Article

There is good news and bad news regarding the use of tobacco products by young people in the United States, according to the recently released findings from the 2021 Youth Risk Behavior Survey (YRBS).¹ The use of cigarettes among high school students declined from 36.4% in 1997 to 6.0% in 2019.² However, young people have replaced cigarettes with other tobacco products, including electronic vapor products (EVPs). So we need to ask specifically about these products.

Known by many names. EVPs are referred to as e-cigarettes, vapes, hookah pens, and mods. They usually contain nicotine, which is highly addictive, can affect brain development, and may lead to smoking of cigarettes.³ The most common reasons young people say they use EVPs are feelings of anxiety, stress, and depression, as well as the “high” associated with nicotine use.⁴

Use of EVPs among youth. The YRBS, which includes a representative sample of public and private school students in grades 9 to 12 in the 50 states, categorizes the use of EVPs as

• ever use
• current use (≥ 1 use during the 30 days before the survey), and
• daily use (during the 30 days before the survey).

In 2021, 36.2% of young people reported ever use of EVPs (40.9% of females; 32.1% of males), 18% reported current use (21.4% of females; 14.9% of males), and 5% reported daily use (5.6% of females; 4.5% of males). Differences between racial and ethnic groups were minor, except for markedly lower rates in Asian youth (19.5% ever use, 5.5% current use, and 1.2% daily use).⁵

Current recommendations. The US Preventive Services Task Force (USPSTF) recommends education and brief counseling for school-age children and adolescents to prevent them from starting to use tobacco (including use of EVPs).⁶ The USPSTF also recommends tobacco cessation using behavioral interventions and/or pharmacotherapy for those ages 18 years and older.⁷

The USPSTF makes no recommendation on cessation for those younger than 18 years, citing weak evidence. However, it would be reasonable to offer behavioral interventions to younger current users. (Pharmacotherapy is not approved for use in children and adolescents.)

The take-home message. When we ask children and adolescents about use of tobacco products, we need to specifically mention EVPs and advise against their use.

There is good news and bad news regarding the use of tobacco products by young people in the United States, according to the recently released findings from the 2021 Youth Risk Behavior Survey (YRBS).¹ The use of cigarettes among high school students declined from 36.4% in 1997 to 6.0% in 2019.² However, young people have replaced cigarettes with other tobacco products, including electronic vapor products (EVPs). So we need to ask specifically about these products.

Known by many names. EVPs are referred to as e-cigarettes, vapes, hookah pens, and mods. They usually contain nicotine, which is highly addictive, can affect brain development, and may lead to smoking of cigarettes.³ The most common reasons young people say they use EVPs are feelings of anxiety, stress, and depression, as well as the “high” associated with nicotine use.⁴

Use of EVPs among youth. The YRBS, which includes a representative sample of public and private school students in grades 9 to 12 in the 50 states, categorizes the use of EVPs as

• ever use
• current use (≥ 1 use during the 30 days before the survey), and
• daily use (during the 30 days before the survey).

In 2021, 36.2% of young people reported ever use of EVPs (40.9% of females; 32.1% of males), 18% reported current use (21.4% of females; 14.9% of males), and 5% reported daily use (5.6% of females; 4.5% of males). Differences between racial and ethnic groups were minor, except for markedly lower rates in Asian youth (19.5% ever use, 5.5% current use, and 1.2% daily use).⁵

Current recommendations. The US Preventive Services Task Force (USPSTF) recommends education and brief counseling for school-age children and adolescents to prevent them from starting to use tobacco (including use of EVPs).⁶ The USPSTF also recommends tobacco cessation using behavioral interventions and/or pharmacotherapy for those ages 18 years and older.⁷

The USPSTF makes no recommendation on cessation for those younger than 18 years, citing weak evidence. However, it would be reasonable to offer behavioral interventions to younger current users. (Pharmacotherapy is not approved for use in children and adolescents.)

The take-home message. When we ask children and adolescents about use of tobacco products, we need to specifically mention EVPs and advise against their use.

There is good news and bad news regarding the use of tobacco products by young people in the United States, according to the recently released findings from the 2021 Youth Risk Behavior Survey (YRBS).¹ The use of cigarettes among high school students declined from 36.4% in 1997 to 6.0% in 2019.² However, young people have replaced cigarettes with other tobacco products, including electronic vapor products (EVPs). So we need to ask specifically about these products.

Known by many names. EVPs are referred to as e-cigarettes, vapes, hookah pens, and mods. They usually contain nicotine, which is highly addictive, can affect brain development, and may lead to smoking of cigarettes.³ The most common reasons young people say they use EVPs are feelings of anxiety, stress, and depression, as well as the “high” associated with nicotine use.⁴

Use of EVPs among youth. The YRBS, which includes a representative sample of public and private school students in grades 9 to 12 in the 50 states, categorizes the use of EVPs as

• ever use
• current use (≥ 1 use during the 30 days before the survey), and
• daily use (during the 30 days before the survey).

In 2021, 36.2% of young people reported ever use of EVPs (40.9% of females; 32.1% of males), 18% reported current use (21.4% of females; 14.9% of males), and 5% reported daily use (5.6% of females; 4.5% of males). Differences between racial and ethnic groups were minor, except for markedly lower rates in Asian youth (19.5% ever use, 5.5% current use, and 1.2% daily use).⁵

Current recommendations. The US Preventive Services Task Force (USPSTF) recommends education and brief counseling for school-age children and adolescents to prevent them from starting to use tobacco (including use of EVPs).⁶ The USPSTF also recommends tobacco cessation using behavioral interventions and/or pharmacotherapy for those ages 18 years and older.⁷

The USPSTF makes no recommendation on cessation for those younger than 18 years, citing weak evidence. However, it would be reasonable to offer behavioral interventions to younger current users. (Pharmacotherapy is not approved for use in children and adolescents.)

The take-home message. When we ask children and adolescents about use of tobacco products, we need to specifically mention EVPs and advise against their use.

An elevated serum level of cholesterol has been recognized as a risk factor for atherosclerotic cardiovascular disease (ASCVD) since the publication of the Framingham Study in 1961.¹ Although clinical outcomes related to ASCVD have improved in recent decades, ASCVD remains the leading cause of morbidity and mortality across the globe and remains, in the United States, the leading cause of death among most racial and ethnic groups. Much of this persistent disease burden can be attributed to inadequate control of ASCVD risk factors and suboptimal implementation of prevention strategies in the general population.²

The most recent (2019) iteration of the American College of Cardiology/American Heart Association (ACC/AHA) Guideline on the Primary Prevention of Cardiovascular Disease emphasizes a comprehensive, patient-centered, team-based approach to the management of ASCVD risk factors.² In this article, I review how, first, medication to reduce ASCVD risk should be considered only when a patient’s risk is sufficiently high and, second, shared decision-making and social determinants of health should, in all cases, guide and inform optimal implementation of treatment.²

Estimating risk for ASCVD by ascertaining LDL-C

• The Friedewald equation. Traditionally, low-density lipoprotein cholesterol (LDL-C) is estimated using the Friedewald equation^a applied to a fasting lipid profile. In patients who have a low level of LDL-C (< 70 mg/dL), however, the Friedewald equation becomes less accurate; in patients with hypertriglyceridemia (TG ≥ 400 mg/dL),estimation of LDL-C is invalid.
• The Martin–Hopkins equation offers a validated estimation of LDL-C when the LDL-C value is < 70 mg/dL.³ This equation—in which the fixed factor of 5 used in the Friedewald equation to estimate very low-density lipoprotein cholesterol is replaced by an adjustable factor that is based on the patient’s non-HDL-C (ie, TC–HDL-C) and TG values—is preferred by the ACC/AHA Task Force on Clinical Practice Guidelines in this clinical circumstance.⁴
• National Institutes of Health equation. This newer equation provides an accurate estimate of the LDL-C level in patients whose TG value is ≤ 800 mg/dL. The equation has not been fully validated for clinical use, however.⁵
• Direct measurement obviates the need for an equation to estimate LDL-C, but the test is not available in all health care settings.

For adults ≥ 20 years of age who are not receiving lipid-lowering therapy, a nonfasting lipid profile can be used to estimate ASCVD risk and document the baseline LDL-C level. If the TG level is ≥ 400 mg/dL, the test should be administered in the fasting state.⁴

• Apolipoprotein B. Alternatively, apolipoprotein B (apoB) can be measured. Because each LDL-C particle contains 1 apoB molecule, the apoB level describes the LDL-C level more accurately than a calculation of LDL-C. Many patients with type 2 diabetes and metabolic syndrome have a relatively low calculated LDL-C (thereby falsely reassuring the testing clinician) but have an elevated apoB level. An apoB level ≥ 130 mg/dL corresponds to an LDL-C level >160 mg/dL.⁴
• Calculation of non-HDL-C. Because the nonfasting state does not have a significant impact on a patient’s TC and HDL-C levels, the non-HDL-C level also can be calculated from the results of a nonfasting lipid profile.

Non-HDL-C and apoB are equivalent predictors of ASCVD risk. These 2 assessments might offer better risk estimation than other available tools in patients who have type 2 diabetes and metabolic syndrome.⁶

Continue to: Applying the estimate of 10-year ASCVD risk...

 

 

Applying the estimate of 10-year ASCVD risk

Your recommendation for preventive intervention, such as lipid-lowering therapy, should be based on the estimated 10-year risk for ASCVD. Although multiple validated risk assessment tools are available, ACC/AHA recommends the pooled cohort risk equations (PCE), introduced in the 2013 ACC/AHA cholesterol treatment guidelines. The Framingham Heart Study now recommends the ACC/AHA PCE for risk assessment as well.⁷

The PCE, developed from 5 large cohorts, is based on hard atherosclerotic events: nonfatal myocardial infarction, death from coronary artery disease, and stroke. The ACC/AHA PCE is the only risk assessment tool developed using a significant percentage of patients who self-identify as Black.⁸ Alternatives to the ACC/AHA PCE include:

• Multi-ethnic Study of Atherosclerosis (MESA) 10-year ASCVD risk calculator, which incorporates the coronary artery calcium (CAC) score.
• Reynolds Risk Score, which incorporates high-sensitivity C-reactive protein measurement and a family history of premature ASCVD.⁹

How much does lifestyle modification actually matter?

The absolute impact of diet and exercise on lipid parameters is relatively modest. No studies have demonstrated a reduction in adverse cardiovascular outcomes with specific interventions regarding diet or activity.

• Diet. Nevertheless, ACC/AHA recommends that at-risk patients follow a dietary pattern that (1) emphasizes vegetables, fruits, and whole grains and (2) limits sweets, sugar-sweetened beverages, and red meat.

Saturated fat should constitute no more than 5% or 6% of total calories. In controlled-feeding trials,¹⁰ for every 1% of calories from saturated fat that are replaced with carbohydrate or monounsaturated or polyunsaturated fat, the LDL-C level was found to decline by as much as 1.8 mg/dL. Evidence is insufficient to assert that lowering dietary cholesterol reduces LDL-C.¹¹

• Activity. Trials of aerobic physical activity, compared with a more sedentary activity pattern, have demonstrated a reduction in the LDL-C level of as much as 6 mg/dL. All adult patients should be counseled to engage in aerobic physical activity of moderate or vigorous intensity—averaging ≥ 40 minutes per session, 3 or 4 sessions per week.¹¹

Primary prevention: Stratification by age

• 40 to 75 years. ACC/AHA recommends that you routinely assess traditional cardiovascular risk factors for these patients and calculate their 10-year risk for ASCVD using the PCE. Statin therapy as primary prevention is indicated for 3 major groups (TABLE 1).⁴ The US Preventive Services Task Force (USPSTF) recommends a 10-year ASCVD risk ≥ 10%, in conjunction with 1 or more additional CVD risk factors (dyslipidemia, diabetes, hypertension, smoking), as the threshold for initiating low- or moderate-intensity statin therapy in this age group.¹²

In adults at borderline risk (5% to < 7.5% 10-year ASCVD risk) or intermediate risk (≥ 7.5% to < 20% 10-year ASCVD risk), consider risk-enhancing factors to better inform your recommendation for preventive interventions. In these 2 groups, the presence of risk-enhancing factors might justify moderate-intensity statin therapy (TABLE 2⁴).

If your decision regarding preventive intervention remains uncertain, measuring CAC might further guide your discussion with the patient.⁴ When the CAC score is:

• 0 Agatston units and higher-risk conditions (eg, diabetes, family history of premature coronary artery disease, smoking) are absent, statin therapy can be withheld; reassess ASCVD risk in 5 to 10 years.
• 1-99 Agatston units, statin therapy can be started, especially for patients ≥ 55 years of age.
• ≥ 100 Agatston units or ≥ 75th percentile, statin therapy is indicated for all patients, regardless of additional risk factors.⁴

Because statins promote progression from unstable, inflammatory atherosclerotic plaque to more stable, calcified plaque, CAC scoring is not valid in patients already on statin therapy.¹³

In primary prevention, patients who have been classified as having low or intermediate risk, based on ASCVD risk scoring, with a CAC score of 0 Agatston units, have an annual all-cause mortality < 1%, regardless of age and gender. Patients classified as being at high risk, based on ASCVD risk scoring, with a CAC score of 0 Agatston units, have a significantly lower annual mortality than low- or intermediate-risk patients with a CAC score > 0 Agatston units.¹⁴

• 20 to 39 years. Focus on evaluation of lifetime ASCVD risk, rather than short-term (10-year) risk. Lifestyle modification is the primary intervention for younger patients; for those with moderate hypercholesterolemia (LDL-C, 160-189 mg/dL) and a family history of premature ASCVD, however, consider statin therapy. For patients with LDL-C ≥ 190 mg/dL, lifetime ASCVD risk is markedly increased, and high-intensity statin therapy is recommended, regardless of age. In this group, reassess ASCVD risk factors every 4 to 6 years.⁴
• > 75 years, without ASCVD. In this group, the benefit of statin therapy is less clear and might be lessened by an increased potential for adverse effects. A meta-analysis of 28 trials demonstrated that people ages > 75 years had a 24% relative reduction in major coronary events for every 38.7 mg/dL (1.0 mmol/L) reduction in LDL-C, which is comparable to the risk reduction seen in people ages 40 to 75 years.¹⁵

With increasing age, however, the relative reduction in major coronary events with statin therapy decreased,¹⁵ although other trials have not demonstrated age heterogeneity.¹⁶ Because people > 75 years of age have a significantly higher ASCVD event rate, a comparable relative rate reduction with statin therapy results in a larger absolute rate reduction (ARR) and, therefore, a smaller number needed to treat (NNT) to prevent an event, compared to the NNT in younger people.

Secondary prevention

ACC/AHA guidelines define clinical ASCVD as a history of:

• acute coronary syndrome
• myocardial infarction
• coronary or other arterial revascularization
• cerebrovascular event
• symptomatic peripheral artery disease, including aortic aneurysm.

High-intensity statin therapy is indicated for all patients ≤ 75 years who have clinical ASCVD. In patients > 75 years, consider a taper to moderate-intensity statin therapy. An upper age limit for seeing benefit from statin therapy in secondary prevention has not been identified.⁴

In high-risk patients, if LDL-C remains ≥ 70 mg/dL despite maximally tolerated statin therapy, ezetimibe (discussed in the next section) can be added. In very-high-risk patients, if LDL-C remains ≥ 70 mg/dL despite maximally tolerated statin therapy plus ezetimibe, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor (also discussed next) can be added. Always precede initiation of a PCSK9 inhibitor with a discussion of the net benefit, safety, and cost with the patient.⁴

Continue to: Options for lipid-lowering pharmacotherapy...

 

 

Options for lipid-lowering pharmacotherapy

• Statins (formally, hydroxymethylglutaryl-coenzyme A reductase inhibitors) offer the most predictable reduction in ASCVD risk of any lipid-lowering therapy. The evidence report that accompanied the 2016 USPSTF guidelines on statins for the prevention of cardiovascular disease (CVD) stated that low- or moderate-dosage statin therapy is associated with approximately a 30% relative risk reduction (RRR) in CVD events and CVD deaths and a 10% to 15% RRR in all-cause mortality.¹⁷

High-intensity statin therapy reduces LDL-C by ≥ 50%. Moderate-intensity statin therapy reduces LDL-C by 30% to 49% (TABLE 3).⁴

Statins are not without risk: A 2016 report¹⁸ estimated that treating 10,000 patients with a statin for 5 years would cause 1 case of rhabdomyolysis, 5 cases of myopathy, 75 new cases of diabetes, and 7 cases of hemorrhagic stroke. The same treatment would, however, avert approximately 1000 CVD events among patients with preexisting disease and approximately 500 CVD events among patients at elevated risk but without preexisting disease.¹⁸

• Ezetimibe, a selective cholesterol-absorption inhibitor, lowers LDL-C by 13% to 20% and typically is well tolerated. The use of ezetimibe in ASCVD risk reduction is supported by a single randomized controlled trial of more than 18,000 patients with recent acute coronary syndrome. Adding ezetimibe to simvastatin 40 mg resulted in a 2% absolute reduction in major adverse cardiovascular events over a median follow-up of 6 years (NNT = 50), compared to simvastatin alone.¹⁹ ACC/AHA guidelines recommend adding ezetimibe to maximally tolerated statin therapy in patients with clinical ASCVD who do not reach their goal LDL reduction with a statin alone. Ezetimibe also can be considered a statin alternative in patients who are statin intolerant.⁴
• PCSK9 inhibitors. When added to statin therapy, evolocumab and alirocumab—monoclonal antibodies that inhibit PCSK9—offer an incremental decrease in LDL-C of approximately 60%.^20-22 In a meta-analysis of 35 trials evaluating the incremental benefit of PCSK9 inhibitor therapy, a significant reduction in cardiovascular events, including myocardial infarction (ARR = 1.3%; NNT = 77), stroke (ARR = 0.4%; NNT = 250), and coronary revascularization (ARR = 1.6%; NNT = 63) was reported. No significant difference was observed in all-cause or cardiovascular mortality.^21,23
• Inclisiran, an injectable small-interfering RNA that inhibits PCSK9 synthesis, provides an incremental decrease in LDL-C of > 50% in patients already receiving statin therapy. Meta-analysis of 3 small cardiovascular outcomes trials revealed no significant difference in the rate of myocardial infarction, stroke, or cardiovascular mortality with inclisiran compared to placebo. Larger outcomes trials are underway and might offer additional insight into this agent’s role in ASCVD risk management.²⁴
• Omega-3 fatty acids. Multiple trials have demonstrated that adding omega-3 fatty acids to usual lipid-lowering therapy does not offer a consistent reduction in adverse cardiovascular outcomes, despite providing a significant reduction in TG levels. In a high-risk population with persistently elevated TG despite statin therapy, icosapent ethyl, a purified eicosapentaenoic acid ethyl ester, reduced major ASCVD outcomes by 25% over a median 4.9 years (ARR = 4.8%; NNT = 21), and cardiovascular death by 20% (ARR = 0.9%; NNT = 111), compared with a mineral oil placebo.²⁵ Subsequent trials, using a corn oil placebo, failed to duplicate these data²⁶—raising concern that the mineral oil comparator might have altered results of the eicosapentaenoic acid ethyl ester study.^27,28
• Bempedoic acid is a small-molecule inhibitor of ATP citrate lyase that increases LDL uptake by the liver. Pooled data from studies of bempedoic acid show, on average, a 15% reduction in TC, a 23% reduction in LDL-C, and a 6% increase in HDL-C, without a significant change in TG.²⁹ In statin-intolerant patients, bempedoicacid reduced major ASCVD outcomes by 13% over a median 40 months (ARR = 1.6%; NNT = 63), with no significant reduction in cardiovascular death.³⁰
• Niacin. Two large trials failed to demonstrate improvement in major cardiovascular events or other clinical benefit when niacin is added to moderate-intensity statin therapy, despite a significant increase in the HDL-C level (on average, 6 mg/dL) and a decrease in the LDL-C level (10-12 mg/dL)and TG (42 mg/dL).^31,32
• Fenofibrate lowers TG and increases HDL-C but does not consistently improve cardiovascular outcomes.³³ In a trial of patients with type 2 diabetes and persistent dyslipidemia (serum TG > 204 mg/dL; HDL-C< 34 mg/dL) despite statin therapy, adding fenofibrate reduced CVD outcomes by 4.9%—although this absolute difference did not reach statistical significance.³⁴

Neither niacin nor fenofibrate is considered useful for reducing ASCVD risk across broad populations.⁴

Follow-up to assess progress toward goals

Recheck the lipid profile 4 to 12 weeks after starting lipid-lowering therapy to verify adherence to medication and assess response. The primary goal is the percentage reduction in LDL-C based on ASCVD risk. An additional goal for very-high-risk patients is an LDL-C value ≤ 70 mg/dL. If the reduction in LDL-C is less than desired and adherence is assured, consider titrating the statin dosage or augmenting statin therapy with a nonstatin drug (eg, ezetimibe), or both.⁴ ●

CORRESPONDENCE

Jonathon M. Firnhaber, MD, MAEd, MBA, East Carolina University, Family Medicine Center, 101 Heart Drive, Greenville, NC 27834; firnhaberj@ecu.edu

An elevated serum level of cholesterol has been recognized as a risk factor for atherosclerotic cardiovascular disease (ASCVD) since the publication of the Framingham Study in 1961.¹ Although clinical outcomes related to ASCVD have improved in recent decades, ASCVD remains the leading cause of morbidity and mortality across the globe and remains, in the United States, the leading cause of death among most racial and ethnic groups. Much of this persistent disease burden can be attributed to inadequate control of ASCVD risk factors and suboptimal implementation of prevention strategies in the general population.²

The most recent (2019) iteration of the American College of Cardiology/American Heart Association (ACC/AHA) Guideline on the Primary Prevention of Cardiovascular Disease emphasizes a comprehensive, patient-centered, team-based approach to the management of ASCVD risk factors.² In this article, I review how, first, medication to reduce ASCVD risk should be considered only when a patient’s risk is sufficiently high and, second, shared decision-making and social determinants of health should, in all cases, guide and inform optimal implementation of treatment.²

Estimating risk for ASCVD by ascertaining LDL-C

• The Friedewald equation. Traditionally, low-density lipoprotein cholesterol (LDL-C) is estimated using the Friedewald equation^a applied to a fasting lipid profile. In patients who have a low level of LDL-C (< 70 mg/dL), however, the Friedewald equation becomes less accurate; in patients with hypertriglyceridemia (TG ≥ 400 mg/dL),estimation of LDL-C is invalid.
• The Martin–Hopkins equation offers a validated estimation of LDL-C when the LDL-C value is < 70 mg/dL.³ This equation—in which the fixed factor of 5 used in the Friedewald equation to estimate very low-density lipoprotein cholesterol is replaced by an adjustable factor that is based on the patient’s non-HDL-C (ie, TC–HDL-C) and TG values—is preferred by the ACC/AHA Task Force on Clinical Practice Guidelines in this clinical circumstance.⁴
• National Institutes of Health equation. This newer equation provides an accurate estimate of the LDL-C level in patients whose TG value is ≤ 800 mg/dL. The equation has not been fully validated for clinical use, however.⁵
• Direct measurement obviates the need for an equation to estimate LDL-C, but the test is not available in all health care settings.

For adults ≥ 20 years of age who are not receiving lipid-lowering therapy, a nonfasting lipid profile can be used to estimate ASCVD risk and document the baseline LDL-C level. If the TG level is ≥ 400 mg/dL, the test should be administered in the fasting state.⁴

• Apolipoprotein B. Alternatively, apolipoprotein B (apoB) can be measured. Because each LDL-C particle contains 1 apoB molecule, the apoB level describes the LDL-C level more accurately than a calculation of LDL-C. Many patients with type 2 diabetes and metabolic syndrome have a relatively low calculated LDL-C (thereby falsely reassuring the testing clinician) but have an elevated apoB level. An apoB level ≥ 130 mg/dL corresponds to an LDL-C level >160 mg/dL.⁴
• Calculation of non-HDL-C. Because the nonfasting state does not have a significant impact on a patient’s TC and HDL-C levels, the non-HDL-C level also can be calculated from the results of a nonfasting lipid profile.

Non-HDL-C and apoB are equivalent predictors of ASCVD risk. These 2 assessments might offer better risk estimation than other available tools in patients who have type 2 diabetes and metabolic syndrome.⁶

Continue to: Applying the estimate of 10-year ASCVD risk...

 

 

Applying the estimate of 10-year ASCVD risk

Your recommendation for preventive intervention, such as lipid-lowering therapy, should be based on the estimated 10-year risk for ASCVD. Although multiple validated risk assessment tools are available, ACC/AHA recommends the pooled cohort risk equations (PCE), introduced in the 2013 ACC/AHA cholesterol treatment guidelines. The Framingham Heart Study now recommends the ACC/AHA PCE for risk assessment as well.⁷

The PCE, developed from 5 large cohorts, is based on hard atherosclerotic events: nonfatal myocardial infarction, death from coronary artery disease, and stroke. The ACC/AHA PCE is the only risk assessment tool developed using a significant percentage of patients who self-identify as Black.⁸ Alternatives to the ACC/AHA PCE include:

• Multi-ethnic Study of Atherosclerosis (MESA) 10-year ASCVD risk calculator, which incorporates the coronary artery calcium (CAC) score.
• Reynolds Risk Score, which incorporates high-sensitivity C-reactive protein measurement and a family history of premature ASCVD.⁹

How much does lifestyle modification actually matter?

The absolute impact of diet and exercise on lipid parameters is relatively modest. No studies have demonstrated a reduction in adverse cardiovascular outcomes with specific interventions regarding diet or activity.

• Diet. Nevertheless, ACC/AHA recommends that at-risk patients follow a dietary pattern that (1) emphasizes vegetables, fruits, and whole grains and (2) limits sweets, sugar-sweetened beverages, and red meat.

Saturated fat should constitute no more than 5% or 6% of total calories. In controlled-feeding trials,¹⁰ for every 1% of calories from saturated fat that are replaced with carbohydrate or monounsaturated or polyunsaturated fat, the LDL-C level was found to decline by as much as 1.8 mg/dL. Evidence is insufficient to assert that lowering dietary cholesterol reduces LDL-C.¹¹

• Activity. Trials of aerobic physical activity, compared with a more sedentary activity pattern, have demonstrated a reduction in the LDL-C level of as much as 6 mg/dL. All adult patients should be counseled to engage in aerobic physical activity of moderate or vigorous intensity—averaging ≥ 40 minutes per session, 3 or 4 sessions per week.¹¹

Primary prevention: Stratification by age

• 40 to 75 years. ACC/AHA recommends that you routinely assess traditional cardiovascular risk factors for these patients and calculate their 10-year risk for ASCVD using the PCE. Statin therapy as primary prevention is indicated for 3 major groups (TABLE 1).⁴ The US Preventive Services Task Force (USPSTF) recommends a 10-year ASCVD risk ≥ 10%, in conjunction with 1 or more additional CVD risk factors (dyslipidemia, diabetes, hypertension, smoking), as the threshold for initiating low- or moderate-intensity statin therapy in this age group.¹²

In adults at borderline risk (5% to < 7.5% 10-year ASCVD risk) or intermediate risk (≥ 7.5% to < 20% 10-year ASCVD risk), consider risk-enhancing factors to better inform your recommendation for preventive interventions. In these 2 groups, the presence of risk-enhancing factors might justify moderate-intensity statin therapy (TABLE 2⁴).

If your decision regarding preventive intervention remains uncertain, measuring CAC might further guide your discussion with the patient.⁴ When the CAC score is:

• 0 Agatston units and higher-risk conditions (eg, diabetes, family history of premature coronary artery disease, smoking) are absent, statin therapy can be withheld; reassess ASCVD risk in 5 to 10 years.
• 1-99 Agatston units, statin therapy can be started, especially for patients ≥ 55 years of age.
• ≥ 100 Agatston units or ≥ 75th percentile, statin therapy is indicated for all patients, regardless of additional risk factors.⁴

Because statins promote progression from unstable, inflammatory atherosclerotic plaque to more stable, calcified plaque, CAC scoring is not valid in patients already on statin therapy.¹³

In primary prevention, patients who have been classified as having low or intermediate risk, based on ASCVD risk scoring, with a CAC score of 0 Agatston units, have an annual all-cause mortality < 1%, regardless of age and gender. Patients classified as being at high risk, based on ASCVD risk scoring, with a CAC score of 0 Agatston units, have a significantly lower annual mortality than low- or intermediate-risk patients with a CAC score > 0 Agatston units.¹⁴

• 20 to 39 years. Focus on evaluation of lifetime ASCVD risk, rather than short-term (10-year) risk. Lifestyle modification is the primary intervention for younger patients; for those with moderate hypercholesterolemia (LDL-C, 160-189 mg/dL) and a family history of premature ASCVD, however, consider statin therapy. For patients with LDL-C ≥ 190 mg/dL, lifetime ASCVD risk is markedly increased, and high-intensity statin therapy is recommended, regardless of age. In this group, reassess ASCVD risk factors every 4 to 6 years.⁴
• > 75 years, without ASCVD. In this group, the benefit of statin therapy is less clear and might be lessened by an increased potential for adverse effects. A meta-analysis of 28 trials demonstrated that people ages > 75 years had a 24% relative reduction in major coronary events for every 38.7 mg/dL (1.0 mmol/L) reduction in LDL-C, which is comparable to the risk reduction seen in people ages 40 to 75 years.¹⁵

With increasing age, however, the relative reduction in major coronary events with statin therapy decreased,¹⁵ although other trials have not demonstrated age heterogeneity.¹⁶ Because people > 75 years of age have a significantly higher ASCVD event rate, a comparable relative rate reduction with statin therapy results in a larger absolute rate reduction (ARR) and, therefore, a smaller number needed to treat (NNT) to prevent an event, compared to the NNT in younger people.

Secondary prevention

ACC/AHA guidelines define clinical ASCVD as a history of:

• acute coronary syndrome
• myocardial infarction
• coronary or other arterial revascularization
• cerebrovascular event
• symptomatic peripheral artery disease, including aortic aneurysm.

High-intensity statin therapy is indicated for all patients ≤ 75 years who have clinical ASCVD. In patients > 75 years, consider a taper to moderate-intensity statin therapy. An upper age limit for seeing benefit from statin therapy in secondary prevention has not been identified.⁴

In high-risk patients, if LDL-C remains ≥ 70 mg/dL despite maximally tolerated statin therapy, ezetimibe (discussed in the next section) can be added. In very-high-risk patients, if LDL-C remains ≥ 70 mg/dL despite maximally tolerated statin therapy plus ezetimibe, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor (also discussed next) can be added. Always precede initiation of a PCSK9 inhibitor with a discussion of the net benefit, safety, and cost with the patient.⁴

Continue to: Options for lipid-lowering pharmacotherapy...

