Clinical Review

Atopic dermatitis (AD) is a chronic inflammatory disorder that affects individuals worldwide.¹ Although AD previously was commonly described as a skin-limited disease of childhood characterized by eczema in the flexural folds and pruritus, our current understanding supports a more heterogeneous condition.² We review the wide range of cutaneous presentations of AD with a focus on clinical and morphological presentations across diverse skin types—commonly referred to as skin of color (SOC).

Defining SOC in Relation to AD

The terms SOC, race, and ethnicity are used interchangeably, but their true meanings are distinct. Traditionally, race has been defined as a biological concept, grouping cohorts of individuals with a large degree of shared ancestry and genetic similarities,³ and ethnicity as a social construct, grouping individuals with common racial, national, tribal, religious, linguistic, or cultural backgrounds.⁴ In practice, both concepts can broadly be envisioned as mixed social, political, and economic constructs, as no one gene or biologic characteristic distinguishes one racial or ethnic group from another.⁵

The US Census Bureau recognizes 5 racial groupings: White, Black or African American, American Indian or Alaska Native, Asian, and Native Hawaiian or other Pacific Islander.⁶ Hispanic or Latinx origin is considered an ethnicity. It is important to note the limitations of these labels, as they do not completely encapsulate the heterogeneity of the US population. Overgeneralization of racial and ethnic categories may dull or obscure true differences among populations.⁷

From an evolutionary perspective, skin pigmentation represents the product of 2 opposing clines produced by natural selection in response to both need for and protection from UV radiation across lattitudes.⁸ Defining SOC is not quite as simple. Skin of color often is equated with certain racial/ethnic groups, or even binary categories of Black vs non-Black or White vs non-White. Others may use the Fitzpatrick scale to discuss SOC, though this scale was originally created to measure the response of skin to UVA radiation exposure.⁹ The reality is that SOC is a complex term that cannot simply be defined by a certain group of skin tones, races, ethnicities, and/or Fitzpatrick skin types. With this in mind, SOC in the context of this article will often refer to non-White individuals based on the investigators’ terminology, but this definition is not all-encompassing.

Historically in medicine, racial/ethnic differences in outcomes have been equated to differences in biology/genetics without consideration of many external factors.¹⁰ The effects of racism, economic stability, health care access, environment, and education quality rarely are discussed, though they have a major impact on health and may better define associations with race or an SOC population. A discussion of the structural and social determinants of health contributing to disease outcomes should accompany any race-based guidelines to prevent inaccurately pathologizing race or SOC.¹⁰

Within the scope of AD, social determinants of health play an important role in contributing to disease morbidity. Environmental factors, including tobacco smoke, climate, pollutants, water hardness, und urban living, are related to AD prevalence and severity.¹¹ Higher socioeconomic status is associated with increased AD rates,¹² yet lower socioeconomic status is associated with more severe disease.¹³ Barriers to health care access and suboptimal care drive worse AD outcomes.¹⁴ Underrepresentation in clinical trials prevents the generalizability and safety of AD treatments.¹⁵ Disparities in these health determinants associated with AD likely are among the most important drivers of observed differences in disease presentation, severity, burden, and even prevalence—more so than genetics or ancestry alone¹⁶—yet this relationship is poorly understood and often presented as a consequence of race. It is critical to redefine the narrative when considering the heterogeneous presentations of AD in patients with SOC and acknowledge the limitations of current terminology when attempting to capture clinical diversity in AD, including in this review, where published findings often are limited by race-based analysis.

Epidemiology

The prevalence of AD has been increasing over the last few decades, and rates vary by region. In the United States, the prevalence of childhood and adult AD is 13% and 7%, respectively.^17,18 Globally, higher rates of pediatric AD are seen in Africa, Oceania, Southeast Asia (SEA), and Latin America compared to South Asia, Northern Europe, and Eastern Europe.¹⁹ The prevalence of AD varies widely within the same continent and country; for example, throughout Africa, prevalence was found to be anywhere between 4.7% and 23.3%.²⁰

Although AD lesions often are described as pruritic erythematous papules and plaques, other common morphologies in SOC populations include prurigo nodules, lichenoid papules, perifollicular papules, nummular lesions, and psoriasiform lesions (Table). Instead of applying normative terms such as classic vs atypical to AD morphology, we urge clinicians to be familiar with the full spectrum of AD skin signs.

Prurigo Nodules—Prurigo nodules are hyperkeratotic or erosive nodules with severe pruritus, often grouped symmetrically on the extensor surfaces of the arms, legs, and trunk (Figure 1).^14,21 The skin between lesions usually is unaffected but can be dry or lichenified or display postinflammatory pigmentary changes.¹⁴ Prurigo nodules are common. In a study of a cohort of patients with prurigo nodularis (N=108), nearly half (46.3%) were determined to have either an atopic predisposition or underlying AD as a contributing cause of the lesions.²¹

Prurigo nodules as a phenotype of AD may be more common in certain SOC populations. Studies from SEA have reported a higher prevalence of prurigo nodules among patients with AD.²⁸ Although there are limited formal studies assessing the true prevalence of this lesion type in African American AD patients in the United States, clinical evidence supports more frequent appearance of prurigo nodules in non-White patients.²⁹ Contributing factors include suboptimal care for AD in SOC populations and/or barriers to health care access, resulting in more severe disease that increases the risk for this lesion type.¹⁴

Lichenoid Papules—Papular lichenoid lesions often present on the extensor surfaces of the arms and legs in AD (Figure 2).²² In a study of Nigerian patients with AD (N=1019), 54.1% had lichenoid papules.²⁴ A systematic review of AD characteristics by region similarly reported an increased prevalence of this lesion type in African studies.²⁸ Lichenoid variants of AD have been well described in SOC patients in the United States.²³ In contrast to the lesions of lichen planus, the lichenoid papules of AD usually are round, rarely display koebnerization, do not have Wickham striae, and predominantly are located on extensor surfaces.

Perifollicular Papules—Perifollicular accentuation—dermatitis enhanced around hair follicles—is a well-described lesional morphology of AD that is noted in all racial/ethnic groups (Figure 3).²² In fact, perifollicular accentuation is included as one of the Hanifin and Rajka minor criteria for AD.³⁰ Studies performed in Nigeria and India showed perifollicular accentuation in up to 70% of AD patients.^24,31 In a study of adult Thai patients (N=56), follicular lesions were found more frequently in intrinsic AD (29%) compared with extrinsic AD (12%).³²

Nummular and Psoriasiform Lesions—Nummular lesions may be red, oozing, excoriated, studded with pustules and/or present on the extensor extremities (Figure 4). In SOC patients, these lesions often occur in areas where hyperpigmentation is noted.²² Studies in the United States and Mexico demonstrated that 15% to 17% of AD patients displayed nummular lesions.^23,33 Similar to follicular papules, nummular lesions were linked to intrinsic AD in a study of adult Thai patients.³²

Psoriasiform lesions show prominent scaling, lichenification, and clear demarcation.²⁵ It has been reported that the psoriasiform phenotype of AD is more common in Asian patients,²⁵ though this is likely an oversimplification. The participants in these studies were of Japanese and Korean ancestry, which covers a broad geographic region, and the grouping of individuals under a heterogeneous Asian category is unlikely to convey generalizable biologic or clinical information. Unsurprisingly, a systematic review of AD characteristics by region noted considerable phenotypical differences among patients in SEA, East Asia, Iran, and India.²⁸

Disease Severity

Several factors contribute to AD disease severity,³⁴ including objective assessments of inflammation, such as erythema and lichenification (Table), as well as subjective measures of symptoms, such as itch. The severity of AD is exacerbated by the social determinants of health, and a lower socioeconomic status, lower household income, lower parental education level and health, dilapidated housing, and presence of garbage on the street are among factors linked to worse AD disease severity.^13,17 Although non-White individuals with AD often are reported to have more severe disease than their White counterparts,³⁵ these types of health determinants may be the most relevant causes of observed differences.

Erythema—Erythema is a feature of inflammation used in the AD severity assessment. Erythema may appear in shades beyond red, including maroon, violaceous, or brown, in patients with darker pigmented skin, which may contribute to diagnosis of AD at a later disease stage.²⁶ Multiple AD severity scoring tools, such as the SCORing Atopic Dermatitis and Eczema Area and Severity Index, include erythema as a measure, which can lead to underestimation of AD severity in SOC populations. After adjusting for erythema score, one study found that Black children with AD had a risk for severe disease that was 6-times higher than White children.³⁶ Dermatological training must adequately teach physicians to recognize erythema across all skin tones.³⁷

Erythroderma (also known as exfoliative dermatitis) is rapidly spreading erythema on at least 90% of the total body surface area, often sparing the palms and soles.³² Erythroderma is a potentially life-threatening manifestation of severe AD. Although erythroderma may have many underlying causes, AD has been reported to be the cause in 5% to 24% of cases,³⁸ and compared to studies in Europe, the prevalence of erythroderma was higher in East Asian studies of AD.²⁸

Excoriation and Pruritus—Pruritus is a defining characteristic of AD, and the resulting excoriations often are predominant on physical examination, which is a key part of severity scores. Itch is the most prevalent symptom among patients with AD, and a greater itch severity has been linked to decreased health-related quality of life, increased mental health symptoms, impaired sleep, and decreased daily function.^39,40 The burden of itch may be greater in SOC populations. The impact of itch on quality of life among US military veterans was significantly higher in those who identified as non-White (P=.05).⁴¹ In another study of US military veterans, African American individuals reported a significantly higher emotional impact from itch (P<.05).⁴²

Lichenification—Lichenification is thickening of the skin due to chronic rubbing and scratching that causes a leathery elevated appearance with exaggerated skin lines.²⁷ Lichenification is included as a factor in common clinical scoring tools, with greater lichenification indicating greater disease severity. Studies from SEA and Africa suggested a higher prevalence of lichenification in AD patients.²⁸ A greater itch burden and thus increased rubbing/scratching in these populations may contribute to some of these findings.^42,43

Xerosis—Xerosis (or dry skin) is a common finding in AD that results from increased transepidermal water loss due to a dysfunctional epidermal barrier.⁴⁴ In a systematic review of AD characteristics by region, xerosis was among the top 5 most reported AD features globally in all regions except SEA.²⁸ Xerosis may be more stigmatizing in SOC populations because of the greater visibility of scaling and dryness on darker skin tones.¹

Postinflammatory Dyspigmentation—Postinflammatory pigment alteration may be a consequence of AD lesions, resulting in hyperpigmented and hypopigmented macules and patches. Patients with AD with darker skin tones are more likely to develop postinflammatory dyspigmentation.²⁶ A study of AD patients in Nigeria found that 63% displayed postinflammatory dyspigmentation.⁴⁵ Dyschromia, including postinflammatory hyperpigmentation, is one of the most common reasons for SOC patients to seek dermatologic care.⁴⁶ Postinflammatory pigment alteration can cause severe distress in patients, even more so than the cutaneous findings of AD. Although altered skin pigmentation usually returns to normal over weeks to months, skin depigmentation from chronic excoriation may be permanent.²⁶ Appropriately treating hyperpigmentation and hypopigmentation in SOC populations can greatly improve quality of life.⁴⁷

Conclusion

Atopic dermatitis is a cutaneous inflammatory disease that presents with many clinical phenotypes. Dermatologists should be trained to recognize the heterogeneous signs of AD present across the diverse skin types in SOC patients. Future research should move away from race-based analyses and focus on the complex interplay of environmental factors, social determinants of health, and skin pigmentation, as well as how these factors drive variations in AD lesional morphology and inflammation.

Atopic dermatitis (AD) is a chronic inflammatory disorder that affects individuals worldwide.¹ Although AD previously was commonly described as a skin-limited disease of childhood characterized by eczema in the flexural folds and pruritus, our current understanding supports a more heterogeneous condition.² We review the wide range of cutaneous presentations of AD with a focus on clinical and morphological presentations across diverse skin types—commonly referred to as skin of color (SOC).

Defining SOC in Relation to AD

The terms SOC, race, and ethnicity are used interchangeably, but their true meanings are distinct. Traditionally, race has been defined as a biological concept, grouping cohorts of individuals with a large degree of shared ancestry and genetic similarities,³ and ethnicity as a social construct, grouping individuals with common racial, national, tribal, religious, linguistic, or cultural backgrounds.⁴ In practice, both concepts can broadly be envisioned as mixed social, political, and economic constructs, as no one gene or biologic characteristic distinguishes one racial or ethnic group from another.⁵

The US Census Bureau recognizes 5 racial groupings: White, Black or African American, American Indian or Alaska Native, Asian, and Native Hawaiian or other Pacific Islander.⁶ Hispanic or Latinx origin is considered an ethnicity. It is important to note the limitations of these labels, as they do not completely encapsulate the heterogeneity of the US population. Overgeneralization of racial and ethnic categories may dull or obscure true differences among populations.⁷

From an evolutionary perspective, skin pigmentation represents the product of 2 opposing clines produced by natural selection in response to both need for and protection from UV radiation across lattitudes.⁸ Defining SOC is not quite as simple. Skin of color often is equated with certain racial/ethnic groups, or even binary categories of Black vs non-Black or White vs non-White. Others may use the Fitzpatrick scale to discuss SOC, though this scale was originally created to measure the response of skin to UVA radiation exposure.⁹ The reality is that SOC is a complex term that cannot simply be defined by a certain group of skin tones, races, ethnicities, and/or Fitzpatrick skin types. With this in mind, SOC in the context of this article will often refer to non-White individuals based on the investigators’ terminology, but this definition is not all-encompassing.

Historically in medicine, racial/ethnic differences in outcomes have been equated to differences in biology/genetics without consideration of many external factors.¹⁰ The effects of racism, economic stability, health care access, environment, and education quality rarely are discussed, though they have a major impact on health and may better define associations with race or an SOC population. A discussion of the structural and social determinants of health contributing to disease outcomes should accompany any race-based guidelines to prevent inaccurately pathologizing race or SOC.¹⁰

Within the scope of AD, social determinants of health play an important role in contributing to disease morbidity. Environmental factors, including tobacco smoke, climate, pollutants, water hardness, und urban living, are related to AD prevalence and severity.¹¹ Higher socioeconomic status is associated with increased AD rates,¹² yet lower socioeconomic status is associated with more severe disease.¹³ Barriers to health care access and suboptimal care drive worse AD outcomes.¹⁴ Underrepresentation in clinical trials prevents the generalizability and safety of AD treatments.¹⁵ Disparities in these health determinants associated with AD likely are among the most important drivers of observed differences in disease presentation, severity, burden, and even prevalence—more so than genetics or ancestry alone¹⁶—yet this relationship is poorly understood and often presented as a consequence of race. It is critical to redefine the narrative when considering the heterogeneous presentations of AD in patients with SOC and acknowledge the limitations of current terminology when attempting to capture clinical diversity in AD, including in this review, where published findings often are limited by race-based analysis.

Epidemiology

The prevalence of AD has been increasing over the last few decades, and rates vary by region. In the United States, the prevalence of childhood and adult AD is 13% and 7%, respectively.^17,18 Globally, higher rates of pediatric AD are seen in Africa, Oceania, Southeast Asia (SEA), and Latin America compared to South Asia, Northern Europe, and Eastern Europe.¹⁹ The prevalence of AD varies widely within the same continent and country; for example, throughout Africa, prevalence was found to be anywhere between 4.7% and 23.3%.²⁰

Although AD lesions often are described as pruritic erythematous papules and plaques, other common morphologies in SOC populations include prurigo nodules, lichenoid papules, perifollicular papules, nummular lesions, and psoriasiform lesions (Table). Instead of applying normative terms such as classic vs atypical to AD morphology, we urge clinicians to be familiar with the full spectrum of AD skin signs.

Prurigo Nodules—Prurigo nodules are hyperkeratotic or erosive nodules with severe pruritus, often grouped symmetrically on the extensor surfaces of the arms, legs, and trunk (Figure 1).^14,21 The skin between lesions usually is unaffected but can be dry or lichenified or display postinflammatory pigmentary changes.¹⁴ Prurigo nodules are common. In a study of a cohort of patients with prurigo nodularis (N=108), nearly half (46.3%) were determined to have either an atopic predisposition or underlying AD as a contributing cause of the lesions.²¹

Prurigo nodules as a phenotype of AD may be more common in certain SOC populations. Studies from SEA have reported a higher prevalence of prurigo nodules among patients with AD.²⁸ Although there are limited formal studies assessing the true prevalence of this lesion type in African American AD patients in the United States, clinical evidence supports more frequent appearance of prurigo nodules in non-White patients.²⁹ Contributing factors include suboptimal care for AD in SOC populations and/or barriers to health care access, resulting in more severe disease that increases the risk for this lesion type.¹⁴

Lichenoid Papules—Papular lichenoid lesions often present on the extensor surfaces of the arms and legs in AD (Figure 2).²² In a study of Nigerian patients with AD (N=1019), 54.1% had lichenoid papules.²⁴ A systematic review of AD characteristics by region similarly reported an increased prevalence of this lesion type in African studies.²⁸ Lichenoid variants of AD have been well described in SOC patients in the United States.²³ In contrast to the lesions of lichen planus, the lichenoid papules of AD usually are round, rarely display koebnerization, do not have Wickham striae, and predominantly are located on extensor surfaces.

Perifollicular Papules—Perifollicular accentuation—dermatitis enhanced around hair follicles—is a well-described lesional morphology of AD that is noted in all racial/ethnic groups (Figure 3).²² In fact, perifollicular accentuation is included as one of the Hanifin and Rajka minor criteria for AD.³⁰ Studies performed in Nigeria and India showed perifollicular accentuation in up to 70% of AD patients.^24,31 In a study of adult Thai patients (N=56), follicular lesions were found more frequently in intrinsic AD (29%) compared with extrinsic AD (12%).³²

Nummular and Psoriasiform Lesions—Nummular lesions may be red, oozing, excoriated, studded with pustules and/or present on the extensor extremities (Figure 4). In SOC patients, these lesions often occur in areas where hyperpigmentation is noted.²² Studies in the United States and Mexico demonstrated that 15% to 17% of AD patients displayed nummular lesions.^23,33 Similar to follicular papules, nummular lesions were linked to intrinsic AD in a study of adult Thai patients.³²

Psoriasiform lesions show prominent scaling, lichenification, and clear demarcation.²⁵ It has been reported that the psoriasiform phenotype of AD is more common in Asian patients,²⁵ though this is likely an oversimplification. The participants in these studies were of Japanese and Korean ancestry, which covers a broad geographic region, and the grouping of individuals under a heterogeneous Asian category is unlikely to convey generalizable biologic or clinical information. Unsurprisingly, a systematic review of AD characteristics by region noted considerable phenotypical differences among patients in SEA, East Asia, Iran, and India.²⁸

Disease Severity

Several factors contribute to AD disease severity,³⁴ including objective assessments of inflammation, such as erythema and lichenification (Table), as well as subjective measures of symptoms, such as itch. The severity of AD is exacerbated by the social determinants of health, and a lower socioeconomic status, lower household income, lower parental education level and health, dilapidated housing, and presence of garbage on the street are among factors linked to worse AD disease severity.^13,17 Although non-White individuals with AD often are reported to have more severe disease than their White counterparts,³⁵ these types of health determinants may be the most relevant causes of observed differences.

Erythema—Erythema is a feature of inflammation used in the AD severity assessment. Erythema may appear in shades beyond red, including maroon, violaceous, or brown, in patients with darker pigmented skin, which may contribute to diagnosis of AD at a later disease stage.²⁶ Multiple AD severity scoring tools, such as the SCORing Atopic Dermatitis and Eczema Area and Severity Index, include erythema as a measure, which can lead to underestimation of AD severity in SOC populations. After adjusting for erythema score, one study found that Black children with AD had a risk for severe disease that was 6-times higher than White children.³⁶ Dermatological training must adequately teach physicians to recognize erythema across all skin tones.³⁷

Erythroderma (also known as exfoliative dermatitis) is rapidly spreading erythema on at least 90% of the total body surface area, often sparing the palms and soles.³² Erythroderma is a potentially life-threatening manifestation of severe AD. Although erythroderma may have many underlying causes, AD has been reported to be the cause in 5% to 24% of cases,³⁸ and compared to studies in Europe, the prevalence of erythroderma was higher in East Asian studies of AD.²⁸

Excoriation and Pruritus—Pruritus is a defining characteristic of AD, and the resulting excoriations often are predominant on physical examination, which is a key part of severity scores. Itch is the most prevalent symptom among patients with AD, and a greater itch severity has been linked to decreased health-related quality of life, increased mental health symptoms, impaired sleep, and decreased daily function.^39,40 The burden of itch may be greater in SOC populations. The impact of itch on quality of life among US military veterans was significantly higher in those who identified as non-White (P=.05).⁴¹ In another study of US military veterans, African American individuals reported a significantly higher emotional impact from itch (P<.05).⁴²

Lichenification—Lichenification is thickening of the skin due to chronic rubbing and scratching that causes a leathery elevated appearance with exaggerated skin lines.²⁷ Lichenification is included as a factor in common clinical scoring tools, with greater lichenification indicating greater disease severity. Studies from SEA and Africa suggested a higher prevalence of lichenification in AD patients.²⁸ A greater itch burden and thus increased rubbing/scratching in these populations may contribute to some of these findings.^42,43

Xerosis—Xerosis (or dry skin) is a common finding in AD that results from increased transepidermal water loss due to a dysfunctional epidermal barrier.⁴⁴ In a systematic review of AD characteristics by region, xerosis was among the top 5 most reported AD features globally in all regions except SEA.²⁸ Xerosis may be more stigmatizing in SOC populations because of the greater visibility of scaling and dryness on darker skin tones.¹

Postinflammatory Dyspigmentation—Postinflammatory pigment alteration may be a consequence of AD lesions, resulting in hyperpigmented and hypopigmented macules and patches. Patients with AD with darker skin tones are more likely to develop postinflammatory dyspigmentation.²⁶ A study of AD patients in Nigeria found that 63% displayed postinflammatory dyspigmentation.⁴⁵ Dyschromia, including postinflammatory hyperpigmentation, is one of the most common reasons for SOC patients to seek dermatologic care.⁴⁶ Postinflammatory pigment alteration can cause severe distress in patients, even more so than the cutaneous findings of AD. Although altered skin pigmentation usually returns to normal over weeks to months, skin depigmentation from chronic excoriation may be permanent.²⁶ Appropriately treating hyperpigmentation and hypopigmentation in SOC populations can greatly improve quality of life.⁴⁷

Conclusion

Atopic dermatitis is a cutaneous inflammatory disease that presents with many clinical phenotypes. Dermatologists should be trained to recognize the heterogeneous signs of AD present across the diverse skin types in SOC patients. Future research should move away from race-based analyses and focus on the complex interplay of environmental factors, social determinants of health, and skin pigmentation, as well as how these factors drive variations in AD lesional morphology and inflammation.

Atopic dermatitis (AD) is a chronic inflammatory disorder that affects individuals worldwide.¹ Although AD previously was commonly described as a skin-limited disease of childhood characterized by eczema in the flexural folds and pruritus, our current understanding supports a more heterogeneous condition.² We review the wide range of cutaneous presentations of AD with a focus on clinical and morphological presentations across diverse skin types—commonly referred to as skin of color (SOC).

Defining SOC in Relation to AD

The terms SOC, race, and ethnicity are used interchangeably, but their true meanings are distinct. Traditionally, race has been defined as a biological concept, grouping cohorts of individuals with a large degree of shared ancestry and genetic similarities,³ and ethnicity as a social construct, grouping individuals with common racial, national, tribal, religious, linguistic, or cultural backgrounds.⁴ In practice, both concepts can broadly be envisioned as mixed social, political, and economic constructs, as no one gene or biologic characteristic distinguishes one racial or ethnic group from another.⁵

The US Census Bureau recognizes 5 racial groupings: White, Black or African American, American Indian or Alaska Native, Asian, and Native Hawaiian or other Pacific Islander.⁶ Hispanic or Latinx origin is considered an ethnicity. It is important to note the limitations of these labels, as they do not completely encapsulate the heterogeneity of the US population. Overgeneralization of racial and ethnic categories may dull or obscure true differences among populations.⁷

From an evolutionary perspective, skin pigmentation represents the product of 2 opposing clines produced by natural selection in response to both need for and protection from UV radiation across lattitudes.⁸ Defining SOC is not quite as simple. Skin of color often is equated with certain racial/ethnic groups, or even binary categories of Black vs non-Black or White vs non-White. Others may use the Fitzpatrick scale to discuss SOC, though this scale was originally created to measure the response of skin to UVA radiation exposure.⁹ The reality is that SOC is a complex term that cannot simply be defined by a certain group of skin tones, races, ethnicities, and/or Fitzpatrick skin types. With this in mind, SOC in the context of this article will often refer to non-White individuals based on the investigators’ terminology, but this definition is not all-encompassing.

Historically in medicine, racial/ethnic differences in outcomes have been equated to differences in biology/genetics without consideration of many external factors.¹⁰ The effects of racism, economic stability, health care access, environment, and education quality rarely are discussed, though they have a major impact on health and may better define associations with race or an SOC population. A discussion of the structural and social determinants of health contributing to disease outcomes should accompany any race-based guidelines to prevent inaccurately pathologizing race or SOC.¹⁰

Within the scope of AD, social determinants of health play an important role in contributing to disease morbidity. Environmental factors, including tobacco smoke, climate, pollutants, water hardness, und urban living, are related to AD prevalence and severity.¹¹ Higher socioeconomic status is associated with increased AD rates,¹² yet lower socioeconomic status is associated with more severe disease.¹³ Barriers to health care access and suboptimal care drive worse AD outcomes.¹⁴ Underrepresentation in clinical trials prevents the generalizability and safety of AD treatments.¹⁵ Disparities in these health determinants associated with AD likely are among the most important drivers of observed differences in disease presentation, severity, burden, and even prevalence—more so than genetics or ancestry alone¹⁶—yet this relationship is poorly understood and often presented as a consequence of race. It is critical to redefine the narrative when considering the heterogeneous presentations of AD in patients with SOC and acknowledge the limitations of current terminology when attempting to capture clinical diversity in AD, including in this review, where published findings often are limited by race-based analysis.

Epidemiology

The prevalence of AD has been increasing over the last few decades, and rates vary by region. In the United States, the prevalence of childhood and adult AD is 13% and 7%, respectively.^17,18 Globally, higher rates of pediatric AD are seen in Africa, Oceania, Southeast Asia (SEA), and Latin America compared to South Asia, Northern Europe, and Eastern Europe.¹⁹ The prevalence of AD varies widely within the same continent and country; for example, throughout Africa, prevalence was found to be anywhere between 4.7% and 23.3%.²⁰

Although AD lesions often are described as pruritic erythematous papules and plaques, other common morphologies in SOC populations include prurigo nodules, lichenoid papules, perifollicular papules, nummular lesions, and psoriasiform lesions (Table). Instead of applying normative terms such as classic vs atypical to AD morphology, we urge clinicians to be familiar with the full spectrum of AD skin signs.

Prurigo Nodules—Prurigo nodules are hyperkeratotic or erosive nodules with severe pruritus, often grouped symmetrically on the extensor surfaces of the arms, legs, and trunk (Figure 1).^14,21 The skin between lesions usually is unaffected but can be dry or lichenified or display postinflammatory pigmentary changes.¹⁴ Prurigo nodules are common. In a study of a cohort of patients with prurigo nodularis (N=108), nearly half (46.3%) were determined to have either an atopic predisposition or underlying AD as a contributing cause of the lesions.²¹

Prurigo nodules as a phenotype of AD may be more common in certain SOC populations. Studies from SEA have reported a higher prevalence of prurigo nodules among patients with AD.²⁸ Although there are limited formal studies assessing the true prevalence of this lesion type in African American AD patients in the United States, clinical evidence supports more frequent appearance of prurigo nodules in non-White patients.²⁹ Contributing factors include suboptimal care for AD in SOC populations and/or barriers to health care access, resulting in more severe disease that increases the risk for this lesion type.¹⁴

Lichenoid Papules—Papular lichenoid lesions often present on the extensor surfaces of the arms and legs in AD (Figure 2).²² In a study of Nigerian patients with AD (N=1019), 54.1% had lichenoid papules.²⁴ A systematic review of AD characteristics by region similarly reported an increased prevalence of this lesion type in African studies.²⁸ Lichenoid variants of AD have been well described in SOC patients in the United States.²³ In contrast to the lesions of lichen planus, the lichenoid papules of AD usually are round, rarely display koebnerization, do not have Wickham striae, and predominantly are located on extensor surfaces.

Perifollicular Papules—Perifollicular accentuation—dermatitis enhanced around hair follicles—is a well-described lesional morphology of AD that is noted in all racial/ethnic groups (Figure 3).²² In fact, perifollicular accentuation is included as one of the Hanifin and Rajka minor criteria for AD.³⁰ Studies performed in Nigeria and India showed perifollicular accentuation in up to 70% of AD patients.^24,31 In a study of adult Thai patients (N=56), follicular lesions were found more frequently in intrinsic AD (29%) compared with extrinsic AD (12%).³²

Nummular and Psoriasiform Lesions—Nummular lesions may be red, oozing, excoriated, studded with pustules and/or present on the extensor extremities (Figure 4). In SOC patients, these lesions often occur in areas where hyperpigmentation is noted.²² Studies in the United States and Mexico demonstrated that 15% to 17% of AD patients displayed nummular lesions.^23,33 Similar to follicular papules, nummular lesions were linked to intrinsic AD in a study of adult Thai patients.³²

Psoriasiform lesions show prominent scaling, lichenification, and clear demarcation.²⁵ It has been reported that the psoriasiform phenotype of AD is more common in Asian patients,²⁵ though this is likely an oversimplification. The participants in these studies were of Japanese and Korean ancestry, which covers a broad geographic region, and the grouping of individuals under a heterogeneous Asian category is unlikely to convey generalizable biologic or clinical information. Unsurprisingly, a systematic review of AD characteristics by region noted considerable phenotypical differences among patients in SEA, East Asia, Iran, and India.²⁸

Disease Severity

Several factors contribute to AD disease severity,³⁴ including objective assessments of inflammation, such as erythema and lichenification (Table), as well as subjective measures of symptoms, such as itch. The severity of AD is exacerbated by the social determinants of health, and a lower socioeconomic status, lower household income, lower parental education level and health, dilapidated housing, and presence of garbage on the street are among factors linked to worse AD disease severity.^13,17 Although non-White individuals with AD often are reported to have more severe disease than their White counterparts,³⁵ these types of health determinants may be the most relevant causes of observed differences.

Erythema—Erythema is a feature of inflammation used in the AD severity assessment. Erythema may appear in shades beyond red, including maroon, violaceous, or brown, in patients with darker pigmented skin, which may contribute to diagnosis of AD at a later disease stage.²⁶ Multiple AD severity scoring tools, such as the SCORing Atopic Dermatitis and Eczema Area and Severity Index, include erythema as a measure, which can lead to underestimation of AD severity in SOC populations. After adjusting for erythema score, one study found that Black children with AD had a risk for severe disease that was 6-times higher than White children.³⁶ Dermatological training must adequately teach physicians to recognize erythema across all skin tones.³⁷

Erythroderma (also known as exfoliative dermatitis) is rapidly spreading erythema on at least 90% of the total body surface area, often sparing the palms and soles.³² Erythroderma is a potentially life-threatening manifestation of severe AD. Although erythroderma may have many underlying causes, AD has been reported to be the cause in 5% to 24% of cases,³⁸ and compared to studies in Europe, the prevalence of erythroderma was higher in East Asian studies of AD.²⁸

Excoriation and Pruritus—Pruritus is a defining characteristic of AD, and the resulting excoriations often are predominant on physical examination, which is a key part of severity scores. Itch is the most prevalent symptom among patients with AD, and a greater itch severity has been linked to decreased health-related quality of life, increased mental health symptoms, impaired sleep, and decreased daily function.^39,40 The burden of itch may be greater in SOC populations. The impact of itch on quality of life among US military veterans was significantly higher in those who identified as non-White (P=.05).⁴¹ In another study of US military veterans, African American individuals reported a significantly higher emotional impact from itch (P<.05).⁴²

Lichenification—Lichenification is thickening of the skin due to chronic rubbing and scratching that causes a leathery elevated appearance with exaggerated skin lines.²⁷ Lichenification is included as a factor in common clinical scoring tools, with greater lichenification indicating greater disease severity. Studies from SEA and Africa suggested a higher prevalence of lichenification in AD patients.²⁸ A greater itch burden and thus increased rubbing/scratching in these populations may contribute to some of these findings.^42,43

Xerosis—Xerosis (or dry skin) is a common finding in AD that results from increased transepidermal water loss due to a dysfunctional epidermal barrier.⁴⁴ In a systematic review of AD characteristics by region, xerosis was among the top 5 most reported AD features globally in all regions except SEA.²⁸ Xerosis may be more stigmatizing in SOC populations because of the greater visibility of scaling and dryness on darker skin tones.¹

Postinflammatory Dyspigmentation—Postinflammatory pigment alteration may be a consequence of AD lesions, resulting in hyperpigmented and hypopigmented macules and patches. Patients with AD with darker skin tones are more likely to develop postinflammatory dyspigmentation.²⁶ A study of AD patients in Nigeria found that 63% displayed postinflammatory dyspigmentation.⁴⁵ Dyschromia, including postinflammatory hyperpigmentation, is one of the most common reasons for SOC patients to seek dermatologic care.⁴⁶ Postinflammatory pigment alteration can cause severe distress in patients, even more so than the cutaneous findings of AD. Although altered skin pigmentation usually returns to normal over weeks to months, skin depigmentation from chronic excoriation may be permanent.²⁶ Appropriately treating hyperpigmentation and hypopigmentation in SOC populations can greatly improve quality of life.⁴⁷

Conclusion

Atopic dermatitis is a cutaneous inflammatory disease that presents with many clinical phenotypes. Dermatologists should be trained to recognize the heterogeneous signs of AD present across the diverse skin types in SOC patients. Future research should move away from race-based analyses and focus on the complex interplay of environmental factors, social determinants of health, and skin pigmentation, as well as how these factors drive variations in AD lesional morphology and inflammation.

CASE The TeamBirth experience: Making a difference

“At a community hospital in Washington where we had implemented TeamBirth (a labor and delivery shared decision making model), a patient, her partner, a labor and delivery nurse, and myself (an ObGyn) were making a plan for the patient’s induction of labor admission. I asked the patient, a 29-year-old (G2P1001), how we could improve her care in relation to her first birth. Her answer was simple: I want to be treated with respect. Her partner went on to describe their past experience in which the provider was inappropriately texting while in between the patient’s knees during delivery. Our team had the opportunity to undo some of the trauma from her first birth. That’s what I like about TeamBirth. It gives every patient the opportunity, regardless of their background, to define safety and participate in their care experience.”

–Angela Chien, MD, Obstetrician and Quality Improvement leader, Washington

Unfortunately, disrespect and mistreatment are far from an anomaly in the obstetrics setting. In a systematic review of respectful maternity care, the World Health Organization delineated 7 dimensions of maternal mistreatment: physical abuse, sexual abuse, verbal abuse, stigma and discrimination, failure to meet professional standards of care, poor rapport between women and providers, and poor conditions and constraints presented by the health system.¹ In 2019, the Giving Voice to Mothers study showed that 17% of birthing people in the United States reported experiencing 1 or more types of maternal mistreatment.² Rates of mistreatment were disproportionately greater in populations of color, hospital-based births, and among those with social, economic, or health challenges.² It is well known that Black and African American and American Indian and Alaska Native populations experience the rare events of severe maternal morbidity and mortality more frequently than their White counterparts; the disproportionate burden of mistreatment is lesser known and far more common.

Overlooking the longitudinal harm of a negative birth experience has cascading impact. While an empowering perinatal experience can foster preventive screening and management of chronic disease, a poor experience conversely can seed mistrust at an individual, generational, and community level.

The patient quality enterprise is beginning to shift attention toward maternal experience with the development of PREMs (patient-reported experience measures), PROMs (patient-reported outcome measures), and novel validated scales that assess autonomy and trust.³ Development of a maternal Consumer Assessment of Healthcare Providers and Systems (CAHPS) survey on childbirth is forthcoming.⁴ Of course, continuing to prioritize physical safety through initiatives on blood pressure monitoring and severe maternal morbidity and mortality remains paramount. Yet emotional and psychological safety also must be recognized as essential pillars of patient safety. Transgressions related to autonomy and dignity, as well as racism, sexism, classicism, and ableism, should be treated as “adverse and never events.”⁵

How the TeamBirth model works

Shared decision making (SDM) is cited in medical pedagogy as the solution to respectfullyrecognizing social context, integrating subjective experience, and honoring patient autonomy.⁶ The onus has always been on individual clinicians to exercise SDM. A new practice model, TeamBirth, embeds SDM into the culture and workflow. It offers a behavioral framework to mitigate implicit bias and operationalizes SDM tools, such that every patient is an empowered participant in their care.

TeamBirth was created through Ariadne Labs’ Delivery Decisions Initiative, a research and social impact program that designs, tests, and scales transformative, systems-level solutions that promote quality, equity, and dignity in childbirth. By the end of 2023, TeamBirth will be implemented in more than 100 hospitals across the United States, cumulatively touching over 200,000 lives. (For more information on the TeamBirth model, view the “Why TeamBirth” video at: https://www.youtube.com/watch?v=EoVrSaGk7gc.)

The tenets of TeamBirth are enacted through a patient-facing, shared whiteboard or dry-erase planning board in the labor room (FIGURE 1). Research has demonstrated how dry-erase boards in clinical settings can support safety and dignity in care, especially to improve patient-provider communication, teamwork, and patient satisfaction.^7,8 The planning board is initially filled out by a clinical team member and is updated during team “huddles” throughout labor.

ILLUSTRATION: KIMBERLY MARTINS FOR OBG MANAGEMENT

Continue to: Patient response to TeamBirth is positive...

Patients and providers alike have endorsed TeamBirth. In initial pilot testing across 4 sites, 99% of all patients surveyed “definitely” or “somewhat” had the role they wanted in making decisions about their labor.⁹

In partnership with the Oklahoma Perinatal Quality Improvement Collaborative (OPQIC), the impact of TeamBirth was assessed in a statewide patient cohort (n = 3,121) using the validated Mothers Autonomy in Decision Making (MADM) scale created by the Birth Place Lab at the University of British Columbia. The percentage of patients who scored in the highest MADM quartile was 31.3% higher for patients who indicated participation in a huddle during labor compared with those who did not participate in a huddle. This trend held across all racial and ethnic groups: For example, 93% of non-Hispanic Black/African American patients who had a TeamBirth huddle reported high autonomy, a nearly 20 percentage point increase from those without a huddle (FIGURE 2). Similarly, a higher percentage of agreement was observed across all 7 items in the MADM scale for patients who reported a TeamBirth huddle (FIGURE 3). TeamBirth’s effect has been observed across surveys and multiple validated metrics.

Continue to: Patient testimonials...

Patient testimonials

The following testimonials were obtained from a TeamBirth survey that patients in participating Massachusetts hospitals completed in the postpartum unit prior to discharge.

According to one patient, “TeamBirth is great, feels like all obstacles are covered by multiple people with many talents, expertise. Feels like mom is part of the process, much different than my delivery 2 years ago when I felt like things were decided for me/I was ‘told’ what we were doing and questioned if I felt uneasy about it…. We felt safe and like all things were covered no matter what may happen.”

Another patient, also at a Massachusetts hospital, offered these comments about TeamBirth: “The entire staff was very genuine and my experience the best it could be. They deserve updated whiteboards in every room. I found them to be very useful.”

The clinician perspective

To be certain, clinician workflow must be a consideration for any practice change. The feasibility, acceptability, and safety of the TeamBirth model to clinicians was validated through a study at 4 community hospitals across the United States in which TeamBirth had been implemented in the 8 months prior.⁹

The clinician response rate was an impressive 78%. Ninety percent of clinicians, including physicians, midwives, and nurses, indicated that they would “definitely” (68%) or “probably” (22%) recommend TeamBirth for use in other labor and delivery units. None of the clinicians surveyed (n = 375) reported that TeamBirth negatively impacted care delivery.⁹

Obstetricians also provided qualitative commentary, noting that, while at times huddling infringed on efficiency, it also enhanced staff fulfillment. An obstetrician at a Massachusetts hospital observed, “Overall I think [TeamBirth is] helpful in slowing us down a little bit to really make sure that we’re providing the human part of the care, like the communication, and not just the medical care. And I think most providers value the human part and the communication. You know, we all think most providers value good communication with the patients, but when you’re in the middle of running around doing a bunch of stuff, you don’t always remember to prioritize it. And I think that at the end of the day…when you know you’ve communicated well with your patients, you end up feeling better about what you’re doing.”

