may lead to the Jarisch-Herxheimer reaction, which is an acute systemic reaction to inflammatory cytokines produced in response to lipopolysaccharide released by dying spirochetes.⁵ This reaction is characterized by fever, chills, myalgia, headache, hypotension, and worsening of cutaneous lesions. Preterm labor and delivery and fetal heart rate tracing abnormalities also have been documented in pregnant women experiencing this reaction, particularly during the second half of pregnancy.¹⁶ Prior to the start of treatment, a detailed sonographic assessment should be performed to assess the fetus for signs of early syphilis, including hepatomegaly, elevated peak systolic velocity of the middle cerebral artery (indicative of fetal anemia), polyhydramnios, placentomegaly, or hydrops.^5,7

CASE Resolved

The combination of the patient’s test results—positive FTA, negative RPR, and negative TP-PA—suggest a false-positive treponemal assay. This sequence of tests excludes a diagnosis of syphilis; therefore, no treatment is necessary. Depending on the prevalence of syphilis in the patient’s geographic location, as well as her sexual history, rescreening between 28 and 32 weeks may be warranted. ●