 

 

Options for lipid-lowering pharmacotherapy

• Statins (formally, hydroxymethylglutaryl-coenzyme A reductase inhibitors) offer the most predictable reduction in ASCVD risk of any lipid-lowering therapy. The evidence report that accompanied the 2016 USPSTF guidelines on statins for the prevention of cardiovascular disease (CVD) stated that low- or moderate-dosage statin therapy is associated with approximately a 30% relative risk reduction (RRR) in CVD events and CVD deaths and a 10% to 15% RRR in all-cause mortality.¹⁷

High-intensity statin therapy reduces LDL-C by ≥ 50%. Moderate-intensity statin therapy reduces LDL-C by 30% to 49% (TABLE 3).⁴

Statins are not without risk: A 2016 report¹⁸ estimated that treating 10,000 patients with a statin for 5 years would cause 1 case of rhabdomyolysis, 5 cases of myopathy, 75 new cases of diabetes, and 7 cases of hemorrhagic stroke. The same treatment would, however, avert approximately 1000 CVD events among patients with preexisting disease and approximately 500 CVD events among patients at elevated risk but without preexisting disease.¹⁸

• Ezetimibe, a selective cholesterol-absorption inhibitor, lowers LDL-C by 13% to 20% and typically is well tolerated. The use of ezetimibe in ASCVD risk reduction is supported by a single randomized controlled trial of more than 18,000 patients with recent acute coronary syndrome. Adding ezetimibe to simvastatin 40 mg resulted in a 2% absolute reduction in major adverse cardiovascular events over a median follow-up of 6 years (NNT = 50), compared to simvastatin alone.¹⁹ ACC/AHA guidelines recommend adding ezetimibe to maximally tolerated statin therapy in patients with clinical ASCVD who do not reach their goal LDL reduction with a statin alone. Ezetimibe also can be considered a statin alternative in patients who are statin intolerant.⁴
• PCSK9 inhibitors. When added to statin therapy, evolocumab and alirocumab—monoclonal antibodies that inhibit PCSK9—offer an incremental decrease in LDL-C of approximately 60%.^20-22 In a meta-analysis of 35 trials evaluating the incremental benefit of PCSK9 inhibitor therapy, a significant reduction in cardiovascular events, including myocardial infarction (ARR = 1.3%; NNT = 77), stroke (ARR = 0.4%; NNT = 250), and coronary revascularization (ARR = 1.6%; NNT = 63) was reported. No significant difference was observed in all-cause or cardiovascular mortality.^21,23
• Inclisiran, an injectable small-interfering RNA that inhibits PCSK9 synthesis, provides an incremental decrease in LDL-C of > 50% in patients already receiving statin therapy. Meta-analysis of 3 small cardiovascular outcomes trials revealed no significant difference in the rate of myocardial infarction, stroke, or cardiovascular mortality with inclisiran compared to placebo. Larger outcomes trials are underway and might offer additional insight into this agent’s role in ASCVD risk management.²⁴
• Omega-3 fatty acids. Multiple trials have demonstrated that adding omega-3 fatty acids to usual lipid-lowering therapy does not offer a consistent reduction in adverse cardiovascular outcomes, despite providing a significant reduction in TG levels. In a high-risk population with persistently elevated TG despite statin therapy, icosapent ethyl, a purified eicosapentaenoic acid ethyl ester, reduced major ASCVD outcomes by 25% over a median 4.9 years (ARR = 4.8%; NNT = 21), and cardiovascular death by 20% (ARR = 0.9%; NNT = 111), compared with a mineral oil placebo.²⁵ Subsequent trials, using a corn oil placebo, failed to duplicate these data²⁶—raising concern that the mineral oil comparator might have altered results of the eicosapentaenoic acid ethyl ester study.^27,28
• Bempedoic acid is a small-molecule inhibitor of ATP citrate lyase that increases LDL uptake by the liver. Pooled data from studies of bempedoic acid show, on average, a 15% reduction in TC, a 23% reduction in LDL-C, and a 6% increase in HDL-C, without a significant change in TG.²⁹ In statin-intolerant patients, bempedoicacid reduced major ASCVD outcomes by 13% over a median 40 months (ARR = 1.6%; NNT = 63), with no significant reduction in cardiovascular death.³⁰
• Niacin. Two large trials failed to demonstrate improvement in major cardiovascular events or other clinical benefit when niacin is added to moderate-intensity statin therapy, despite a significant increase in the HDL-C level (on average, 6 mg/dL) and a decrease in the LDL-C level (10-12 mg/dL)and TG (42 mg/dL).^31,32
• Fenofibrate lowers TG and increases HDL-C but does not consistently improve cardiovascular outcomes.³³ In a trial of patients with type 2 diabetes and persistent dyslipidemia (serum TG > 204 mg/dL; HDL-C< 34 mg/dL) despite statin therapy, adding fenofibrate reduced CVD outcomes by 4.9%—although this absolute difference did not reach statistical significance.³⁴

Neither niacin nor fenofibrate is considered useful for reducing ASCVD risk across broad populations.⁴

Follow-up to assess progress toward goals

Recheck the lipid profile 4 to 12 weeks after starting lipid-lowering therapy to verify adherence to medication and assess response. The primary goal is the percentage reduction in LDL-C based on ASCVD risk. An additional goal for very-high-risk patients is an LDL-C value ≤ 70 mg/dL. If the reduction in LDL-C is less than desired and adherence is assured, consider titrating the statin dosage or augmenting statin therapy with a nonstatin drug (eg, ezetimibe), or both.⁴ ●

CORRESPONDENCE

Jonathon M. Firnhaber, MD, MAEd, MBA, East Carolina University, Family Medicine Center, 101 Heart Drive, Greenville, NC 27834; firnhaberj@ecu.edu

An elevated serum level of cholesterol has been recognized as a risk factor for atherosclerotic cardiovascular disease (ASCVD) since the publication of the Framingham Study in 1961.¹ Although clinical outcomes related to ASCVD have improved in recent decades, ASCVD remains the leading cause of morbidity and mortality across the globe and remains, in the United States, the leading cause of death among most racial and ethnic groups. Much of this persistent disease burden can be attributed to inadequate control of ASCVD risk factors and suboptimal implementation of prevention strategies in the general population.²

The most recent (2019) iteration of the American College of Cardiology/American Heart Association (ACC/AHA) Guideline on the Primary Prevention of Cardiovascular Disease emphasizes a comprehensive, patient-centered, team-based approach to the management of ASCVD risk factors.² In this article, I review how, first, medication to reduce ASCVD risk should be considered only when a patient’s risk is sufficiently high and, second, shared decision-making and social determinants of health should, in all cases, guide and inform optimal implementation of treatment.²

Estimating risk for ASCVD by ascertaining LDL-C

• The Friedewald equation. Traditionally, low-density lipoprotein cholesterol (LDL-C) is estimated using the Friedewald equation^a applied to a fasting lipid profile. In patients who have a low level of LDL-C (< 70 mg/dL), however, the Friedewald equation becomes less accurate; in patients with hypertriglyceridemia (TG ≥ 400 mg/dL),estimation of LDL-C is invalid.
• The Martin–Hopkins equation offers a validated estimation of LDL-C when the LDL-C value is < 70 mg/dL.³ This equation—in which the fixed factor of 5 used in the Friedewald equation to estimate very low-density lipoprotein cholesterol is replaced by an adjustable factor that is based on the patient’s non-HDL-C (ie, TC–HDL-C) and TG values—is preferred by the ACC/AHA Task Force on Clinical Practice Guidelines in this clinical circumstance.⁴
• National Institutes of Health equation. This newer equation provides an accurate estimate of the LDL-C level in patients whose TG value is ≤ 800 mg/dL. The equation has not been fully validated for clinical use, however.⁵
• Direct measurement obviates the need for an equation to estimate LDL-C, but the test is not available in all health care settings.

For adults ≥ 20 years of age who are not receiving lipid-lowering therapy, a nonfasting lipid profile can be used to estimate ASCVD risk and document the baseline LDL-C level. If the TG level is ≥ 400 mg/dL, the test should be administered in the fasting state.⁴

• Apolipoprotein B. Alternatively, apolipoprotein B (apoB) can be measured. Because each LDL-C particle contains 1 apoB molecule, the apoB level describes the LDL-C level more accurately than a calculation of LDL-C. Many patients with type 2 diabetes and metabolic syndrome have a relatively low calculated LDL-C (thereby falsely reassuring the testing clinician) but have an elevated apoB level. An apoB level ≥ 130 mg/dL corresponds to an LDL-C level >160 mg/dL.⁴
• Calculation of non-HDL-C. Because the nonfasting state does not have a significant impact on a patient’s TC and HDL-C levels, the non-HDL-C level also can be calculated from the results of a nonfasting lipid profile.

Non-HDL-C and apoB are equivalent predictors of ASCVD risk. These 2 assessments might offer better risk estimation than other available tools in patients who have type 2 diabetes and metabolic syndrome.⁶

Continue to: Applying the estimate of 10-year ASCVD risk...

 

 

Applying the estimate of 10-year ASCVD risk

Your recommendation for preventive intervention, such as lipid-lowering therapy, should be based on the estimated 10-year risk for ASCVD. Although multiple validated risk assessment tools are available, ACC/AHA recommends the pooled cohort risk equations (PCE), introduced in the 2013 ACC/AHA cholesterol treatment guidelines. The Framingham Heart Study now recommends the ACC/AHA PCE for risk assessment as well.⁷

The PCE, developed from 5 large cohorts, is based on hard atherosclerotic events: nonfatal myocardial infarction, death from coronary artery disease, and stroke. The ACC/AHA PCE is the only risk assessment tool developed using a significant percentage of patients who self-identify as Black.⁸ Alternatives to the ACC/AHA PCE include:

• Multi-ethnic Study of Atherosclerosis (MESA) 10-year ASCVD risk calculator, which incorporates the coronary artery calcium (CAC) score.
• Reynolds Risk Score, which incorporates high-sensitivity C-reactive protein measurement and a family history of premature ASCVD.⁹

How much does lifestyle modification actually matter?

The absolute impact of diet and exercise on lipid parameters is relatively modest. No studies have demonstrated a reduction in adverse cardiovascular outcomes with specific interventions regarding diet or activity.

• Diet. Nevertheless, ACC/AHA recommends that at-risk patients follow a dietary pattern that (1) emphasizes vegetables, fruits, and whole grains and (2) limits sweets, sugar-sweetened beverages, and red meat.

Saturated fat should constitute no more than 5% or 6% of total calories. In controlled-feeding trials,¹⁰ for every 1% of calories from saturated fat that are replaced with carbohydrate or monounsaturated or polyunsaturated fat, the LDL-C level was found to decline by as much as 1.8 mg/dL. Evidence is insufficient to assert that lowering dietary cholesterol reduces LDL-C.¹¹

• Activity. Trials of aerobic physical activity, compared with a more sedentary activity pattern, have demonstrated a reduction in the LDL-C level of as much as 6 mg/dL. All adult patients should be counseled to engage in aerobic physical activity of moderate or vigorous intensity—averaging ≥ 40 minutes per session, 3 or 4 sessions per week.¹¹

Primary prevention: Stratification by age

• 40 to 75 years. ACC/AHA recommends that you routinely assess traditional cardiovascular risk factors for these patients and calculate their 10-year risk for ASCVD using the PCE. Statin therapy as primary prevention is indicated for 3 major groups (TABLE 1).⁴ The US Preventive Services Task Force (USPSTF) recommends a 10-year ASCVD risk ≥ 10%, in conjunction with 1 or more additional CVD risk factors (dyslipidemia, diabetes, hypertension, smoking), as the threshold for initiating low- or moderate-intensity statin therapy in this age group.¹²

In adults at borderline risk (5% to < 7.5% 10-year ASCVD risk) or intermediate risk (≥ 7.5% to < 20% 10-year ASCVD risk), consider risk-enhancing factors to better inform your recommendation for preventive interventions. In these 2 groups, the presence of risk-enhancing factors might justify moderate-intensity statin therapy (TABLE 2⁴).

If your decision regarding preventive intervention remains uncertain, measuring CAC might further guide your discussion with the patient.⁴ When the CAC score is:

• 0 Agatston units and higher-risk conditions (eg, diabetes, family history of premature coronary artery disease, smoking) are absent, statin therapy can be withheld; reassess ASCVD risk in 5 to 10 years.
• 1-99 Agatston units, statin therapy can be started, especially for patients ≥ 55 years of age.
• ≥ 100 Agatston units or ≥ 75th percentile, statin therapy is indicated for all patients, regardless of additional risk factors.⁴

Because statins promote progression from unstable, inflammatory atherosclerotic plaque to more stable, calcified plaque, CAC scoring is not valid in patients already on statin therapy.¹³

In primary prevention, patients who have been classified as having low or intermediate risk, based on ASCVD risk scoring, with a CAC score of 0 Agatston units, have an annual all-cause mortality < 1%, regardless of age and gender. Patients classified as being at high risk, based on ASCVD risk scoring, with a CAC score of 0 Agatston units, have a significantly lower annual mortality than low- or intermediate-risk patients with a CAC score > 0 Agatston units.¹⁴

• 20 to 39 years. Focus on evaluation of lifetime ASCVD risk, rather than short-term (10-year) risk. Lifestyle modification is the primary intervention for younger patients; for those with moderate hypercholesterolemia (LDL-C, 160-189 mg/dL) and a family history of premature ASCVD, however, consider statin therapy. For patients with LDL-C ≥ 190 mg/dL, lifetime ASCVD risk is markedly increased, and high-intensity statin therapy is recommended, regardless of age. In this group, reassess ASCVD risk factors every 4 to 6 years.⁴
• > 75 years, without ASCVD. In this group, the benefit of statin therapy is less clear and might be lessened by an increased potential for adverse effects. A meta-analysis of 28 trials demonstrated that people ages > 75 years had a 24% relative reduction in major coronary events for every 38.7 mg/dL (1.0 mmol/L) reduction in LDL-C, which is comparable to the risk reduction seen in people ages 40 to 75 years.¹⁵

With increasing age, however, the relative reduction in major coronary events with statin therapy decreased,¹⁵ although other trials have not demonstrated age heterogeneity.¹⁶ Because people > 75 years of age have a significantly higher ASCVD event rate, a comparable relative rate reduction with statin therapy results in a larger absolute rate reduction (ARR) and, therefore, a smaller number needed to treat (NNT) to prevent an event, compared to the NNT in younger people.

Secondary prevention

ACC/AHA guidelines define clinical ASCVD as a history of:

• acute coronary syndrome
• myocardial infarction
• coronary or other arterial revascularization
• cerebrovascular event
• symptomatic peripheral artery disease, including aortic aneurysm.

High-intensity statin therapy is indicated for all patients ≤ 75 years who have clinical ASCVD. In patients > 75 years, consider a taper to moderate-intensity statin therapy. An upper age limit for seeing benefit from statin therapy in secondary prevention has not been identified.⁴

In high-risk patients, if LDL-C remains ≥ 70 mg/dL despite maximally tolerated statin therapy, ezetimibe (discussed in the next section) can be added. In very-high-risk patients, if LDL-C remains ≥ 70 mg/dL despite maximally tolerated statin therapy plus ezetimibe, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor (also discussed next) can be added. Always precede initiation of a PCSK9 inhibitor with a discussion of the net benefit, safety, and cost with the patient.⁴

Continue to: Options for lipid-lowering pharmacotherapy...

 

 

Options for lipid-lowering pharmacotherapy

• Statins (formally, hydroxymethylglutaryl-coenzyme A reductase inhibitors) offer the most predictable reduction in ASCVD risk of any lipid-lowering therapy. The evidence report that accompanied the 2016 USPSTF guidelines on statins for the prevention of cardiovascular disease (CVD) stated that low- or moderate-dosage statin therapy is associated with approximately a 30% relative risk reduction (RRR) in CVD events and CVD deaths and a 10% to 15% RRR in all-cause mortality.¹⁷

High-intensity statin therapy reduces LDL-C by ≥ 50%. Moderate-intensity statin therapy reduces LDL-C by 30% to 49% (TABLE 3).⁴

Statins are not without risk: A 2016 report¹⁸ estimated that treating 10,000 patients with a statin for 5 years would cause 1 case of rhabdomyolysis, 5 cases of myopathy, 75 new cases of diabetes, and 7 cases of hemorrhagic stroke. The same treatment would, however, avert approximately 1000 CVD events among patients with preexisting disease and approximately 500 CVD events among patients at elevated risk but without preexisting disease.¹⁸

• Ezetimibe, a selective cholesterol-absorption inhibitor, lowers LDL-C by 13% to 20% and typically is well tolerated. The use of ezetimibe in ASCVD risk reduction is supported by a single randomized controlled trial of more than 18,000 patients with recent acute coronary syndrome. Adding ezetimibe to simvastatin 40 mg resulted in a 2% absolute reduction in major adverse cardiovascular events over a median follow-up of 6 years (NNT = 50), compared to simvastatin alone.¹⁹ ACC/AHA guidelines recommend adding ezetimibe to maximally tolerated statin therapy in patients with clinical ASCVD who do not reach their goal LDL reduction with a statin alone. Ezetimibe also can be considered a statin alternative in patients who are statin intolerant.⁴
• PCSK9 inhibitors. When added to statin therapy, evolocumab and alirocumab—monoclonal antibodies that inhibit PCSK9—offer an incremental decrease in LDL-C of approximately 60%.^20-22 In a meta-analysis of 35 trials evaluating the incremental benefit of PCSK9 inhibitor therapy, a significant reduction in cardiovascular events, including myocardial infarction (ARR = 1.3%; NNT = 77), stroke (ARR = 0.4%; NNT = 250), and coronary revascularization (ARR = 1.6%; NNT = 63) was reported. No significant difference was observed in all-cause or cardiovascular mortality.^21,23
• Inclisiran, an injectable small-interfering RNA that inhibits PCSK9 synthesis, provides an incremental decrease in LDL-C of > 50% in patients already receiving statin therapy. Meta-analysis of 3 small cardiovascular outcomes trials revealed no significant difference in the rate of myocardial infarction, stroke, or cardiovascular mortality with inclisiran compared to placebo. Larger outcomes trials are underway and might offer additional insight into this agent’s role in ASCVD risk management.²⁴
• Omega-3 fatty acids. Multiple trials have demonstrated that adding omega-3 fatty acids to usual lipid-lowering therapy does not offer a consistent reduction in adverse cardiovascular outcomes, despite providing a significant reduction in TG levels. In a high-risk population with persistently elevated TG despite statin therapy, icosapent ethyl, a purified eicosapentaenoic acid ethyl ester, reduced major ASCVD outcomes by 25% over a median 4.9 years (ARR = 4.8%; NNT = 21), and cardiovascular death by 20% (ARR = 0.9%; NNT = 111), compared with a mineral oil placebo.²⁵ Subsequent trials, using a corn oil placebo, failed to duplicate these data²⁶—raising concern that the mineral oil comparator might have altered results of the eicosapentaenoic acid ethyl ester study.^27,28
• Bempedoic acid is a small-molecule inhibitor of ATP citrate lyase that increases LDL uptake by the liver. Pooled data from studies of bempedoic acid show, on average, a 15% reduction in TC, a 23% reduction in LDL-C, and a 6% increase in HDL-C, without a significant change in TG.²⁹ In statin-intolerant patients, bempedoicacid reduced major ASCVD outcomes by 13% over a median 40 months (ARR = 1.6%; NNT = 63), with no significant reduction in cardiovascular death.³⁰
• Niacin. Two large trials failed to demonstrate improvement in major cardiovascular events or other clinical benefit when niacin is added to moderate-intensity statin therapy, despite a significant increase in the HDL-C level (on average, 6 mg/dL) and a decrease in the LDL-C level (10-12 mg/dL)and TG (42 mg/dL).^31,32
• Fenofibrate lowers TG and increases HDL-C but does not consistently improve cardiovascular outcomes.³³ In a trial of patients with type 2 diabetes and persistent dyslipidemia (serum TG > 204 mg/dL; HDL-C< 34 mg/dL) despite statin therapy, adding fenofibrate reduced CVD outcomes by 4.9%—although this absolute difference did not reach statistical significance.³⁴

Neither niacin nor fenofibrate is considered useful for reducing ASCVD risk across broad populations.⁴

Follow-up to assess progress toward goals

Recheck the lipid profile 4 to 12 weeks after starting lipid-lowering therapy to verify adherence to medication and assess response. The primary goal is the percentage reduction in LDL-C based on ASCVD risk. An additional goal for very-high-risk patients is an LDL-C value ≤ 70 mg/dL. If the reduction in LDL-C is less than desired and adherence is assured, consider titrating the statin dosage or augmenting statin therapy with a nonstatin drug (eg, ezetimibe), or both.⁴ ●

CORRESPONDENCE

Jonathon M. Firnhaber, MD, MAEd, MBA, East Carolina University, Family Medicine Center, 101 Heart Drive, Greenville, NC 27834; firnhaberj@ecu.edu

Whole exome sequencing’s role in diagnosing genetic causes of FGR with and without associated anomalies

Mone F, Mellis R, Gabriel H, et al. Should we offer prenatal exome sequencing for intrauterine growth restriction or short long bones? A systematic review and meta-analysis. Am J Obstet Gynecol. Published online October 7, 2022. doi:10.1016/j.ajog.2022.09.045

Multiple factors can play a role in FGR, including inherent maternal, placental, or fetal factors; the environment; and/or nutrition. However, prenatal diagnosis is an important consideration when exploring the underlying etiology for a growth-restricted fetus, especially in severe or early-onset cases. Many genetic conditions do not result in structural anomalies but can disrupt overall growth. Additionally, phenotyping in the prenatal period is limited and can miss more subtle physical differences that could point to a genetic cause. 

When compared with karyotype, chromosomal microarray (CMA) has been shown to increase the diagnostic yield in cases of isolated early FGR by 5%,^1,2 and the incidence of chromosomal abnormalities has been reported to be as high as 19% in this population. Let’s explore the data on exome sequencing for prenatal diagnosis in cases of isolated FGR. 

Meta-analysis details

In this meta-analysis, the authors reviewed 19 cohort studies or case series that investigated the yield of prenatal sequencing in fetuses with intrauterine growth restriction (IUGR) or short long bones, both in association with and without additional anomalies. All cases had nondiagnostic cytogenetic results. Fetal DNA in most cases was obtained through amniocentesis. Variants classified as likely pathogenic and pathogenic were considered diagnostic. The authors then calculated the incremental yield of prenatal sequencing over cytogenetic studies as a pooled value, comparing the following groups:

• isolated FGR
• growth restriction with associated anomalies
• isolated short long bones
• short long bones with additional skeletal features.  

Study outcomes 

The total number of cases were as follows: isolated IUGR (n = 71), IUGR associated with additional anomalies (n = 45), isolated short long bones (n = 84), and short long bones associated with additional skeletal findings (n = 252). Causative pathogenic or likely pathogenic variants were identified in 224 (50%) cases. Apparent incremental yields with prenatal sequencing were as follows for the 4 groups (as illustrated in the FIGURE):

• 4% in isolated IUGR (95% confidence interval [CI], -5%–12%)
• 30% in IUGR with additional anomalies (95% CI, 13%–47%)
• 48% in isolated short long bones (95% CI, 26%–70%)
• 68% in short long bones with additional skeletal changes (95% CI, 58%–77%).

Overall, the authors concluded that prenatal sequencing does not improve prenatal diagnosis in cases of isolated IUGR. The majority of these cases were thought to be related to placental insufficiency.

Strengths and limitations 

The main limitation of this study with regard to our discussion is the small study populationof isolated growth restriction. The authors indicate that the number of cases of isolated IUGR were too small to draw firm conclusions. Another limitation was the heterogeneity of the isolated FGR population, which was not limited to severe or early-onset cases. However, the authors did demonstrate that growth restriction in association with fetal anomalies has very high genetic yield rates with prenatal sequencing. 

Continue to: Can whole exome sequencing diagnose genetic causes in cases of severe isolated FGR?...

 

 

Can whole exome sequencing diagnose genetic causes in cases of severe isolated FGR? 

Zhou H, Fu F, Wang Y, et al. Genetic causes of isolated and severe fetal growth restriction in normal chromosomal microarray analysis. Int J Gynaecol Obstet. Published online December 10, 2022. doi:10.1002/ijgo.14620

Severe FGR is diagnosed based on an estimated fetal weight (EFW) or abdominal circumference (AC) below the third percentile. As we discussed in the above study by Mone and colleagues, it does not appear that prenatal sequencing significantly improves the diagnostic yield in all isolated FGR cases. However, this has not been previously explored in isolated severe FGR or cases of early-onset FGR (<32 weeks’ gestation). We know that several monogenic conditions are associated with severe and early-onset isolated fetal growth impairment, including but not limited to Cornelia de Lange syndrome, Smith-Lemli-Opitz syndrome, and Meier-Gorlin syndrome. Often, these syndromes can present in the prenatal period without other phenotypic findings. Therefore, this study explored the possibility that prenatal sequencing plays an important role for severe cases of FGR with nondiagnostic CMA and/or karyotype. 

Retrospective study details 

Zhou and colleagues retrospectively analyzed 51 cases of severe (EFW or AC below the third percentile) isolated FGR with negative CMA who underwent trio whole exome sequencing, which includes submitting fetal cells as well as both parental samples for testing. Patients with abnormal toxoplasmosis, rubella, cytomegalovirus, and herpes simplex virus (TORCH) tests; structural anomalies; and multiple gestation were excluded from the analysis. As in the study by Mone et al, variants classified as likely pathogenic and pathogenic were categorized as diagnostic. 

Results

Eight of 51 cases (15.7%) with severe isolated FGR had diagnostic findings on trio whole exome sequencing as shown in the TABLE. Another 8 cases (15.7%) were found to have variants of unknown significance, of which 2 were later determined to be novel pathogenic variants. Genetic conditions uncovered in this cohort include Cornelia de Lange syndrome, pyruvate dehydrogenase deficiency, Dent disease, trichohepaticenteric syndrome, achondroplasia, osteogenesis imperfecta, Pendred syndrome, and both autosomal dominant type 3A and autosomal recessive type 1A deafness. All 10 cases with diagnostic whole exome sequencing or identified novel pathogenic variants were affected by early-onset FGR (<32 weeks’ gestation). Of these 10 cases, 7 patients underwent pregnancy termination.

To summarize, a total of 10 cases (19.6%) of severe isolated early-onset FGR with negative cytogenetic studies were subsequently diagnosed with an underlying genetic condition using prenatal trio whole exome sequencing. 

Strengths and limitations 

This study is retrospective and has a small sample size (n = 51) that was mostly limited to early-onset isolated severe FGR. However, the diagnostic yield (19.6%) of whole exome sequencing after negative CMA testing was noteworthy and shows that monogenic conditions are an important consideration in the evaluation of severe early-onset FGR, even in the absence of structural abnormalities. 

Could epigenetic mechanisms of placental dysregulation explain low birthweight and future cardiometabolic disease?  

Tekola-Ayele F, Zeng X, Chatterjee S, et al. Placental multi-omics integration identifies candidate functional genes for birthweight. Nat Commun. 2022;13:2384.

FGR has been linked to greater mortality in childhood and increased risk for cardiometabolic disease in adulthood. While genomewide associations studies (GWAS) have defined areas of interest linking genetic variants to low birthweight, their relationship to epigenetic changes in the placenta as well as biologic and functional mechanisms are not yet well understood.  

Multiomics used to identify candidate functional genes for birthweight 

This study analyzed the methylation and gene expression patterns of 291 placental samples, integrating findings into pathways of previously defined GWAS variants. Patient samples were obtained from participants in the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Fetal Growth Studies–Singleton cohort. The cohort is ethnically diverse, with 97 Hispanic, 74 White, 71 Black, and 49 Asian participants. Of 286 single nucleotide polymorphisms (SNPs) found to be associated with birthweight, 273 were analyzed as part of the authors’ data set. These were found to have 7,901 unique protein-coding mRNAs (expression quantitative trait loci [eQTL]) and more than 100,000 nearby (within 1 Mb) CpG islands thought to be involved in changes in DNA methylation (methylation quantitative trait loci [mQTL]). Each functionally connected GWAS-eQTL-mQTL association is referred to as a triplet.

The next arm of the study investigatedthe connections and pathways within each triplet. Three possible scenarios were explored for birthweight GWAS SNPs using a causal interference test (CIT):

1. the SNP alters placental DNA methylation, which then influences gene expression
2. the SNP first alters placental DNA expression, which then influences methylation
3. the SNP influences placental DNA expression and methylation independently, with no notable crossover between their pathways.

Triplets were investigated using the Mendelian randomization (MR) Steiger directionality test to validate the directionality of the pathways found by CIT. Lastly, the possibility of linkage disequilibrium was also studied using the moloc test. 

Results

Using CIT, a causal relationship was predicted in 88 of 197 triplets, in which 84 (95.5%) indicated DNA methylation influences gene expression, and 4 (4.5%) indicated gene expression influences DNA methylation. The authors also used the MR Steiger test to investigate triplets to identify possible causal pathways. Using the MR Steiger test, only 3 of 45 (7%) triplets were found to have independent gene expression and methylation pathways. Thirty-eight of 45 (84%) triplets indicated that gene expression influences DNA methylation, and 7 (15%)triplets demonstrated that DNA methylation influences gene expression. Consistent predictions between CIT and the MR Steiger test revealed 3 triplets in which DNA methylation influences gene expression for the following genes: WNT3A, CTDNEP1, and RANBP2. Additionally, a strong colocalization signal was found among birthweight, DNA methylation, and gene expression for the following genes: PLEKHA1, FES, PRMT7, and CTDNEP1. Gene set enrichment analysis was performed as well and found that low birthweight is associated in substantial upregulation of genes associated with oxidative stress, immune response, adipogenesis, myogenesis, and the production of pancreatic ß cells.  

Study strengths and limitations

The study is one of the first to identify regulatory targets for placental DNA methylation and gene expression in previously identified GWAS loci associated with low birthweight. For example, DNA methylation was found to influence gene expression of WNT3A, CTDNEP1, and RANBP2, which have previously been shown in animal studies to impact the vascularization and development of the placenta, embryogenesis, and fetal growth. The study also identified 4 genes (PLEKHA1, FES, PRMT7, and CTDNEP1) thought to have direct regulatory influence on placental DNA methylation and gene expression.

A limitation of the study is that it could not distinguish between whether the epigenetic changes we outlined have a maternal or fetal origin. Another limitation is that tissue used by the authors for analysis was a small placental biopsy, which does not accurately reflect the genetic heterogeneity of the placenta. Finally, this study does not establish causality between the identified epigenetic pathways and low birthweight. ●

Whole exome sequencing’s role in diagnosing genetic causes of FGR with and without associated anomalies

Mone F, Mellis R, Gabriel H, et al. Should we offer prenatal exome sequencing for intrauterine growth restriction or short long bones? A systematic review and meta-analysis. Am J Obstet Gynecol. Published online October 7, 2022. doi:10.1016/j.ajog.2022.09.045

Multiple factors can play a role in FGR, including inherent maternal, placental, or fetal factors; the environment; and/or nutrition. However, prenatal diagnosis is an important consideration when exploring the underlying etiology for a growth-restricted fetus, especially in severe or early-onset cases. Many genetic conditions do not result in structural anomalies but can disrupt overall growth. Additionally, phenotyping in the prenatal period is limited and can miss more subtle physical differences that could point to a genetic cause. 