As with most cross-sectional survey studies, selection bias remains an important caveat; patients and providers may decide to complete or not complete voluntary surveys based on particularly positive or negative experiences.

Metrics aside, obstetricians have an ethical duty to provide dignified and safe care, both physically and psychologically. Collectively, as a specialty, we share the responsibility to mitigate maternal mistreatment. As individuals, we can prevent perpetuation of birth trauma and foster healing and empowerment, one patient at a time, by employing tenets of TeamBirth.

Steps for implementing the TeamBirth model

To incorporate TeamBirth into your practice:

• Make patients the “team captain” and center them as the primary decision maker.
• Elicit patient preferences and subjective experiences to develop a collaborative plan on admission and when changes occur in clinical status.
• Round with and utilize the expertise of the full care team—nurse and midwife or obstetrician, as well as support person(s) and/or doula, learners, interpreter, and social worker as applicable.
• Ensure that the patient knows the names and roles of the care team members and provide updates at shift change.
• If your birthing rooms have a whiteboard, use it to keep the patient and team informed of the plan.
• Delineate status updates by maternal condition, fetal condition, and labor progress.
• Provide explicit permission for patients to call for a team huddle at any time and encourage support from their support people and/or doula. ●

CASE The TeamBirth experience: Making a difference

“At a community hospital in Washington where we had implemented TeamBirth (a labor and delivery shared decision making model), a patient, her partner, a labor and delivery nurse, and myself (an ObGyn) were making a plan for the patient’s induction of labor admission. I asked the patient, a 29-year-old (G2P1001), how we could improve her care in relation to her first birth. Her answer was simple: I want to be treated with respect. Her partner went on to describe their past experience in which the provider was inappropriately texting while in between the patient’s knees during delivery. Our team had the opportunity to undo some of the trauma from her first birth. That’s what I like about TeamBirth. It gives every patient the opportunity, regardless of their background, to define safety and participate in their care experience.”

–Angela Chien, MD, Obstetrician and Quality Improvement leader, Washington

Unfortunately, disrespect and mistreatment are far from an anomaly in the obstetrics setting. In a systematic review of respectful maternity care, the World Health Organization delineated 7 dimensions of maternal mistreatment: physical abuse, sexual abuse, verbal abuse, stigma and discrimination, failure to meet professional standards of care, poor rapport between women and providers, and poor conditions and constraints presented by the health system.¹ In 2019, the Giving Voice to Mothers study showed that 17% of birthing people in the United States reported experiencing 1 or more types of maternal mistreatment.² Rates of mistreatment were disproportionately greater in populations of color, hospital-based births, and among those with social, economic, or health challenges.² It is well known that Black and African American and American Indian and Alaska Native populations experience the rare events of severe maternal morbidity and mortality more frequently than their White counterparts; the disproportionate burden of mistreatment is lesser known and far more common.

Overlooking the longitudinal harm of a negative birth experience has cascading impact. While an empowering perinatal experience can foster preventive screening and management of chronic disease, a poor experience conversely can seed mistrust at an individual, generational, and community level.

The patient quality enterprise is beginning to shift attention toward maternal experience with the development of PREMs (patient-reported experience measures), PROMs (patient-reported outcome measures), and novel validated scales that assess autonomy and trust.³ Development of a maternal Consumer Assessment of Healthcare Providers and Systems (CAHPS) survey on childbirth is forthcoming.⁴ Of course, continuing to prioritize physical safety through initiatives on blood pressure monitoring and severe maternal morbidity and mortality remains paramount. Yet emotional and psychological safety also must be recognized as essential pillars of patient safety. Transgressions related to autonomy and dignity, as well as racism, sexism, classicism, and ableism, should be treated as “adverse and never events.”⁵

How the TeamBirth model works

Shared decision making (SDM) is cited in medical pedagogy as the solution to respectfullyrecognizing social context, integrating subjective experience, and honoring patient autonomy.⁶ The onus has always been on individual clinicians to exercise SDM. A new practice model, TeamBirth, embeds SDM into the culture and workflow. It offers a behavioral framework to mitigate implicit bias and operationalizes SDM tools, such that every patient is an empowered participant in their care.

TeamBirth was created through Ariadne Labs’ Delivery Decisions Initiative, a research and social impact program that designs, tests, and scales transformative, systems-level solutions that promote quality, equity, and dignity in childbirth. By the end of 2023, TeamBirth will be implemented in more than 100 hospitals across the United States, cumulatively touching over 200,000 lives. (For more information on the TeamBirth model, view the “Why TeamBirth” video at: https://www.youtube.com/watch?v=EoVrSaGk7gc.)

The tenets of TeamBirth are enacted through a patient-facing, shared whiteboard or dry-erase planning board in the labor room (FIGURE 1). Research has demonstrated how dry-erase boards in clinical settings can support safety and dignity in care, especially to improve patient-provider communication, teamwork, and patient satisfaction.^7,8 The planning board is initially filled out by a clinical team member and is updated during team “huddles” throughout labor.

ILLUSTRATION: KIMBERLY MARTINS FOR OBG MANAGEMENT

Continue to: Patient response to TeamBirth is positive...

Patients and providers alike have endorsed TeamBirth. In initial pilot testing across 4 sites, 99% of all patients surveyed “definitely” or “somewhat” had the role they wanted in making decisions about their labor.⁹

In partnership with the Oklahoma Perinatal Quality Improvement Collaborative (OPQIC), the impact of TeamBirth was assessed in a statewide patient cohort (n = 3,121) using the validated Mothers Autonomy in Decision Making (MADM) scale created by the Birth Place Lab at the University of British Columbia. The percentage of patients who scored in the highest MADM quartile was 31.3% higher for patients who indicated participation in a huddle during labor compared with those who did not participate in a huddle. This trend held across all racial and ethnic groups: For example, 93% of non-Hispanic Black/African American patients who had a TeamBirth huddle reported high autonomy, a nearly 20 percentage point increase from those without a huddle (FIGURE 2). Similarly, a higher percentage of agreement was observed across all 7 items in the MADM scale for patients who reported a TeamBirth huddle (FIGURE 3). TeamBirth’s effect has been observed across surveys and multiple validated metrics.

Continue to: Patient testimonials...

Patient testimonials

The following testimonials were obtained from a TeamBirth survey that patients in participating Massachusetts hospitals completed in the postpartum unit prior to discharge.

According to one patient, “TeamBirth is great, feels like all obstacles are covered by multiple people with many talents, expertise. Feels like mom is part of the process, much different than my delivery 2 years ago when I felt like things were decided for me/I was ‘told’ what we were doing and questioned if I felt uneasy about it…. We felt safe and like all things were covered no matter what may happen.”

Another patient, also at a Massachusetts hospital, offered these comments about TeamBirth: “The entire staff was very genuine and my experience the best it could be. They deserve updated whiteboards in every room. I found them to be very useful.”

The clinician perspective

To be certain, clinician workflow must be a consideration for any practice change. The feasibility, acceptability, and safety of the TeamBirth model to clinicians was validated through a study at 4 community hospitals across the United States in which TeamBirth had been implemented in the 8 months prior.⁹

The clinician response rate was an impressive 78%. Ninety percent of clinicians, including physicians, midwives, and nurses, indicated that they would “definitely” (68%) or “probably” (22%) recommend TeamBirth for use in other labor and delivery units. None of the clinicians surveyed (n = 375) reported that TeamBirth negatively impacted care delivery.⁹

Obstetricians also provided qualitative commentary, noting that, while at times huddling infringed on efficiency, it also enhanced staff fulfillment. An obstetrician at a Massachusetts hospital observed, “Overall I think [TeamBirth is] helpful in slowing us down a little bit to really make sure that we’re providing the human part of the care, like the communication, and not just the medical care. And I think most providers value the human part and the communication. You know, we all think most providers value good communication with the patients, but when you’re in the middle of running around doing a bunch of stuff, you don’t always remember to prioritize it. And I think that at the end of the day…when you know you’ve communicated well with your patients, you end up feeling better about what you’re doing.”

As with most cross-sectional survey studies, selection bias remains an important caveat; patients and providers may decide to complete or not complete voluntary surveys based on particularly positive or negative experiences.

Metrics aside, obstetricians have an ethical duty to provide dignified and safe care, both physically and psychologically. Collectively, as a specialty, we share the responsibility to mitigate maternal mistreatment. As individuals, we can prevent perpetuation of birth trauma and foster healing and empowerment, one patient at a time, by employing tenets of TeamBirth.

Steps for implementing the TeamBirth model

To incorporate TeamBirth into your practice:

• Make patients the “team captain” and center them as the primary decision maker.
• Elicit patient preferences and subjective experiences to develop a collaborative plan on admission and when changes occur in clinical status.
• Round with and utilize the expertise of the full care team—nurse and midwife or obstetrician, as well as support person(s) and/or doula, learners, interpreter, and social worker as applicable.
• Ensure that the patient knows the names and roles of the care team members and provide updates at shift change.
• If your birthing rooms have a whiteboard, use it to keep the patient and team informed of the plan.
• Delineate status updates by maternal condition, fetal condition, and labor progress.
• Provide explicit permission for patients to call for a team huddle at any time and encourage support from their support people and/or doula. ●

CASE The TeamBirth experience: Making a difference

“At a community hospital in Washington where we had implemented TeamBirth (a labor and delivery shared decision making model), a patient, her partner, a labor and delivery nurse, and myself (an ObGyn) were making a plan for the patient’s induction of labor admission. I asked the patient, a 29-year-old (G2P1001), how we could improve her care in relation to her first birth. Her answer was simple: I want to be treated with respect. Her partner went on to describe their past experience in which the provider was inappropriately texting while in between the patient’s knees during delivery. Our team had the opportunity to undo some of the trauma from her first birth. That’s what I like about TeamBirth. It gives every patient the opportunity, regardless of their background, to define safety and participate in their care experience.”

–Angela Chien, MD, Obstetrician and Quality Improvement leader, Washington

Unfortunately, disrespect and mistreatment are far from an anomaly in the obstetrics setting. In a systematic review of respectful maternity care, the World Health Organization delineated 7 dimensions of maternal mistreatment: physical abuse, sexual abuse, verbal abuse, stigma and discrimination, failure to meet professional standards of care, poor rapport between women and providers, and poor conditions and constraints presented by the health system.¹ In 2019, the Giving Voice to Mothers study showed that 17% of birthing people in the United States reported experiencing 1 or more types of maternal mistreatment.² Rates of mistreatment were disproportionately greater in populations of color, hospital-based births, and among those with social, economic, or health challenges.² It is well known that Black and African American and American Indian and Alaska Native populations experience the rare events of severe maternal morbidity and mortality more frequently than their White counterparts; the disproportionate burden of mistreatment is lesser known and far more common.

Overlooking the longitudinal harm of a negative birth experience has cascading impact. While an empowering perinatal experience can foster preventive screening and management of chronic disease, a poor experience conversely can seed mistrust at an individual, generational, and community level.

The patient quality enterprise is beginning to shift attention toward maternal experience with the development of PREMs (patient-reported experience measures), PROMs (patient-reported outcome measures), and novel validated scales that assess autonomy and trust.³ Development of a maternal Consumer Assessment of Healthcare Providers and Systems (CAHPS) survey on childbirth is forthcoming.⁴ Of course, continuing to prioritize physical safety through initiatives on blood pressure monitoring and severe maternal morbidity and mortality remains paramount. Yet emotional and psychological safety also must be recognized as essential pillars of patient safety. Transgressions related to autonomy and dignity, as well as racism, sexism, classicism, and ableism, should be treated as “adverse and never events.”⁵

How the TeamBirth model works

Shared decision making (SDM) is cited in medical pedagogy as the solution to respectfullyrecognizing social context, integrating subjective experience, and honoring patient autonomy.⁶ The onus has always been on individual clinicians to exercise SDM. A new practice model, TeamBirth, embeds SDM into the culture and workflow. It offers a behavioral framework to mitigate implicit bias and operationalizes SDM tools, such that every patient is an empowered participant in their care.

TeamBirth was created through Ariadne Labs’ Delivery Decisions Initiative, a research and social impact program that designs, tests, and scales transformative, systems-level solutions that promote quality, equity, and dignity in childbirth. By the end of 2023, TeamBirth will be implemented in more than 100 hospitals across the United States, cumulatively touching over 200,000 lives. (For more information on the TeamBirth model, view the “Why TeamBirth” video at: https://www.youtube.com/watch?v=EoVrSaGk7gc.)

The tenets of TeamBirth are enacted through a patient-facing, shared whiteboard or dry-erase planning board in the labor room (FIGURE 1). Research has demonstrated how dry-erase boards in clinical settings can support safety and dignity in care, especially to improve patient-provider communication, teamwork, and patient satisfaction.^7,8 The planning board is initially filled out by a clinical team member and is updated during team “huddles” throughout labor.

ILLUSTRATION: KIMBERLY MARTINS FOR OBG MANAGEMENT

Continue to: Patient response to TeamBirth is positive...

Patients and providers alike have endorsed TeamBirth. In initial pilot testing across 4 sites, 99% of all patients surveyed “definitely” or “somewhat” had the role they wanted in making decisions about their labor.⁹

In partnership with the Oklahoma Perinatal Quality Improvement Collaborative (OPQIC), the impact of TeamBirth was assessed in a statewide patient cohort (n = 3,121) using the validated Mothers Autonomy in Decision Making (MADM) scale created by the Birth Place Lab at the University of British Columbia. The percentage of patients who scored in the highest MADM quartile was 31.3% higher for patients who indicated participation in a huddle during labor compared with those who did not participate in a huddle. This trend held across all racial and ethnic groups: For example, 93% of non-Hispanic Black/African American patients who had a TeamBirth huddle reported high autonomy, a nearly 20 percentage point increase from those without a huddle (FIGURE 2). Similarly, a higher percentage of agreement was observed across all 7 items in the MADM scale for patients who reported a TeamBirth huddle (FIGURE 3). TeamBirth’s effect has been observed across surveys and multiple validated metrics.

Continue to: Patient testimonials...

Patient testimonials

The following testimonials were obtained from a TeamBirth survey that patients in participating Massachusetts hospitals completed in the postpartum unit prior to discharge.

According to one patient, “TeamBirth is great, feels like all obstacles are covered by multiple people with many talents, expertise. Feels like mom is part of the process, much different than my delivery 2 years ago when I felt like things were decided for me/I was ‘told’ what we were doing and questioned if I felt uneasy about it…. We felt safe and like all things were covered no matter what may happen.”

Another patient, also at a Massachusetts hospital, offered these comments about TeamBirth: “The entire staff was very genuine and my experience the best it could be. They deserve updated whiteboards in every room. I found them to be very useful.”

The clinician perspective

To be certain, clinician workflow must be a consideration for any practice change. The feasibility, acceptability, and safety of the TeamBirth model to clinicians was validated through a study at 4 community hospitals across the United States in which TeamBirth had been implemented in the 8 months prior.⁹

The clinician response rate was an impressive 78%. Ninety percent of clinicians, including physicians, midwives, and nurses, indicated that they would “definitely” (68%) or “probably” (22%) recommend TeamBirth for use in other labor and delivery units. None of the clinicians surveyed (n = 375) reported that TeamBirth negatively impacted care delivery.⁹

Obstetricians also provided qualitative commentary, noting that, while at times huddling infringed on efficiency, it also enhanced staff fulfillment. An obstetrician at a Massachusetts hospital observed, “Overall I think [TeamBirth is] helpful in slowing us down a little bit to really make sure that we’re providing the human part of the care, like the communication, and not just the medical care. And I think most providers value the human part and the communication. You know, we all think most providers value good communication with the patients, but when you’re in the middle of running around doing a bunch of stuff, you don’t always remember to prioritize it. And I think that at the end of the day…when you know you’ve communicated well with your patients, you end up feeling better about what you’re doing.”

As with most cross-sectional survey studies, selection bias remains an important caveat; patients and providers may decide to complete or not complete voluntary surveys based on particularly positive or negative experiences.

Metrics aside, obstetricians have an ethical duty to provide dignified and safe care, both physically and psychologically. Collectively, as a specialty, we share the responsibility to mitigate maternal mistreatment. As individuals, we can prevent perpetuation of birth trauma and foster healing and empowerment, one patient at a time, by employing tenets of TeamBirth.

Steps for implementing the TeamBirth model

To incorporate TeamBirth into your practice:

• Make patients the “team captain” and center them as the primary decision maker.
• Elicit patient preferences and subjective experiences to develop a collaborative plan on admission and when changes occur in clinical status.
• Round with and utilize the expertise of the full care team—nurse and midwife or obstetrician, as well as support person(s) and/or doula, learners, interpreter, and social worker as applicable.
• Ensure that the patient knows the names and roles of the care team members and provide updates at shift change.
• If your birthing rooms have a whiteboard, use it to keep the patient and team informed of the plan.
• Delineate status updates by maternal condition, fetal condition, and labor progress.
• Provide explicit permission for patients to call for a team huddle at any time and encourage support from their support people and/or doula. ●

More US women are using IUDs than ever before. With more use comes the potential for complications and more requests related to non-contraceptive benefits. New information provides contemporary insight into rare IUD complications and the use of hormonal IUDs for treatment of HMB.

The first intrauterine device (IUD) to be approved in the United States, the Lippes Loop, became available in 1964. Sixty years later, more US women are using IUDs than ever before, and numbers are trending upward (FIGURE).^1,2 Over the past year, contemporary information has become available to further inform IUD management when pregnancy occurs with an IUD in situ, as well as counseling about device breakage. Additionally, new data help clinicians expand which patients can use a levonorgestrel (LNG) 52-mg IUD for heavy menstrual bleeding (HMB) treatment.

As the total absolute number of IUD users increases, so do the absolute numbers of rare outcomes, such as pregnancy among IUD users. These highly effective contraceptives have a failure rate within the first year after placement ranging from 0.1% for the LNG 52-mg IUD to 0.8% for the copper 380-mm² IUD.³ Although the possibility for extrauterine gestation is higher when pregnancy occurs while a patient is using an IUD as compared with most other contraceptive methods, most pregnancies that occur with an IUD in situ are intrauterine.⁴

The high contraceptive efficacy of IUDs make pregnancy with a retained IUD rare; therefore, it is difficult to perform a study with a large enough population to evaluate management of pregnancy complicated by an IUD in situ. Clinical management recommendations for these situations are 20 years old and are supported by limited data from case reports and series with fewer than 200 patients.^5,6

Intrauterine device breakage is another rare event that is poorly understood due to the low absolute number of cases. Information about breakage has similarly been limited to case reports and case series.^7,8 This past year, contemporary data were published to provide more insight into both intrauterine pregnancy with an IUD in situ and IUD breakage.

Beyond contraception, hormonal IUDs have become a popular and evidence-based treatment option for patients with HMB. The initial LNG 52-mg IUD (Mirena) regulatory approval studies for HMB treatment included data limited to parous patients and users with a body mass index (BMI) less than 35 kg/m².⁹ Since that time, no studies have explored these populations. Although current practice has commonly extended use to include patients with these characteristics, we have lacked outcome data. New phase 3 data on the LNG 52-mg IUD (Liletta) included a broader range of participants and provide evidence to support this practice.

Removing retained copper 380-mm² IUDs improves pregnancy outcomes

Panchal VR, Rau AR, Mandelbaum RS, et al. Pregnancy with retained intrauterine device: national-level assessment of characteristics and outcomes. Am J Obstet Gynecol MFM. 2023;5:101056. doi:10.1016/j.ajogmf.2023.101056

Karakuş SS, Karakuş R, Akalın EE, et al. Pregnancy outcomes with a copper 380 mm2 intrauterine device in place: a retrospective cohort study in Turkey, 2011-2021. Contraception. 2023;125:110090. doi:10.1016/j.contraception.2023.110090
 

To update our understanding of outcomes of pregnancy with an IUD in situ, Panchal and colleagues performed a cross-sectional study using the Healthcare Cost and Utilization Project’s National Inpatient Sample. This data set represents 85% of US hospital discharges. The population investigated included hospital deliveries from 2016 to 2020 with an ICD-10 (International Classification of Diseases, Tenth Revision) code of retained IUD. Those without the code were assigned to the comparison non-retained IUD group.

The primary outcome studied was the incidence rate of retained IUD, patient and pregnancy characteristics, and delivery outcomes including but not limited to gestational age at delivery, placental abnormalities, intrauterine fetal demise (IUFD), preterm premature rupture of membranes (PPROM), cesarean delivery, postpartum hemorrhage, and hysterectomy.

Outcomes were worse with retained IUD, regardless of IUD removal status

The authors found that an IUD in situ was reported in 1 out of 8,307 pregnancies and was associated with PPROM, fetal malpresentation, IUFD, placental abnormalities including abruption, accreta spectrum, retained placenta, and need for manual removal (TABLE 1). About three-quarters (76.3%) of patients had a term delivery (≥37 weeks).

Retained IUD was associated with previable loss, defined as less than 22 weeks’ gestation (adjusted odds ratio [aOR], 5.49; 95% confidence interval [CI], 3.30–9.15) and periviable delivery, defined as 22 to 25 weeks’ gestation (aOR, 2.81; 95% CI, 1.63–4.85). Retained IUD was not associated with preterm delivery beyond 26 weeks’ gestation, cesarean delivery, postpartum hemorrhage, or hysterectomy.

Important limitations of this study are the lack of information on IUD type (copper vs hormonal) and the timing of removal or attempted removal in relation to measured pregnancy outcomes.

Continue to: Removal of copper IUD improves, but does not eliminate, poor pregnancy outcomes...

Karakus and colleagues conducted a retrospective cohort study of 233 patients in Turkey with pregnancies that occurred during copper 380-mm² IUD use from 2011 to 2021. The authors reported that, at the time of first contact with the health system and diagnosis of retained IUD, 18.9% of the pregnancies were ectopic, 13.2% were first trimester losses, and 67.5% were ongoing pregnancies.

The authors assessed outcomes in patients with ongoing pregnancies based on whether or not the IUD was removed or retained. Outcomes included gestational age at delivery and adverse pregnancy outcomes, assessed as a composite of preterm delivery, PPROM, chorioamnionitis, placental abruption, and postpartum hemorrhage.

Of those with ongoing pregnancies, 13.3% chose to have an abortion, leaving 137 (86.7%) with continuing pregnancy. The IUD was able to be removed in 39.4% of the sample, with an average gestational age of 7 weeks at the time of removal.

Compared with those with a retained IUD, patients in the removal group had a lower rate of pregnancy loss (33.3% vs 61.4%; P<.001) and a lower rate of the composite adverse pregnancy outcomes (53.1% vs 27.8%; P=.03). TABLE 2 shows the approximate rate of ongoing pregnancy by gestational age in patients with retained and removed copper 380-mm² IUDs. Notably, the largest change occurred periviably, with the proportion of patients with an ongoing pregnancy after 26 weeks reducing to about half for patients with a retained IUD as compared with patients with a removed IUD; this proportion of ongoing pregnancies held through the remainder of gestation.

Do national data reveal more breakage reports for copper 380-mm² or LNG IUDs?

Latack KR, Nguyen BT. Trends in copper versus hormonal intrauterine device breakage reporting within the United States’ Food and Drug Administration Adverse Event Reporting System. Contraception. 2023;118:109909. doi:10.1016/j.contraception.2022.10.011

Latack and Nguyen reviewed postmarket surveillance data of IUD adverse events in the US Food and Drug Administration’s (FDA) Adverse Event Reporting System (FAERS) from 1998 to 2022. The FAERS is a voluntary, or passive, reporting system.

Study findings

Of the approximately 170,000 IUD-related adverse events reported to the agency during the 24-year timeframe, 25.4% were for copper IUDs and 74.6% were for hormonal IUDs. Slightly more than 4,000 reports were specific for device breakage, which the authors grouped into copper (copper 380-mm²)and hormonal (LNG 52 mg, 19.5 mg, and 13.5 mg) IUDs.

The copper 380-mm² IUD was 6.19 times more likely to have a breakage report than hormonal IUDs (9.6% vs 1.7%; 95% CI, 5.87–6.53).

Continue to: Data support the LNG 52-mg IUD for HMB in nulliparous and obese patients...

Data support the LNG 52-mg IUD for HMB in nulliparous and obese patients

Creinin MD, Barnhart KT, Gawron LM, et al. Heavy menstrual bleeding treatment with a levonorgestrel 52-mg intrauterine device. Obstet Gynecol. 2023;141:971-978. doi:10.1097AOG.0000000000005137

Creinin and colleagues conducted a study for US regulatory product approval of the LNG 52-mg IUD (Liletta) for HMB. This multicenter phase 3 open-label clinical trial recruited nonpregnant participants aged 18 to 50 years with HMB at 29 clinical sites in the United States. No BMI cutoff was used.

Baseline menstrual flow data were obtained over 2 to 3 screening cycles by collection of menstrual products and quantification of blood loss using alkaline hematin measurement. Patients with 2 cycles with a blood loss exceeding 80 mL had an IUD placement, with similar flow evaluations during the third and sixth postplacement cycles.

Treatment success was defined as a reduction in blood loss by more than 50% as compared with baseline (during screening) and measured blood loss of less than 80 mL. The enrolled population (n=105) included 28% nulliparous users, with 49% and 28% of participants having a BMI of 30 kg/m² or higher and higher than 35 kg/m², respectively.

Treatment highly successful in reducing blood loss

Participants in this trial had a 93% and a 98% reduction in blood loss at the third and sixth cycles of use, respectively. Additionally, during the sixth cycle of use, 19% of users had no bleeding. Treatment success occurred in about 80% of participants overall and occurred regardless of parity or BMI.

To assess a subjective measure of success, participants were asked to evaluate their menstrual bleeding and dysmenorrhea severity, acceptability, and overall impact on quality of life at 3 time points: during prior typical menses, cycle 3, and cycle 6. At cycle 6, all participants reported significantly improved acceptability of bleeding and uterine pain and, importantly, decreased overall menstrual interference with the ability to complete daily activities (TABLE 3).

IUD expulsion and replacement rates

Although bleeding greatly decreased in all participants, 13% (n=14) discontinued before cycle 6 due to expulsion or IUD-related symptoms, with the majority citing bleeding irregularities. Expulsion occurred in 9% (n=5) of users, with the majority (2/3) occurring in the first 3 months of use and more commonly in obese and/or parous users. About half of participants with expulsion had the IUD replaced during the study. ●

More US women are using IUDs than ever before. With more use comes the potential for complications and more requests related to non-contraceptive benefits. New information provides contemporary insight into rare IUD complications and the use of hormonal IUDs for treatment of HMB.

The first intrauterine device (IUD) to be approved in the United States, the Lippes Loop, became available in 1964. Sixty years later, more US women are using IUDs than ever before, and numbers are trending upward (FIGURE).^1,2 Over the past year, contemporary information has become available to further inform IUD management when pregnancy occurs with an IUD in situ, as well as counseling about device breakage. Additionally, new data help clinicians expand which patients can use a levonorgestrel (LNG) 52-mg IUD for heavy menstrual bleeding (HMB) treatment.

As the total absolute number of IUD users increases, so do the absolute numbers of rare outcomes, such as pregnancy among IUD users. These highly effective contraceptives have a failure rate within the first year after placement ranging from 0.1% for the LNG 52-mg IUD to 0.8% for the copper 380-mm² IUD.³ Although the possibility for extrauterine gestation is higher when pregnancy occurs while a patient is using an IUD as compared with most other contraceptive methods, most pregnancies that occur with an IUD in situ are intrauterine.⁴

The high contraceptive efficacy of IUDs make pregnancy with a retained IUD rare; therefore, it is difficult to perform a study with a large enough population to evaluate management of pregnancy complicated by an IUD in situ. Clinical management recommendations for these situations are 20 years old and are supported by limited data from case reports and series with fewer than 200 patients.^5,6

Intrauterine device breakage is another rare event that is poorly understood due to the low absolute number of cases. Information about breakage has similarly been limited to case reports and case series.^7,8 This past year, contemporary data were published to provide more insight into both intrauterine pregnancy with an IUD in situ and IUD breakage.

Beyond contraception, hormonal IUDs have become a popular and evidence-based treatment option for patients with HMB. The initial LNG 52-mg IUD (Mirena) regulatory approval studies for HMB treatment included data limited to parous patients and users with a body mass index (BMI) less than 35 kg/m².⁹ Since that time, no studies have explored these populations. Although current practice has commonly extended use to include patients with these characteristics, we have lacked outcome data. New phase 3 data on the LNG 52-mg IUD (Liletta) included a broader range of participants and provide evidence to support this practice.

Removing retained copper 380-mm² IUDs improves pregnancy outcomes

Panchal VR, Rau AR, Mandelbaum RS, et al. Pregnancy with retained intrauterine device: national-level assessment of characteristics and outcomes. Am J Obstet Gynecol MFM. 2023;5:101056. doi:10.1016/j.ajogmf.2023.101056

Karakuş SS, Karakuş R, Akalın EE, et al. Pregnancy outcomes with a copper 380 mm2 intrauterine device in place: a retrospective cohort study in Turkey, 2011-2021. Contraception. 2023;125:110090. doi:10.1016/j.contraception.2023.110090
 

To update our understanding of outcomes of pregnancy with an IUD in situ, Panchal and colleagues performed a cross-sectional study using the Healthcare Cost and Utilization Project’s National Inpatient Sample. This data set represents 85% of US hospital discharges. The population investigated included hospital deliveries from 2016 to 2020 with an ICD-10 (International Classification of Diseases, Tenth Revision) code of retained IUD. Those without the code were assigned to the comparison non-retained IUD group.

The primary outcome studied was the incidence rate of retained IUD, patient and pregnancy characteristics, and delivery outcomes including but not limited to gestational age at delivery, placental abnormalities, intrauterine fetal demise (IUFD), preterm premature rupture of membranes (PPROM), cesarean delivery, postpartum hemorrhage, and hysterectomy.

Outcomes were worse with retained IUD, regardless of IUD removal status

The authors found that an IUD in situ was reported in 1 out of 8,307 pregnancies and was associated with PPROM, fetal malpresentation, IUFD, placental abnormalities including abruption, accreta spectrum, retained placenta, and need for manual removal (TABLE 1). About three-quarters (76.3%) of patients had a term delivery (≥37 weeks).

Retained IUD was associated with previable loss, defined as less than 22 weeks’ gestation (adjusted odds ratio [aOR], 5.49; 95% confidence interval [CI], 3.30–9.15) and periviable delivery, defined as 22 to 25 weeks’ gestation (aOR, 2.81; 95% CI, 1.63–4.85). Retained IUD was not associated with preterm delivery beyond 26 weeks’ gestation, cesarean delivery, postpartum hemorrhage, or hysterectomy.

Important limitations of this study are the lack of information on IUD type (copper vs hormonal) and the timing of removal or attempted removal in relation to measured pregnancy outcomes.

Continue to: Removal of copper IUD improves, but does not eliminate, poor pregnancy outcomes...

Karakus and colleagues conducted a retrospective cohort study of 233 patients in Turkey with pregnancies that occurred during copper 380-mm² IUD use from 2011 to 2021. The authors reported that, at the time of first contact with the health system and diagnosis of retained IUD, 18.9% of the pregnancies were ectopic, 13.2% were first trimester losses, and 67.5% were ongoing pregnancies.

The authors assessed outcomes in patients with ongoing pregnancies based on whether or not the IUD was removed or retained. Outcomes included gestational age at delivery and adverse pregnancy outcomes, assessed as a composite of preterm delivery, PPROM, chorioamnionitis, placental abruption, and postpartum hemorrhage.

Of those with ongoing pregnancies, 13.3% chose to have an abortion, leaving 137 (86.7%) with continuing pregnancy. The IUD was able to be removed in 39.4% of the sample, with an average gestational age of 7 weeks at the time of removal.

Compared with those with a retained IUD, patients in the removal group had a lower rate of pregnancy loss (33.3% vs 61.4%; P<.001) and a lower rate of the composite adverse pregnancy outcomes (53.1% vs 27.8%; P=.03). TABLE 2 shows the approximate rate of ongoing pregnancy by gestational age in patients with retained and removed copper 380-mm² IUDs. Notably, the largest change occurred periviably, with the proportion of patients with an ongoing pregnancy after 26 weeks reducing to about half for patients with a retained IUD as compared with patients with a removed IUD; this proportion of ongoing pregnancies held through the remainder of gestation.

Do national data reveal more breakage reports for copper 380-mm² or LNG IUDs?

Latack KR, Nguyen BT. Trends in copper versus hormonal intrauterine device breakage reporting within the United States’ Food and Drug Administration Adverse Event Reporting System. Contraception. 2023;118:109909. doi:10.1016/j.contraception.2022.10.011

Latack and Nguyen reviewed postmarket surveillance data of IUD adverse events in the US Food and Drug Administration’s (FDA) Adverse Event Reporting System (FAERS) from 1998 to 2022. The FAERS is a voluntary, or passive, reporting system.

Study findings

Of the approximately 170,000 IUD-related adverse events reported to the agency during the 24-year timeframe, 25.4% were for copper IUDs and 74.6% were for hormonal IUDs. Slightly more than 4,000 reports were specific for device breakage, which the authors grouped into copper (copper 380-mm²)and hormonal (LNG 52 mg, 19.5 mg, and 13.5 mg) IUDs.

The copper 380-mm² IUD was 6.19 times more likely to have a breakage report than hormonal IUDs (9.6% vs 1.7%; 95% CI, 5.87–6.53).

Continue to: Data support the LNG 52-mg IUD for HMB in nulliparous and obese patients...

Data support the LNG 52-mg IUD for HMB in nulliparous and obese patients

Creinin MD, Barnhart KT, Gawron LM, et al. Heavy menstrual bleeding treatment with a levonorgestrel 52-mg intrauterine device. Obstet Gynecol. 2023;141:971-978. doi:10.1097AOG.0000000000005137

Creinin and colleagues conducted a study for US regulatory product approval of the LNG 52-mg IUD (Liletta) for HMB. This multicenter phase 3 open-label clinical trial recruited nonpregnant participants aged 18 to 50 years with HMB at 29 clinical sites in the United States. No BMI cutoff was used.

Baseline menstrual flow data were obtained over 2 to 3 screening cycles by collection of menstrual products and quantification of blood loss using alkaline hematin measurement. Patients with 2 cycles with a blood loss exceeding 80 mL had an IUD placement, with similar flow evaluations during the third and sixth postplacement cycles.

Treatment success was defined as a reduction in blood loss by more than 50% as compared with baseline (during screening) and measured blood loss of less than 80 mL. The enrolled population (n=105) included 28% nulliparous users, with 49% and 28% of participants having a BMI of 30 kg/m² or higher and higher than 35 kg/m², respectively.

Treatment highly successful in reducing blood loss

Participants in this trial had a 93% and a 98% reduction in blood loss at the third and sixth cycles of use, respectively. Additionally, during the sixth cycle of use, 19% of users had no bleeding. Treatment success occurred in about 80% of participants overall and occurred regardless of parity or BMI.

To assess a subjective measure of success, participants were asked to evaluate their menstrual bleeding and dysmenorrhea severity, acceptability, and overall impact on quality of life at 3 time points: during prior typical menses, cycle 3, and cycle 6. At cycle 6, all participants reported significantly improved acceptability of bleeding and uterine pain and, importantly, decreased overall menstrual interference with the ability to complete daily activities (TABLE 3).

IUD expulsion and replacement rates

Although bleeding greatly decreased in all participants, 13% (n=14) discontinued before cycle 6 due to expulsion or IUD-related symptoms, with the majority citing bleeding irregularities. Expulsion occurred in 9% (n=5) of users, with the majority (2/3) occurring in the first 3 months of use and more commonly in obese and/or parous users. About half of participants with expulsion had the IUD replaced during the study. ●

More US women are using IUDs than ever before. With more use comes the potential for complications and more requests related to non-contraceptive benefits. New information provides contemporary insight into rare IUD complications and the use of hormonal IUDs for treatment of HMB.

The first intrauterine device (IUD) to be approved in the United States, the Lippes Loop, became available in 1964. Sixty years later, more US women are using IUDs than ever before, and numbers are trending upward (FIGURE).^1,2 Over the past year, contemporary information has become available to further inform IUD management when pregnancy occurs with an IUD in situ, as well as counseling about device breakage. Additionally, new data help clinicians expand which patients can use a levonorgestrel (LNG) 52-mg IUD for heavy menstrual bleeding (HMB) treatment.

As the total absolute number of IUD users increases, so do the absolute numbers of rare outcomes, such as pregnancy among IUD users. These highly effective contraceptives have a failure rate within the first year after placement ranging from 0.1% for the LNG 52-mg IUD to 0.8% for the copper 380-mm² IUD.³ Although the possibility for extrauterine gestation is higher when pregnancy occurs while a patient is using an IUD as compared with most other contraceptive methods, most pregnancies that occur with an IUD in situ are intrauterine.⁴

The high contraceptive efficacy of IUDs make pregnancy with a retained IUD rare; therefore, it is difficult to perform a study with a large enough population to evaluate management of pregnancy complicated by an IUD in situ. Clinical management recommendations for these situations are 20 years old and are supported by limited data from case reports and series with fewer than 200 patients.^5,6

Intrauterine device breakage is another rare event that is poorly understood due to the low absolute number of cases. Information about breakage has similarly been limited to case reports and case series.^7,8 This past year, contemporary data were published to provide more insight into both intrauterine pregnancy with an IUD in situ and IUD breakage.

Beyond contraception, hormonal IUDs have become a popular and evidence-based treatment option for patients with HMB. The initial LNG 52-mg IUD (Mirena) regulatory approval studies for HMB treatment included data limited to parous patients and users with a body mass index (BMI) less than 35 kg/m².⁹ Since that time, no studies have explored these populations. Although current practice has commonly extended use to include patients with these characteristics, we have lacked outcome data. New phase 3 data on the LNG 52-mg IUD (Liletta) included a broader range of participants and provide evidence to support this practice.

Removing retained copper 380-mm² IUDs improves pregnancy outcomes

Panchal VR, Rau AR, Mandelbaum RS, et al. Pregnancy with retained intrauterine device: national-level assessment of characteristics and outcomes. Am J Obstet Gynecol MFM. 2023;5:101056. doi:10.1016/j.ajogmf.2023.101056

Karakuş SS, Karakuş R, Akalın EE, et al. Pregnancy outcomes with a copper 380 mm2 intrauterine device in place: a retrospective cohort study in Turkey, 2011-2021. Contraception. 2023;125:110090. doi:10.1016/j.contraception.2023.110090
 

To update our understanding of outcomes of pregnancy with an IUD in situ, Panchal and colleagues performed a cross-sectional study using the Healthcare Cost and Utilization Project’s National Inpatient Sample. This data set represents 85% of US hospital discharges. The population investigated included hospital deliveries from 2016 to 2020 with an ICD-10 (International Classification of Diseases, Tenth Revision) code of retained IUD. Those without the code were assigned to the comparison non-retained IUD group.

The primary outcome studied was the incidence rate of retained IUD, patient and pregnancy characteristics, and delivery outcomes including but not limited to gestational age at delivery, placental abnormalities, intrauterine fetal demise (IUFD), preterm premature rupture of membranes (PPROM), cesarean delivery, postpartum hemorrhage, and hysterectomy.

Outcomes were worse with retained IUD, regardless of IUD removal status

The authors found that an IUD in situ was reported in 1 out of 8,307 pregnancies and was associated with PPROM, fetal malpresentation, IUFD, placental abnormalities including abruption, accreta spectrum, retained placenta, and need for manual removal (TABLE 1). About three-quarters (76.3%) of patients had a term delivery (≥37 weeks).

Retained IUD was associated with previable loss, defined as less than 22 weeks’ gestation (adjusted odds ratio [aOR], 5.49; 95% confidence interval [CI], 3.30–9.15) and periviable delivery, defined as 22 to 25 weeks’ gestation (aOR, 2.81; 95% CI, 1.63–4.85). Retained IUD was not associated with preterm delivery beyond 26 weeks’ gestation, cesarean delivery, postpartum hemorrhage, or hysterectomy.

Important limitations of this study are the lack of information on IUD type (copper vs hormonal) and the timing of removal or attempted removal in relation to measured pregnancy outcomes.

Continue to: Removal of copper IUD improves, but does not eliminate, poor pregnancy outcomes...