When compared with karyotype, chromosomal microarray (CMA) has been shown to increase the diagnostic yield in cases of isolated early FGR by 5%,^1,2 and the incidence of chromosomal abnormalities has been reported to be as high as 19% in this population. Let’s explore the data on exome sequencing for prenatal diagnosis in cases of isolated FGR. 

Meta-analysis details

In this meta-analysis, the authors reviewed 19 cohort studies or case series that investigated the yield of prenatal sequencing in fetuses with intrauterine growth restriction (IUGR) or short long bones, both in association with and without additional anomalies. All cases had nondiagnostic cytogenetic results. Fetal DNA in most cases was obtained through amniocentesis. Variants classified as likely pathogenic and pathogenic were considered diagnostic. The authors then calculated the incremental yield of prenatal sequencing over cytogenetic studies as a pooled value, comparing the following groups:

• isolated FGR
• growth restriction with associated anomalies
• isolated short long bones
• short long bones with additional skeletal features.  

Study outcomes 

The total number of cases were as follows: isolated IUGR (n = 71), IUGR associated with additional anomalies (n = 45), isolated short long bones (n = 84), and short long bones associated with additional skeletal findings (n = 252). Causative pathogenic or likely pathogenic variants were identified in 224 (50%) cases. Apparent incremental yields with prenatal sequencing were as follows for the 4 groups (as illustrated in the FIGURE):

• 4% in isolated IUGR (95% confidence interval [CI], -5%–12%)
• 30% in IUGR with additional anomalies (95% CI, 13%–47%)
• 48% in isolated short long bones (95% CI, 26%–70%)
• 68% in short long bones with additional skeletal changes (95% CI, 58%–77%).

Overall, the authors concluded that prenatal sequencing does not improve prenatal diagnosis in cases of isolated IUGR. The majority of these cases were thought to be related to placental insufficiency.

Strengths and limitations 

The main limitation of this study with regard to our discussion is the small study populationof isolated growth restriction. The authors indicate that the number of cases of isolated IUGR were too small to draw firm conclusions. Another limitation was the heterogeneity of the isolated FGR population, which was not limited to severe or early-onset cases. However, the authors did demonstrate that growth restriction in association with fetal anomalies has very high genetic yield rates with prenatal sequencing. 

Continue to: Can whole exome sequencing diagnose genetic causes in cases of severe isolated FGR?...

 

 

Can whole exome sequencing diagnose genetic causes in cases of severe isolated FGR? 

Zhou H, Fu F, Wang Y, et al. Genetic causes of isolated and severe fetal growth restriction in normal chromosomal microarray analysis. Int J Gynaecol Obstet. Published online December 10, 2022. doi:10.1002/ijgo.14620

Severe FGR is diagnosed based on an estimated fetal weight (EFW) or abdominal circumference (AC) below the third percentile. As we discussed in the above study by Mone and colleagues, it does not appear that prenatal sequencing significantly improves the diagnostic yield in all isolated FGR cases. However, this has not been previously explored in isolated severe FGR or cases of early-onset FGR (<32 weeks’ gestation). We know that several monogenic conditions are associated with severe and early-onset isolated fetal growth impairment, including but not limited to Cornelia de Lange syndrome, Smith-Lemli-Opitz syndrome, and Meier-Gorlin syndrome. Often, these syndromes can present in the prenatal period without other phenotypic findings. Therefore, this study explored the possibility that prenatal sequencing plays an important role for severe cases of FGR with nondiagnostic CMA and/or karyotype. 

Retrospective study details 

Zhou and colleagues retrospectively analyzed 51 cases of severe (EFW or AC below the third percentile) isolated FGR with negative CMA who underwent trio whole exome sequencing, which includes submitting fetal cells as well as both parental samples for testing. Patients with abnormal toxoplasmosis, rubella, cytomegalovirus, and herpes simplex virus (TORCH) tests; structural anomalies; and multiple gestation were excluded from the analysis. As in the study by Mone et al, variants classified as likely pathogenic and pathogenic were categorized as diagnostic. 

Results

Eight of 51 cases (15.7%) with severe isolated FGR had diagnostic findings on trio whole exome sequencing as shown in the TABLE. Another 8 cases (15.7%) were found to have variants of unknown significance, of which 2 were later determined to be novel pathogenic variants. Genetic conditions uncovered in this cohort include Cornelia de Lange syndrome, pyruvate dehydrogenase deficiency, Dent disease, trichohepaticenteric syndrome, achondroplasia, osteogenesis imperfecta, Pendred syndrome, and both autosomal dominant type 3A and autosomal recessive type 1A deafness. All 10 cases with diagnostic whole exome sequencing or identified novel pathogenic variants were affected by early-onset FGR (<32 weeks’ gestation). Of these 10 cases, 7 patients underwent pregnancy termination.

To summarize, a total of 10 cases (19.6%) of severe isolated early-onset FGR with negative cytogenetic studies were subsequently diagnosed with an underlying genetic condition using prenatal trio whole exome sequencing. 

Strengths and limitations 

This study is retrospective and has a small sample size (n = 51) that was mostly limited to early-onset isolated severe FGR. However, the diagnostic yield (19.6%) of whole exome sequencing after negative CMA testing was noteworthy and shows that monogenic conditions are an important consideration in the evaluation of severe early-onset FGR, even in the absence of structural abnormalities. 

Could epigenetic mechanisms of placental dysregulation explain low birthweight and future cardiometabolic disease?  

Tekola-Ayele F, Zeng X, Chatterjee S, et al. Placental multi-omics integration identifies candidate functional genes for birthweight. Nat Commun. 2022;13:2384.

FGR has been linked to greater mortality in childhood and increased risk for cardiometabolic disease in adulthood. While genomewide associations studies (GWAS) have defined areas of interest linking genetic variants to low birthweight, their relationship to epigenetic changes in the placenta as well as biologic and functional mechanisms are not yet well understood.  

Multiomics used to identify candidate functional genes for birthweight 

This study analyzed the methylation and gene expression patterns of 291 placental samples, integrating findings into pathways of previously defined GWAS variants. Patient samples were obtained from participants in the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Fetal Growth Studies–Singleton cohort. The cohort is ethnically diverse, with 97 Hispanic, 74 White, 71 Black, and 49 Asian participants. Of 286 single nucleotide polymorphisms (SNPs) found to be associated with birthweight, 273 were analyzed as part of the authors’ data set. These were found to have 7,901 unique protein-coding mRNAs (expression quantitative trait loci [eQTL]) and more than 100,000 nearby (within 1 Mb) CpG islands thought to be involved in changes in DNA methylation (methylation quantitative trait loci [mQTL]). Each functionally connected GWAS-eQTL-mQTL association is referred to as a triplet.

The next arm of the study investigatedthe connections and pathways within each triplet. Three possible scenarios were explored for birthweight GWAS SNPs using a causal interference test (CIT):

1. the SNP alters placental DNA methylation, which then influences gene expression
2. the SNP first alters placental DNA expression, which then influences methylation
3. the SNP influences placental DNA expression and methylation independently, with no notable crossover between their pathways.

Triplets were investigated using the Mendelian randomization (MR) Steiger directionality test to validate the directionality of the pathways found by CIT. Lastly, the possibility of linkage disequilibrium was also studied using the moloc test. 

Results

Using CIT, a causal relationship was predicted in 88 of 197 triplets, in which 84 (95.5%) indicated DNA methylation influences gene expression, and 4 (4.5%) indicated gene expression influences DNA methylation. The authors also used the MR Steiger test to investigate triplets to identify possible causal pathways. Using the MR Steiger test, only 3 of 45 (7%) triplets were found to have independent gene expression and methylation pathways. Thirty-eight of 45 (84%) triplets indicated that gene expression influences DNA methylation, and 7 (15%)triplets demonstrated that DNA methylation influences gene expression. Consistent predictions between CIT and the MR Steiger test revealed 3 triplets in which DNA methylation influences gene expression for the following genes: WNT3A, CTDNEP1, and RANBP2. Additionally, a strong colocalization signal was found among birthweight, DNA methylation, and gene expression for the following genes: PLEKHA1, FES, PRMT7, and CTDNEP1. Gene set enrichment analysis was performed as well and found that low birthweight is associated in substantial upregulation of genes associated with oxidative stress, immune response, adipogenesis, myogenesis, and the production of pancreatic ß cells.  

Study strengths and limitations

The study is one of the first to identify regulatory targets for placental DNA methylation and gene expression in previously identified GWAS loci associated with low birthweight. For example, DNA methylation was found to influence gene expression of WNT3A, CTDNEP1, and RANBP2, which have previously been shown in animal studies to impact the vascularization and development of the placenta, embryogenesis, and fetal growth. The study also identified 4 genes (PLEKHA1, FES, PRMT7, and CTDNEP1) thought to have direct regulatory influence on placental DNA methylation and gene expression.

A limitation of the study is that it could not distinguish between whether the epigenetic changes we outlined have a maternal or fetal origin. Another limitation is that tissue used by the authors for analysis was a small placental biopsy, which does not accurately reflect the genetic heterogeneity of the placenta. Finally, this study does not establish causality between the identified epigenetic pathways and low birthweight. ●

Whole exome sequencing’s role in diagnosing genetic causes of FGR with and without associated anomalies

Mone F, Mellis R, Gabriel H, et al. Should we offer prenatal exome sequencing for intrauterine growth restriction or short long bones? A systematic review and meta-analysis. Am J Obstet Gynecol. Published online October 7, 2022. doi:10.1016/j.ajog.2022.09.045

Multiple factors can play a role in FGR, including inherent maternal, placental, or fetal factors; the environment; and/or nutrition. However, prenatal diagnosis is an important consideration when exploring the underlying etiology for a growth-restricted fetus, especially in severe or early-onset cases. Many genetic conditions do not result in structural anomalies but can disrupt overall growth. Additionally, phenotyping in the prenatal period is limited and can miss more subtle physical differences that could point to a genetic cause. 

When compared with karyotype, chromosomal microarray (CMA) has been shown to increase the diagnostic yield in cases of isolated early FGR by 5%,^1,2 and the incidence of chromosomal abnormalities has been reported to be as high as 19% in this population. Let’s explore the data on exome sequencing for prenatal diagnosis in cases of isolated FGR. 

Meta-analysis details

In this meta-analysis, the authors reviewed 19 cohort studies or case series that investigated the yield of prenatal sequencing in fetuses with intrauterine growth restriction (IUGR) or short long bones, both in association with and without additional anomalies. All cases had nondiagnostic cytogenetic results. Fetal DNA in most cases was obtained through amniocentesis. Variants classified as likely pathogenic and pathogenic were considered diagnostic. The authors then calculated the incremental yield of prenatal sequencing over cytogenetic studies as a pooled value, comparing the following groups:

• isolated FGR
• growth restriction with associated anomalies
• isolated short long bones
• short long bones with additional skeletal features.  

Study outcomes 

The total number of cases were as follows: isolated IUGR (n = 71), IUGR associated with additional anomalies (n = 45), isolated short long bones (n = 84), and short long bones associated with additional skeletal findings (n = 252). Causative pathogenic or likely pathogenic variants were identified in 224 (50%) cases. Apparent incremental yields with prenatal sequencing were as follows for the 4 groups (as illustrated in the FIGURE):

• 4% in isolated IUGR (95% confidence interval [CI], -5%–12%)
• 30% in IUGR with additional anomalies (95% CI, 13%–47%)
• 48% in isolated short long bones (95% CI, 26%–70%)
• 68% in short long bones with additional skeletal changes (95% CI, 58%–77%).

Overall, the authors concluded that prenatal sequencing does not improve prenatal diagnosis in cases of isolated IUGR. The majority of these cases were thought to be related to placental insufficiency.

Strengths and limitations 

The main limitation of this study with regard to our discussion is the small study populationof isolated growth restriction. The authors indicate that the number of cases of isolated IUGR were too small to draw firm conclusions. Another limitation was the heterogeneity of the isolated FGR population, which was not limited to severe or early-onset cases. However, the authors did demonstrate that growth restriction in association with fetal anomalies has very high genetic yield rates with prenatal sequencing. 

Continue to: Can whole exome sequencing diagnose genetic causes in cases of severe isolated FGR?...

 

 

Can whole exome sequencing diagnose genetic causes in cases of severe isolated FGR? 

Zhou H, Fu F, Wang Y, et al. Genetic causes of isolated and severe fetal growth restriction in normal chromosomal microarray analysis. Int J Gynaecol Obstet. Published online December 10, 2022. doi:10.1002/ijgo.14620

Severe FGR is diagnosed based on an estimated fetal weight (EFW) or abdominal circumference (AC) below the third percentile. As we discussed in the above study by Mone and colleagues, it does not appear that prenatal sequencing significantly improves the diagnostic yield in all isolated FGR cases. However, this has not been previously explored in isolated severe FGR or cases of early-onset FGR (<32 weeks’ gestation). We know that several monogenic conditions are associated with severe and early-onset isolated fetal growth impairment, including but not limited to Cornelia de Lange syndrome, Smith-Lemli-Opitz syndrome, and Meier-Gorlin syndrome. Often, these syndromes can present in the prenatal period without other phenotypic findings. Therefore, this study explored the possibility that prenatal sequencing plays an important role for severe cases of FGR with nondiagnostic CMA and/or karyotype. 

Retrospective study details 

Zhou and colleagues retrospectively analyzed 51 cases of severe (EFW or AC below the third percentile) isolated FGR with negative CMA who underwent trio whole exome sequencing, which includes submitting fetal cells as well as both parental samples for testing. Patients with abnormal toxoplasmosis, rubella, cytomegalovirus, and herpes simplex virus (TORCH) tests; structural anomalies; and multiple gestation were excluded from the analysis. As in the study by Mone et al, variants classified as likely pathogenic and pathogenic were categorized as diagnostic. 

Results

Eight of 51 cases (15.7%) with severe isolated FGR had diagnostic findings on trio whole exome sequencing as shown in the TABLE. Another 8 cases (15.7%) were found to have variants of unknown significance, of which 2 were later determined to be novel pathogenic variants. Genetic conditions uncovered in this cohort include Cornelia de Lange syndrome, pyruvate dehydrogenase deficiency, Dent disease, trichohepaticenteric syndrome, achondroplasia, osteogenesis imperfecta, Pendred syndrome, and both autosomal dominant type 3A and autosomal recessive type 1A deafness. All 10 cases with diagnostic whole exome sequencing or identified novel pathogenic variants were affected by early-onset FGR (<32 weeks’ gestation). Of these 10 cases, 7 patients underwent pregnancy termination.

To summarize, a total of 10 cases (19.6%) of severe isolated early-onset FGR with negative cytogenetic studies were subsequently diagnosed with an underlying genetic condition using prenatal trio whole exome sequencing. 

Strengths and limitations 

This study is retrospective and has a small sample size (n = 51) that was mostly limited to early-onset isolated severe FGR. However, the diagnostic yield (19.6%) of whole exome sequencing after negative CMA testing was noteworthy and shows that monogenic conditions are an important consideration in the evaluation of severe early-onset FGR, even in the absence of structural abnormalities. 

Could epigenetic mechanisms of placental dysregulation explain low birthweight and future cardiometabolic disease?  

Tekola-Ayele F, Zeng X, Chatterjee S, et al. Placental multi-omics integration identifies candidate functional genes for birthweight. Nat Commun. 2022;13:2384.

FGR has been linked to greater mortality in childhood and increased risk for cardiometabolic disease in adulthood. While genomewide associations studies (GWAS) have defined areas of interest linking genetic variants to low birthweight, their relationship to epigenetic changes in the placenta as well as biologic and functional mechanisms are not yet well understood.  

Multiomics used to identify candidate functional genes for birthweight 

This study analyzed the methylation and gene expression patterns of 291 placental samples, integrating findings into pathways of previously defined GWAS variants. Patient samples were obtained from participants in the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Fetal Growth Studies–Singleton cohort. The cohort is ethnically diverse, with 97 Hispanic, 74 White, 71 Black, and 49 Asian participants. Of 286 single nucleotide polymorphisms (SNPs) found to be associated with birthweight, 273 were analyzed as part of the authors’ data set. These were found to have 7,901 unique protein-coding mRNAs (expression quantitative trait loci [eQTL]) and more than 100,000 nearby (within 1 Mb) CpG islands thought to be involved in changes in DNA methylation (methylation quantitative trait loci [mQTL]). Each functionally connected GWAS-eQTL-mQTL association is referred to as a triplet.

The next arm of the study investigatedthe connections and pathways within each triplet. Three possible scenarios were explored for birthweight GWAS SNPs using a causal interference test (CIT):

1. the SNP alters placental DNA methylation, which then influences gene expression
2. the SNP first alters placental DNA expression, which then influences methylation
3. the SNP influences placental DNA expression and methylation independently, with no notable crossover between their pathways.

Triplets were investigated using the Mendelian randomization (MR) Steiger directionality test to validate the directionality of the pathways found by CIT. Lastly, the possibility of linkage disequilibrium was also studied using the moloc test. 

Results

Using CIT, a causal relationship was predicted in 88 of 197 triplets, in which 84 (95.5%) indicated DNA methylation influences gene expression, and 4 (4.5%) indicated gene expression influences DNA methylation. The authors also used the MR Steiger test to investigate triplets to identify possible causal pathways. Using the MR Steiger test, only 3 of 45 (7%) triplets were found to have independent gene expression and methylation pathways. Thirty-eight of 45 (84%) triplets indicated that gene expression influences DNA methylation, and 7 (15%)triplets demonstrated that DNA methylation influences gene expression. Consistent predictions between CIT and the MR Steiger test revealed 3 triplets in which DNA methylation influences gene expression for the following genes: WNT3A, CTDNEP1, and RANBP2. Additionally, a strong colocalization signal was found among birthweight, DNA methylation, and gene expression for the following genes: PLEKHA1, FES, PRMT7, and CTDNEP1. Gene set enrichment analysis was performed as well and found that low birthweight is associated in substantial upregulation of genes associated with oxidative stress, immune response, adipogenesis, myogenesis, and the production of pancreatic ß cells.  

Study strengths and limitations

The study is one of the first to identify regulatory targets for placental DNA methylation and gene expression in previously identified GWAS loci associated with low birthweight. For example, DNA methylation was found to influence gene expression of WNT3A, CTDNEP1, and RANBP2, which have previously been shown in animal studies to impact the vascularization and development of the placenta, embryogenesis, and fetal growth. The study also identified 4 genes (PLEKHA1, FES, PRMT7, and CTDNEP1) thought to have direct regulatory influence on placental DNA methylation and gene expression.

A limitation of the study is that it could not distinguish between whether the epigenetic changes we outlined have a maternal or fetal origin. Another limitation is that tissue used by the authors for analysis was a small placental biopsy, which does not accurately reflect the genetic heterogeneity of the placenta. Finally, this study does not establish causality between the identified epigenetic pathways and low birthweight. ●

Illustration: Kimberly Martens for OBG Management

Intrauterine devices (IUDs) are now used by more than 15% of US contraceptors. The majority of these IUDs release the progestin levonorgestrel, and with now longer extended use of the IUDs approved by the US Food and Drug Administration (FDA),^1-3 they become even more attractive for use for contraception,control of menorrhagia or heavy menstrual bleeding (HMB) during reproductive years and perimenopause, and potentially, although not FDA approved for this purpose, postmenopause for endometrial protection in estrogen users. In this roundtable discussion, we will look at some of the benefits of the IUD for contraception effectiveness and control of bleeding, as well as the potential risks if used for postmenopausal women.

Progestin IUDs and contraception

JoAnn V. Pinkerton, MD, NCMP: Dr. Kaunitz, what are the contraceptive benefits of progestin IUDs during perimenopause?
 

Andrew M. Kaunitz, MD, NCMP: We know fertility declines as women approach menopause. However, when pregnancy occurs in older reproductive-age women, the pregnancies are often unintended, as reflected by high rates of induced abortion in this population. In addition, the prevalence of maternal comorbidities (during pregnancy and delivery) is higher in older reproductive-age women, with the maternal mortality rate more than 5 times higher compared with that of younger women.⁴ Two recently published clinical trials assessed the extended use of full-size IUDs containing 52 mg of levonor-gestrel (LNG), with the brand names Mirena and Liletta.^1,2 The data from these trials confirmed that both IUDs remain highly effective for up to 8 years of use, and currently, both devices are approved for up to 8 years of use. One caveat is that, in the unusual occurrence of a pregnancy being diagnosed in a woman using an IUD, we as clinicians, must be alert to the high prevalence of ectopic pregnancies in this setting.

Progestin IUDs and HMB

Dr. Pinkerton: Dr. Goldstein, can you comment on how well progestin IUDs work for HMB?

Steven R. Goldstein, MD, NCMP, CCD: Many women who need contraception will use these devices for suppressing HMB, and they can be quite effective, if the diagnosis truly is HMB, at reducing bleeding.⁵ But that efficacy in bleeding reduction may not be quite as long as the efficacy in pregnancy prevention.⁶ In my experience, among women using IUDs specifically for their HMB, good bleeding control may require changing the IUD at 3 to 5 years.

Barbara S. Levy, MD: When inserting a LNG-IUD for menorrhagia in the perimenopausal time frame, sometimes I will do a progestin withdrawal first, which will thin the endometrium and induce withdrawal bleeding because, in my experience, if you place an IUD in someone with perimenopausal bleeding, you may end up with a lot of breakthrough bleeding.

Perimenopause and hot flashes

Dr. Pinkerton: Dr. Kaunitz, we have learned that hot flashes often occur and become bothersome to women during perimenopause. Many women have IUDs placed during perimenopause for bleeding. Can you comment about IUD use during perimenopause and postmenopause?
 

Dr. Kaunitz: In older reproductive-age women who already have a progestin-releasing IUD placed, as they get closer to menopause when vasomotor symptoms (VMS) might occur, if these symptoms are bothersome, the presence or placement of a progestin-releasing IUD can facilitate treatment of perimenopausal VMS with estrogen therapy.

Progestin IUDs cause profound endometrial suppression, reduce bleeding and often, over time, cause users to become amenorrheic.⁷

The Mirena package insert states, “Amenorrhea develops in about 20% of users by one year.”² By year 3 and continuing through year 8, the prevalence of amenorrhea with the 52-mg LNG-IUD is 35% to 40%.⁸ From a study by Nanette Santoro, MD, and colleagues, we know that, in perimenopausal women with a progestin-releasing IUD in place, who are experiencing bothersome VMS, adding transdermal estrogen is very effective in treating and suppressing those hot flashes. In her small clinical trial, among participants with perimenopausal bothersome VMS with an IUD in place, half were randomized to use of transdermal estradiol and then compared with women who did not get the estradiol patch. There was excellent relief of perimenopausal hot flashes with the combination of the progestin IUD for endometrial suppression and transdermal estrogen to relieve hot flashes.⁹

Dr. Pinkerton: Which women would not be good candidates for the use of this combination?

Dr. Kaunitz: We know that, as women age, the prevalence of conditions that are contraindications to combination contraceptives (estrogen-progestin pills, patches, or rings) starts to increase. Specifically, we see more: hypertension, diabetes, and high body mass index (BMI), or obesity. We also know that migraine headaches in women older than age 35 years is another condition in which ACOG and the Centers for Disease Control and Prevention (CDC) would not recommend use of combination contraceptives.^10,11 These older perimenopausal women may be excellent candidates for a progestin-only releasing IUD combined with use of transdermal menopausal doses of estradiol if needed for VMS.

Dr. Goldstein: I do want to add that, in those patients who don’t have these comorbidities, combination estrogen-progestin contraceptives do a very nice job of ovarian suppression and will prevent the erratic production of estradiol, which, in my experience, often results in not only irregular bleeding but also possible exacerbation of perimenopausal mood symptoms.

Dr. Kaunitz: I agree, Steve. The ideal older reproductive-age candidate for combination pills, patch, or ring would be a slender, healthy, nonsmoking woman with normal blood pressure. Such women would be a fairly small subgroup of my practice, but they can safely continue combination contraceptives right through menopause. Consistent with CDC and ACOG guidance, rather than checking gonadotropins to “determine when menopause has occurred,” (which is, in fact, not an evidence-based approach to diagnosing menopause in this setting), such women can continue the combination contraceptive right up until age 55—the likelihood that women are still going to be ovulating or at risk for pregnancy becomes vanishingly small at that age.^11,12 Women in their mid-50s can either seamlessly transition to use of systemic estrogen-progestin menopausal therapy or go off hormones completely.

Continue to: The IUD and HMB...

The IUD and HMB

Dr. Pinkerton: Dr. Goldstein, there’s been some good literature on the best management options for women with HMB. What is the most current evidence?

Dr. Goldstein: I think that the retiring of the terms menorrhagia and metrorrhagia may have been premature because HMB implies cyclical bleeding, and this population of women with HMB will typically do quite well. Women who have what we used to call metrorrhagia or irregular bleeding, by definition, need endometrial evaluation to be sure they don’t have some sort of organic pathology. It would be a mistake for clinicians to use an LNG-IUD in patients with abnormal uterine bleeding (AUB) that has not been appropriately evaluated.

If we understand that we are discussing HMB, a Cochrane Review from 2022¹³ suggests that an LNG intrauterine system is the best first-line treatment for reducing menstrual blood loss in perimenopausal women with HMB. Antifibrinolytics appeared second best, while long-cycle progestogens came in third place. Evidence on perception of improvement in satisfaction was ranked as low certainty. That same review found that hysterectomy was the best treatment for reducing bleeding, obviously, followed by resectoscopic endometrial ablation or a nonresectoscopic global endometrial ablation.

The evidence rating was low certainty regarding the likelihood that placing an LNG-IUD in women with HMB will result in amenorrhea, and I think that’s a very important point. The expectation of patients should be reduced or a significantly reduced amount of their HMB, not necessarily amenorrhea. Certainly, minimally invasive hysterectomy will result in total amenorrhea and may have a larger increase in satisfaction, but it has its own set of other kinds of possible complications.

Dr. Kaunitz: In an industry-funded, international multicenter trial,¹⁴ women with documented HMB (hemoglobin was eluted from soiled sanitary products), with menstrual blood loss of 80 mL or more per cycle, were randomized to placement of an LNG 52-mg IUD (Mirena) or cyclical medroxyprogesterone acetate (MPA)—oral progestin use.

Although menstrual blood loss declined in both groups, it declined dramatically more in women with an IUD placed, and specifically with the IUD, menstrual blood loss declined by 129 mL on average, whereas the decline in menstrual blood loss with cyclical MPA was 18 mL. This data, along with earlier European data,¹⁵ which showed similar findings in women with HMB led to the approval of the Mirena progestin IUD for a second indication to treat HMB in 2009.

I also want to point out that, in the May 2023 issue of Obstetrics & Gynecology, Creinin and colleagues published a similar trial in women with HMB showing, once again, that progestin IUDs (52-mg LNG-IUD, Liletta) are extremely effective in reducing HMB.¹⁶ There is crystal clear evidence from randomized trials that both 52-mg LNG-IUDs, Mirena and Liletta, are very effective in reducing HMB and, in fact, are contributing to many women who in the past would have proceeded with surgery, such as ablation or hysterectomy, to control their HMB.

Oral contraception

Dr. Pinkerton: What about using low-dose continuous oral contraceptives noncyclically for women with HMB?

Dr. Goldstein: I do that all the time. It is interesting that Dr. Kaunitz mentions his patient population. It’s why we understand that one size does not fit all. You need to see patients one at a time, and if they are good candidates for a combined estrogen-progestin contraception, whether it’s pills, patches, or rings, giving that continuously does a very nice job in reducing HMB and straightening out some of the other symptoms that these perimenopausal women will have.

IUD risks

Dr. Pinkerton: We all know about use of low-dose oral contraceptives for management of AUB, and we use them, although we worry a little bit about breast cancer risk. Dr. Levy, please comment on the risks with IUDs of expulsions and perforations. What are the downsides of IUDs?

Dr. Levy: Beyond the cost, although it is a minimally invasive procedure, IUD insertion can be an invasive procedure for a patient to undergo; expulsions can occur.¹⁷ We know that a substantial percentage of perimenopausal women will have fibroids. Although many fibroids are not located in the uterine cavity, the expulsion rate with HMB for an LNG-IUD can be higher,^13,16,18,19 perhaps because of local prostaglandin release with an increase in uterine contractility. There is a low incidence of perforations, but they do happen, particularly among women with scars in the uterus or who have a severely anteflexed or retroflexed uterus, and women with cervical stenosis, for example, if they have had a LEEP procedure, etc. Even though progestin IUDs are outstanding tools in our toolbox, they are invasive to some extent, and they do have the possibility of complications.

Dr. Kaunitz: As Dr. Levy points out, although placement of an IUD may be considered an invasive procedure, it is also an office-based procedure, so women can drive home or drive back to work afterwards without the disruption in their life and the potential complications associated with surgery and anesthesia.

Continue to: Concerns with malpositioning...

 

 

Concerns with malpositioning

Dr. Pinkerton: After placement of an IUD, during a follow-up visit, sometimes you can’t visualize the string. The ultrasonography report may reveal, “IUD appears to be in the right place within the endometrium.” Dr. Goldstein, can you comment on how we should use ultrasound when we can’t visualize or find the IUD string, or if the patient complains of abdominal pain, lower abdominal discomfort, or irregular bleeding or spotting and we become concerned about IUD malposition?

Dr. Goldstein: Ultrasound is not really required after an uncomplicated placement of an IUD or during routine management of women who have no problems who are using an IUD. In patients who present with pain or some abnormal bleeding, however, sometimes it is the IUD being malpositioned. A very interesting study by the late great Beryl Benacerraf²⁰ showed that there was a statistically significant higher incidence of the IUD being poorly positioned when patients have pain or bleeding (FIGURE 1). It was not always apparent on 2D ultrasonography. Using a standard transvaginal ultrasound of the long access plane, the IUD may appear to be very centrally located. However, if you do a 3D coronal section, not infrequently in these patients with any pain or bleeding, one of the arms has pierced the myometrium (FIGURE 2). This can actually be a source of pain and bleeding.

It’s also very interesting when you talk about perforation. I became aware of a big to-do in the medical/legal world about the possibility of the IUD migrating through the uterine cavity.²¹ This just does not exist, as was already pointed out. If the IUD is really going to go anywhere, if it’s properly placed, it’s going to be expelled through an open cervix. I do believe that, if you have pierced the myometrium through uterine contractility over time, some of these IUDs could work their way through the myometrium and somehow come out of the uterus either totally or partially. I think ultrasound is invaluable in patients with pain and bleeding, but I think you need to have an ultrasound lab capable of doing a 3D coronal section.