Karakus and colleagues conducted a retrospective cohort study of 233 patients in Turkey with pregnancies that occurred during copper 380-mm² IUD use from 2011 to 2021. The authors reported that, at the time of first contact with the health system and diagnosis of retained IUD, 18.9% of the pregnancies were ectopic, 13.2% were first trimester losses, and 67.5% were ongoing pregnancies.

The authors assessed outcomes in patients with ongoing pregnancies based on whether or not the IUD was removed or retained. Outcomes included gestational age at delivery and adverse pregnancy outcomes, assessed as a composite of preterm delivery, PPROM, chorioamnionitis, placental abruption, and postpartum hemorrhage.

Of those with ongoing pregnancies, 13.3% chose to have an abortion, leaving 137 (86.7%) with continuing pregnancy. The IUD was able to be removed in 39.4% of the sample, with an average gestational age of 7 weeks at the time of removal.

Compared with those with a retained IUD, patients in the removal group had a lower rate of pregnancy loss (33.3% vs 61.4%; P<.001) and a lower rate of the composite adverse pregnancy outcomes (53.1% vs 27.8%; P=.03). TABLE 2 shows the approximate rate of ongoing pregnancy by gestational age in patients with retained and removed copper 380-mm² IUDs. Notably, the largest change occurred periviably, with the proportion of patients with an ongoing pregnancy after 26 weeks reducing to about half for patients with a retained IUD as compared with patients with a removed IUD; this proportion of ongoing pregnancies held through the remainder of gestation.

Do national data reveal more breakage reports for copper 380-mm² or LNG IUDs?

Latack KR, Nguyen BT. Trends in copper versus hormonal intrauterine device breakage reporting within the United States’ Food and Drug Administration Adverse Event Reporting System. Contraception. 2023;118:109909. doi:10.1016/j.contraception.2022.10.011

Latack and Nguyen reviewed postmarket surveillance data of IUD adverse events in the US Food and Drug Administration’s (FDA) Adverse Event Reporting System (FAERS) from 1998 to 2022. The FAERS is a voluntary, or passive, reporting system.

Study findings

Of the approximately 170,000 IUD-related adverse events reported to the agency during the 24-year timeframe, 25.4% were for copper IUDs and 74.6% were for hormonal IUDs. Slightly more than 4,000 reports were specific for device breakage, which the authors grouped into copper (copper 380-mm²)and hormonal (LNG 52 mg, 19.5 mg, and 13.5 mg) IUDs.

The copper 380-mm² IUD was 6.19 times more likely to have a breakage report than hormonal IUDs (9.6% vs 1.7%; 95% CI, 5.87–6.53).

Continue to: Data support the LNG 52-mg IUD for HMB in nulliparous and obese patients...

Data support the LNG 52-mg IUD for HMB in nulliparous and obese patients

Creinin MD, Barnhart KT, Gawron LM, et al. Heavy menstrual bleeding treatment with a levonorgestrel 52-mg intrauterine device. Obstet Gynecol. 2023;141:971-978. doi:10.1097AOG.0000000000005137

Creinin and colleagues conducted a study for US regulatory product approval of the LNG 52-mg IUD (Liletta) for HMB. This multicenter phase 3 open-label clinical trial recruited nonpregnant participants aged 18 to 50 years with HMB at 29 clinical sites in the United States. No BMI cutoff was used.

Baseline menstrual flow data were obtained over 2 to 3 screening cycles by collection of menstrual products and quantification of blood loss using alkaline hematin measurement. Patients with 2 cycles with a blood loss exceeding 80 mL had an IUD placement, with similar flow evaluations during the third and sixth postplacement cycles.

Treatment success was defined as a reduction in blood loss by more than 50% as compared with baseline (during screening) and measured blood loss of less than 80 mL. The enrolled population (n=105) included 28% nulliparous users, with 49% and 28% of participants having a BMI of 30 kg/m² or higher and higher than 35 kg/m², respectively.

Treatment highly successful in reducing blood loss

Participants in this trial had a 93% and a 98% reduction in blood loss at the third and sixth cycles of use, respectively. Additionally, during the sixth cycle of use, 19% of users had no bleeding. Treatment success occurred in about 80% of participants overall and occurred regardless of parity or BMI.

To assess a subjective measure of success, participants were asked to evaluate their menstrual bleeding and dysmenorrhea severity, acceptability, and overall impact on quality of life at 3 time points: during prior typical menses, cycle 3, and cycle 6. At cycle 6, all participants reported significantly improved acceptability of bleeding and uterine pain and, importantly, decreased overall menstrual interference with the ability to complete daily activities (TABLE 3).

IUD expulsion and replacement rates

Although bleeding greatly decreased in all participants, 13% (n=14) discontinued before cycle 6 due to expulsion or IUD-related symptoms, with the majority citing bleeding irregularities. Expulsion occurred in 9% (n=5) of users, with the majority (2/3) occurring in the first 3 months of use and more commonly in obese and/or parous users. About half of participants with expulsion had the IUD replaced during the study. ●

There has been increasing awareness of a need for creating a more patient-centered experience with outpatient gynecology; however, very little data exist about what interventions are important to patients. Given social media’s ease of use and ability for widespread access to a diverse group of users, it has the potential to be a powerful tool for qualitative research questions without the difficulties of cost, transportation, transcription, etc. required of a focus group. Crowdsourced public opinion also has the advantage of producing qualitative metrics in the form of “likes” that, at scale, can provide a reliable measure of public support or engagement for a particular concept.¹ Particularly for topics that are controversial or novel, X (formerly Twitter, and referred to as Twitter intermittently throughout this article based on the time the study was conducted), with 300 million monthly users,² has become a popular tool for general and health care ̶ focused content and sentiment analysis.^3,4 This study presents a qualitative analysis of themes from a crowdsourced request on Twitter to design the ideal outpatient gynecologic experience that subsequently went “viral”.^5,6

Why the need for our research question on patient-centered gyn care

While the body of literature on patient-centered health care has grown rapidly in recent years, a patient-centered outpatient gynecology experience has not yet been described in the medical literature.

Patient-centered office design, driven by cultural sensitivity, has been shown in other studies to be both appreciated by established patients and a viable business strategy to attract new patients.⁷ Topics such as pain control, trauma-informed care in gynecologyclinics,⁸ and diverse representation in patient materials and illustrations⁹ have been popular topics in medicine and in the lay press. Our primary aim in our research was to utilize feedback from the question posed to quantify and rank patient-centered interventions in a gynecology office. These themes and others that emerged in our analysis were used to suggest best-practice guidelines for the outpatient gynecology experience (see “Checklist for ObGyn outpatient experience improvement").

What we asked social media users. The survey query to social media users, “I have the opportunity to design my office from scratch. I’m asking women: How would you design/optimize a visit to the gynecologist’s office?” was crowd-sourced via Twitter on December 5, 2021.⁵ Given a robust response to the query, it provided an opportunity for a qualitative research study exploring social media users’ perspectives on optimizing outpatient gynecologic care, although the original question was not planned for research utilization.

What we found

By December 27, 2021, the original tweet had earned 9,411 likes; 2,143 retweets; and 3,400 replies. Of this group, we analyzed 131 tweets, all of which had 100 or greater likes on Twitter at the time of the review. The majority of analyzed tweets earned between 100 ̶ 500 likes (75/131; 57.3%), while 22.9% (30/131) had 501 ̶ 1,000 likes, 11.5% (15/131) had >2,000 likes, and 8.4% (11/131) had 1,001 ̶ 1,999 likes.

Identified themes within the tweets analyzed included: medical education, comfort improvements, continuity of care, disability accommodations/accessibility, economic accessibility, nonbinary/transgender care and inclusivity, general layout/floorplan, hospitality, aid for intimate partner violence, childcare accessibility, multi-disciplinary care access, pain/anxiety control, sensitivity toward pregnancy loss/fertility issues, privacy issues, professionalism, representation (subdivided into race, LGBTQIA+, age, and weight/body type), trauma-informed care, and acknowledgement of voluntary nulliparity/support for reproductive choices (TABLE 1). TABLE 2 lists examples of popular tweets by selected themes.

Frequent themes. The most frequently occurring themes within the 131 analyzed tweets (FIGURE 1) were:

• hospitality (77 occurrences)
• comfort improvements (75 occurrences)
• general layout/floorplan (75 occurrences)
• pain/anxiety control (55 occurrences)
• representation (53 occurrences).

Popular themes. Defined as those with more than 1,000 likes at the time of analysis (FIGURE 2), the most popular themes included:

• privacy issues (48.5% of related tweets with >1,000 likes)
• voluntary nulliparity (37.0% of related tweets with >1,000 likes)
• general layout/floorplan (33.4% of related tweets with >1,000 likes)
• representation (32.1% of related tweets with >1,000 likes)
• hospitality (31.3% of related tweets with >1,000 likes).

A sub-analysis of themes related to specific types of representation—race, LGBTQIA+, age, and weight/body type was performed. Tweets related to diverse weight/body type representation occurred most frequently (19 code occurrences; FIGURE 3). Similarly, tweets related to the representation of diverse races and the LGBTQIA+ community each comprised 26% of the total representation-based tweets. In terms of popularity as described above, 51.4% of tweets describing racial representation earned >1,000 likes (FIGURE 4).

Tweet demographics. Seven (7/131; 5.3%) of the tweet authors were verified Twitter users and 35 (35/131; 26.7%) authors reported working in the health care field within their Twitter profile description.

Continue to: Implementing our feedback can enhance patient experience and care...

Our study provides a unique view of the patient perspective through analyzed crowdsourced public opinion via Twitter. To our knowledge, an optimized patient-centered outpatient gynecology experience has not previously been described in the medical literature. Optimizing the found domains of hospitality, comfort measures, pain and anxiety control, privacy, and diverse representationin the outpatient gynecologic experience within the outpatient care setting may ultimately result in improved patient satisfaction, patient well-being, and adherence to care through maximizing patient-centered care. We created a checklist of suggestions, including offering analgesics during office-based procedures and tailoring the floorplan to maximize privacy (FIGURE 5), for improving the outpatient gynecology experience based on our findings.

Prior data on patient satisfaction and outcomes

Improving patient satisfaction with health care is a priority for both clinicians and hospital systems. Prior studies have revealed only variable associations between patient satisfaction, safety, and clinical outcomes. One study involving the analysis of clinical and operational data from 171 hospitals found that hospital size, surgical volume, and low mortality rates were associated with higher patient satisfaction, while favorable surgical outcomes did not consistently correlate with higher Hospital Consumer Assessment of Healthcare Provers and Systems (HCAHPS) scores.¹⁰ Smaller, lower-volume hospitals earned higher satisfaction scores related to cleanliness, quietness, and receiving help measures.¹⁰ It has also been shown that the strongest predictors of patient satisfaction with the hospital childbirth experience included items related to staff communication, compassion, empathy, and respect.¹¹ These data suggest that patient satisfaction is likely more significantly impacted by factors other than patient safety and effectiveness, and this was supported by the findings of our analysis. The growing body of literature associating a sense of psychological and physical safety within the health care system and improved patient outcomes and experience suggests that the data gathered from public commentary such as that presented here is extremely important for galvanizing change within the US health care system.

In one systematic review, the relationship between patient-centered care and clinical outcomes was mixed, although generally the association was positive.¹² Additionally, patient-centered care was often associated with increased patient satisfaction and well-being. Some studies suggest that patient well-being and satisfaction also may be associated with improved adherence and self-management behaviors.^12,13 Overall, optimizing patient-centered care may lead to improved patient satisfaction and potentially improved clinical outcomes.

Additionally, increasing diverse representation in patient materials and illustrations may help to improve the patient experience. Louie and colleagues found that dark skin tones were represented in only 4.5% of 4,146 images from anatomy texts analyzed in 2018.¹⁴ Similarly, a photogrammetric analysis of medical images utilized in New England Journal of Medicine found that only 18% of images depicted non-white skin.¹⁵ More recent efforts to create a royalty-free digital gallery of images reflecting bodies with diverse skin tones, body shapes, body hair, and age as well as transgender and nonbinary people have been discussed in the lay press.⁹ Based on our findings, social media users value and are actively seeking diversity in representation and imagery during their outpatient gynecology experience.

Opportunities for future study

Our research utilized social media as a diverse and accessible source of information; however, there are significant opportunities to refine the methodologic approach to answering the fundamental question of creating the patient-centered gynecologic experience. This type of study has not yet been conducted; however, the richness of the information from this current analysis could be informative to survey creation. Future research on this subject outside of social media could bolster the generalizability of our conclusions and the ability to report on qualitative findings in the setting of known patient demographics.

Social media remains a powerful tool as evidenced by this study, and continued use and observation of trending themes among patients is essential. The influence of social media will remain important for answering questions in gynecology and beyond.

Our work is strengthened by social media’s low threshold for use and the ability for widespread access to a diverse group of users. Additionally, social media allows for many responses to be collected in a timely manner, giving strength to the abstracted themes. The constant production of data by X users and their accessibility provide the opportunity for greater geographic coverage in those surveyed.⁴ Crowdsourced public opinion also has the advantage of producing qualitative metrics in the form of likes and retweets that may provide a reliable measure of public support or engagement.¹

Future studies should examine ways to implement the suggested improvements to the office setting in a cost-effective manner and follow both subjective patient-reported outcomes as well as objective data after implementation, as these changes may have implications for much broader public health crises, such as maternal morbidity and mortality.

Study limitations. Our study is limited by the inherent biases and confounders associated with utilizing data derived from social media. Specifically, not all patients who seek outpatient gynecologic care utilize social media and/or X; using a “like” as a surrogate for endorsement of an idea by an identified party limits the generalizability of the data.

The initial Twitter query specified, “I’m asking women”, which may have altered the intended study population, influenced the analysis, and affected the representativeness of the sample through utilizing non ̶inclusive language. While non-binary/transgender care and inclusivity emerged as a theme discussed with the tweets, it is unclear if this represents an independent theme or rather a reaction to the non–inclusive language within the original tweet. ●

There has been increasing awareness of a need for creating a more patient-centered experience with outpatient gynecology; however, very little data exist about what interventions are important to patients. Given social media’s ease of use and ability for widespread access to a diverse group of users, it has the potential to be a powerful tool for qualitative research questions without the difficulties of cost, transportation, transcription, etc. required of a focus group. Crowdsourced public opinion also has the advantage of producing qualitative metrics in the form of “likes” that, at scale, can provide a reliable measure of public support or engagement for a particular concept.¹ Particularly for topics that are controversial or novel, X (formerly Twitter, and referred to as Twitter intermittently throughout this article based on the time the study was conducted), with 300 million monthly users,² has become a popular tool for general and health care ̶ focused content and sentiment analysis.^3,4 This study presents a qualitative analysis of themes from a crowdsourced request on Twitter to design the ideal outpatient gynecologic experience that subsequently went “viral”.^5,6

Why the need for our research question on patient-centered gyn care

While the body of literature on patient-centered health care has grown rapidly in recent years, a patient-centered outpatient gynecology experience has not yet been described in the medical literature.

Patient-centered office design, driven by cultural sensitivity, has been shown in other studies to be both appreciated by established patients and a viable business strategy to attract new patients.⁷ Topics such as pain control, trauma-informed care in gynecologyclinics,⁸ and diverse representation in patient materials and illustrations⁹ have been popular topics in medicine and in the lay press. Our primary aim in our research was to utilize feedback from the question posed to quantify and rank patient-centered interventions in a gynecology office. These themes and others that emerged in our analysis were used to suggest best-practice guidelines for the outpatient gynecology experience (see “Checklist for ObGyn outpatient experience improvement").

What we asked social media users. The survey query to social media users, “I have the opportunity to design my office from scratch. I’m asking women: How would you design/optimize a visit to the gynecologist’s office?” was crowd-sourced via Twitter on December 5, 2021.⁵ Given a robust response to the query, it provided an opportunity for a qualitative research study exploring social media users’ perspectives on optimizing outpatient gynecologic care, although the original question was not planned for research utilization.

What we found

By December 27, 2021, the original tweet had earned 9,411 likes; 2,143 retweets; and 3,400 replies. Of this group, we analyzed 131 tweets, all of which had 100 or greater likes on Twitter at the time of the review. The majority of analyzed tweets earned between 100 ̶ 500 likes (75/131; 57.3%), while 22.9% (30/131) had 501 ̶ 1,000 likes, 11.5% (15/131) had >2,000 likes, and 8.4% (11/131) had 1,001 ̶ 1,999 likes.

Identified themes within the tweets analyzed included: medical education, comfort improvements, continuity of care, disability accommodations/accessibility, economic accessibility, nonbinary/transgender care and inclusivity, general layout/floorplan, hospitality, aid for intimate partner violence, childcare accessibility, multi-disciplinary care access, pain/anxiety control, sensitivity toward pregnancy loss/fertility issues, privacy issues, professionalism, representation (subdivided into race, LGBTQIA+, age, and weight/body type), trauma-informed care, and acknowledgement of voluntary nulliparity/support for reproductive choices (TABLE 1). TABLE 2 lists examples of popular tweets by selected themes.

Frequent themes. The most frequently occurring themes within the 131 analyzed tweets (FIGURE 1) were:

• hospitality (77 occurrences)
• comfort improvements (75 occurrences)
• general layout/floorplan (75 occurrences)
• pain/anxiety control (55 occurrences)
• representation (53 occurrences).

Popular themes. Defined as those with more than 1,000 likes at the time of analysis (FIGURE 2), the most popular themes included:

• privacy issues (48.5% of related tweets with >1,000 likes)
• voluntary nulliparity (37.0% of related tweets with >1,000 likes)
• general layout/floorplan (33.4% of related tweets with >1,000 likes)
• representation (32.1% of related tweets with >1,000 likes)
• hospitality (31.3% of related tweets with >1,000 likes).

A sub-analysis of themes related to specific types of representation—race, LGBTQIA+, age, and weight/body type was performed. Tweets related to diverse weight/body type representation occurred most frequently (19 code occurrences; FIGURE 3). Similarly, tweets related to the representation of diverse races and the LGBTQIA+ community each comprised 26% of the total representation-based tweets. In terms of popularity as described above, 51.4% of tweets describing racial representation earned >1,000 likes (FIGURE 4).

Tweet demographics. Seven (7/131; 5.3%) of the tweet authors were verified Twitter users and 35 (35/131; 26.7%) authors reported working in the health care field within their Twitter profile description.

Continue to: Implementing our feedback can enhance patient experience and care...

Our study provides a unique view of the patient perspective through analyzed crowdsourced public opinion via Twitter. To our knowledge, an optimized patient-centered outpatient gynecology experience has not previously been described in the medical literature. Optimizing the found domains of hospitality, comfort measures, pain and anxiety control, privacy, and diverse representationin the outpatient gynecologic experience within the outpatient care setting may ultimately result in improved patient satisfaction, patient well-being, and adherence to care through maximizing patient-centered care. We created a checklist of suggestions, including offering analgesics during office-based procedures and tailoring the floorplan to maximize privacy (FIGURE 5), for improving the outpatient gynecology experience based on our findings.

Prior data on patient satisfaction and outcomes

Improving patient satisfaction with health care is a priority for both clinicians and hospital systems. Prior studies have revealed only variable associations between patient satisfaction, safety, and clinical outcomes. One study involving the analysis of clinical and operational data from 171 hospitals found that hospital size, surgical volume, and low mortality rates were associated with higher patient satisfaction, while favorable surgical outcomes did not consistently correlate with higher Hospital Consumer Assessment of Healthcare Provers and Systems (HCAHPS) scores.¹⁰ Smaller, lower-volume hospitals earned higher satisfaction scores related to cleanliness, quietness, and receiving help measures.¹⁰ It has also been shown that the strongest predictors of patient satisfaction with the hospital childbirth experience included items related to staff communication, compassion, empathy, and respect.¹¹ These data suggest that patient satisfaction is likely more significantly impacted by factors other than patient safety and effectiveness, and this was supported by the findings of our analysis. The growing body of literature associating a sense of psychological and physical safety within the health care system and improved patient outcomes and experience suggests that the data gathered from public commentary such as that presented here is extremely important for galvanizing change within the US health care system.

In one systematic review, the relationship between patient-centered care and clinical outcomes was mixed, although generally the association was positive.¹² Additionally, patient-centered care was often associated with increased patient satisfaction and well-being. Some studies suggest that patient well-being and satisfaction also may be associated with improved adherence and self-management behaviors.^12,13 Overall, optimizing patient-centered care may lead to improved patient satisfaction and potentially improved clinical outcomes.

Additionally, increasing diverse representation in patient materials and illustrations may help to improve the patient experience. Louie and colleagues found that dark skin tones were represented in only 4.5% of 4,146 images from anatomy texts analyzed in 2018.¹⁴ Similarly, a photogrammetric analysis of medical images utilized in New England Journal of Medicine found that only 18% of images depicted non-white skin.¹⁵ More recent efforts to create a royalty-free digital gallery of images reflecting bodies with diverse skin tones, body shapes, body hair, and age as well as transgender and nonbinary people have been discussed in the lay press.⁹ Based on our findings, social media users value and are actively seeking diversity in representation and imagery during their outpatient gynecology experience.

Opportunities for future study

Our research utilized social media as a diverse and accessible source of information; however, there are significant opportunities to refine the methodologic approach to answering the fundamental question of creating the patient-centered gynecologic experience. This type of study has not yet been conducted; however, the richness of the information from this current analysis could be informative to survey creation. Future research on this subject outside of social media could bolster the generalizability of our conclusions and the ability to report on qualitative findings in the setting of known patient demographics.

Social media remains a powerful tool as evidenced by this study, and continued use and observation of trending themes among patients is essential. The influence of social media will remain important for answering questions in gynecology and beyond.

Our work is strengthened by social media’s low threshold for use and the ability for widespread access to a diverse group of users. Additionally, social media allows for many responses to be collected in a timely manner, giving strength to the abstracted themes. The constant production of data by X users and their accessibility provide the opportunity for greater geographic coverage in those surveyed.⁴ Crowdsourced public opinion also has the advantage of producing qualitative metrics in the form of likes and retweets that may provide a reliable measure of public support or engagement.¹

Future studies should examine ways to implement the suggested improvements to the office setting in a cost-effective manner and follow both subjective patient-reported outcomes as well as objective data after implementation, as these changes may have implications for much broader public health crises, such as maternal morbidity and mortality.

Study limitations. Our study is limited by the inherent biases and confounders associated with utilizing data derived from social media. Specifically, not all patients who seek outpatient gynecologic care utilize social media and/or X; using a “like” as a surrogate for endorsement of an idea by an identified party limits the generalizability of the data.

The initial Twitter query specified, “I’m asking women”, which may have altered the intended study population, influenced the analysis, and affected the representativeness of the sample through utilizing non ̶inclusive language. While non-binary/transgender care and inclusivity emerged as a theme discussed with the tweets, it is unclear if this represents an independent theme or rather a reaction to the non–inclusive language within the original tweet. ●

There has been increasing awareness of a need for creating a more patient-centered experience with outpatient gynecology; however, very little data exist about what interventions are important to patients. Given social media’s ease of use and ability for widespread access to a diverse group of users, it has the potential to be a powerful tool for qualitative research questions without the difficulties of cost, transportation, transcription, etc. required of a focus group. Crowdsourced public opinion also has the advantage of producing qualitative metrics in the form of “likes” that, at scale, can provide a reliable measure of public support or engagement for a particular concept.¹ Particularly for topics that are controversial or novel, X (formerly Twitter, and referred to as Twitter intermittently throughout this article based on the time the study was conducted), with 300 million monthly users,² has become a popular tool for general and health care ̶ focused content and sentiment analysis.^3,4 This study presents a qualitative analysis of themes from a crowdsourced request on Twitter to design the ideal outpatient gynecologic experience that subsequently went “viral”.^5,6

Why the need for our research question on patient-centered gyn care

While the body of literature on patient-centered health care has grown rapidly in recent years, a patient-centered outpatient gynecology experience has not yet been described in the medical literature.

Patient-centered office design, driven by cultural sensitivity, has been shown in other studies to be both appreciated by established patients and a viable business strategy to attract new patients.⁷ Topics such as pain control, trauma-informed care in gynecologyclinics,⁸ and diverse representation in patient materials and illustrations⁹ have been popular topics in medicine and in the lay press. Our primary aim in our research was to utilize feedback from the question posed to quantify and rank patient-centered interventions in a gynecology office. These themes and others that emerged in our analysis were used to suggest best-practice guidelines for the outpatient gynecology experience (see “Checklist for ObGyn outpatient experience improvement").

What we asked social media users. The survey query to social media users, “I have the opportunity to design my office from scratch. I’m asking women: How would you design/optimize a visit to the gynecologist’s office?” was crowd-sourced via Twitter on December 5, 2021.⁵ Given a robust response to the query, it provided an opportunity for a qualitative research study exploring social media users’ perspectives on optimizing outpatient gynecologic care, although the original question was not planned for research utilization.

What we found

By December 27, 2021, the original tweet had earned 9,411 likes; 2,143 retweets; and 3,400 replies. Of this group, we analyzed 131 tweets, all of which had 100 or greater likes on Twitter at the time of the review. The majority of analyzed tweets earned between 100 ̶ 500 likes (75/131; 57.3%), while 22.9% (30/131) had 501 ̶ 1,000 likes, 11.5% (15/131) had >2,000 likes, and 8.4% (11/131) had 1,001 ̶ 1,999 likes.

Identified themes within the tweets analyzed included: medical education, comfort improvements, continuity of care, disability accommodations/accessibility, economic accessibility, nonbinary/transgender care and inclusivity, general layout/floorplan, hospitality, aid for intimate partner violence, childcare accessibility, multi-disciplinary care access, pain/anxiety control, sensitivity toward pregnancy loss/fertility issues, privacy issues, professionalism, representation (subdivided into race, LGBTQIA+, age, and weight/body type), trauma-informed care, and acknowledgement of voluntary nulliparity/support for reproductive choices (TABLE 1). TABLE 2 lists examples of popular tweets by selected themes.

Frequent themes. The most frequently occurring themes within the 131 analyzed tweets (FIGURE 1) were:

• hospitality (77 occurrences)
• comfort improvements (75 occurrences)
• general layout/floorplan (75 occurrences)
• pain/anxiety control (55 occurrences)
• representation (53 occurrences).

Popular themes. Defined as those with more than 1,000 likes at the time of analysis (FIGURE 2), the most popular themes included:

• privacy issues (48.5% of related tweets with >1,000 likes)
• voluntary nulliparity (37.0% of related tweets with >1,000 likes)
• general layout/floorplan (33.4% of related tweets with >1,000 likes)
• representation (32.1% of related tweets with >1,000 likes)
• hospitality (31.3% of related tweets with >1,000 likes).

A sub-analysis of themes related to specific types of representation—race, LGBTQIA+, age, and weight/body type was performed. Tweets related to diverse weight/body type representation occurred most frequently (19 code occurrences; FIGURE 3). Similarly, tweets related to the representation of diverse races and the LGBTQIA+ community each comprised 26% of the total representation-based tweets. In terms of popularity as described above, 51.4% of tweets describing racial representation earned >1,000 likes (FIGURE 4).

Tweet demographics. Seven (7/131; 5.3%) of the tweet authors were verified Twitter users and 35 (35/131; 26.7%) authors reported working in the health care field within their Twitter profile description.

Continue to: Implementing our feedback can enhance patient experience and care...

Our study provides a unique view of the patient perspective through analyzed crowdsourced public opinion via Twitter. To our knowledge, an optimized patient-centered outpatient gynecology experience has not previously been described in the medical literature. Optimizing the found domains of hospitality, comfort measures, pain and anxiety control, privacy, and diverse representationin the outpatient gynecologic experience within the outpatient care setting may ultimately result in improved patient satisfaction, patient well-being, and adherence to care through maximizing patient-centered care. We created a checklist of suggestions, including offering analgesics during office-based procedures and tailoring the floorplan to maximize privacy (FIGURE 5), for improving the outpatient gynecology experience based on our findings.

Prior data on patient satisfaction and outcomes

Improving patient satisfaction with health care is a priority for both clinicians and hospital systems. Prior studies have revealed only variable associations between patient satisfaction, safety, and clinical outcomes. One study involving the analysis of clinical and operational data from 171 hospitals found that hospital size, surgical volume, and low mortality rates were associated with higher patient satisfaction, while favorable surgical outcomes did not consistently correlate with higher Hospital Consumer Assessment of Healthcare Provers and Systems (HCAHPS) scores.¹⁰ Smaller, lower-volume hospitals earned higher satisfaction scores related to cleanliness, quietness, and receiving help measures.¹⁰ It has also been shown that the strongest predictors of patient satisfaction with the hospital childbirth experience included items related to staff communication, compassion, empathy, and respect.¹¹ These data suggest that patient satisfaction is likely more significantly impacted by factors other than patient safety and effectiveness, and this was supported by the findings of our analysis. The growing body of literature associating a sense of psychological and physical safety within the health care system and improved patient outcomes and experience suggests that the data gathered from public commentary such as that presented here is extremely important for galvanizing change within the US health care system.

In one systematic review, the relationship between patient-centered care and clinical outcomes was mixed, although generally the association was positive.¹² Additionally, patient-centered care was often associated with increased patient satisfaction and well-being. Some studies suggest that patient well-being and satisfaction also may be associated with improved adherence and self-management behaviors.^12,13 Overall, optimizing patient-centered care may lead to improved patient satisfaction and potentially improved clinical outcomes.

Additionally, increasing diverse representation in patient materials and illustrations may help to improve the patient experience. Louie and colleagues found that dark skin tones were represented in only 4.5% of 4,146 images from anatomy texts analyzed in 2018.¹⁴ Similarly, a photogrammetric analysis of medical images utilized in New England Journal of Medicine found that only 18% of images depicted non-white skin.¹⁵ More recent efforts to create a royalty-free digital gallery of images reflecting bodies with diverse skin tones, body shapes, body hair, and age as well as transgender and nonbinary people have been discussed in the lay press.⁹ Based on our findings, social media users value and are actively seeking diversity in representation and imagery during their outpatient gynecology experience.

Opportunities for future study

Our research utilized social media as a diverse and accessible source of information; however, there are significant opportunities to refine the methodologic approach to answering the fundamental question of creating the patient-centered gynecologic experience. This type of study has not yet been conducted; however, the richness of the information from this current analysis could be informative to survey creation. Future research on this subject outside of social media could bolster the generalizability of our conclusions and the ability to report on qualitative findings in the setting of known patient demographics.

Social media remains a powerful tool as evidenced by this study, and continued use and observation of trending themes among patients is essential. The influence of social media will remain important for answering questions in gynecology and beyond.

Our work is strengthened by social media’s low threshold for use and the ability for widespread access to a diverse group of users. Additionally, social media allows for many responses to be collected in a timely manner, giving strength to the abstracted themes. The constant production of data by X users and their accessibility provide the opportunity for greater geographic coverage in those surveyed.⁴ Crowdsourced public opinion also has the advantage of producing qualitative metrics in the form of likes and retweets that may provide a reliable measure of public support or engagement.¹

Future studies should examine ways to implement the suggested improvements to the office setting in a cost-effective manner and follow both subjective patient-reported outcomes as well as objective data after implementation, as these changes may have implications for much broader public health crises, such as maternal morbidity and mortality.

Study limitations. Our study is limited by the inherent biases and confounders associated with utilizing data derived from social media. Specifically, not all patients who seek outpatient gynecologic care utilize social media and/or X; using a “like” as a surrogate for endorsement of an idea by an identified party limits the generalizability of the data.

The initial Twitter query specified, “I’m asking women”, which may have altered the intended study population, influenced the analysis, and affected the representativeness of the sample through utilizing non ̶inclusive language. While non-binary/transgender care and inclusivity emerged as a theme discussed with the tweets, it is unclear if this represents an independent theme or rather a reaction to the non–inclusive language within the original tweet. ●

Endometrial ablation continues to be performed in significant numbers in the United States, with an estimated 500,000 cases annually. Several nonresectoscopic endometrial ablation devices have been approved for use, and some are now discontinued. The newest endometrial ablation therapy to gain US Food and Drug Administration (FDA) approval and to have published outcomes is the Cerene cryotherapy ablation device (Channel Medsystems, Inc). The results of 36-month outcomes from the CLARITY study were published last year, and we have chosen to review these long-term data in addition to that of a second study in which investigators assessed the ability to access the endometrial cavity postcryoablation. We believe this is important because of concerns about the inability to access the endometrial cavity after ablation, as well as the potential for delay in the diagnosis of endometrial cancer. It is interesting that 2 publications simultaneously reviewed the incidence of endometrial cancer after endometrial ablation within the past 12 months, and we therefore present those findings as they provide valuable information.

Our second focus in this year’s Update is to provide additional information about the burgeoning data on gonadotropin-releasing hormone (GnRH) antagonists. We review evidence on linzagolix from the PRIMROSE 1 and PRIMROSE 2 trials and longer-term data on relugolix combination therapy for symptomatic uterine fibroids.

Three-year follow-up after endometrial cryoablation with the Cerene device found high patient satisfaction, low hysterectomy rates

Curlin HL, Cintron LC, Anderson TL. A prospective, multicenter, clinical trial evaluating the safety and effectiveness of the Cerene device to treat heavy menstrual bleeding. J Minim Invasive Gynecol. 2021;28;899-908.

Curlin HL, Anderson TL. Endometrial cryoablation for the treatment of heavy menstrual bleeding: 36-month outcomes from the CLARITY study. Int J Womens Health. 2022;14:1083-1092.
 

The 12-month data on the clinical safety and effectiveness of the Cerene cryoablation device were published in 2021 in the CLARITY trial.¹ The 36-month outcomes were published in 2022 and showed sustained clinical effects through month 36 with a low risk of adverse outcomes.² The interesting aspect of this trial is that although the amenorrhea rate was relatively low at 12 months (6.5%), it continued to remain relatively low compared with rates found with other devices, but the amenorrhea rate increased at 36 months (14.4%). This was the percentage of patients who reported, “I no longer get my period.”

Patient satisfaction was high

Despite a relatively low amenorrhea rate, study participants had a high satisfaction rate and a low 3-year hysterectomy rate. Eighty-five percent of the participants were satisfied or very satisfied, and the cumulative hysterectomy rate was low at 5%.

The overall reintervention rate was 8.7%. Six patients were treated with medications, 2 patients underwent repeat endometrial ablation, 1 received a levonorgestrel-releasing intrauterine device, and 12 underwent hysterectomy.

At 36 months, 201 of the original 242 participants were available for assessment. Unfortunately, 5 pregnancies were reported through the 6-month posttreatment period, which emphasizes the importance of having reliable contraception. However, there were no reports of hematometra or postablation tubal sterilization syndrome (PATSS).

Effect on bleeding was long term

The main finding of the CLARITY study is that the Cerene cryoablation device appears to have a relatively stable effect on bleedingfor the first 3 years after therapy, with minimal risk of hematometra and PATSS. What we find interesting is that despite Cerene cryoablation having one of the lowest amenorrhea rates, it not only had a satisfaction rate in line with that of other devices but also had a low hysterectomy rate—only 5%—at 3 years.

The study authors pointed out that there is a lack of scarring within the endometrial cavity with the Cerene device. Some may find less endometrial scarring worth a low amenorrhea rate in the context of a favorable satisfaction rate. This begs the question, how well can the endometrial cavity be assessed? For answers, keep reading.

Can the endometrial cavity be reliably accessed after Cerene cryoablation?

Endometrial ablation has been associated with intracavitary scarring that results in hematometra, PATSS, and a concern for difficulty in performing an adequate endometrial assessment in patients who develop postablation abnormal uterine bleeding.

In a prospective study, 230 participants (of an initial 242) treated with Cerene cyroablation were studied with hysteroscopic evaluation of the endometrial cavity 12 months after surgery.³ The uterine cavity was accessible in 98.7% of participants. The cavity was not accessible in 3 participants due to pain or cervical stenosis.

Visualization of the uterine cavity was possible by hysteroscopy in 92.7% of study participants (204 of 220), with 1 or both tubal ostia identified in 89.2%. Both tubal ostia were visible in 78.4% and 1 ostium was visible in 10.8%. The cavity was not visualized in 16 of the 220 patients (7.2%) due to intrauterine adhesions, technical difficulties, or menstruation. Also of note, 97 of the 230 participants available at the 12-month follow-up had undergone tubal sterilization before cryoablation and none reported symptoms of PATSS or hematometra, which may be considered surrogate markers for adhesions.

Continue to: Tissue effects differ with ablation technique...

Tissue effects differ with ablation technique

The study authors suggested that different tissue effects occur with freezing compared with heating ablation techniques. With freezing, over weeks to months the chronic inflammatory tissue is eventually replaced by a fibrous scar of collagen, with some preservation of the collagen matrix during tissue repair. This may be different from the charring and boiling of heated tissue that results in architectural tissue loss and may interfere with wound repair and tissue remodeling. Although the incidence of postoperative adhesions after endometrial ablation is not well studied, it is encouraging that most patients who received cryoablation with the Cerene device were able to undergo an evaluation of the endometrium without general anesthesia.

Key takeaway

The main idea from this study is that the endometrium can be assessed by office hysteroscopy in most patients who undergo cryoablation with the Cerene device. This may have advantages in terms of reducing the risk of PATSS and hematometra, and it may allow easier evaluation of the endometrium for patients who have postablation abnormal uterine bleeding. This begs the question, does intrauterine scarring influence the detection of endometrial cancer? For answers, keep reading.

Does endometrial ablation place a patient at higher risk for a delay in the diagnosis of endometrial cancer?

Radestad AF, Dahm-Kahler P, Holmberg E, et al. Long-term incidence of endometrial cancer after endometrial resection and ablation: a population based Swedish gynecologic cancer group (SweGCG) study. Acta Obstet Gynecol Scand. 2022;101:923-930.
 

Oderkerk TJ, van de Kar MRD, Cornel KMC, et al. Endometrial cancer after endometrial ablation: a systematic review. Int J Gynecol Cancer. 2022;32:1555-1560.

The answer to this question appears to be no, based on 2 different types of studies. One study was a 20-year population database review from Sweden,⁴ and the other was a systematic review of 11 cohort studies.⁵

Population-based study findings

The data from the Swedish population database is interesting because since 1994 all Swedish citizens have been allocated a unique personal identification number at birth or immigration that enables official registries and research. In reviewing their data from 1997 through 2017, Radestad and colleagues compared transcervical resection of the endometrium (TCRE) and other forms of endometrial ablation against the Swedish National Patient Register data for endometrial cancer.⁴ They found no increase in the incidence of endometrial cancer after TCRE (0.3%) or after endometrial ablation (0.02%) and suggested a significantly lower incidence of endometrial cancer after endometrial ablation.

This study is beneficial because it is the largest study to explore the long-term incidence of endometrial cancer after TCRE and endometrial ablation. The investigators hypothesized that, as an explanation for the difference between rates, ablation may burn deeper into the myometrium and treat adenomyosis compared with TCRE. However, they also were cautious to note that although this was a 20-year study, the incidence of endometrial carcinoma likely will reach a peak in the next few years.

Systematic review conclusions

In the systematic review, out of 890 publications from the authors’ database search, 11 articles were eventually included for review.⁵ A total of 29,102 patients with endometrial ablation were followed for a period of up to 25 years, and the incidence of endometrial cancer after endometrial ablation varied from 0.0% to 1.6%. A total of 38 cases of endometrial cancer after endometrial ablation have been described in the literature. Of those cases, bleeding was the most common presenting symptom of the disease. Endometrial sampling was successful in 89% of cases, and in 90% of cases, histological exam showed an early-stage endometrial adenocarcinoma.

Based on their review, the authors concluded that the incidence of endometrial cancer was not increased in patients who received endometrial ablation, and more importantly, there was no apparent delay in the diagnosis of endometrial cancer after endometrial ablation. They further suggested that diagnostic management with endometrial sampling did not appear to be a barrier.

Longer-term data for relugolix combination treatment of symptomatic uterine bleeding from fibroids shows sustained efficacy

Al-Hendy A, Lukes AS, Poindexter AN, et al. Long-term relugolix combination therapy for symptomatic uterine leiomyomas. Obstet Gynecol. 2022;140:920-930.

Relugolix combination therapy was previously reported to be effective for the treatment of fibroids based on the 24-week trials LIBERTY 1 and LIBERTY 2. We now have information about longer-term therapy for up to 52 weeks of treatment.⁶

Relugolix combination therapy is a once-daily single tablet for the treatment of heavy menstrual bleeding thought to be due to uterine fibroids in premenopausal women. It is comprised of relugolix 40 mg (a GnRH antagonist), estradiol 1.0 mg, and norethindrone acetate 0.5 mg.