Progestin IUDs for HT replacement: Benefits/risks

Dr. Pinkerton: Many clinicians are excited that they can use essentially estrogen alone for women who have a progestin IUD in place. What about the possible off-label use of the progestin IUD to replace oral progestogen for hormone therapy (HT)? Dr. Kaunitz, are there any studies using this for postmenopausal HT (with a reminder that the IUD is not FDA approved for this purpose)?

Dr. Kaunitz: We have data from Europe indicating that, in menopausal women using systemic estrogen, the full-size LNG 52 IUD—Mirena or Liletta—provides excellent endometrial suppression.²² Where we don’t have data is with the smaller IUDs, which would be Kyleena and Skyla, which release smaller amounts of progestin each day into the endometrial cavity.

I have a number of patients, most of them women who started use of a progestin IUD as older reproductive-age women and then started systemic estrogen for treatment of perimenopausal hot flashes and then continued the use of their IUD plus systemic estrogen in treating postmenopausal hot flashes. The IUD is very useful in this setting, but as you pointed out, Dr. Pinkerton, this does represent off-label use.

Dr. Pinkerton: I know this use does not affect plasma lipids or cardiovascular risk markers, although users seem to report that the IUD has improved their quality of life. The question comes up, what are the benefits on cancer risk for using an IUD?

Dr. Levy: It’s such a great question because, as we talk about the balance of risks and benefits for anything that we are offering to our patients, it is really important to focus on some of the benefits. For both the copper and the LNG-IUD, there is a reduction in endometrial cancer,²² as well as pretty good data with the copper IUD about a reduction in cervical cancer.²³ Those data are a little bit less clear for the LNG-IUD.

Interestingly, at least one meta-analysis published in 2020 shows about a 30% reduction in ovarian cancer risk with the LNG-IUD.²⁴ We need to focus our patients on these other benefits. They tend to focus on the risks, and, of course, the media blows up the risks, but the benefits are quite substantial beyond just reducing HMB and providing contraception.

Dr. Pinkerton: As Dr. Kaunitz said, when you use this IUD, with its primarily local uterine progestin effects, it’s more like using estrogen alone without as much systemic progestin. Recently I wrote an editorial on the benefits of estrogen alone on the risk of breast cancer, primarily based on the Women’s Health Initiative (WHI) observational long-term 18-year cumulative follow-up. When estrogen alone was prescribed to women after a hysterectomy, estrogen therapy used at menopause did not increase the risk of invasive breast cancer, and was associated with decreased mortality.²⁵ However, the nurse’s health study has suggested that longer-term use may be increased with estrogen alone.²⁶ For women in the WHI with an intact uterus who used estrogen, oral MPA slightly increased the risk for breast cancer, and this elevated risk persisted even after discontinuation. This leads us to the question, what are the risks of breast cancer with progestin IUD use?

I recently reviewed the literature, and the answer is, it’s mixed. The FDA has put language into the package label that acknowledges a potential breast cancer risk for women who use a progestin IUD,²⁷ and that warning states, “Women who currently have or have had breast cancer or suspect breast cancer should not use hormonal contraception because some breast cancers are hormone sensitive.” The label goes on to say, “Observational studies of the risk of breast cancer with the use of a levonorgestrel-releasing IUS don’t provide conclusive evidence of increased risk.” Thus, there is no conclusive answer as to whether there is a possible link of progestin IUDs to breast cancer.

What I tell my patients is that research is inconclusive. However, it’s unlikely for a 52-mg LNG-IUD to significantly increase a woman’s breast cancer risk, except possibly in those already at high risk from other risk factors. I tell them that breast cancer is listed in the package insert as a potential risk. I could not find any data on whether adding a low-dose estradiol patch would further increase that risk. So I counsel women about potential risk, but tell them that I don’t have any strong evidence of risk.

Continue to: Dr. Goldstein...

Dr. Goldstein: If you look in the package insert for Mirena,² similar to Liletta, certainly the serum levels of LNG are lower than that for combination oral contraceptives. For the IUD progestins, they are not localized only to the uterus, and LNG levels range from about 150 to 200 µg/mL up to 60 months. It’s greater at 12 months, at about 180 µg/mL,at 24 months it was 192 µg/mL, and by 60 months it was 159 µg/mL. It’s important to realize that there is some systemic absorption of progestin with progestin IUDs, and it is not completely a local effect.

JoAnn, you mentioned the WHI data,²⁵ and just to specify, it was not the estrogen-only arm, it was the conjugated equine estrogen-only arm of the WHI. I don’t think that estradiol alone increases breast cancer risk (although there are no good prospective, follow-through, 18-year study data, like the WHI), but I think readers need to understand the difference in the estrogen type.

Endometrial evaluation. My question for the panel is as follows. I agree that the use of the progestin-releasing IUD is very nice for that transition to menopause. I do believe it provides endometrial protection, but we know from other studies that, when we give continuous combined HT, about 21% to 26% of patients will experience some bleeding/staining, responding in the first 4-week cycles, and it can be as high as 9% at 1 year. If I have a patient who bleeds on continuous combined HT, I will evaluate her endometrium, usually just with a simple transvaginal ultrasound. If an IUD is in place, and the patient now begins to have some irregular bleeding, how do you evaluate her with the IUD in place?

Dr. Levy: That is a huge challenge. We know from a recent paper,²⁸ that the endometrial thickness, while an excellent measure for Caucasian and European women, may be a poor marker for endometrial pathology in African-American women. What we thought we knew, which was, if the stripe is 4 mL or less, we can forget about it, I think in our more recent research that is not so true. So you bring up a great point, what do you do? The most reliable evaluation will be with an office hysteroscopy, where you can really look at the entire cavity and for tiny, little polyps and other things. But then we are off label because the use of hysteroscopy with an IUD in place is off label. So we are really in a conundrum.

Dr. Pinkerton: Also, if you do an endometrial biopsy, you might dislodge the IUD. If you think that you are going to take the IUD out, it may not matter if you dislodge it. I will often obtain a transvaginal ultrasound to help me figure out the next step, and maybe look at the dosing of the estrogen and progestin—but you can’t monitor an IUD with blood levels. You are in a vacuum of trying to figure out the best thing to do.

Dr. Kaunitz: One of the hats I wear here in Jacksonville is Director of GYN Ultrasound. I have a fair amount of experience doing endometrial biopsies in women with progestin IUDs in place under abdominal ultrasound guidance and keeping a close eye on the position of the IUD. In the first dozen or so such procedures I did, I was quite concerned about dislodging the IUD. It hasn’t happened yet, and it gives me some reassurance to be able to image the IUD and your endometrial suction curette inside the cavity as you are obtaining endometrial sampling. I have substantial experience now doing that, and so far, no problems. I do counsel all such women in advance that there is some chance I could dislodge their IUD.

Dr. Goldstein: In addition to dislodging the IUD, are you not concerned that, if the pathology is not global, that a blind endometrial sampling may be fraught with some error?

Dr. Kaunitz: The endometrium in women with a progestin-releasing IUD in place tends to be very well suppressed. Although one might occasionally find, for instance, a polyp in that setting, I have not run into, and I don’t expect to encounter going forward, endometrial hyperplasia or cancer in women with current use of a progestin IUD. It’s possible but unlikely.

Dr. Levy: The progestin IUD will counterbalance a type-1 endometrial cancer—an endometrial cancer related to hyperstimulation by estrogen. It will not do anything, to my knowledge, to counterbalance a type 2. I think the art of medicine is, you do the best you can with the first episode of bleeding, and if she persists in her bleeding, we have to persevere and continue to evaluate her.

Dr. Goldstein: I agree 100%.

Dr. Pinkerton: We all agree with you. That’s a really good point.

Continue to: Case examinations...

Case examinations

CASE 1 Woman with intramural fibroids

Dr. Pinkerton: Dr. Goldstein, you have a 48-year-old Black woman who has heavy but regular menstrual bleeding with multiple fibroids (the largest is about 4 to 5 cm, they look intramural, with some distortion of the cavity but not a submucous myoma, and the endometrial depth is 9 cm). Would you insert an IUD, and would you recommend an endometrial biopsy first?

Dr. Goldstein: I am not a huge fan of blind endometrial sampling, and I do think that we use the “biopsy” somewhat inappropriately since sampling is not a directed biopsy. This became obvious in the landmark paper by Guido et al in 1995 and was adopted by ACOG only in 2012.²⁹ Cancers that occupy less than 50% of the endometrial surface area are often missed with such blind sampling. Thus I would not perform an endometrial biopsy first, but would rather rely on properly timed and performed transvaginal ultrasound to rule out any concurrent endometrial disease. I think a lot of patients who have HMB, not only because of their fibroids but also often just due to the surface area of their uterine cavity being increased—so essentially there is more blood volume when they bleed. However, you said that in this case the patient has regular menstrual bleeding, so I am assuming that she is still ovulatory. She may have some adenomyosis. She may have a large uterine cavity. I think she is an excellent candidate for an LNG-releasing IUD to reduce menstrual blood flow significantly. It will not necessarily give her amenorrhea, and it may give her some irregular bleeding. Then at some distant point, say in 5 or 6 months if she does have some irregular staining or bleeding, I would feel much better about the fact that nothing has developed as long as I knew that the endometrium was devoid of pathology when I started.

CASE 2 Woman with family history of breast cancer

Dr. Pinkerton: Dr. Levy, a 44-year-old woman has a family history of breast cancer in her mother at age 72, but she still needs contraceptionbecause of that unintended pregnancy risk in the 40s, and she wants something that is not going to increase her risk of breast cancer. What would you use, and how would you counsel her if you decided to use a progestin IUD?

Dr. Levy: The data are mixed,^30-33 but whatever the risk, it is miniscule, and I would bring up the CDC Medical Eligibility Criteria.¹¹ For a patient with a family history of breast cancer, for use of the progestin IUD, it is a 1—no contraindications. What I tend to tell my patients is, if you are worried about breast cancer, watch how much alcohol you are drinking and maintain regular exercise. There are so many preventive things that we can do to reduce risk of breast cancer when she needs contraception. If there is any increase in risk, it is so miniscule that I would very strongly recommend a progestin IUD for her.

Dr. Pinkerton: In addition, in recognizing the different densities of breast, dense breast density could lead to supplemental screening, which also could give her some reassurance that we are adequately screening for breast cancer.

CASE 3 Woman with IUD and VMS
 

Dr. Pinkerton: Dr. Kaunitz, you have a 52-year-old overweight female. She has been using a progestin IUD for 4 years, is amenorrheic, but now she is having moderate to severe vasomotor symptoms despite the IUD in place. You have talked to her about risks and benefits of HT, and she is interested in starting it. I know we talked about the studies, but I want to know what you are going to tell her. How do you counsel her about off-label use?

Dr. Kaunitz: The most important issue related to treating vasomotor symptoms in this patient is the route of systemic estrogen. Understandably, women’s biggest concern regarding the risks of systemic estrogen-progestin therapy is breast cancer. However, statistically, by far the biggest risk associated with oral estrogen-progestogen therapy, is elevated risk of venous thrombosis and pulmonary embolism. We have seen this, with a number of studies, and the WHI made it crystal clear with risks of oral conjugated equine estrogen at the dose of 0.625 mg daily. Oral estradiol 1 mg daily is also associated with a similar elevated risk of venous thrombosis. We also know that age and BMI are both independent risk factors for thrombosis. So, for a woman in her 50s who has a BMI > 30 mg/kg², I don’t want to further elevate her risk of thrombosis by giving her oral estrogen, whether it is estradiol or conjugated equine estrogen. This is a patient in whom I would be comfortable using transdermal (patch) estradiol, perhaps starting with a standard dose of 0.05 mg weekly or twice weekly patch, keeping in mind that 0.05 mg in the setting of transdermal estrogen refer to the daily or to the 24-hour release rate. The 1.0 mg of oral estradiol and 0.625 mg of conjugated equine estrogen refers to the mg quantity of estrogen in each tablet. This is a source of great confusion for clinicians.

If, during follow-up, the 0.05 mg estradiol patch is not sufficient to substantially reduce symptoms, we could go up, for instance, to a 0.075 mg estradiol patch. We know very clearly from a variety of observational studies, including a very large UK study,³⁴ that in contrast with oral estrogen, transdermal estradiol is safer from the perspective of thrombosis.

Insurance coverage for IUDs

Dr. Pinkerton: Dr. Levy: Can you discuss IUDs and the Affordable Care Act’s requirement to cover contraceptive services?

Dr. Levy: Unfortunately, we do not know whether this benefit will continue based on a very recent finding from a judge in Texas that ruled the preventive benefits of the ACA were illegal.³⁵ We don’t know what will happen going forward. What I will say is that, unfortunately, many insurance companies have not preserved the meaning of “cover all things,” so what we are finding is that, for example, they only have to cover one type in a class. The FDA defined 18 classes of contraceptives, and a hormonal IUD is one class, so they can decide that they are only going to cover one of the four IUDS. And then women don’t have access to the other three, some of which might be more appropriate for them than another.

The other thing very relevant to this conversation is that, if you use an ICD-10 code for menorrhagia, for HMB, it no longer lives within that ACA preventive care requirement of coverage for contraceptives, and now she is going to owe a big deductible or a copay. If you are practicing in an institution that does not allow the use of IUDs for contraception, like a Catholic institution where I used to practice, you will want to use that ICD-10 code for HMB. But if you want it offered with no out-of-pocket cost for the patient, you need to use the preventive medicine codes and the contraception code. These little nuances for us can make a huge difference for our patients.

Dr. Pinkerton: Thank you for that reminder. I want to thank our panelists, Dr. Levy, Dr. Goldstein, and Dr. Kaunitz, for providing us with such a great mix of evidence and expert opinion and also giving a benefit of their vast experience as award-winning gynecologists. Hopefully, today you have learned the benefits of the progestin IUD not only for contraception in reproductive years and perimenopause but also for treatment of HMB, and the potential benefit due to the more prolonged effectiveness of the IUDs for endometrial protection in postmenopause. This allows less progestin risk, essentially estrogen alone for postmenopausal HT. Unsolved questions remain about whether there is a risk of breast cancer with their use, but there is a clear benefit of protecting against pregnancy and endometrial cancer. ●

Illustration: Kimberly Martens for OBG Management

Intrauterine devices (IUDs) are now used by more than 15% of US contraceptors. The majority of these IUDs release the progestin levonorgestrel, and with now longer extended use of the IUDs approved by the US Food and Drug Administration (FDA),^1-3 they become even more attractive for use for contraception,control of menorrhagia or heavy menstrual bleeding (HMB) during reproductive years and perimenopause, and potentially, although not FDA approved for this purpose, postmenopause for endometrial protection in estrogen users. In this roundtable discussion, we will look at some of the benefits of the IUD for contraception effectiveness and control of bleeding, as well as the potential risks if used for postmenopausal women.

Progestin IUDs and contraception

JoAnn V. Pinkerton, MD, NCMP: Dr. Kaunitz, what are the contraceptive benefits of progestin IUDs during perimenopause?
 

Andrew M. Kaunitz, MD, NCMP: We know fertility declines as women approach menopause. However, when pregnancy occurs in older reproductive-age women, the pregnancies are often unintended, as reflected by high rates of induced abortion in this population. In addition, the prevalence of maternal comorbidities (during pregnancy and delivery) is higher in older reproductive-age women, with the maternal mortality rate more than 5 times higher compared with that of younger women.⁴ Two recently published clinical trials assessed the extended use of full-size IUDs containing 52 mg of levonor-gestrel (LNG), with the brand names Mirena and Liletta.^1,2 The data from these trials confirmed that both IUDs remain highly effective for up to 8 years of use, and currently, both devices are approved for up to 8 years of use. One caveat is that, in the unusual occurrence of a pregnancy being diagnosed in a woman using an IUD, we as clinicians, must be alert to the high prevalence of ectopic pregnancies in this setting.

Progestin IUDs and HMB

Dr. Pinkerton: Dr. Goldstein, can you comment on how well progestin IUDs work for HMB?

Steven R. Goldstein, MD, NCMP, CCD: Many women who need contraception will use these devices for suppressing HMB, and they can be quite effective, if the diagnosis truly is HMB, at reducing bleeding.⁵ But that efficacy in bleeding reduction may not be quite as long as the efficacy in pregnancy prevention.⁶ In my experience, among women using IUDs specifically for their HMB, good bleeding control may require changing the IUD at 3 to 5 years.

Barbara S. Levy, MD: When inserting a LNG-IUD for menorrhagia in the perimenopausal time frame, sometimes I will do a progestin withdrawal first, which will thin the endometrium and induce withdrawal bleeding because, in my experience, if you place an IUD in someone with perimenopausal bleeding, you may end up with a lot of breakthrough bleeding.

Perimenopause and hot flashes

Dr. Pinkerton: Dr. Kaunitz, we have learned that hot flashes often occur and become bothersome to women during perimenopause. Many women have IUDs placed during perimenopause for bleeding. Can you comment about IUD use during perimenopause and postmenopause?
 

Dr. Kaunitz: In older reproductive-age women who already have a progestin-releasing IUD placed, as they get closer to menopause when vasomotor symptoms (VMS) might occur, if these symptoms are bothersome, the presence or placement of a progestin-releasing IUD can facilitate treatment of perimenopausal VMS with estrogen therapy.

Progestin IUDs cause profound endometrial suppression, reduce bleeding and often, over time, cause users to become amenorrheic.⁷

The Mirena package insert states, “Amenorrhea develops in about 20% of users by one year.”² By year 3 and continuing through year 8, the prevalence of amenorrhea with the 52-mg LNG-IUD is 35% to 40%.⁸ From a study by Nanette Santoro, MD, and colleagues, we know that, in perimenopausal women with a progestin-releasing IUD in place, who are experiencing bothersome VMS, adding transdermal estrogen is very effective in treating and suppressing those hot flashes. In her small clinical trial, among participants with perimenopausal bothersome VMS with an IUD in place, half were randomized to use of transdermal estradiol and then compared with women who did not get the estradiol patch. There was excellent relief of perimenopausal hot flashes with the combination of the progestin IUD for endometrial suppression and transdermal estrogen to relieve hot flashes.⁹

Dr. Pinkerton: Which women would not be good candidates for the use of this combination?

Dr. Kaunitz: We know that, as women age, the prevalence of conditions that are contraindications to combination contraceptives (estrogen-progestin pills, patches, or rings) starts to increase. Specifically, we see more: hypertension, diabetes, and high body mass index (BMI), or obesity. We also know that migraine headaches in women older than age 35 years is another condition in which ACOG and the Centers for Disease Control and Prevention (CDC) would not recommend use of combination contraceptives.^10,11 These older perimenopausal women may be excellent candidates for a progestin-only releasing IUD combined with use of transdermal menopausal doses of estradiol if needed for VMS.

Dr. Goldstein: I do want to add that, in those patients who don’t have these comorbidities, combination estrogen-progestin contraceptives do a very nice job of ovarian suppression and will prevent the erratic production of estradiol, which, in my experience, often results in not only irregular bleeding but also possible exacerbation of perimenopausal mood symptoms.

Dr. Kaunitz: I agree, Steve. The ideal older reproductive-age candidate for combination pills, patch, or ring would be a slender, healthy, nonsmoking woman with normal blood pressure. Such women would be a fairly small subgroup of my practice, but they can safely continue combination contraceptives right through menopause. Consistent with CDC and ACOG guidance, rather than checking gonadotropins to “determine when menopause has occurred,” (which is, in fact, not an evidence-based approach to diagnosing menopause in this setting), such women can continue the combination contraceptive right up until age 55—the likelihood that women are still going to be ovulating or at risk for pregnancy becomes vanishingly small at that age.^11,12 Women in their mid-50s can either seamlessly transition to use of systemic estrogen-progestin menopausal therapy or go off hormones completely.

Continue to: The IUD and HMB...

The IUD and HMB

Dr. Pinkerton: Dr. Goldstein, there’s been some good literature on the best management options for women with HMB. What is the most current evidence?

Dr. Goldstein: I think that the retiring of the terms menorrhagia and metrorrhagia may have been premature because HMB implies cyclical bleeding, and this population of women with HMB will typically do quite well. Women who have what we used to call metrorrhagia or irregular bleeding, by definition, need endometrial evaluation to be sure they don’t have some sort of organic pathology. It would be a mistake for clinicians to use an LNG-IUD in patients with abnormal uterine bleeding (AUB) that has not been appropriately evaluated.

If we understand that we are discussing HMB, a Cochrane Review from 2022¹³ suggests that an LNG intrauterine system is the best first-line treatment for reducing menstrual blood loss in perimenopausal women with HMB. Antifibrinolytics appeared second best, while long-cycle progestogens came in third place. Evidence on perception of improvement in satisfaction was ranked as low certainty. That same review found that hysterectomy was the best treatment for reducing bleeding, obviously, followed by resectoscopic endometrial ablation or a nonresectoscopic global endometrial ablation.

The evidence rating was low certainty regarding the likelihood that placing an LNG-IUD in women with HMB will result in amenorrhea, and I think that’s a very important point. The expectation of patients should be reduced or a significantly reduced amount of their HMB, not necessarily amenorrhea. Certainly, minimally invasive hysterectomy will result in total amenorrhea and may have a larger increase in satisfaction, but it has its own set of other kinds of possible complications.

Dr. Kaunitz: In an industry-funded, international multicenter trial,¹⁴ women with documented HMB (hemoglobin was eluted from soiled sanitary products), with menstrual blood loss of 80 mL or more per cycle, were randomized to placement of an LNG 52-mg IUD (Mirena) or cyclical medroxyprogesterone acetate (MPA)—oral progestin use.

Although menstrual blood loss declined in both groups, it declined dramatically more in women with an IUD placed, and specifically with the IUD, menstrual blood loss declined by 129 mL on average, whereas the decline in menstrual blood loss with cyclical MPA was 18 mL. This data, along with earlier European data,¹⁵ which showed similar findings in women with HMB led to the approval of the Mirena progestin IUD for a second indication to treat HMB in 2009.

I also want to point out that, in the May 2023 issue of Obstetrics & Gynecology, Creinin and colleagues published a similar trial in women with HMB showing, once again, that progestin IUDs (52-mg LNG-IUD, Liletta) are extremely effective in reducing HMB.¹⁶ There is crystal clear evidence from randomized trials that both 52-mg LNG-IUDs, Mirena and Liletta, are very effective in reducing HMB and, in fact, are contributing to many women who in the past would have proceeded with surgery, such as ablation or hysterectomy, to control their HMB.

Oral contraception

Dr. Pinkerton: What about using low-dose continuous oral contraceptives noncyclically for women with HMB?

Dr. Goldstein: I do that all the time. It is interesting that Dr. Kaunitz mentions his patient population. It’s why we understand that one size does not fit all. You need to see patients one at a time, and if they are good candidates for a combined estrogen-progestin contraception, whether it’s pills, patches, or rings, giving that continuously does a very nice job in reducing HMB and straightening out some of the other symptoms that these perimenopausal women will have.

IUD risks

Dr. Pinkerton: We all know about use of low-dose oral contraceptives for management of AUB, and we use them, although we worry a little bit about breast cancer risk. Dr. Levy, please comment on the risks with IUDs of expulsions and perforations. What are the downsides of IUDs?

Dr. Levy: Beyond the cost, although it is a minimally invasive procedure, IUD insertion can be an invasive procedure for a patient to undergo; expulsions can occur.¹⁷ We know that a substantial percentage of perimenopausal women will have fibroids. Although many fibroids are not located in the uterine cavity, the expulsion rate with HMB for an LNG-IUD can be higher,^13,16,18,19 perhaps because of local prostaglandin release with an increase in uterine contractility. There is a low incidence of perforations, but they do happen, particularly among women with scars in the uterus or who have a severely anteflexed or retroflexed uterus, and women with cervical stenosis, for example, if they have had a LEEP procedure, etc. Even though progestin IUDs are outstanding tools in our toolbox, they are invasive to some extent, and they do have the possibility of complications.

Dr. Kaunitz: As Dr. Levy points out, although placement of an IUD may be considered an invasive procedure, it is also an office-based procedure, so women can drive home or drive back to work afterwards without the disruption in their life and the potential complications associated with surgery and anesthesia.

Continue to: Concerns with malpositioning...

 

 

Concerns with malpositioning

Dr. Pinkerton: After placement of an IUD, during a follow-up visit, sometimes you can’t visualize the string. The ultrasonography report may reveal, “IUD appears to be in the right place within the endometrium.” Dr. Goldstein, can you comment on how we should use ultrasound when we can’t visualize or find the IUD string, or if the patient complains of abdominal pain, lower abdominal discomfort, or irregular bleeding or spotting and we become concerned about IUD malposition?

Dr. Goldstein: Ultrasound is not really required after an uncomplicated placement of an IUD or during routine management of women who have no problems who are using an IUD. In patients who present with pain or some abnormal bleeding, however, sometimes it is the IUD being malpositioned. A very interesting study by the late great Beryl Benacerraf²⁰ showed that there was a statistically significant higher incidence of the IUD being poorly positioned when patients have pain or bleeding (FIGURE 1). It was not always apparent on 2D ultrasonography. Using a standard transvaginal ultrasound of the long access plane, the IUD may appear to be very centrally located. However, if you do a 3D coronal section, not infrequently in these patients with any pain or bleeding, one of the arms has pierced the myometrium (FIGURE 2). This can actually be a source of pain and bleeding.

It’s also very interesting when you talk about perforation. I became aware of a big to-do in the medical/legal world about the possibility of the IUD migrating through the uterine cavity.²¹ This just does not exist, as was already pointed out. If the IUD is really going to go anywhere, if it’s properly placed, it’s going to be expelled through an open cervix. I do believe that, if you have pierced the myometrium through uterine contractility over time, some of these IUDs could work their way through the myometrium and somehow come out of the uterus either totally or partially. I think ultrasound is invaluable in patients with pain and bleeding, but I think you need to have an ultrasound lab capable of doing a 3D coronal section.

Progestin IUDs for HT replacement: Benefits/risks

Dr. Pinkerton: Many clinicians are excited that they can use essentially estrogen alone for women who have a progestin IUD in place. What about the possible off-label use of the progestin IUD to replace oral progestogen for hormone therapy (HT)? Dr. Kaunitz, are there any studies using this for postmenopausal HT (with a reminder that the IUD is not FDA approved for this purpose)?

Dr. Kaunitz: We have data from Europe indicating that, in menopausal women using systemic estrogen, the full-size LNG 52 IUD—Mirena or Liletta—provides excellent endometrial suppression.²² Where we don’t have data is with the smaller IUDs, which would be Kyleena and Skyla, which release smaller amounts of progestin each day into the endometrial cavity.

I have a number of patients, most of them women who started use of a progestin IUD as older reproductive-age women and then started systemic estrogen for treatment of perimenopausal hot flashes and then continued the use of their IUD plus systemic estrogen in treating postmenopausal hot flashes. The IUD is very useful in this setting, but as you pointed out, Dr. Pinkerton, this does represent off-label use.

Dr. Pinkerton: I know this use does not affect plasma lipids or cardiovascular risk markers, although users seem to report that the IUD has improved their quality of life. The question comes up, what are the benefits on cancer risk for using an IUD?

Dr. Levy: It’s such a great question because, as we talk about the balance of risks and benefits for anything that we are offering to our patients, it is really important to focus on some of the benefits. For both the copper and the LNG-IUD, there is a reduction in endometrial cancer,²² as well as pretty good data with the copper IUD about a reduction in cervical cancer.²³ Those data are a little bit less clear for the LNG-IUD.

Interestingly, at least one meta-analysis published in 2020 shows about a 30% reduction in ovarian cancer risk with the LNG-IUD.²⁴ We need to focus our patients on these other benefits. They tend to focus on the risks, and, of course, the media blows up the risks, but the benefits are quite substantial beyond just reducing HMB and providing contraception.

Dr. Pinkerton: As Dr. Kaunitz said, when you use this IUD, with its primarily local uterine progestin effects, it’s more like using estrogen alone without as much systemic progestin. Recently I wrote an editorial on the benefits of estrogen alone on the risk of breast cancer, primarily based on the Women’s Health Initiative (WHI) observational long-term 18-year cumulative follow-up. When estrogen alone was prescribed to women after a hysterectomy, estrogen therapy used at menopause did not increase the risk of invasive breast cancer, and was associated with decreased mortality.²⁵ However, the nurse’s health study has suggested that longer-term use may be increased with estrogen alone.²⁶ For women in the WHI with an intact uterus who used estrogen, oral MPA slightly increased the risk for breast cancer, and this elevated risk persisted even after discontinuation. This leads us to the question, what are the risks of breast cancer with progestin IUD use?

I recently reviewed the literature, and the answer is, it’s mixed. The FDA has put language into the package label that acknowledges a potential breast cancer risk for women who use a progestin IUD,²⁷ and that warning states, “Women who currently have or have had breast cancer or suspect breast cancer should not use hormonal contraception because some breast cancers are hormone sensitive.” The label goes on to say, “Observational studies of the risk of breast cancer with the use of a levonorgestrel-releasing IUS don’t provide conclusive evidence of increased risk.” Thus, there is no conclusive answer as to whether there is a possible link of progestin IUDs to breast cancer.

What I tell my patients is that research is inconclusive. However, it’s unlikely for a 52-mg LNG-IUD to significantly increase a woman’s breast cancer risk, except possibly in those already at high risk from other risk factors. I tell them that breast cancer is listed in the package insert as a potential risk. I could not find any data on whether adding a low-dose estradiol patch would further increase that risk. So I counsel women about potential risk, but tell them that I don’t have any strong evidence of risk.

Continue to: Dr. Goldstein...

Dr. Goldstein: If you look in the package insert for Mirena,² similar to Liletta, certainly the serum levels of LNG are lower than that for combination oral contraceptives. For the IUD progestins, they are not localized only to the uterus, and LNG levels range from about 150 to 200 µg/mL up to 60 months. It’s greater at 12 months, at about 180 µg/mL,at 24 months it was 192 µg/mL, and by 60 months it was 159 µg/mL. It’s important to realize that there is some systemic absorption of progestin with progestin IUDs, and it is not completely a local effect.

JoAnn, you mentioned the WHI data,²⁵ and just to specify, it was not the estrogen-only arm, it was the conjugated equine estrogen-only arm of the WHI. I don’t think that estradiol alone increases breast cancer risk (although there are no good prospective, follow-through, 18-year study data, like the WHI), but I think readers need to understand the difference in the estrogen type.

Endometrial evaluation. My question for the panel is as follows. I agree that the use of the progestin-releasing IUD is very nice for that transition to menopause. I do believe it provides endometrial protection, but we know from other studies that, when we give continuous combined HT, about 21% to 26% of patients will experience some bleeding/staining, responding in the first 4-week cycles, and it can be as high as 9% at 1 year. If I have a patient who bleeds on continuous combined HT, I will evaluate her endometrium, usually just with a simple transvaginal ultrasound. If an IUD is in place, and the patient now begins to have some irregular bleeding, how do you evaluate her with the IUD in place?