Continue to: Extension study showed sustained efficacy...

The study by Al-Hendy and colleagues showed that the relugolix combination not only was well tolerated but also that there was sustained improvement in heavy bleeding, with the average patient having an approximately 90% decrease in menstrual bleeding from baseline.⁶ It was noted that 70.6% of patients achieved amenorrhea over the last 35 days of treatment.

Importantly, the treatment effect was independent of race, body mass index, baseline menstrual blood loss, and uterine fibroid volume. The bone mineral density (BMD) change trajectory was similar to what was observed in the pivotal study. No new safety concerns were identified, and BMD generally was preserved.

Linzagolix is the newest GnRH antagonist to be studied in a randomized, placebo-controlled trial

Donnez J, Taylor HS, Stewart EA, et al. Linzagolix with and without hormonal add-back therapy for the treatment of symptomatic uterine fibroids: two randomised, placebo-controlled, phase 3 trials. Lancet. 2022;400:896-907.

At the time of this writing, linzagolix was not approved by the FDA. The results of the PRIMROSE 1 (P1) and PRIMROSE 2 (P2) trials were published last year as 2 identical 52-week randomized, parallel, double-blind, placebo-controlled, phase 3 trials.⁷ The difference between the development of linzagolix as a GnRH antagonist and other similar medications is the strategy of potential partial hypothalamic pituitary ovarian axis suppression at 100 mg versus complete suppression at 200 mg. In this trial by Donnez and colleagues, both linzagolix doses were evaluated with and without add-back hormonal therapy and also were compared with placebo in a 1:1:1:1:1 ratio.⁷

Study details and results

To be eligible for this study, participants had to have heavy menstrual bleeding, defined as more than 80 mL for at least 2 cycles, and have at least 1 fibroid that was 2 cm in diameter or multiple small fibroids with the calculated uterine volume of more than 200 cm³. No fibroid larger than 12 cm in diameter was included.

The primary end point was a menstrual blood loss of 80 mL or less and a 50% or more reduction in menstrual blood loss from baseline in the 28 days before week 24. Uterine fibroid volume reduction and a safety assessment, including BMD assessment, also were studied.

In the P1 trial, which was conducted in US sites, the response rate for the primary objective was 56.4% in the linzagolix 100-mg group, 66.4% in the 100-mg plus add-back therapy group, 71.4% in the 200-mg group, and 75.5% in the 200-mg plus add-back group, compared with 35.0% in the placebo group.

In the P2 trial, which included sites in both Europe and the United States, the response rates were 56.7% in the 100-mg group, 77.2% in the 100-mg plus add-back therapy group, 77.7% in the 200-mg group, and 93.9% in the 200-mg plus add-back therapy group, compared with 29.4% in the placebo group. Thus, in both trials a significantly higher proportion of menstrual reduction occurred in all linzagolix treatment groups compared with placebo.

As expected, the incidence of hot flushes was the highest in participants taking the linzagolix 200-mg dose without add-back hormonal therapy, with hot flushes occurring in 35% (P1) and 32% (P2) of patients, compared with all other groups, which was 3% to 14%. All treatment groups showed improvement in quality-of-life scores compared with placebo. Of note, to achieve reduction of fibroid volume in the 40% to 50% range, this was observed consistently only with the linzagolix 200-mg alone dose.

Linzagolix effect on bone

Decreases in BMD appeared to be dose dependent, as lumbar spine losses of up to 4% were noted with the linzgolix 200-mg dose, and a 2% loss was observed with the 100-mg dose at 24 weeks. However, these were improved with add-back therapy. There were continued BMD decreases at 52 weeks, with up to 2.4% with 100 mg of linzagolix and up to 1.5% with 100 mg plus add-back therapy, and up to 2% with 200 mg of linzagolix plus add-back therapy. ●

Endometrial ablation continues to be performed in significant numbers in the United States, with an estimated 500,000 cases annually. Several nonresectoscopic endometrial ablation devices have been approved for use, and some are now discontinued. The newest endometrial ablation therapy to gain US Food and Drug Administration (FDA) approval and to have published outcomes is the Cerene cryotherapy ablation device (Channel Medsystems, Inc). The results of 36-month outcomes from the CLARITY study were published last year, and we have chosen to review these long-term data in addition to that of a second study in which investigators assessed the ability to access the endometrial cavity postcryoablation. We believe this is important because of concerns about the inability to access the endometrial cavity after ablation, as well as the potential for delay in the diagnosis of endometrial cancer. It is interesting that 2 publications simultaneously reviewed the incidence of endometrial cancer after endometrial ablation within the past 12 months, and we therefore present those findings as they provide valuable information.

Our second focus in this year’s Update is to provide additional information about the burgeoning data on gonadotropin-releasing hormone (GnRH) antagonists. We review evidence on linzagolix from the PRIMROSE 1 and PRIMROSE 2 trials and longer-term data on relugolix combination therapy for symptomatic uterine fibroids.

Three-year follow-up after endometrial cryoablation with the Cerene device found high patient satisfaction, low hysterectomy rates

Curlin HL, Cintron LC, Anderson TL. A prospective, multicenter, clinical trial evaluating the safety and effectiveness of the Cerene device to treat heavy menstrual bleeding. J Minim Invasive Gynecol. 2021;28;899-908.

Curlin HL, Anderson TL. Endometrial cryoablation for the treatment of heavy menstrual bleeding: 36-month outcomes from the CLARITY study. Int J Womens Health. 2022;14:1083-1092.
 

The 12-month data on the clinical safety and effectiveness of the Cerene cryoablation device were published in 2021 in the CLARITY trial.¹ The 36-month outcomes were published in 2022 and showed sustained clinical effects through month 36 with a low risk of adverse outcomes.² The interesting aspect of this trial is that although the amenorrhea rate was relatively low at 12 months (6.5%), it continued to remain relatively low compared with rates found with other devices, but the amenorrhea rate increased at 36 months (14.4%). This was the percentage of patients who reported, “I no longer get my period.”

Patient satisfaction was high

Despite a relatively low amenorrhea rate, study participants had a high satisfaction rate and a low 3-year hysterectomy rate. Eighty-five percent of the participants were satisfied or very satisfied, and the cumulative hysterectomy rate was low at 5%.

The overall reintervention rate was 8.7%. Six patients were treated with medications, 2 patients underwent repeat endometrial ablation, 1 received a levonorgestrel-releasing intrauterine device, and 12 underwent hysterectomy.

At 36 months, 201 of the original 242 participants were available for assessment. Unfortunately, 5 pregnancies were reported through the 6-month posttreatment period, which emphasizes the importance of having reliable contraception. However, there were no reports of hematometra or postablation tubal sterilization syndrome (PATSS).

Effect on bleeding was long term

The main finding of the CLARITY study is that the Cerene cryoablation device appears to have a relatively stable effect on bleedingfor the first 3 years after therapy, with minimal risk of hematometra and PATSS. What we find interesting is that despite Cerene cryoablation having one of the lowest amenorrhea rates, it not only had a satisfaction rate in line with that of other devices but also had a low hysterectomy rate—only 5%—at 3 years.

The study authors pointed out that there is a lack of scarring within the endometrial cavity with the Cerene device. Some may find less endometrial scarring worth a low amenorrhea rate in the context of a favorable satisfaction rate. This begs the question, how well can the endometrial cavity be assessed? For answers, keep reading.

Can the endometrial cavity be reliably accessed after Cerene cryoablation?

Endometrial ablation has been associated with intracavitary scarring that results in hematometra, PATSS, and a concern for difficulty in performing an adequate endometrial assessment in patients who develop postablation abnormal uterine bleeding.

In a prospective study, 230 participants (of an initial 242) treated with Cerene cyroablation were studied with hysteroscopic evaluation of the endometrial cavity 12 months after surgery.³ The uterine cavity was accessible in 98.7% of participants. The cavity was not accessible in 3 participants due to pain or cervical stenosis.

Visualization of the uterine cavity was possible by hysteroscopy in 92.7% of study participants (204 of 220), with 1 or both tubal ostia identified in 89.2%. Both tubal ostia were visible in 78.4% and 1 ostium was visible in 10.8%. The cavity was not visualized in 16 of the 220 patients (7.2%) due to intrauterine adhesions, technical difficulties, or menstruation. Also of note, 97 of the 230 participants available at the 12-month follow-up had undergone tubal sterilization before cryoablation and none reported symptoms of PATSS or hematometra, which may be considered surrogate markers for adhesions.

Continue to: Tissue effects differ with ablation technique...

Tissue effects differ with ablation technique

The study authors suggested that different tissue effects occur with freezing compared with heating ablation techniques. With freezing, over weeks to months the chronic inflammatory tissue is eventually replaced by a fibrous scar of collagen, with some preservation of the collagen matrix during tissue repair. This may be different from the charring and boiling of heated tissue that results in architectural tissue loss and may interfere with wound repair and tissue remodeling. Although the incidence of postoperative adhesions after endometrial ablation is not well studied, it is encouraging that most patients who received cryoablation with the Cerene device were able to undergo an evaluation of the endometrium without general anesthesia.

Key takeaway

The main idea from this study is that the endometrium can be assessed by office hysteroscopy in most patients who undergo cryoablation with the Cerene device. This may have advantages in terms of reducing the risk of PATSS and hematometra, and it may allow easier evaluation of the endometrium for patients who have postablation abnormal uterine bleeding. This begs the question, does intrauterine scarring influence the detection of endometrial cancer? For answers, keep reading.

Does endometrial ablation place a patient at higher risk for a delay in the diagnosis of endometrial cancer?

Radestad AF, Dahm-Kahler P, Holmberg E, et al. Long-term incidence of endometrial cancer after endometrial resection and ablation: a population based Swedish gynecologic cancer group (SweGCG) study. Acta Obstet Gynecol Scand. 2022;101:923-930.
 

Oderkerk TJ, van de Kar MRD, Cornel KMC, et al. Endometrial cancer after endometrial ablation: a systematic review. Int J Gynecol Cancer. 2022;32:1555-1560.

The answer to this question appears to be no, based on 2 different types of studies. One study was a 20-year population database review from Sweden,⁴ and the other was a systematic review of 11 cohort studies.⁵

Population-based study findings

The data from the Swedish population database is interesting because since 1994 all Swedish citizens have been allocated a unique personal identification number at birth or immigration that enables official registries and research. In reviewing their data from 1997 through 2017, Radestad and colleagues compared transcervical resection of the endometrium (TCRE) and other forms of endometrial ablation against the Swedish National Patient Register data for endometrial cancer.⁴ They found no increase in the incidence of endometrial cancer after TCRE (0.3%) or after endometrial ablation (0.02%) and suggested a significantly lower incidence of endometrial cancer after endometrial ablation.

This study is beneficial because it is the largest study to explore the long-term incidence of endometrial cancer after TCRE and endometrial ablation. The investigators hypothesized that, as an explanation for the difference between rates, ablation may burn deeper into the myometrium and treat adenomyosis compared with TCRE. However, they also were cautious to note that although this was a 20-year study, the incidence of endometrial carcinoma likely will reach a peak in the next few years.

Systematic review conclusions

In the systematic review, out of 890 publications from the authors’ database search, 11 articles were eventually included for review.⁵ A total of 29,102 patients with endometrial ablation were followed for a period of up to 25 years, and the incidence of endometrial cancer after endometrial ablation varied from 0.0% to 1.6%. A total of 38 cases of endometrial cancer after endometrial ablation have been described in the literature. Of those cases, bleeding was the most common presenting symptom of the disease. Endometrial sampling was successful in 89% of cases, and in 90% of cases, histological exam showed an early-stage endometrial adenocarcinoma.

Based on their review, the authors concluded that the incidence of endometrial cancer was not increased in patients who received endometrial ablation, and more importantly, there was no apparent delay in the diagnosis of endometrial cancer after endometrial ablation. They further suggested that diagnostic management with endometrial sampling did not appear to be a barrier.

Longer-term data for relugolix combination treatment of symptomatic uterine bleeding from fibroids shows sustained efficacy

Al-Hendy A, Lukes AS, Poindexter AN, et al. Long-term relugolix combination therapy for symptomatic uterine leiomyomas. Obstet Gynecol. 2022;140:920-930.

Relugolix combination therapy was previously reported to be effective for the treatment of fibroids based on the 24-week trials LIBERTY 1 and LIBERTY 2. We now have information about longer-term therapy for up to 52 weeks of treatment.⁶

Relugolix combination therapy is a once-daily single tablet for the treatment of heavy menstrual bleeding thought to be due to uterine fibroids in premenopausal women. It is comprised of relugolix 40 mg (a GnRH antagonist), estradiol 1.0 mg, and norethindrone acetate 0.5 mg.

Continue to: Extension study showed sustained efficacy...

The study by Al-Hendy and colleagues showed that the relugolix combination not only was well tolerated but also that there was sustained improvement in heavy bleeding, with the average patient having an approximately 90% decrease in menstrual bleeding from baseline.⁶ It was noted that 70.6% of patients achieved amenorrhea over the last 35 days of treatment.

Importantly, the treatment effect was independent of race, body mass index, baseline menstrual blood loss, and uterine fibroid volume. The bone mineral density (BMD) change trajectory was similar to what was observed in the pivotal study. No new safety concerns were identified, and BMD generally was preserved.

Linzagolix is the newest GnRH antagonist to be studied in a randomized, placebo-controlled trial

Donnez J, Taylor HS, Stewart EA, et al. Linzagolix with and without hormonal add-back therapy for the treatment of symptomatic uterine fibroids: two randomised, placebo-controlled, phase 3 trials. Lancet. 2022;400:896-907.

At the time of this writing, linzagolix was not approved by the FDA. The results of the PRIMROSE 1 (P1) and PRIMROSE 2 (P2) trials were published last year as 2 identical 52-week randomized, parallel, double-blind, placebo-controlled, phase 3 trials.⁷ The difference between the development of linzagolix as a GnRH antagonist and other similar medications is the strategy of potential partial hypothalamic pituitary ovarian axis suppression at 100 mg versus complete suppression at 200 mg. In this trial by Donnez and colleagues, both linzagolix doses were evaluated with and without add-back hormonal therapy and also were compared with placebo in a 1:1:1:1:1 ratio.⁷

Study details and results

To be eligible for this study, participants had to have heavy menstrual bleeding, defined as more than 80 mL for at least 2 cycles, and have at least 1 fibroid that was 2 cm in diameter or multiple small fibroids with the calculated uterine volume of more than 200 cm³. No fibroid larger than 12 cm in diameter was included.

The primary end point was a menstrual blood loss of 80 mL or less and a 50% or more reduction in menstrual blood loss from baseline in the 28 days before week 24. Uterine fibroid volume reduction and a safety assessment, including BMD assessment, also were studied.

In the P1 trial, which was conducted in US sites, the response rate for the primary objective was 56.4% in the linzagolix 100-mg group, 66.4% in the 100-mg plus add-back therapy group, 71.4% in the 200-mg group, and 75.5% in the 200-mg plus add-back group, compared with 35.0% in the placebo group.

In the P2 trial, which included sites in both Europe and the United States, the response rates were 56.7% in the 100-mg group, 77.2% in the 100-mg plus add-back therapy group, 77.7% in the 200-mg group, and 93.9% in the 200-mg plus add-back therapy group, compared with 29.4% in the placebo group. Thus, in both trials a significantly higher proportion of menstrual reduction occurred in all linzagolix treatment groups compared with placebo.

As expected, the incidence of hot flushes was the highest in participants taking the linzagolix 200-mg dose without add-back hormonal therapy, with hot flushes occurring in 35% (P1) and 32% (P2) of patients, compared with all other groups, which was 3% to 14%. All treatment groups showed improvement in quality-of-life scores compared with placebo. Of note, to achieve reduction of fibroid volume in the 40% to 50% range, this was observed consistently only with the linzagolix 200-mg alone dose.

Linzagolix effect on bone

Decreases in BMD appeared to be dose dependent, as lumbar spine losses of up to 4% were noted with the linzgolix 200-mg dose, and a 2% loss was observed with the 100-mg dose at 24 weeks. However, these were improved with add-back therapy. There were continued BMD decreases at 52 weeks, with up to 2.4% with 100 mg of linzagolix and up to 1.5% with 100 mg plus add-back therapy, and up to 2% with 200 mg of linzagolix plus add-back therapy. ●

Endometrial ablation continues to be performed in significant numbers in the United States, with an estimated 500,000 cases annually. Several nonresectoscopic endometrial ablation devices have been approved for use, and some are now discontinued. The newest endometrial ablation therapy to gain US Food and Drug Administration (FDA) approval and to have published outcomes is the Cerene cryotherapy ablation device (Channel Medsystems, Inc). The results of 36-month outcomes from the CLARITY study were published last year, and we have chosen to review these long-term data in addition to that of a second study in which investigators assessed the ability to access the endometrial cavity postcryoablation. We believe this is important because of concerns about the inability to access the endometrial cavity after ablation, as well as the potential for delay in the diagnosis of endometrial cancer. It is interesting that 2 publications simultaneously reviewed the incidence of endometrial cancer after endometrial ablation within the past 12 months, and we therefore present those findings as they provide valuable information.

Our second focus in this year’s Update is to provide additional information about the burgeoning data on gonadotropin-releasing hormone (GnRH) antagonists. We review evidence on linzagolix from the PRIMROSE 1 and PRIMROSE 2 trials and longer-term data on relugolix combination therapy for symptomatic uterine fibroids.

Three-year follow-up after endometrial cryoablation with the Cerene device found high patient satisfaction, low hysterectomy rates

Curlin HL, Cintron LC, Anderson TL. A prospective, multicenter, clinical trial evaluating the safety and effectiveness of the Cerene device to treat heavy menstrual bleeding. J Minim Invasive Gynecol. 2021;28;899-908.

Curlin HL, Anderson TL. Endometrial cryoablation for the treatment of heavy menstrual bleeding: 36-month outcomes from the CLARITY study. Int J Womens Health. 2022;14:1083-1092.
 

The 12-month data on the clinical safety and effectiveness of the Cerene cryoablation device were published in 2021 in the CLARITY trial.¹ The 36-month outcomes were published in 2022 and showed sustained clinical effects through month 36 with a low risk of adverse outcomes.² The interesting aspect of this trial is that although the amenorrhea rate was relatively low at 12 months (6.5%), it continued to remain relatively low compared with rates found with other devices, but the amenorrhea rate increased at 36 months (14.4%). This was the percentage of patients who reported, “I no longer get my period.”

Patient satisfaction was high

Despite a relatively low amenorrhea rate, study participants had a high satisfaction rate and a low 3-year hysterectomy rate. Eighty-five percent of the participants were satisfied or very satisfied, and the cumulative hysterectomy rate was low at 5%.

The overall reintervention rate was 8.7%. Six patients were treated with medications, 2 patients underwent repeat endometrial ablation, 1 received a levonorgestrel-releasing intrauterine device, and 12 underwent hysterectomy.

At 36 months, 201 of the original 242 participants were available for assessment. Unfortunately, 5 pregnancies were reported through the 6-month posttreatment period, which emphasizes the importance of having reliable contraception. However, there were no reports of hematometra or postablation tubal sterilization syndrome (PATSS).

Effect on bleeding was long term

The main finding of the CLARITY study is that the Cerene cryoablation device appears to have a relatively stable effect on bleedingfor the first 3 years after therapy, with minimal risk of hematometra and PATSS. What we find interesting is that despite Cerene cryoablation having one of the lowest amenorrhea rates, it not only had a satisfaction rate in line with that of other devices but also had a low hysterectomy rate—only 5%—at 3 years.

The study authors pointed out that there is a lack of scarring within the endometrial cavity with the Cerene device. Some may find less endometrial scarring worth a low amenorrhea rate in the context of a favorable satisfaction rate. This begs the question, how well can the endometrial cavity be assessed? For answers, keep reading.

Can the endometrial cavity be reliably accessed after Cerene cryoablation?

Endometrial ablation has been associated with intracavitary scarring that results in hematometra, PATSS, and a concern for difficulty in performing an adequate endometrial assessment in patients who develop postablation abnormal uterine bleeding.

In a prospective study, 230 participants (of an initial 242) treated with Cerene cyroablation were studied with hysteroscopic evaluation of the endometrial cavity 12 months after surgery.³ The uterine cavity was accessible in 98.7% of participants. The cavity was not accessible in 3 participants due to pain or cervical stenosis.

Visualization of the uterine cavity was possible by hysteroscopy in 92.7% of study participants (204 of 220), with 1 or both tubal ostia identified in 89.2%. Both tubal ostia were visible in 78.4% and 1 ostium was visible in 10.8%. The cavity was not visualized in 16 of the 220 patients (7.2%) due to intrauterine adhesions, technical difficulties, or menstruation. Also of note, 97 of the 230 participants available at the 12-month follow-up had undergone tubal sterilization before cryoablation and none reported symptoms of PATSS or hematometra, which may be considered surrogate markers for adhesions.

Continue to: Tissue effects differ with ablation technique...

Tissue effects differ with ablation technique

The study authors suggested that different tissue effects occur with freezing compared with heating ablation techniques. With freezing, over weeks to months the chronic inflammatory tissue is eventually replaced by a fibrous scar of collagen, with some preservation of the collagen matrix during tissue repair. This may be different from the charring and boiling of heated tissue that results in architectural tissue loss and may interfere with wound repair and tissue remodeling. Although the incidence of postoperative adhesions after endometrial ablation is not well studied, it is encouraging that most patients who received cryoablation with the Cerene device were able to undergo an evaluation of the endometrium without general anesthesia.

Key takeaway

The main idea from this study is that the endometrium can be assessed by office hysteroscopy in most patients who undergo cryoablation with the Cerene device. This may have advantages in terms of reducing the risk of PATSS and hematometra, and it may allow easier evaluation of the endometrium for patients who have postablation abnormal uterine bleeding. This begs the question, does intrauterine scarring influence the detection of endometrial cancer? For answers, keep reading.

Does endometrial ablation place a patient at higher risk for a delay in the diagnosis of endometrial cancer?

Radestad AF, Dahm-Kahler P, Holmberg E, et al. Long-term incidence of endometrial cancer after endometrial resection and ablation: a population based Swedish gynecologic cancer group (SweGCG) study. Acta Obstet Gynecol Scand. 2022;101:923-930.
 

Oderkerk TJ, van de Kar MRD, Cornel KMC, et al. Endometrial cancer after endometrial ablation: a systematic review. Int J Gynecol Cancer. 2022;32:1555-1560.

The answer to this question appears to be no, based on 2 different types of studies. One study was a 20-year population database review from Sweden,⁴ and the other was a systematic review of 11 cohort studies.⁵

Population-based study findings

The data from the Swedish population database is interesting because since 1994 all Swedish citizens have been allocated a unique personal identification number at birth or immigration that enables official registries and research. In reviewing their data from 1997 through 2017, Radestad and colleagues compared transcervical resection of the endometrium (TCRE) and other forms of endometrial ablation against the Swedish National Patient Register data for endometrial cancer.⁴ They found no increase in the incidence of endometrial cancer after TCRE (0.3%) or after endometrial ablation (0.02%) and suggested a significantly lower incidence of endometrial cancer after endometrial ablation.

This study is beneficial because it is the largest study to explore the long-term incidence of endometrial cancer after TCRE and endometrial ablation. The investigators hypothesized that, as an explanation for the difference between rates, ablation may burn deeper into the myometrium and treat adenomyosis compared with TCRE. However, they also were cautious to note that although this was a 20-year study, the incidence of endometrial carcinoma likely will reach a peak in the next few years.

Systematic review conclusions

In the systematic review, out of 890 publications from the authors’ database search, 11 articles were eventually included for review.⁵ A total of 29,102 patients with endometrial ablation were followed for a period of up to 25 years, and the incidence of endometrial cancer after endometrial ablation varied from 0.0% to 1.6%. A total of 38 cases of endometrial cancer after endometrial ablation have been described in the literature. Of those cases, bleeding was the most common presenting symptom of the disease. Endometrial sampling was successful in 89% of cases, and in 90% of cases, histological exam showed an early-stage endometrial adenocarcinoma.

Based on their review, the authors concluded that the incidence of endometrial cancer was not increased in patients who received endometrial ablation, and more importantly, there was no apparent delay in the diagnosis of endometrial cancer after endometrial ablation. They further suggested that diagnostic management with endometrial sampling did not appear to be a barrier.

Longer-term data for relugolix combination treatment of symptomatic uterine bleeding from fibroids shows sustained efficacy

Al-Hendy A, Lukes AS, Poindexter AN, et al. Long-term relugolix combination therapy for symptomatic uterine leiomyomas. Obstet Gynecol. 2022;140:920-930.

Relugolix combination therapy was previously reported to be effective for the treatment of fibroids based on the 24-week trials LIBERTY 1 and LIBERTY 2. We now have information about longer-term therapy for up to 52 weeks of treatment.⁶

Relugolix combination therapy is a once-daily single tablet for the treatment of heavy menstrual bleeding thought to be due to uterine fibroids in premenopausal women. It is comprised of relugolix 40 mg (a GnRH antagonist), estradiol 1.0 mg, and norethindrone acetate 0.5 mg.

Continue to: Extension study showed sustained efficacy...

The study by Al-Hendy and colleagues showed that the relugolix combination not only was well tolerated but also that there was sustained improvement in heavy bleeding, with the average patient having an approximately 90% decrease in menstrual bleeding from baseline.⁶ It was noted that 70.6% of patients achieved amenorrhea over the last 35 days of treatment.

Importantly, the treatment effect was independent of race, body mass index, baseline menstrual blood loss, and uterine fibroid volume. The bone mineral density (BMD) change trajectory was similar to what was observed in the pivotal study. No new safety concerns were identified, and BMD generally was preserved.

Linzagolix is the newest GnRH antagonist to be studied in a randomized, placebo-controlled trial

Donnez J, Taylor HS, Stewart EA, et al. Linzagolix with and without hormonal add-back therapy for the treatment of symptomatic uterine fibroids: two randomised, placebo-controlled, phase 3 trials. Lancet. 2022;400:896-907.

At the time of this writing, linzagolix was not approved by the FDA. The results of the PRIMROSE 1 (P1) and PRIMROSE 2 (P2) trials were published last year as 2 identical 52-week randomized, parallel, double-blind, placebo-controlled, phase 3 trials.⁷ The difference between the development of linzagolix as a GnRH antagonist and other similar medications is the strategy of potential partial hypothalamic pituitary ovarian axis suppression at 100 mg versus complete suppression at 200 mg. In this trial by Donnez and colleagues, both linzagolix doses were evaluated with and without add-back hormonal therapy and also were compared with placebo in a 1:1:1:1:1 ratio.⁷

Study details and results

To be eligible for this study, participants had to have heavy menstrual bleeding, defined as more than 80 mL for at least 2 cycles, and have at least 1 fibroid that was 2 cm in diameter or multiple small fibroids with the calculated uterine volume of more than 200 cm³. No fibroid larger than 12 cm in diameter was included.

The primary end point was a menstrual blood loss of 80 mL or less and a 50% or more reduction in menstrual blood loss from baseline in the 28 days before week 24. Uterine fibroid volume reduction and a safety assessment, including BMD assessment, also were studied.

In the P1 trial, which was conducted in US sites, the response rate for the primary objective was 56.4% in the linzagolix 100-mg group, 66.4% in the 100-mg plus add-back therapy group, 71.4% in the 200-mg group, and 75.5% in the 200-mg plus add-back group, compared with 35.0% in the placebo group.

In the P2 trial, which included sites in both Europe and the United States, the response rates were 56.7% in the 100-mg group, 77.2% in the 100-mg plus add-back therapy group, 77.7% in the 200-mg group, and 93.9% in the 200-mg plus add-back therapy group, compared with 29.4% in the placebo group. Thus, in both trials a significantly higher proportion of menstrual reduction occurred in all linzagolix treatment groups compared with placebo.

As expected, the incidence of hot flushes was the highest in participants taking the linzagolix 200-mg dose without add-back hormonal therapy, with hot flushes occurring in 35% (P1) and 32% (P2) of patients, compared with all other groups, which was 3% to 14%. All treatment groups showed improvement in quality-of-life scores compared with placebo. Of note, to achieve reduction of fibroid volume in the 40% to 50% range, this was observed consistently only with the linzagolix 200-mg alone dose.

Linzagolix effect on bone

Decreases in BMD appeared to be dose dependent, as lumbar spine losses of up to 4% were noted with the linzgolix 200-mg dose, and a 2% loss was observed with the 100-mg dose at 24 weeks. However, these were improved with add-back therapy. There were continued BMD decreases at 52 weeks, with up to 2.4% with 100 mg of linzagolix and up to 1.5% with 100 mg plus add-back therapy, and up to 2% with 200 mg of linzagolix plus add-back therapy. ●

The 2022-2023 Term of the Supreme Court illustrates how important the Court has become to health-related matters, including decisions regarding the selection and training of new professionals, the daily practice of medicine, and the future availability of new drugs. The importance of several cases is reinforced by the fact that major medical organizations filed amicus curiae (“friend of the court”) briefs in those cases.

Amicus briefs are filed by individuals or organizations with something significant to say about a case to the court—most often to present a point of view, make an argument, or provide information that the parties to the case may not have communicated. Amicus briefs are burdensome in terms of the time, energy, and cost of preparing and filing. Thus, they are not undertaken lightly. Medical organizations submitted amicus briefs in the first 3 cases we consider.

Admissions, race, and diversity

The case: Students for Fair Admissions v President and Fellows of Harvard College

The American College of Obstetricians and Gynecologists (ACOG) joined an amici curiae brief in Students for Fair Admissions v President and Fellows of Harvard College (and the University of North Carolina [UNC]).¹ This case challenged the use of racial preferences in college admissions. The Association of American Medical Colleges (AAMC) was the lead organization; nearly 40 other health-related organizations joined the brief.

The legal claim. Those filing the suits asserted that racial preferences by public colleges violate the 14th Amendment’s Equal Protection Clause (“no state shall deny to any person … the equal protection of the law”). That is, if a state university gives racial preferences in selective admissions, it denies some other applicant the equal protection of the law. As for private schools (in this case, Harvard), Title VI of the Civil Rights Act of 1964 has the same standards as the Equal Protection Clause. Thus, the Court consolidated the cases and used the same legal standard in considering public and private colleges (with “colleges” including professional and graduate programs as well as undergraduate institutions).

Background. For nearly 50 years, the Supreme Court has allowed limited racial preferences in college admissions. Those preferences could only operate as a plus, however, and not a negative for applicants and be narrowly tailored. The measure was instituted temporarily; in a 2003 case, the Court said, “We expect that 25 years from now, the use of racial preferences will no longer be necessary.”²

Decision. In a 6-3 decision, the Court held (in the UNC case) that racial preferences generally violate the Constitution, and by a 6-2 decision (in the Harvard case) these preferences violate the Civil Rights Act of 1964. (Justice Jackson was recused in the Harvard case because of a conflict.) The opinion covered 237 pages in the US Reports, so any summary is incomplete.

The majority concluded, “The Harvard and UNC admissions programs cannot be reconciled with the guarantees of the Equal Protection Clause. Both programs lack sufficiently focused and measurable objectives warranting the use of race, unavoidably employ race in a negative manner, involve racial stereotyping, and lack meaningful end points. We have never permitted admissions programs to work in that way, and we will not do so today.”³

There were 3 concurring opinions and 2 dissents in the case. The concurrences reviewed the history of the Equal Protection Clause and the Civil Rights Act, the damage racial preferences can do, and the explicit limits the Court said there must be on racial preferences in higher education. The dissents had a different view of the legal history of the 14th Amendment. They said the majority was turning a blind eye to segregation in society and the race-based gap in America.

As a practical matter, this case means that colleges, including professional schools, cannot use racial preferences. The Court said that universities may consider essays and the like in which applicants describe how their own experiences as an individual (including race) have affected their own lives. However, the Court cautioned that “universities may not simply establish through application essays or other means the regime we hold unlawful today.”³

Continue to: The amici brief...

ACOG joined 40 other health-related organizations in filing an amici brief (multiple “friends”) in Students for Fair Admission. The AAMC led the brief, with the others signing as amici.⁴ The brief made 3 essential points: diversity in medical education “markedly improves health outcomes,” and a loss of diversity “threaten[s] patients’ health; medical schools engage in an intense “holistic” review of applicants for admission; and medical schools must consider applicants’ “full background” (including race) to achieve their educational and professional goals.⁴

A powerful part of the brief described the medical school admissions process, particularly the very “holistic” review that is not entirely dependent on admissions scores. The brief effectively weaves the consideration of race into this process, mentioning race (on page 22) only after discussing many other admissions factors.

Child custody decisions related to the Indian Child Welfare Act

The case: Haaland v Brackeen

The American Medical Association (AMA) and the American Academy of Pediatrics filed a brief in Haaland v Brackeen⁵ involving the constitutionality of the 1978 Indian Child Welfare Act (ICWA). The statute followed a terrible history of Indian children being removed from their families inappropriately, as detailed in a concurring opinion by Justice Gorsuch.⁵ The two purposes of the act were to promote raising Native American children in their culture and stem the downward trend in tribal membership.

The legal claim. The Court consolidated several cases. Essentially, a 10-month-old child (A.L.M.) was placed in foster care with the Brackeens in Texas. After more than 1 year, the Brackeens sought adoption; the biological father, mother, and grandparents all supported it. The Navajo and Cherokee Nations objected and informed the Texas court that they had found alternative placement with (nonrelative) tribal members in New Mexico. The “court-appointed guardian and a psychological expert … described the strong emotional bond between A.L.M. and his foster parents.” The court denied the adoption petition based on ICWA’s preference for tribe custody, and the Brackeens filed a lawsuit. The Court noted that the act “requires a state court to place an Indian child with an Indian caretaker, if one is available, even if the child is already living with a non-Indian family and the state court thinks it in the child’s best interest to stay there.” That is, the ICWA may require a placement that the court believes is not in the child’s best interest.⁵

Decision. The constitutional claim in the case was that Congress lacked the authority to impose these substantial rules on states in making child custody decisions. The Supreme Court, in a 7-2 decision, upheld the constitutionality of the ICWA. The Court found the authority primarily in Article 1, Section 8, giving Congress the power to “regulate Commerce with foreign Nations, and among the several States, and with the Indian Tribes.” In addition, the Court suggested that the treaty power and “principles inherent in the Constitution’s structure may empower Congress to act in the field of Indian affairs.”

The amici brief

The joint amici brief of the American Academy of Pediatrics (AAP) and the AMA argued that tribes are “extended families” of Native American children.⁶ It noted the destructive history of removing Native American children from their families and suggested that kinship care improves children’s health. To its credit, the brief also honestly noted the serious mental health and suicide rates in some tribes, which suggest issues that might arise in child custody and adoption cases.

The Court did not, in this case, take up another constitutional issue that the parties raised—whether the strong preference for Native American over non ̶ Native American custody violates the Equal Protection Clause of the 14th Amendment. The Court said the parties to this case did not have standing to raise the issue. Justice Kavanaugh, concurring, said it was a “serious” issue and invited it to be raised in another case.⁵

False Claims Act cases

The case: Costs for SuperValu prescriptions

For physicians and health care organizations, False Claims Act (FCA) cases are an ongoing burden and, some would say, threat. (There are also state FCAs, but here we are discussing the federal act.) The federal government has recovered more than $70 billion since 1986, most from health care entities.⁷The Justice Department identifies “health care fraud” as the largest area of FCA recovery and provides annual details on frauds resulting in liability.⁸

The legal claim. One FCA case this Term involved billings SuperValu made for outpatient prescriptions in Medicare-Medicaid programs. As its “usual and customary” costs, it essentially reported a list price that did not include the substantial discounts it commonly gave.⁹ The charge was that it “knowingly” made a false claim regarding the price of prescriptions. The question was what state of mind, or “scienter,” is required for “knowingly.” Should it be objective (what a reasonable person would know) or subjective (the defendant’s “knowledge and subjective beliefs”)?

Background. Subjective knowledge (what the defendant actually knows) may seem impossible to prove—the defendant could just say, “I did not know I was doing wrong.” Over time the law has developed several ways of demonstrating “knowing.” Justice Thomas, writing for a unanimous Court, held that whistleblowers or the government might prove “knowing” in 3 ways:

1. defendants “actually knew that their reported prices were not their ‘usual and customary’ prices when they reported them”

2. were aware of a substantial risk that their higher, retail prices were not their “usual and customary” prices and intentionally avoided learning whether their reports were accurate

3. were aware of such a substantial and unjustifiable risk but submitted the claims anyway.⁹

Of course, records of the company, information from the whistleblower, and circumstantial evidence may be used to prove any of these; it does not require the company’s admission.

The Court said that if the government or whistleblowers make a showing of any of these 3 things, it is enough.

Decision. The case was returned to the lower court to apply these rules.

The amici brief

The American Hospital Association and America’s Health Insurance Plans filed an amici brief.¹⁰ It reminded the Court that many reimbursement regulations are unclear. Therefore, it is inappropriate to impose FCA liability for guessing incorrectly what the regulations mean. Having to check on every possible ambiguity was unworkable. The Court declined, however, the suggestion that defendants should be able to use any one of many “objectively” reasonable interpretations of regulations.

Continue to: The case: Polansky v Executive Health Resources...

The case: Polansky v Executive Health Resources

Health care providers who dislike the FCA may find solace this Term in this second FCA case.¹¹

The legal claim. Polansky, a physician employed by a medical billing company, became an “intervenor” in a suit claiming the company assisted hospitals in false billing (inpatient claims for outpatient services). The government sought to dismiss the case, but Polansky refused.

Decision. The case eventually reached the Supreme Court, which held that the government may enter an FCA case at any time and move to dismiss the case even over the objection of a whistleblower. The government does not seek to enter a case in order to file dismissal motions often. When it does so, whistleblowers are protected by the fact that the dismissal motion requires a hearing before the federal court.

An important part of this case has escaped much attention. Justices Thomas, Kavanaugh, and Barrett invited litigation to determine if allowing private whistleblowers to represent the government’s interest is consistent with Article II of the Constitution.¹¹ The invitation will likely be accepted. We expect to see cases challenging the place of “intervenors” pursuing claims when the government has declined to take up the case. The private intervenor is a crucial provision of the current FCA, and if such a challenge were successful, it could substantially reduce FCA cases.

Criminal false claims

Another case this Term is cautionary about the consequences of health care misbilling. It resulted in a criminal charge. More importantly, in addition to a basic fraud charge, the government added a charge of aggravated identity theft,¹² which carries a mandatory 2-year prison sentence.

Dubin overbilled Medicaid for psychological testing by saying the testing was done by a licensed psychologist rather than an assistant. The government claimed the “identity theft” was using the patient’s (actual) Medicaid number in submitting the bill.¹² The Court unanimously held the overbilling was not aggravated identity theft as defined in federal law. Dubin could be convicted of fraudulent billing but not aggravated identity theft, thereby avoiding the mandatory prison term.

Patents of “genus” targets

The case: Amgen v Sanofi

This case, which corrected an error of the patent office, received little attention but was likely a turning point in the next generation of pharmaceuticals.¹³

Background. “Genus” patents allow a single pharmaceutical company to patent every antibody that binds to a specific amino acid on a naturally occurring protein. In this case, the patent office had granted a “genus” patent on “all antibodies” that bind to the naturally occurring protein PCSK9 and block it from hindering the body’s mechanism for removing low-density lipoprotein (LDL) cholesterol from the bloodstream,¹³ helping to reduce LDL cholesterol levels. These patents could involve millions of antibodies—and Amgen was claiming a patent on all of them. Amgen and Sanofi marketed their products, each with their own unique amino acid sequence.¹³ Amgen sued Sanofi for violating its patent rights.

Decision. The Court unanimously held that Amgen did not have a valid patent on all antibodies targeting PCSK9, only those that it had explicitly described in its patent application—a ruling based on a 150-year-old technical requirement for receiving a patent. An applicant for a patent must include “a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art…to make and use the same.”¹³ Amgen’s patent provided the description for only a few of the antibodies, but from the description in its application others could not “make and use” all of the antibodies targeting PCSK9.

While the decision was vital for future pharmaceuticals, the patent principle on which it was based has an interesting history. The Court noted that it affected the telegraph (Morse lost part of his patent), electric lights (Edison won his case against other inventors), and the glue for wood veneering (Perkins Glue Company lost).¹³

Continue to: Other notable decisions...