Dr. Levy: That is a huge challenge. We know from a recent paper,²⁸ that the endometrial thickness, while an excellent measure for Caucasian and European women, may be a poor marker for endometrial pathology in African-American women. What we thought we knew, which was, if the stripe is 4 mL or less, we can forget about it, I think in our more recent research that is not so true. So you bring up a great point, what do you do? The most reliable evaluation will be with an office hysteroscopy, where you can really look at the entire cavity and for tiny, little polyps and other things. But then we are off label because the use of hysteroscopy with an IUD in place is off label. So we are really in a conundrum.

Dr. Pinkerton: Also, if you do an endometrial biopsy, you might dislodge the IUD. If you think that you are going to take the IUD out, it may not matter if you dislodge it. I will often obtain a transvaginal ultrasound to help me figure out the next step, and maybe look at the dosing of the estrogen and progestin—but you can’t monitor an IUD with blood levels. You are in a vacuum of trying to figure out the best thing to do.

Dr. Kaunitz: One of the hats I wear here in Jacksonville is Director of GYN Ultrasound. I have a fair amount of experience doing endometrial biopsies in women with progestin IUDs in place under abdominal ultrasound guidance and keeping a close eye on the position of the IUD. In the first dozen or so such procedures I did, I was quite concerned about dislodging the IUD. It hasn’t happened yet, and it gives me some reassurance to be able to image the IUD and your endometrial suction curette inside the cavity as you are obtaining endometrial sampling. I have substantial experience now doing that, and so far, no problems. I do counsel all such women in advance that there is some chance I could dislodge their IUD.

Dr. Goldstein: In addition to dislodging the IUD, are you not concerned that, if the pathology is not global, that a blind endometrial sampling may be fraught with some error?

Dr. Kaunitz: The endometrium in women with a progestin-releasing IUD in place tends to be very well suppressed. Although one might occasionally find, for instance, a polyp in that setting, I have not run into, and I don’t expect to encounter going forward, endometrial hyperplasia or cancer in women with current use of a progestin IUD. It’s possible but unlikely.

Dr. Levy: The progestin IUD will counterbalance a type-1 endometrial cancer—an endometrial cancer related to hyperstimulation by estrogen. It will not do anything, to my knowledge, to counterbalance a type 2. I think the art of medicine is, you do the best you can with the first episode of bleeding, and if she persists in her bleeding, we have to persevere and continue to evaluate her.

Dr. Goldstein: I agree 100%.

Dr. Pinkerton: We all agree with you. That’s a really good point.

Continue to: Case examinations...

Case examinations

CASE 1 Woman with intramural fibroids

Dr. Pinkerton: Dr. Goldstein, you have a 48-year-old Black woman who has heavy but regular menstrual bleeding with multiple fibroids (the largest is about 4 to 5 cm, they look intramural, with some distortion of the cavity but not a submucous myoma, and the endometrial depth is 9 cm). Would you insert an IUD, and would you recommend an endometrial biopsy first?

Dr. Goldstein: I am not a huge fan of blind endometrial sampling, and I do think that we use the “biopsy” somewhat inappropriately since sampling is not a directed biopsy. This became obvious in the landmark paper by Guido et al in 1995 and was adopted by ACOG only in 2012.²⁹ Cancers that occupy less than 50% of the endometrial surface area are often missed with such blind sampling. Thus I would not perform an endometrial biopsy first, but would rather rely on properly timed and performed transvaginal ultrasound to rule out any concurrent endometrial disease. I think a lot of patients who have HMB, not only because of their fibroids but also often just due to the surface area of their uterine cavity being increased—so essentially there is more blood volume when they bleed. However, you said that in this case the patient has regular menstrual bleeding, so I am assuming that she is still ovulatory. She may have some adenomyosis. She may have a large uterine cavity. I think she is an excellent candidate for an LNG-releasing IUD to reduce menstrual blood flow significantly. It will not necessarily give her amenorrhea, and it may give her some irregular bleeding. Then at some distant point, say in 5 or 6 months if she does have some irregular staining or bleeding, I would feel much better about the fact that nothing has developed as long as I knew that the endometrium was devoid of pathology when I started.

CASE 2 Woman with family history of breast cancer

Dr. Pinkerton: Dr. Levy, a 44-year-old woman has a family history of breast cancer in her mother at age 72, but she still needs contraceptionbecause of that unintended pregnancy risk in the 40s, and she wants something that is not going to increase her risk of breast cancer. What would you use, and how would you counsel her if you decided to use a progestin IUD?

Dr. Levy: The data are mixed,^30-33 but whatever the risk, it is miniscule, and I would bring up the CDC Medical Eligibility Criteria.¹¹ For a patient with a family history of breast cancer, for use of the progestin IUD, it is a 1—no contraindications. What I tend to tell my patients is, if you are worried about breast cancer, watch how much alcohol you are drinking and maintain regular exercise. There are so many preventive things that we can do to reduce risk of breast cancer when she needs contraception. If there is any increase in risk, it is so miniscule that I would very strongly recommend a progestin IUD for her.

Dr. Pinkerton: In addition, in recognizing the different densities of breast, dense breast density could lead to supplemental screening, which also could give her some reassurance that we are adequately screening for breast cancer.

CASE 3 Woman with IUD and VMS
 

Dr. Pinkerton: Dr. Kaunitz, you have a 52-year-old overweight female. She has been using a progestin IUD for 4 years, is amenorrheic, but now she is having moderate to severe vasomotor symptoms despite the IUD in place. You have talked to her about risks and benefits of HT, and she is interested in starting it. I know we talked about the studies, but I want to know what you are going to tell her. How do you counsel her about off-label use?

Dr. Kaunitz: The most important issue related to treating vasomotor symptoms in this patient is the route of systemic estrogen. Understandably, women’s biggest concern regarding the risks of systemic estrogen-progestin therapy is breast cancer. However, statistically, by far the biggest risk associated with oral estrogen-progestogen therapy, is elevated risk of venous thrombosis and pulmonary embolism. We have seen this, with a number of studies, and the WHI made it crystal clear with risks of oral conjugated equine estrogen at the dose of 0.625 mg daily. Oral estradiol 1 mg daily is also associated with a similar elevated risk of venous thrombosis. We also know that age and BMI are both independent risk factors for thrombosis. So, for a woman in her 50s who has a BMI > 30 mg/kg², I don’t want to further elevate her risk of thrombosis by giving her oral estrogen, whether it is estradiol or conjugated equine estrogen. This is a patient in whom I would be comfortable using transdermal (patch) estradiol, perhaps starting with a standard dose of 0.05 mg weekly or twice weekly patch, keeping in mind that 0.05 mg in the setting of transdermal estrogen refer to the daily or to the 24-hour release rate. The 1.0 mg of oral estradiol and 0.625 mg of conjugated equine estrogen refers to the mg quantity of estrogen in each tablet. This is a source of great confusion for clinicians.

If, during follow-up, the 0.05 mg estradiol patch is not sufficient to substantially reduce symptoms, we could go up, for instance, to a 0.075 mg estradiol patch. We know very clearly from a variety of observational studies, including a very large UK study,³⁴ that in contrast with oral estrogen, transdermal estradiol is safer from the perspective of thrombosis.

Insurance coverage for IUDs

Dr. Pinkerton: Dr. Levy: Can you discuss IUDs and the Affordable Care Act’s requirement to cover contraceptive services?

Dr. Levy: Unfortunately, we do not know whether this benefit will continue based on a very recent finding from a judge in Texas that ruled the preventive benefits of the ACA were illegal.³⁵ We don’t know what will happen going forward. What I will say is that, unfortunately, many insurance companies have not preserved the meaning of “cover all things,” so what we are finding is that, for example, they only have to cover one type in a class. The FDA defined 18 classes of contraceptives, and a hormonal IUD is one class, so they can decide that they are only going to cover one of the four IUDS. And then women don’t have access to the other three, some of which might be more appropriate for them than another.

The other thing very relevant to this conversation is that, if you use an ICD-10 code for menorrhagia, for HMB, it no longer lives within that ACA preventive care requirement of coverage for contraceptives, and now she is going to owe a big deductible or a copay. If you are practicing in an institution that does not allow the use of IUDs for contraception, like a Catholic institution where I used to practice, you will want to use that ICD-10 code for HMB. But if you want it offered with no out-of-pocket cost for the patient, you need to use the preventive medicine codes and the contraception code. These little nuances for us can make a huge difference for our patients.

Dr. Pinkerton: Thank you for that reminder. I want to thank our panelists, Dr. Levy, Dr. Goldstein, and Dr. Kaunitz, for providing us with such a great mix of evidence and expert opinion and also giving a benefit of their vast experience as award-winning gynecologists. Hopefully, today you have learned the benefits of the progestin IUD not only for contraception in reproductive years and perimenopause but also for treatment of HMB, and the potential benefit due to the more prolonged effectiveness of the IUDs for endometrial protection in postmenopause. This allows less progestin risk, essentially estrogen alone for postmenopausal HT. Unsolved questions remain about whether there is a risk of breast cancer with their use, but there is a clear benefit of protecting against pregnancy and endometrial cancer. ●

Illustration: Kimberly Martens for OBG Management

Intrauterine devices (IUDs) are now used by more than 15% of US contraceptors. The majority of these IUDs release the progestin levonorgestrel, and with now longer extended use of the IUDs approved by the US Food and Drug Administration (FDA),^1-3 they become even more attractive for use for contraception,control of menorrhagia or heavy menstrual bleeding (HMB) during reproductive years and perimenopause, and potentially, although not FDA approved for this purpose, postmenopause for endometrial protection in estrogen users. In this roundtable discussion, we will look at some of the benefits of the IUD for contraception effectiveness and control of bleeding, as well as the potential risks if used for postmenopausal women.

Progestin IUDs and contraception

JoAnn V. Pinkerton, MD, NCMP: Dr. Kaunitz, what are the contraceptive benefits of progestin IUDs during perimenopause?
 

Andrew M. Kaunitz, MD, NCMP: We know fertility declines as women approach menopause. However, when pregnancy occurs in older reproductive-age women, the pregnancies are often unintended, as reflected by high rates of induced abortion in this population. In addition, the prevalence of maternal comorbidities (during pregnancy and delivery) is higher in older reproductive-age women, with the maternal mortality rate more than 5 times higher compared with that of younger women.⁴ Two recently published clinical trials assessed the extended use of full-size IUDs containing 52 mg of levonor-gestrel (LNG), with the brand names Mirena and Liletta.^1,2 The data from these trials confirmed that both IUDs remain highly effective for up to 8 years of use, and currently, both devices are approved for up to 8 years of use. One caveat is that, in the unusual occurrence of a pregnancy being diagnosed in a woman using an IUD, we as clinicians, must be alert to the high prevalence of ectopic pregnancies in this setting.

Progestin IUDs and HMB

Dr. Pinkerton: Dr. Goldstein, can you comment on how well progestin IUDs work for HMB?

Steven R. Goldstein, MD, NCMP, CCD: Many women who need contraception will use these devices for suppressing HMB, and they can be quite effective, if the diagnosis truly is HMB, at reducing bleeding.⁵ But that efficacy in bleeding reduction may not be quite as long as the efficacy in pregnancy prevention.⁶ In my experience, among women using IUDs specifically for their HMB, good bleeding control may require changing the IUD at 3 to 5 years.

Barbara S. Levy, MD: When inserting a LNG-IUD for menorrhagia in the perimenopausal time frame, sometimes I will do a progestin withdrawal first, which will thin the endometrium and induce withdrawal bleeding because, in my experience, if you place an IUD in someone with perimenopausal bleeding, you may end up with a lot of breakthrough bleeding.

Perimenopause and hot flashes

Dr. Pinkerton: Dr. Kaunitz, we have learned that hot flashes often occur and become bothersome to women during perimenopause. Many women have IUDs placed during perimenopause for bleeding. Can you comment about IUD use during perimenopause and postmenopause?
 

Dr. Kaunitz: In older reproductive-age women who already have a progestin-releasing IUD placed, as they get closer to menopause when vasomotor symptoms (VMS) might occur, if these symptoms are bothersome, the presence or placement of a progestin-releasing IUD can facilitate treatment of perimenopausal VMS with estrogen therapy.

Progestin IUDs cause profound endometrial suppression, reduce bleeding and often, over time, cause users to become amenorrheic.⁷

The Mirena package insert states, “Amenorrhea develops in about 20% of users by one year.”² By year 3 and continuing through year 8, the prevalence of amenorrhea with the 52-mg LNG-IUD is 35% to 40%.⁸ From a study by Nanette Santoro, MD, and colleagues, we know that, in perimenopausal women with a progestin-releasing IUD in place, who are experiencing bothersome VMS, adding transdermal estrogen is very effective in treating and suppressing those hot flashes. In her small clinical trial, among participants with perimenopausal bothersome VMS with an IUD in place, half were randomized to use of transdermal estradiol and then compared with women who did not get the estradiol patch. There was excellent relief of perimenopausal hot flashes with the combination of the progestin IUD for endometrial suppression and transdermal estrogen to relieve hot flashes.⁹

Dr. Pinkerton: Which women would not be good candidates for the use of this combination?

Dr. Kaunitz: We know that, as women age, the prevalence of conditions that are contraindications to combination contraceptives (estrogen-progestin pills, patches, or rings) starts to increase. Specifically, we see more: hypertension, diabetes, and high body mass index (BMI), or obesity. We also know that migraine headaches in women older than age 35 years is another condition in which ACOG and the Centers for Disease Control and Prevention (CDC) would not recommend use of combination contraceptives.^10,11 These older perimenopausal women may be excellent candidates for a progestin-only releasing IUD combined with use of transdermal menopausal doses of estradiol if needed for VMS.

Dr. Goldstein: I do want to add that, in those patients who don’t have these comorbidities, combination estrogen-progestin contraceptives do a very nice job of ovarian suppression and will prevent the erratic production of estradiol, which, in my experience, often results in not only irregular bleeding but also possible exacerbation of perimenopausal mood symptoms.

Dr. Kaunitz: I agree, Steve. The ideal older reproductive-age candidate for combination pills, patch, or ring would be a slender, healthy, nonsmoking woman with normal blood pressure. Such women would be a fairly small subgroup of my practice, but they can safely continue combination contraceptives right through menopause. Consistent with CDC and ACOG guidance, rather than checking gonadotropins to “determine when menopause has occurred,” (which is, in fact, not an evidence-based approach to diagnosing menopause in this setting), such women can continue the combination contraceptive right up until age 55—the likelihood that women are still going to be ovulating or at risk for pregnancy becomes vanishingly small at that age.^11,12 Women in their mid-50s can either seamlessly transition to use of systemic estrogen-progestin menopausal therapy or go off hormones completely.

Continue to: The IUD and HMB...

The IUD and HMB

Dr. Pinkerton: Dr. Goldstein, there’s been some good literature on the best management options for women with HMB. What is the most current evidence?

Dr. Goldstein: I think that the retiring of the terms menorrhagia and metrorrhagia may have been premature because HMB implies cyclical bleeding, and this population of women with HMB will typically do quite well. Women who have what we used to call metrorrhagia or irregular bleeding, by definition, need endometrial evaluation to be sure they don’t have some sort of organic pathology. It would be a mistake for clinicians to use an LNG-IUD in patients with abnormal uterine bleeding (AUB) that has not been appropriately evaluated.

If we understand that we are discussing HMB, a Cochrane Review from 2022¹³ suggests that an LNG intrauterine system is the best first-line treatment for reducing menstrual blood loss in perimenopausal women with HMB. Antifibrinolytics appeared second best, while long-cycle progestogens came in third place. Evidence on perception of improvement in satisfaction was ranked as low certainty. That same review found that hysterectomy was the best treatment for reducing bleeding, obviously, followed by resectoscopic endometrial ablation or a nonresectoscopic global endometrial ablation.

The evidence rating was low certainty regarding the likelihood that placing an LNG-IUD in women with HMB will result in amenorrhea, and I think that’s a very important point. The expectation of patients should be reduced or a significantly reduced amount of their HMB, not necessarily amenorrhea. Certainly, minimally invasive hysterectomy will result in total amenorrhea and may have a larger increase in satisfaction, but it has its own set of other kinds of possible complications.

Dr. Kaunitz: In an industry-funded, international multicenter trial,¹⁴ women with documented HMB (hemoglobin was eluted from soiled sanitary products), with menstrual blood loss of 80 mL or more per cycle, were randomized to placement of an LNG 52-mg IUD (Mirena) or cyclical medroxyprogesterone acetate (MPA)—oral progestin use.

Although menstrual blood loss declined in both groups, it declined dramatically more in women with an IUD placed, and specifically with the IUD, menstrual blood loss declined by 129 mL on average, whereas the decline in menstrual blood loss with cyclical MPA was 18 mL. This data, along with earlier European data,¹⁵ which showed similar findings in women with HMB led to the approval of the Mirena progestin IUD for a second indication to treat HMB in 2009.

I also want to point out that, in the May 2023 issue of Obstetrics & Gynecology, Creinin and colleagues published a similar trial in women with HMB showing, once again, that progestin IUDs (52-mg LNG-IUD, Liletta) are extremely effective in reducing HMB.¹⁶ There is crystal clear evidence from randomized trials that both 52-mg LNG-IUDs, Mirena and Liletta, are very effective in reducing HMB and, in fact, are contributing to many women who in the past would have proceeded with surgery, such as ablation or hysterectomy, to control their HMB.

Oral contraception

Dr. Pinkerton: What about using low-dose continuous oral contraceptives noncyclically for women with HMB?

Dr. Goldstein: I do that all the time. It is interesting that Dr. Kaunitz mentions his patient population. It’s why we understand that one size does not fit all. You need to see patients one at a time, and if they are good candidates for a combined estrogen-progestin contraception, whether it’s pills, patches, or rings, giving that continuously does a very nice job in reducing HMB and straightening out some of the other symptoms that these perimenopausal women will have.

IUD risks

Dr. Pinkerton: We all know about use of low-dose oral contraceptives for management of AUB, and we use them, although we worry a little bit about breast cancer risk. Dr. Levy, please comment on the risks with IUDs of expulsions and perforations. What are the downsides of IUDs?

Dr. Levy: Beyond the cost, although it is a minimally invasive procedure, IUD insertion can be an invasive procedure for a patient to undergo; expulsions can occur.¹⁷ We know that a substantial percentage of perimenopausal women will have fibroids. Although many fibroids are not located in the uterine cavity, the expulsion rate with HMB for an LNG-IUD can be higher,^13,16,18,19 perhaps because of local prostaglandin release with an increase in uterine contractility. There is a low incidence of perforations, but they do happen, particularly among women with scars in the uterus or who have a severely anteflexed or retroflexed uterus, and women with cervical stenosis, for example, if they have had a LEEP procedure, etc. Even though progestin IUDs are outstanding tools in our toolbox, they are invasive to some extent, and they do have the possibility of complications.

Dr. Kaunitz: As Dr. Levy points out, although placement of an IUD may be considered an invasive procedure, it is also an office-based procedure, so women can drive home or drive back to work afterwards without the disruption in their life and the potential complications associated with surgery and anesthesia.

Continue to: Concerns with malpositioning...

 

 

Concerns with malpositioning

Dr. Pinkerton: After placement of an IUD, during a follow-up visit, sometimes you can’t visualize the string. The ultrasonography report may reveal, “IUD appears to be in the right place within the endometrium.” Dr. Goldstein, can you comment on how we should use ultrasound when we can’t visualize or find the IUD string, or if the patient complains of abdominal pain, lower abdominal discomfort, or irregular bleeding or spotting and we become concerned about IUD malposition?

Dr. Goldstein: Ultrasound is not really required after an uncomplicated placement of an IUD or during routine management of women who have no problems who are using an IUD. In patients who present with pain or some abnormal bleeding, however, sometimes it is the IUD being malpositioned. A very interesting study by the late great Beryl Benacerraf²⁰ showed that there was a statistically significant higher incidence of the IUD being poorly positioned when patients have pain or bleeding (FIGURE 1). It was not always apparent on 2D ultrasonography. Using a standard transvaginal ultrasound of the long access plane, the IUD may appear to be very centrally located. However, if you do a 3D coronal section, not infrequently in these patients with any pain or bleeding, one of the arms has pierced the myometrium (FIGURE 2). This can actually be a source of pain and bleeding.

It’s also very interesting when you talk about perforation. I became aware of a big to-do in the medical/legal world about the possibility of the IUD migrating through the uterine cavity.²¹ This just does not exist, as was already pointed out. If the IUD is really going to go anywhere, if it’s properly placed, it’s going to be expelled through an open cervix. I do believe that, if you have pierced the myometrium through uterine contractility over time, some of these IUDs could work their way through the myometrium and somehow come out of the uterus either totally or partially. I think ultrasound is invaluable in patients with pain and bleeding, but I think you need to have an ultrasound lab capable of doing a 3D coronal section.

Progestin IUDs for HT replacement: Benefits/risks

Dr. Pinkerton: Many clinicians are excited that they can use essentially estrogen alone for women who have a progestin IUD in place. What about the possible off-label use of the progestin IUD to replace oral progestogen for hormone therapy (HT)? Dr. Kaunitz, are there any studies using this for postmenopausal HT (with a reminder that the IUD is not FDA approved for this purpose)?

Dr. Kaunitz: We have data from Europe indicating that, in menopausal women using systemic estrogen, the full-size LNG 52 IUD—Mirena or Liletta—provides excellent endometrial suppression.²² Where we don’t have data is with the smaller IUDs, which would be Kyleena and Skyla, which release smaller amounts of progestin each day into the endometrial cavity.

I have a number of patients, most of them women who started use of a progestin IUD as older reproductive-age women and then started systemic estrogen for treatment of perimenopausal hot flashes and then continued the use of their IUD plus systemic estrogen in treating postmenopausal hot flashes. The IUD is very useful in this setting, but as you pointed out, Dr. Pinkerton, this does represent off-label use.

Dr. Pinkerton: I know this use does not affect plasma lipids or cardiovascular risk markers, although users seem to report that the IUD has improved their quality of life. The question comes up, what are the benefits on cancer risk for using an IUD?

Dr. Levy: It’s such a great question because, as we talk about the balance of risks and benefits for anything that we are offering to our patients, it is really important to focus on some of the benefits. For both the copper and the LNG-IUD, there is a reduction in endometrial cancer,²² as well as pretty good data with the copper IUD about a reduction in cervical cancer.²³ Those data are a little bit less clear for the LNG-IUD.

Interestingly, at least one meta-analysis published in 2020 shows about a 30% reduction in ovarian cancer risk with the LNG-IUD.²⁴ We need to focus our patients on these other benefits. They tend to focus on the risks, and, of course, the media blows up the risks, but the benefits are quite substantial beyond just reducing HMB and providing contraception.

Dr. Pinkerton: As Dr. Kaunitz said, when you use this IUD, with its primarily local uterine progestin effects, it’s more like using estrogen alone without as much systemic progestin. Recently I wrote an editorial on the benefits of estrogen alone on the risk of breast cancer, primarily based on the Women’s Health Initiative (WHI) observational long-term 18-year cumulative follow-up. When estrogen alone was prescribed to women after a hysterectomy, estrogen therapy used at menopause did not increase the risk of invasive breast cancer, and was associated with decreased mortality.²⁵ However, the nurse’s health study has suggested that longer-term use may be increased with estrogen alone.²⁶ For women in the WHI with an intact uterus who used estrogen, oral MPA slightly increased the risk for breast cancer, and this elevated risk persisted even after discontinuation. This leads us to the question, what are the risks of breast cancer with progestin IUD use?

I recently reviewed the literature, and the answer is, it’s mixed. The FDA has put language into the package label that acknowledges a potential breast cancer risk for women who use a progestin IUD,²⁷ and that warning states, “Women who currently have or have had breast cancer or suspect breast cancer should not use hormonal contraception because some breast cancers are hormone sensitive.” The label goes on to say, “Observational studies of the risk of breast cancer with the use of a levonorgestrel-releasing IUS don’t provide conclusive evidence of increased risk.” Thus, there is no conclusive answer as to whether there is a possible link of progestin IUDs to breast cancer.

What I tell my patients is that research is inconclusive. However, it’s unlikely for a 52-mg LNG-IUD to significantly increase a woman’s breast cancer risk, except possibly in those already at high risk from other risk factors. I tell them that breast cancer is listed in the package insert as a potential risk. I could not find any data on whether adding a low-dose estradiol patch would further increase that risk. So I counsel women about potential risk, but tell them that I don’t have any strong evidence of risk.

Continue to: Dr. Goldstein...

Dr. Goldstein: If you look in the package insert for Mirena,² similar to Liletta, certainly the serum levels of LNG are lower than that for combination oral contraceptives. For the IUD progestins, they are not localized only to the uterus, and LNG levels range from about 150 to 200 µg/mL up to 60 months. It’s greater at 12 months, at about 180 µg/mL,at 24 months it was 192 µg/mL, and by 60 months it was 159 µg/mL. It’s important to realize that there is some systemic absorption of progestin with progestin IUDs, and it is not completely a local effect.

JoAnn, you mentioned the WHI data,²⁵ and just to specify, it was not the estrogen-only arm, it was the conjugated equine estrogen-only arm of the WHI. I don’t think that estradiol alone increases breast cancer risk (although there are no good prospective, follow-through, 18-year study data, like the WHI), but I think readers need to understand the difference in the estrogen type.

Endometrial evaluation. My question for the panel is as follows. I agree that the use of the progestin-releasing IUD is very nice for that transition to menopause. I do believe it provides endometrial protection, but we know from other studies that, when we give continuous combined HT, about 21% to 26% of patients will experience some bleeding/staining, responding in the first 4-week cycles, and it can be as high as 9% at 1 year. If I have a patient who bleeds on continuous combined HT, I will evaluate her endometrium, usually just with a simple transvaginal ultrasound. If an IUD is in place, and the patient now begins to have some irregular bleeding, how do you evaluate her with the IUD in place?

Dr. Levy: That is a huge challenge. We know from a recent paper,²⁸ that the endometrial thickness, while an excellent measure for Caucasian and European women, may be a poor marker for endometrial pathology in African-American women. What we thought we knew, which was, if the stripe is 4 mL or less, we can forget about it, I think in our more recent research that is not so true. So you bring up a great point, what do you do? The most reliable evaluation will be with an office hysteroscopy, where you can really look at the entire cavity and for tiny, little polyps and other things. But then we are off label because the use of hysteroscopy with an IUD in place is off label. So we are really in a conundrum.

Dr. Pinkerton: Also, if you do an endometrial biopsy, you might dislodge the IUD. If you think that you are going to take the IUD out, it may not matter if you dislodge it. I will often obtain a transvaginal ultrasound to help me figure out the next step, and maybe look at the dosing of the estrogen and progestin—but you can’t monitor an IUD with blood levels. You are in a vacuum of trying to figure out the best thing to do.

Dr. Kaunitz: One of the hats I wear here in Jacksonville is Director of GYN Ultrasound. I have a fair amount of experience doing endometrial biopsies in women with progestin IUDs in place under abdominal ultrasound guidance and keeping a close eye on the position of the IUD. In the first dozen or so such procedures I did, I was quite concerned about dislodging the IUD. It hasn’t happened yet, and it gives me some reassurance to be able to image the IUD and your endometrial suction curette inside the cavity as you are obtaining endometrial sampling. I have substantial experience now doing that, and so far, no problems. I do counsel all such women in advance that there is some chance I could dislodge their IUD.

Dr. Goldstein: In addition to dislodging the IUD, are you not concerned that, if the pathology is not global, that a blind endometrial sampling may be fraught with some error?

Dr. Kaunitz: The endometrium in women with a progestin-releasing IUD in place tends to be very well suppressed. Although one might occasionally find, for instance, a polyp in that setting, I have not run into, and I don’t expect to encounter going forward, endometrial hyperplasia or cancer in women with current use of a progestin IUD. It’s possible but unlikely.

Dr. Levy: The progestin IUD will counterbalance a type-1 endometrial cancer—an endometrial cancer related to hyperstimulation by estrogen. It will not do anything, to my knowledge, to counterbalance a type 2. I think the art of medicine is, you do the best you can with the first episode of bleeding, and if she persists in her bleeding, we have to persevere and continue to evaluate her.

Dr. Goldstein: I agree 100%.

Dr. Pinkerton: We all agree with you. That’s a really good point.

Continue to: Case examinations...

Case examinations

CASE 1 Woman with intramural fibroids

Dr. Pinkerton: Dr. Goldstein, you have a 48-year-old Black woman who has heavy but regular menstrual bleeding with multiple fibroids (the largest is about 4 to 5 cm, they look intramural, with some distortion of the cavity but not a submucous myoma, and the endometrial depth is 9 cm). Would you insert an IUD, and would you recommend an endometrial biopsy first?

Dr. Goldstein: I am not a huge fan of blind endometrial sampling, and I do think that we use the “biopsy” somewhat inappropriately since sampling is not a directed biopsy. This became obvious in the landmark paper by Guido et al in 1995 and was adopted by ACOG only in 2012.²⁹ Cancers that occupy less than 50% of the endometrial surface area are often missed with such blind sampling. Thus I would not perform an endometrial biopsy first, but would rather rely on properly timed and performed transvaginal ultrasound to rule out any concurrent endometrial disease. I think a lot of patients who have HMB, not only because of their fibroids but also often just due to the surface area of their uterine cavity being increased—so essentially there is more blood volume when they bleed. However, you said that in this case the patient has regular menstrual bleeding, so I am assuming that she is still ovulatory. She may have some adenomyosis. She may have a large uterine cavity. I think she is an excellent candidate for an LNG-releasing IUD to reduce menstrual blood flow significantly. It will not necessarily give her amenorrhea, and it may give her some irregular bleeding. Then at some distant point, say in 5 or 6 months if she does have some irregular staining or bleeding, I would feel much better about the fact that nothing has developed as long as I knew that the endometrium was devoid of pathology when I started.

CASE 2 Woman with family history of breast cancer

Dr. Pinkerton: Dr. Levy, a 44-year-old woman has a family history of breast cancer in her mother at age 72, but she still needs contraceptionbecause of that unintended pregnancy risk in the 40s, and she wants something that is not going to increase her risk of breast cancer. What would you use, and how would you counsel her if you decided to use a progestin IUD?

Dr. Levy: The data are mixed,^30-33 but whatever the risk, it is miniscule, and I would bring up the CDC Medical Eligibility Criteria.¹¹ For a patient with a family history of breast cancer, for use of the progestin IUD, it is a 1—no contraindications. What I tend to tell my patients is, if you are worried about breast cancer, watch how much alcohol you are drinking and maintain regular exercise. There are so many preventive things that we can do to reduce risk of breast cancer when she needs contraception. If there is any increase in risk, it is so miniscule that I would very strongly recommend a progestin IUD for her.

Dr. Pinkerton: In addition, in recognizing the different densities of breast, dense breast density could lead to supplemental screening, which also could give her some reassurance that we are adequately screening for breast cancer.

CASE 3 Woman with IUD and VMS
 

Dr. Pinkerton: Dr. Kaunitz, you have a 52-year-old overweight female. She has been using a progestin IUD for 4 years, is amenorrheic, but now she is having moderate to severe vasomotor symptoms despite the IUD in place. You have talked to her about risks and benefits of HT, and she is interested in starting it. I know we talked about the studies, but I want to know what you are going to tell her. How do you counsel her about off-label use?

Dr. Kaunitz: The most important issue related to treating vasomotor symptoms in this patient is the route of systemic estrogen. Understandably, women’s biggest concern regarding the risks of systemic estrogen-progestin therapy is breast cancer. However, statistically, by far the biggest risk associated with oral estrogen-progestogen therapy, is elevated risk of venous thrombosis and pulmonary embolism. We have seen this, with a number of studies, and the WHI made it crystal clear with risks of oral conjugated equine estrogen at the dose of 0.625 mg daily. Oral estradiol 1 mg daily is also associated with a similar elevated risk of venous thrombosis. We also know that age and BMI are both independent risk factors for thrombosis. So, for a woman in her 50s who has a BMI > 30 mg/kg², I don’t want to further elevate her risk of thrombosis by giving her oral estrogen, whether it is estradiol or conjugated equine estrogen. This is a patient in whom I would be comfortable using transdermal (patch) estradiol, perhaps starting with a standard dose of 0.05 mg weekly or twice weekly patch, keeping in mind that 0.05 mg in the setting of transdermal estrogen refer to the daily or to the 24-hour release rate. The 1.0 mg of oral estradiol and 0.625 mg of conjugated equine estrogen refers to the mg quantity of estrogen in each tablet. This is a source of great confusion for clinicians.

If, during follow-up, the 0.05 mg estradiol patch is not sufficient to substantially reduce symptoms, we could go up, for instance, to a 0.075 mg estradiol patch. We know very clearly from a variety of observational studies, including a very large UK study,³⁴ that in contrast with oral estrogen, transdermal estradiol is safer from the perspective of thrombosis.

Insurance coverage for IUDs

Dr. Pinkerton: Dr. Levy: Can you discuss IUDs and the Affordable Care Act’s requirement to cover contraceptive services?

Dr. Levy: Unfortunately, we do not know whether this benefit will continue based on a very recent finding from a judge in Texas that ruled the preventive benefits of the ACA were illegal.³⁵ We don’t know what will happen going forward. What I will say is that, unfortunately, many insurance companies have not preserved the meaning of “cover all things,” so what we are finding is that, for example, they only have to cover one type in a class. The FDA defined 18 classes of contraceptives, and a hormonal IUD is one class, so they can decide that they are only going to cover one of the four IUDS. And then women don’t have access to the other three, some of which might be more appropriate for them than another.

The other thing very relevant to this conversation is that, if you use an ICD-10 code for menorrhagia, for HMB, it no longer lives within that ACA preventive care requirement of coverage for contraceptives, and now she is going to owe a big deductible or a copay. If you are practicing in an institution that does not allow the use of IUDs for contraception, like a Catholic institution where I used to practice, you will want to use that ICD-10 code for HMB. But if you want it offered with no out-of-pocket cost for the patient, you need to use the preventive medicine codes and the contraception code. These little nuances for us can make a huge difference for our patients.

Dr. Pinkerton: Thank you for that reminder. I want to thank our panelists, Dr. Levy, Dr. Goldstein, and Dr. Kaunitz, for providing us with such a great mix of evidence and expert opinion and also giving a benefit of their vast experience as award-winning gynecologists. Hopefully, today you have learned the benefits of the progestin IUD not only for contraception in reproductive years and perimenopause but also for treatment of HMB, and the potential benefit due to the more prolonged effectiveness of the IUDs for endometrial protection in postmenopause. This allows less progestin risk, essentially estrogen alone for postmenopausal HT. Unsolved questions remain about whether there is a risk of breast cancer with their use, but there is a clear benefit of protecting against pregnancy and endometrial cancer. ●

To the Editor:

Squamous cell carcinoma (SCC) is the second most common cancer of the scalp.¹ Mohs micrographic surgery is used to treat SCC, and it commonly generates a 2.5×2.5-cm open wound with exposed bone.² Although Mohs micrographic surgery effectively treats cutaneous lesions, it carries a high risk for complications such as infection, wound dehiscence, and partial or full-thickness skin graft necrosis.³ Recommended therapies to decrease these complications include linear closures, flaps, and peripheral autograft tissue.⁴ However, these procedures do not come without risks and carry their own complications. Therefore, we suggest a safe, less-invasive initial approach using a synthetic extracellular matrix (ECM)–based collagen dressing for secondary wound closure.

A 76-year-old woman presented to the infectious disease clinic at Monument Health Rapid City Clinic (Rapid City, South Dakota) for evaluation of a dehisced scalp wound 3 months following Mohs micrographic surgery for scalp SCC. The wound underwent primary closure following surgery and dehisced shortly after (Figure 1A). Various oral antimicrobials were used by the dermatologist to assist with wound closure but without success. The patient was referred to the wound clinic for management. At the first appointment, all necrotic tissue was debrided and the cranium was exposed in the wound base (Figure 1B). The wound measured 2.3×2.3×0.2 cm. An ECM-containing collagen dressing (Endoform Natural Restorative Bioscaffold [Aroa Biosurgery Inc]) was used to provide a scaffold for wound closure (Figure 2A). It was dressed with the petroleum-based gauze Xeroform (Cardinal Health) and covered with dry gauze to prevent evaporation and provide moist wound healing. The wound developed some budding tissue islands 3 weeks after weekly ECM-based collagen dressing applications (Figure 3A). The wound continued to decrease in size and formed an isthmus by the second month of therapy (Figure 3B). The wound fully closed within 3 months and showed minimal scarring after 3 years (Figure 2B).

Chronic wounds usually get trapped in the inflammatory stage of wound healing due to destruction of growth factors and ECM by metalloproteases (MMPs), which creates a vicious cycle and wound stalling. Wound debridement converts a chronic wound back into an acute wound, which is the first step of healing. Following wound debridement, collagen-based dressings can assist with healing by binding the destructive MMPs, and ECM matrix promotes the building of new tissue. The 3 most commonly used ECM-based collagen dressings are Endoform, PuraPly AM (Organogenesis Inc), and Puracol Ultra ECM (Medline Industries, Inc).

Endoform is ovine-based collagen and provides a natural porous bioscaffold for rapid cell infiltration.⁵ It contains more than 150 ECM proteins along with residual vascular channels that help re-establish new vasculature. Ovine-based collagen contains collagen types I, III, and IV arranged as native fibers that retain the 3-dimensional architecture present in tissue ECM.⁵ Although MMPs are essential in normal healing, the elevated presence of MMPs has been linked to stalled wound healing. Clinical observation and assessment may not be sufficient to identify a wound with elevated protease activity that can break down ECM, affect wound fibroblasts, and impair growth factor response. Although collagen ECM itself does not contain any growth factors, it preserves the destruction of native ECM and growth factors by MMPs by functioning as a sacrificial substrate. The addition of 0.3% ionic silver to the ECM has been shown to decrease bacterial growth and prevent biofilm formation.⁶

PuraPly AM is a native, type I porcine collagen matrix embedded with the polyhexamethylene biguanide for the management of chronic wounds.⁷ The addition of polyhexamethylene biguanide to the ECM matrix provides bactericidal activity against biofilm formation.⁸ PuraPly AM reduced the counts of biofilm-producing pathogens such as Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Candida species, and Aspergillus niger in nonclinical studies. Use of polyhexamethylene biguanide has been seen within ECM grafts (PuraPly AM).

Puracol Ultra ECM is made of porcine mesothelium and is comprised of types I, III, and IV collagens; elastin; fibronectin; laminin; and proteoglycans. It also contains fibroblast growth factors, contributing to angiogenesis in the wound.⁹

Application of ECM-based collagen dressings on debrided wounds requires moisture for absorption. Because cranium wounds lack sufficient exudate production, dermal templates need to be hydrated with sterile normal saline before application and covered with a moisture-retaining dressing. Extracellular matrix–based dressings are biodegradable and can be reapplied every 5 to 7 days. For chronic wounds, application of collagen dressings, such as Endoform, is essential and could be considered as the first step prior to switching to more advanced wound care modalities.^6,10 Additional studies investigating ECM-containing may determine their comparative efficacy.

To the Editor:

Squamous cell carcinoma (SCC) is the second most common cancer of the scalp.¹ Mohs micrographic surgery is used to treat SCC, and it commonly generates a 2.5×2.5-cm open wound with exposed bone.² Although Mohs micrographic surgery effectively treats cutaneous lesions, it carries a high risk for complications such as infection, wound dehiscence, and partial or full-thickness skin graft necrosis.³ Recommended therapies to decrease these complications include linear closures, flaps, and peripheral autograft tissue.⁴ However, these procedures do not come without risks and carry their own complications. Therefore, we suggest a safe, less-invasive initial approach using a synthetic extracellular matrix (ECM)–based collagen dressing for secondary wound closure.

A 76-year-old woman presented to the infectious disease clinic at Monument Health Rapid City Clinic (Rapid City, South Dakota) for evaluation of a dehisced scalp wound 3 months following Mohs micrographic surgery for scalp SCC. The wound underwent primary closure following surgery and dehisced shortly after (Figure 1A). Various oral antimicrobials were used by the dermatologist to assist with wound closure but without success. The patient was referred to the wound clinic for management. At the first appointment, all necrotic tissue was debrided and the cranium was exposed in the wound base (Figure 1B). The wound measured 2.3×2.3×0.2 cm. An ECM-containing collagen dressing (Endoform Natural Restorative Bioscaffold [Aroa Biosurgery Inc]) was used to provide a scaffold for wound closure (Figure 2A). It was dressed with the petroleum-based gauze Xeroform (Cardinal Health) and covered with dry gauze to prevent evaporation and provide moist wound healing. The wound developed some budding tissue islands 3 weeks after weekly ECM-based collagen dressing applications (Figure 3A). The wound continued to decrease in size and formed an isthmus by the second month of therapy (Figure 3B). The wound fully closed within 3 months and showed minimal scarring after 3 years (Figure 2B).

Chronic wounds usually get trapped in the inflammatory stage of wound healing due to destruction of growth factors and ECM by metalloproteases (MMPs), which creates a vicious cycle and wound stalling. Wound debridement converts a chronic wound back into an acute wound, which is the first step of healing. Following wound debridement, collagen-based dressings can assist with healing by binding the destructive MMPs, and ECM matrix promotes the building of new tissue. The 3 most commonly used ECM-based collagen dressings are Endoform, PuraPly AM (Organogenesis Inc), and Puracol Ultra ECM (Medline Industries, Inc).

Endoform is ovine-based collagen and provides a natural porous bioscaffold for rapid cell infiltration.⁵ It contains more than 150 ECM proteins along with residual vascular channels that help re-establish new vasculature. Ovine-based collagen contains collagen types I, III, and IV arranged as native fibers that retain the 3-dimensional architecture present in tissue ECM.⁵ Although MMPs are essential in normal healing, the elevated presence of MMPs has been linked to stalled wound healing. Clinical observation and assessment may not be sufficient to identify a wound with elevated protease activity that can break down ECM, affect wound fibroblasts, and impair growth factor response. Although collagen ECM itself does not contain any growth factors, it preserves the destruction of native ECM and growth factors by MMPs by functioning as a sacrificial substrate. The addition of 0.3% ionic silver to the ECM has been shown to decrease bacterial growth and prevent biofilm formation.⁶

PuraPly AM is a native, type I porcine collagen matrix embedded with the polyhexamethylene biguanide for the management of chronic wounds.⁷ The addition of polyhexamethylene biguanide to the ECM matrix provides bactericidal activity against biofilm formation.⁸ PuraPly AM reduced the counts of biofilm-producing pathogens such as Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Candida species, and Aspergillus niger in nonclinical studies. Use of polyhexamethylene biguanide has been seen within ECM grafts (PuraPly AM).

Puracol Ultra ECM is made of porcine mesothelium and is comprised of types I, III, and IV collagens; elastin; fibronectin; laminin; and proteoglycans. It also contains fibroblast growth factors, contributing to angiogenesis in the wound.⁹

Application of ECM-based collagen dressings on debrided wounds requires moisture for absorption. Because cranium wounds lack sufficient exudate production, dermal templates need to be hydrated with sterile normal saline before application and covered with a moisture-retaining dressing. Extracellular matrix–based dressings are biodegradable and can be reapplied every 5 to 7 days. For chronic wounds, application of collagen dressings, such as Endoform, is essential and could be considered as the first step prior to switching to more advanced wound care modalities.^6,10 Additional studies investigating ECM-containing may determine their comparative efficacy.

To the Editor:

Squamous cell carcinoma (SCC) is the second most common cancer of the scalp.¹ Mohs micrographic surgery is used to treat SCC, and it commonly generates a 2.5×2.5-cm open wound with exposed bone.² Although Mohs micrographic surgery effectively treats cutaneous lesions, it carries a high risk for complications such as infection, wound dehiscence, and partial or full-thickness skin graft necrosis.³ Recommended therapies to decrease these complications include linear closures, flaps, and peripheral autograft tissue.⁴ However, these procedures do not come without risks and carry their own complications. Therefore, we suggest a safe, less-invasive initial approach using a synthetic extracellular matrix (ECM)–based collagen dressing for secondary wound closure.

A 76-year-old woman presented to the infectious disease clinic at Monument Health Rapid City Clinic (Rapid City, South Dakota) for evaluation of a dehisced scalp wound 3 months following Mohs micrographic surgery for scalp SCC. The wound underwent primary closure following surgery and dehisced shortly after (Figure 1A). Various oral antimicrobials were used by the dermatologist to assist with wound closure but without success. The patient was referred to the wound clinic for management. At the first appointment, all necrotic tissue was debrided and the cranium was exposed in the wound base (Figure 1B). The wound measured 2.3×2.3×0.2 cm. An ECM-containing collagen dressing (Endoform Natural Restorative Bioscaffold [Aroa Biosurgery Inc]) was used to provide a scaffold for wound closure (Figure 2A). It was dressed with the petroleum-based gauze Xeroform (Cardinal Health) and covered with dry gauze to prevent evaporation and provide moist wound healing. The wound developed some budding tissue islands 3 weeks after weekly ECM-based collagen dressing applications (Figure 3A). The wound continued to decrease in size and formed an isthmus by the second month of therapy (Figure 3B). The wound fully closed within 3 months and showed minimal scarring after 3 years (Figure 2B).

Chronic wounds usually get trapped in the inflammatory stage of wound healing due to destruction of growth factors and ECM by metalloproteases (MMPs), which creates a vicious cycle and wound stalling. Wound debridement converts a chronic wound back into an acute wound, which is the first step of healing. Following wound debridement, collagen-based dressings can assist with healing by binding the destructive MMPs, and ECM matrix promotes the building of new tissue. The 3 most commonly used ECM-based collagen dressings are Endoform, PuraPly AM (Organogenesis Inc), and Puracol Ultra ECM (Medline Industries, Inc).

Endoform is ovine-based collagen and provides a natural porous bioscaffold for rapid cell infiltration.⁵ It contains more than 150 ECM proteins along with residual vascular channels that help re-establish new vasculature. Ovine-based collagen contains collagen types I, III, and IV arranged as native fibers that retain the 3-dimensional architecture present in tissue ECM.⁵ Although MMPs are essential in normal healing, the elevated presence of MMPs has been linked to stalled wound healing. Clinical observation and assessment may not be sufficient to identify a wound with elevated protease activity that can break down ECM, affect wound fibroblasts, and impair growth factor response. Although collagen ECM itself does not contain any growth factors, it preserves the destruction of native ECM and growth factors by MMPs by functioning as a sacrificial substrate. The addition of 0.3% ionic silver to the ECM has been shown to decrease bacterial growth and prevent biofilm formation.⁶

PuraPly AM is a native, type I porcine collagen matrix embedded with the polyhexamethylene biguanide for the management of chronic wounds.⁷ The addition of polyhexamethylene biguanide to the ECM matrix provides bactericidal activity against biofilm formation.⁸ PuraPly AM reduced the counts of biofilm-producing pathogens such as Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Candida species, and Aspergillus niger in nonclinical studies. Use of polyhexamethylene biguanide has been seen within ECM grafts (PuraPly AM).

Puracol Ultra ECM is made of porcine mesothelium and is comprised of types I, III, and IV collagens; elastin; fibronectin; laminin; and proteoglycans. It also contains fibroblast growth factors, contributing to angiogenesis in the wound.⁹

Application of ECM-based collagen dressings on debrided wounds requires moisture for absorption. Because cranium wounds lack sufficient exudate production, dermal templates need to be hydrated with sterile normal saline before application and covered with a moisture-retaining dressing. Extracellular matrix–based dressings are biodegradable and can be reapplied every 5 to 7 days. For chronic wounds, application of collagen dressings, such as Endoform, is essential and could be considered as the first step prior to switching to more advanced wound care modalities.^6,10 Additional studies investigating ECM-containing may determine their comparative efficacy.

To the Editor:

A 12-year-old girl presented to the dermatology clinic for evaluation of a congenital scalp lesion. The patient was diagnosed with alopecia areata by a dermatologist at 4 years of age, and she was treated with topical corticosteroids and minoxidil, which failed to resolve her condition. Physical examination revealed an 8×10-cm, well-demarcated, yellowish-pink plaque located over the vertex and right parietal scalp (Figure 1A), extending down to the right preauricular cheek (Figure 1B) in a linear configuration with blaschkoid features. The scalp plaque appeared bald and completely lacking in terminal hairs but contained numerous fine vellus hairs (Figure 1A). A 6-mm, oval-appearing, pigmented papule was present in the plaque, and a few smaller, scattered, pigmented papules were noted in the vertex region (Figure 1A).

The cutaneous examination was otherwise unremarkable. A review of systems was negative, except for a history of attention-deficit/hyperactivity disorder. There was no history of seizures or other neurocognitive developmental abnormalities.

A 4-mm punch biopsy of the vertex scalp included the pigmented lesion but excluded an adnexal neoplasm. Epidermal acanthosis and mild papillomatosis were reported on microscopic examination. Multiple prominent sebaceous glands without associated hair follicles, which emptied directly onto the epidermal surface, were noted in the dermis (Figure 2). Several apocrine glands were observed (Figure 3). Epidermal and dermal melanocytic nests were highlighted with SOX-10 and Melan-A immunohistochemical stains, confirming the presence of a benign compound nevus. The punch biopsy analysis confirmed the diagnosis of a nevus sebaceus (NS) of Jadassohn (organoid nevus) with incidental compound nevus. Additional 4-mm punch biopsies were obtained for genetic testing, performed by the Genomics and Pathology Services at Washington University (St. Louis, Missouri). A missense HRAS p.G12V variant was observed in the tissue. A negative blood test result ruled out a germline mutation. The patient was managed with active observation of the lesion to evaluate for potential formation of neoplasms, as well as continuity of care with the dermatology clinic, considering the extent of the lesions, to monitor the development of any new medical conditions that would be concerning for syndromes associated with NS.

Nevus sebaceus is a benign skin hamartoma caused by a congenital defect in the pilosebaceous follicular unit and consists of epidermal, sebaceous, and apocrine elements.^1,2 In dermatology patients, the prevalence of NS ranges from 0.05% to 1%.¹ In 90% of cases, NS presents at birth as a 1- to 10-cm, round or linear, yellowish-orange, hairless plaque located on the scalp. It also may appear on the face, neck, trunk, oral mucosa, or labia minora.^1,3 Although NS is a benign condition, secondary tumors may form within the lesion.³

The physical and histologic characteristics of NS evolve as the patient ages. In childhood, NS typically appears as a yellow-pink macule or patch with mild to moderate epidermal hyperplasia. Patients exhibit underdeveloped sebaceous glands, immature hair follicles, hyperkeratosis, and acanthosis.^1,3,4 The development of early lesions can be quite subtle and can lead to diagnostic uncertainty, as described in our patient. During puberty, lesions thicken due to papillomatous hyperplasia in the epidermis, and the number and size of sebaceous and apocrine glands increase.⁴ In adults, the risk for secondary tumor formation increases. These physical and histologic transformations, including secondary tumor formation, are thought to be stimulated by the action of postpubertal androgens.¹

Nevus sebaceus is associated with both benign and malignant secondary tumor formation; however, fewer than 1% of tumors are malignant.¹ In a retrospective analysis, Idriss and Elston⁵ (N=707) reported that 21.4% of patients with NS had secondary neoplasms; 18.9% of the secondary neoplasms were benign, and 2.5% were malignant. Additionally, this study showed that secondary tumor formation can occur in children, though it typically occurs in adults. Benign neoplasms were reported in 5 children in the subset aged 0 to 10 years and 10 children in the subset aged 11 to 17 years; 1 child developed a malignant neoplasm in the latter subset.⁵ The most common NS-associated benign neoplasms include trichoblastoma and syringocystadenoma papilliferum. Others include trichilemmoma, apocrine/eccrine adenoma, and sebaceoma.¹ Nevus sebaceus–associated malignant neoplasms include basal cell carcinoma, squamous cell carcinoma, adenocarcinoma, carcinosarcoma, and sebaceous carcinoma.³

Our patient was incorrectly diagnosed and treated for alopecia areata before an eventual diagnosis of NS was confirmed by biopsy. Additional genetic studies revealed a novel mutation in the HRAS gene, the most commonly affected gene in NS. The most common mutation location seen in more than 90% of NS lesions is HRAS c.37G>C (p.G13R), while KRAS mutations account for almost all the remaining cases.³ In our patient, a pathogenic missense HRAS p.G12V variant of somatic origin was detected with DNA extraction and sequencing from a fresh tissue sample acquired from two 4-mm punch biopsies performed on the lesion. The following genes were sequenced and found to be uninvolved: BRAF, FGFR1, FGFR2, FGFR3, GNA11, GNAQ, KRAS, MAP3K3, NRAS, PIK3CA, and TEK. The Sanger sequencing method for comparative analysis performed on peripheral blood was negative.

Nevus sebaceus typically is caused by a sporadic mutation, though familial cases have been reported.¹ Additionally, germline HRAS mutations can lead to Costello syndrome, an autosomal-dominant disorder characterized by short stature; intellectual disabilities; coarse facial features; facial and perianal papillomata; cardiac defects; loose skin; joint hyperflexibility; and an increased risk for malignant tumors including rhabdomyosarcoma, neuroblastoma, and transitional cell carcinoma of the bladder.⁶

The diagnosis of NS often can be made clinically but can be difficult to confirm in underdeveloped lesions in young children. The differential diagnosis can include alopecia areata, aplasia cutis congenita, juvenile xanthogranuloma, epidermal nevus, de novo syringocystadenoma papilliferum, and solitary mastocytoma.¹ Nevus sebaceus can be associated with 4 additional syndromes: Schimmelpenning syndrome; phacomatosis pigmentokeratotica; didymosis aplasticosebacea; and SCALP (sebaceus nevus, central nervous system malformations, aplasia cutis congenital, limbal dermoid, pigmented nevus) syndrome.¹ Approximately 7% of NS cases may be associated with Schimmelpenning-Feuerstein-Mims (SFM) syndrome, a more severe condition that leads to systemic involvement and abnormalities in the neurological, ophthalmological, cardiovascular, genitourological, and skeletal systems.^1,3 Phacomatosis pigmentokeratotica has speckled lentiginous nevi, as well as abnormalities in the neurological, ophthalmological, cardiovascular, genitourological, and skeletal systems.¹ Didymosis aplasticosebacea is the concurrence of NS and aplasia cutis congenita.

The definitive treatment of NS is surgical excision. Alternative therapies include photodynamic therapy, fractional laser resurfacing, and dermabrasion; these are not definitive treatments, and patients must be monitored for the development of secondary neoplasms. Multiple variables must be considered when determining treatment, including patient age, risk potential for malignancy, and surgery-associated risks.¹ In our patient, given the extent of the lesions, active observation and follow-up was agreed upon for management.

This case demonstrates the importance of considering NS as an alternative diagnosis when alopecia areata has been diagnosed in a child who is unresponsive to treatments. After the diagnosis of NS is confirmed, more serious associated syndromes should be ruled out, and treatment should be tailored to each case.

To the Editor:

A 12-year-old girl presented to the dermatology clinic for evaluation of a congenital scalp lesion. The patient was diagnosed with alopecia areata by a dermatologist at 4 years of age, and she was treated with topical corticosteroids and minoxidil, which failed to resolve her condition. Physical examination revealed an 8×10-cm, well-demarcated, yellowish-pink plaque located over the vertex and right parietal scalp (Figure 1A), extending down to the right preauricular cheek (Figure 1B) in a linear configuration with blaschkoid features. The scalp plaque appeared bald and completely lacking in terminal hairs but contained numerous fine vellus hairs (Figure 1A). A 6-mm, oval-appearing, pigmented papule was present in the plaque, and a few smaller, scattered, pigmented papules were noted in the vertex region (Figure 1A).

The cutaneous examination was otherwise unremarkable. A review of systems was negative, except for a history of attention-deficit/hyperactivity disorder. There was no history of seizures or other neurocognitive developmental abnormalities.

A 4-mm punch biopsy of the vertex scalp included the pigmented lesion but excluded an adnexal neoplasm. Epidermal acanthosis and mild papillomatosis were reported on microscopic examination. Multiple prominent sebaceous glands without associated hair follicles, which emptied directly onto the epidermal surface, were noted in the dermis (Figure 2). Several apocrine glands were observed (Figure 3). Epidermal and dermal melanocytic nests were highlighted with SOX-10 and Melan-A immunohistochemical stains, confirming the presence of a benign compound nevus. The punch biopsy analysis confirmed the diagnosis of a nevus sebaceus (NS) of Jadassohn (organoid nevus) with incidental compound nevus. Additional 4-mm punch biopsies were obtained for genetic testing, performed by the Genomics and Pathology Services at Washington University (St. Louis, Missouri). A missense HRAS p.G12V variant was observed in the tissue. A negative blood test result ruled out a germline mutation. The patient was managed with active observation of the lesion to evaluate for potential formation of neoplasms, as well as continuity of care with the dermatology clinic, considering the extent of the lesions, to monitor the development of any new medical conditions that would be concerning for syndromes associated with NS.

Nevus sebaceus is a benign skin hamartoma caused by a congenital defect in the pilosebaceous follicular unit and consists of epidermal, sebaceous, and apocrine elements.^1,2 In dermatology patients, the prevalence of NS ranges from 0.05% to 1%.¹ In 90% of cases, NS presents at birth as a 1- to 10-cm, round or linear, yellowish-orange, hairless plaque located on the scalp. It also may appear on the face, neck, trunk, oral mucosa, or labia minora.^1,3 Although NS is a benign condition, secondary tumors may form within the lesion.³

The physical and histologic characteristics of NS evolve as the patient ages. In childhood, NS typically appears as a yellow-pink macule or patch with mild to moderate epidermal hyperplasia. Patients exhibit underdeveloped sebaceous glands, immature hair follicles, hyperkeratosis, and acanthosis.^1,3,4 The development of early lesions can be quite subtle and can lead to diagnostic uncertainty, as described in our patient. During puberty, lesions thicken due to papillomatous hyperplasia in the epidermis, and the number and size of sebaceous and apocrine glands increase.⁴ In adults, the risk for secondary tumor formation increases. These physical and histologic transformations, including secondary tumor formation, are thought to be stimulated by the action of postpubertal androgens.¹

Nevus sebaceus is associated with both benign and malignant secondary tumor formation; however, fewer than 1% of tumors are malignant.¹ In a retrospective analysis, Idriss and Elston⁵ (N=707) reported that 21.4% of patients with NS had secondary neoplasms; 18.9% of the secondary neoplasms were benign, and 2.5% were malignant. Additionally, this study showed that secondary tumor formation can occur in children, though it typically occurs in adults. Benign neoplasms were reported in 5 children in the subset aged 0 to 10 years and 10 children in the subset aged 11 to 17 years; 1 child developed a malignant neoplasm in the latter subset.⁵ The most common NS-associated benign neoplasms include trichoblastoma and syringocystadenoma papilliferum. Others include trichilemmoma, apocrine/eccrine adenoma, and sebaceoma.¹ Nevus sebaceus–associated malignant neoplasms include basal cell carcinoma, squamous cell carcinoma, adenocarcinoma, carcinosarcoma, and sebaceous carcinoma.³

Our patient was incorrectly diagnosed and treated for alopecia areata before an eventual diagnosis of NS was confirmed by biopsy. Additional genetic studies revealed a novel mutation in the HRAS gene, the most commonly affected gene in NS. The most common mutation location seen in more than 90% of NS lesions is HRAS c.37G>C (p.G13R), while KRAS mutations account for almost all the remaining cases.³ In our patient, a pathogenic missense HRAS p.G12V variant of somatic origin was detected with DNA extraction and sequencing from a fresh tissue sample acquired from two 4-mm punch biopsies performed on the lesion. The following genes were sequenced and found to be uninvolved: BRAF, FGFR1, FGFR2, FGFR3, GNA11, GNAQ, KRAS, MAP3K3, NRAS, PIK3CA, and TEK. The Sanger sequencing method for comparative analysis performed on peripheral blood was negative.

Nevus sebaceus typically is caused by a sporadic mutation, though familial cases have been reported.¹ Additionally, germline HRAS mutations can lead to Costello syndrome, an autosomal-dominant disorder characterized by short stature; intellectual disabilities; coarse facial features; facial and perianal papillomata; cardiac defects; loose skin; joint hyperflexibility; and an increased risk for malignant tumors including rhabdomyosarcoma, neuroblastoma, and transitional cell carcinoma of the bladder.⁶

The diagnosis of NS often can be made clinically but can be difficult to confirm in underdeveloped lesions in young children. The differential diagnosis can include alopecia areata, aplasia cutis congenita, juvenile xanthogranuloma, epidermal nevus, de novo syringocystadenoma papilliferum, and solitary mastocytoma.¹ Nevus sebaceus can be associated with 4 additional syndromes: Schimmelpenning syndrome; phacomatosis pigmentokeratotica; didymosis aplasticosebacea; and SCALP (sebaceus nevus, central nervous system malformations, aplasia cutis congenital, limbal dermoid, pigmented nevus) syndrome.¹ Approximately 7% of NS cases may be associated with Schimmelpenning-Feuerstein-Mims (SFM) syndrome, a more severe condition that leads to systemic involvement and abnormalities in the neurological, ophthalmological, cardiovascular, genitourological, and skeletal systems.^1,3 Phacomatosis pigmentokeratotica has speckled lentiginous nevi, as well as abnormalities in the neurological, ophthalmological, cardiovascular, genitourological, and skeletal systems.¹ Didymosis aplasticosebacea is the concurrence of NS and aplasia cutis congenita.