Student loans

The Court struck down the Biden Administration’s student loan forgiveness program, which would have cost approximately $430 billion.¹⁴ The central issue was whether the administration had the authority for such massive loan forgiveness; that is, whether Congress had authorized the broad loan forgiveness. The administration claimed authority from the post ̶ 9/11 HEROES Act, which allows the Secretary of Education to “waive or modify” loan provisions during national emergencies. The temporary hold on loan payments during COVID was based on this provision. However, in a 6-3 decision, the Court held that the act did not allow the secretary to cancel $430 billion in loans. “The Act allows the Secretary to ‘waive or modify’ existing statutory or regulatory provisions applicable to financial assistance programs under the Education Act, not to rewrite that statute from the ground up.”¹⁴

Free speech and the wedding web designer

303 Creative v Elenis involved a creative website designer who did not want to be required to create a website for a gay wedding.¹⁵ The designer had strong beliefs against same-sex marriages, but Colorado sought to force her to do so under the state “public accommodations” law. In a 6-3 decision, the Court held that the designer had a “free speech” right. That is, the state could not compel her to undertake speech expressing things she did not believe. This was because the website design was an expressive, creative activity and therefore was “speech” under the First Amendment.

Wetlands and the Clean Water Act

The essential issue in Sackett v Environmental Protection Agency (EPA) was the definitions of waters of the United States and related wetlands. The broad definition the EPA used meant it had jurisdiction to regulate an extraordinary amount of territory. It had, for example, prevented the Sacketts from building a modest house claiming it was part of the “waters of the United States because they were near a ditch that fed into a creek, which fed into Priest Lake, a navigable, intrastate lake.” The Court held that the EPA exceeded its statutory authority to define “wetlands.”¹⁶

The Court held that under the Clean Water Act, for the EPA to establish jurisdiction over adjacent wetlands, it must demonstrate that¹⁶:

1. “the adjacent body of water constitutes waters of the United States (ie, a relatively permanent body of water connected to traditional interstate navigable waters)…”

2. “…the wetland has a continuous surface connection with that water, making it difficult to determine where the water ends, and the wetland begins.”

Under this definition, the Sacketts could build their house. This was a statutory interpretation case. Therefore, Congress can expand or otherwise change the EPA’s authority under the Clean Water Act and other legislation.

Conclusions: A new justice, “shadow docket,” and ethics rules

SCOTUS’ newest member. When the Marshall called the Court into session on October 3, 2022, it had a new member, Justice Ketanji Brown Jackson. She was sworn in on June 30, 2022, when her predecessor (Justice Breyer) officially retired. She had been a law clerk for Justice Breyer in 1999, as well as a district court judge and court of appeals judge. Those who count such things described her as the “chattiest justice.”¹⁷ She spoke more than any other justice—by one count, a total of 75,632 words (an average of 1,300 words in each of the 58 arguments).

A more balanced Court? Most commentators view the Court as more balanced or less conservative than the previous Term. For example, Justice Sotomayor was in the majority 40% last Term but 65% this Term. Justice Thomas was in the majority 75% last Term but 55% this Term. Put another way, this Term in the divided cases, the liberal justices were in the majority 64% of the time, compared with the conservative justices 73%.¹⁸ Of course, these differences may reflect a different set of cases rather than a change in the direction of the Court. There were 11 (or 12, depending on how 1 case is counted) 6-3 cases, but only 5 were considered ideological. That suggests that, in many cases, the coalitions were somewhat fluid.

“Shadow docket” controversy continues.¹⁹ Shadow docket refers to orders the Court makes that do not follow oral arguments and often do not have written opinions. The orders are all publicly available. This Term a close examination of the approximately 30 shadow docket opinions shows that the overwhelming majority were dissents or explanations about denials of certiorari. The Court ordered only a few stays or injunctions via the shadow docket. One shadow docket stay (that prevented a lower court order from going into effect) is particularly noteworthy. A federal judge had ordered the suspension of the distribution of mifepristone while courts considered claims that the US Food and Drug Administration (FDA) had improperly approved the drug. In a shadow docket order, the Court issued the stay to allow mifepristone to be sold while the case challenging its approval was heard.²⁰ The only opinion was a dissent from Justice Alito. But it also demonstrates the importance of the shadow docket. Without this intervention, in at least part of the country, the distribution of mifepristone would have been interrupted pending the outcome of the FDA cases.

In August, the Court delayed a settlement in the Purdue Pharma liability bankruptcy case.²¹ It also stayed an injunction of a lower court, thereby permitting federal “ghost guns” regulations to go into effect at least temporarily.²²

More ethics rules to come? Another area in which the Court faced criticism was formal ethics rules. The justices make financial disclosures, but these are somewhat ambiguous. There is likely to be increasing pressure for a more complete disclosure of non-financial relationships and more formal ethics rules. ●

The 2022-2023 Term of the Supreme Court illustrates how important the Court has become to health-related matters, including decisions regarding the selection and training of new professionals, the daily practice of medicine, and the future availability of new drugs. The importance of several cases is reinforced by the fact that major medical organizations filed amicus curiae (“friend of the court”) briefs in those cases.

Amicus briefs are filed by individuals or organizations with something significant to say about a case to the court—most often to present a point of view, make an argument, or provide information that the parties to the case may not have communicated. Amicus briefs are burdensome in terms of the time, energy, and cost of preparing and filing. Thus, they are not undertaken lightly. Medical organizations submitted amicus briefs in the first 3 cases we consider.

Admissions, race, and diversity

The case: Students for Fair Admissions v President and Fellows of Harvard College

The American College of Obstetricians and Gynecologists (ACOG) joined an amici curiae brief in Students for Fair Admissions v President and Fellows of Harvard College (and the University of North Carolina [UNC]).¹ This case challenged the use of racial preferences in college admissions. The Association of American Medical Colleges (AAMC) was the lead organization; nearly 40 other health-related organizations joined the brief.

The legal claim. Those filing the suits asserted that racial preferences by public colleges violate the 14th Amendment’s Equal Protection Clause (“no state shall deny to any person … the equal protection of the law”). That is, if a state university gives racial preferences in selective admissions, it denies some other applicant the equal protection of the law. As for private schools (in this case, Harvard), Title VI of the Civil Rights Act of 1964 has the same standards as the Equal Protection Clause. Thus, the Court consolidated the cases and used the same legal standard in considering public and private colleges (with “colleges” including professional and graduate programs as well as undergraduate institutions).

Background. For nearly 50 years, the Supreme Court has allowed limited racial preferences in college admissions. Those preferences could only operate as a plus, however, and not a negative for applicants and be narrowly tailored. The measure was instituted temporarily; in a 2003 case, the Court said, “We expect that 25 years from now, the use of racial preferences will no longer be necessary.”²

Decision. In a 6-3 decision, the Court held (in the UNC case) that racial preferences generally violate the Constitution, and by a 6-2 decision (in the Harvard case) these preferences violate the Civil Rights Act of 1964. (Justice Jackson was recused in the Harvard case because of a conflict.) The opinion covered 237 pages in the US Reports, so any summary is incomplete.

The majority concluded, “The Harvard and UNC admissions programs cannot be reconciled with the guarantees of the Equal Protection Clause. Both programs lack sufficiently focused and measurable objectives warranting the use of race, unavoidably employ race in a negative manner, involve racial stereotyping, and lack meaningful end points. We have never permitted admissions programs to work in that way, and we will not do so today.”³

There were 3 concurring opinions and 2 dissents in the case. The concurrences reviewed the history of the Equal Protection Clause and the Civil Rights Act, the damage racial preferences can do, and the explicit limits the Court said there must be on racial preferences in higher education. The dissents had a different view of the legal history of the 14th Amendment. They said the majority was turning a blind eye to segregation in society and the race-based gap in America.

As a practical matter, this case means that colleges, including professional schools, cannot use racial preferences. The Court said that universities may consider essays and the like in which applicants describe how their own experiences as an individual (including race) have affected their own lives. However, the Court cautioned that “universities may not simply establish through application essays or other means the regime we hold unlawful today.”³

Continue to: The amici brief...

ACOG joined 40 other health-related organizations in filing an amici brief (multiple “friends”) in Students for Fair Admission. The AAMC led the brief, with the others signing as amici.⁴ The brief made 3 essential points: diversity in medical education “markedly improves health outcomes,” and a loss of diversity “threaten[s] patients’ health; medical schools engage in an intense “holistic” review of applicants for admission; and medical schools must consider applicants’ “full background” (including race) to achieve their educational and professional goals.⁴

A powerful part of the brief described the medical school admissions process, particularly the very “holistic” review that is not entirely dependent on admissions scores. The brief effectively weaves the consideration of race into this process, mentioning race (on page 22) only after discussing many other admissions factors.

Child custody decisions related to the Indian Child Welfare Act

The case: Haaland v Brackeen

The American Medical Association (AMA) and the American Academy of Pediatrics filed a brief in Haaland v Brackeen⁵ involving the constitutionality of the 1978 Indian Child Welfare Act (ICWA). The statute followed a terrible history of Indian children being removed from their families inappropriately, as detailed in a concurring opinion by Justice Gorsuch.⁵ The two purposes of the act were to promote raising Native American children in their culture and stem the downward trend in tribal membership.

The legal claim. The Court consolidated several cases. Essentially, a 10-month-old child (A.L.M.) was placed in foster care with the Brackeens in Texas. After more than 1 year, the Brackeens sought adoption; the biological father, mother, and grandparents all supported it. The Navajo and Cherokee Nations objected and informed the Texas court that they had found alternative placement with (nonrelative) tribal members in New Mexico. The “court-appointed guardian and a psychological expert … described the strong emotional bond between A.L.M. and his foster parents.” The court denied the adoption petition based on ICWA’s preference for tribe custody, and the Brackeens filed a lawsuit. The Court noted that the act “requires a state court to place an Indian child with an Indian caretaker, if one is available, even if the child is already living with a non-Indian family and the state court thinks it in the child’s best interest to stay there.” That is, the ICWA may require a placement that the court believes is not in the child’s best interest.⁵

Decision. The constitutional claim in the case was that Congress lacked the authority to impose these substantial rules on states in making child custody decisions. The Supreme Court, in a 7-2 decision, upheld the constitutionality of the ICWA. The Court found the authority primarily in Article 1, Section 8, giving Congress the power to “regulate Commerce with foreign Nations, and among the several States, and with the Indian Tribes.” In addition, the Court suggested that the treaty power and “principles inherent in the Constitution’s structure may empower Congress to act in the field of Indian affairs.”

The amici brief

The joint amici brief of the American Academy of Pediatrics (AAP) and the AMA argued that tribes are “extended families” of Native American children.⁶ It noted the destructive history of removing Native American children from their families and suggested that kinship care improves children’s health. To its credit, the brief also honestly noted the serious mental health and suicide rates in some tribes, which suggest issues that might arise in child custody and adoption cases.

The Court did not, in this case, take up another constitutional issue that the parties raised—whether the strong preference for Native American over non ̶ Native American custody violates the Equal Protection Clause of the 14th Amendment. The Court said the parties to this case did not have standing to raise the issue. Justice Kavanaugh, concurring, said it was a “serious” issue and invited it to be raised in another case.⁵

False Claims Act cases

The case: Costs for SuperValu prescriptions

For physicians and health care organizations, False Claims Act (FCA) cases are an ongoing burden and, some would say, threat. (There are also state FCAs, but here we are discussing the federal act.) The federal government has recovered more than $70 billion since 1986, most from health care entities.⁷The Justice Department identifies “health care fraud” as the largest area of FCA recovery and provides annual details on frauds resulting in liability.⁸

The legal claim. One FCA case this Term involved billings SuperValu made for outpatient prescriptions in Medicare-Medicaid programs. As its “usual and customary” costs, it essentially reported a list price that did not include the substantial discounts it commonly gave.⁹ The charge was that it “knowingly” made a false claim regarding the price of prescriptions. The question was what state of mind, or “scienter,” is required for “knowingly.” Should it be objective (what a reasonable person would know) or subjective (the defendant’s “knowledge and subjective beliefs”)?

Background. Subjective knowledge (what the defendant actually knows) may seem impossible to prove—the defendant could just say, “I did not know I was doing wrong.” Over time the law has developed several ways of demonstrating “knowing.” Justice Thomas, writing for a unanimous Court, held that whistleblowers or the government might prove “knowing” in 3 ways:

1. defendants “actually knew that their reported prices were not their ‘usual and customary’ prices when they reported them”

2. were aware of a substantial risk that their higher, retail prices were not their “usual and customary” prices and intentionally avoided learning whether their reports were accurate

3. were aware of such a substantial and unjustifiable risk but submitted the claims anyway.⁹

Of course, records of the company, information from the whistleblower, and circumstantial evidence may be used to prove any of these; it does not require the company’s admission.

The Court said that if the government or whistleblowers make a showing of any of these 3 things, it is enough.

Decision. The case was returned to the lower court to apply these rules.

The amici brief

The American Hospital Association and America’s Health Insurance Plans filed an amici brief.¹⁰ It reminded the Court that many reimbursement regulations are unclear. Therefore, it is inappropriate to impose FCA liability for guessing incorrectly what the regulations mean. Having to check on every possible ambiguity was unworkable. The Court declined, however, the suggestion that defendants should be able to use any one of many “objectively” reasonable interpretations of regulations.

Continue to: The case: Polansky v Executive Health Resources...

The case: Polansky v Executive Health Resources

Health care providers who dislike the FCA may find solace this Term in this second FCA case.¹¹

The legal claim. Polansky, a physician employed by a medical billing company, became an “intervenor” in a suit claiming the company assisted hospitals in false billing (inpatient claims for outpatient services). The government sought to dismiss the case, but Polansky refused.

Decision. The case eventually reached the Supreme Court, which held that the government may enter an FCA case at any time and move to dismiss the case even over the objection of a whistleblower. The government does not seek to enter a case in order to file dismissal motions often. When it does so, whistleblowers are protected by the fact that the dismissal motion requires a hearing before the federal court.

An important part of this case has escaped much attention. Justices Thomas, Kavanaugh, and Barrett invited litigation to determine if allowing private whistleblowers to represent the government’s interest is consistent with Article II of the Constitution.¹¹ The invitation will likely be accepted. We expect to see cases challenging the place of “intervenors” pursuing claims when the government has declined to take up the case. The private intervenor is a crucial provision of the current FCA, and if such a challenge were successful, it could substantially reduce FCA cases.

Criminal false claims

Another case this Term is cautionary about the consequences of health care misbilling. It resulted in a criminal charge. More importantly, in addition to a basic fraud charge, the government added a charge of aggravated identity theft,¹² which carries a mandatory 2-year prison sentence.

Dubin overbilled Medicaid for psychological testing by saying the testing was done by a licensed psychologist rather than an assistant. The government claimed the “identity theft” was using the patient’s (actual) Medicaid number in submitting the bill.¹² The Court unanimously held the overbilling was not aggravated identity theft as defined in federal law. Dubin could be convicted of fraudulent billing but not aggravated identity theft, thereby avoiding the mandatory prison term.

Patents of “genus” targets

The case: Amgen v Sanofi

This case, which corrected an error of the patent office, received little attention but was likely a turning point in the next generation of pharmaceuticals.¹³

Background. “Genus” patents allow a single pharmaceutical company to patent every antibody that binds to a specific amino acid on a naturally occurring protein. In this case, the patent office had granted a “genus” patent on “all antibodies” that bind to the naturally occurring protein PCSK9 and block it from hindering the body’s mechanism for removing low-density lipoprotein (LDL) cholesterol from the bloodstream,¹³ helping to reduce LDL cholesterol levels. These patents could involve millions of antibodies—and Amgen was claiming a patent on all of them. Amgen and Sanofi marketed their products, each with their own unique amino acid sequence.¹³ Amgen sued Sanofi for violating its patent rights.

Decision. The Court unanimously held that Amgen did not have a valid patent on all antibodies targeting PCSK9, only those that it had explicitly described in its patent application—a ruling based on a 150-year-old technical requirement for receiving a patent. An applicant for a patent must include “a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art…to make and use the same.”¹³ Amgen’s patent provided the description for only a few of the antibodies, but from the description in its application others could not “make and use” all of the antibodies targeting PCSK9.

While the decision was vital for future pharmaceuticals, the patent principle on which it was based has an interesting history. The Court noted that it affected the telegraph (Morse lost part of his patent), electric lights (Edison won his case against other inventors), and the glue for wood veneering (Perkins Glue Company lost).¹³

Continue to: Other notable decisions...

Student loans

The Court struck down the Biden Administration’s student loan forgiveness program, which would have cost approximately $430 billion.¹⁴ The central issue was whether the administration had the authority for such massive loan forgiveness; that is, whether Congress had authorized the broad loan forgiveness. The administration claimed authority from the post ̶ 9/11 HEROES Act, which allows the Secretary of Education to “waive or modify” loan provisions during national emergencies. The temporary hold on loan payments during COVID was based on this provision. However, in a 6-3 decision, the Court held that the act did not allow the secretary to cancel $430 billion in loans. “The Act allows the Secretary to ‘waive or modify’ existing statutory or regulatory provisions applicable to financial assistance programs under the Education Act, not to rewrite that statute from the ground up.”¹⁴

Free speech and the wedding web designer

303 Creative v Elenis involved a creative website designer who did not want to be required to create a website for a gay wedding.¹⁵ The designer had strong beliefs against same-sex marriages, but Colorado sought to force her to do so under the state “public accommodations” law. In a 6-3 decision, the Court held that the designer had a “free speech” right. That is, the state could not compel her to undertake speech expressing things she did not believe. This was because the website design was an expressive, creative activity and therefore was “speech” under the First Amendment.

Wetlands and the Clean Water Act

The essential issue in Sackett v Environmental Protection Agency (EPA) was the definitions of waters of the United States and related wetlands. The broad definition the EPA used meant it had jurisdiction to regulate an extraordinary amount of territory. It had, for example, prevented the Sacketts from building a modest house claiming it was part of the “waters of the United States because they were near a ditch that fed into a creek, which fed into Priest Lake, a navigable, intrastate lake.” The Court held that the EPA exceeded its statutory authority to define “wetlands.”¹⁶

The Court held that under the Clean Water Act, for the EPA to establish jurisdiction over adjacent wetlands, it must demonstrate that¹⁶:

1. “the adjacent body of water constitutes waters of the United States (ie, a relatively permanent body of water connected to traditional interstate navigable waters)…”

2. “…the wetland has a continuous surface connection with that water, making it difficult to determine where the water ends, and the wetland begins.”

Under this definition, the Sacketts could build their house. This was a statutory interpretation case. Therefore, Congress can expand or otherwise change the EPA’s authority under the Clean Water Act and other legislation.

Conclusions: A new justice, “shadow docket,” and ethics rules

SCOTUS’ newest member. When the Marshall called the Court into session on October 3, 2022, it had a new member, Justice Ketanji Brown Jackson. She was sworn in on June 30, 2022, when her predecessor (Justice Breyer) officially retired. She had been a law clerk for Justice Breyer in 1999, as well as a district court judge and court of appeals judge. Those who count such things described her as the “chattiest justice.”¹⁷ She spoke more than any other justice—by one count, a total of 75,632 words (an average of 1,300 words in each of the 58 arguments).

A more balanced Court? Most commentators view the Court as more balanced or less conservative than the previous Term. For example, Justice Sotomayor was in the majority 40% last Term but 65% this Term. Justice Thomas was in the majority 75% last Term but 55% this Term. Put another way, this Term in the divided cases, the liberal justices were in the majority 64% of the time, compared with the conservative justices 73%.¹⁸ Of course, these differences may reflect a different set of cases rather than a change in the direction of the Court. There were 11 (or 12, depending on how 1 case is counted) 6-3 cases, but only 5 were considered ideological. That suggests that, in many cases, the coalitions were somewhat fluid.

“Shadow docket” controversy continues.¹⁹ Shadow docket refers to orders the Court makes that do not follow oral arguments and often do not have written opinions. The orders are all publicly available. This Term a close examination of the approximately 30 shadow docket opinions shows that the overwhelming majority were dissents or explanations about denials of certiorari. The Court ordered only a few stays or injunctions via the shadow docket. One shadow docket stay (that prevented a lower court order from going into effect) is particularly noteworthy. A federal judge had ordered the suspension of the distribution of mifepristone while courts considered claims that the US Food and Drug Administration (FDA) had improperly approved the drug. In a shadow docket order, the Court issued the stay to allow mifepristone to be sold while the case challenging its approval was heard.²⁰ The only opinion was a dissent from Justice Alito. But it also demonstrates the importance of the shadow docket. Without this intervention, in at least part of the country, the distribution of mifepristone would have been interrupted pending the outcome of the FDA cases.

In August, the Court delayed a settlement in the Purdue Pharma liability bankruptcy case.²¹ It also stayed an injunction of a lower court, thereby permitting federal “ghost guns” regulations to go into effect at least temporarily.²²

More ethics rules to come? Another area in which the Court faced criticism was formal ethics rules. The justices make financial disclosures, but these are somewhat ambiguous. There is likely to be increasing pressure for a more complete disclosure of non-financial relationships and more formal ethics rules. ●

The 2022-2023 Term of the Supreme Court illustrates how important the Court has become to health-related matters, including decisions regarding the selection and training of new professionals, the daily practice of medicine, and the future availability of new drugs. The importance of several cases is reinforced by the fact that major medical organizations filed amicus curiae (“friend of the court”) briefs in those cases.

Amicus briefs are filed by individuals or organizations with something significant to say about a case to the court—most often to present a point of view, make an argument, or provide information that the parties to the case may not have communicated. Amicus briefs are burdensome in terms of the time, energy, and cost of preparing and filing. Thus, they are not undertaken lightly. Medical organizations submitted amicus briefs in the first 3 cases we consider.

Admissions, race, and diversity

The case: Students for Fair Admissions v President and Fellows of Harvard College

The American College of Obstetricians and Gynecologists (ACOG) joined an amici curiae brief in Students for Fair Admissions v President and Fellows of Harvard College (and the University of North Carolina [UNC]).¹ This case challenged the use of racial preferences in college admissions. The Association of American Medical Colleges (AAMC) was the lead organization; nearly 40 other health-related organizations joined the brief.

The legal claim. Those filing the suits asserted that racial preferences by public colleges violate the 14th Amendment’s Equal Protection Clause (“no state shall deny to any person … the equal protection of the law”). That is, if a state university gives racial preferences in selective admissions, it denies some other applicant the equal protection of the law. As for private schools (in this case, Harvard), Title VI of the Civil Rights Act of 1964 has the same standards as the Equal Protection Clause. Thus, the Court consolidated the cases and used the same legal standard in considering public and private colleges (with “colleges” including professional and graduate programs as well as undergraduate institutions).

Background. For nearly 50 years, the Supreme Court has allowed limited racial preferences in college admissions. Those preferences could only operate as a plus, however, and not a negative for applicants and be narrowly tailored. The measure was instituted temporarily; in a 2003 case, the Court said, “We expect that 25 years from now, the use of racial preferences will no longer be necessary.”²

Decision. In a 6-3 decision, the Court held (in the UNC case) that racial preferences generally violate the Constitution, and by a 6-2 decision (in the Harvard case) these preferences violate the Civil Rights Act of 1964. (Justice Jackson was recused in the Harvard case because of a conflict.) The opinion covered 237 pages in the US Reports, so any summary is incomplete.

The majority concluded, “The Harvard and UNC admissions programs cannot be reconciled with the guarantees of the Equal Protection Clause. Both programs lack sufficiently focused and measurable objectives warranting the use of race, unavoidably employ race in a negative manner, involve racial stereotyping, and lack meaningful end points. We have never permitted admissions programs to work in that way, and we will not do so today.”³

There were 3 concurring opinions and 2 dissents in the case. The concurrences reviewed the history of the Equal Protection Clause and the Civil Rights Act, the damage racial preferences can do, and the explicit limits the Court said there must be on racial preferences in higher education. The dissents had a different view of the legal history of the 14th Amendment. They said the majority was turning a blind eye to segregation in society and the race-based gap in America.

As a practical matter, this case means that colleges, including professional schools, cannot use racial preferences. The Court said that universities may consider essays and the like in which applicants describe how their own experiences as an individual (including race) have affected their own lives. However, the Court cautioned that “universities may not simply establish through application essays or other means the regime we hold unlawful today.”³

Continue to: The amici brief...

ACOG joined 40 other health-related organizations in filing an amici brief (multiple “friends”) in Students for Fair Admission. The AAMC led the brief, with the others signing as amici.⁴ The brief made 3 essential points: diversity in medical education “markedly improves health outcomes,” and a loss of diversity “threaten[s] patients’ health; medical schools engage in an intense “holistic” review of applicants for admission; and medical schools must consider applicants’ “full background” (including race) to achieve their educational and professional goals.⁴

A powerful part of the brief described the medical school admissions process, particularly the very “holistic” review that is not entirely dependent on admissions scores. The brief effectively weaves the consideration of race into this process, mentioning race (on page 22) only after discussing many other admissions factors.

Child custody decisions related to the Indian Child Welfare Act

The case: Haaland v Brackeen

The American Medical Association (AMA) and the American Academy of Pediatrics filed a brief in Haaland v Brackeen⁵ involving the constitutionality of the 1978 Indian Child Welfare Act (ICWA). The statute followed a terrible history of Indian children being removed from their families inappropriately, as detailed in a concurring opinion by Justice Gorsuch.⁵ The two purposes of the act were to promote raising Native American children in their culture and stem the downward trend in tribal membership.

The legal claim. The Court consolidated several cases. Essentially, a 10-month-old child (A.L.M.) was placed in foster care with the Brackeens in Texas. After more than 1 year, the Brackeens sought adoption; the biological father, mother, and grandparents all supported it. The Navajo and Cherokee Nations objected and informed the Texas court that they had found alternative placement with (nonrelative) tribal members in New Mexico. The “court-appointed guardian and a psychological expert … described the strong emotional bond between A.L.M. and his foster parents.” The court denied the adoption petition based on ICWA’s preference for tribe custody, and the Brackeens filed a lawsuit. The Court noted that the act “requires a state court to place an Indian child with an Indian caretaker, if one is available, even if the child is already living with a non-Indian family and the state court thinks it in the child’s best interest to stay there.” That is, the ICWA may require a placement that the court believes is not in the child’s best interest.⁵

Decision. The constitutional claim in the case was that Congress lacked the authority to impose these substantial rules on states in making child custody decisions. The Supreme Court, in a 7-2 decision, upheld the constitutionality of the ICWA. The Court found the authority primarily in Article 1, Section 8, giving Congress the power to “regulate Commerce with foreign Nations, and among the several States, and with the Indian Tribes.” In addition, the Court suggested that the treaty power and “principles inherent in the Constitution’s structure may empower Congress to act in the field of Indian affairs.”

The amici brief

The joint amici brief of the American Academy of Pediatrics (AAP) and the AMA argued that tribes are “extended families” of Native American children.⁶ It noted the destructive history of removing Native American children from their families and suggested that kinship care improves children’s health. To its credit, the brief also honestly noted the serious mental health and suicide rates in some tribes, which suggest issues that might arise in child custody and adoption cases.

The Court did not, in this case, take up another constitutional issue that the parties raised—whether the strong preference for Native American over non ̶ Native American custody violates the Equal Protection Clause of the 14th Amendment. The Court said the parties to this case did not have standing to raise the issue. Justice Kavanaugh, concurring, said it was a “serious” issue and invited it to be raised in another case.⁵

False Claims Act cases

The case: Costs for SuperValu prescriptions

For physicians and health care organizations, False Claims Act (FCA) cases are an ongoing burden and, some would say, threat. (There are also state FCAs, but here we are discussing the federal act.) The federal government has recovered more than $70 billion since 1986, most from health care entities.⁷The Justice Department identifies “health care fraud” as the largest area of FCA recovery and provides annual details on frauds resulting in liability.⁸

The legal claim. One FCA case this Term involved billings SuperValu made for outpatient prescriptions in Medicare-Medicaid programs. As its “usual and customary” costs, it essentially reported a list price that did not include the substantial discounts it commonly gave.⁹ The charge was that it “knowingly” made a false claim regarding the price of prescriptions. The question was what state of mind, or “scienter,” is required for “knowingly.” Should it be objective (what a reasonable person would know) or subjective (the defendant’s “knowledge and subjective beliefs”)?

Background. Subjective knowledge (what the defendant actually knows) may seem impossible to prove—the defendant could just say, “I did not know I was doing wrong.” Over time the law has developed several ways of demonstrating “knowing.” Justice Thomas, writing for a unanimous Court, held that whistleblowers or the government might prove “knowing” in 3 ways:

1. defendants “actually knew that their reported prices were not their ‘usual and customary’ prices when they reported them”

2. were aware of a substantial risk that their higher, retail prices were not their “usual and customary” prices and intentionally avoided learning whether their reports were accurate

3. were aware of such a substantial and unjustifiable risk but submitted the claims anyway.⁹

Of course, records of the company, information from the whistleblower, and circumstantial evidence may be used to prove any of these; it does not require the company’s admission.

The Court said that if the government or whistleblowers make a showing of any of these 3 things, it is enough.

Decision. The case was returned to the lower court to apply these rules.

The amici brief

The American Hospital Association and America’s Health Insurance Plans filed an amici brief.¹⁰ It reminded the Court that many reimbursement regulations are unclear. Therefore, it is inappropriate to impose FCA liability for guessing incorrectly what the regulations mean. Having to check on every possible ambiguity was unworkable. The Court declined, however, the suggestion that defendants should be able to use any one of many “objectively” reasonable interpretations of regulations.

Continue to: The case: Polansky v Executive Health Resources...

The case: Polansky v Executive Health Resources

Health care providers who dislike the FCA may find solace this Term in this second FCA case.¹¹

The legal claim. Polansky, a physician employed by a medical billing company, became an “intervenor” in a suit claiming the company assisted hospitals in false billing (inpatient claims for outpatient services). The government sought to dismiss the case, but Polansky refused.

Decision. The case eventually reached the Supreme Court, which held that the government may enter an FCA case at any time and move to dismiss the case even over the objection of a whistleblower. The government does not seek to enter a case in order to file dismissal motions often. When it does so, whistleblowers are protected by the fact that the dismissal motion requires a hearing before the federal court.

An important part of this case has escaped much attention. Justices Thomas, Kavanaugh, and Barrett invited litigation to determine if allowing private whistleblowers to represent the government’s interest is consistent with Article II of the Constitution.¹¹ The invitation will likely be accepted. We expect to see cases challenging the place of “intervenors” pursuing claims when the government has declined to take up the case. The private intervenor is a crucial provision of the current FCA, and if such a challenge were successful, it could substantially reduce FCA cases.

Criminal false claims

Another case this Term is cautionary about the consequences of health care misbilling. It resulted in a criminal charge. More importantly, in addition to a basic fraud charge, the government added a charge of aggravated identity theft,¹² which carries a mandatory 2-year prison sentence.

Dubin overbilled Medicaid for psychological testing by saying the testing was done by a licensed psychologist rather than an assistant. The government claimed the “identity theft” was using the patient’s (actual) Medicaid number in submitting the bill.¹² The Court unanimously held the overbilling was not aggravated identity theft as defined in federal law. Dubin could be convicted of fraudulent billing but not aggravated identity theft, thereby avoiding the mandatory prison term.

Patents of “genus” targets

The case: Amgen v Sanofi

This case, which corrected an error of the patent office, received little attention but was likely a turning point in the next generation of pharmaceuticals.¹³

Background. “Genus” patents allow a single pharmaceutical company to patent every antibody that binds to a specific amino acid on a naturally occurring protein. In this case, the patent office had granted a “genus” patent on “all antibodies” that bind to the naturally occurring protein PCSK9 and block it from hindering the body’s mechanism for removing low-density lipoprotein (LDL) cholesterol from the bloodstream,¹³ helping to reduce LDL cholesterol levels. These patents could involve millions of antibodies—and Amgen was claiming a patent on all of them. Amgen and Sanofi marketed their products, each with their own unique amino acid sequence.¹³ Amgen sued Sanofi for violating its patent rights.

Decision. The Court unanimously held that Amgen did not have a valid patent on all antibodies targeting PCSK9, only those that it had explicitly described in its patent application—a ruling based on a 150-year-old technical requirement for receiving a patent. An applicant for a patent must include “a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art…to make and use the same.”¹³ Amgen’s patent provided the description for only a few of the antibodies, but from the description in its application others could not “make and use” all of the antibodies targeting PCSK9.

While the decision was vital for future pharmaceuticals, the patent principle on which it was based has an interesting history. The Court noted that it affected the telegraph (Morse lost part of his patent), electric lights (Edison won his case against other inventors), and the glue for wood veneering (Perkins Glue Company lost).¹³

Continue to: Other notable decisions...

Student loans

The Court struck down the Biden Administration’s student loan forgiveness program, which would have cost approximately $430 billion.¹⁴ The central issue was whether the administration had the authority for such massive loan forgiveness; that is, whether Congress had authorized the broad loan forgiveness. The administration claimed authority from the post ̶ 9/11 HEROES Act, which allows the Secretary of Education to “waive or modify” loan provisions during national emergencies. The temporary hold on loan payments during COVID was based on this provision. However, in a 6-3 decision, the Court held that the act did not allow the secretary to cancel $430 billion in loans. “The Act allows the Secretary to ‘waive or modify’ existing statutory or regulatory provisions applicable to financial assistance programs under the Education Act, not to rewrite that statute from the ground up.”¹⁴

Free speech and the wedding web designer

303 Creative v Elenis involved a creative website designer who did not want to be required to create a website for a gay wedding.¹⁵ The designer had strong beliefs against same-sex marriages, but Colorado sought to force her to do so under the state “public accommodations” law. In a 6-3 decision, the Court held that the designer had a “free speech” right. That is, the state could not compel her to undertake speech expressing things she did not believe. This was because the website design was an expressive, creative activity and therefore was “speech” under the First Amendment.

Wetlands and the Clean Water Act

The essential issue in Sackett v Environmental Protection Agency (EPA) was the definitions of waters of the United States and related wetlands. The broad definition the EPA used meant it had jurisdiction to regulate an extraordinary amount of territory. It had, for example, prevented the Sacketts from building a modest house claiming it was part of the “waters of the United States because they were near a ditch that fed into a creek, which fed into Priest Lake, a navigable, intrastate lake.” The Court held that the EPA exceeded its statutory authority to define “wetlands.”¹⁶

The Court held that under the Clean Water Act, for the EPA to establish jurisdiction over adjacent wetlands, it must demonstrate that¹⁶:

1. “the adjacent body of water constitutes waters of the United States (ie, a relatively permanent body of water connected to traditional interstate navigable waters)…”

2. “…the wetland has a continuous surface connection with that water, making it difficult to determine where the water ends, and the wetland begins.”

Under this definition, the Sacketts could build their house. This was a statutory interpretation case. Therefore, Congress can expand or otherwise change the EPA’s authority under the Clean Water Act and other legislation.

Conclusions: A new justice, “shadow docket,” and ethics rules

SCOTUS’ newest member. When the Marshall called the Court into session on October 3, 2022, it had a new member, Justice Ketanji Brown Jackson. She was sworn in on June 30, 2022, when her predecessor (Justice Breyer) officially retired. She had been a law clerk for Justice Breyer in 1999, as well as a district court judge and court of appeals judge. Those who count such things described her as the “chattiest justice.”¹⁷ She spoke more than any other justice—by one count, a total of 75,632 words (an average of 1,300 words in each of the 58 arguments).

A more balanced Court? Most commentators view the Court as more balanced or less conservative than the previous Term. For example, Justice Sotomayor was in the majority 40% last Term but 65% this Term. Justice Thomas was in the majority 75% last Term but 55% this Term. Put another way, this Term in the divided cases, the liberal justices were in the majority 64% of the time, compared with the conservative justices 73%.¹⁸ Of course, these differences may reflect a different set of cases rather than a change in the direction of the Court. There were 11 (or 12, depending on how 1 case is counted) 6-3 cases, but only 5 were considered ideological. That suggests that, in many cases, the coalitions were somewhat fluid.

“Shadow docket” controversy continues.¹⁹ Shadow docket refers to orders the Court makes that do not follow oral arguments and often do not have written opinions. The orders are all publicly available. This Term a close examination of the approximately 30 shadow docket opinions shows that the overwhelming majority were dissents or explanations about denials of certiorari. The Court ordered only a few stays or injunctions via the shadow docket. One shadow docket stay (that prevented a lower court order from going into effect) is particularly noteworthy. A federal judge had ordered the suspension of the distribution of mifepristone while courts considered claims that the US Food and Drug Administration (FDA) had improperly approved the drug. In a shadow docket order, the Court issued the stay to allow mifepristone to be sold while the case challenging its approval was heard.²⁰ The only opinion was a dissent from Justice Alito. But it also demonstrates the importance of the shadow docket. Without this intervention, in at least part of the country, the distribution of mifepristone would have been interrupted pending the outcome of the FDA cases.

In August, the Court delayed a settlement in the Purdue Pharma liability bankruptcy case.²¹ It also stayed an injunction of a lower court, thereby permitting federal “ghost guns” regulations to go into effect at least temporarily.²²

More ethics rules to come? Another area in which the Court faced criticism was formal ethics rules. The justices make financial disclosures, but these are somewhat ambiguous. There is likely to be increasing pressure for a more complete disclosure of non-financial relationships and more formal ethics rules. ●

ILLUSTRATION: KIMBERLY MARTENS FOR OBG MANAGEMENT

Hepatitis B is one of the more common infections encountered in the daily practice of obstetrics. It is responsible for 40% to 45% of all cases of viral hepatitis.^1,2 Hepatitis B may cause serious complications in both the infected mother and neonate.

In this article, I review the virology, epidemiology, and clinical presentation of hepatitis B and then discuss the key diagnostic tests and, subsequently, the clinical management for both the mother and neonate. I focus particular attention on relatively new information about the value of specific antiviral medication to enhance the protective effect of conventional neonatal immunoprophylaxis.

To set the framework for the discussion, consider the following 2 case studies.

CASE 1 Undetectable level of hepatitis B surface antibody in a pregnant woman

A 25-year-old healthy primigravid woman at 10 weeks’ gestation had a series of laboratory studies that included a test for hepatitis B surface antigen (HBsAg) and hepatitis B surface antibody (HBsAb). The test for the surface antigen was negative. The test for the surface antibody was below the level of detection. Upon questioning, the patient indicates that she received the 3-dose hepatitis B vaccine when she was age 13 years.

• What treatment, if any, is indicated for this patient?
• What treatment is indicated for her neonate?

CASE 2 Pregnant woman tests positive for hepatitis B surface antigen

A 31-year-old woman (G3P2002) at 12 weeks’ gestation tested positive for HBsAg. She indicates that she never has had symptomatic hepatitis and that she considers herself to be in excellent health.

• What additional laboratory tests are indicated at this time?
• What additional laboratory test should be performed at the end of the second trimester?
• What treatment is indicated for the mother and neonate?

Virology and epidemiology of hepatitis B

Hepatitis B is caused by a double-stranded, enveloped DNA virus. The virus has 10 genotypes and 24 subtypes.³ The organism contains 3 major antigens. Detection of these antigens and their corresponding antibodies is an essential step in the diagnostic workup of patients who may be infected.

The surface antigen (HBsAg) confers infectivity and is the most valuable serologic marker of infection. The e antigen (HBeAg) is not present in every infected patient. It is secreted from infected cells, but it is not incorporated into the viral particle. When present, it denotes a high level of viral replication and exceptionally high infectivity. The core antigen (HBcAg) is a valuable serologic marker for distinguishing between acute and chronic infection.^1-3

Hepatitis B is highly infectious, much more so than HIV or hepatitis C. The virus has an incubation period of 4 weeks to 6 months, and the duration of incubation is inversely related to the size of the viral inoculum. The virus is transmitted in 3 principal ways: sexual contact with contaminated genital tract secretions, contact with infected blood from sharing contaminated drug-injecting paraphernalia or from receiving a blood transfusion (extremely rare today), and transmission from an infected mother to her neonate. Perinatal transmission occurs primarily during the delivery process as opposed to transplacental infection. Transmission also can occur by more casual household contact, such as sharing eating utensils, kissing, and handling an infant.^1,2,4,5

Worldwide, more than 400 million people have chronic hepatitis B infection. In the United States, approximately 1.25 to 1.5 million individuals are infected. Several groups are at particularly high risk for being infected, including^1-3:

• Asians
• Alaska Natives
• sub-Saharan Africans
• sex workers
• intravenous drug users
• individuals with hemophilia
• international travelers
• staff and residents of long-term care facilities
• tattoo recipients.

Continue to: Clinical presentation...