The definitive treatment of NS is surgical excision. Alternative therapies include photodynamic therapy, fractional laser resurfacing, and dermabrasion; these are not definitive treatments, and patients must be monitored for the development of secondary neoplasms. Multiple variables must be considered when determining treatment, including patient age, risk potential for malignancy, and surgery-associated risks.¹ In our patient, given the extent of the lesions, active observation and follow-up was agreed upon for management.

This case demonstrates the importance of considering NS as an alternative diagnosis when alopecia areata has been diagnosed in a child who is unresponsive to treatments. After the diagnosis of NS is confirmed, more serious associated syndromes should be ruled out, and treatment should be tailored to each case.

To the Editor:

A 12-year-old girl presented to the dermatology clinic for evaluation of a congenital scalp lesion. The patient was diagnosed with alopecia areata by a dermatologist at 4 years of age, and she was treated with topical corticosteroids and minoxidil, which failed to resolve her condition. Physical examination revealed an 8×10-cm, well-demarcated, yellowish-pink plaque located over the vertex and right parietal scalp (Figure 1A), extending down to the right preauricular cheek (Figure 1B) in a linear configuration with blaschkoid features. The scalp plaque appeared bald and completely lacking in terminal hairs but contained numerous fine vellus hairs (Figure 1A). A 6-mm, oval-appearing, pigmented papule was present in the plaque, and a few smaller, scattered, pigmented papules were noted in the vertex region (Figure 1A).

The cutaneous examination was otherwise unremarkable. A review of systems was negative, except for a history of attention-deficit/hyperactivity disorder. There was no history of seizures or other neurocognitive developmental abnormalities.

A 4-mm punch biopsy of the vertex scalp included the pigmented lesion but excluded an adnexal neoplasm. Epidermal acanthosis and mild papillomatosis were reported on microscopic examination. Multiple prominent sebaceous glands without associated hair follicles, which emptied directly onto the epidermal surface, were noted in the dermis (Figure 2). Several apocrine glands were observed (Figure 3). Epidermal and dermal melanocytic nests were highlighted with SOX-10 and Melan-A immunohistochemical stains, confirming the presence of a benign compound nevus. The punch biopsy analysis confirmed the diagnosis of a nevus sebaceus (NS) of Jadassohn (organoid nevus) with incidental compound nevus. Additional 4-mm punch biopsies were obtained for genetic testing, performed by the Genomics and Pathology Services at Washington University (St. Louis, Missouri). A missense HRAS p.G12V variant was observed in the tissue. A negative blood test result ruled out a germline mutation. The patient was managed with active observation of the lesion to evaluate for potential formation of neoplasms, as well as continuity of care with the dermatology clinic, considering the extent of the lesions, to monitor the development of any new medical conditions that would be concerning for syndromes associated with NS.

Nevus sebaceus is a benign skin hamartoma caused by a congenital defect in the pilosebaceous follicular unit and consists of epidermal, sebaceous, and apocrine elements.^1,2 In dermatology patients, the prevalence of NS ranges from 0.05% to 1%.¹ In 90% of cases, NS presents at birth as a 1- to 10-cm, round or linear, yellowish-orange, hairless plaque located on the scalp. It also may appear on the face, neck, trunk, oral mucosa, or labia minora.^1,3 Although NS is a benign condition, secondary tumors may form within the lesion.³

The physical and histologic characteristics of NS evolve as the patient ages. In childhood, NS typically appears as a yellow-pink macule or patch with mild to moderate epidermal hyperplasia. Patients exhibit underdeveloped sebaceous glands, immature hair follicles, hyperkeratosis, and acanthosis.^1,3,4 The development of early lesions can be quite subtle and can lead to diagnostic uncertainty, as described in our patient. During puberty, lesions thicken due to papillomatous hyperplasia in the epidermis, and the number and size of sebaceous and apocrine glands increase.⁴ In adults, the risk for secondary tumor formation increases. These physical and histologic transformations, including secondary tumor formation, are thought to be stimulated by the action of postpubertal androgens.¹

Nevus sebaceus is associated with both benign and malignant secondary tumor formation; however, fewer than 1% of tumors are malignant.¹ In a retrospective analysis, Idriss and Elston⁵ (N=707) reported that 21.4% of patients with NS had secondary neoplasms; 18.9% of the secondary neoplasms were benign, and 2.5% were malignant. Additionally, this study showed that secondary tumor formation can occur in children, though it typically occurs in adults. Benign neoplasms were reported in 5 children in the subset aged 0 to 10 years and 10 children in the subset aged 11 to 17 years; 1 child developed a malignant neoplasm in the latter subset.⁵ The most common NS-associated benign neoplasms include trichoblastoma and syringocystadenoma papilliferum. Others include trichilemmoma, apocrine/eccrine adenoma, and sebaceoma.¹ Nevus sebaceus–associated malignant neoplasms include basal cell carcinoma, squamous cell carcinoma, adenocarcinoma, carcinosarcoma, and sebaceous carcinoma.³

Our patient was incorrectly diagnosed and treated for alopecia areata before an eventual diagnosis of NS was confirmed by biopsy. Additional genetic studies revealed a novel mutation in the HRAS gene, the most commonly affected gene in NS. The most common mutation location seen in more than 90% of NS lesions is HRAS c.37G>C (p.G13R), while KRAS mutations account for almost all the remaining cases.³ In our patient, a pathogenic missense HRAS p.G12V variant of somatic origin was detected with DNA extraction and sequencing from a fresh tissue sample acquired from two 4-mm punch biopsies performed on the lesion. The following genes were sequenced and found to be uninvolved: BRAF, FGFR1, FGFR2, FGFR3, GNA11, GNAQ, KRAS, MAP3K3, NRAS, PIK3CA, and TEK. The Sanger sequencing method for comparative analysis performed on peripheral blood was negative.

Nevus sebaceus typically is caused by a sporadic mutation, though familial cases have been reported.¹ Additionally, germline HRAS mutations can lead to Costello syndrome, an autosomal-dominant disorder characterized by short stature; intellectual disabilities; coarse facial features; facial and perianal papillomata; cardiac defects; loose skin; joint hyperflexibility; and an increased risk for malignant tumors including rhabdomyosarcoma, neuroblastoma, and transitional cell carcinoma of the bladder.⁶

The diagnosis of NS often can be made clinically but can be difficult to confirm in underdeveloped lesions in young children. The differential diagnosis can include alopecia areata, aplasia cutis congenita, juvenile xanthogranuloma, epidermal nevus, de novo syringocystadenoma papilliferum, and solitary mastocytoma.¹ Nevus sebaceus can be associated with 4 additional syndromes: Schimmelpenning syndrome; phacomatosis pigmentokeratotica; didymosis aplasticosebacea; and SCALP (sebaceus nevus, central nervous system malformations, aplasia cutis congenital, limbal dermoid, pigmented nevus) syndrome.¹ Approximately 7% of NS cases may be associated with Schimmelpenning-Feuerstein-Mims (SFM) syndrome, a more severe condition that leads to systemic involvement and abnormalities in the neurological, ophthalmological, cardiovascular, genitourological, and skeletal systems.^1,3 Phacomatosis pigmentokeratotica has speckled lentiginous nevi, as well as abnormalities in the neurological, ophthalmological, cardiovascular, genitourological, and skeletal systems.¹ Didymosis aplasticosebacea is the concurrence of NS and aplasia cutis congenita.

The definitive treatment of NS is surgical excision. Alternative therapies include photodynamic therapy, fractional laser resurfacing, and dermabrasion; these are not definitive treatments, and patients must be monitored for the development of secondary neoplasms. Multiple variables must be considered when determining treatment, including patient age, risk potential for malignancy, and surgery-associated risks.¹ In our patient, given the extent of the lesions, active observation and follow-up was agreed upon for management.

This case demonstrates the importance of considering NS as an alternative diagnosis when alopecia areata has been diagnosed in a child who is unresponsive to treatments. After the diagnosis of NS is confirmed, more serious associated syndromes should be ruled out, and treatment should be tailored to each case.

To the Editor:

Chondrodermatitis nodularis helicis (CNH) is a benign inflammatory condition of the cartilage of the helix or antihelix as well as the overlying skin. Inflammation produces a firm painful nodule that often forms a central crust and enlarges rapidly, mimicking cutaneous malignancy. Chondrodermatitis nodularis helicis is believed to be caused by chronic pressure on the pinna, usually from sleeping, which causes compromised blood supply. However, there is a wide range of additional risk factors,¹ including trauma (eg, pressure), environmental insult (eg, sun or cold exposure), and autoimmune processes (eg, systemic lupus erythematosus, scleroderma). Chondrodermatitis nodularis helicis after Mohs micrographic surgery (MMS) is rare. We report a novel case of CNH as a postoperative complication of MMS following adjuvant radiation therapy.

A 61-year-old man presented to the MMS clinic for treatment of a primary squamous cell carcinoma of the right posterior helix. Stage I MMS demonstrated tumor invasion in the deep dermis directly overlying the auricular cartilage, as well as large-nerve (ie, >0.1 mm) perineural invasion. Two additional stages were taken; negative margins were obtained on Stage III. The defect was repaired by primary closure (Figure 1). Considering the presence of perineural invasion around a large nerve, the patient elected to receive adjuvant radiation therapy consisting of 50 Gy in 20 fractions administered to the right ear over 1 month.

Two months after completion of adjuvant radiation therapy, the patient returned to the clinic with a tender pink papule on the right crus within the radiation portal but nonadjacent to the surgical scar (Figure 2). Histopathology from a tangential biopsy revealed acanthosis, dermal sclerosis, and degenerated cartilage, consistent with CNH. Stellate fibroblasts also were seen, suggesting changes related to prior radiation therapy (Figure 3).

Although CNH is a benign condition, it can be concerning in the context of patient follow-up after MMS given its clinical appearance, which is similar to nonmelanoma skin cancer. The differential diagnosis of CNH includes hypertrophic actinic keratosis, basal cell carcinoma, and squamous cell carcinoma. The diagnosis is based on clinical history and confirmed by histopathologic examination.

Chondrodermatitis nodularis helicis in close proximity to a prior MMS site should lower the threshold for biopsy because the area is already known to be affected by actinic damage and cutaneous carcinogenesis. The histopathology of CNH often is characterized by epidermal acanthosis with ulceration, perichondral fibrosis, and a variable degree of cartilage degeneration associated with granulation tissue.²

The scarce subcutaneous tissue and limited blood supply of the pinna offer minimal cushioning and poor circulation to underlying cartilage. These anatomic features predispose the pinna to inflammation and ischemia.¹ Mohs micrographic surgery may inadvertently cause damage to surrounding tissue because of excision of cartilage, mechanical manipulation, severance of the extant blood supply, electrocautery, fenestration in preparation for skin grafting, compression from a wound dressing, and other factors related to surgery. In addition, following MMS, scar tissue and swelling with compression of adjacent structures can further inhibit circulation and lead to CNH.

In our case, multiple factors may have contributed to CNH after MMS, including postoperative swelling and compression, prior actinic damage, and other environmental factors. Given that CNH occurred within the radiation portal, we postulated that adjuvant radiation may have played a role in the pathogenesis of the patient’s CNH. Pandya et al³ reported CNH after radiation therapy for a brain tumor.

One prior study showed that CNH treated by surgical excision recurred in 34% of patients.⁴ In all of these patients, the CNH was completely excised; however, trauma from the surgical procedure itself likely resulted in recurrence of CNH. Darragh et al⁵ reported a case of CNH after MMS on the right nasal vestibule following wound reconstruction that utilized a cartilage graft from the right ear.

Our patient demonstrated an unusual but concerning complication associated with MMS. The location of CNH also was not in a traditional location but rather near the superior helical crus. Although CNH is benign by nature, it can mimic recurrence of a tumor when it presents close to the site of prior MMS. Diagnostic biopsy of CNH should be considered to rule out recurrence of skin cancer.

To the Editor:

Chondrodermatitis nodularis helicis (CNH) is a benign inflammatory condition of the cartilage of the helix or antihelix as well as the overlying skin. Inflammation produces a firm painful nodule that often forms a central crust and enlarges rapidly, mimicking cutaneous malignancy. Chondrodermatitis nodularis helicis is believed to be caused by chronic pressure on the pinna, usually from sleeping, which causes compromised blood supply. However, there is a wide range of additional risk factors,¹ including trauma (eg, pressure), environmental insult (eg, sun or cold exposure), and autoimmune processes (eg, systemic lupus erythematosus, scleroderma). Chondrodermatitis nodularis helicis after Mohs micrographic surgery (MMS) is rare. We report a novel case of CNH as a postoperative complication of MMS following adjuvant radiation therapy.

A 61-year-old man presented to the MMS clinic for treatment of a primary squamous cell carcinoma of the right posterior helix. Stage I MMS demonstrated tumor invasion in the deep dermis directly overlying the auricular cartilage, as well as large-nerve (ie, >0.1 mm) perineural invasion. Two additional stages were taken; negative margins were obtained on Stage III. The defect was repaired by primary closure (Figure 1). Considering the presence of perineural invasion around a large nerve, the patient elected to receive adjuvant radiation therapy consisting of 50 Gy in 20 fractions administered to the right ear over 1 month.

Two months after completion of adjuvant radiation therapy, the patient returned to the clinic with a tender pink papule on the right crus within the radiation portal but nonadjacent to the surgical scar (Figure 2). Histopathology from a tangential biopsy revealed acanthosis, dermal sclerosis, and degenerated cartilage, consistent with CNH. Stellate fibroblasts also were seen, suggesting changes related to prior radiation therapy (Figure 3).

Although CNH is a benign condition, it can be concerning in the context of patient follow-up after MMS given its clinical appearance, which is similar to nonmelanoma skin cancer. The differential diagnosis of CNH includes hypertrophic actinic keratosis, basal cell carcinoma, and squamous cell carcinoma. The diagnosis is based on clinical history and confirmed by histopathologic examination.

Chondrodermatitis nodularis helicis in close proximity to a prior MMS site should lower the threshold for biopsy because the area is already known to be affected by actinic damage and cutaneous carcinogenesis. The histopathology of CNH often is characterized by epidermal acanthosis with ulceration, perichondral fibrosis, and a variable degree of cartilage degeneration associated with granulation tissue.²

The scarce subcutaneous tissue and limited blood supply of the pinna offer minimal cushioning and poor circulation to underlying cartilage. These anatomic features predispose the pinna to inflammation and ischemia.¹ Mohs micrographic surgery may inadvertently cause damage to surrounding tissue because of excision of cartilage, mechanical manipulation, severance of the extant blood supply, electrocautery, fenestration in preparation for skin grafting, compression from a wound dressing, and other factors related to surgery. In addition, following MMS, scar tissue and swelling with compression of adjacent structures can further inhibit circulation and lead to CNH.

In our case, multiple factors may have contributed to CNH after MMS, including postoperative swelling and compression, prior actinic damage, and other environmental factors. Given that CNH occurred within the radiation portal, we postulated that adjuvant radiation may have played a role in the pathogenesis of the patient’s CNH. Pandya et al³ reported CNH after radiation therapy for a brain tumor.

One prior study showed that CNH treated by surgical excision recurred in 34% of patients.⁴ In all of these patients, the CNH was completely excised; however, trauma from the surgical procedure itself likely resulted in recurrence of CNH. Darragh et al⁵ reported a case of CNH after MMS on the right nasal vestibule following wound reconstruction that utilized a cartilage graft from the right ear.

Our patient demonstrated an unusual but concerning complication associated with MMS. The location of CNH also was not in a traditional location but rather near the superior helical crus. Although CNH is benign by nature, it can mimic recurrence of a tumor when it presents close to the site of prior MMS. Diagnostic biopsy of CNH should be considered to rule out recurrence of skin cancer.

To the Editor:

Chondrodermatitis nodularis helicis (CNH) is a benign inflammatory condition of the cartilage of the helix or antihelix as well as the overlying skin. Inflammation produces a firm painful nodule that often forms a central crust and enlarges rapidly, mimicking cutaneous malignancy. Chondrodermatitis nodularis helicis is believed to be caused by chronic pressure on the pinna, usually from sleeping, which causes compromised blood supply. However, there is a wide range of additional risk factors,¹ including trauma (eg, pressure), environmental insult (eg, sun or cold exposure), and autoimmune processes (eg, systemic lupus erythematosus, scleroderma). Chondrodermatitis nodularis helicis after Mohs micrographic surgery (MMS) is rare. We report a novel case of CNH as a postoperative complication of MMS following adjuvant radiation therapy.

A 61-year-old man presented to the MMS clinic for treatment of a primary squamous cell carcinoma of the right posterior helix. Stage I MMS demonstrated tumor invasion in the deep dermis directly overlying the auricular cartilage, as well as large-nerve (ie, >0.1 mm) perineural invasion. Two additional stages were taken; negative margins were obtained on Stage III. The defect was repaired by primary closure (Figure 1). Considering the presence of perineural invasion around a large nerve, the patient elected to receive adjuvant radiation therapy consisting of 50 Gy in 20 fractions administered to the right ear over 1 month.

Two months after completion of adjuvant radiation therapy, the patient returned to the clinic with a tender pink papule on the right crus within the radiation portal but nonadjacent to the surgical scar (Figure 2). Histopathology from a tangential biopsy revealed acanthosis, dermal sclerosis, and degenerated cartilage, consistent with CNH. Stellate fibroblasts also were seen, suggesting changes related to prior radiation therapy (Figure 3).

Although CNH is a benign condition, it can be concerning in the context of patient follow-up after MMS given its clinical appearance, which is similar to nonmelanoma skin cancer. The differential diagnosis of CNH includes hypertrophic actinic keratosis, basal cell carcinoma, and squamous cell carcinoma. The diagnosis is based on clinical history and confirmed by histopathologic examination.

Chondrodermatitis nodularis helicis in close proximity to a prior MMS site should lower the threshold for biopsy because the area is already known to be affected by actinic damage and cutaneous carcinogenesis. The histopathology of CNH often is characterized by epidermal acanthosis with ulceration, perichondral fibrosis, and a variable degree of cartilage degeneration associated with granulation tissue.²

The scarce subcutaneous tissue and limited blood supply of the pinna offer minimal cushioning and poor circulation to underlying cartilage. These anatomic features predispose the pinna to inflammation and ischemia.¹ Mohs micrographic surgery may inadvertently cause damage to surrounding tissue because of excision of cartilage, mechanical manipulation, severance of the extant blood supply, electrocautery, fenestration in preparation for skin grafting, compression from a wound dressing, and other factors related to surgery. In addition, following MMS, scar tissue and swelling with compression of adjacent structures can further inhibit circulation and lead to CNH.

In our case, multiple factors may have contributed to CNH after MMS, including postoperative swelling and compression, prior actinic damage, and other environmental factors. Given that CNH occurred within the radiation portal, we postulated that adjuvant radiation may have played a role in the pathogenesis of the patient’s CNH. Pandya et al³ reported CNH after radiation therapy for a brain tumor.

One prior study showed that CNH treated by surgical excision recurred in 34% of patients.⁴ In all of these patients, the CNH was completely excised; however, trauma from the surgical procedure itself likely resulted in recurrence of CNH. Darragh et al⁵ reported a case of CNH after MMS on the right nasal vestibule following wound reconstruction that utilized a cartilage graft from the right ear.

Our patient demonstrated an unusual but concerning complication associated with MMS. The location of CNH also was not in a traditional location but rather near the superior helical crus. Although CNH is benign by nature, it can mimic recurrence of a tumor when it presents close to the site of prior MMS. Diagnostic biopsy of CNH should be considered to rule out recurrence of skin cancer.

Psoriasis is an inflammatory autoimmune skin condition that affects approximately 125 million individuals worldwide, with approximately 8 million patients in the United States.¹ Psoriasis not only involves a cosmetic component but also comprises other comorbidities, such as psoriatic arthritis, cardiovascular disease, and psychiatric disorders, that can influence patient quality of life.^2-4 In addition, the costs associated with psoriasis are substantial, with an estimated economic burden of $35.2 billion in the United States in 2015.⁵ Given the prevalence of psoriasis and its many effects on patients, it is important that providers have high-quality evidence regarding efficacious treatment options.

Systematic reviews, which compile all available evidence on a subject to answer a specific question, represent the gold standard of research.⁶ However, studies have demonstrated that when referencing research literature, physicians tend to read only the abstract of a study rather than the entire article.^7,8 A study by Marcelo et al⁸ showed that residents at a tertiary care center answered clinical questions using only the abstract of a paper 69% of the time. Based on these findings, it is imperative that the results of systematic reviews be accurately reported in their abstracts because they can influence patient care.

Referencing only the abstracts of systematic reviews can be problematic if the abstract contains spin. Spin is a form of reporting that inappropriately highlights the benefits of a treatment with greater emphasis than what is shown by the results.⁹ Research has identified the presence of spin in the abstracts of randomized controlled trials.^10-12 For example, Cooper et al¹⁰ found that 70% (33/47) of abstracts in otolaryngology randomized controlled trials contained spin. Additionally, Arthur et al¹¹ and Austin et al¹² had similar findings within abstracts of orthopedic and obesity trials, where 44.8% (112/250) and 46.7% (21/45) contained spin, respectively. Ottwell et al¹³ found that the presence of spin in abstracts is not limited to randomized controlled trials; they demonstrated that the abstracts of nearly one-third (31% [11/36]) of systematic reviews focused on the treatment of acne vulgaris contained spin.

In our study, we aimed to evaluate the presence of spin in the abstracts of systematic reviews focused on the treatment of psoriasis.

Methods

Reproducibility and Reporting—Our study did not meet the regulatory definition for human subjects research per the US Code of Federal Regulations because the study did not involve human research subjects. The study also was not subject to review by the institutional review board. Our protocol, data set, analysis scripts, extraction forms, and other material related to the study have been placed on Open Science Framework to provide transparency and ensure reproducibility. To further allow for analytic reproducibility, our data set was given to an independent laboratory and reanalyzed with a masked approach. Our study was carried out alongside other studies assessing spin in systematic reviews regarding different specialties and disease states. Because these studies were similar in design, this methodology also has been reported elsewhere. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA)¹⁴ and the guidelines for meta-epidemiological studies developed by Murad and Wang¹⁵ were used in drafting this article.

Search Strategy—The search strategies for the MEDLINE (Ovid) and Embase (Ovid) databases were created by a systematic review librarian (D.N.W.) to identify systematic reviews and meta-analyses regarding treatments for psoriasis (Figure 1). The searches were performed on June 2, 2020, and uploaded to Rayyan, a systematic review screening platform.¹⁶ After duplicates were removed, the records were screened for eligibility by 2 authors (C.H. and A.L.) using the titles and abstracts. Screening was conducted independently while each of these authors was masked to the other’s results; disagreements were resolved through discussion.

Eligibility Criteria—An article had to meet the following criteria for inclusion in our study: (1) be a systematic review with or without a meta-analysis; (2) relate to the treatment of psoriasis; and (3) be written in English and include human patients only. The PRISMA definition of systematic reviews and meta-analyses was applied.¹⁷

Training—Various training occurred throughout our study to ensure understanding of each step and mitigate subjectivity. Before beginning screening, 2 investigators (C.H. and A.L.) completed the Introduction to Systematic Review and Meta-Analysis course offered by Johns Hopkins University.¹⁸ They also underwent 2 days of online and in-person training on the definition and interpretation of the 9 most severe types of spin found in the abstracts of systematic reviews as defined by Yavchitz et al.⁹ Finally, they were trained to use A MeaSurement Tool to Assess systematic Reviews (AMSTAR-2) to appraise the methodological quality of each systematic review. Our protocol contained an outline of all training modules used.

Data Extraction—The investigators (C.H. and A.L.) analyzed included abstracts for the 9 most severe types of spin (Table 1). Data were extracted in a masked duplicate fashion using the Google form. AMSTAR-2 was used to assess systematic reviews for methodological quality. AMSTAR-2 is an appraisal tool consisting of a 16-item checklist for systematic reviews or meta-analyses. Scores range from critically low to high based on the methodological quality of the review. Interrater reliability of AMSTAR-2 scores has been moderate to high across studies. Construct validity coefficients have been high with the original AMSTAR instrument (r=0.91) and the Risk of Bias in Systematic Reviews instrument (r=0.84).¹⁹

During data extraction from each included systematic review, the following additional items were obtained: (1) the date the review was received; (2) intervention type (ie, pharmacologic, nonpharmacologic, surgery, light therapy, mixed); (3) the funding source(s) for each systematic review (ie, industry, private, public, none, not mentioned, hospital, a combination of funding not including industry, a combination of funding including industry, other); (4) whether the journal submission guidelines suggested adherence to PRISMA guidelines; (5) whether the review discussed adherence to PRISMA¹⁴ or PRISMA for Abstracts²⁰ (PRISMA-A); (6) the publishing journal’s 5-year impact factor; and (6) the country of the systematic review’s origin. When data extraction was complete, investigators (C.H. and A.L.) were unmasked and met to resolve any disagreements by discussion. Two authors (R.O. or M.V.) served as arbiters in the case that an agreement between C.H. and A.L. could not be reached.

Statistical Analysis—Frequencies and percentages were calculated to evaluate the most common types of spin found within systematic reviews and meta-analyses. One author (M.H.) prespecified the possibility of a binary logistic regression and calculated a power analysis to determine sample size, as stated in our protocol. Our final sample size of 173 was not powered to perform the multivariable logistic regression; therefore, we calculated unadjusted odds ratios to enable assessing relationships between the presence of spin in abstracts and the various study characteristics. We used Stata 16.1 for all analyses, and all analytic decisions can be found in our protocol.

Results

General Characteristics—Our systematic search of MEDLINE and Embase returned 3200 articles, of which 665 were duplicates that were removed. An additional 2253 articles were excluded during initial abstract and title screening, and full-text screening led to the exclusion of another 109 articles. In total, 173 systematic reviews were included for data extraction. Figure 2 illustrates the screening process with the rationale for all exclusions.

Of the 173 included systematic reviews and meta-analyses, 150 (86.7%) focused on pharmacologic interventions. The majority of studies did not mention adhering to PRISMA guidelines (125/173 [72.3%]), and the publishing journals recommended their authors adhere to PRISMA for only 66 (38.2%) of the included articles. For the articles that received funding (90/173 [52.0%]), industry sources were the most common funding source (40/90 [44.4%]), followed by private (27/90 [30%]) and public funding sources (23/90 [25.6%]). Of the remaining studies, 46 articles did not include a funding statement (46/83 [55.4%]), and 37 studies were not funded (37/83 [44.6%]). The average (SD) 5-year impact factor of our included journals was 4.68 (4.64). Systematic reviews were from 31 different countries. All studies were received by their respective journals between the years 2000 and 2020 (Table 2).

Abstracts Containing Spin—We found that 37 (21.4%) of the abstracts of systematic reviews focused on psoriasis treatments contained at least 1 type of spin. Some abstracts had more than 1 type; thus, a total of 51 different instances of spin were detected. Spin type 6—selective reporting of or overemphasis on harm outcomes or analysis favoring the safety of the experimental intervention—was the most common type ofspin, found in 19 of 173 abstracts (11.0%). The most severe type of spin—type 1 (conclusion contains recommendations for clinical practice not supported by the findings)—occurred in only 1 abstract (0.6%). Spin type 8 did not occur in any of the abstracts (Table 1). There was no statistically significant association between the presence of spin and any of the study characteristics (Table 2).

AMSTAR Ratings—After using AMSTAR-2 to appraise the included systematic reviews, we found that 6 (3.5%) of the 173 studies could be rated as high; 36 (20.8%) as moderate; 25 (14.5%) as low; and 106 (61.3%) as critically low. Of the 37 abstracts containing spin, 2 (5.4%) had an AMSTAR-2 rating of high, 10 (27%) had a rating of moderate, 6 (16.2%) had a rating of low, and 19 (51.4%) had a rating of critically low (Table 2). No statistically significant associations were seen between abstracts found to have spin and the AMSTAR-2 rating of the review.

Nearly all (160/173 [92.5%]) of the included reviews were compliant with the inclusion of Population, Intervention, Comparison, and Outcome (PICO) method. Only 17 of 173 (9.8%) reviews reported funding sources for the studies included. See Table 3 for all AMSTAR-2 items.

Comment

Primary Findings—We evaluated the abstracts of systematic reviews for the treatment of psoriasis and found that more than one-fifth of them contained spin. Our study contributes to the existing literature surrounding spin. Spin in randomized controlled trials is well documented across several fields of medicine, including otolaryngology,¹⁰ obesity medicine,¹² dermatology,²¹ anesthesiology,²² psychiatry,²³ orthopedics,²⁴ emergency medicine,²⁵ oncology,²⁶ and cardiology.²⁷ More recently, studies have emerged evaluating the presence of spin in systematic reviews. Specific to dermatology, one study found that 74% (84/113) of systematic reviews related to atopic dermatitis treatment contained spin.²⁸ Additionally, Ottwell et al¹³ identified spin in 31% (11/36) of the systematic reviews related to the treatment of acne vulgaris, which is similar to our results for systematic reviews focused on psoriasis treatments. When comparing the presence of spin in abstracts of systematic reviews from the field of dermatology with other specialties, dermatology-focused systematic reviews appear to contain more spin in the abstract than systematic reviews focused on tinnitus and glaucoma therapies.^29,30 However, systematic reviews from the field of dermatology appear to contain less spin than systematic reviews focused on therapies for lower back pain.³¹ For example, Nascimento et al³¹ found that 80% (53/66) of systematic reviews focused on low-back pain treatments contained spin.

Examples of Spin—The most common type of spin found in our study was type 6.⁹ An example of spin type 6 can be found in an article by Bai et al³² that investigated the short-term efficacy and safety of multiple interleukin inhibitors for the treatment of plaque psoriasis. The conclusion of the abstract states, “Risankizumab appeared to have relatively high efficacy and low risk.” However, in the results section, the authors showed that risankizumab had the highest risk of serious adverse events and was ranked highest for discontinuation because of adverse events when compared with other interleukin inhibitors. Here, the presence of spin in the abstract may mislead the reader to accept the “low risk” of risankizumab without understanding the study’s full results.³²

Another example of selective reporting of harm outcomes in a systematic review can be found in the article by Wu et al,³³ which focused on assessing IL-17 antagonists for the treatment of plaque psoriasis. The conclusion of the abstract indicated that IL-17 antagonists should be accepted as safe; however, in the results section, the authors discussed serious safety concerns with brodalumab, including the death of 4 patients from suicide.³³ This example of spin type 6 highlights how the overgeneralization of a drug’s safety profile neglects serious harm outcomes that are critical to patient safety. In fact, against the safety claims of Wu et al,³³ brodalumab later received a boxed warning from the US Food and Drug Administration after 6 patients died from suicide while receiving the drug, which led to early discontinuation of the trials.^34,35 Although studies suggest this relationship is not causal,^34-36 the purpose of our study was not to investigate this association but to highlight the importance of this finding. Thus, with this example of spin in mind, we offer recommendations that we believe will improve reporting in abstracts as well as quality of patient care.