Approximately 90% of adult patients who contract hepatitis B, either symptomatically or asymptomatically, will develop protective levels of antibody and clear the virus from their system. They will then have lifelong immunity to reinfection. Approximately 10% of patients will fail to develop protective levels of antibody and will become chronically infected, posing a risk to their household members, sexual contacts, and their fetus if they become pregnant. Persistence of the surface antigen in the patient’s serum for more than 6 months denotes chronic infection. A very small number of individuals—less than 1%—will develop acute liver failure and experience a fatal outcome.^1-3,5

In the United States, the prevalence of acute hepatitis B in pregnancy is 1 to 2 per 1,000. Clinical manifestations typically include anorexia, nausea, low-grade fever, right upper quadrant pain and tenderness, passage of clay-colored stools, and jaundice.

The prevalence of chronic infection in pregnancy is significantly higher, approximately 5 to 15 per 1,000. Over the long term, patients with chronic infection are at risk for progressive liver injury, including cirrhosis and even hepatocellular carcinoma. These serious sequelae are particularly likely to occur when the patient is co-infected with hepatitis C, D, or both. The overall risk of progression to chronic cirrhosis is approximately 15% to 30%. In patients who progress to cirrhosis, the annual incidence of hepatocellular carcinoma is 10%.^1-3

Diagnosis of hepatitis B infection

Patients with acute hepatitis B will test positive for HBsAg and immunoglobulin M (IgM) antibody to the core antigen. Some patients will also test positive for HBeAg. Assessment of the patient’s serum by polymerase chain reaction (PCR) allows quantitation of the viral load, which often is expressed as viral copies per milliliter. Alternatively, the quantitative hepatitis B DNA concentration may be expressed as international units per milliliter (IU/mL). The World Health Organization recommends this latter quantitative method. Multiplying the DNA in IU/mL by 5.6 provides the conversion to viral copies per milliliter.

Patients with chronic hepatitis B infection will test positive for the HBsAg and for immunoglobulin G (IgG) antibody to the core antigen. They may also have a positive test for the HBeAg, and PCR may be used to quantify the viral load.^1-3

Managing hepatitis B infection in pregnancy

General supportive measures. All pregnant patients should be tested for the HBsAg and HBsAb at the time of the first prenatal appointment. The tests should be repeated at the beginning of the third trimester in high-risk patients. Seropositive patients should have a hepatitis B genotype, a test for the e antigen, and tests for other sexually transmissible infections (gonorrhea, chlamydia, syphilis, HIV) and for hepatitis C and D. Liver function tests should be performed to assess for elevations in the alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Patients with elevated transaminase enzymes should have a coagulation profile to be certain they are not at risk for a coagulopathy.

At the end of the second trimester, patients should have a PCR assessment to determine the viral load. This assessment will be important for deciding if specific antiviral therapy is indicated during the third trimester to enhance the effects of neonatal immunoprophylaxis (see below). Of note, patients who are positive for the e antigen may have a very high viral load and yet have normal or near-normal transaminase levels. This seemingly paradoxical finding reflects the non-cytopathic nature of hepatitis B.

The patient should optimize her nutrition and sleep. She should avoid, or at least minimize, medications such as acetaminophen that could cause further liver injury. Without question, she should refrain from consuming even small amounts of alcohol. She should be tested for immunity to hepatitis A; if found to be susceptible, she should be vaccinated with the hepatitis A vaccine. This agent is an inactivated vaccine and is safe for administration at any time in pregnancy.^1,2,5

Household contacts. In addition to the measures outlined above, the patient’s household contacts, particularly her sexual partner(s), should be tested for immunity to hepatitis B. If they do not have immunity by virtue of natural infection or previous vaccination, they should receive the hepatitis B vaccine series. It is also prudent to provide the sexual partner(s) with an initial dose of hepatitis B immune globulin (HBIG) to provide a temporary level of passive immunity.

Postdelivery care. After delivery, the patient should be referred to an infectious disease specialist or hepatologist for consideration of long-term treatment with antiviral agents, such as interferon alfa, pegylated interferon alfa, lamivudine, adefovir, entecavir, telbivudine, or tenofovir.⁶ The principal candidates for treatment are those who have cirrhosis and detectable levels of hepatitis B DNA. The ultimate goal of treatment is to reduce the serum hepatitis B DNA concentration to an undetectable level. Once the surface antigenemia is cleared, treatment can be stopped. A cure is defined when the absence of hepa-titis B DNA in the serum is sustained.

Neonatal immunoprophylaxis

The Centers for Disease Control and Prevention recommends universal hepatitis B vaccination for all newborns. The first dose of the vaccine should be administered prior to hospital discharge. The second and third doses should be administered 1 and 6 months later.^1,2,5 There are few, if any, medical contraindications to neonatal vaccination. For the vast majority of infants, the immunity induced by vaccination is lifelong. For a small number, immunity may wane over time. Thus, reassessment of the HBsAb concentration is indicated in selected situations, for example, acute high-risk exposure to an infected person, development of an immunosuppressive disorder, or pregnancy.

Infants delivered to mothers who are infected with hepatitis B also should receive HBIG in addition to the vaccine. HBIG provides passive immunization to counteract the high viral inoculum encountered by the neonate during delivery. This preparation should be administered within 12 hours of birth.^1,2,5

In the absence of immunoprophylaxis, a neonate delivered to a mother who is seropositive for HBsAg has a 20% to 30% probability of becoming chronically infected. If the mother is positive for both the surface antigen and the e antigen, the risk of chronic infection increases to almost 90%. Approximately 90% of infants who are infected in the perinatal period subsequently develop chronic infection. However, with appropriate immunoprophylaxis in the neonatal period, the risk of perinatal transmission is reduced by 85% to 95%.^1,2,5

Cesarean delivery offers no additional protection beyond that provided by immunoprophylaxis. Moreover, because immunoprophylaxis is so effective, infected mothers may breastfeed without fear of transmitting infection to their infant. Shi and colleagues published a systematic review and meta-analysis of the risk associated with breastfeeding in hepatitis B–infected mothers.⁷ Infants who breastfed did not have a higher rate of mother-to-child transmission, regardless of whether they received combined immunoprophylaxis or only hepatitis B vaccine and regardless of whether the HBsAg was detected in the mother’s breast milk. The only precaution is the need to avoid breastfeeding if the nipples are cracked or bleeding or if exudative lesions are present on the skin near the nipple.

Continue to: Maternal antiviral therapy...

Maternal antiviral therapy

As noted above, neonatal immunoprophylaxis is 85% to 95% effective in preventing perinatal transmission of hepatitis B infection. Failures of prophylaxis are primarily due to antenatal transmission in patients who have exceptionally high viral loads. Several cutoffs have been used to define “high viral load,” including greater than 1 to 2 million copies/mL and a hepatitis B DNA concentration greater than 200,000 IU/mL. There is not a perfect consensus on the appropriate cutoff.

In essence, 2 different approaches have been tried to further reduce the risk of perinatal transmission in these high-risk patients.⁸ The first major initiative was administration of HBIG (100–200 IU) intramuscularly to the patient at 28, 32, and 36 weeks. The outcomes with this approach have been inconsistent, due, at least in part, to varying doses of the agent and various cutoffs for defining “high risk,” and this intervention is no longer recommended.^1,2

The second major approach is administration of specific antiviral drugs to the mother during the third trimester. The first agent widely used in clinical practice was lamivudine. In a systematic review and meta-analysis, Shi and colleagues reported that, in infants whose mothers received lamivudine plus conventional neonatal immunuprophylaxis, the risk of perinatal infection was significantly reduced compared with infants who received only immunoprophylaxis.⁹

Although lamivudine is effective, there is considerable concern about the rapid development of viral resistance to the medication. Accordingly, most attention today is focused on the use of tenofovir to prevent perinatal transmission.

In an important early investigation, Pan and colleagues reported the results of a randomized controlled trial conducted in China in women with a hepatitis B DNA concentration greater than 200,000 IU/mL (viral load > 1,120,000 copies/mL).¹⁰ Patients also were positive for the e antigen. Ninety-two patients were assigned to tenofovir disoproxil fumarate (TDF), 300 mg daily, from 30 to 32 weeks until postpartum week 4 plus conventional neonatal immunoprophylaxis, and 100 patients were assigned to immunoprophylaxis alone. In the intention-to-treat analysis, 18 neonates in the control group were infected compared with 5 in the treatment group (P = .007). In the per-protocol analysis, 7 neonates in the control group were infected compared with 0 in the treatment group (P = .01). No clinically significant adverse maternal or neonatal effects occurred in the treatment group.

Subsequently, Jourdain and colleagues reported a multicenter, double-blind trial conducted in 17 public health hospitals in Thailand.¹¹ TDF (300 mg daily) or placebo was administered from 28 weeks’ gestation until 8 weeks postpartum. Patients in both arms of the study were positive for the e antigen; 87% to 90% of the patients had a serum hepatitis B DNA concentration greater than 200,000 IU/mL.Following birth, infants in both groups received an injection of HBIG and then 4 doses of hepatitis B vaccine (0, 1, 2, 4, and 6 months). Both the HBIG and hepatitis B vaccine were administered very promptly after birth (median time, 1.2–1.3 hours).

At 6 months after delivery, 2% of infants in the placebo group (3 of 147) were HBsAg-positive compared with none of the infants in the treatment arm.¹¹ No serious adverse effects occurred in infants in the TDF group. This difference in outcome was not statistically significant, but the overall rate of infection was so low in both groups that the sample size was definitely too small to exclude a type 2 statistical error. Moreover, the fourth dose of neonatal hepatitis B vaccine may have contributed to the surprisingly low rate of perinatal transmission. Of note, the serum hepatitis B DNA concentration in the TDF group declined from a mean of 7.6 log₁₀ IU/mL to a mean of 4.0 log₁₀ IU/mL at delivery.

In the most recent report, Wang and colleagues reported the results of a prospective cohort study in patients with a hepatitis B virus DNA concentration greater than 200,000 IU/mL.¹² Beginning at either 24 or 32 weeks, patients were assigned to treatment with either oral TDF (300 mg daily) or oral telbivudine (LdT, 600 mg daily). The medications were continued for 4 weeks postpartum. In the intention-to-treat analysis, the rates of perinatal transmission were comparable, 1.5% versus 1.8%. In the per-protocol analysis, no infants in either group were infected. However, the predelivery decline in hepatitis Bvirus DNA concentration was greater in the TDF group. The ALT elevation rate was also lower in the TDF group. Patients in the LdT group had fewer problems with anorexia but more instances of arthralgia compared with those in the TDF group.

Based primarily on these 3 investigations, I recommend that all infected patients with a hepatitis B DNA concentration greater than 200,000 IU/mL or a viral load greater than 1,120,000 million copies/mL receive oral TDF, 300 mg daily, from 28 weeks until at least 4 to 8 weeks postpartum. The decision about duration of postpartum treatment should be made in consultation with an infectious disease specialist or hepatologist.

Case studies resolved

CASE 1 No protective level of surface antibody

This patient should promptly receive a single booster dose of the hepatitis B vaccine. The vaccine is an inactivated agent and is safe for administration at any time in pregnancy. Following delivery and prior to discharge from the hospital, the neonate should receive the first dose of the hepatitis B vaccine. A second dose should be administered 1 month later, and a third dose should be administered 6 months after the first dose.

CASE 2 Mother is seropositive for HBsAg

This patient should be tested immediately for HIV infection and hepatitis C and D. The hepatitis B viral genotype should be determined. She also should have a panel of liver function tests. If any of these tests are abnormal, a coagulation profile should be obtained to be certain that the patient is not at risk for a coagulopathy. Near the end of the second trimester, a hepatitis B viral load should be obtained. If the viral DNA concentration is greater than 200,000 IU/mLor a viral load greater than 1,120,000 million copies/mL, the patient should be treated with tenofovir, 300 mg daily, from week 28 until at least 4 weeks after delivery. The neonate should receive an injection of HBIG within 12 hours of birth and the first dose of the hepatitis B vaccine prior to discharge from the hospital. Two additional doses of the vaccine should be administered 1 and 6 months later. ●

ILLUSTRATION: KIMBERLY MARTENS FOR OBG MANAGEMENT

Hepatitis B is one of the more common infections encountered in the daily practice of obstetrics. It is responsible for 40% to 45% of all cases of viral hepatitis.^1,2 Hepatitis B may cause serious complications in both the infected mother and neonate.

In this article, I review the virology, epidemiology, and clinical presentation of hepatitis B and then discuss the key diagnostic tests and, subsequently, the clinical management for both the mother and neonate. I focus particular attention on relatively new information about the value of specific antiviral medication to enhance the protective effect of conventional neonatal immunoprophylaxis.

To set the framework for the discussion, consider the following 2 case studies.

CASE 1 Undetectable level of hepatitis B surface antibody in a pregnant woman

A 25-year-old healthy primigravid woman at 10 weeks’ gestation had a series of laboratory studies that included a test for hepatitis B surface antigen (HBsAg) and hepatitis B surface antibody (HBsAb). The test for the surface antigen was negative. The test for the surface antibody was below the level of detection. Upon questioning, the patient indicates that she received the 3-dose hepatitis B vaccine when she was age 13 years.

• What treatment, if any, is indicated for this patient?
• What treatment is indicated for her neonate?

CASE 2 Pregnant woman tests positive for hepatitis B surface antigen

A 31-year-old woman (G3P2002) at 12 weeks’ gestation tested positive for HBsAg. She indicates that she never has had symptomatic hepatitis and that she considers herself to be in excellent health.

• What additional laboratory tests are indicated at this time?
• What additional laboratory test should be performed at the end of the second trimester?
• What treatment is indicated for the mother and neonate?

Virology and epidemiology of hepatitis B

Hepatitis B is caused by a double-stranded, enveloped DNA virus. The virus has 10 genotypes and 24 subtypes.³ The organism contains 3 major antigens. Detection of these antigens and their corresponding antibodies is an essential step in the diagnostic workup of patients who may be infected.

The surface antigen (HBsAg) confers infectivity and is the most valuable serologic marker of infection. The e antigen (HBeAg) is not present in every infected patient. It is secreted from infected cells, but it is not incorporated into the viral particle. When present, it denotes a high level of viral replication and exceptionally high infectivity. The core antigen (HBcAg) is a valuable serologic marker for distinguishing between acute and chronic infection.^1-3

Hepatitis B is highly infectious, much more so than HIV or hepatitis C. The virus has an incubation period of 4 weeks to 6 months, and the duration of incubation is inversely related to the size of the viral inoculum. The virus is transmitted in 3 principal ways: sexual contact with contaminated genital tract secretions, contact with infected blood from sharing contaminated drug-injecting paraphernalia or from receiving a blood transfusion (extremely rare today), and transmission from an infected mother to her neonate. Perinatal transmission occurs primarily during the delivery process as opposed to transplacental infection. Transmission also can occur by more casual household contact, such as sharing eating utensils, kissing, and handling an infant.^1,2,4,5

Worldwide, more than 400 million people have chronic hepatitis B infection. In the United States, approximately 1.25 to 1.5 million individuals are infected. Several groups are at particularly high risk for being infected, including^1-3:

• Asians
• Alaska Natives
• sub-Saharan Africans
• sex workers
• intravenous drug users
• individuals with hemophilia
• international travelers
• staff and residents of long-term care facilities
• tattoo recipients.

Continue to: Clinical presentation...

Approximately 90% of adult patients who contract hepatitis B, either symptomatically or asymptomatically, will develop protective levels of antibody and clear the virus from their system. They will then have lifelong immunity to reinfection. Approximately 10% of patients will fail to develop protective levels of antibody and will become chronically infected, posing a risk to their household members, sexual contacts, and their fetus if they become pregnant. Persistence of the surface antigen in the patient’s serum for more than 6 months denotes chronic infection. A very small number of individuals—less than 1%—will develop acute liver failure and experience a fatal outcome.^1-3,5

In the United States, the prevalence of acute hepatitis B in pregnancy is 1 to 2 per 1,000. Clinical manifestations typically include anorexia, nausea, low-grade fever, right upper quadrant pain and tenderness, passage of clay-colored stools, and jaundice.

The prevalence of chronic infection in pregnancy is significantly higher, approximately 5 to 15 per 1,000. Over the long term, patients with chronic infection are at risk for progressive liver injury, including cirrhosis and even hepatocellular carcinoma. These serious sequelae are particularly likely to occur when the patient is co-infected with hepatitis C, D, or both. The overall risk of progression to chronic cirrhosis is approximately 15% to 30%. In patients who progress to cirrhosis, the annual incidence of hepatocellular carcinoma is 10%.^1-3

Diagnosis of hepatitis B infection

Patients with acute hepatitis B will test positive for HBsAg and immunoglobulin M (IgM) antibody to the core antigen. Some patients will also test positive for HBeAg. Assessment of the patient’s serum by polymerase chain reaction (PCR) allows quantitation of the viral load, which often is expressed as viral copies per milliliter. Alternatively, the quantitative hepatitis B DNA concentration may be expressed as international units per milliliter (IU/mL). The World Health Organization recommends this latter quantitative method. Multiplying the DNA in IU/mL by 5.6 provides the conversion to viral copies per milliliter.

Patients with chronic hepatitis B infection will test positive for the HBsAg and for immunoglobulin G (IgG) antibody to the core antigen. They may also have a positive test for the HBeAg, and PCR may be used to quantify the viral load.^1-3

Managing hepatitis B infection in pregnancy

General supportive measures. All pregnant patients should be tested for the HBsAg and HBsAb at the time of the first prenatal appointment. The tests should be repeated at the beginning of the third trimester in high-risk patients. Seropositive patients should have a hepatitis B genotype, a test for the e antigen, and tests for other sexually transmissible infections (gonorrhea, chlamydia, syphilis, HIV) and for hepatitis C and D. Liver function tests should be performed to assess for elevations in the alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Patients with elevated transaminase enzymes should have a coagulation profile to be certain they are not at risk for a coagulopathy.

At the end of the second trimester, patients should have a PCR assessment to determine the viral load. This assessment will be important for deciding if specific antiviral therapy is indicated during the third trimester to enhance the effects of neonatal immunoprophylaxis (see below). Of note, patients who are positive for the e antigen may have a very high viral load and yet have normal or near-normal transaminase levels. This seemingly paradoxical finding reflects the non-cytopathic nature of hepatitis B.

The patient should optimize her nutrition and sleep. She should avoid, or at least minimize, medications such as acetaminophen that could cause further liver injury. Without question, she should refrain from consuming even small amounts of alcohol. She should be tested for immunity to hepatitis A; if found to be susceptible, she should be vaccinated with the hepatitis A vaccine. This agent is an inactivated vaccine and is safe for administration at any time in pregnancy.^1,2,5

Household contacts. In addition to the measures outlined above, the patient’s household contacts, particularly her sexual partner(s), should be tested for immunity to hepatitis B. If they do not have immunity by virtue of natural infection or previous vaccination, they should receive the hepatitis B vaccine series. It is also prudent to provide the sexual partner(s) with an initial dose of hepatitis B immune globulin (HBIG) to provide a temporary level of passive immunity.

Postdelivery care. After delivery, the patient should be referred to an infectious disease specialist or hepatologist for consideration of long-term treatment with antiviral agents, such as interferon alfa, pegylated interferon alfa, lamivudine, adefovir, entecavir, telbivudine, or tenofovir.⁶ The principal candidates for treatment are those who have cirrhosis and detectable levels of hepatitis B DNA. The ultimate goal of treatment is to reduce the serum hepatitis B DNA concentration to an undetectable level. Once the surface antigenemia is cleared, treatment can be stopped. A cure is defined when the absence of hepa-titis B DNA in the serum is sustained.

Neonatal immunoprophylaxis

The Centers for Disease Control and Prevention recommends universal hepatitis B vaccination for all newborns. The first dose of the vaccine should be administered prior to hospital discharge. The second and third doses should be administered 1 and 6 months later.^1,2,5 There are few, if any, medical contraindications to neonatal vaccination. For the vast majority of infants, the immunity induced by vaccination is lifelong. For a small number, immunity may wane over time. Thus, reassessment of the HBsAb concentration is indicated in selected situations, for example, acute high-risk exposure to an infected person, development of an immunosuppressive disorder, or pregnancy.

Infants delivered to mothers who are infected with hepatitis B also should receive HBIG in addition to the vaccine. HBIG provides passive immunization to counteract the high viral inoculum encountered by the neonate during delivery. This preparation should be administered within 12 hours of birth.^1,2,5

In the absence of immunoprophylaxis, a neonate delivered to a mother who is seropositive for HBsAg has a 20% to 30% probability of becoming chronically infected. If the mother is positive for both the surface antigen and the e antigen, the risk of chronic infection increases to almost 90%. Approximately 90% of infants who are infected in the perinatal period subsequently develop chronic infection. However, with appropriate immunoprophylaxis in the neonatal period, the risk of perinatal transmission is reduced by 85% to 95%.^1,2,5

Cesarean delivery offers no additional protection beyond that provided by immunoprophylaxis. Moreover, because immunoprophylaxis is so effective, infected mothers may breastfeed without fear of transmitting infection to their infant. Shi and colleagues published a systematic review and meta-analysis of the risk associated with breastfeeding in hepatitis B–infected mothers.⁷ Infants who breastfed did not have a higher rate of mother-to-child transmission, regardless of whether they received combined immunoprophylaxis or only hepatitis B vaccine and regardless of whether the HBsAg was detected in the mother’s breast milk. The only precaution is the need to avoid breastfeeding if the nipples are cracked or bleeding or if exudative lesions are present on the skin near the nipple.

Continue to: Maternal antiviral therapy...

Maternal antiviral therapy

As noted above, neonatal immunoprophylaxis is 85% to 95% effective in preventing perinatal transmission of hepatitis B infection. Failures of prophylaxis are primarily due to antenatal transmission in patients who have exceptionally high viral loads. Several cutoffs have been used to define “high viral load,” including greater than 1 to 2 million copies/mL and a hepatitis B DNA concentration greater than 200,000 IU/mL. There is not a perfect consensus on the appropriate cutoff.

In essence, 2 different approaches have been tried to further reduce the risk of perinatal transmission in these high-risk patients.⁸ The first major initiative was administration of HBIG (100–200 IU) intramuscularly to the patient at 28, 32, and 36 weeks. The outcomes with this approach have been inconsistent, due, at least in part, to varying doses of the agent and various cutoffs for defining “high risk,” and this intervention is no longer recommended.^1,2

The second major approach is administration of specific antiviral drugs to the mother during the third trimester. The first agent widely used in clinical practice was lamivudine. In a systematic review and meta-analysis, Shi and colleagues reported that, in infants whose mothers received lamivudine plus conventional neonatal immunuprophylaxis, the risk of perinatal infection was significantly reduced compared with infants who received only immunoprophylaxis.⁹

Although lamivudine is effective, there is considerable concern about the rapid development of viral resistance to the medication. Accordingly, most attention today is focused on the use of tenofovir to prevent perinatal transmission.

In an important early investigation, Pan and colleagues reported the results of a randomized controlled trial conducted in China in women with a hepatitis B DNA concentration greater than 200,000 IU/mL (viral load > 1,120,000 copies/mL).¹⁰ Patients also were positive for the e antigen. Ninety-two patients were assigned to tenofovir disoproxil fumarate (TDF), 300 mg daily, from 30 to 32 weeks until postpartum week 4 plus conventional neonatal immunoprophylaxis, and 100 patients were assigned to immunoprophylaxis alone. In the intention-to-treat analysis, 18 neonates in the control group were infected compared with 5 in the treatment group (P = .007). In the per-protocol analysis, 7 neonates in the control group were infected compared with 0 in the treatment group (P = .01). No clinically significant adverse maternal or neonatal effects occurred in the treatment group.

Subsequently, Jourdain and colleagues reported a multicenter, double-blind trial conducted in 17 public health hospitals in Thailand.¹¹ TDF (300 mg daily) or placebo was administered from 28 weeks’ gestation until 8 weeks postpartum. Patients in both arms of the study were positive for the e antigen; 87% to 90% of the patients had a serum hepatitis B DNA concentration greater than 200,000 IU/mL.Following birth, infants in both groups received an injection of HBIG and then 4 doses of hepatitis B vaccine (0, 1, 2, 4, and 6 months). Both the HBIG and hepatitis B vaccine were administered very promptly after birth (median time, 1.2–1.3 hours).

At 6 months after delivery, 2% of infants in the placebo group (3 of 147) were HBsAg-positive compared with none of the infants in the treatment arm.¹¹ No serious adverse effects occurred in infants in the TDF group. This difference in outcome was not statistically significant, but the overall rate of infection was so low in both groups that the sample size was definitely too small to exclude a type 2 statistical error. Moreover, the fourth dose of neonatal hepatitis B vaccine may have contributed to the surprisingly low rate of perinatal transmission. Of note, the serum hepatitis B DNA concentration in the TDF group declined from a mean of 7.6 log₁₀ IU/mL to a mean of 4.0 log₁₀ IU/mL at delivery.

In the most recent report, Wang and colleagues reported the results of a prospective cohort study in patients with a hepatitis B virus DNA concentration greater than 200,000 IU/mL.¹² Beginning at either 24 or 32 weeks, patients were assigned to treatment with either oral TDF (300 mg daily) or oral telbivudine (LdT, 600 mg daily). The medications were continued for 4 weeks postpartum. In the intention-to-treat analysis, the rates of perinatal transmission were comparable, 1.5% versus 1.8%. In the per-protocol analysis, no infants in either group were infected. However, the predelivery decline in hepatitis Bvirus DNA concentration was greater in the TDF group. The ALT elevation rate was also lower in the TDF group. Patients in the LdT group had fewer problems with anorexia but more instances of arthralgia compared with those in the TDF group.

Based primarily on these 3 investigations, I recommend that all infected patients with a hepatitis B DNA concentration greater than 200,000 IU/mL or a viral load greater than 1,120,000 million copies/mL receive oral TDF, 300 mg daily, from 28 weeks until at least 4 to 8 weeks postpartum. The decision about duration of postpartum treatment should be made in consultation with an infectious disease specialist or hepatologist.

Case studies resolved

CASE 1 No protective level of surface antibody

This patient should promptly receive a single booster dose of the hepatitis B vaccine. The vaccine is an inactivated agent and is safe for administration at any time in pregnancy. Following delivery and prior to discharge from the hospital, the neonate should receive the first dose of the hepatitis B vaccine. A second dose should be administered 1 month later, and a third dose should be administered 6 months after the first dose.

CASE 2 Mother is seropositive for HBsAg

This patient should be tested immediately for HIV infection and hepatitis C and D. The hepatitis B viral genotype should be determined. She also should have a panel of liver function tests. If any of these tests are abnormal, a coagulation profile should be obtained to be certain that the patient is not at risk for a coagulopathy. Near the end of the second trimester, a hepatitis B viral load should be obtained. If the viral DNA concentration is greater than 200,000 IU/mLor a viral load greater than 1,120,000 million copies/mL, the patient should be treated with tenofovir, 300 mg daily, from week 28 until at least 4 weeks after delivery. The neonate should receive an injection of HBIG within 12 hours of birth and the first dose of the hepatitis B vaccine prior to discharge from the hospital. Two additional doses of the vaccine should be administered 1 and 6 months later. ●

ILLUSTRATION: KIMBERLY MARTENS FOR OBG MANAGEMENT

Hepatitis B is one of the more common infections encountered in the daily practice of obstetrics. It is responsible for 40% to 45% of all cases of viral hepatitis.^1,2 Hepatitis B may cause serious complications in both the infected mother and neonate.

In this article, I review the virology, epidemiology, and clinical presentation of hepatitis B and then discuss the key diagnostic tests and, subsequently, the clinical management for both the mother and neonate. I focus particular attention on relatively new information about the value of specific antiviral medication to enhance the protective effect of conventional neonatal immunoprophylaxis.

To set the framework for the discussion, consider the following 2 case studies.

CASE 1 Undetectable level of hepatitis B surface antibody in a pregnant woman

A 25-year-old healthy primigravid woman at 10 weeks’ gestation had a series of laboratory studies that included a test for hepatitis B surface antigen (HBsAg) and hepatitis B surface antibody (HBsAb). The test for the surface antigen was negative. The test for the surface antibody was below the level of detection. Upon questioning, the patient indicates that she received the 3-dose hepatitis B vaccine when she was age 13 years.

• What treatment, if any, is indicated for this patient?
• What treatment is indicated for her neonate?

CASE 2 Pregnant woman tests positive for hepatitis B surface antigen

A 31-year-old woman (G3P2002) at 12 weeks’ gestation tested positive for HBsAg. She indicates that she never has had symptomatic hepatitis and that she considers herself to be in excellent health.

• What additional laboratory tests are indicated at this time?
• What additional laboratory test should be performed at the end of the second trimester?
• What treatment is indicated for the mother and neonate?

Virology and epidemiology of hepatitis B

Hepatitis B is caused by a double-stranded, enveloped DNA virus. The virus has 10 genotypes and 24 subtypes.³ The organism contains 3 major antigens. Detection of these antigens and their corresponding antibodies is an essential step in the diagnostic workup of patients who may be infected.

The surface antigen (HBsAg) confers infectivity and is the most valuable serologic marker of infection. The e antigen (HBeAg) is not present in every infected patient. It is secreted from infected cells, but it is not incorporated into the viral particle. When present, it denotes a high level of viral replication and exceptionally high infectivity. The core antigen (HBcAg) is a valuable serologic marker for distinguishing between acute and chronic infection.^1-3

Hepatitis B is highly infectious, much more so than HIV or hepatitis C. The virus has an incubation period of 4 weeks to 6 months, and the duration of incubation is inversely related to the size of the viral inoculum. The virus is transmitted in 3 principal ways: sexual contact with contaminated genital tract secretions, contact with infected blood from sharing contaminated drug-injecting paraphernalia or from receiving a blood transfusion (extremely rare today), and transmission from an infected mother to her neonate. Perinatal transmission occurs primarily during the delivery process as opposed to transplacental infection. Transmission also can occur by more casual household contact, such as sharing eating utensils, kissing, and handling an infant.^1,2,4,5

Worldwide, more than 400 million people have chronic hepatitis B infection. In the United States, approximately 1.25 to 1.5 million individuals are infected. Several groups are at particularly high risk for being infected, including^1-3:

• Asians
• Alaska Natives
• sub-Saharan Africans
• sex workers
• intravenous drug users
• individuals with hemophilia
• international travelers
• staff and residents of long-term care facilities
• tattoo recipients.

Continue to: Clinical presentation...

Approximately 90% of adult patients who contract hepatitis B, either symptomatically or asymptomatically, will develop protective levels of antibody and clear the virus from their system. They will then have lifelong immunity to reinfection. Approximately 10% of patients will fail to develop protective levels of antibody and will become chronically infected, posing a risk to their household members, sexual contacts, and their fetus if they become pregnant. Persistence of the surface antigen in the patient’s serum for more than 6 months denotes chronic infection. A very small number of individuals—less than 1%—will develop acute liver failure and experience a fatal outcome.^1-3,5

In the United States, the prevalence of acute hepatitis B in pregnancy is 1 to 2 per 1,000. Clinical manifestations typically include anorexia, nausea, low-grade fever, right upper quadrant pain and tenderness, passage of clay-colored stools, and jaundice.

The prevalence of chronic infection in pregnancy is significantly higher, approximately 5 to 15 per 1,000. Over the long term, patients with chronic infection are at risk for progressive liver injury, including cirrhosis and even hepatocellular carcinoma. These serious sequelae are particularly likely to occur when the patient is co-infected with hepatitis C, D, or both. The overall risk of progression to chronic cirrhosis is approximately 15% to 30%. In patients who progress to cirrhosis, the annual incidence of hepatocellular carcinoma is 10%.^1-3

Diagnosis of hepatitis B infection

Patients with acute hepatitis B will test positive for HBsAg and immunoglobulin M (IgM) antibody to the core antigen. Some patients will also test positive for HBeAg. Assessment of the patient’s serum by polymerase chain reaction (PCR) allows quantitation of the viral load, which often is expressed as viral copies per milliliter. Alternatively, the quantitative hepatitis B DNA concentration may be expressed as international units per milliliter (IU/mL). The World Health Organization recommends this latter quantitative method. Multiplying the DNA in IU/mL by 5.6 provides the conversion to viral copies per milliliter.

Patients with chronic hepatitis B infection will test positive for the HBsAg and for immunoglobulin G (IgG) antibody to the core antigen. They may also have a positive test for the HBeAg, and PCR may be used to quantify the viral load.^1-3

Managing hepatitis B infection in pregnancy

General supportive measures. All pregnant patients should be tested for the HBsAg and HBsAb at the time of the first prenatal appointment. The tests should be repeated at the beginning of the third trimester in high-risk patients. Seropositive patients should have a hepatitis B genotype, a test for the e antigen, and tests for other sexually transmissible infections (gonorrhea, chlamydia, syphilis, HIV) and for hepatitis C and D. Liver function tests should be performed to assess for elevations in the alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Patients with elevated transaminase enzymes should have a coagulation profile to be certain they are not at risk for a coagulopathy.

At the end of the second trimester, patients should have a PCR assessment to determine the viral load. This assessment will be important for deciding if specific antiviral therapy is indicated during the third trimester to enhance the effects of neonatal immunoprophylaxis (see below). Of note, patients who are positive for the e antigen may have a very high viral load and yet have normal or near-normal transaminase levels. This seemingly paradoxical finding reflects the non-cytopathic nature of hepatitis B.

The patient should optimize her nutrition and sleep. She should avoid, or at least minimize, medications such as acetaminophen that could cause further liver injury. Without question, she should refrain from consuming even small amounts of alcohol. She should be tested for immunity to hepatitis A; if found to be susceptible, she should be vaccinated with the hepatitis A vaccine. This agent is an inactivated vaccine and is safe for administration at any time in pregnancy.^1,2,5

Household contacts. In addition to the measures outlined above, the patient’s household contacts, particularly her sexual partner(s), should be tested for immunity to hepatitis B. If they do not have immunity by virtue of natural infection or previous vaccination, they should receive the hepatitis B vaccine series. It is also prudent to provide the sexual partner(s) with an initial dose of hepatitis B immune globulin (HBIG) to provide a temporary level of passive immunity.

Postdelivery care. After delivery, the patient should be referred to an infectious disease specialist or hepatologist for consideration of long-term treatment with antiviral agents, such as interferon alfa, pegylated interferon alfa, lamivudine, adefovir, entecavir, telbivudine, or tenofovir.⁶ The principal candidates for treatment are those who have cirrhosis and detectable levels of hepatitis B DNA. The ultimate goal of treatment is to reduce the serum hepatitis B DNA concentration to an undetectable level. Once the surface antigenemia is cleared, treatment can be stopped. A cure is defined when the absence of hepa-titis B DNA in the serum is sustained.

Neonatal immunoprophylaxis

The Centers for Disease Control and Prevention recommends universal hepatitis B vaccination for all newborns. The first dose of the vaccine should be administered prior to hospital discharge. The second and third doses should be administered 1 and 6 months later.^1,2,5 There are few, if any, medical contraindications to neonatal vaccination. For the vast majority of infants, the immunity induced by vaccination is lifelong. For a small number, immunity may wane over time. Thus, reassessment of the HBsAb concentration is indicated in selected situations, for example, acute high-risk exposure to an infected person, development of an immunosuppressive disorder, or pregnancy.

Infants delivered to mothers who are infected with hepatitis B also should receive HBIG in addition to the vaccine. HBIG provides passive immunization to counteract the high viral inoculum encountered by the neonate during delivery. This preparation should be administered within 12 hours of birth.^1,2,5

In the absence of immunoprophylaxis, a neonate delivered to a mother who is seropositive for HBsAg has a 20% to 30% probability of becoming chronically infected. If the mother is positive for both the surface antigen and the e antigen, the risk of chronic infection increases to almost 90%. Approximately 90% of infants who are infected in the perinatal period subsequently develop chronic infection. However, with appropriate immunoprophylaxis in the neonatal period, the risk of perinatal transmission is reduced by 85% to 95%.^1,2,5

Cesarean delivery offers no additional protection beyond that provided by immunoprophylaxis. Moreover, because immunoprophylaxis is so effective, infected mothers may breastfeed without fear of transmitting infection to their infant. Shi and colleagues published a systematic review and meta-analysis of the risk associated with breastfeeding in hepatitis B–infected mothers.⁷ Infants who breastfed did not have a higher rate of mother-to-child transmission, regardless of whether they received combined immunoprophylaxis or only hepatitis B vaccine and regardless of whether the HBsAg was detected in the mother’s breast milk. The only precaution is the need to avoid breastfeeding if the nipples are cracked or bleeding or if exudative lesions are present on the skin near the nipple.

Continue to: Maternal antiviral therapy...

Maternal antiviral therapy

As noted above, neonatal immunoprophylaxis is 85% to 95% effective in preventing perinatal transmission of hepatitis B infection. Failures of prophylaxis are primarily due to antenatal transmission in patients who have exceptionally high viral loads. Several cutoffs have been used to define “high viral load,” including greater than 1 to 2 million copies/mL and a hepatitis B DNA concentration greater than 200,000 IU/mL. There is not a perfect consensus on the appropriate cutoff.

In essence, 2 different approaches have been tried to further reduce the risk of perinatal transmission in these high-risk patients.⁸ The first major initiative was administration of HBIG (100–200 IU) intramuscularly to the patient at 28, 32, and 36 weeks. The outcomes with this approach have been inconsistent, due, at least in part, to varying doses of the agent and various cutoffs for defining “high risk,” and this intervention is no longer recommended.^1,2

The second major approach is administration of specific antiviral drugs to the mother during the third trimester. The first agent widely used in clinical practice was lamivudine. In a systematic review and meta-analysis, Shi and colleagues reported that, in infants whose mothers received lamivudine plus conventional neonatal immunuprophylaxis, the risk of perinatal infection was significantly reduced compared with infants who received only immunoprophylaxis.⁹

Although lamivudine is effective, there is considerable concern about the rapid development of viral resistance to the medication. Accordingly, most attention today is focused on the use of tenofovir to prevent perinatal transmission.

In an important early investigation, Pan and colleagues reported the results of a randomized controlled trial conducted in China in women with a hepatitis B DNA concentration greater than 200,000 IU/mL (viral load > 1,120,000 copies/mL).¹⁰ Patients also were positive for the e antigen. Ninety-two patients were assigned to tenofovir disoproxil fumarate (TDF), 300 mg daily, from 30 to 32 weeks until postpartum week 4 plus conventional neonatal immunoprophylaxis, and 100 patients were assigned to immunoprophylaxis alone. In the intention-to-treat analysis, 18 neonates in the control group were infected compared with 5 in the treatment group (P = .007). In the per-protocol analysis, 7 neonates in the control group were infected compared with 0 in the treatment group (P = .01). No clinically significant adverse maternal or neonatal effects occurred in the treatment group.

Subsequently, Jourdain and colleagues reported a multicenter, double-blind trial conducted in 17 public health hospitals in Thailand.¹¹ TDF (300 mg daily) or placebo was administered from 28 weeks’ gestation until 8 weeks postpartum. Patients in both arms of the study were positive for the e antigen; 87% to 90% of the patients had a serum hepatitis B DNA concentration greater than 200,000 IU/mL.Following birth, infants in both groups received an injection of HBIG and then 4 doses of hepatitis B vaccine (0, 1, 2, 4, and 6 months). Both the HBIG and hepatitis B vaccine were administered very promptly after birth (median time, 1.2–1.3 hours).

At 6 months after delivery, 2% of infants in the placebo group (3 of 147) were HBsAg-positive compared with none of the infants in the treatment arm.¹¹ No serious adverse effects occurred in infants in the TDF group. This difference in outcome was not statistically significant, but the overall rate of infection was so low in both groups that the sample size was definitely too small to exclude a type 2 statistical error. Moreover, the fourth dose of neonatal hepatitis B vaccine may have contributed to the surprisingly low rate of perinatal transmission. Of note, the serum hepatitis B DNA concentration in the TDF group declined from a mean of 7.6 log₁₀ IU/mL to a mean of 4.0 log₁₀ IU/mL at delivery.

In the most recent report, Wang and colleagues reported the results of a prospective cohort study in patients with a hepatitis B virus DNA concentration greater than 200,000 IU/mL.¹² Beginning at either 24 or 32 weeks, patients were assigned to treatment with either oral TDF (300 mg daily) or oral telbivudine (LdT, 600 mg daily). The medications were continued for 4 weeks postpartum. In the intention-to-treat analysis, the rates of perinatal transmission were comparable, 1.5% versus 1.8%. In the per-protocol analysis, no infants in either group were infected. However, the predelivery decline in hepatitis Bvirus DNA concentration was greater in the TDF group. The ALT elevation rate was also lower in the TDF group. Patients in the LdT group had fewer problems with anorexia but more instances of arthralgia compared with those in the TDF group.

Based primarily on these 3 investigations, I recommend that all infected patients with a hepatitis B DNA concentration greater than 200,000 IU/mL or a viral load greater than 1,120,000 million copies/mL receive oral TDF, 300 mg daily, from 28 weeks until at least 4 to 8 weeks postpartum. The decision about duration of postpartum treatment should be made in consultation with an infectious disease specialist or hepatologist.

Case studies resolved

CASE 1 No protective level of surface antibody

This patient should promptly receive a single booster dose of the hepatitis B vaccine. The vaccine is an inactivated agent and is safe for administration at any time in pregnancy. Following delivery and prior to discharge from the hospital, the neonate should receive the first dose of the hepatitis B vaccine. A second dose should be administered 1 month later, and a third dose should be administered 6 months after the first dose.

CASE 2 Mother is seropositive for HBsAg

This patient should be tested immediately for HIV infection and hepatitis C and D. The hepatitis B viral genotype should be determined. She also should have a panel of liver function tests. If any of these tests are abnormal, a coagulation profile should be obtained to be certain that the patient is not at risk for a coagulopathy. Near the end of the second trimester, a hepatitis B viral load should be obtained. If the viral DNA concentration is greater than 200,000 IU/mLor a viral load greater than 1,120,000 million copies/mL, the patient should be treated with tenofovir, 300 mg daily, from week 28 until at least 4 weeks after delivery. The neonate should receive an injection of HBIG within 12 hours of birth and the first dose of the hepatitis B vaccine prior to discharge from the hospital. Two additional doses of the vaccine should be administered 1 and 6 months later. ●

Throughout the 20th century, the management of ectopic pregnancy evolved from preserving the life of the mother to preserving fertility by utilizing the conservative treatment of methotrexate and/or tubal surgery. I make this, seemingly obscure, reference to managing ectopic pregnancy to consider an analogous shift over time in the management of patients with cancer. Over the next decade, the number of people who have lived 5 or more years after their cancer diagnosis is projected to increase approximately 30%, to 16.3 million. Due to the improved survival rates following a cancer diagnosis,¹ revolutionary developments have been made in fertility preservation to obviate the impact of gonadotoxic therapy. We have evolved, however, from shielding and transposing ovaries to ovarian tissue cryopreservation,² with rapid implementation.

While advances in reproductive cryopreservation have allowed for the delay, or even potential “prevention” of infertility, assisted reproductive technology (ART) cannot yet claim a “cure” in ensuring procreation. Nevertheless, fertility preservation is a burgeoning field that has transitioned from an experimental label to a standard of care in 2012, as designated by the American Society for Reproductive Medicine (ASRM).³ From the original intention of offering oocyte cryopreservation to women at risk of ovarian failure from impending gonadotoxic cancer treatment, fertility preservation has accelerated to include freezing for nonmedical reasons—eg, planned oocyte cryopreservation (POC), or “social” egg freezing, to ovarian tissue cryopreservation to accommodate the expediency needed for the treatment of certain cancer treatments. Additionally, across the United States, the number of donor egg banks, which allow women an easily accessible option, is rivaling enduring sperm banks. Due to the advanced methodology of vitrification and growing demand for the technology due to increasing IVF cycles, cryopreservation has become a specialized area of reproductive medicine, and a target of venture capital and private equity commercialization. This article will review the latest techniques, appropriate counseling, and cost/benefit ratio of fertility preservation, with an emphasis on POC.

CASE 1 Fertility preservation options for patient with breast cancer

A 37-year-old woman with newly diagnosed hormone receptor−positive breast cancer is referred for a fertility preservation consultation prior to initiating treatment. Her oncologist plans chemotherapy, followed by radiation and a minimum of 5 years of tamoxifen therapy.

What is the best consultation approach for this patient?

Consultation involves understanding several factors

The consultation approach to this patient involves ascertaining her medical, social, and family history, along with her reproductive plans.

Medical history. For the medical component, we must focus on her diagnosis, anticipated treatment with timeline, risks of gonadal toxicity with planned treatments, her current medical stability, and prognosis for expected survival.

Social history. Her age, relationship status, and desired family size address her social history.

Family history. Given that her cancer affects the breast, there is the risk of genetic susceptibility and potential for embryo testing for the BRCA gene.

Reproductive plans. These include her and her partner’s, if applicable, number of desired children and their risk factors for infertility.

Regarding the reproductive timeline, the antihormonal therapy that may be required for her treatment may improve overall survival, but it would delay the time to pregnancy. Consequently, the pursuit of fertility preservation prior to cancer treatment is a multidisciplinary approach that can involve medical oncology, radiation oncology, REI, medical genetics, and often, psychology. Fortunately, evidence continues to support fertility preservation, with or without hormonal ovarian stimulation, for patients with breast cancer. Data, with up to 5 years of follow-up, has indicated that it is safe.⁴

Continue to: Oncofertility...

To address the need to maximize the reproductive potential of patients with newly diagnosed cancer, the field of oncofertility combines the specialties of oncology and reproductive medicine. The reproductive risk of cancer treatment is gonadotoxicity, with subsequent iatrogenic primary ovarian insufficiency (POI) and infertility. Alkylating agents (including cyclosphosphamide) have the highest risk for amenorrhea, while antimetabolites (including methotrexate, 5–fluorouracil) have the lowest risk.⁵ Treating bone marrow/stem cell transplantation using high-dose alkylating agents, with or without whole body irradiation, results in ≥80% amenorrhea. The minimum radiation dose to induce ovarian failure decreases with advancing age, from 18.4 Gy at age 10 years to 6 Gy at age 40 years, due to biologically diminishing ovarian reserve and an increase in the radiosensitivity of oocytes.⁶ An online tool—using varying factors including age, chemotherapy dose, prior treatment, smoking, and baseline diminished ovarian reserve—is available to help predict the chance of ovarian failure following chemotherapy.⁷

Cryopreservation to the rescue

Since 2012, when ASRM removed the experimental designation on oocyte cryopreservation (OC), the number of cycles offered for fertility preservation has increased dramatically (FIGURE),⁸ initially being used for patients with cancer and now also including women desiring POC.

OC followed by thawing for subsequent fertilization and embryo transfer is employed as a matter of routine when patients with infertility utilize frozen eggs from a donor. While there remains debate over better live birth rates with frozen eggs versus fresh eggs, clinic experience may be a critical factor.¹⁰

Ovarian tissue cryopreservation. In addition to the fertility preservation procedures of oocytes and embryo cryopreservation, ovarian tissue cryopreservation became a standard option in 2019 when ASRM removed its experimental designation.¹¹ Given the potential time constraints of urgent cancer treatment, ovarian tissue cryopreservation has the advantage of not requiring ovarian stimulation or sexual maturity and is able to be performed while patients are receiving chemotherapy. If successful, ovarian tissue cryopreservation followed by orthotopic transplantation has the potential to restore natural ovarian function and natural conceptions.¹² However, despite first successfully being described in 2004, ovarian tissue cryopreservation, which does require subsequent thawing and tissue transplantation, remains less available to patients due to low usage rates, which have resulted in few clinics having adequate proficiency.^13,14

Ovarian tissue cryopreservation involves obtaining ovarian cortical tissue, dissecting the tissue into small fragments, and cryopreserving it using either a slow-cool technique or vitrification. Orthotopic transplantation has been the most successful method for using ovarian tissue in humans. Live birth rates are modest.¹⁵ In all cancer survivors, particularly those with leukemia, autologous ovarian tissue transplantation may contain malignant cells that could lead to the reintroduction of cancer as the tissue is removed prior to treatment.¹⁶

Pregnancy outcomes using embryos created from ovaries recently exposed to chemotherapy in humans is not known, but animal studies suggest that there may be higher rates of miscarriage and birth defects given the severe DNA damage to oocytes of developing follicles.¹⁷ Hence, ovarian stimulation should be initiated and completed before the start of chemotherapy.

Continue to: Planned oocyte cryopreservation...

Planned oocyte cryopreservation

With advances in ART, POC offers patients the opportunity to preserve fertility until desired. However, despite its potential benefits, POC compels the discussion of various considerations in addition to oncofertility, such as ethical concerns and insurance coverage.

CASE 2 Woman plans for elective egg freezing

A 32-year-old single, professional woman is advancing in her career and wishes to delay childbearing. She is concerned about the potential for age-related fertility decline and wants to explore the option of elective egg freezing. Emily has no medical conditions that would impair her fertility, but she wants to ensure that she has the option of having biological children in the future. She is unsure about the potential financial burden of the procedure and whether her employer’s insurance covers such elective procedures.

How do you counsel her about her options?

Medical considerations

Approximately 25% of reproductive-aged women have considered POC.¹⁸ An analysis revealed POC was more cost-effective than delaying procreation and undergoing IVF with preimplantation genetic testing for aneuploidies at an advanced reproductive age.¹⁹

The process of planned oocyte cryopreservation. POC involves ovarian stimulation, usually with parenteral gonadotropins, to produce multiple mature oocytes for same-day cryopreservation following transvaginal retrieval, typically in an office-based surgery center as an outpatient procedure while the patient is under IV sedation. While the procedure has been proven effective, there are inherent risks and limitations. The success rates of subsequent fertility treatments using the cryopreserved eggs are influenced by the woman’s age at the time of freezing, the number of mature oocytes retrieved and vitrified, and the quality of the oocytes following thaw. A recent study reported a 70% live-birth rate in women aged less than 38 years who cryopreserved ≥ 20 mature eggs.²⁰ To increase the number of cryopreserved oocytes, multiple egg retrievals or “batching” may be of benefit for women with diminished ovarian reserve.²¹

It is important for clinicians to thoroughly assess a patient’s medical history, ovarian reserve (by antral follicle count and levels of anti-müllerian hormone [AMH]), and reproductive goals before recommending proceeding with POC. Of note, AMH is a useful marker for ovarian reserve but has not been shown to predict natural fertility. Its value is in providing a guide to the dosage of ovarian stimulation and an estimation of the number of oocytes to be retrieved. Per ASRM, “Extremely low AMH values should not be used to refuse treatment in IVF.” AMH levels and antral follicle count have only a weak association with such qualitative outcomes as oocyte quality, clinical pregnancy rates, and live birth rates. Complications from egg retrieval, both short and long term, are rare. The inherent risk from POC is the lack of a guaranteed subsequent live birth.²²

Ethical and social considerations

POC raises several ethical considerations, including concerns of perpetuating societal pressure on women to defer procreation to prioritize their careers over family planning.²³ Despite controversies, POC appears as a chosen strategy against age-related infertility and may allow women to feel that they are more socially, psychologically, and financially stable before pursuing motherhood.²⁴ Open and honest discussions between clinicians and patients are crucial to ensure informed decision making and address these ethical concerns.

Per an ACOG statement from February 2023 (https://www.acog.org/womens-health/faqs/having-a-baby-after-age-35-how-aging-affects-fertility-and-pregnancy) “...egg freezing is recommended mainly for patients having cancer treatment that will affect their future fertility. There is not enough research to recommend routine egg freezing for the sole purpose of delaying childbearing.”

A recent survey of patients who had elected egg freezing at some point included more than 80% who were aged 35 or older, and revealed that 93% of the survey participants had not yet returned to use their frozen oocytes.²⁵ The most common reason cited in the survey for a delay in attempted procreation was lack of a partner. Another reason was undergoing oocyte cryopreservation after an optimal reproductive age, with participants concluding that they felt they had improved their reproductive future after undergoing oocyte cryopreservation and feeling empowered by the process. As part of counseling, women should be informed of the possibility of not utilizing their frozen eggs in the future, whether due to natural conception or other personal reasons.

Continue to: Employer insurance coverage...

Access to elective egg freezing is largely influenced by insurance coverage. Currently, employer-provided insurance coverage for this procedure varies widely. While some companies offer comprehensive coverage, others provide limited or no coverage at all. The cost of elective egg freezing can range from $10,000 to $15,000, excluding additional expenses such as medications and annual storage fees. The financial burden can create a gap between patients who desire POC and those with an ability to implement the process. The cost can be a significant barrier for many patients considering this option and perpetuates the lack of universal diversity, equity, and inclusion.

CASE 3 Gender dysphoria and fertility preservation

A 22-year-old transgender man is preparing to undergo gender-affirming hormone therapy and surgery. He is concerned about the potential impact of testosterone therapy on his oocytes and wishes to explore options for fertility preservation prior to oophorectomy.²⁶

What are the patient’s options for fertility preservation?

The patient has the fertility preservation options of OC following ovarian stimulation or ovarian tissue cryopreservation at the time of oophorectomy. Preliminary evidence does not demonstrate impairment of ovarian stimulation and oocyte retrieval number with concurrent testosterone exposure. Ethical considerations, in this case, involve respecting the patient’s autonomy, addressing potential conflicts between gender-affirming care and fertility preservation (eg, a risk of dysphoria in transgender patients preserving biological gametes from a prior assigned gender), and ensuring access to fertility preservation services without discrimination. It is essential to provide the patient in this case with comprehensive information regarding the impact of hormone therapy on fertility, the available options, and the potential financial costs involved. Supportive counseling should also be offered to address any psychological or emotional aspects related to fertility preservation for all patients considering this option.

A call for diversity, equity, and inclusion

To improve access to POC, advocating for employer-offered insurance coverage is paramount. Women’s health providers can encourage dialogue between employers, insurers, and policymakers, which can lead to policy changes that prioritize coverage for fertilitypreservation options. This could include mandating coverage for POC as part of comprehensive health care plans or providing tax incentives to employers who offer coverage for these procedures. Furthermore, public awareness campaigns and advocacy efforts can help educate employers about the importance of including fertility preservation coverage in their employee benefits packages.

Conclusion

Just as physicians must recognize their responsibility to patients to distinguish unproven yet promising science from evidence-based and clinically established science, so too must they advise their patients to consider fertility preservation services in a way that is both clinically justified and ethically appropriate. Informed decisions must be made by appropriate counseling of evidence-based medicine to protect the interest of patients. POC provides patients with an opportunity to preserve their fertility and exercise reproductive autonomy. However, access to this procedure is often hindered by limited or nonexistent employer insurance coverage. By recognizing the medical, ethical, and social implications of POC and implementing strategies to improve coverage, collaborative efforts may increase accessibility and defray costs to provide patients with the option of deferring childbearing and preserving their reproductive potential. ●

Throughout the 20th century, the management of ectopic pregnancy evolved from preserving the life of the mother to preserving fertility by utilizing the conservative treatment of methotrexate and/or tubal surgery. I make this, seemingly obscure, reference to managing ectopic pregnancy to consider an analogous shift over time in the management of patients with cancer. Over the next decade, the number of people who have lived 5 or more years after their cancer diagnosis is projected to increase approximately 30%, to 16.3 million. Due to the improved survival rates following a cancer diagnosis,¹ revolutionary developments have been made in fertility preservation to obviate the impact of gonadotoxic therapy. We have evolved, however, from shielding and transposing ovaries to ovarian tissue cryopreservation,² with rapid implementation.

While advances in reproductive cryopreservation have allowed for the delay, or even potential “prevention” of infertility, assisted reproductive technology (ART) cannot yet claim a “cure” in ensuring procreation. Nevertheless, fertility preservation is a burgeoning field that has transitioned from an experimental label to a standard of care in 2012, as designated by the American Society for Reproductive Medicine (ASRM).³ From the original intention of offering oocyte cryopreservation to women at risk of ovarian failure from impending gonadotoxic cancer treatment, fertility preservation has accelerated to include freezing for nonmedical reasons—eg, planned oocyte cryopreservation (POC), or “social” egg freezing, to ovarian tissue cryopreservation to accommodate the expediency needed for the treatment of certain cancer treatments. Additionally, across the United States, the number of donor egg banks, which allow women an easily accessible option, is rivaling enduring sperm banks. Due to the advanced methodology of vitrification and growing demand for the technology due to increasing IVF cycles, cryopreservation has become a specialized area of reproductive medicine, and a target of venture capital and private equity commercialization. This article will review the latest techniques, appropriate counseling, and cost/benefit ratio of fertility preservation, with an emphasis on POC.

CASE 1 Fertility preservation options for patient with breast cancer

A 37-year-old woman with newly diagnosed hormone receptor−positive breast cancer is referred for a fertility preservation consultation prior to initiating treatment. Her oncologist plans chemotherapy, followed by radiation and a minimum of 5 years of tamoxifen therapy.

What is the best consultation approach for this patient?

Consultation involves understanding several factors

The consultation approach to this patient involves ascertaining her medical, social, and family history, along with her reproductive plans.

Medical history. For the medical component, we must focus on her diagnosis, anticipated treatment with timeline, risks of gonadal toxicity with planned treatments, her current medical stability, and prognosis for expected survival.

Social history. Her age, relationship status, and desired family size address her social history.

Family history. Given that her cancer affects the breast, there is the risk of genetic susceptibility and potential for embryo testing for the BRCA gene.

Reproductive plans. These include her and her partner’s, if applicable, number of desired children and their risk factors for infertility.

Regarding the reproductive timeline, the antihormonal therapy that may be required for her treatment may improve overall survival, but it would delay the time to pregnancy. Consequently, the pursuit of fertility preservation prior to cancer treatment is a multidisciplinary approach that can involve medical oncology, radiation oncology, REI, medical genetics, and often, psychology. Fortunately, evidence continues to support fertility preservation, with or without hormonal ovarian stimulation, for patients with breast cancer. Data, with up to 5 years of follow-up, has indicated that it is safe.⁴

Continue to: Oncofertility...

To address the need to maximize the reproductive potential of patients with newly diagnosed cancer, the field of oncofertility combines the specialties of oncology and reproductive medicine. The reproductive risk of cancer treatment is gonadotoxicity, with subsequent iatrogenic primary ovarian insufficiency (POI) and infertility. Alkylating agents (including cyclosphosphamide) have the highest risk for amenorrhea, while antimetabolites (including methotrexate, 5–fluorouracil) have the lowest risk.⁵ Treating bone marrow/stem cell transplantation using high-dose alkylating agents, with or without whole body irradiation, results in ≥80% amenorrhea. The minimum radiation dose to induce ovarian failure decreases with advancing age, from 18.4 Gy at age 10 years to 6 Gy at age 40 years, due to biologically diminishing ovarian reserve and an increase in the radiosensitivity of oocytes.⁶ An online tool—using varying factors including age, chemotherapy dose, prior treatment, smoking, and baseline diminished ovarian reserve—is available to help predict the chance of ovarian failure following chemotherapy.⁷

Cryopreservation to the rescue

Since 2012, when ASRM removed the experimental designation on oocyte cryopreservation (OC), the number of cycles offered for fertility preservation has increased dramatically (FIGURE),⁸ initially being used for patients with cancer and now also including women desiring POC.

OC followed by thawing for subsequent fertilization and embryo transfer is employed as a matter of routine when patients with infertility utilize frozen eggs from a donor. While there remains debate over better live birth rates with frozen eggs versus fresh eggs, clinic experience may be a critical factor.¹⁰

Ovarian tissue cryopreservation. In addition to the fertility preservation procedures of oocytes and embryo cryopreservation, ovarian tissue cryopreservation became a standard option in 2019 when ASRM removed its experimental designation.¹¹ Given the potential time constraints of urgent cancer treatment, ovarian tissue cryopreservation has the advantage of not requiring ovarian stimulation or sexual maturity and is able to be performed while patients are receiving chemotherapy. If successful, ovarian tissue cryopreservation followed by orthotopic transplantation has the potential to restore natural ovarian function and natural conceptions.¹² However, despite first successfully being described in 2004, ovarian tissue cryopreservation, which does require subsequent thawing and tissue transplantation, remains less available to patients due to low usage rates, which have resulted in few clinics having adequate proficiency.^13,14

Ovarian tissue cryopreservation involves obtaining ovarian cortical tissue, dissecting the tissue into small fragments, and cryopreserving it using either a slow-cool technique or vitrification. Orthotopic transplantation has been the most successful method for using ovarian tissue in humans. Live birth rates are modest.¹⁵ In all cancer survivors, particularly those with leukemia, autologous ovarian tissue transplantation may contain malignant cells that could lead to the reintroduction of cancer as the tissue is removed prior to treatment.¹⁶

Pregnancy outcomes using embryos created from ovaries recently exposed to chemotherapy in humans is not known, but animal studies suggest that there may be higher rates of miscarriage and birth defects given the severe DNA damage to oocytes of developing follicles.¹⁷ Hence, ovarian stimulation should be initiated and completed before the start of chemotherapy.

Continue to: Planned oocyte cryopreservation...

Planned oocyte cryopreservation

With advances in ART, POC offers patients the opportunity to preserve fertility until desired. However, despite its potential benefits, POC compels the discussion of various considerations in addition to oncofertility, such as ethical concerns and insurance coverage.

CASE 2 Woman plans for elective egg freezing

A 32-year-old single, professional woman is advancing in her career and wishes to delay childbearing. She is concerned about the potential for age-related fertility decline and wants to explore the option of elective egg freezing. Emily has no medical conditions that would impair her fertility, but she wants to ensure that she has the option of having biological children in the future. She is unsure about the potential financial burden of the procedure and whether her employer’s insurance covers such elective procedures.

How do you counsel her about her options?

Medical considerations

Approximately 25% of reproductive-aged women have considered POC.¹⁸ An analysis revealed POC was more cost-effective than delaying procreation and undergoing IVF with preimplantation genetic testing for aneuploidies at an advanced reproductive age.¹⁹

The process of planned oocyte cryopreservation. POC involves ovarian stimulation, usually with parenteral gonadotropins, to produce multiple mature oocytes for same-day cryopreservation following transvaginal retrieval, typically in an office-based surgery center as an outpatient procedure while the patient is under IV sedation. While the procedure has been proven effective, there are inherent risks and limitations. The success rates of subsequent fertility treatments using the cryopreserved eggs are influenced by the woman’s age at the time of freezing, the number of mature oocytes retrieved and vitrified, and the quality of the oocytes following thaw. A recent study reported a 70% live-birth rate in women aged less than 38 years who cryopreserved ≥ 20 mature eggs.²⁰ To increase the number of cryopreserved oocytes, multiple egg retrievals or “batching” may be of benefit for women with diminished ovarian reserve.²¹

It is important for clinicians to thoroughly assess a patient’s medical history, ovarian reserve (by antral follicle count and levels of anti-müllerian hormone [AMH]), and reproductive goals before recommending proceeding with POC. Of note, AMH is a useful marker for ovarian reserve but has not been shown to predict natural fertility. Its value is in providing a guide to the dosage of ovarian stimulation and an estimation of the number of oocytes to be retrieved. Per ASRM, “Extremely low AMH values should not be used to refuse treatment in IVF.” AMH levels and antral follicle count have only a weak association with such qualitative outcomes as oocyte quality, clinical pregnancy rates, and live birth rates. Complications from egg retrieval, both short and long term, are rare. The inherent risk from POC is the lack of a guaranteed subsequent live birth.²²

Ethical and social considerations

POC raises several ethical considerations, including concerns of perpetuating societal pressure on women to defer procreation to prioritize their careers over family planning.²³ Despite controversies, POC appears as a chosen strategy against age-related infertility and may allow women to feel that they are more socially, psychologically, and financially stable before pursuing motherhood.²⁴ Open and honest discussions between clinicians and patients are crucial to ensure informed decision making and address these ethical concerns.

Per an ACOG statement from February 2023 (https://www.acog.org/womens-health/faqs/having-a-baby-after-age-35-how-aging-affects-fertility-and-pregnancy) “...egg freezing is recommended mainly for patients having cancer treatment that will affect their future fertility. There is not enough research to recommend routine egg freezing for the sole purpose of delaying childbearing.”

A recent survey of patients who had elected egg freezing at some point included more than 80% who were aged 35 or older, and revealed that 93% of the survey participants had not yet returned to use their frozen oocytes.²⁵ The most common reason cited in the survey for a delay in attempted procreation was lack of a partner. Another reason was undergoing oocyte cryopreservation after an optimal reproductive age, with participants concluding that they felt they had improved their reproductive future after undergoing oocyte cryopreservation and feeling empowered by the process. As part of counseling, women should be informed of the possibility of not utilizing their frozen eggs in the future, whether due to natural conception or other personal reasons.

Continue to: Employer insurance coverage...

Access to elective egg freezing is largely influenced by insurance coverage. Currently, employer-provided insurance coverage for this procedure varies widely. While some companies offer comprehensive coverage, others provide limited or no coverage at all. The cost of elective egg freezing can range from $10,000 to $15,000, excluding additional expenses such as medications and annual storage fees. The financial burden can create a gap between patients who desire POC and those with an ability to implement the process. The cost can be a significant barrier for many patients considering this option and perpetuates the lack of universal diversity, equity, and inclusion.

CASE 3 Gender dysphoria and fertility preservation

A 22-year-old transgender man is preparing to undergo gender-affirming hormone therapy and surgery. He is concerned about the potential impact of testosterone therapy on his oocytes and wishes to explore options for fertility preservation prior to oophorectomy.²⁶

What are the patient’s options for fertility preservation?

The patient has the fertility preservation options of OC following ovarian stimulation or ovarian tissue cryopreservation at the time of oophorectomy. Preliminary evidence does not demonstrate impairment of ovarian stimulation and oocyte retrieval number with concurrent testosterone exposure. Ethical considerations, in this case, involve respecting the patient’s autonomy, addressing potential conflicts between gender-affirming care and fertility preservation (eg, a risk of dysphoria in transgender patients preserving biological gametes from a prior assigned gender), and ensuring access to fertility preservation services without discrimination. It is essential to provide the patient in this case with comprehensive information regarding the impact of hormone therapy on fertility, the available options, and the potential financial costs involved. Supportive counseling should also be offered to address any psychological or emotional aspects related to fertility preservation for all patients considering this option.

A call for diversity, equity, and inclusion

To improve access to POC, advocating for employer-offered insurance coverage is paramount. Women’s health providers can encourage dialogue between employers, insurers, and policymakers, which can lead to policy changes that prioritize coverage for fertilitypreservation options. This could include mandating coverage for POC as part of comprehensive health care plans or providing tax incentives to employers who offer coverage for these procedures. Furthermore, public awareness campaigns and advocacy efforts can help educate employers about the importance of including fertility preservation coverage in their employee benefits packages.

Conclusion

Just as physicians must recognize their responsibility to patients to distinguish unproven yet promising science from evidence-based and clinically established science, so too must they advise their patients to consider fertility preservation services in a way that is both clinically justified and ethically appropriate. Informed decisions must be made by appropriate counseling of evidence-based medicine to protect the interest of patients. POC provides patients with an opportunity to preserve their fertility and exercise reproductive autonomy. However, access to this procedure is often hindered by limited or nonexistent employer insurance coverage. By recognizing the medical, ethical, and social implications of POC and implementing strategies to improve coverage, collaborative efforts may increase accessibility and defray costs to provide patients with the option of deferring childbearing and preserving their reproductive potential. ●

Throughout the 20th century, the management of ectopic pregnancy evolved from preserving the life of the mother to preserving fertility by utilizing the conservative treatment of methotrexate and/or tubal surgery. I make this, seemingly obscure, reference to managing ectopic pregnancy to consider an analogous shift over time in the management of patients with cancer. Over the next decade, the number of people who have lived 5 or more years after their cancer diagnosis is projected to increase approximately 30%, to 16.3 million. Due to the improved survival rates following a cancer diagnosis,¹ revolutionary developments have been made in fertility preservation to obviate the impact of gonadotoxic therapy. We have evolved, however, from shielding and transposing ovaries to ovarian tissue cryopreservation,² with rapid implementation.

While advances in reproductive cryopreservation have allowed for the delay, or even potential “prevention” of infertility, assisted reproductive technology (ART) cannot yet claim a “cure” in ensuring procreation. Nevertheless, fertility preservation is a burgeoning field that has transitioned from an experimental label to a standard of care in 2012, as designated by the American Society for Reproductive Medicine (ASRM).³ From the original intention of offering oocyte cryopreservation to women at risk of ovarian failure from impending gonadotoxic cancer treatment, fertility preservation has accelerated to include freezing for nonmedical reasons—eg, planned oocyte cryopreservation (POC), or “social” egg freezing, to ovarian tissue cryopreservation to accommodate the expediency needed for the treatment of certain cancer treatments. Additionally, across the United States, the number of donor egg banks, which allow women an easily accessible option, is rivaling enduring sperm banks. Due to the advanced methodology of vitrification and growing demand for the technology due to increasing IVF cycles, cryopreservation has become a specialized area of reproductive medicine, and a target of venture capital and private equity commercialization. This article will review the latest techniques, appropriate counseling, and cost/benefit ratio of fertility preservation, with an emphasis on POC.

CASE 1 Fertility preservation options for patient with breast cancer

A 37-year-old woman with newly diagnosed hormone receptor−positive breast cancer is referred for a fertility preservation consultation prior to initiating treatment. Her oncologist plans chemotherapy, followed by radiation and a minimum of 5 years of tamoxifen therapy.

What is the best consultation approach for this patient?

Consultation involves understanding several factors

The consultation approach to this patient involves ascertaining her medical, social, and family history, along with her reproductive plans.

Medical history. For the medical component, we must focus on her diagnosis, anticipated treatment with timeline, risks of gonadal toxicity with planned treatments, her current medical stability, and prognosis for expected survival.

Social history. Her age, relationship status, and desired family size address her social history.

Family history. Given that her cancer affects the breast, there is the risk of genetic susceptibility and potential for embryo testing for the BRCA gene.

Reproductive plans. These include her and her partner’s, if applicable, number of desired children and their risk factors for infertility.

Regarding the reproductive timeline, the antihormonal therapy that may be required for her treatment may improve overall survival, but it would delay the time to pregnancy. Consequently, the pursuit of fertility preservation prior to cancer treatment is a multidisciplinary approach that can involve medical oncology, radiation oncology, REI, medical genetics, and often, psychology. Fortunately, evidence continues to support fertility preservation, with or without hormonal ovarian stimulation, for patients with breast cancer. Data, with up to 5 years of follow-up, has indicated that it is safe.⁴

Continue to: Oncofertility...

To address the need to maximize the reproductive potential of patients with newly diagnosed cancer, the field of oncofertility combines the specialties of oncology and reproductive medicine. The reproductive risk of cancer treatment is gonadotoxicity, with subsequent iatrogenic primary ovarian insufficiency (POI) and infertility. Alkylating agents (including cyclosphosphamide) have the highest risk for amenorrhea, while antimetabolites (including methotrexate, 5–fluorouracil) have the lowest risk.⁵ Treating bone marrow/stem cell transplantation using high-dose alkylating agents, with or without whole body irradiation, results in ≥80% amenorrhea. The minimum radiation dose to induce ovarian failure decreases with advancing age, from 18.4 Gy at age 10 years to 6 Gy at age 40 years, due to biologically diminishing ovarian reserve and an increase in the radiosensitivity of oocytes.⁶ An online tool—using varying factors including age, chemotherapy dose, prior treatment, smoking, and baseline diminished ovarian reserve—is available to help predict the chance of ovarian failure following chemotherapy.⁷

Cryopreservation to the rescue

Since 2012, when ASRM removed the experimental designation on oocyte cryopreservation (OC), the number of cycles offered for fertility preservation has increased dramatically (FIGURE),⁸ initially being used for patients with cancer and now also including women desiring POC.

OC followed by thawing for subsequent fertilization and embryo transfer is employed as a matter of routine when patients with infertility utilize frozen eggs from a donor. While there remains debate over better live birth rates with frozen eggs versus fresh eggs, clinic experience may be a critical factor.¹⁰

Ovarian tissue cryopreservation. In addition to the fertility preservation procedures of oocytes and embryo cryopreservation, ovarian tissue cryopreservation became a standard option in 2019 when ASRM removed its experimental designation.¹¹ Given the potential time constraints of urgent cancer treatment, ovarian tissue cryopreservation has the advantage of not requiring ovarian stimulation or sexual maturity and is able to be performed while patients are receiving chemotherapy. If successful, ovarian tissue cryopreservation followed by orthotopic transplantation has the potential to restore natural ovarian function and natural conceptions.¹² However, despite first successfully being described in 2004, ovarian tissue cryopreservation, which does require subsequent thawing and tissue transplantation, remains less available to patients due to low usage rates, which have resulted in few clinics having adequate proficiency.^13,14

Ovarian tissue cryopreservation involves obtaining ovarian cortical tissue, dissecting the tissue into small fragments, and cryopreserving it using either a slow-cool technique or vitrification. Orthotopic transplantation has been the most successful method for using ovarian tissue in humans. Live birth rates are modest.¹⁵ In all cancer survivors, particularly those with leukemia, autologous ovarian tissue transplantation may contain malignant cells that could lead to the reintroduction of cancer as the tissue is removed prior to treatment.¹⁶

Pregnancy outcomes using embryos created from ovaries recently exposed to chemotherapy in humans is not known, but animal studies suggest that there may be higher rates of miscarriage and birth defects given the severe DNA damage to oocytes of developing follicles.¹⁷ Hence, ovarian stimulation should be initiated and completed before the start of chemotherapy.

Continue to: Planned oocyte cryopreservation...

Planned oocyte cryopreservation

With advances in ART, POC offers patients the opportunity to preserve fertility until desired. However, despite its potential benefits, POC compels the discussion of various considerations in addition to oncofertility, such as ethical concerns and insurance coverage.

CASE 2 Woman plans for elective egg freezing

A 32-year-old single, professional woman is advancing in her career and wishes to delay childbearing. She is concerned about the potential for age-related fertility decline and wants to explore the option of elective egg freezing. Emily has no medical conditions that would impair her fertility, but she wants to ensure that she has the option of having biological children in the future. She is unsure about the potential financial burden of the procedure and whether her employer’s insurance covers such elective procedures.

How do you counsel her about her options?

Medical considerations

Approximately 25% of reproductive-aged women have considered POC.¹⁸ An analysis revealed POC was more cost-effective than delaying procreation and undergoing IVF with preimplantation genetic testing for aneuploidies at an advanced reproductive age.¹⁹

The process of planned oocyte cryopreservation. POC involves ovarian stimulation, usually with parenteral gonadotropins, to produce multiple mature oocytes for same-day cryopreservation following transvaginal retrieval, typically in an office-based surgery center as an outpatient procedure while the patient is under IV sedation. While the procedure has been proven effective, there are inherent risks and limitations. The success rates of subsequent fertility treatments using the cryopreserved eggs are influenced by the woman’s age at the time of freezing, the number of mature oocytes retrieved and vitrified, and the quality of the oocytes following thaw. A recent study reported a 70% live-birth rate in women aged less than 38 years who cryopreserved ≥ 20 mature eggs.²⁰ To increase the number of cryopreserved oocytes, multiple egg retrievals or “batching” may be of benefit for women with diminished ovarian reserve.²¹

It is important for clinicians to thoroughly assess a patient’s medical history, ovarian reserve (by antral follicle count and levels of anti-müllerian hormone [AMH]), and reproductive goals before recommending proceeding with POC. Of note, AMH is a useful marker for ovarian reserve but has not been shown to predict natural fertility. Its value is in providing a guide to the dosage of ovarian stimulation and an estimation of the number of oocytes to be retrieved. Per ASRM, “Extremely low AMH values should not be used to refuse treatment in IVF.” AMH levels and antral follicle count have only a weak association with such qualitative outcomes as oocyte quality, clinical pregnancy rates, and live birth rates. Complications from egg retrieval, both short and long term, are rare. The inherent risk from POC is the lack of a guaranteed subsequent live birth.²²

Ethical and social considerations

POC raises several ethical considerations, including concerns of perpetuating societal pressure on women to defer procreation to prioritize their careers over family planning.²³ Despite controversies, POC appears as a chosen strategy against age-related infertility and may allow women to feel that they are more socially, psychologically, and financially stable before pursuing motherhood.²⁴ Open and honest discussions between clinicians and patients are crucial to ensure informed decision making and address these ethical concerns.

Per an ACOG statement from February 2023 (https://www.acog.org/womens-health/faqs/having-a-baby-after-age-35-how-aging-affects-fertility-and-pregnancy) “...egg freezing is recommended mainly for patients having cancer treatment that will affect their future fertility. There is not enough research to recommend routine egg freezing for the sole purpose of delaying childbearing.”

A recent survey of patients who had elected egg freezing at some point included more than 80% who were aged 35 or older, and revealed that 93% of the survey participants had not yet returned to use their frozen oocytes.²⁵ The most common reason cited in the survey for a delay in attempted procreation was lack of a partner. Another reason was undergoing oocyte cryopreservation after an optimal reproductive age, with participants concluding that they felt they had improved their reproductive future after undergoing oocyte cryopreservation and feeling empowered by the process. As part of counseling, women should be informed of the possibility of not utilizing their frozen eggs in the future, whether due to natural conception or other personal reasons.

Continue to: Employer insurance coverage...

Access to elective egg freezing is largely influenced by insurance coverage. Currently, employer-provided insurance coverage for this procedure varies widely. While some companies offer comprehensive coverage, others provide limited or no coverage at all. The cost of elective egg freezing can range from $10,000 to $15,000, excluding additional expenses such as medications and annual storage fees. The financial burden can create a gap between patients who desire POC and those with an ability to implement the process. The cost can be a significant barrier for many patients considering this option and perpetuates the lack of universal diversity, equity, and inclusion.

CASE 3 Gender dysphoria and fertility preservation

A 22-year-old transgender man is preparing to undergo gender-affirming hormone therapy and surgery. He is concerned about the potential impact of testosterone therapy on his oocytes and wishes to explore options for fertility preservation prior to oophorectomy.²⁶

What are the patient’s options for fertility preservation?

The patient has the fertility preservation options of OC following ovarian stimulation or ovarian tissue cryopreservation at the time of oophorectomy. Preliminary evidence does not demonstrate impairment of ovarian stimulation and oocyte retrieval number with concurrent testosterone exposure. Ethical considerations, in this case, involve respecting the patient’s autonomy, addressing potential conflicts between gender-affirming care and fertility preservation (eg, a risk of dysphoria in transgender patients preserving biological gametes from a prior assigned gender), and ensuring access to fertility preservation services without discrimination. It is essential to provide the patient in this case with comprehensive information regarding the impact of hormone therapy on fertility, the available options, and the potential financial costs involved. Supportive counseling should also be offered to address any psychological or emotional aspects related to fertility preservation for all patients considering this option.

A call for diversity, equity, and inclusion

To improve access to POC, advocating for employer-offered insurance coverage is paramount. Women’s health providers can encourage dialogue between employers, insurers, and policymakers, which can lead to policy changes that prioritize coverage for fertilitypreservation options. This could include mandating coverage for POC as part of comprehensive health care plans or providing tax incentives to employers who offer coverage for these procedures. Furthermore, public awareness campaigns and advocacy efforts can help educate employers about the importance of including fertility preservation coverage in their employee benefits packages.

Conclusion

Just as physicians must recognize their responsibility to patients to distinguish unproven yet promising science from evidence-based and clinically established science, so too must they advise their patients to consider fertility preservation services in a way that is both clinically justified and ethically appropriate. Informed decisions must be made by appropriate counseling of evidence-based medicine to protect the interest of patients. POC provides patients with an opportunity to preserve their fertility and exercise reproductive autonomy. However, access to this procedure is often hindered by limited or nonexistent employer insurance coverage. By recognizing the medical, ethical, and social implications of POC and implementing strategies to improve coverage, collaborative efforts may increase accessibility and defray costs to provide patients with the option of deferring childbearing and preserving their reproductive potential. ●

In the United States, acne affects 85% of adolescents and can persist into adulthood at a prevalence of 30% to 50% in adult women. ^1,2 The pathogenesis of acne is multifactorial and involves hyperkeratinization of the follicle, bacterial colonization with Cutibacterium acnes , and increased androgen-induced sebum production, which together lead to inflammation. ^3,4 A wide range of treatment guideline–recommended options are available, including benzoyl peroxide (BPO), topical retinoids, topical and oral antibiotics, antiandrogens, and isotretinoin. ⁵ However, these options vary widely in their clinical uses, effectiveness, and costs.