Recommendations for Reporting in Abstracts—Regarding the boxed warning³⁷ for brodalumab because of suicidal ideation and behavior, the US Food and Drug Administration recommends that prior to prescribing brodalumab, clinicians consider the potential benefits and risks in patients with a history of depression and/or suicidal ideation or behavior. However, a clinician would not adequately assess the full risks and benefits when an abstract, such as that for the article by Wu et al,³³ contains spin through selectively reporting harm outcomes. Arguably, clinicians could just read the full text; however, research confirms that abstracts often are utilized by clinicians and commonly are used to guide clinical decisions.^7,38 It is reasonable that clinicians would use abstracts in this fashion because they provide a quick synopsis of the full article’s findings and are widely available to clinicians who may not have access to article databases. Initiatives are in place to improve the quality of reporting in an abstract, such as PRISMA-A,²⁰ but even this fails to address spin. In fact, it may suggest spin because checklist item 10 of PRISMA-A advises authors of systematic reviews to provide a “general interpretation of the results and important implications.” This item is concerning because it suggests that the authors interpret importance rather than the clinician who prescribes the drug and is ultimately responsible for patient safety. Therefore, we recommend a reform to abstract reporting and an update to PRISMA-A that leads authors to report all benefits and risks encountered instead of reporting what the authors define as important.

Strengths and Limitations—Our study has several strengths as well as limitations. One of these strengths is that our protocol was strictly adhered to; any deviations were noted and added as an amendment. Our protocol, data, and all study artifacts were made freely available online on the Open Science Framework to strengthen reproducibility (https://osf.io/zrxh8/). Investigators underwent training to ensure comprehension of spin and systematic review designs. All data were extracted in masked duplicate fashion per the Cochrane Handbook for Systematic Reviews of Interventions.³⁹

Regarding limitations, only 2 databases were searched—MEDLINE and Embase. Therefore, our screening process may not have included every available systematic review on the treatment of psoriasis. Journal impact factors may be inaccurate for the systematic reviews that were published earlier in our data date range; however, we attempted to negate this limitation by using a 5-year average. Our study characteristic regarding PRISMA adherence did not account for studies published before the PRISMA statement release; we also could not access prior submission guidelines to determine when a journal began recommending PRISMA adherence. Another limitation of our study was the intrinsic subjectivity behind spin. Some may disagree with our classifications. Finally, our cross-sectional design should not be generalized to study types that are not systematic reviews or published in other journals during different periods.

Conclusion

Evidence of spin was present in many of the abstracts of systematic reviews pertaining to the treatment of psoriasis. Future clinical research should investigate any reporting of spin and search for ways to better reduce spin within literature. Continued research is necessary to evaluate the presence of spin within dermatology and other specialties.

Psoriasis is an inflammatory autoimmune skin condition that affects approximately 125 million individuals worldwide, with approximately 8 million patients in the United States.¹ Psoriasis not only involves a cosmetic component but also comprises other comorbidities, such as psoriatic arthritis, cardiovascular disease, and psychiatric disorders, that can influence patient quality of life.^2-4 In addition, the costs associated with psoriasis are substantial, with an estimated economic burden of $35.2 billion in the United States in 2015.⁵ Given the prevalence of psoriasis and its many effects on patients, it is important that providers have high-quality evidence regarding efficacious treatment options.

Systematic reviews, which compile all available evidence on a subject to answer a specific question, represent the gold standard of research.⁶ However, studies have demonstrated that when referencing research literature, physicians tend to read only the abstract of a study rather than the entire article.^7,8 A study by Marcelo et al⁸ showed that residents at a tertiary care center answered clinical questions using only the abstract of a paper 69% of the time. Based on these findings, it is imperative that the results of systematic reviews be accurately reported in their abstracts because they can influence patient care.

Referencing only the abstracts of systematic reviews can be problematic if the abstract contains spin. Spin is a form of reporting that inappropriately highlights the benefits of a treatment with greater emphasis than what is shown by the results.⁹ Research has identified the presence of spin in the abstracts of randomized controlled trials.^10-12 For example, Cooper et al¹⁰ found that 70% (33/47) of abstracts in otolaryngology randomized controlled trials contained spin. Additionally, Arthur et al¹¹ and Austin et al¹² had similar findings within abstracts of orthopedic and obesity trials, where 44.8% (112/250) and 46.7% (21/45) contained spin, respectively. Ottwell et al¹³ found that the presence of spin in abstracts is not limited to randomized controlled trials; they demonstrated that the abstracts of nearly one-third (31% [11/36]) of systematic reviews focused on the treatment of acne vulgaris contained spin.

In our study, we aimed to evaluate the presence of spin in the abstracts of systematic reviews focused on the treatment of psoriasis.

Methods

Reproducibility and Reporting—Our study did not meet the regulatory definition for human subjects research per the US Code of Federal Regulations because the study did not involve human research subjects. The study also was not subject to review by the institutional review board. Our protocol, data set, analysis scripts, extraction forms, and other material related to the study have been placed on Open Science Framework to provide transparency and ensure reproducibility. To further allow for analytic reproducibility, our data set was given to an independent laboratory and reanalyzed with a masked approach. Our study was carried out alongside other studies assessing spin in systematic reviews regarding different specialties and disease states. Because these studies were similar in design, this methodology also has been reported elsewhere. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA)¹⁴ and the guidelines for meta-epidemiological studies developed by Murad and Wang¹⁵ were used in drafting this article.

Search Strategy—The search strategies for the MEDLINE (Ovid) and Embase (Ovid) databases were created by a systematic review librarian (D.N.W.) to identify systematic reviews and meta-analyses regarding treatments for psoriasis (Figure 1). The searches were performed on June 2, 2020, and uploaded to Rayyan, a systematic review screening platform.¹⁶ After duplicates were removed, the records were screened for eligibility by 2 authors (C.H. and A.L.) using the titles and abstracts. Screening was conducted independently while each of these authors was masked to the other’s results; disagreements were resolved through discussion.

Eligibility Criteria—An article had to meet the following criteria for inclusion in our study: (1) be a systematic review with or without a meta-analysis; (2) relate to the treatment of psoriasis; and (3) be written in English and include human patients only. The PRISMA definition of systematic reviews and meta-analyses was applied.¹⁷

Training—Various training occurred throughout our study to ensure understanding of each step and mitigate subjectivity. Before beginning screening, 2 investigators (C.H. and A.L.) completed the Introduction to Systematic Review and Meta-Analysis course offered by Johns Hopkins University.¹⁸ They also underwent 2 days of online and in-person training on the definition and interpretation of the 9 most severe types of spin found in the abstracts of systematic reviews as defined by Yavchitz et al.⁹ Finally, they were trained to use A MeaSurement Tool to Assess systematic Reviews (AMSTAR-2) to appraise the methodological quality of each systematic review. Our protocol contained an outline of all training modules used.

Data Extraction—The investigators (C.H. and A.L.) analyzed included abstracts for the 9 most severe types of spin (Table 1). Data were extracted in a masked duplicate fashion using the Google form. AMSTAR-2 was used to assess systematic reviews for methodological quality. AMSTAR-2 is an appraisal tool consisting of a 16-item checklist for systematic reviews or meta-analyses. Scores range from critically low to high based on the methodological quality of the review. Interrater reliability of AMSTAR-2 scores has been moderate to high across studies. Construct validity coefficients have been high with the original AMSTAR instrument (r=0.91) and the Risk of Bias in Systematic Reviews instrument (r=0.84).¹⁹

During data extraction from each included systematic review, the following additional items were obtained: (1) the date the review was received; (2) intervention type (ie, pharmacologic, nonpharmacologic, surgery, light therapy, mixed); (3) the funding source(s) for each systematic review (ie, industry, private, public, none, not mentioned, hospital, a combination of funding not including industry, a combination of funding including industry, other); (4) whether the journal submission guidelines suggested adherence to PRISMA guidelines; (5) whether the review discussed adherence to PRISMA¹⁴ or PRISMA for Abstracts²⁰ (PRISMA-A); (6) the publishing journal’s 5-year impact factor; and (6) the country of the systematic review’s origin. When data extraction was complete, investigators (C.H. and A.L.) were unmasked and met to resolve any disagreements by discussion. Two authors (R.O. or M.V.) served as arbiters in the case that an agreement between C.H. and A.L. could not be reached.

Statistical Analysis—Frequencies and percentages were calculated to evaluate the most common types of spin found within systematic reviews and meta-analyses. One author (M.H.) prespecified the possibility of a binary logistic regression and calculated a power analysis to determine sample size, as stated in our protocol. Our final sample size of 173 was not powered to perform the multivariable logistic regression; therefore, we calculated unadjusted odds ratios to enable assessing relationships between the presence of spin in abstracts and the various study characteristics. We used Stata 16.1 for all analyses, and all analytic decisions can be found in our protocol.

Results

General Characteristics—Our systematic search of MEDLINE and Embase returned 3200 articles, of which 665 were duplicates that were removed. An additional 2253 articles were excluded during initial abstract and title screening, and full-text screening led to the exclusion of another 109 articles. In total, 173 systematic reviews were included for data extraction. Figure 2 illustrates the screening process with the rationale for all exclusions.

Of the 173 included systematic reviews and meta-analyses, 150 (86.7%) focused on pharmacologic interventions. The majority of studies did not mention adhering to PRISMA guidelines (125/173 [72.3%]), and the publishing journals recommended their authors adhere to PRISMA for only 66 (38.2%) of the included articles. For the articles that received funding (90/173 [52.0%]), industry sources were the most common funding source (40/90 [44.4%]), followed by private (27/90 [30%]) and public funding sources (23/90 [25.6%]). Of the remaining studies, 46 articles did not include a funding statement (46/83 [55.4%]), and 37 studies were not funded (37/83 [44.6%]). The average (SD) 5-year impact factor of our included journals was 4.68 (4.64). Systematic reviews were from 31 different countries. All studies were received by their respective journals between the years 2000 and 2020 (Table 2).

Abstracts Containing Spin—We found that 37 (21.4%) of the abstracts of systematic reviews focused on psoriasis treatments contained at least 1 type of spin. Some abstracts had more than 1 type; thus, a total of 51 different instances of spin were detected. Spin type 6—selective reporting of or overemphasis on harm outcomes or analysis favoring the safety of the experimental intervention—was the most common type ofspin, found in 19 of 173 abstracts (11.0%). The most severe type of spin—type 1 (conclusion contains recommendations for clinical practice not supported by the findings)—occurred in only 1 abstract (0.6%). Spin type 8 did not occur in any of the abstracts (Table 1). There was no statistically significant association between the presence of spin and any of the study characteristics (Table 2).

AMSTAR Ratings—After using AMSTAR-2 to appraise the included systematic reviews, we found that 6 (3.5%) of the 173 studies could be rated as high; 36 (20.8%) as moderate; 25 (14.5%) as low; and 106 (61.3%) as critically low. Of the 37 abstracts containing spin, 2 (5.4%) had an AMSTAR-2 rating of high, 10 (27%) had a rating of moderate, 6 (16.2%) had a rating of low, and 19 (51.4%) had a rating of critically low (Table 2). No statistically significant associations were seen between abstracts found to have spin and the AMSTAR-2 rating of the review.

Nearly all (160/173 [92.5%]) of the included reviews were compliant with the inclusion of Population, Intervention, Comparison, and Outcome (PICO) method. Only 17 of 173 (9.8%) reviews reported funding sources for the studies included. See Table 3 for all AMSTAR-2 items.

Comment

Primary Findings—We evaluated the abstracts of systematic reviews for the treatment of psoriasis and found that more than one-fifth of them contained spin. Our study contributes to the existing literature surrounding spin. Spin in randomized controlled trials is well documented across several fields of medicine, including otolaryngology,¹⁰ obesity medicine,¹² dermatology,²¹ anesthesiology,²² psychiatry,²³ orthopedics,²⁴ emergency medicine,²⁵ oncology,²⁶ and cardiology.²⁷ More recently, studies have emerged evaluating the presence of spin in systematic reviews. Specific to dermatology, one study found that 74% (84/113) of systematic reviews related to atopic dermatitis treatment contained spin.²⁸ Additionally, Ottwell et al¹³ identified spin in 31% (11/36) of the systematic reviews related to the treatment of acne vulgaris, which is similar to our results for systematic reviews focused on psoriasis treatments. When comparing the presence of spin in abstracts of systematic reviews from the field of dermatology with other specialties, dermatology-focused systematic reviews appear to contain more spin in the abstract than systematic reviews focused on tinnitus and glaucoma therapies.^29,30 However, systematic reviews from the field of dermatology appear to contain less spin than systematic reviews focused on therapies for lower back pain.³¹ For example, Nascimento et al³¹ found that 80% (53/66) of systematic reviews focused on low-back pain treatments contained spin.

Examples of Spin—The most common type of spin found in our study was type 6.⁹ An example of spin type 6 can be found in an article by Bai et al³² that investigated the short-term efficacy and safety of multiple interleukin inhibitors for the treatment of plaque psoriasis. The conclusion of the abstract states, “Risankizumab appeared to have relatively high efficacy and low risk.” However, in the results section, the authors showed that risankizumab had the highest risk of serious adverse events and was ranked highest for discontinuation because of adverse events when compared with other interleukin inhibitors. Here, the presence of spin in the abstract may mislead the reader to accept the “low risk” of risankizumab without understanding the study’s full results.³²

Another example of selective reporting of harm outcomes in a systematic review can be found in the article by Wu et al,³³ which focused on assessing IL-17 antagonists for the treatment of plaque psoriasis. The conclusion of the abstract indicated that IL-17 antagonists should be accepted as safe; however, in the results section, the authors discussed serious safety concerns with brodalumab, including the death of 4 patients from suicide.³³ This example of spin type 6 highlights how the overgeneralization of a drug’s safety profile neglects serious harm outcomes that are critical to patient safety. In fact, against the safety claims of Wu et al,³³ brodalumab later received a boxed warning from the US Food and Drug Administration after 6 patients died from suicide while receiving the drug, which led to early discontinuation of the trials.^34,35 Although studies suggest this relationship is not causal,^34-36 the purpose of our study was not to investigate this association but to highlight the importance of this finding. Thus, with this example of spin in mind, we offer recommendations that we believe will improve reporting in abstracts as well as quality of patient care.

Recommendations for Reporting in Abstracts—Regarding the boxed warning³⁷ for brodalumab because of suicidal ideation and behavior, the US Food and Drug Administration recommends that prior to prescribing brodalumab, clinicians consider the potential benefits and risks in patients with a history of depression and/or suicidal ideation or behavior. However, a clinician would not adequately assess the full risks and benefits when an abstract, such as that for the article by Wu et al,³³ contains spin through selectively reporting harm outcomes. Arguably, clinicians could just read the full text; however, research confirms that abstracts often are utilized by clinicians and commonly are used to guide clinical decisions.^7,38 It is reasonable that clinicians would use abstracts in this fashion because they provide a quick synopsis of the full article’s findings and are widely available to clinicians who may not have access to article databases. Initiatives are in place to improve the quality of reporting in an abstract, such as PRISMA-A,²⁰ but even this fails to address spin. In fact, it may suggest spin because checklist item 10 of PRISMA-A advises authors of systematic reviews to provide a “general interpretation of the results and important implications.” This item is concerning because it suggests that the authors interpret importance rather than the clinician who prescribes the drug and is ultimately responsible for patient safety. Therefore, we recommend a reform to abstract reporting and an update to PRISMA-A that leads authors to report all benefits and risks encountered instead of reporting what the authors define as important.

Strengths and Limitations—Our study has several strengths as well as limitations. One of these strengths is that our protocol was strictly adhered to; any deviations were noted and added as an amendment. Our protocol, data, and all study artifacts were made freely available online on the Open Science Framework to strengthen reproducibility (https://osf.io/zrxh8/). Investigators underwent training to ensure comprehension of spin and systematic review designs. All data were extracted in masked duplicate fashion per the Cochrane Handbook for Systematic Reviews of Interventions.³⁹

Regarding limitations, only 2 databases were searched—MEDLINE and Embase. Therefore, our screening process may not have included every available systematic review on the treatment of psoriasis. Journal impact factors may be inaccurate for the systematic reviews that were published earlier in our data date range; however, we attempted to negate this limitation by using a 5-year average. Our study characteristic regarding PRISMA adherence did not account for studies published before the PRISMA statement release; we also could not access prior submission guidelines to determine when a journal began recommending PRISMA adherence. Another limitation of our study was the intrinsic subjectivity behind spin. Some may disagree with our classifications. Finally, our cross-sectional design should not be generalized to study types that are not systematic reviews or published in other journals during different periods.

Conclusion

Evidence of spin was present in many of the abstracts of systematic reviews pertaining to the treatment of psoriasis. Future clinical research should investigate any reporting of spin and search for ways to better reduce spin within literature. Continued research is necessary to evaluate the presence of spin within dermatology and other specialties.

Psoriasis is an inflammatory autoimmune skin condition that affects approximately 125 million individuals worldwide, with approximately 8 million patients in the United States.¹ Psoriasis not only involves a cosmetic component but also comprises other comorbidities, such as psoriatic arthritis, cardiovascular disease, and psychiatric disorders, that can influence patient quality of life.^2-4 In addition, the costs associated with psoriasis are substantial, with an estimated economic burden of $35.2 billion in the United States in 2015.⁵ Given the prevalence of psoriasis and its many effects on patients, it is important that providers have high-quality evidence regarding efficacious treatment options.

Systematic reviews, which compile all available evidence on a subject to answer a specific question, represent the gold standard of research.⁶ However, studies have demonstrated that when referencing research literature, physicians tend to read only the abstract of a study rather than the entire article.^7,8 A study by Marcelo et al⁸ showed that residents at a tertiary care center answered clinical questions using only the abstract of a paper 69% of the time. Based on these findings, it is imperative that the results of systematic reviews be accurately reported in their abstracts because they can influence patient care.

Referencing only the abstracts of systematic reviews can be problematic if the abstract contains spin. Spin is a form of reporting that inappropriately highlights the benefits of a treatment with greater emphasis than what is shown by the results.⁹ Research has identified the presence of spin in the abstracts of randomized controlled trials.^10-12 For example, Cooper et al¹⁰ found that 70% (33/47) of abstracts in otolaryngology randomized controlled trials contained spin. Additionally, Arthur et al¹¹ and Austin et al¹² had similar findings within abstracts of orthopedic and obesity trials, where 44.8% (112/250) and 46.7% (21/45) contained spin, respectively. Ottwell et al¹³ found that the presence of spin in abstracts is not limited to randomized controlled trials; they demonstrated that the abstracts of nearly one-third (31% [11/36]) of systematic reviews focused on the treatment of acne vulgaris contained spin.

In our study, we aimed to evaluate the presence of spin in the abstracts of systematic reviews focused on the treatment of psoriasis.

Methods

Reproducibility and Reporting—Our study did not meet the regulatory definition for human subjects research per the US Code of Federal Regulations because the study did not involve human research subjects. The study also was not subject to review by the institutional review board. Our protocol, data set, analysis scripts, extraction forms, and other material related to the study have been placed on Open Science Framework to provide transparency and ensure reproducibility. To further allow for analytic reproducibility, our data set was given to an independent laboratory and reanalyzed with a masked approach. Our study was carried out alongside other studies assessing spin in systematic reviews regarding different specialties and disease states. Because these studies were similar in design, this methodology also has been reported elsewhere. The Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA)¹⁴ and the guidelines for meta-epidemiological studies developed by Murad and Wang¹⁵ were used in drafting this article.

Search Strategy—The search strategies for the MEDLINE (Ovid) and Embase (Ovid) databases were created by a systematic review librarian (D.N.W.) to identify systematic reviews and meta-analyses regarding treatments for psoriasis (Figure 1). The searches were performed on June 2, 2020, and uploaded to Rayyan, a systematic review screening platform.¹⁶ After duplicates were removed, the records were screened for eligibility by 2 authors (C.H. and A.L.) using the titles and abstracts. Screening was conducted independently while each of these authors was masked to the other’s results; disagreements were resolved through discussion.

Eligibility Criteria—An article had to meet the following criteria for inclusion in our study: (1) be a systematic review with or without a meta-analysis; (2) relate to the treatment of psoriasis; and (3) be written in English and include human patients only. The PRISMA definition of systematic reviews and meta-analyses was applied.¹⁷

Training—Various training occurred throughout our study to ensure understanding of each step and mitigate subjectivity. Before beginning screening, 2 investigators (C.H. and A.L.) completed the Introduction to Systematic Review and Meta-Analysis course offered by Johns Hopkins University.¹⁸ They also underwent 2 days of online and in-person training on the definition and interpretation of the 9 most severe types of spin found in the abstracts of systematic reviews as defined by Yavchitz et al.⁹ Finally, they were trained to use A MeaSurement Tool to Assess systematic Reviews (AMSTAR-2) to appraise the methodological quality of each systematic review. Our protocol contained an outline of all training modules used.

Data Extraction—The investigators (C.H. and A.L.) analyzed included abstracts for the 9 most severe types of spin (Table 1). Data were extracted in a masked duplicate fashion using the Google form. AMSTAR-2 was used to assess systematic reviews for methodological quality. AMSTAR-2 is an appraisal tool consisting of a 16-item checklist for systematic reviews or meta-analyses. Scores range from critically low to high based on the methodological quality of the review. Interrater reliability of AMSTAR-2 scores has been moderate to high across studies. Construct validity coefficients have been high with the original AMSTAR instrument (r=0.91) and the Risk of Bias in Systematic Reviews instrument (r=0.84).¹⁹

During data extraction from each included systematic review, the following additional items were obtained: (1) the date the review was received; (2) intervention type (ie, pharmacologic, nonpharmacologic, surgery, light therapy, mixed); (3) the funding source(s) for each systematic review (ie, industry, private, public, none, not mentioned, hospital, a combination of funding not including industry, a combination of funding including industry, other); (4) whether the journal submission guidelines suggested adherence to PRISMA guidelines; (5) whether the review discussed adherence to PRISMA¹⁴ or PRISMA for Abstracts²⁰ (PRISMA-A); (6) the publishing journal’s 5-year impact factor; and (6) the country of the systematic review’s origin. When data extraction was complete, investigators (C.H. and A.L.) were unmasked and met to resolve any disagreements by discussion. Two authors (R.O. or M.V.) served as arbiters in the case that an agreement between C.H. and A.L. could not be reached.

Statistical Analysis—Frequencies and percentages were calculated to evaluate the most common types of spin found within systematic reviews and meta-analyses. One author (M.H.) prespecified the possibility of a binary logistic regression and calculated a power analysis to determine sample size, as stated in our protocol. Our final sample size of 173 was not powered to perform the multivariable logistic regression; therefore, we calculated unadjusted odds ratios to enable assessing relationships between the presence of spin in abstracts and the various study characteristics. We used Stata 16.1 for all analyses, and all analytic decisions can be found in our protocol.

Results

General Characteristics—Our systematic search of MEDLINE and Embase returned 3200 articles, of which 665 were duplicates that were removed. An additional 2253 articles were excluded during initial abstract and title screening, and full-text screening led to the exclusion of another 109 articles. In total, 173 systematic reviews were included for data extraction. Figure 2 illustrates the screening process with the rationale for all exclusions.

Of the 173 included systematic reviews and meta-analyses, 150 (86.7%) focused on pharmacologic interventions. The majority of studies did not mention adhering to PRISMA guidelines (125/173 [72.3%]), and the publishing journals recommended their authors adhere to PRISMA for only 66 (38.2%) of the included articles. For the articles that received funding (90/173 [52.0%]), industry sources were the most common funding source (40/90 [44.4%]), followed by private (27/90 [30%]) and public funding sources (23/90 [25.6%]). Of the remaining studies, 46 articles did not include a funding statement (46/83 [55.4%]), and 37 studies were not funded (37/83 [44.6%]). The average (SD) 5-year impact factor of our included journals was 4.68 (4.64). Systematic reviews were from 31 different countries. All studies were received by their respective journals between the years 2000 and 2020 (Table 2).

Abstracts Containing Spin—We found that 37 (21.4%) of the abstracts of systematic reviews focused on psoriasis treatments contained at least 1 type of spin. Some abstracts had more than 1 type; thus, a total of 51 different instances of spin were detected. Spin type 6—selective reporting of or overemphasis on harm outcomes or analysis favoring the safety of the experimental intervention—was the most common type ofspin, found in 19 of 173 abstracts (11.0%). The most severe type of spin—type 1 (conclusion contains recommendations for clinical practice not supported by the findings)—occurred in only 1 abstract (0.6%). Spin type 8 did not occur in any of the abstracts (Table 1). There was no statistically significant association between the presence of spin and any of the study characteristics (Table 2).

AMSTAR Ratings—After using AMSTAR-2 to appraise the included systematic reviews, we found that 6 (3.5%) of the 173 studies could be rated as high; 36 (20.8%) as moderate; 25 (14.5%) as low; and 106 (61.3%) as critically low. Of the 37 abstracts containing spin, 2 (5.4%) had an AMSTAR-2 rating of high, 10 (27%) had a rating of moderate, 6 (16.2%) had a rating of low, and 19 (51.4%) had a rating of critically low (Table 2). No statistically significant associations were seen between abstracts found to have spin and the AMSTAR-2 rating of the review.

Nearly all (160/173 [92.5%]) of the included reviews were compliant with the inclusion of Population, Intervention, Comparison, and Outcome (PICO) method. Only 17 of 173 (9.8%) reviews reported funding sources for the studies included. See Table 3 for all AMSTAR-2 items.

Comment

Primary Findings—We evaluated the abstracts of systematic reviews for the treatment of psoriasis and found that more than one-fifth of them contained spin. Our study contributes to the existing literature surrounding spin. Spin in randomized controlled trials is well documented across several fields of medicine, including otolaryngology,¹⁰ obesity medicine,¹² dermatology,²¹ anesthesiology,²² psychiatry,²³ orthopedics,²⁴ emergency medicine,²⁵ oncology,²⁶ and cardiology.²⁷ More recently, studies have emerged evaluating the presence of spin in systematic reviews. Specific to dermatology, one study found that 74% (84/113) of systematic reviews related to atopic dermatitis treatment contained spin.²⁸ Additionally, Ottwell et al¹³ identified spin in 31% (11/36) of the systematic reviews related to the treatment of acne vulgaris, which is similar to our results for systematic reviews focused on psoriasis treatments. When comparing the presence of spin in abstracts of systematic reviews from the field of dermatology with other specialties, dermatology-focused systematic reviews appear to contain more spin in the abstract than systematic reviews focused on tinnitus and glaucoma therapies.^29,30 However, systematic reviews from the field of dermatology appear to contain less spin than systematic reviews focused on therapies for lower back pain.³¹ For example, Nascimento et al³¹ found that 80% (53/66) of systematic reviews focused on low-back pain treatments contained spin.

Examples of Spin—The most common type of spin found in our study was type 6.⁹ An example of spin type 6 can be found in an article by Bai et al³² that investigated the short-term efficacy and safety of multiple interleukin inhibitors for the treatment of plaque psoriasis. The conclusion of the abstract states, “Risankizumab appeared to have relatively high efficacy and low risk.” However, in the results section, the authors showed that risankizumab had the highest risk of serious adverse events and was ranked highest for discontinuation because of adverse events when compared with other interleukin inhibitors. Here, the presence of spin in the abstract may mislead the reader to accept the “low risk” of risankizumab without understanding the study’s full results.³²

Another example of selective reporting of harm outcomes in a systematic review can be found in the article by Wu et al,³³ which focused on assessing IL-17 antagonists for the treatment of plaque psoriasis. The conclusion of the abstract indicated that IL-17 antagonists should be accepted as safe; however, in the results section, the authors discussed serious safety concerns with brodalumab, including the death of 4 patients from suicide.³³ This example of spin type 6 highlights how the overgeneralization of a drug’s safety profile neglects serious harm outcomes that are critical to patient safety. In fact, against the safety claims of Wu et al,³³ brodalumab later received a boxed warning from the US Food and Drug Administration after 6 patients died from suicide while receiving the drug, which led to early discontinuation of the trials.^34,35 Although studies suggest this relationship is not causal,^34-36 the purpose of our study was not to investigate this association but to highlight the importance of this finding. Thus, with this example of spin in mind, we offer recommendations that we believe will improve reporting in abstracts as well as quality of patient care.

Recommendations for Reporting in Abstracts—Regarding the boxed warning³⁷ for brodalumab because of suicidal ideation and behavior, the US Food and Drug Administration recommends that prior to prescribing brodalumab, clinicians consider the potential benefits and risks in patients with a history of depression and/or suicidal ideation or behavior. However, a clinician would not adequately assess the full risks and benefits when an abstract, such as that for the article by Wu et al,³³ contains spin through selectively reporting harm outcomes. Arguably, clinicians could just read the full text; however, research confirms that abstracts often are utilized by clinicians and commonly are used to guide clinical decisions.^7,38 It is reasonable that clinicians would use abstracts in this fashion because they provide a quick synopsis of the full article’s findings and are widely available to clinicians who may not have access to article databases. Initiatives are in place to improve the quality of reporting in an abstract, such as PRISMA-A,²⁰ but even this fails to address spin. In fact, it may suggest spin because checklist item 10 of PRISMA-A advises authors of systematic reviews to provide a “general interpretation of the results and important implications.” This item is concerning because it suggests that the authors interpret importance rather than the clinician who prescribes the drug and is ultimately responsible for patient safety. Therefore, we recommend a reform to abstract reporting and an update to PRISMA-A that leads authors to report all benefits and risks encountered instead of reporting what the authors define as important.

Strengths and Limitations—Our study has several strengths as well as limitations. One of these strengths is that our protocol was strictly adhered to; any deviations were noted and added as an amendment. Our protocol, data, and all study artifacts were made freely available online on the Open Science Framework to strengthen reproducibility (https://osf.io/zrxh8/). Investigators underwent training to ensure comprehension of spin and systematic review designs. All data were extracted in masked duplicate fashion per the Cochrane Handbook for Systematic Reviews of Interventions.³⁹

Regarding limitations, only 2 databases were searched—MEDLINE and Embase. Therefore, our screening process may not have included every available systematic review on the treatment of psoriasis. Journal impact factors may be inaccurate for the systematic reviews that were published earlier in our data date range; however, we attempted to negate this limitation by using a 5-year average. Our study characteristic regarding PRISMA adherence did not account for studies published before the PRISMA statement release; we also could not access prior submission guidelines to determine when a journal began recommending PRISMA adherence. Another limitation of our study was the intrinsic subjectivity behind spin. Some may disagree with our classifications. Finally, our cross-sectional design should not be generalized to study types that are not systematic reviews or published in other journals during different periods.

Conclusion

Evidence of spin was present in many of the abstracts of systematic reviews pertaining to the treatment of psoriasis. Future clinical research should investigate any reporting of spin and search for ways to better reduce spin within literature. Continued research is necessary to evaluate the presence of spin within dermatology and other specialties.