Why Cost-effective Acne Care Matters

Out-of-pocket spending by patients on acne treatments can be substantial, with surveys finding that acne patients often spend hundreds to thousands of dollars per year.^6,7 In a poll conducted in 2019 by the Kaiser Family Foundation, 3 in 10 patients said they had not taken their medicine as prescribed because of costs.⁸ A mixed methods study by Ryskina et al⁹ found that 65% (17/26) of participants who reported primary nonadherence—intended to fill prescriptions but were unable to do so—cited cost or coverage-related barriers as the reason. With the continued rise of dermatologic drug prices and increased prevalence of high-deductible health plans, cost-effective treatment continues to grow in importance. Failure to consider cost-effective, patient-centered care may lead to increased financial toxicity, reduced adherence, and ultimately worse outcomes and patient satisfaction. We aim to review the cost-effectiveness of current prescription therapies for acne management and highlight the most cost-effective approaches to patients with mild to moderate acne as well as moderate to severe acne.

In this review, we will take a value-oriented framework.¹⁰ Value can be defined as the cost per outcome of interest. Therefore, a treatment does not necessarily need to be inexpensive to provide high value if it delivers outstanding clinical outcomes. In addition, we will focus on incremental cost-effectiveness relative to common alternatives (eg, a retinoid could deliver high value relative to a vehicle but still provide limited value compared to other available retinoids if it is more expensive but not more efficacious). When possible, we present data from cost-effectiveness studies.^11,12 We also use recent available price data obtained from GoodRx on August 11, 2023, to guide this discussion.¹³ However, as comparative-effectiveness and cost-effectiveness studies rarely are performed for acne medications, much of this discussion will be based on expert opinion.

Treatment Categories

Topical Retinoids—There currently are 4 topical retinoids that are approved by the US Food and Drug Administration (FDA) for the treatment of acne: tretinoin, tazarotene, trifarotene, and adapalene. These drugs are vitamin A derivatives that bind retinoic acid receptors and function as comedolytic and anti-inflammatory agents.⁵ In general, generic tretinoin and adapalene products have the lowest cost (Table).

In network meta-analyses, tretinoin and adapalene often are highly ranked topical treatment options with respect to efficacy.¹⁴ Combined with their low cost, generic tretinoin and adapalene likely are excellent initial options for topical therapy from the standpoint of cost-effectiveness.¹⁵ Adapalene may be preferred in many situations because of its better photostability and compatibility with BPO.

Due to the importance of the vehicle in determining retinoid tolerability, efforts have been made to use encapsulation and polymeric emulsion technology to improve tolerability. Recently, polymeric lotion formulations of tretinoin and tazarotene have become available. In a phase 2 study, tazarotene lotion 0.045% was found to have equivalent efficacy and superior tolerability to tazarotene cream 0.1%.¹⁶ Although head-to-head data are not available, it is likely that tretinoin lotion may offer similar tolerability improvements.¹⁷ Although these formulations currently are more costly, this improved tolerability may be critical for some patients to be able to use topical retinoids, and the additional cost may be worthwhile. In addition, as these products lose market exclusivity, they may become more affordable and similarly priced to other topical retinoids. It is important to keep in mind that in clinical trials of tretinoin and adapalene, rates of dropout due to adverse events typically were 1% to 2%; therefore, because many patients can tolerate generic tretinoin and adapalene, at current prices the lotion formulations of retinoids may not be cost-effective relative to these generics.¹⁴

Trifarotene cream 0.005%, a fourth-generation topical retinoid that is highly sensitive for retinoic acid receptor γ, recently was FDA approved for the treatment of acne. Although trifarotene is efficacious for both facial and truncal acne, there is a lack of active comparator data compared to other topical retinoids.¹⁸ In a 2023 network meta-analysis, trifarotene was found to be both less efficacious and less tolerable compared to other topical retinoids.¹⁹ Thus, it is unclear if trifarotene offers any improved efficacy compared to other options, and it comes at a much higher cost (Table). In a tolerability study, trifarotene was found to be significantly more irritating than tazarotene lotion 0.045% and adapalene gel 0.3% (P<.05).²⁰ Therefore, trifarotene cream 0.005% is unlikely to be a cost-effective option; in fact, it may be overall inferior to other topical retinoids, given its potentially lower tolerability.

Topical Antibiotics—There are 4 commonly prescribed topical antibiotics that are approved by the FDA for the treatment of acne: clindamycin, erythromycin, dapsone, and minocycline. The American Academy of Dermatology guidelines for the treatment of acne recommend concomitant use of BPO to prevent antibiotic resistance.⁵ Clindamycin is favored over erythromycin because of increasing antibiotic resistance to erythromycin.²¹ Inexpensive generic options in multiple vehicles (eg, solution, foam, gel) make clindamycin a highly cost-effective option when antibiotic therapy is desired as part of a topical regimen (Table).

The cost-effectiveness of dapsone gel and minocycline foam relative to clindamycin are less certain. Rates of resistance to minocycline are lower than clindamycin, and minocycline foam may be a reasonable alternative in patients who have not had success with other topical antibiotics, such as clindamycin.²² However, given the absence of comparative effectiveness data to suggest minocycline is more effective than clindamycin, it is difficult to justify the substantially higher cost for the typical patient. Although dapsone gel has been suggested as an option for adult women with acne, there are no data to support that it is any more effective than other topical antibiotics in this patient population.²³ As generic dapsone prices decrease, it may become a reasonable alternative to clindamycin. In addition, the antineutrophil properties of dapsone may be useful in other acneform and inflammatory eruptions, such as scalp folliculitis and folliculitis decalvans.²⁴

Combination Topicals—Current combination topical products include antibiotic and BPO, antibiotic and retinoid, and retinoid and BPO. Use of combination agents is recommended to reduce the risk for resistance and to enhance effectiveness. Combination products offer improved convenience, which is associated with better adherence and outcomes.²⁵ Generic fixed-dose adapalene-BPO can be a highly cost-effective option that can sometimes be less expensive than the individual component products (Table). Similarly, fixed-dose clindamycin-BPO also is likely to be highly cost-effective. A network meta-analysis found fixed-dose adapalene-BPO to be the most efficacious topical treatment, though it also was found to be the most irritating—more so than fixed-dose clindamycin-BPO, which may have similar efficacy.^14,26,27 Generic fixed-dose tretinoin-clindamycin offers improved convenience and adherence compared to the individual components, but it is more expensive, and its cost-effectiveness may be influenced by the importance of convenience for the patient.²⁵ An encapsulated, fixed-dose tretinoin 0.1%–BPO 3% cream is FDA approved for acne, but the cost is high and there is a lack of comparative effectiveness data demonstrating advantages over generic fixed-dose adapalene-BPO products.

Topical Antiandrogen—Clascoterone was introduced in 2020 as the first FDA-approved topical medication to target the hormonal pathogenesis of acne, inhibiting the androgen receptors in the sebaceous gland.²⁸ Because it is rapidly metabolized to cortexolone and does not have systemic antiandrogen effects, clascoterone can be used in both men and women with acne. In clinical trials, it had minimal side effects, including no evidence of irritability, which is an advantage over topical retinoids and BPO.²⁹ In addition, a phase 2 study found that clascoterone may have similar to superior efficacy to tretinoin cream 0.05%.³⁰ Although clascoterone has several strengths, including its efficacy, tolerability, and unique mechanism of action, its cost-effectiveness is limited due to its high cost (Table) and the need for twice-daily application, which reduces convenience. Clascoterone likely is best reserved for patients with a strong hormonal pathogenesis of their acne or difficulty tolerating other topicals, or as an additional therapy to complement other topicals.

Oral Antibiotics—Oral antibiotics are the most commonly prescribed systemic treatments for acne, particularly tetracyclines such as doxycycline, minocycline, and sarecycline.^31-34 Doxycycline and minocycline are considered first-line oral antibiotic therapy in the United States and are inexpensive and easily accessible.⁵ Doxycycline generally is recommended over minocycline given lack of evidence of superior efficacy of minocycline and concerns about severe adverse cutaneous reactions and drug-induced lupus with minocycline.³⁵

In recent years, there has been growing concern of the development of antibiotic resistance.⁵ Sarecycline is a narrow-spectrum tetracycline that was FDA approved for acne in 2018. In vitro studies demonstrate sarecycline maintains high efficacy against C acnes with less activity against other bacteria, particularly gram-negative enterobes.³⁶ The selectivity of sarecycline may lessen alterations of the gut microbiome seen with other oral antibiotics and reduce gastrointestinal tract side effects. Although comparative effectiveness studies are lacking, sarecycline was efficacious in phase 3 trials with few side effects compared with placebo.³⁷ However, at this time, given the absence of comparative effectiveness data and its high cost (Table), sarecycline likely is best reserved for patients with comorbidities (eg, gastrointestinal disease), those requiring long-term antibiotic therapy, or those with acne that has failed to respond to other oral antibiotics.

Hormonal Treatments—Hormonal treatments such as combined oral contraceptives (COCs) and spironolactone often are considered second-line options, though they may represent cost-effective and safe alternatives to oral antibiotics for women with moderate to severe acne.^38-41 There currently are 4 COCs approved by the FDA for the treatment of moderate acne in postmenarcheal females: drospirenone-ethinyl estradiol (Yaz [Bayer HealthCare Pharmaceuticals, Inc]), ethinyl estradiol-norgestimate (Ortho Tri-Cyclen [Ortho-McNeil Pharmaceuticals, Inc]), drospirenone-ethinyl estradiol-levomefolate (Beyaz [Bayer HealthCare Pharmaceuticals, Inc]), and ethinyl estradiol-norethindrone acetate-ferrous fumarate (Estrostep Fe [Allergan USA, Inc]).⁵ Treatment with COCs has been shown to cause substantial reductions in lesion counts across all lesion types compared to placebo, and a meta-analysis of 24 randomized trials conducted by Arowojolu et al⁴² demonstrated no consistent differences in acne reduction among different COCs.^43,44 Although oral antibiotics are associated with faster improvement than COCs, there is some evidence that they have similar efficacy at 6 months of therapy.⁴⁵ Combined oral contraceptives are inexpensive and likely reflect a highly cost-effective option (Table).

Spironolactone is an aldosterone inhibitor and androgen receptor blocker that is used off label to treat acne. It is one of the least expensive systemic medications for acne (Table). Although randomized controlled trials are lacking, several large case series support the effectiveness of spironolactone for women with acne.^38,46 In addition, observational data suggest spironolactone may have similar effectiveness to oral antibiotics.⁴¹ Spironolactone generally is well tolerated, with the most common adverse effects being menstrual irregularities, breast tenderness, and diuresis.^47,48 Many of these adverse effects are dose dependent and less likely with the dosing used in acne care. Additionally, menstrual irregularities can be reduced by concomitant use of a COC.⁴⁸

Although frequent potassium monitoring remains common among patients being treated with spironolactone, there is growing evidence to suggest that potassium monitoring is of low value in young healthy women with acne.^49-51 Reducing this laboratory monitoring likely represents an opportunity to provide higher-value care to patients being treated with spironolactone. However, laboratory monitoring should be considered if risk factors for hyperkalemia are present (eg, older age, comorbidities, medications).⁵¹

Isotretinoin—Isotretinoin is the most efficacious treatment available for acne and has the unique property of being able to induce a remission of acne activity for many patients.⁵ Although it remains modestly expensive (Table), it may be less costly overall relative to other treatments that may need continued use over many years because it can induce a remission of acne activity. As with spironolactone, frequent laboratory monitoring remains common among patients being treated with isotretinoin. There is no evidence to support checking complete blood cell counts.⁵² Several observational studies and a Delphi consensus support reduced monitoring, such as checking lipids and alanine aminotransferase at baseline and peak dose in otherwise young healthy patients.^53,54 A recent critically appraised topic published in the British Journal of Dermatology has proposed eliminating laboratory monitoring entirely.⁵⁵ Reducing laboratory monitoring for patients being treated with isotretinoin has been estimated to potentially save $100 million to $200 million per year in the United States.^52-54

Other Strategies to Reduce Patient Costs

Although choosing a cost-effective treatment approach is critical to preventing financial toxicity given poor coverage for acne care and the growth of high-deductible insurance plans, some patients may still experience high treatment costs.⁵⁶ Because pharmacy costs often are inflated, potentially related to practices of pharmacy benefit managers, it often is possible to find better prices than the presented list price, either by using platforms such as GoodRx or through direct-to-patient mail-order pharmacies such as Cost Plus Drug.⁵⁷ For branded medications, some patients may be eligible for patient-assistance programs, though they typically are not available for those with public insurance such as Medicare or Medicaid. Compounding pharmacies offer another approach to reduce cost and improve convenience for patients, but because the vehicle can influence the efficacy and tolerability of some topical medications, it is possible that these compounded formulations may not perform similarly to the original FDA-approved products.

Conclusion

For mild to moderate acne, multimodal topical therapy often is required. Fixed-dose combination adapalene-BPO and clindamycin-BPO are highly cost-effective options for most patients. Lotion formulations of topical retinoids may be useful in patients with difficulty tolerating other formulations. Clascoterone is a novel topical antiandrogen that is more expensive than other topical therapies but can complement other topical therapies and is well tolerated.

For moderate to severe acne, doxycycline or hormonal therapy (ie, COCs, spironolactone) are highly cost-effective options. Isotretinoin is recommended for severe or scarring acne. Reduced laboratory monitoring for spironolactone and isotretinoin is an opportunity to provide higher-value care.

In the United States, acne affects 85% of adolescents and can persist into adulthood at a prevalence of 30% to 50% in adult women. ^1,2 The pathogenesis of acne is multifactorial and involves hyperkeratinization of the follicle, bacterial colonization with Cutibacterium acnes , and increased androgen-induced sebum production, which together lead to inflammation. ^3,4 A wide range of treatment guideline–recommended options are available, including benzoyl peroxide (BPO), topical retinoids, topical and oral antibiotics, antiandrogens, and isotretinoin. ⁵ However, these options vary widely in their clinical uses, effectiveness, and costs.

Why Cost-effective Acne Care Matters

Out-of-pocket spending by patients on acne treatments can be substantial, with surveys finding that acne patients often spend hundreds to thousands of dollars per year.^6,7 In a poll conducted in 2019 by the Kaiser Family Foundation, 3 in 10 patients said they had not taken their medicine as prescribed because of costs.⁸ A mixed methods study by Ryskina et al⁹ found that 65% (17/26) of participants who reported primary nonadherence—intended to fill prescriptions but were unable to do so—cited cost or coverage-related barriers as the reason. With the continued rise of dermatologic drug prices and increased prevalence of high-deductible health plans, cost-effective treatment continues to grow in importance. Failure to consider cost-effective, patient-centered care may lead to increased financial toxicity, reduced adherence, and ultimately worse outcomes and patient satisfaction. We aim to review the cost-effectiveness of current prescription therapies for acne management and highlight the most cost-effective approaches to patients with mild to moderate acne as well as moderate to severe acne.

In this review, we will take a value-oriented framework.¹⁰ Value can be defined as the cost per outcome of interest. Therefore, a treatment does not necessarily need to be inexpensive to provide high value if it delivers outstanding clinical outcomes. In addition, we will focus on incremental cost-effectiveness relative to common alternatives (eg, a retinoid could deliver high value relative to a vehicle but still provide limited value compared to other available retinoids if it is more expensive but not more efficacious). When possible, we present data from cost-effectiveness studies.^11,12 We also use recent available price data obtained from GoodRx on August 11, 2023, to guide this discussion.¹³ However, as comparative-effectiveness and cost-effectiveness studies rarely are performed for acne medications, much of this discussion will be based on expert opinion.

Treatment Categories

Topical Retinoids—There currently are 4 topical retinoids that are approved by the US Food and Drug Administration (FDA) for the treatment of acne: tretinoin, tazarotene, trifarotene, and adapalene. These drugs are vitamin A derivatives that bind retinoic acid receptors and function as comedolytic and anti-inflammatory agents.⁵ In general, generic tretinoin and adapalene products have the lowest cost (Table).

In network meta-analyses, tretinoin and adapalene often are highly ranked topical treatment options with respect to efficacy.¹⁴ Combined with their low cost, generic tretinoin and adapalene likely are excellent initial options for topical therapy from the standpoint of cost-effectiveness.¹⁵ Adapalene may be preferred in many situations because of its better photostability and compatibility with BPO.

Due to the importance of the vehicle in determining retinoid tolerability, efforts have been made to use encapsulation and polymeric emulsion technology to improve tolerability. Recently, polymeric lotion formulations of tretinoin and tazarotene have become available. In a phase 2 study, tazarotene lotion 0.045% was found to have equivalent efficacy and superior tolerability to tazarotene cream 0.1%.¹⁶ Although head-to-head data are not available, it is likely that tretinoin lotion may offer similar tolerability improvements.¹⁷ Although these formulations currently are more costly, this improved tolerability may be critical for some patients to be able to use topical retinoids, and the additional cost may be worthwhile. In addition, as these products lose market exclusivity, they may become more affordable and similarly priced to other topical retinoids. It is important to keep in mind that in clinical trials of tretinoin and adapalene, rates of dropout due to adverse events typically were 1% to 2%; therefore, because many patients can tolerate generic tretinoin and adapalene, at current prices the lotion formulations of retinoids may not be cost-effective relative to these generics.¹⁴

Trifarotene cream 0.005%, a fourth-generation topical retinoid that is highly sensitive for retinoic acid receptor γ, recently was FDA approved for the treatment of acne. Although trifarotene is efficacious for both facial and truncal acne, there is a lack of active comparator data compared to other topical retinoids.¹⁸ In a 2023 network meta-analysis, trifarotene was found to be both less efficacious and less tolerable compared to other topical retinoids.¹⁹ Thus, it is unclear if trifarotene offers any improved efficacy compared to other options, and it comes at a much higher cost (Table). In a tolerability study, trifarotene was found to be significantly more irritating than tazarotene lotion 0.045% and adapalene gel 0.3% (P<.05).²⁰ Therefore, trifarotene cream 0.005% is unlikely to be a cost-effective option; in fact, it may be overall inferior to other topical retinoids, given its potentially lower tolerability.

Topical Antibiotics—There are 4 commonly prescribed topical antibiotics that are approved by the FDA for the treatment of acne: clindamycin, erythromycin, dapsone, and minocycline. The American Academy of Dermatology guidelines for the treatment of acne recommend concomitant use of BPO to prevent antibiotic resistance.⁵ Clindamycin is favored over erythromycin because of increasing antibiotic resistance to erythromycin.²¹ Inexpensive generic options in multiple vehicles (eg, solution, foam, gel) make clindamycin a highly cost-effective option when antibiotic therapy is desired as part of a topical regimen (Table).

The cost-effectiveness of dapsone gel and minocycline foam relative to clindamycin are less certain. Rates of resistance to minocycline are lower than clindamycin, and minocycline foam may be a reasonable alternative in patients who have not had success with other topical antibiotics, such as clindamycin.²² However, given the absence of comparative effectiveness data to suggest minocycline is more effective than clindamycin, it is difficult to justify the substantially higher cost for the typical patient. Although dapsone gel has been suggested as an option for adult women with acne, there are no data to support that it is any more effective than other topical antibiotics in this patient population.²³ As generic dapsone prices decrease, it may become a reasonable alternative to clindamycin. In addition, the antineutrophil properties of dapsone may be useful in other acneform and inflammatory eruptions, such as scalp folliculitis and folliculitis decalvans.²⁴

Combination Topicals—Current combination topical products include antibiotic and BPO, antibiotic and retinoid, and retinoid and BPO. Use of combination agents is recommended to reduce the risk for resistance and to enhance effectiveness. Combination products offer improved convenience, which is associated with better adherence and outcomes.²⁵ Generic fixed-dose adapalene-BPO can be a highly cost-effective option that can sometimes be less expensive than the individual component products (Table). Similarly, fixed-dose clindamycin-BPO also is likely to be highly cost-effective. A network meta-analysis found fixed-dose adapalene-BPO to be the most efficacious topical treatment, though it also was found to be the most irritating—more so than fixed-dose clindamycin-BPO, which may have similar efficacy.^14,26,27 Generic fixed-dose tretinoin-clindamycin offers improved convenience and adherence compared to the individual components, but it is more expensive, and its cost-effectiveness may be influenced by the importance of convenience for the patient.²⁵ An encapsulated, fixed-dose tretinoin 0.1%–BPO 3% cream is FDA approved for acne, but the cost is high and there is a lack of comparative effectiveness data demonstrating advantages over generic fixed-dose adapalene-BPO products.

Topical Antiandrogen—Clascoterone was introduced in 2020 as the first FDA-approved topical medication to target the hormonal pathogenesis of acne, inhibiting the androgen receptors in the sebaceous gland.²⁸ Because it is rapidly metabolized to cortexolone and does not have systemic antiandrogen effects, clascoterone can be used in both men and women with acne. In clinical trials, it had minimal side effects, including no evidence of irritability, which is an advantage over topical retinoids and BPO.²⁹ In addition, a phase 2 study found that clascoterone may have similar to superior efficacy to tretinoin cream 0.05%.³⁰ Although clascoterone has several strengths, including its efficacy, tolerability, and unique mechanism of action, its cost-effectiveness is limited due to its high cost (Table) and the need for twice-daily application, which reduces convenience. Clascoterone likely is best reserved for patients with a strong hormonal pathogenesis of their acne or difficulty tolerating other topicals, or as an additional therapy to complement other topicals.

Oral Antibiotics—Oral antibiotics are the most commonly prescribed systemic treatments for acne, particularly tetracyclines such as doxycycline, minocycline, and sarecycline.^31-34 Doxycycline and minocycline are considered first-line oral antibiotic therapy in the United States and are inexpensive and easily accessible.⁵ Doxycycline generally is recommended over minocycline given lack of evidence of superior efficacy of minocycline and concerns about severe adverse cutaneous reactions and drug-induced lupus with minocycline.³⁵

In recent years, there has been growing concern of the development of antibiotic resistance.⁵ Sarecycline is a narrow-spectrum tetracycline that was FDA approved for acne in 2018. In vitro studies demonstrate sarecycline maintains high efficacy against C acnes with less activity against other bacteria, particularly gram-negative enterobes.³⁶ The selectivity of sarecycline may lessen alterations of the gut microbiome seen with other oral antibiotics and reduce gastrointestinal tract side effects. Although comparative effectiveness studies are lacking, sarecycline was efficacious in phase 3 trials with few side effects compared with placebo.³⁷ However, at this time, given the absence of comparative effectiveness data and its high cost (Table), sarecycline likely is best reserved for patients with comorbidities (eg, gastrointestinal disease), those requiring long-term antibiotic therapy, or those with acne that has failed to respond to other oral antibiotics.

Hormonal Treatments—Hormonal treatments such as combined oral contraceptives (COCs) and spironolactone often are considered second-line options, though they may represent cost-effective and safe alternatives to oral antibiotics for women with moderate to severe acne.^38-41 There currently are 4 COCs approved by the FDA for the treatment of moderate acne in postmenarcheal females: drospirenone-ethinyl estradiol (Yaz [Bayer HealthCare Pharmaceuticals, Inc]), ethinyl estradiol-norgestimate (Ortho Tri-Cyclen [Ortho-McNeil Pharmaceuticals, Inc]), drospirenone-ethinyl estradiol-levomefolate (Beyaz [Bayer HealthCare Pharmaceuticals, Inc]), and ethinyl estradiol-norethindrone acetate-ferrous fumarate (Estrostep Fe [Allergan USA, Inc]).⁵ Treatment with COCs has been shown to cause substantial reductions in lesion counts across all lesion types compared to placebo, and a meta-analysis of 24 randomized trials conducted by Arowojolu et al⁴² demonstrated no consistent differences in acne reduction among different COCs.^43,44 Although oral antibiotics are associated with faster improvement than COCs, there is some evidence that they have similar efficacy at 6 months of therapy.⁴⁵ Combined oral contraceptives are inexpensive and likely reflect a highly cost-effective option (Table).

Spironolactone is an aldosterone inhibitor and androgen receptor blocker that is used off label to treat acne. It is one of the least expensive systemic medications for acne (Table). Although randomized controlled trials are lacking, several large case series support the effectiveness of spironolactone for women with acne.^38,46 In addition, observational data suggest spironolactone may have similar effectiveness to oral antibiotics.⁴¹ Spironolactone generally is well tolerated, with the most common adverse effects being menstrual irregularities, breast tenderness, and diuresis.^47,48 Many of these adverse effects are dose dependent and less likely with the dosing used in acne care. Additionally, menstrual irregularities can be reduced by concomitant use of a COC.⁴⁸

Although frequent potassium monitoring remains common among patients being treated with spironolactone, there is growing evidence to suggest that potassium monitoring is of low value in young healthy women with acne.^49-51 Reducing this laboratory monitoring likely represents an opportunity to provide higher-value care to patients being treated with spironolactone. However, laboratory monitoring should be considered if risk factors for hyperkalemia are present (eg, older age, comorbidities, medications).⁵¹

Isotretinoin—Isotretinoin is the most efficacious treatment available for acne and has the unique property of being able to induce a remission of acne activity for many patients.⁵ Although it remains modestly expensive (Table), it may be less costly overall relative to other treatments that may need continued use over many years because it can induce a remission of acne activity. As with spironolactone, frequent laboratory monitoring remains common among patients being treated with isotretinoin. There is no evidence to support checking complete blood cell counts.⁵² Several observational studies and a Delphi consensus support reduced monitoring, such as checking lipids and alanine aminotransferase at baseline and peak dose in otherwise young healthy patients.^53,54 A recent critically appraised topic published in the British Journal of Dermatology has proposed eliminating laboratory monitoring entirely.⁵⁵ Reducing laboratory monitoring for patients being treated with isotretinoin has been estimated to potentially save $100 million to $200 million per year in the United States.^52-54

Other Strategies to Reduce Patient Costs

Although choosing a cost-effective treatment approach is critical to preventing financial toxicity given poor coverage for acne care and the growth of high-deductible insurance plans, some patients may still experience high treatment costs.⁵⁶ Because pharmacy costs often are inflated, potentially related to practices of pharmacy benefit managers, it often is possible to find better prices than the presented list price, either by using platforms such as GoodRx or through direct-to-patient mail-order pharmacies such as Cost Plus Drug.⁵⁷ For branded medications, some patients may be eligible for patient-assistance programs, though they typically are not available for those with public insurance such as Medicare or Medicaid. Compounding pharmacies offer another approach to reduce cost and improve convenience for patients, but because the vehicle can influence the efficacy and tolerability of some topical medications, it is possible that these compounded formulations may not perform similarly to the original FDA-approved products.

Conclusion

For mild to moderate acne, multimodal topical therapy often is required. Fixed-dose combination adapalene-BPO and clindamycin-BPO are highly cost-effective options for most patients. Lotion formulations of topical retinoids may be useful in patients with difficulty tolerating other formulations. Clascoterone is a novel topical antiandrogen that is more expensive than other topical therapies but can complement other topical therapies and is well tolerated.

For moderate to severe acne, doxycycline or hormonal therapy (ie, COCs, spironolactone) are highly cost-effective options. Isotretinoin is recommended for severe or scarring acne. Reduced laboratory monitoring for spironolactone and isotretinoin is an opportunity to provide higher-value care.

In the United States, acne affects 85% of adolescents and can persist into adulthood at a prevalence of 30% to 50% in adult women. ^1,2 The pathogenesis of acne is multifactorial and involves hyperkeratinization of the follicle, bacterial colonization with Cutibacterium acnes , and increased androgen-induced sebum production, which together lead to inflammation. ^3,4 A wide range of treatment guideline–recommended options are available, including benzoyl peroxide (BPO), topical retinoids, topical and oral antibiotics, antiandrogens, and isotretinoin. ⁵ However, these options vary widely in their clinical uses, effectiveness, and costs.

Why Cost-effective Acne Care Matters

Out-of-pocket spending by patients on acne treatments can be substantial, with surveys finding that acne patients often spend hundreds to thousands of dollars per year.^6,7 In a poll conducted in 2019 by the Kaiser Family Foundation, 3 in 10 patients said they had not taken their medicine as prescribed because of costs.⁸ A mixed methods study by Ryskina et al⁹ found that 65% (17/26) of participants who reported primary nonadherence—intended to fill prescriptions but were unable to do so—cited cost or coverage-related barriers as the reason. With the continued rise of dermatologic drug prices and increased prevalence of high-deductible health plans, cost-effective treatment continues to grow in importance. Failure to consider cost-effective, patient-centered care may lead to increased financial toxicity, reduced adherence, and ultimately worse outcomes and patient satisfaction. We aim to review the cost-effectiveness of current prescription therapies for acne management and highlight the most cost-effective approaches to patients with mild to moderate acne as well as moderate to severe acne.

In this review, we will take a value-oriented framework.¹⁰ Value can be defined as the cost per outcome of interest. Therefore, a treatment does not necessarily need to be inexpensive to provide high value if it delivers outstanding clinical outcomes. In addition, we will focus on incremental cost-effectiveness relative to common alternatives (eg, a retinoid could deliver high value relative to a vehicle but still provide limited value compared to other available retinoids if it is more expensive but not more efficacious). When possible, we present data from cost-effectiveness studies.^11,12 We also use recent available price data obtained from GoodRx on August 11, 2023, to guide this discussion.¹³ However, as comparative-effectiveness and cost-effectiveness studies rarely are performed for acne medications, much of this discussion will be based on expert opinion.

Treatment Categories

Topical Retinoids—There currently are 4 topical retinoids that are approved by the US Food and Drug Administration (FDA) for the treatment of acne: tretinoin, tazarotene, trifarotene, and adapalene. These drugs are vitamin A derivatives that bind retinoic acid receptors and function as comedolytic and anti-inflammatory agents.⁵ In general, generic tretinoin and adapalene products have the lowest cost (Table).

In network meta-analyses, tretinoin and adapalene often are highly ranked topical treatment options with respect to efficacy.¹⁴ Combined with their low cost, generic tretinoin and adapalene likely are excellent initial options for topical therapy from the standpoint of cost-effectiveness.¹⁵ Adapalene may be preferred in many situations because of its better photostability and compatibility with BPO.

Due to the importance of the vehicle in determining retinoid tolerability, efforts have been made to use encapsulation and polymeric emulsion technology to improve tolerability. Recently, polymeric lotion formulations of tretinoin and tazarotene have become available. In a phase 2 study, tazarotene lotion 0.045% was found to have equivalent efficacy and superior tolerability to tazarotene cream 0.1%.¹⁶ Although head-to-head data are not available, it is likely that tretinoin lotion may offer similar tolerability improvements.¹⁷ Although these formulations currently are more costly, this improved tolerability may be critical for some patients to be able to use topical retinoids, and the additional cost may be worthwhile. In addition, as these products lose market exclusivity, they may become more affordable and similarly priced to other topical retinoids. It is important to keep in mind that in clinical trials of tretinoin and adapalene, rates of dropout due to adverse events typically were 1% to 2%; therefore, because many patients can tolerate generic tretinoin and adapalene, at current prices the lotion formulations of retinoids may not be cost-effective relative to these generics.¹⁴

Trifarotene cream 0.005%, a fourth-generation topical retinoid that is highly sensitive for retinoic acid receptor γ, recently was FDA approved for the treatment of acne. Although trifarotene is efficacious for both facial and truncal acne, there is a lack of active comparator data compared to other topical retinoids.¹⁸ In a 2023 network meta-analysis, trifarotene was found to be both less efficacious and less tolerable compared to other topical retinoids.¹⁹ Thus, it is unclear if trifarotene offers any improved efficacy compared to other options, and it comes at a much higher cost (Table). In a tolerability study, trifarotene was found to be significantly more irritating than tazarotene lotion 0.045% and adapalene gel 0.3% (P<.05).²⁰ Therefore, trifarotene cream 0.005% is unlikely to be a cost-effective option; in fact, it may be overall inferior to other topical retinoids, given its potentially lower tolerability.

Topical Antibiotics—There are 4 commonly prescribed topical antibiotics that are approved by the FDA for the treatment of acne: clindamycin, erythromycin, dapsone, and minocycline. The American Academy of Dermatology guidelines for the treatment of acne recommend concomitant use of BPO to prevent antibiotic resistance.⁵ Clindamycin is favored over erythromycin because of increasing antibiotic resistance to erythromycin.²¹ Inexpensive generic options in multiple vehicles (eg, solution, foam, gel) make clindamycin a highly cost-effective option when antibiotic therapy is desired as part of a topical regimen (Table).

The cost-effectiveness of dapsone gel and minocycline foam relative to clindamycin are less certain. Rates of resistance to minocycline are lower than clindamycin, and minocycline foam may be a reasonable alternative in patients who have not had success with other topical antibiotics, such as clindamycin.²² However, given the absence of comparative effectiveness data to suggest minocycline is more effective than clindamycin, it is difficult to justify the substantially higher cost for the typical patient. Although dapsone gel has been suggested as an option for adult women with acne, there are no data to support that it is any more effective than other topical antibiotics in this patient population.²³ As generic dapsone prices decrease, it may become a reasonable alternative to clindamycin. In addition, the antineutrophil properties of dapsone may be useful in other acneform and inflammatory eruptions, such as scalp folliculitis and folliculitis decalvans.²⁴

Combination Topicals—Current combination topical products include antibiotic and BPO, antibiotic and retinoid, and retinoid and BPO. Use of combination agents is recommended to reduce the risk for resistance and to enhance effectiveness. Combination products offer improved convenience, which is associated with better adherence and outcomes.²⁵ Generic fixed-dose adapalene-BPO can be a highly cost-effective option that can sometimes be less expensive than the individual component products (Table). Similarly, fixed-dose clindamycin-BPO also is likely to be highly cost-effective. A network meta-analysis found fixed-dose adapalene-BPO to be the most efficacious topical treatment, though it also was found to be the most irritating—more so than fixed-dose clindamycin-BPO, which may have similar efficacy.^14,26,27 Generic fixed-dose tretinoin-clindamycin offers improved convenience and adherence compared to the individual components, but it is more expensive, and its cost-effectiveness may be influenced by the importance of convenience for the patient.²⁵ An encapsulated, fixed-dose tretinoin 0.1%–BPO 3% cream is FDA approved for acne, but the cost is high and there is a lack of comparative effectiveness data demonstrating advantages over generic fixed-dose adapalene-BPO products.

Topical Antiandrogen—Clascoterone was introduced in 2020 as the first FDA-approved topical medication to target the hormonal pathogenesis of acne, inhibiting the androgen receptors in the sebaceous gland.²⁸ Because it is rapidly metabolized to cortexolone and does not have systemic antiandrogen effects, clascoterone can be used in both men and women with acne. In clinical trials, it had minimal side effects, including no evidence of irritability, which is an advantage over topical retinoids and BPO.²⁹ In addition, a phase 2 study found that clascoterone may have similar to superior efficacy to tretinoin cream 0.05%.³⁰ Although clascoterone has several strengths, including its efficacy, tolerability, and unique mechanism of action, its cost-effectiveness is limited due to its high cost (Table) and the need for twice-daily application, which reduces convenience. Clascoterone likely is best reserved for patients with a strong hormonal pathogenesis of their acne or difficulty tolerating other topicals, or as an additional therapy to complement other topicals.

Oral Antibiotics—Oral antibiotics are the most commonly prescribed systemic treatments for acne, particularly tetracyclines such as doxycycline, minocycline, and sarecycline.^31-34 Doxycycline and minocycline are considered first-line oral antibiotic therapy in the United States and are inexpensive and easily accessible.⁵ Doxycycline generally is recommended over minocycline given lack of evidence of superior efficacy of minocycline and concerns about severe adverse cutaneous reactions and drug-induced lupus with minocycline.³⁵

In recent years, there has been growing concern of the development of antibiotic resistance.⁵ Sarecycline is a narrow-spectrum tetracycline that was FDA approved for acne in 2018. In vitro studies demonstrate sarecycline maintains high efficacy against C acnes with less activity against other bacteria, particularly gram-negative enterobes.³⁶ The selectivity of sarecycline may lessen alterations of the gut microbiome seen with other oral antibiotics and reduce gastrointestinal tract side effects. Although comparative effectiveness studies are lacking, sarecycline was efficacious in phase 3 trials with few side effects compared with placebo.³⁷ However, at this time, given the absence of comparative effectiveness data and its high cost (Table), sarecycline likely is best reserved for patients with comorbidities (eg, gastrointestinal disease), those requiring long-term antibiotic therapy, or those with acne that has failed to respond to other oral antibiotics.

Hormonal Treatments—Hormonal treatments such as combined oral contraceptives (COCs) and spironolactone often are considered second-line options, though they may represent cost-effective and safe alternatives to oral antibiotics for women with moderate to severe acne.^38-41 There currently are 4 COCs approved by the FDA for the treatment of moderate acne in postmenarcheal females: drospirenone-ethinyl estradiol (Yaz [Bayer HealthCare Pharmaceuticals, Inc]), ethinyl estradiol-norgestimate (Ortho Tri-Cyclen [Ortho-McNeil Pharmaceuticals, Inc]), drospirenone-ethinyl estradiol-levomefolate (Beyaz [Bayer HealthCare Pharmaceuticals, Inc]), and ethinyl estradiol-norethindrone acetate-ferrous fumarate (Estrostep Fe [Allergan USA, Inc]).⁵ Treatment with COCs has been shown to cause substantial reductions in lesion counts across all lesion types compared to placebo, and a meta-analysis of 24 randomized trials conducted by Arowojolu et al⁴² demonstrated no consistent differences in acne reduction among different COCs.^43,44 Although oral antibiotics are associated with faster improvement than COCs, there is some evidence that they have similar efficacy at 6 months of therapy.⁴⁵ Combined oral contraceptives are inexpensive and likely reflect a highly cost-effective option (Table).

Spironolactone is an aldosterone inhibitor and androgen receptor blocker that is used off label to treat acne. It is one of the least expensive systemic medications for acne (Table). Although randomized controlled trials are lacking, several large case series support the effectiveness of spironolactone for women with acne.^38,46 In addition, observational data suggest spironolactone may have similar effectiveness to oral antibiotics.⁴¹ Spironolactone generally is well tolerated, with the most common adverse effects being menstrual irregularities, breast tenderness, and diuresis.^47,48 Many of these adverse effects are dose dependent and less likely with the dosing used in acne care. Additionally, menstrual irregularities can be reduced by concomitant use of a COC.⁴⁸

Although frequent potassium monitoring remains common among patients being treated with spironolactone, there is growing evidence to suggest that potassium monitoring is of low value in young healthy women with acne.^49-51 Reducing this laboratory monitoring likely represents an opportunity to provide higher-value care to patients being treated with spironolactone. However, laboratory monitoring should be considered if risk factors for hyperkalemia are present (eg, older age, comorbidities, medications).⁵¹

Isotretinoin—Isotretinoin is the most efficacious treatment available for acne and has the unique property of being able to induce a remission of acne activity for many patients.⁵ Although it remains modestly expensive (Table), it may be less costly overall relative to other treatments that may need continued use over many years because it can induce a remission of acne activity. As with spironolactone, frequent laboratory monitoring remains common among patients being treated with isotretinoin. There is no evidence to support checking complete blood cell counts.⁵² Several observational studies and a Delphi consensus support reduced monitoring, such as checking lipids and alanine aminotransferase at baseline and peak dose in otherwise young healthy patients.^53,54 A recent critically appraised topic published in the British Journal of Dermatology has proposed eliminating laboratory monitoring entirely.⁵⁵ Reducing laboratory monitoring for patients being treated with isotretinoin has been estimated to potentially save $100 million to $200 million per year in the United States.^52-54

Other Strategies to Reduce Patient Costs

Although choosing a cost-effective treatment approach is critical to preventing financial toxicity given poor coverage for acne care and the growth of high-deductible insurance plans, some patients may still experience high treatment costs.⁵⁶ Because pharmacy costs often are inflated, potentially related to practices of pharmacy benefit managers, it often is possible to find better prices than the presented list price, either by using platforms such as GoodRx or through direct-to-patient mail-order pharmacies such as Cost Plus Drug.⁵⁷ For branded medications, some patients may be eligible for patient-assistance programs, though they typically are not available for those with public insurance such as Medicare or Medicaid. Compounding pharmacies offer another approach to reduce cost and improve convenience for patients, but because the vehicle can influence the efficacy and tolerability of some topical medications, it is possible that these compounded formulations may not perform similarly to the original FDA-approved products.

Conclusion

For mild to moderate acne, multimodal topical therapy often is required. Fixed-dose combination adapalene-BPO and clindamycin-BPO are highly cost-effective options for most patients. Lotion formulations of topical retinoids may be useful in patients with difficulty tolerating other formulations. Clascoterone is a novel topical antiandrogen that is more expensive than other topical therapies but can complement other topical therapies and is well tolerated.

For moderate to severe acne, doxycycline or hormonal therapy (ie, COCs, spironolactone) are highly cost-effective options. Isotretinoin is recommended for severe or scarring acne. Reduced laboratory monitoring for spironolactone and isotretinoin is an opportunity to provide higher-value care.